Write a small discussion on ONE of the topics we learned below.

This week, we reviewed all course concepts. Select a topic from your readings, outcomes, objectives, concepts, and sub-concepts (below) and present a question that applies to a concept or a disease process, wellness, or illness. Submit your question in the following formats: audio, text, or webcam. Once your comment has been posted, submit responses to your peers’ questions and comments. Consider the outcomes, objectives, and concepts below when formulating your initial question.

Your question and response should explain, illustrate, justify, trace, discuss, compare, contrast, agree or disagree, interpret, evaluate, and summarize.

Weekly Outcomes & Weekly Objectives

1. Explain the pathophysiologic processes of select health conditions.
2. Predict clinical manifestations and complications for select disease processes.
3. Correlate lifestyle, environmental, and other influences with changes in levels of wellness.
4. Review normal physiology.
5. Describe common types of disorders: causes, clinical manifestations, diagnostic tests, and treatments.
6. Compare and contrast common conditions: causes, clinical manifestations, diagnostic tests, and treatments.
7. Apply understanding of alterations across the lifespan to formulate care priorities.
8. Review responses to aging and its impact on pathophysiologic changes in all systems.
9. Review how heredity and genetics influence pathophysiology.

Main Topics and Concepts/ Subconcepts With Exemplar

1. Review of materials

   Active Learning Templates completed
   Chapter readings
   Study guide sheets completed
   Notes from in-class discussions

2. Acid-base imbalance: respiratory failure
3. Acute versus chronic conditions: heart failure
4. Cellular regulation: leukemia
5. Fluid imbalances: dehydration
6. Perfusion: myocardial infarction
7. Elimination: gastroenteritis
8. Nutrition: anorexia
9. Tissue integrity: venous stasis ulcer
10. Infection: meningitis
11. Genetics: sickle-cell anemia

 

For full credit, your initial post should:  

-introduce the question

-include 2 scholarly sources (one is the book posted below, the other is a journal article or credible website)

SECTION I Pathophysiology: Background and
Overview, 1
CHAPTER 1 Introduction to Pathophysiology, 1
CHAPTER 2 Fluid, Electrolyte, and Acid-Base
Imbalances, 14
CHAPTER 3 Introduction to Basic Pharmacology and
Other Common Therapies, 40
CHAPTER 4 Pain, 53
SECTION II Defense/Protective Mechanisms, 65
CHAPTER 5 Inflammation and Healing, 65
CHAPTER 6 Infection, 88
CHAPTER 7 Immunity, 114
SECTION III Pathophysiology of Body Systems, 142
CHAPTER 8 Skin Disorders, 142
CHAPTER 9 Musculoskeletal System Disorders, 161
CHAPTER 10 Blood and Circulatory System
Disorders, 184
CHAPTER 11 Lymphatic System Disorders, 213
CHAPTER 12 Cardiovascular System Disorders, 223
CHAPTER 13 Respiratory System Disorders, 272
CHAPTER 14 Nervous System Disorders, 325
CHAPTER 15 Disorders of the Eyes, Ears, and Other
Sensory Organs, 385
CHAPTER 16 Endocrine System Disorders, 400
CHAPTER 17 Digestive System Disorders, 427
CHAPTER 18 Urinary System Disorders, 488
CHAPTER 19 Reproductive System Disorders, 514
SECTION IV Factors Contributing to
Pathophysiology, 545
CHAPTER 20 Neoplasms and Cancer, 545
CHAPTER 21 Congenital and Genetic Disorders, 565
CHAPTER 22 Complications of Pregnancy, 579
CHAPTER 23 Complications of Adolescence, 588
CHAPTER 24 Complications of Aging, 597
Section V Environmental Factors and
Pathophysiology, 606
CHAPTER 25 Immobility and Associated Problems, 606
CHAPTER 26 Stress and Associated Problems, 611
CHAPTER 27 Substance Abuse and Associated
Problems, 617
CHAPTER 28 Environmental Hazards and
Associated Problems, 624
Appendices, 631
Glossary, 654
Index, 663

GOULD’S
Pathophysiology for the
Health Professions
SIXTH EDITION

Evolve Student Resources for Gould’s Pathophysiology for
the Health Professions, Sixth Edition, include the following:
• Animations
• Answer Key for Study Questions in the book
Activate the complete learning experience that comes with each
textbook purchase by registering at
http://evolve.elsevier.com/Hubert/Goulds/
YOU’VE JUST PURCHASED
MORE THAN
A TEXTBOOK!
REGISTER TODAY!
You can now purchase Elsevier products on Evolve!
Go to evolve.elsevier.com/html/shop-promo.html to search and browse for products.
2015v1.0

http://evolve.elsevier.com/Hubert/Goulds/

http://evolve.elsevier.com/html/shop-promo.html

GOULD’S
Pathophysiology for the
Health Professions
SIXTH EDITION
Robert J. Hubert, BS
Laboratory Coordinator
Iowa State University
Department of Animal Sciences
Ames, Iowa
Karin C. VanMeter, PhD
Independent Consultant, Biomedical
Sciences
Ames, Iowa

3251 Riverport Lane
St. Louis, Missouri 63043
GOULD’S PATHOPHYSIOLOGY FOR THE HEALTH
PROFESSIONS, SIXTH EDITION
ISBN: 978-0-323-41442-5
Copyright © 2018, 2014, 2011, 2006, 2002, 1997 by Saunders, an imprint of Elsevier Inc.
No part of this publication may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopying, recording, or any information storage and
retrieval system, without permission in writing from the publisher. Details on how to seek
permission, further information about the Publisher’s permissions policies and our arrangements
with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency,
can be found at our website: www.elsevier.com/permissions
Senior Content Development Manager: Luke Held
Content Development Specialist: Jennifer Wade
Publishing Services Manager: Julie Eddy
Senior Project Manager: Richard Barber
Design Direction: Brian Salisbury
Printed in Canada
Last digit is the print number: 9 8 7 6 5 4 3 2 1
Notices
Practitioners and researchers must always rely on their own experience and knowledge in evaluating
and using any information, methods, compounds or experiments described herein. Because of
rapid advances in the medical sciences, in particular, independent verification of diagnoses and
drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by
Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as
a matter of products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.
ISBN: 978-0-323-41442-5

http://www.elsevier.com/permissions

We would like to dedicate this book to the memory of Barbara E.
Gould, MEd. We hope that this book, the legacy of her work, will
instill her passion for teaching and learning and will continue to
inspire health profession students and educators worldwide.
Robert Hubert
Karin VanMeter

This page intentionally left blank

vii
Reviewers
Julie Alles, MSCTE, RHIA
Assistant Professor/Program Director Health
Information Management
Allied Health Sciences
Grand Valley State University
Grand Rapids, Michigan
Zoe Atamanchuk
Canada
Janet Ballard, Med., BSN, RN
Director of Allied Health and Practical Nursing
EHOVE Adult Career Center
Allied Health Department
Milan, Ohio
Jason Berry, MSN, RN
Nursing Instructor
Nursing Department
Winston Salem State University
Winston Salem, North Carolina
Bonnie Carmack, MN, ARNP, NP
Adjunct Faculty
Seminole State College
Department of Health Sciences
Sanford, Florida
Teresa Cowan, DA, BS, MS
Department Chair of Health Sciences
Baker College of Auburn Hills
Health Sciences Department
Auburn Hills, Michigan
Heather Duval-Foote, BAS, RDMS
Instructor/Clinical Coordinator Diagnostic Medical
Sonography
The University of Findlay
Diagnostic Services Department
College of Health Professions
Findlay, Ohio
Daniel F. Muñoz González, MSMLS, MLS(ASCP)
CMPBT MB
Assistant Professor of Medical Laboratory Sciences,
Clinical Chemistry, and Molecular Diagnostics
Department of Medical Laboratory Sciences
School of Health Professions
Andrews University
Berrien Springs, Michigan
Marina Hdeib, MA, RDMS
Clinical Associate Professor
School of Health Professions
University of Missouri-Columbia
Department of Clinical and Diagnostic Sciences
Columbia, Missouri
Lily Mauer, RPh, BSc. Pharm. PEBC
Registered Pharmacist
Instructor
NorQuest College
Allied Health Careers, Faculty of Health and
Community Studies
Edmonton, Alberta, Canada
Susan Stout, MHS, BS, RN
Program Director of Science
Baker College of Muskegon, Michigan
Department of Health Science
Muskegon, Michigan

viii
Preface
This textbook provides an introduction to pathophysiology
for students in a variety of academic programs for the
health professions at colleges and universities. Major
disorders are described as well as selected additional
diseases with the intention of providing information on a
broad spectrum of diseases with one or more distinguish-
ing features for each. It is anticipated that additional
information and resources pertinent to the individual’s
professional needs may be added to classroom presenta-
tions and assignments. We trust that students will enjoy
studying these topics and proceed with enthusiasm to
more detailed studies within their individual specialties.
Organization
The textbook is organized into five major sections followed
by the appendices:
Section I—Basic Concepts of Disease Processes
• Introduction to pathophysiology includes medical
terminology and basic cellular changes.
• Topics such as fluid, electrolyte, and acid-base imbal-
ances, basic pharmacology and pain are covered.
• The core information for each topic is complemented
by the inclusion of a specific disease/condition as an
immediate clinical application at the end of each
chapter.
Section II—Defense/Protective Mechanisms
• Topics such as inflammation and healing, infection,
and immunity are covered.
• Specific areas included are a review of body defenses,
healing involved in specific trauma such as burns,
basic microbiology, review of the immune system
components, and mechanisms.
Section III—Pathophysiology of Body Systems
• Selection of specific disorders is based on incidence
and occurrence, as well as on the need to present a
variety of pathophysiological processes and etiologies
to the student.
• For major disorders, information is provided on
pathophysiology, etiology, clinical manifestations,
significant diagnostic tests, common treatment modali-
ties, and potential complications.
• Other selected diseases are presented in less detail,
but significant, unique features are highlighted.
Section IV: Factors Contributing to Pathophysiology
• Normal physiological changes related to cancer,
adolescence, pregnancy, and aging, with their relevance
and effect on disease processes and the treatment of
the affected individual, are described.
• Specific disorders associated with cancer and the
developmental stages are discussed.
Section V: Environmental Factors and Pathophysiology
• Factors such as immobility, stress, substance abuse,
and environmental hazards are the major components
in this section.
• Effects of the various environmental factors on the
various body systems and potential complications
beyond physical pathologies are discussed.
• New research and data are included as these are areas
of increasing concern with regard to pathophysiology
and patient health.
Appendices—additional information:
• Ready References include lists of anatomic terms,
abbreviations and acronyms, a selection of diagnostic
tests, an example of a medical history, a disease index,
and drug index.
• A glossary and a list of additional resources complete
this resource.
Format and Features
The basic format as well as the straightforward, concise
approach remains unchanged from the previous editions.
Some material has been reorganized to improve the flow
of information and facilitate comprehension. Many
features related to the presentation of information in this
textbook continue as before.
• Generic learning objectives are included in each chapter.
Instructors may modify or add applicable objectives
for a specific professional program.

P R E FAC E ix
What’s New?
• Information on specific diseases has been updated
throughout.
• The specific disorders for each body system have been
expanded to reflect current trends and research.
• A broader emphasis on all allied health professions
has been incorporated.
• Sections and chapters have been reorganized to
present the student with a building block approach:
basic science and how it relates to human biology,
the body’s various mechanisms that respond to the
disorders/diseases, the general overview of body
systems and their specific disorders, other biological
factors outside of the physiology of each system that
contribute to instances of disorders/disease and, finally,
those environmental factors not directly attributed to
a biological function or condition that may contribute
to pathophysiology throughout a number of body
systems.
• Figures have been updated with new photographs and
illustrations to help in the recognition and identification
of the various concepts and specific disorders.
• Tables have been updated with new information that
has been made available since the previous edition.
• Additional resources have been expanded and updated.
• Study questions and Think About questions have been
reviewed and updated to cover new material in the
chapter. The Apply Your Knowledge questions have
replaced the Challenge questions in the previous
editions.
• The Study Guide associated with this text has been
updated to reflect the most recent information regard-
ing various disorders.
Guidelines for Users
Certain guidelines were developed to facilitate the use
of this textbook by students with diverse backgrounds
studying in various health science programs. As well as
ongoing general changes, some professional groups have
developed unique practice models and language. In some
disciplines, rapid changes in terminology have occurred,
creating difficulty for some students. For example, current
terms such as chemical dependency or cognitive impairment
have many synonyms, and some of these are included
to enable students to relate to a more familiar phrase.
To avoid confusion, the common, traditional terminology
has been retained in this text.
• The recipient of care or service is referred to as a patient.
• When a disease entity refers to a group of related
disorders, discussion focuses on either a typical rep-
resentative of the group or on the general characteristics
of the group.
• Key terms are listed at the beginning of the chapter.
They are presented in bold print and defined when
initially used in the chapter. Key terms are not indicated
• Cross-references are included, facilitating access to
information.
• In the discussion of a particular disorder, the pathophysi-
ology is presented first because this “sets the stage,”
describing the basic change(s) in the body. Once the
student understands the essence of the problem, he or
she can easily identify the role of predisposing factors
or causes and relate the resulting signs and symptoms
or complications. Diagnostic tests and treatment also
follow directly from the pathophysiology.
• Changes at the cellular level are included when
significant.
• Brief reviews of normal anatomy and physiology are
presented at the beginning of each chapter, to remind
students of the structures and functions that are fre-
quently affected by pathological processes. A review
of basic microbiology is incorporated into the chapter
on infections. Additional review material, such as the
pH scale or the location of body cavities, may be found
in the Appendices.
• Numerous illustrations, including flow charts, schematic
diagrams, and photographs, clarify and reinforce
textual information, as well as offer an alternative
visual learning mode, particularly when complex
processes are involved. Illustrations are fully labeled,
including anatomical structures and pathologic
changes. Different colors may be used in a figure to
distinguish between the various stages or factors in
a process.
• Tables summarize information or offer comparisons,
which are helpful to the student in selecting the more
significant information and for review purposes.
• Brief reference to diagnostic tests and treatment measures
promotes understanding of the changes occurring
during a disease.
• Questions are found in boxes throughout the text to
stimulate application and review of new concepts.
“Apply Your Knowledge” questions are based on
review of normal physiology and its application, “Think
About” questions follow each small section of informa-
tion, and “Study Questions” are located at the end of
each chapter. Questions may relate to simple, factual
information, potential applications, or the integration
of several concepts. These questions are helpful in
alerting a student to points initially overlooked and
are useful for student self-evaluation before proceeding
to the next section. These features may also serve as
a tool for review and test preparation. Brief answers
are provided on the Evolve website.
• Brief, adaptable case studies with questions are incor-
porated at the end of many chapters and are intended
to provide a basis for discussion in a tutorial, an
assignment, or an alternative learning mode. It is
expected that specific clinical applications may be
added by instructors for each professional group.
• Chapter summaries precede the review questions in
each chapter.

x P R E FAC E
as such in subsequent chapters, but may be found in
the glossary at the back of the book.
• Italics are used to emphasize significant words.
• It is assumed that students have studied anatomy and
physiology prior to commencing a pathophysiology
course.
• Concise, readable style includes sufficient scientific
and medical terminology to help the student acquire
a professional vocabulary and appropriate communica-
tion skills. An effort has been made to avoid over-
whelming the student with a highly technical approach
or impeding the learning process in a student who
comes with little scientific background.
• The presence of numeric values within textual informa-
tion often confuses students and detracts from the
basic concepts being presented; therefore, specific
numbers are included only when they promote
understanding of a principle.
• Suggested diagnostic tests and treatments are not
individualized or necessarily complete but are pre-
sented generally to assist the student’s application of
the pathophysiology. They are also intended to provide
students with an awareness of the impact of certain
diseases on a client and of possible modifications in
the individualized care required. Diagnostic tests
increase student cognizance of the extent of data
collection and sifting that may be necessary before
making a diagnosis, as well as the importance of
monitoring the course of a disease or the response to
treatment.
• A brief introduction to pharmacology is included in
Section I and specific drugs are referred to during the
discussion of certain disorders. Drugs are identified
by generic name, followed by a trade name. Examples
provided in the appropriate chapter are not recom-
mendations, but are suggested only as frequently used
representatives of a drug classification. A drug index
with references to the applicable chapter is located in
the appendices.
• Information regarding adverse effects of drugs or other
treatment is included when there may be potential
problems such as high risk for infection or special
precautions required of members of the health care
team.
• Every effort has been made to present current informa-
tion and concepts simply but accurately. This content
provides the practitioner in a health profession with
the prerequisite knowledge to recognize and under-
stand a client’s problems and the limitations and
implications of certain treatment measures; to reduce
exacerbating factors; to participate in preventive
programs; and to be an effective member of a health
care team. The student will develop a knowledge base
from which to seek additional information. Individual
instructors may emphasize certain aspects or topics,
as is most appropriate for students in a specialty area.
Resources
In the textbook:
• Selected additional resources are listed in the appen-
dices in Ready Reference 9.
• Reference tables are located inside the front book cover.
These comprise common normal values for blood,
cerebrospinal fluid, and urine; a pH scale for body
fluids; a list of blood clotting factors; and diagnostic
tests.
• The chapter introducing pharmacology and therapeu-
tics is limited in content, but combined with the brief
references to treatments with individual disorders, is
intended to complement the pathophysiology. This
chapter also introduces a few traditional and non-
traditional therapeutic modalities to facilitate the
student’s understanding of various therapies and of
the impact of diverse treatments on the patient and
on care by all members of the health care team. Also
included are brief descriptions of a few selected forms
of therapy, for example, physiotherapy, in hopes of
clarifying the roles of different members of a health
care team.
• The appendices at the back of the textbook are intended
to promote effective use of study time. They include:
• A brief review of anatomical terms describing body
cavities and planes with accompanying illustrations as
well as basic body movements
• Selected numerical conversions for temperature,
weights, and volumes
• Lists of anatomical terms and combining forms, common
abbreviations, and acronyms; because of the broad scope
of pathophysiology, a medical dictionary is a useful
adjunct for any student in the health-related professions
• A brief description with illustrations of common
diagnostic tests such as ultrasound and magnetic
resonance imaging
• An example of a medical history, which can be modified
to fit the needs of a particular professional group
• A disease index, with a brief description and references
to the relevant chapter
• A drug index, identifying the principal action and
references to the appropriate chapters
• A list of additional resources; websites consist primarily
of health care groups or professional organizations
that will provide accurate information and are likely
to persist. Additional specific journals and websites
are available for individual professions.
• A glossary, including significant terms used to describe
diseases as well as key words
• Accompanying this textbook and developed for it, the
ancillaries available include:
A study guide for students provides learning activities
such as complex test questions, matching exercises,
crossword puzzles, diagrams to label, and other
assignments

P R E FAC E xi
The interactive Evolve web site includes self-evaluation
tools, and can be found at http://evolve.elsevier.
com/Hubert/Goulds/
We appreciate the time and effort of reviewers and
users of this text, of sales representatives, and of the
editors, who have forwarded comments regarding the
first four editions. We have attempted to respond to these
suggestions while recognizing that comments come from
a variety of perspectives, and there is a need to respect
the primary focus of this textbook, space constraints, and
student concerns.
We hope that teachers and students will enjoy using
this textbook, and that it will stimulate interest in the
acquisition of additional knowledge in this dynamic
field.
Robert Hubert
Karin VanMeter

http://evolve.elsevier.com/Hubert/Goulds/

http://evolve.elsevier.com/Hubert/Goulds/

xii
Acknowledgments
The authors would like to acknowledge and dedicate
this edition to the original author, Barbara E. Gould, who
passed away. Dr. Gould always kept “student learning”
in the forefront as the guideline for writing this book.
We also would like to thank all the editorial and produc-
tion staff at Elsevier for their support and encouragement.
Furthermore, we would like to thank the reviewers for
their valuable input.
I would first like to thank my co-author and friend
Karin VanMeter. This is our third major project together
and it is her continued dedication to education and
professionalism that has contributed so much to the
overall teamwork and fun working relationship that we
enjoy. I would also like to thank Dr. Joan Cunnick and
all of the faculty and staff in the microbiology program
at Iowa State University for all of your encouragement
and support. As with any and all challenges I have tackled
in my life, I give my love and thanks to my family—my
parents, John and Ann, and my sister Donna, for their
unwavering love and support throughout my life. Finally,
I lift up my thanks to Jesus Christ, my Lord and Savior,
who makes this all possible—to Him be the glory and
honor forever.
Robert J. Hubert
My special thanks goes to my co-author Rob Hubert. He
has been my friend and collaborator for many years and
I am looking forward to many years of working together.
Without him all the projects we have done together would
have lacked his incredible insight into the topics we have
addressed in this new edition. I also would like to thank
my mother, Theresia, and my brother, Hermann, and his
family for the love, support, and understanding. To my
children, Christine and Andrew—thanks for your continu-
ous love.
Karin C. VanMeter

xiii
SECTION I Pathophysiology: Background and
Overview, 1
CHAPTER 1 Introduction to Pathophysiology, 1
What Is Pathophysiology and Why Study It?, 1
Understanding Health and Disease, 2
Concept and Scope of Pathophysiology, 2
Beginning the Process: A Medical History, 4
New Developments and Trends, 4
Basic Terminology of Pathophysiology, 5
Introduction to Cellular Changes, 8
Terms Used for Common Cellular Adaptations,
8
Cell Damage and Necrosis, 9
CHAPTER 2 Fluid, Electrolyte, and Acid-Base
Imbalances, 14
Fluid Imbalance, 15
Review of Concepts and Processes, 15
Fluid Excess: Edema, 16
Fluid Deficit: Dehydration, 20
Third-Spacing: Fluid Deficit and Fluid Excess,
21
Electrolyte Imbalances, 21
Sodium Imbalance, 21
Potassium Imbalance, 24
Calcium Imbalance, 26
Other Electrolytes, 28
Acid-Base Imbalance, 29
Review of Concepts and Processes, 29
Control of Serum pH, 30
Acid-Base Imbalance, 32
Treatment of Imbalances, 36
CHAPTER 3 Introduction to Basic Pharmacology and
Other Common Therapies, 40
Pharmacology, 40
Basic Principles, 40
Drug Effects, 41
Administration and Distribution of Drugs, 42
Drug Mechanisms and Receptors, 45
Responses, 46
Drug Classifications and Prescriptions, 46
Traditional Forms of Therapy, 48
Physiotherapy, 48
Occupational Therapy, 48
Speech/Language Therapy, 48
Nutrition/Diet, 48
Registered Massage Therapy, 48
Contents
Osteopathy, 48
Chiropractic, 49
Complementary or Alternative Therapies, 49
Noncontact Therapeutic Touch, 49
Naturopathy, 49
Homeopathy, 49
Herbal Medicine, 49
Aromatherapy, 49
Asian Concepts of Disease and Healing, 49
CHAPTER 4 Pain, 53
Etiology and Sources of Pain, 53
Structures and Pain Pathways, 54
Physiology of Pain and Pain Control, 55
Characteristics of Pain, 57
Signs and Symptoms, 57
Young Children and Pain, 57
Referred Pain, 57
Phantom Pain, 57
Pain Perception and Response, 57
Basic Classifications of Pain, 59
Acute Pain, 59
Chronic Pain, 59
Headache, 59
Central Pain, 60
Neuropathic Pain, 60
Ischemic Pain, 61
Cancer-Related Pain, 61
Pain Control, 61
Methods of Managing Pain, 61
Anesthesia, 62
SECTION II Defense/Protective Mechanisms, 65
CHAPTER 5 Inflammation and Healing, 65
Review of Body Defenses, 66
Review of Normal Capillary Exchange, 67
Physiology of Inflammation, 67
Definition, 67
Causes, 67
Steps of Inflammation, 67
Acute Inflammation, 69
Pathophysiology and General Characteristics,
69
Local Effects, 70
Systemic Effects, 71
Diagnostic Tests, 71
Potential Complications, 72

xiv CO N T E N TS
Chronic Inflammation, 72
Pathophysiology and General
Characteristics, 72
Potential Complications, 73
Treatment of Inflammation, 73
Drugs, 73
First Aid Measures, 75
Other Therapies, 75
Healing, 75
Types of Healing, 75
Healing Process, 76
Factors Affecting Healing, 76
Complications Due to Scar Formation, 78
Example of Inflammation and Healing, 78
Burns, 78
Classifications of Burns, 79
CHAPTER 6 Infection, 88
Review of Microbiology, 89
Microorganisms, 89
Types of Microorganisms, 90
Other Agents of Disease, 99
Resident Flora (Indigenous Normal Flora,
Resident Microbiota), 99
Principles of Infection, 100
Transmission of Infectious Agents, 100
Host Resistance, 101
Virulence and Pathogenicity of
Microorganisms, 102
New Issues Affecting Infections and
Transmission, 102
Control of Transmission and Infection, 103
Physiology of Infection, 105
Onset and Development, 105
Patterns of Infection, 106
Signs and Symptoms of Infection, 106
Methods of Diagnosis, 107
Treatment and Antimicrobial Drugs, 107
Example of Infection: Influenza (Flu), 110
CHAPTER 7 Immunity, 114
Review of the Immune System, 115
Components of the Immune System, 115
Elements of the Immune System, 115
Immune Response, 118
Diagnostic Tests, 119
Process of Acquiring Immunity, 120
Outcome of Infectious Disease, 121
Emerging and Reemerging Infectious Diseases
and Immunity, 121
Bioterrorism, 121
Tissue and Organ Transplant Rejection, 121
Rejection Process, 122
Treatment and Prevention, 122
Hypersensitivity Reactions, 122
Type I: Allergic Reactions, 123
Type II: Cytotoxic Hypersensitivity, 126
Type III: Immune Complex
Hypersensitivity, 127
Type IV: Cell-Mediated or Delayed
Hypersensitivity, 127
Autoimmune Disorders, 128
Mechanism, 128
Example: Systemic Lupus Erythematosus,
128
Immunodeficiency, 131
Causes of Immunodeficiency, 131
Effects of Immunodeficiency, 132
Acquired Immunodeficiency Syndrome, 132
SECTION III Pathophysiology of Body Systems, 142
CHAPTER 8 Skin Disorders, 142
Review of the Skin, 143
Resident Microbial Flora, 144
Skin Lesions, 144
Diagnostic Tests, 146
Skin Inflammatory Disorders, 146
Contact Dermatitis, 146
Urticaria (Hives), 147
Atopic Dermatitis, 147
Psoriasis, 148
Pemphigus, 149
Scleroderma, 149
Skin Infections, 150
Bacterial Infections, 150
Viral Infections, 152
Fungal Infections, 154
Other Infections, 155
Skin Tumors, 157
Malignant Melanoma, 157
Kaposi Sarcoma, 158
CHAPTER 9 Musculoskeletal System Disorders, 161
Review of the Musculoskeletal
System, 162
Bone, 162
Skeletal Muscle, 164
Joints, 166
Diagnostic Tests, 166
Trauma, 167
Fractures, 167
Bone Disorders, 172
Osteoporosis, 172
Rickets and Osteomalacia, 173
Paget Disease (Osteitis Deformans), 173
Osteomyelitis, 173
Abnormal Curvatures of the Spine, 173
Bone Tumors, 174
Disorders of Muscle, Tendons, and
Ligaments, 175
Muscular Dystrophy, 175
Primary Fibromyalgia Syndrome, 176
Joint Disorders, 176
Osteoarthritis, 176
Rheumatoid Arthritis, 178
Juvenile Rheumatoid Arthritis, 180
Infectious (Septic) Arthritis, 180
Gout (Gouty Arthritis), 180
Ankylosing Spondylitis, 181
Other Inflammatory Joint Disorders, 182
CHAPTER 10 Blood and Circulatory System
Disorders, 184
Review of the Circulatory System and
Blood, 185

CO N T E N TS xv
Anatomy, Structures, and Components, 185
Blood Vessels, 185
Blood, 186
Blood Dyscrasias, 195
Anemias, 195
Blood-Clotting Disorders, 204
Myelodysplastic Syndrome, 207
Neoplastic Blood Disorders, 208
Polycythemia, 208
Leukemias, 208
CHAPTER 11 Lymphatic System Disorders, 213
Review of the Lymphatic System, 213
Structures and Function, 213
Composition and Production of Lymph, 215
Lymphatic Disorders, 217
Lymphomas, 217
Multiple Myeloma or Plasma Cell Myeloma,
220
Lymphedema, 220
Elephantiasis (Filariasis), 221
Castleman Disease, 221
CHAPTER 12 Cardiovascular System Disorders, 223
Review of the Cardiovascular System, 224
Heart, 224
Blood Pressure, 229
Heart Disorders, 230
Diagnostic Tests for Cardiovascular
Function, 230
General Treatment Measures for Cardiac
Disorders, 231
Coronary Artery Disease, Ischemic Heart
Disease, or Acute Coronary
Syndrome, 233
Cardiac Dysrhythmias (Arrhythmias), 242
Congestive Heart Failure, 245
Young Children With Congestive Heart
Failure, 249
Congenital Heart Defects, 250
Inflammation and Infection in the
Heart, 255
Vascular Disorders, 258
Arterial Disorders, 258
Venous Disorders, 262
Shock, 264
CHAPTER 13 Respiratory System Disorders, 272
Review of Structures of the Respiratory
System, 273
Purpose and General Organization, 273
Structures in the Respiratory System, 273
Ventilation, 275
Gas Exchange, 278
Diagnostic Tests, 280
General Manifestations of Respiratory
Disease, 281
Common Treatment Measures for
Respiratory Disorders, 283
Infectious Diseases, 283
Upper Respiratory Tract Infections, 283
Lower Respiratory Tract Infections, 286
Obstructive Lung Diseases, 294
Cystic Fibrosis, 294
Lung Cancer, 296
Aspiration, 298
Obstructive Sleep Apnea, 300
Asthma, 300
Chronic Obstructive Pulmonary Disease, 302
Emphysema, 303
Chronic Bronchitis, 307
Bronchiectasis, 307
Restrictive Lung Disorders, 308
Pneumoconioses, 308
Vascular Disorders, 309
Pulmonary Edema, 309
Pulmonary Embolus, 309
Expansion Disorders, 312
Atelectasis, 312
Pleural Effusion, 313
Pneumothorax, 314
Flail Chest, 315
Infant Respiratory Distress Syndrome, 317
Adult or Acute Respiratory Distress
Syndrome, 319
Acute Respiratory Failure, 320
CHAPTER 14 Nervous System Disorders, 325
Review of Nervous System Anatomy and
Physiology, 326
Brain, 326
Spinal Cord, 331
Neurons and Conduction of Impulses, 334
Autonomic Nervous System, 335
General Effects of Neurologic Dysfunction, 338
Local (Focal) Effects, 338
Supratentorial and Infratentorial Lesions, 338
Left and Right Hemispheres, 338
Level of Consciousness, 338
Motor Dysfunction, 339
Sensory Deficits, 339
Visual Loss: Hemianopia, 339
Language Disorders, 340
Seizures, 341
Increased Intracranial Pressure, 341
Herniation, 343
Diagnostic Tests, 344
Acute Neurologic Problems, 344
Brain Tumors, 344
Vascular Disorders, 345
Infections, 350
Brain Injuries, 354
Spinal Cord Injury, 358
Congenital Neurologic Disorders, 363
Hydrocephalus, 363
Spina Bifida, 364
Cerebral Palsy, 365
Seizure Disorders, 367
Chronic Degenerative Disorders, 370
Multiple Sclerosis, 370
Parkinson Disease (Paralysis Agitans), 372
Amyotrophic Lateral Sclerosis, 373
Myasthenia Gravis, 374
Huntington Disease, 374
Dementia, 375

xvi CO N T E N TS
Alzheimer Disease, 375
Other Forms of Dementia, 377
Mental Disorders, 377
Schizophrenia, 378
Depression, 378
Panic Disorders, 379
Spinal Cord Disorder, 380
Herniated Intervertebral Disc, 380
CHAPTER 15 Disorders of the Eyes, Ears, and Other
Sensory Organs, 385
Sensory Receptors, 385
The Eye, 386
Review of Structure and Function, 386
Diagnostic Tests, 388
Structural Defects, 388
Infections and Trauma, 389
Glaucoma, 390
Cataracts, 392
Detached Retina, 393
Macular Degeneration, 393
The Ear, 394
Review of Structure and Function, 394
Hearing Loss, 395
Ear Infections, 396
Chronic Disorders of the Ear, 398
CHAPTER 16 Endocrine System Disorders, 400
Review of the Endocrine System, 400
Endocrine Disorders, 403
Insulin and Diabetes Mellitus, 404
Type 1 and Type 2 Diabetes, 404
Parathyroid Hormone and Calcium, 413
Pituitary Hormones, 414
Growth Hormone, 414
Antidiuretic Hormone (Vasopressin), 416
Diabetes Insipidus, 416
Inappropriate Antidiuretic Hormone
Syndrome, 416
Thyroid Disorders, 417
Goiter, 417
Hyperthyroidism (Graves Disease), 418
Hypothyroidism, 420
Diagnostic Tests, 420
Adrenal Glands, 420
Adrenal Medulla, 420
Adrenal Cortex, 421
CHAPTER 17 Digestive System Disorders, 427
Review of the Digestive System, 428
Structures and Their Functions, 428
Neural and Hormonal Controls, 433
Digestion and Absorption, 434
Common Manifestations of Digestive System
Disorders, 435
Anorexia, Vomiting, and Bulimia, 435
Diarrhea, 436
Constipation, 437
Fluid and Electrolyte Imbalances, 437
Pain, 438
Malnutrition, 438
Basic Diagnostic Tests, 439
Common Therapies and Prevention, 439
Upper Gastrointestinal Tract Disorders, 441
Disorders of the Oral Cavity, 441
Dysphagia, 446
Esophageal Cancer, 448
Hiatal Hernia, 448
Gastroesophageal Reflux Disease, 449
Gastritis, 449
Peptic Ulcer, 451
Gastric Cancer, 454
Dumping Syndrome, 455
Pyloric Stenosis, 456
Disorders of the Liver and Pancreas, 456
Gallbladder Disorders, 456
Jaundice, 457
Hepatitis, 458
Cirrhosis, 463
Liver Cancer, 467
Acute Pancreatitis, 468
Pancreatic Cancer, 469
Lower Gastrointestinal Tract Disorders, 469
Celiac Disease, 469
Chronic Inflammatory Bowel Disease, 469
Irritable Bowel Syndrome, 473
Appendicitis, 473
Diverticular Disease, 475
Colorectal Cancer, 476
Intestinal Obstruction, 479
Peritonitis, 482
CHAPTER 18 Urinary System Disorders, 488
Review of the Urinary System, 489
Structures and Anatomy, 489
Kidneys, 489
Renal Arteries and Veins, 490
Incontinence and Retention, 493
Diagnostic Tests, 494
Urinalysis, 494
Blood Tests, 495
Other Tests, 496
Diuretic Drugs, 496
Dialysis, 497
Disorders of the Urinary System, 498
Urinary Tract Infections, 498
Inflammatory Disorders, 500
Urinary Tract Obstructions, 503
Urolithiasis (Calculi, or Kidney Stones), 503
Hydronephrosis, 504
Tumors, 505
Vascular Disorders, 505
Nephrosclerosis, 505
Congenital Disorders, 506
Adult Polycystic Kidney, 507
Wilms Tumor (Nephroblastoma), 507
Renal Failure, 507
Acute Renal Failure, 507
Chronic Renal Failure, 509
CHAPTER 19 Reproductive System Disorders, 514
Disorders of the Male Reproductive
System, 515
Review of the Male Reproductive System, 515
Congenital Abnormalities of the Penis, 516
Disorders of the Testes and Scrotum, 516
Inflammation and Infections, 518

CO N T E N TS xvii
Disorders of the Female Reproductive
System, 521
Review of the Female Reproductive
System, 521
Structural Abnormalities, 525
Menstrual Disorders, 526
Infections and Inflammation, 527
Benign Tumors, 530
Malignant Tumors, 532
Infertility, 537
Sexually Transmitted Diseases, 538
Bacterial Infections, 538
Viral Infections, 541
Protozoan Infection, 542
SECTION IV Factors Contributing to
Pathophysiology, 545
CHAPTER 20 Neoplasms and Cancer, 545
Review of Normal Cells, 546
Benign and Malignant Tumors, 546
Nomenclature, 547
Characteristics of Benign and Malignant
Tumors, 547
Malignant Tumors: Cancer, 547
Examples of Malignant Tumors, 561
Skin Cancer, 561
Ovarian Cancer, 561
Brain Cancer, 561
Cancer Incidences, 563
CHAPTER 21 Congenital and Genetic Disorders, 565
Review of Genetic Control, 565
Congenital Anomalies, 567
Genetic Disorders, 570
Single-Gene Disorders, 570
Chromosomal Disorders, 572
Multifactorial Disorders, 572
Developmental Disorders, 573
Diagnostic Tools, 574
Genetic Technology, 575
Genetic Engineering and Gene Therapy, 575
Genetic Diagnosis and DNA Testing, 575
Proteomic Research and Designer
Drugs, 576
Down Syndrome, 576
CHAPTER 22 Complications of Pregnancy, 579
Embryonic and Fetal Development, 579
Physiologic Changes During Pregnancy, 580
Diagnosis of Pregnancy, 580
Physiologic Changes and Their Implications,
581
Potential Complications of Pregnancy, 583
Ectopic Pregnancy, 583
Preeclampsia and Eclampsia:
Pregnancy-Induced Hypertension, 583
Gestational Diabetes Mellitus, 583
Placental Disorders, 584
Blood Clotting Disorders, 584
Rh Incompatibility, 584
Infection, 585
Adolescent Pregnancy, 586
CHAPTER 23 Complications of Adolescence, 588
Review of Changes During Adolescence, 588
Obesity and Metabolic Syndrome, 589
Musculoskeletal Abnormalities, 590
Kyphosis and Lordosis, 590
Scoliosis, 590
Osteomyelitis, 591
Juvenile Rheumatoid Arthritis, 591
Eating Disorders, 593
Anorexia Nervosa, 593
Bulimia Nervosa, 593
Skin Disorders, 593
Acne Vulgaris, 593
Infection, 594
Infectious Mononucleosis, 594
Disorders Affecting Sexual Development, 595
Chromosomal Disorders, 595
Tumors, 595
Menstrual Abnormalities, 595
CHAPTER 24 Complications of Aging, 597
The Aging Process, 597
Physiological Changes With Aging, 598
Hormonal Changes, 598
Reproductive System Changes, 598
Changes in the Skin and Mucosa, 599
Cardiovascular System Changes, 599
Musculoskeletal System Changes, 600
Respiratory System Changes, 601
Nervous System Changes, 602
Digestive System Changes and Nutrition, 602
Urinary System Changes, 603
Other Factors, 603
Multiple Disorders, 603
Section V Environmental Factors and
Pathophysiology, 606
CHAPTER 25 Immobility and Associated Problems, 606
Factors Involving Immobility, 606
Musculoskeletal System Effects, 607
Cutaneous Effects, 607
Cardiovascular System Effects, 608
Respiratory System Effects, 608
Digestive System Effects, 609
Urinary System Effects, 609
Neurologic/Psychological Effects, 609
Effects of Immobility on Children, 610
CHAPTER 26 Stress and Associated Problems, 611
Review of the Stress Response, 611
Stress and Disease, 612
Potential Effects of Prolonged or
Severe Stress, 614
Coping With Stress, 615
CHAPTER 27 Substance Abuse and Associated
Problems, 617
Terminology, 618
Predisposing Factors, 619
Environmental/Behavioral Risk Factors, 619
Indications/Recognition of Abuse, 620
Potential Complications of Substance Abuse, 620

xviii CO N T E N TS
Overdose, 620
Withdrawal, 621
Effects on Pregnancy, 621
Cardiovascular Problems, 621
Infection, 621
Neurologic/Psychological Effects, 621
Alcohol, 621
Treatment for Substance Abuse, 622
CHAPTER 28 Environmental Hazards and
Associated Problems, 624
Chemicals, 625
Heavy Metals, 626
Acids/Bases, 626
Inhalants, 626
Asbestos, 627
Pesticides, 627
Physical Agents, 627
Temperature Hazards, 627
Radiation Hazards, 628
Noise Hazards, 629
Food and Waterborne Hazards, 629
Biologic Agents, 629
Bites and Stings, 629
Appendices, 631
Glossary, 654
Index, 663

1
Introduction to Pathophysiology
S E C T I O N I
Pathophysiology: Background and Overview
C H A P T E R 1
What Is Pathophysiology and Why Study
It?
Understanding Health and Disease
Concept and Scope of Pathophysiology
Beginning the Process: A Medical
History
New Developments and Trends
Basic Terminology of Pathophysiology
The Disease Process
Etiology-Causes of Disease
Characteristics of Disease
Disease Prognosis
Introduction to Cellular Changes
Terms Used for Common Cellular
Adaptations
Cell Damage and Necrosis
Case Studies
Chapter Summary
Study Questions
C H A P T E R O U T L I N E
After studying this chapter, the student is expected to:
1. Explain the role of pathophysiology in the diagnosis and
treatment of disease.
2. Use the terminology appropriate for pathophysiology.
3. Explain the importance of a patient’s medical history.
4. Describe common cellular adaptations and possible reasons
for the occurrence of each.
5. Identify precancerous cellular changes.
6. List the common causes of cell damage.
7. Describe the common types of cell necrosis and possible
outcomes.
L E A R N I N G O B J E C T I V E S
anaerobic
apoptosis
autopsy
biopsy
endogenous
exogenous
gangrene
homeostasis
hypoxia
iatrogenic
idiopathic
inflammation
ischemia
lysis
lysosomal
microorganisms
microscopic
morphologic
necrosis
probability
pyroptosis
K E Y T E R M S
What Is Pathophysiology and Why Study It?
Pathophysiology involves the study of functional or physi-
ologic changes in the body that result from disease
processes. This subject builds on knowledge of the normal
structure and function of the human body. Disease
development and the associated changes to normal
anatomy or physiology may be obvious or may be hidden
with its quiet beginning at the cellular level. As such,
pathophysiology includes some aspects of pathology, the
laboratory study of cell and tissue changes associated
with disease.

2 SECTION I Pathophysiology: Background and Overview
position, and even emotions. Therefore it is impossible
to state a single normal value for blood pressure or pulse
rate. It is also important to remember that any one indica-
tor or lab value must be considered within the total
assessment for the individual client.
Likewise, a discussion of a specific disease in a text
presents a general description of the typical characteristics
of that disease, but some differences in the clinical picture
can be expected to occur in a specific individual, based
on similar variables.
Concept and Scope of Pathophysiology
Pathophysiology requires the use of knowledge of basic
anatomy and physiology and is based on a loss of or a
change in normal structure and function. This basis also
saves relearning many facts! Many disorders affecting a
particular system or organ—for example, the liver—
display a set of common signs and symptoms directly
related to that organ’s normal structure and function.
For example, when the liver is damaged, many clotting
factors cannot be produced; therefore excessive bleeding
results. Jaundice, a yellow color in the skin, is another
sign of liver disease, resulting from the liver’s inability
to excrete bilirubin. Also, basic pathophysiologic concepts
related to the causative factors of a disease, such as the
processes of inflammation or infection, are common to
many diseases. Inflammation in the liver causes swelling
of the tissue and stretching of the liver capsule, resulting
in pain, as does inflammation of the kidneys. This cause-
and-effect relationship, defined by signs and symptoms,
facilitates the study of a specific disease.
To provide a comprehensive overview of disease
processes, this text focuses on major diseases. Other
disorders are included when appropriate to provide
exposure to a broad range of diseases. The principles
illustrated by these diseases can then be applied to other
conditions encountered in practice. In addition, a general
approach is used to describe diseases in which there may
be several subtypes. For example, only one type of
glomerulonephritis, a kidney disease, is described in the
text—acute poststreptococcal glomerulonephritis, which
represents the many forms of glomerulonephritis.
Prevention of disease has become a primary focus in
health care. The known causes of and factors predisposing
to specific diseases are being used in the development
of more effective preventive programs, and it is important
to continue efforts to detect additional significant factors
and gather data to further decrease the incidence of certain
diseases. The Centers for Disease Control and Prevention
in the United States have a significant role in collection
of data about all types of disease and provide evidence-
based recommendations for prevention. Prevention
includes activities such as maintaining routine vaccination
programs and encouraging participation in screening
programs such as blood pressure clinics and vision
screening (Box 1.2). As more community health programs
Understanding Health and Disease
Disease may be defined as a deviation from the normal
structure or function of any part, organ, system (or
combination of these), or from a state of wellness. The
World Health Organization includes physical, mental,
and social well-being in its definition of health.
A state of health is difficult to define because the genetic
differences among individuals as well as the many varia-
tions in life experiences and environmental influences
create a variable base. The context in which health is
measured is also a consideration. A person who is blind
can be in good general health. Injury or surgery may
create a temporary impairment in a specific area, but the
person’s overall health status is not altered.
Homeostasis is the maintenance of a relatively stable
internal environment regardless of external changes.
Disease develops when significant changes occur in the
body, leading to a state in which homeostasis cannot be
maintained without intervention. Under normal condi-
tions homeostasis is maintained within the body with
regard to factors such as blood pressure, body temperature,
and fluid balance. As frequent minor changes occur in
the body, the compensation mechanisms respond, and
homeostasis is quickly restored. Usually the individual
is not aware of these changes or the compensations taking
place.
Steps to Health (Box 1.1) are recommended to prevent
disease.
When one is defining “normal” limits for health
indicators such as blood pressure, pulse, or laboratory
data, the values used usually represent an average or a
range. These values represent what is expected in a typical
individual but are not absolutes. Among normal healthy
individuals, the actual values may be adjusted for factors
such as age, gender, genetics, environment, and activity
level. Well-trained athletes often have a slower pulse or
heart rate than the average person. Blood pressure usually
increases slightly with age, even in healthy individuals.
Also, small daily fluctuations in blood pressure occur as
the body responds to minor changes in activity, body
1. Be a nonsmoker and avoid second-hand smoke.
2. Eat 5 to 10 servings of vegetables and fruit a day. Choose
high-fiber, lower-fat foods. If you drink alcohol, limit your
intake to one to two drinks a day.
3. Be physically active on a regular basis. This will also help
you to maintain a healthy body weight.
4. Protect yourself and your family from the sun.
5. Follow cancer screening guidelines.
6. Visit your doctor or dentist if you notice any change in
your normal state of health.
7. Follow health and safety instructions at home and at work
when using, storing, and disposing of hazardous
materials.
BOX 1.1 Seven Steps to Health

CHAPTER 1 Introduction to Pathophysiology 3
the pathophysiology of a disease, comprehension of its
manifestations and potential complications, and its treat-
ment, usually follow. A solid knowledge base enables
health care professionals to meet these increased demands
with appropriate information.
Individuals working in health care have found that
many new scientific developments have raised ethical,
legal, and social issues. For example, the explosion in
genetic information and related technologies has raised
many ethical concerns (see Chapter 21). In relatively new
areas of research such as genetics, discussion and resolu-
tion of the legal and ethical issues lag far behind the
scientific advances. Health research is most often funded
by commercial sources (up to 80% according to some
studies), and new breakthrough therapies are often
announced before the start of any clinical trials. This
causes increased hope and immediate demand for such
treatments often as much as a decade before they become
available. Understanding the research process and the
time required for clinical trials of new therapies is crucial
for answering questions about new therapies.
The research process in the health sciences is a lengthy
three-stage process that aims to demonstrate both the
safety and effectiveness of a new therapy:
• The first stage in this process is often referred to as
“basic science” in which researchers work to identify
a technology that will limit or prevent the disease
process. This stage is carried out in the laboratory
and often requires the use of animals or cell cultures.
• The second stage involves a small number of
human subjects to determine if the therapy is safe
for humans.
• The third stage only takes place if the results of the
previous research are positive; the majority of
therapies do not make it to this point. In the third
stage of research, a large number of patients with
the disease or at risk for the disease are enrolled in
clinical trials. These are usually double blind studies
in which the research subject and the person
administering the treatment do not know if the
subject is receiving a standard, proven therapy or
the therapy being tested. The subject is identified
by number only without the particular therapy
administered. All results are recorded by the sub-
ject’s identification number. The principal investiga-
tor is responsible for tracking data collected in trials
with many patients, often in several different health
centers. The data are then analyzed to determine
if the new therapy is more effective than the tradi-
tional therapy. In studies of vaccines or other preven-
tive measures, data are collected about the occurrence
of disease in both the control group and the
experimental group to determine if the new measure
reduces the incidence of the specific disease.
Research findings that demonstrate merit after this three-
stage process are often referred to as “evidence-based
research findings.” The research data collected up to this
develop, and with the increase in information available
on the Internet, health care workers are becoming more
involved in responding to questions from many sources
and have an opportunity to promote appropriate preven-
tive measures in their communities. A sound knowledge
of pathophysiology is the basis for preventive teaching
in your profession.
While studying pathophysiology, the student becomes
aware of the complexity of many diseases, the difficulties
encountered in diagnosis and treatment, and the possible
implications arising from a list of signs and symptoms
or a prognosis. Sophisticated and expensive diagnostic
tests are now available. The availability of these tests,
however, also depends on the geographic location of
individuals, including their access to large, well-equipped
medical facilities. More limited resources may restrict
the number of diagnostic tests available to an individual,
or a long waiting period may be necessary before testing
and treatment are available. When a student understands
the pathophysiology, comprehension of the manifestations
and potential complications of a disease, and its treatment,
From http://www.iwh.on.ca/wrmb/primary-secondary-and-tertiary-prevention.
Primary Prevention
The goal is to protect healthy people from developing a disease
or experiencing an injury in the first place. For example:
• Education about good nutrition, the importance of
regular exercise, and the dangers of tobacco, alcohol, and
other drugs
• Education and legislation about proper seat belt and
helmet use
• Regular exams and screening tests to monitor risk factors
for illness
• Immunization against infectious disease
• Controlling potential hazards at home and in the
workplace
Secondary Prevention
These interventions happen after an illness or serious risk factors
have already been diagnosed. The goal is to halt or slow the
progress of disease (if possible) in its earliest stages; in the
case of injury, goals include limiting long-term disability and
preventing reinjury. For example:
• Telling people to take daily, low-dose aspirin to prevent a
first or second heart attack or stroke
• Recommending regular exams and screening tests in
people with known risk factors for illness
• Providing suitably modified work for injured workers
Tertiary Prevention
This phase focuses on helping people manage complicated,
long-term health problems such as diabetes, heart disease,
cancer, and chronic musculoskeletal pain. The goals include
preventing further physical deterioration and maximizing quality
of life. For example:
• Cardiac or stroke rehabilitation programs
• Chronic pain management programs
• Patient support groups
BOX 1.2 Primary, Secondary, and Tertiary Prevention

http://www.iwh.on.ca/wrmb/primary-secondary-and-tertiary-prevention

4 SECTION I Pathophysiology: Background and Overview
Clinical research funding is being directed to identifying
treatments as well as preventive measures that are more
effective on a cost-per-patient basis.
Many options other than traditional therapies are now
available. Treatment by acupuncture or naturopathy may
be preferred (see Chapter 3). These options may replace
traditional therapies or may be used in conjunction with
them. A patient may seek an alternative or complementary
mode of treatment to supplement traditional care; thus
knowledge of these complementary therapies is often
needed. It is also recognized that such therapies and
practices should be part of a health history for any client
seeking care.
Beginning the Process: A Medical History
Many individuals in the health professions will be
contributing to, completing, or updating a patient’s
medical or health history (see Ready Reference 6 for an
example). This information is essential to identify any
impact health care activities might have on a patient’s
condition, or how a patient’s illness might complicate
care. The assessment includes questions on current and
prior illnesses, allergies, hospitalizations, and treatment.
Current health status is particularly important and should
include specific difficulties and any type of therapy or
drugs, prescription, nonprescription, and herbal items,
including food supplements.
A basic form is usually provided for the patient to fill
out, and then it is completed by the health professional
asking appropriate follow-up questions to clarify the
patient’s current condition and identify any potential
problems. Knowledge of pathophysiology is essential to
developing useful questions, understanding the implica-
tions of this information, and deciding on the necessary
precautions or modifications required to prevent complica-
tions. For example, a patient with severe respiratory
problems or congestive heart failure would have difficulty
breathing in a supine position. Reducing stress may be
important for a patient with high blood pressure. Pro-
phylactic medication may be necessary for some patients
to prevent infection or excessive bleeding. In some cases,
additional problems or undesirable effects of medications
may be detected.
New Developments and Trends
Both students and practitioners must constantly update
their information and knowledge. Developments in all
areas of health care are occurring at a rapid rate primarily
due to changes in technologies. New causes of disease
and more detail regarding the pathophysiology of a
disorder are uncovered, diagnostic tests are improved,
and more effective drugs are formulated. Technology
has greatly altered many aspects of health care.
Extensive research projects continue in efforts to
prevent, control, or cure many disorders. For example,
point are then passed on to regulatory bodies such as the
Food and Drug Administration for review. If the therapy
is deemed safe and better than the standard therapy used
in the past, the data will be approved for use for the
specific disease identified in the research protocol.
Evidence-based research does not take into account
cost, availability, or social and cultural factors that may
influence use and acceptance of a therapy. These factors
may be quite significant and affect the physician’s or
patient’s acceptance of a therapy.
In rare cases, research trials in the third stage will be
stopped if there is a significant difference in the mortality
rate for the experimental group versus the control group.
Research on the first antiretroviral agent, azidothymidine
(AZT), was stopped 6 months early when the research
showed a striking difference in survival rates. Those in
the experimental group receiving AZT were outliving
the control group in significant numbers. When the results
were analyzed, trials stopped and all patients were given
the option of receiving AZT.
Once a therapy is approved for use, it may show
additional potential to treat a different disease. Such use
is termed “off-label” use. For the manufacturer to advertise
the drug or therapy for use in different diseases, it must
go through the third stage of clinical trials in patients
having the new disease. An example is research using
the drug thalidomide to treat malignancies such as
multiple myeloma.
Other issues may affect professional practice. Current
technology provides an opportunity to prolong life
through the use of various machines, many advances in
surgery, and the use of organ transplants. Legal and ethical
issues about fetal tissue transplants, stem cell therapies,
experimental drugs or treatments, and genetic engineering
continue to be difficult topics to address. In these develop-
ing areas, the primary goal is to reduce the incidence of
disease and improve recovery rates. Concerns about new
medical and health technologies include issues of access
to therapy, costs, and relative risk versus benefits of new
treatments. Questions have also been raised about the
allocation of health care resources for new therapies such
as heart transplants or in vitro fertilization (test-tube
babies), which are very costly. A public health dilemma
results because a choice must be made between a high-cost
treatment for one person and a low-cost treatment for
many people, given the limited resources available. In
many cases evidence-based research is demonstrating
little significant difference in outcomes for newer versus
older technologies. A skilled and trained professional is
essential in the use and interpretation of any technology.
THINK ABOUT 1.1
a. What is the purpose of a double-blind research trial?
b. What is a placebo, and why is it used in some studies?

CHAPTER 1 Introduction to Pathophysiology 5
mechanisms. The significance of these effects on another
system can be more easily understood and remembered
when prior knowledge of normal physiology can be
quickly applied to the altered function.
A disease or abnormal condition usually involves
changes at the organ or system (gross) level as well as
at the cellular, or microscopic, level. Pathophysiology
focuses on the effects of abnormalities at the organ
level, but cellular changes are usually integral to a full
understanding of these effects. Pathology laboratory
studies, which are particularly useful in establishing the
cause of a disease, examine tissue specimens from biopsy
procedures (excision of very small amounts of living
tissue), surgical specimens, or examination after death
(autopsy). Analysis of body fluids is another essential
diagnostic tool in a pathology laboratory. As indicated,
the pathophysiologic changes at a particular site also
include evidence of the basic cause of disease, whether
it is an infection, a neoplasm, or a genetic defect.
The Disease Process
Following are a few terms frequently used in the discus-
sion of disease processes. Not all of these terms are
necessarily used when describing any one disorder.
• Diagnosis refers to the identification of a specific disease
through evaluation of signs and symptoms, laboratory
tests (see front inside cover and Ready Reference 5 in
the Appendix) or other tools. More than one factor is
usually required to verify a diagnosis. For example, a
diagnosis of diabetes mellitus could be confirmed by a
blood test following consideration of the patient’s signs,
and a fractured leg bone is indicated by pain, swelling,
perhaps the position of the leg, but it is confirmed by
x-ray.
• Etiology concerns the causative factors in a particular
disease. There may be one or several causative factors.
Etiologic agents include congenital defects, inherited
or genetic disorders, microorganisms such as viruses
or bacteria, immunologic dysfunction, metabolic
derangements, degenerative changes, malignancy,
burns and other trauma, environmental factors, and
nutritional deficiencies.
research indicated that most cases of cervical cancer
resulted from infection by human papillomavirus (HPV).
The next step involved development of a vaccine effective
against the most common strains of the virus. In clinical
trials, use of the vaccine showed a reduction in the number
of women developing cervical cancer. This vaccine is
now available to young women to prevent cervical cancer
in later years. It does not provide 100% prevention and
other health prevention behaviors, such as routine screen-
ing, need to be maintained, but the number of actual
cases of cervical cancer and the cost of treatment are
expected to decline dramatically in the coming decades.
It is essential for the student and practitioner to continu-
ally check for new information, employing reliable,
accurate resources such as professional websites, journals,
or seminars. Many changes in health care are anticipated
in the near future as electronic devices are more frequently
used. For example, sensors implanted under the skin
may measure blood glucose levels in diabetic patients
or release the amount of insulin appropriate to the
patient’s needs. The increased costs associated with
technologic advances then are balanced against the costs
of hospitalization or chronic care.
Reports from health professionals are gathered by the
World Health Organization (WHO), United States Public
Health Service, Centers for Disease Control and Prevention
(CDC), and state and local authorities, as well as agencies
in countries around the world. These data are organized
and published, leading to new research efforts, tracking
new or deadly diseases or, in some cases, signaling a
warning about predisposing conditions or current treat-
ments. Awareness of deviations from the expected out-
comes is a responsibility of those working in health care.
Keeping up with new discoveries may sometimes feel
like information overload, but it is a critical part of profes-
sional practice (Box 1.3).
New Challenges: the Zika Virus
First discovered in 1947, Zika virus infections were isolated
to tropical Africa, Southeast Asia, and the Pacific Islands. In
2015 a case was confirmed in Brazil, which prompted the WHO
to declare the virus a public health emergency of international
concern. Since identifying this new potential threat as an
international concern, the CDC elevated its response to the
highest level in the agency, thus expanding the research on
the diagnosis, spread, and treatment/prevention of the virus.
This type of timely sharing of information and support among
various health agencies and organizations (including private
industries) at all levels is necessary to effectively face potential
epidemics in the future.
BOX 1.3
Basic Terminology of Pathophysiology
Understanding basic terminology is the essential first
step in learning a new subject. Second, a review of past
learning in normal anatomy and physiology, along with
the associated proper names and terms, is needed in
the study of pathophysiology. Selected anatomic terms
may be reviewed in Ready References 1 and 2 in the
appendices at the back of the text. A firm foundation in
anatomy and physiology is particularly important when
a disease affects several organs or systems in the body.
For example, kidney disease often affects cardiovascular
function through the renin, angiotensin, and aldosterone
APPLY YOUR KNOWLEDGE 1.1
Using the heart and the lungs, show how you can apply your
prior knowledge of anatomy and physiology to your study of
pathophysiology. (Hint: Change part of the normal structure
and predict the resulting loss of function.)

6 SECTION I Pathophysiology: Background and Overview
quietly in this way. There may be several stages in the
development of a single disease.
• An acute disease indicates a short-term illness that
develops quickly with marked signs such as high fever
or severe pain—for example, acute appendicitis.
• A chronic disease is often a milder condition developing
gradually, such as rheumatoid arthritis, but it persists
for a long time and usually causes more permanent
tissue damage. Often a chronic disease is marked by
intermittent acute episodes.
• A subclinical state exists in some conditions in which
pathologic changes occur but the patient exhibits no
obvious manifestations, perhaps because of the great
reserve capacity of some organs. For example, kidney
damage may progress to an advanced stage of renal
failure before symptoms are manifested.
• An initial latent or “silent” stage, in which no clinical
signs are evident, characterizes some diseases. In
infectious diseases this stage may be referred to as the
incubation period, which is the time between exposure
to the microorganism and the onset of signs or symp-
toms; it may last for a day or so or may be prolonged,
perhaps for days or weeks. Often the disease agent
may be communicable during this incubation period.
• The prodromal period comprises the time in the early
development of a disease when one is aware of a
change in the body, but the signs are nonspecific;
for example, fatigue, loss of appetite, or headache. A
sense of feeling threatened often develops in the early
stage of infections. Laboratory tests are negative during
the prodromal period; thus it is difficult to confirm a
diagnosis.
• The manifestations of a disease are the clinical evidence
or effects, the signs and symptoms, of disease. These
manifestations, such as redness and swelling, may be
local, or found at the site of the problem. Or signs and
symptoms may be systemic, meaning they are general
indicators of illness, such as fever.
• Signs are objective indicators of disease that are obvious
to someone other than the affected individual. Signs
can be either local, found at the site of the problem
(such as a skin rash) or systemic, which are general
indicators (such as a fever).
• Symptoms are subjective feelings, such as pain or nausea.
Both signs and symptoms are significant in diagnosing
a particular problem.
• Lesion is the term used to describe a specific local change
in the tissue. Such a change may be microscopic, as
when liver cells are examined for pathologic change,
or highly visible, such as a blister or pimple observed
on the skin.
• A syndrome is a collection of signs and symptoms,
often affecting more than one organ, that usually occur
together in response to a certain condition.
• Diagnostic tests are laboratory tests that assist in the
diagnosis of a specific disease. The appropriate tests
are ordered on the basis of the patient’s manifestations
Etiology-Causes of Disease
When the cause of a disease is unknown, it is termed
idiopathic. In some cases, a treatment, a procedure, or
an error may cause a disease, which is then described as
iatrogenic. Examples of iatrogenic disease are a bladder
infection following catheterization, or bone marrow
damage caused by a prescribed drug. In some cases,
a difficult decision must be made about a treatment
that involves an additional serious risk, with careful
assessment of the benefits versus the risks of a specific
treatment. For example, certain forms of chemotherapy
and radiation used in the treatment of cancer may cause
other serious complications for the patient. In these situa-
tions, the client and practitioner must make an informed
choice.
• Predisposing factors encompass the tendencies that
promote development of a disease in an individual.
A predisposing factor indicates a high risk for the
disease but not certain development. Predisposing or
high-risk factors may include age, gender, inherited
factors, occupational exposure, or certain dietary
practices. For example, insufficient calcium intake
predisposes to osteoporosis. Exposure to asbestos is
known to increase the risk of developing cancer. A
high dietary intake of cholesterol and saturated fats,
cigarette smoking, obesity, and a sedentary lifestyle
are factors that increase the risk of heart attacks. By
promoting avoidance of predisposing factors, the
number of individuals developing the disorder could
be greatly reduced.
• A prophylaxis is a measure designed to preserve health
(as of an individual or society) and prevent the spread
of disease. Prophylactic treatment for myocardial
infarction for high-risk patients is a baby aspirin
daily.
• Prevention of disease is closely linked to etiology and
predisposing factors for a specific disease. Preventive
measures include vaccinations, dietary or lifestyle
modifications, removal of harmful materials in the
environment, and cessation of potentially harmful
activities such as smoking. The health professional
can provide appropriate and reliable information about
the activities that support the client’s needs and allow
him or her to make better decisions about his or her
personal health.
Characteristics of Disease
In describing the characteristics of a particular disease,
certain terms are standard:
• Pathogenesis refers to the development of the disease
or the sequence of events involved in the tissue changes
related to the specific disease process.
• The onset of a disease may be sudden and obvious or
acute—for example, gastroenteritis with vomiting,
cramps, and diarrhea—or the onset may be insidious,
best described as a gradual progression with only
vague or very mild signs. Hepatitis may manifest

CHAPTER 1 Introduction to Pathophysiology 7
for diseases that affect a small group of clients or in
which outcomes vary unpredictably.
• Morbidity indicates the disease rates within a group;
this term is sometimes used to indicate the functional
impairment that certain conditions such as stroke cause
within a population.
• Mortality figures indicate the relative number of deaths
resulting from a particular disease.
• An autopsy or postmortem examination may be performed
after death to determine the exact cause of death or
determine the course of the illness and effectiveness
of treatment. An autopsy is an examination of all or
part of the body by a pathologist. It includes gross
and microscopic examination of tissues, organs, and
fluids and can include a variety of tests depending
on individual circumstances.
• Epidemiology is the science of tracking the pattern or
occurrence of disease. Epidemiologic records include
data on the transmission and distribution of diseases
and are particularly important in the control of infec-
tious diseases and environmentally related diseases.
Data may be presented in graphs, tables, or on maps to
provide a visible pattern. For example, epidemiologic
information is used to determine the components of the
influenza vaccine to be administered each year based on
the currently active strains and geographic movement
of the influenza virus. Major data collection centers
are the World Health Organization and the Centers for
Disease Control and Prevention in Atlanta, Georgia,
and Ottawa, Canada. Notification and reporting of
disease is required to provide data for epidemiologic
studies and prevent occurrence of diseases.
• The occurrence of a disease is tracked by recording two
factors, the incidence and the prevalence. The incidence
of a disease indicates the number of new cases in a
given population noted within a stated time period
(Fig. 1.1). A significant increase or decrease in incidence
of a specific disease may be analyzed to determine
the responsible factors. Prevalence refers to the number
of new and old or existing cases within a specific
population and time period. Note that prevalence is
always a larger figure than incidence.
• Epidemics occur when there are a higher than expected
number of cases of an infectious disease within a given
area, whereas pandemics involve higher numbers of
cases in many regions of the globe (see Fig. 1.1).
Influenza may occur sporadically as well as in epidemic
or pandemic outbreaks.
• Communicable diseases are infections that can be spread
from one person to another. Some of these must be
reported to health authorities.
• Notifiable or reportable diseases must be reported by
the physician to certain designated authorities. The
authority varies with the local jurisdiction. The specific
diseases required to be reported may change over time.
The requirement of reporting is intended to prevent
further spread of the disease and maintain public
and medical history, the clinical examination, and the
patient’s answers to specific questions. These tests may
also be used for monitoring the response to treatment
or the progress of the disease. Such tests may involve
chemical analysis of body fluids such as blood, exami-
nation of tissues and cells from specimens (eg, biopsies
or body secretions), identification of microorganisms
in body fluids or tissue specimens, or radiologic
examination of the body. It is important that medical
laboratories have a quality assurance (QA) program
in place to ensure accurate test results. Also, it is often
helpful for a patient to have any future or repeated
tests done by the same laboratory to provide a more
accurate comparison of results.
• Remissions and exacerbations may mark the course or
progress of a disease. A remission is a period or condi-
tion in which the manifestations of the disease subside,
either permanently or temporarily. An exacerbation
is a worsening in the severity of the disease or in its
signs/symptoms. Rheumatoid arthritis typically has
periods of remission when pain and swelling are
minimal, alternating with acute periods when swelling
and pain are severe. An example of the exacerbation
of asthma might include excessive pollen or air pol-
lution leading to serious breathing problems.
• A precipitating factor is a condition that triggers an
acute episode, such as a seizure in an individual with
a seizure disorder. Note that a precipitating factor
differs from a predisposing factor. For example, a
patient may be predisposed to coronary artery disease
and angina because of a high-cholesterol diet. An
angina attack can be precipitated by shoveling snow
on a very cold day.
• Complications are new secondary or additional problems
that arise after the original disease begins. For example,
following a heart attack, a person may develop conges-
tive heart failure, a complication.
• Therapy or therapeutic interventions are treatment
measures used to promote recovery or slow the
progress of a disease. These measures may include
surgery, drugs, physiotherapy, alternative therapies,
or behavior modification (see Chapter 3).
• Sequelae are the potential unwanted outcomes of the
primary condition, such as paralysis following recovery
from a stroke.
• Convalescence or rehabilitation is the period of recovery
and return to the normal healthy state; it may last for
several days or months.
Disease Prognosis
Prognosis defines the probability or likelihood for recovery
or other outcomes. The probability figures used in
prognosis are based on average outcomes, and there may
be considerable variation among affected individuals. It
is important to consider the basis of the statistics used
to form such conclusions. How big was the clinical group?
How long was the study? It is difficult to state a prognosis

8 SECTION I Pathophysiology: Background and Overview
consequences. Cells may be damaged or destroyed
by changes in metabolic processes, reduced levels of
adenosine triphosphate (ATP), altered pH in the cells,
or damage to the cell membrane and receptors.
Terms Used for Common Cellular Adaptations
• Atrophy refers to a decrease in the size of cells, resulting
in a reduced tissue mass (Fig. 1.2). Common causes
include reduced use of the tissue, insufficient nutrition,
decreased neurologic or hormonal stimulation, and
aging. An example is the shrinkage of skeletal muscle
that occurs when a limb is immobilized in a cast for
several weeks.
• Hypertrophy refers to an increase in the size of individual
cells, resulting in an enlarged tissue mass. This increase
may be caused by additional work by the tissue, as
demonstrated by an enlarged heart muscle resulting
from increased demands (see Fig. 12.23). A common
example of hypertrophy is the effect of consistent
exercise on skeletal muscle, leading to an enlarged
muscle mass. Excessive hormonal stimulation may
also stimulate cell growth.
• Hyperplasia is defined as an increased number of cells
resulting in an enlarged tissue mass. In some cases,
hypertrophy and hyperplasia occur simultaneously,
as in the uterine enlargement that occurs during
pregnancy. Hyperplasia may be a compensatory
mechanism to meet increased demands, or it may be
pathologic when there is a hormonal imbalance. In
certain instances there may be an increased risk of
cancer when hyperplasia occurs.
• Metaplasia occurs when one mature cell type is replaced
by a different mature cell type. This change may result
from a deficit of vitamin A. Sometimes metaplasia
may be an adaptive mechanism that provides a more
resistant tissue—for instance, when stratified squamous
epithelium replaces ciliated columnar epithelium in
the respiratory tracts of cigarette smokers. Although
the new cells present a stronger barrier, they decrease
defenses for the lungs because cilia are no longer
present as a defense mechanism for the simpler
squamous cells in the mucosa.
• Dysplasia is the term applied to tissue in which the
cells vary in size and shape, large nuclei are frequently
present, and the rate of mitosis is increased. This situ-
ation may result from chronic irritation infection, or it
may be a precancerous change. Detection of dysplasia
is the basis of routine screening tests for atypical cells
such as the Pap smear (Papanicolaou test on cervical
cells).
• Anaplasia refers to cells that are undifferentiated with
variable nuclear and cell structures and numerous
mitotic figures. Anaplasia is seen in most but not all
malignant tumors and is the basis for grading the
aggressiveness of a tumor.
• Neoplasia means “new growth,” and a neoplasm is
commonly called a tumor. Tumors are of two types,
health. Infections such as measles, severe acute respira-
tory syndrome (SARS), and human immunodeficiency
virus (HIV) or acquired immunodeficiency syndrome
(AIDS) may be included in some jurisdictions.
N
um
be
r
of
c
as
es
p
er
10
0,
00
0
po
pu
la
tio
n
Months
PREVALENCE:
Number of new and old cases
INCIDENCE:
Number of new cases
EPIDEMIC:
Large temporary
increase in cases
11109876543210 12
FIG. 1.1 Graph illustrating the occurrence of disease.
Introduction to Cellular Changes
The cells have mechanisms by which they can adapt
their growth and differentiation to altered conditions in
the body. Some minor alterations, such as increases in
breast and uterine tissue during pregnancy, are normal
adaptations to change in the body. Tissues are frequently
modified as a response to hormonal stimulation or
environmental stimuli such as irritation. Frequently such
changes are reversible after the stimulus is removed.
However, disease may develop when cell structure and
function change and homeostasis cannot be maintained
as a result. Irreversible changes in a cell signal a change
in DNA structure or function. (See Fig. 21.2 for an illustra-
tion of DNA, the controlling nuclear material in a cell.)
Abnormal changes are not necessarily a precursor to
permanent tissue damage or the development of tumors
or cancer, but it is important to determine the cause and
monitor any abnormality to reduce the risk of serious
THINK ABOUT 1.2
Rheumatoid arthritis is defined as a chronic systemic disorder
with remissions and exacerbations, resulting in permanent joint
damage. Describe this disease in terms of manifestations, etiol-
ogy, predisposing factors, pathogenesis, and treatments.

CHAPTER 1 Introduction to Pathophysiology 9
There are many ways of injuring cells in the body,
including the following:
• Ischemia, a decreased supply of oxygenated blood to
a tissue or organ, due to circulatory obstruction
• Physical agents, excessive heat or cold, or radiation
exposure
• Mechanical damage such as pressure or tearing of
tissue
• Chemical toxins
• Microorganisms such as bacteria, viruses, and
parasites
• Abnormal metabolites accumulating in cells
• Nutritional deficits
• Imbalance of fluids or electrolytes
Decreased oxygen in the tissue may occur locally
because of a blocked artery or systemically because of
respiratory impairment. Cells with a high demand for
oxygen, such as those of the brain, heart, and kidney,
are quickly affected by hypoxia (reduced oxygen in the
tissue). A severe oxygen deficit interferes with energy
(ATP) production in the cell, leading to loss of the sodium
pump at the cell membrane as well as loss of other cell
functions. An increase in sodium ions inside the cell leads
to swelling of the cell and eventually to rupture of the
cell membrane. At the same time, in the absence of oxygen,
anaerobic metabolism occurs in the cell, leading to a
decrease in pH from buildup of lactic acid and further
metabolic impairment. A deficit of other essential nutrients
such as vitamins may also damage cells because normal
metabolic processes cannot take place.
benign and malignant (see Figs. 20.1 and 20.2). Malig-
nant neoplasms are referred to as cancer. Benign tumors
do not necessarily become malignant. Benign tumors
are usually considered less serious because they do
not spread and are not life threatening unless they are
found in certain locations, such as the brain, where
they can cause pressure problems. The characteristics
of each tumor depend on the specific type of cell from
which the tumor arises, resulting in a unique appear-
ance and growth pattern. Neoplasms are discussed
further in Chapter 20.
Normal cells
Dysplasia
Atrophy
Hyperplasia
Hypertrophy
Neoplasia
(malignancy)
Metaplasia
Normal cells
Different
replacement cells
FIG. 1.2 Abnormal cellular growth patterns.
Cell Damage and Necrosis
Apoptosis refers to programmed cell death, a normal
occurrence in the body, which may increase when cell
development is abnormal, cell numbers are excessive,
or cells are injured or aged. Cells self-destruct, appearing
to digest themselves enzymatically, and then disintegrate
into vesicles called apoptotic bodies. These vesicles are
quickly engulfed through phagocytic activity without
eliciting an inflammatory response.
Necrosis refers to the death of one or more cells or a
portion of tissue or organ as a result of irreversible damage
and not a programmed cellular event.
THINK ABOUT 1.3
Differentiate among hypertrophy, hyperplasia, anaplasia, and
dysplasia.

10 SECTION I Pathophysiology: Background and Overview
enzymes such as creatine phosphokinase (CPK) and
troponin in the blood.
Necrosis is the term used when a group of cells die
and cause further damage due to cellular disintegration.
The process of cell death varies with the cause of the
damage (Fig. 1.3):
• Liquefaction necrosis refers to the process by which dead
cells liquefy under the influence of certain cell enzymes.
This process occurs when brain tissue dies or in certain
bacterial infections in which a cavity or ulcer may
develop in the infected area (Fig. 1.3B).
• Coagulative necrosis occurs when the cell proteins are
altered or denatured (similar to the coagulation that
occurs when cooking eggs), and the cells retain some
form for a time after death. This process typically
occurs in a myocardial infarction (heart attack) when
a lack of oxygen causes cell death (Fig. 1.3A).
• Fat necrosis occurs when fatty tissue is broken down
into fatty acids in the presence of infection or certain
enzymes (Fig. 1.3C). These compounds may increase
inflammation.
• Caseous necrosis is a form of coagulation necrosis in
which a thick, yellowish, “cheesy” substance forms.
Tuberculosis (TB) offers an interesting example of
caseous necrosis (Fig. 1.4). When tuberculosis develops,
the first stage is characterized by development of a
granuloma, a small solid mass of macrophages and
lymphocytes, often covered by connective tissue, which
forms in some types of chronic inflammation (see
Chapter 5). With TB, caseous necrosis can be seen
inside this mass. The granuloma associated with
tuberculosis is called a Ghon focus or complex, and
it usually heals like a scar, containing the infection. If
the infection continues to develop, this area may
undergo liquefaction necrosis, forming a cavity. (See
Chapter 13 for more details on tuberculosis.)
• Infarction is the term applied to an area of dead cells
resulting from lack of oxygen (see Fig. 12.16B). When
a large number of cells in an area die, the functional
loss can be significant. For example, when part of the
heart muscle is infarcted or dies, that area can no longer
contract to pump blood (see Chapter 12). After tissue
dies, it is eventually replaced either by tissue regener-
ated from nearby similar cells or connective tissue or
scar tissue that fills the gap. Myocardial or heart muscle
cells do not undergo mitosis; therefore scar tissue must
replace the dead tissue.
Gangrene refers to an area of necrotic tissue, usually
associated with a lack or loss of blood supply that is
followed by invasion of bacteria (see Fig. 1.3D). Necrotic
tissue can provide a good medium for infection by
microorganisms. Such an infection frequently occurs after
an infarction in the intestines or in a limb in which blood
supply is deficient and bacteria are normally present.
Depending on its location, gangrene may be described
as wet or dry. Dry gangrene is often caused by coagulative
necrosis in which the tissue dries, shrinks, and blackens.
Another cause of cellular damage is physical injury
related to thermal (heat) or mechanical pressures. These
may impair blood supply to the cells or affect metabolic
processes in the cells. Radiation exposure may damage
cells by interfering with their blood supply or directly
altering their chemical constituents, creating toxic materi-
als inside the cells or changing DNA. Chemicals from
both the environment (exogenous) and inside the body
(endogenous) may damage cells, either by altering cell
membrane permeability or producing other reactive
chemicals, known as free radicals, which continue to
damage cell components. Infectious diseases cause cell
injury through the actions of microorganisms (living
organisms too small to be seen with the naked eye) such
as bacteria and viruses. Certain types of intracellular
microorganisms induce a type of cell death referred to
as pyroptosis. Pyroptosis differs from apoptosis in that
pyroptosis results in the lysis or dissolution of the cell,
releasing destructive lysosomal enzymes into the tissue,
which cause inflammation (swelling, redness, and pain)
as well as damage to nearby cells and reduced function
(see Chapter 5). The apoptotic bodies formed through
apoptosis do not cause an inflammatory response as they
are quickly engulfed through phagocytosis. Some genetic
defects or inborn errors of metabolism can lead to
abnormal metabolic processes. Altered metabolism leads
to the accumulation of toxic intermediary compounds
inside the cells, ultimately destroying them.
Cell damage usually occurs in two stages. In general,
the initial cell damage causes an alteration in a metabolic
reaction, which leads to a loss of function of the cell. If
the factor causing the damage is removed quickly, the
cell may be able to recover and return to its normal
state, and the damage is said to be reversible. As the
amount of damage increases, detectable morphologic
or structural changes occur in the nucleus and the cell
as well.
Cell death as a result of external damage may take on
a variety of forms. Generally these involve cellular swell-
ing and rupture if the cell membrane is affected or
accumulations of lipid inside the cell if metabolic derange-
ments are present. If the noxious factor remains, the
damage becomes irreversible and the cell dies.
Following cell death, the nucleus of the cell disinte-
grates. The cells undergo lysis or dissolution, releasing
destructive lysosomal enzymes into the tissue, which
cause inflammation (swelling, redness, and pain) as well
as damage to nearby cells and reduced function (see
Chapter 5). If a large number of cells have died, inflam-
mation can be extensive, causing the destruction of
additional cells. The enzymes released from the dead
cells can diffuse into the blood, providing helpful clues
in blood tests that indicate the type of cells damaged.
Diagnostic tests for specific enzymes present in the blood
may determine the site and source of the problem—for
example, a heart attack, in which part of the heart muscle
is destroyed, which is indicated by the presence of cardiac

CHAPTER 1 Introduction to Pathophysiology 11
BA
C D
FIG. 1.3 A, Coagulative necrosis of the kidney caused by ischemia. The necrotic area is pale
yellow, in contrast to the normal reddish-brown tissue. B, Liquefactive necrosis (darkened area)
as a result of brain infarction. C, Fat necrosis in the mesentery. The areas of white chalky deposits
represent calcium soap formation at sites of lipid breakdown. D, Dry gangrene of the toe. (A, D
From Damjanov I: Pathology for the Health Professions, ed 3, Philadelphia, 2006, WB Saunders.
B From Cotran R et al: Robbins Pathologic Basis of Disease, ed 6, Philadelphia, 1999, WB Saunders.
C From Kumar V, Abbas AK, Fausto M: Robbins and Cotran Pathologic Basis of Disease, ed 7, Phila-
delphia, 2005, WB Saunders.)

12 SECTION I Pathophysiology: Background and Overview
A B
CAVITATION
–Mycobacterium tuberculosis
erodes into blood vessels and
spreads to other organs
–M. tuberculosis
spreads through
lungs
Infected
sputum
coughed up
PRIMARY
TUBERCULOSIS
–Calcified lymph nodes
–Healed tubercle with
caseation necrosis

Spread of
tuberculosis via
bronchi
C
FIG. 1.4 A, B, Pulmonary tuberculosis. C, Tuber-
culosis in the upper lobe of the lung with areas of
caseation and scar tissue (arrows). (A, B Drawing
by Margot Mackay, University of Toronto Faculty of
Medicine, Department of Surgery, Division of Biomedi-
cal Communications, Toronto. Reprinted from Walter
JB: An Introduction to the Principles of Diseases ed
3, 1992, WB Saunders. C From Cotran RS, et al: Robbins
Pathologic Basis of Disease, ed 6, Philadelphia, 1999,
WB Saunders.)
Wet gangrene is a result of liquefaction causing the tissue
to become cold, swollen, and black. Gas gangrene is
caused by the buildup of gases within tissue and further
reduces blood supply. Gangrenous tissue frequently must
be removed surgically (eg, by amputation) to prevent
the spread of infection to other parts of the body.
C H A P T E R S U M M A R Y
• Disease is defined as a deviation from the individual’s
normal state of physical, mental, and social well-being,
leading to a loss of homeostasis in the body.
THINK ABOUT 1.4
Describe the different types of necrosis and identify conditions
in which amputation may be necessary.
Specific types of cells die at different rates. Brain cells die
quickly (4–5 minutes) when deprived of oxygen, whereas heart
muscle can survive for approximately 30 minutes. Formerly death
of the body (somatic death) was assumed to occur when heart
action and respiration ceased. Now because cardiac and respira-
tory function can be maintained artificially, the diagnosis of
death is more complex. Currently brain death provides the criteria
for somatic death. A diagnosis of brain death is made following
a set protocol of tests and examinations including a lack of
responses to stimuli, EEG changes, and decreased perfusion in
the brain (see Chapter 14).
CASE STUDY A
Ms. A, age 35, was given a Pap test during a routine medical
checkup. The test showed marked dysplasia of cervical cells but
no sign of infection.
1. Discuss the purposes and uses of diagnostic testing and
how it applies in this scenario. (See Diagnostic Testing.)
2. Discuss how the following terms might apply to this
scenario: prognosis, latent stage, remission, exacerbations,
predisposing factors. (See The Language of
Pathophysiology—terms frequently used.)
3. Compare and contrast the various types of common
cellular adaptations, focusing on dysplasia and the testing
for this condition. (See Terms Used for Common Cellular
Adaptations.)

CHAPTER 1 Introduction to Pathophysiology 13
a disease; etiology or the cause of disease; pathologic
changes in the tissues or organs, or signs and symptoms
of disease; and prognosis, or the probable outcomes.
• Cell and tissue changes such as atrophy and hyper-
trophy are frequently linked to changes in demand
or use of the tissue. Metaplasia often occurs as an
adaptive change, replacing the normal cell with a more
resistant cell. Dysplasia and anaplasia are connected
to malignant changes.
• Cell damage for any reason may be reversible, causing
temporary loss of function. Severe damage to a cell
causes necrosis and loss of function.
• Causes of cell damage include ischemia or lack of
oxygen, toxic substances, changes in pH, or microorgan-
isms such as bacteria and viruses.
Pathophysiology is the study of the structural and
functional changes related to disease processes.
• Effects of a specific disease depend on the organ or
tissue affected and the cause of the disease—for
example, infection or malignant tumor.
• Disease prevention campaigns or screening programs
for early diagnosis are based on factors such as causes,
predisposing factors, and incidence of specific disease.
• Health professionals need to be aware of the new
information, diagnostic tests, and therapies that are
constantly emerging. The allocation of resources for
health care and the ethical issues related to new
technologies are concerns.
• The discussion of disease processes includes topics
such as occurrence, diagnosis, or the identification of
S T U D Y Q U E S T I O N S
1. Choose a specific disease and prepare an
appropriate list of six terms that you could use to
describe this disease, and define each of the terms.
2. Define and give an example of the following:
a. etiology
b. incidence
c. precipitating factor
d. complication
e. prognosis
f. iatrogenic
g. sequelae
3. Differentiate between the terms metaplasia and
malignant neoplasm.
4. Describe the changes in a cell that lead to the
following:
a. loss of function
b. necrosis
5. Define the following terms:
a. apoptosis
b. gangrene
6. What preventive practices can be used to reduce
disease?
7. CJ is having surgery next week to remove a
malignant breast tumor, following discovery of a
lump in the breast and a biopsy. Her mother and
aunt have had breast cancer. CJ is taking
medication for high blood pressure.
Match the significant information in the
preceding question to the appropriate term:
diagnosis, medical history, etiology, prognosis,
benign neoplasm, iatrogenic, signs, complication,
treatment, cancer, and examination of living tissue.
Some terms may not be used or may be used more
than once.

14
Fluid Imbalance
Review of Concepts and Processes
Fluid Compartments
Movement of Water
Fluid Excess: Edema
Causes of Edema
Effects of Edema
Fluid Deficit: Dehydration
Causes of Dehydration
Effects of Dehydration
Third-Spacing: Fluid Deficit and Fluid
Excess
Electrolyte Imbalances
Sodium Imbalance
Review of Sodium
Hyponatremia
Hypernatremia
Potassium Imbalance
Review of Potassium
Hypokalemia
Hyperkalemia
Calcium Imbalance
Review of Calcium
Hypocalcemia
Hypercalcemia
Other Electrolytes
Magnesium
Phosphate
Chloride
Acid-Base Imbalance
Review of Concepts and Processes
Control of Serum pH
Buffer Systems
Bicarbonate-Carbonic Acid Buffer
System and Maintenance of
Serum pH
Respiratory System
Renal System
Acid-Base Imbalance
Compensation
Decompensation
Acidosis
Alkalosis
Treatment of Imbalances
Case Studies
Chapter Summary
Study Questions
C H A P T E R O U T L I N E
After studying this chapter, the student is expected to:
1. Explain the movement of water between body
compartments that results in edema.
2. Describe the causes and effects of dehydration.
3. Explain the meaning of third-spacing.
4. Discuss the causes and signs of hyponatremia and
hypernatremia.
5. Explain the causes and signs of hypokalemia and
hyperkalemia.
6. Describe the causes and signs of hypocalcemia and
hypercalcemia.
7. Describe the causes and effects of hypomagnesemia,
hypophosphatemia, hypochloremia, and hyperchloremia.
8. Explain how metabolic acidosis, metabolic alkalosis,
respiratory acidosis, and respiratory alkalosis develop and
their effects on the body.
9. Explain how decompensation develops and its effects on
the central nervous system.
10. Explain the normal function of atrial natriuretic peptide in
maintaining fluid and electrolyte balance.
L E A R N I N G O B J E C T I V E S
aldosterone
anion
anorexia
antidiuretic hormone
ascites
atrial natriuretic peptide
capillary permeability
carpopedal spasm
cation
diffusion
diuretic
dysrhythmia
edema
electrocardiogram
extracellular
filtration
hydrogen ions
hydrostatic pressure
hypertonic/hyper-osmolar
hypervolemia
hypomagnesemia
hypothalamus
hypotonic/hypo-osmolar
hypovolemia
interstitial fluid
intracellular
intravascular fluid
isotonic/iso-osmolar
laryngospasm
milliequivalent
nonvolatile metabolic acids
osmoreceptor
osmosis
osmotic pressure
paresthesias
skin turgor
tetany
transcellular
K E Y T E R M S
C H A P T E R 2
Fluid, Electrolyte, and
Acid-Base Imbalances

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 15
• Transcellular fluids present in various secretions, such
as those in the pericardial (heart) cavity or the synovial
cavities of the joints
In an adult male, blood constitutes about 4% of body
weight and interstitial fluid about 15%; the remaining
transcellular fluids amount to about 1% of total body
weight. Water constantly circulates within the body and
moves between various compartments. For example, CSF
forms continuously from the blood and is reabsorbed
back into the general circulation. A large volume of water
(up to 8 liters in 24 hours) is present in the digestive
secretions entering the stomach and small intestine, and
this fluid is reabsorbed in the colon, making up a very
efficient water-recycling system.
Fluid Imbalance
Review of Concepts and Processes
Water is a major component of the body and is found
both within and outside the cells. It is essential to homeo-
stasis, the maintenance of a relatively constant and
favorable environment for the cells. Water is the medium
within which metabolic reactions and other processes
take place. It also constitutes the transportation system
for the body. For example, water carries nutrients into
cells and removes wastes, transports enzymes in digestive
secretions, and moves blood cells around the body.
Without adequate fluid, cells cannot continue to function,
and death results. Fluid also facilitates the movement of
body parts—for example, the joints and the lungs.
TABLE 2.1 Fluid Compartments in the Body
Volume
Approximate Percentage
of Body Weight
Adult
Male (L)
Male
(%)
Female
(%)
Infant
(%)
Intracellular fluid 28 40 33 40
Extracellular fluid 15 20 17 30
Plasma (4.5) (4) (4) (4)
Interstitial fluid (10.5) (15) (9) (25)
Other (1) (1) (1)
Total water 43 60 50 70
Note: In elderly women, water content is reduced to approximately 45%
of body weight.
THINK ABOUT 2.2
a. Which body compartment contains the most water?
b. Suggest why diarrhea may cause a fluid deficit more
rapidly than coughing and sneezing with a cold.
THINK ABOUT 2.1
Suggest several functions performed by water in the body and
the significance of each.
Fluid Compartments
Although the body appears to be a solid object, approxi-
mately 60% of an adult’s body weight consists of water,
and an infant’s body is about 70% water (Table 2.1).
Female bodies, which contain a higher proportion of fatty
tissue, have a lower percentage of water than male bodies.
The elderly and the obese also have a lower proportion
of water in their bodies. Individuals with less fluid reserve
are more likely to be adversely affected by any fluid or
electrolyte imbalance.
Fluid is distributed between the intracellular compart-
ment (ICF), or fluid inside the cells, and the extracellular
compartment (ECF). See Ready Reference 1 for a diagram
showing fluid compartments of the body.
ECF includes the following:
• Intravascular fluid (IVF) or blood
• Interstitial fluid (ISF) or intercellular fluid
• Cerebrospinal fluid (CSF)
Movement of Water
To maintain a constant level of body fluid, the amount
of water entering the body should equal the amount of
water leaving the body. Fluid is added to the body through
the ingestion of solid food and fluids and as a product
of cell metabolism (Table 2.2). Fluid is lost in the urine
and feces as well as through insensible (unapparent) losses
through the skin (perspiration) and exhaled air.
The balance of water and electrolytes is maintained
by the following:
• The thirst mechanism in the hypothalamus, the
osmoreceptor cells of which sense the internal environ-
ment, both fluid volume and concentration, and then
promote the intake of fluid when needed.
• The hormone antidiuretic hormone (ADH) controls
the amount of fluid leaving the body in the urine (see
Chapters 16 and 18); ADH promotes reabsorption of
water into the blood from the kidney tubules.
• The hormone aldosterone determines the reabsorption
of both sodium ions and water from the kidney tubules;
these hormones conserve more fluid when there is a
fluid deficit in the body.
• The natriuretic peptide hormones: atrial natriuretic
peptide (ANP) and B-type natriuretic peptide (BNP).
TABLE 2.2 Sources and Losses of Water
Sources (mL) Losses (mL)
Liquids 1200 Urine 1400
Solid foods 1000 Feces 200
Cell metabolism 300 Insensible losses
Lungs 400
Skin 500
Total 2500 2500

16 SECTION I Pathophysiology: Background and Overview
pressure of a fluid and therefore are very important in
maintaining fluid volumes in various compartments.
Hydrostatic pressure may be viewed as the “push” force
and osmotic pressure as the “pull” or attraction force in
such fluid movements. Changes in either force will alter
fluid movement and volume in the compartments.
At the arteriolar end of the capillary, the blood
hydrostatic pressure (or blood pressure) exceeds the
opposing interstitial hydrostatic pressure and the plasma
colloid osmotic pressure of the blood, and therefore fluid
moves out from (or is “pushed” out of) the capillary
into the interstitial compartment. At the venous end of
the capillary, the blood hydrostatic pressure is greatly
decreased and osmotic pressure higher, therefore fluid
tends to shift (or is “pulled”) back into the capillary. It
is easier to remember the direction of movement if one
thinks of the movement of nutrients and oxygen out of
the arterial blood toward the cells and the flow of wastes
and carbon dioxide from the cell back into the venous
blood. Excess fluid and any protein in the interstitial
compartment are returned to the circulation through the
lymphatic capillaries.
These hormones, released by the cardiac muscle
fibers in response to increased pressure within the
cardiac chambers, stimulate the elimination of water
and sodium in the urine to prevent salt-induced
hypertension.
STIMULUS HORMONE SECRETED SITE OF ACTION EFFECT
Decrease in blood flow to the renal afferent arteriole and
decrease in plasma sodium Aldosterone Nephron: Distal
tubule and collecting ducts Increase sodium and water
reabsorption. Small increase in chloride reabsorption.
Increased ECF volume, increased volume pressure within the
cardiac chambers Natriuretic Peptide Hormones (ANP,
BNP, and derivatives) Nephron: collecting ducts Decrease
sodium and water reabsorption
Increase in blood osmolality (refer to the concept of
osmolality) Antidiuretic Hormone or ADH Nephron: Distal
tubule and collecting duct Increase in water reabsorption
• The hormone atrial natriuretic peptide (ANP) is a
hormone synthesized and released by the myocardial
cells in the atrium of the heart. Its role in homeostasis
relates to reduction of workload on the heart by
regulating fluid, sodium, and potassium levels. In
the kidney ANP increases glomerular filtration rate
(GFR) by altering pressure in the glomerular capil-
laries; it also reduces the reabsorption of sodium in
the distal convoluted tubules through inhibition of
ADH. Renin secretion is also reduced and thus the
renin-angiotensin system is inhibited. The result is fluid
loss from the extracellular compartment and lowered
blood pressure. It also reduces aldosterone secretion,
leading to retention of potassium. Research has shown
that ANP is elevated in patients with congestive heart
failure who have increased blood volume in the atria
(see Chapter 12). Research is ongoing on this peptide
and its possible use in the treatment of hypertension
and congestive heart failure.
THINK ABOUT 2.3
a. Describe how excessive fluid is lost from the body during
strenuous exercise on a very hot day. Explain how the
body can respond to this fluid loss to maintain
homeostasis.
b. What factors may limit such responses?
APPLY YOUR KNOWLEDGE 2.1
Predict three changes that could alter normal movement of fluid
in the body.
THINK ABOUT 2.4
a. Explain how a very high hydrostatic pressure in the venule
end of a capillary affects fluid shift.
b. Explain how a loss of plasma protein affects fluid shift at
the capillaries.
c. Explain how a high concentration of sodium ions in the
interstitial fluid affects intracellular fluid levels.
Many cells have mechanisms to control intracellular
volume. A major factor in the movement of water through
cell membranes is the difference in osmotic pressure
between the cell and the interstitial fluids. As the relative
concentrations of electrolytes in the interstitial fluid and
intracellular fluid change, the osmotic pressure also
changes, causing water to move across the cell membrane
by osmosis. For example, if an erythrocyte is placed in
a dilute hypotonic solution (low osmotic pressure), water
may enter the cell, causing it to swell and malfunction.
Fluid constantly circulates throughout the body and moves
relatively freely, depending on the permeability of the
membranes between compartments, by the processes of
filtration or osmosis (Fig. 2.1). Water moves between
the vascular compartment or blood and the interstitial
compartment through the semipermeable capillary
membranes, depending on the relative hydrostatic and
osmotic pressures within the compartments (see Fig.
2.1). Proteins and electrolytes contribute to the osmotic
Fluid Excess: Edema
Fluid excess occurs in the extracellular compartment and
may be referred to as isotonic/iso-osmolar, hypotonic/
hypo-osmolar, or hypertonic/hyper-osmolar, depending
on the cause. The osmolarity or the concentration of solute
in the fluid affects fluid shifts between compartments,
including the cells.

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 17
Cell wastes
VENULE
Semipermeable
membrane
Osmotic
pressure — ISF
(e.g., 3 mm Hg)
Osmotic
pressure — blood
(e.g., 25 mm Hg)
Hydrostatic
pressure — ISF
(e.g., 2 mm Hg)
Hydrostatic
pressure — IVF
(e.g., 30 mm Hg)
CAPILLARY
ARTERIOLE
+ + + +
+ + + +
+ + + +
+ + + +
+ +
x
x x
x xx
x x x x
x x x
+
x
+
+ +
+
+ +
+ +
+
+
+
+
+
+
+
++
+ +
+
++
+
+
+
+
+
+ +
+
+
+
+
+
+
+
+
+ +
Intracellular
compartment
Cell
ICF
+C E
D
ACTIVE
TRANSPORT
D. ACTIVE
TRANSPORT
Movement of solute
using carrier and energy
from low concentration (ISF)
to high concentration (cell)
B
DIFFUSION
Movement of
solutes (e.g., Na+,
glucose) from high
concentration to low
concentration
A
FILTRATION
CAPILLARY EXCHANGE
E
Movement of water
and solutes from blood
(high pressure) to ISF
(low pressure) area
C
OSMOSIS
Movement of water from
low solute concentration (ISF)
to high concentration (blood)
ISF ISF
CAPILLARYISF ISF
CAPILLARYISF ISF
P P P
P
P
ISF – Interstitial fluid
ICF – Intracellular fluid
+ – Solute (e.g., Na+, glucose)
P- Protein
X – Waste (e.g., urea)
C – Carrier
E – Energy or ATP
Pressure
Movement
Legend
Cell wastes
VENULE
Semipermeable
membrane
Osmotic
pressure — ISF
(e.g., 3 mm Hg)
Osmotic
pressure — blood
(e.g., 25 mm Hg)
Hydrostatic
pressure — ISF
(e.g., 2 mm Hg)
Hydrostatic
pressure — IVF
(e.g., 30 mm Hg)
CAPILLARY
+ + + +
+ + + +
+ + + +
+ + + +
+ +
x
x x
x xx
x x x x
x x x
+
x
+
+ +
+
+ +
+ +
+
+
+
+
+
+
+
++
+ +
+
++
+
+
+
+
+
+ +
+
+
+
+
+
+
+
++ +
ICF
+C E
ISF ISF
P P P
P
P
A. FILTRATION
C. OSMOSIS
B. DIFFUSION
FIG. 2.1 Movement of water and electrolytes between compartments.
Edema refers to an excessive amount of fluid in the
interstitial compartment, which causes a swelling or
enlargement of the tissues. Edema may be localized in
one area or generalized throughout the body. Depending
on the type of tissue and the area of the body, edema
may be highly visible or relatively invisible, or it may
not accurately reflect the amount of fluid hidden in the
area; for example, facial edema is usually visible but
edema of the liver or a limb may not be. Edema is usually
more severe in dependent areas of the body, where the

18 SECTION I Pathophysiology: Background and Overview
1. The first cause is increased capillary hydrostatic pressure
(equivalent to higher blood pressure [BP]), which
prevents the return of fluid from the interstitial com-
partment to the venous end of the capillary, or forces
excessive amounts of fluid out of the capillaries into
the tissues. The latter is a cause of pulmonary edema,
in which excessive pressure, often due to increased
force of gravity is greatest, such as the buttocks, ankles,
or feet of a person in a wheelchair. Prolonged edema
interferes with venous return, arterial circulation, and
cell function in the affected area.
Causes of Edema
Edema has four general causes (Fig. 2.2):
Capillary hydrostatic
pressure
Capillary
osmotic pressure
Arterial end
of capillary
Venous end
of capillary
Interstitial fluid
hydrostatic pressure
Interstitial fluid
osmotic pressure
Interstitial
fluid
Interstitial
fluid
Normal Capillary Filtration
A
B C
Albumin
Albumin
Lymphatic vessel
Increased capillary
hydrostatic pressure
Edema
Edema
Increased interstitial
fluid osmotic pressure
Edema
Edema
Tumor blocking
lymphatic drainage
Edema
Edema
Edema
Edema
Low blood albumin Decreased capillary
osmotic pressure
D E
FIG. 2.2 Causes of edema. A, Normal capillary filtration without edema. B, Edema due to increased
capillary hydrostatic pressure. C, Edema due to increased interstitial fluid osmotic pressure from
increased capillary permeability. D, Edema due to blocked lymphatic drainage. E, Edema due to
decreased capillary osmotic pressure from hypoalbuminemia. (From Copstead-Kirkorn LC: Patho-
physiology, ed 4, St. Louis, 2009.)

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 19
large burn wounds, leading to both hypovolemia and
shock.
blood volume, can force fluid into the alveoli, interfer-
ing with respiratory function.
Specific causes of edema related to increased hydro-
static pressure include increased blood volume (hyper-
volemia) associated with kidney failure, pregnancy,
congestive heart failure, or administration of excessive
fluids. In pregnancy, the enlarged uterus compresses
the pelvic veins in the seated position and when a
pregnant woman must stand still for long periods of
time, the pressure in the leg veins can become quite
elevated, causing edema in the feet and legs. In some
people with congestive heart failure, the blood cannot
return easily through the veins to the heart, raising the
hydrostatic pressure in the legs and abdominal organs
and causing ascites, or fluid in the abdominal cavity.
2. Second, edema may be related to the loss of plasma
proteins, particularly albumin, which results in a
decrease in plasma osmotic pressure. Plasma proteins
usually remain inside the capillary and seldom move
through the semipermeable capillary membrane. The
presence of fewer plasma proteins in the capillary
allows more fluid to leave the capillary and less fluid
to return to the venous end of the capillary.
Protein may be lost in the urine through kidney
disease, or synthesis of protein may be impaired in
patients with malnutrition and malabsorption diseases
or with liver disease. Protein levels may drop acutely
in burn patients who have large areas of burned skin;
the subsequent inflammation and loss of the skin
barrier allow protein to easily leak out of the body.
Frequently excessive sodium levels in the extracellular
fluid accompany the two causes just mentioned. When
sodium ions are retained, they promote accumulation
of fluid in the interstitial compartment by increasing
the ISF osmotic pressure and decreasing the return of
fluid to the blood. Blood volume and blood pressure
are usually elevated as well. High sodium levels are
common in patients with heart failure, high blood
pressure, kidney disease, and increased aldosterone
secretion.
3. Edema may result from obstruction of the lymphatic
circulation. Such an obstruction usually causes a local-
ized edema because excessive fluid and protein are
not returned to the general circulation. This situation
may develop if a tumor or infection damages a lymph
node or if lymph nodes are removed, as they may be
in cancer surgery.
4. The fourth cause of edema is increased capillary perme-
ability. This usually causes localized edema and may
result from an inflammatory response or infection (see
Chapter 5). In this case, histamine and other chemical
mediators released from cells following tissue injury
cause increased capillary permeability and increased
fluid movement into the interstitial area. Protein also
leaks into the interstitial compartment, increasing the
osmotic pressure in ISF and thus holding more fluid
in the interstitial area. A general increase in capillary
permeability can result from some bacterial toxins or
THINK ABOUT 2.5
a. In some cases of breast cancer, many of the axillary lymph
nodes are removed. Why are injections not usually done
on the affected arm?
b. Explain why severe kidney disease may cause generalized
edema.
c. Explain why the feet may become swollen when one sits
for long periods of time, but the swelling decreases when
one lies recumbent in bed.
d. Explain how protein-calorie malnutrition results in ascites.
TABLE 2.3 Comparison of Signs and Symptoms
of Fluid Excess (Edema) and Fluid
Deficit (Dehydration)
Fluid Excess (Edema) Fluid Deficit (Dehydration)
Localized swelling (feet, hands,
periorbital area, ascites)
Sunken, soft eyes
Pale, gray, or red skin color Decreased skin turgor, dry
mucous membranes
Weight gain Thirst, weight loss
Slow, bounding pulse, high
blood pressure
Rapid, weak, thready pulse,
low blood pressure, and
orthostatic hypotension
Lethargy, possible seizures Fatigue, weakness,
dizziness, possible stupor
Pulmonary congestion, cough,
rales
Increased body
temperature
Laboratory values: Laboratory values:
Decreased hematocrit Increased hematocrit
Decreased serum sodium Increased electrolytes (or
variable)
Urine: low specific gravity,
high volume
Urine: high specific
gravity, low volume
Note: Signs may vary depending on the cause of the imbalance.
Effects of Edema
• A local area of swelling may be visible and may be pale
or red in color, depending on the cause (Table 2.3).
• Pitting edema occurs in the presence of excess inter-
stitial fluid, which moves aside when firm pressure
is applied by the fingers. A depression or “pit” remains
after the finger is removed.
• In people with generalized edema there is a significant
increase in body weight, which may indicate a problem
before there are other visible signs (Fig. 2.3).
• Functional impairment due to edema may occur, for
example, when it restricts range of movement of joints.
Edema of the intestinal wall may interfere with diges-
tion and absorption. Edema or accumulated fluid
around the heart or lungs impairs the movement and
function of these organs.
• Pain may occur if edema exerts pressure on the nerves
locally, as with the headache that develops in patients

20 SECTION I Pathophysiology: Background and Overview
Fluid Deficit: Dehydration
Dehydration refers to insufficient body fluid resulting
from inadequate intake or excessive loss of fluids or a
combination of the two. Losses are more common and
affect the extracellular compartment first. Water can shift
within the extracellular compartments. For example, if
fluid is lost from the digestive tract because of vomiting,
water shifts from the vascular compartment into the
digestive tract to replace the lost secretions. If the deficit
continues, eventually fluid is lost from the cells, impairing
cell function.
Fluid loss is often measured by a change in body
weight; knowing the usual body weight of a person is
helpful for assessing the extent of loss. As a general guide
to extracellular fluid loss, a mild deficit is defined as a
decrease of 2% in body weight, a moderate deficit as a
5% weight loss, and severe dehydration is a decrease of
8%. This figure should be adjusted for the individual’s
age, body size, and condition.
Dehydration is a more serious problem for infants
and elderly people, who lack significant fluid reserves
as well as the ability to conserve fluid quickly. Infants
also experience not only greater insensible water losses
through their proportionately larger body surface area
but also an increased need for water owing to their higher
metabolic rate. The vascular compartment is rapidly
depleted in an infant (hypovolemia), affecting the heart,
brain, and kidneys. This is indicated by decreased urine
output (number of wet diapers), increased lethargy, and
dry mucosal membranes.
Water loss is often accompanied by a loss of electrolytes
and sometimes of proteins, depending on the specific
cause of the loss. For example, sweating results in a loss of
water and sodium chloride. Electrolyte losses can influence
water balance significantly because electrolyte changes
lead to osmotic pressure change between compartments.
To restore balance, electrolytes as well as fluid must be
replaced. Isotonic dehydration refers to a proportionate
loss of fluid and electrolytes, hypotonic dehydration refers
to a loss of more electrolytes than water, and hypertonic
dehydration refers to a loss of more fluid than electrolytes.
The latter two types of dehydration cause signs of elec-
trolyte imbalance and influence the movement of water
between the intracellular and extracellular compartments
(see Electrolyte Imbalances).
with cerebral edema. If cerebral edema becomes severe,
the pressure can impair brain function because of
ischemia and can cause death. When viscera such as
the kidney or liver are edematous, the capsule is
stretched, causing pain.
• With sustained edema, the arterial circulation may be
impaired. The increased interstitial pressure may
restrict arterial blood flow into the area, preventing
the fluid shift that carries nutrients into the cells. This
can prevent normal cell function and reproduction
and eventually results in tissue necrosis or the develop-
ment of ulcers. This situation is evident in individuals
with severe varicose veins in the legs—large, dilated
veins that have a high hydrostatic pressure. Varicose
veins can lead to fatigue, skin breakdown, and varicose
ulcers (see Chapter 12). These ulcers do not heal easily
because of the continued insufficient blood supply.
• In the dental practice, it is difficult to take accurate
impressions when the tissues are swollen; dentures
do not fit well, and sores may develop that often are
slow to heal and become infected because the blood
flow is impaired to the gingival tissues.
• Edematous tissue in the skin is susceptible to tissue
breakdown from pressure, abrasion, and external
chemicals. Proper skin care is essential to prevent
ulceration, particularly in an immobilized patient (see
Chapter 25).
THINK ABOUT 2.7
a. Explain why an infant is more vulnerable than a young
adult to fluid loss.
b. If more sodium is lost from the extracellular fluid
compartment than water, how will fluid move between the
cell and the interstitial fluid compartment? Explain the
result.
THINK ABOUT 2.6
a. List three signs of local edema in the knee.
b. Explain why persistent edema in a leg could cause
weakness and skin breakdown.
FIG. 2.3 Pitting edema. Note the finger-shaped depressions that
do not rapidly refill after an examiner has exerted pressure. (From
Bloom A, Ireland J: Color Atlas of Diabetes, ed 2, St. Louis, 1992, Mosby.)

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 21
FIG. 2.4 Poor turgor is evident in severe dehydration. (From Jarvis
J: Physical Examination and Health Assessment, ed 7, St. Louis, 2016,
Elsevier.)
THINK ABOUT 2.8
Describe three signs or symptoms of dehydration that are direct
effects, and describe three signs that indicate the compensation
that is occurring in response to dehydration.
THINK ABOUT 2.9
Based on the information given previously on fluid excess and
fluid deficit, describe three signs and symptoms of third-spacing
related to a large burn area.
Third-Spacing: Fluid Deficit and Fluid Excess
Third-spacing refers to a situation in which fluid shifts
out of the blood into a body cavity or tissue where it is
no longer available as circulating fluid. Examples include
peritonitis, the inflammation and infection of the peri-
toneal membranes, and burns. The result of this shift is
a fluid deficit in the vascular compartment (hypovolemia)
and a fluid excess in the interstitial space. Until the basic
cause is removed, fluid remains in the “third space”—in
the body, but is not a functional part of the circulating
fluids. Simply weighing the patient will not reflect this
shift in fluid distribution. Laboratory tests such as
hematocrit and electrolyte concentrations will be necessary
to identify third-spacing. In the case of burns, the third-
spacing is evident as edema in the area of the wounds.
Causes of Dehydration
Common causes of dehydration include the following:
• Vomiting and diarrhea, both of which result in loss
of numerous electrolytes and nutrients, such as glucose,
as well as water; drainage or suction of any portion
of the digestive system can also result in deficits
• Excessive sweating with loss of sodium and water
• Diabetic ketoacidosis with loss of fluid, electrolytes,
and glucose in the urine
• Insufficient water intake in an elderly or unconscious
person
• Use of a concentrated formula in an attempt to provide
more nutrition to an infant
Effects of Dehydration
Initially, dehydration involves a decrease in interstitial
and intravascular fluids. These losses may produce direct
effects such as the following:
• Dry mucous membranes in the mouth (see Table 2.3)
• Decreased skin turgor or elasticity (Fig. 2.4)
• Lower blood pressure, weak pulse, and a feeling of
fatigue
• Increased hematocrit, indicating a higher proportion
of red blood cells compared with water in the blood
• Decreasing mental function, confusion, and loss of
consciousness, which develop as brain cells lose water
and reduce function
The body attempts to compensate for the fluid loss by
doing the following:
• Increasing thirst
• Increasing the heart rate
• Constricting the cutaneous blood vessels, leading to
pale and cool skin
• Producing less urine and concentrating the urine,
increasing the specific gravity, as a result of renal
vasoconstriction and increased secretion of ADH and
aldosterone
Electrolyte Imbalances
Sodium Imbalance
Review of Sodium
Sodium (Na+) is the primary cation (positively charged
ion) in the extracellular fluid (Table 2.4). Diffusion of
sodium occurs between the vascular and interstitial fluids.
Sodium transport across the cell membrane is controlled
by the sodium-potassium pump or active transport,
resulting in sodium levels that are high in extracellular
fluids and low inside the cell. Sodium is actively secreted
into mucus and other body secretions. It exists in the
body primarily in the form of the salts sodium chloride
and sodium bicarbonate. It is ingested in food and bever-
ages, usually in more than adequate amounts, and is lost
from the body in perspiration, urine, and feces. Sodium
levels in the body are primarily controlled by the kidneys
through the action of aldosterone.
Sodium is important for the maintenance of extracel-
lular fluid volume through its effect on osmotic pressure
because it makes up approximately 90% of the solute
in extracellular fluid. Sodium also is essential in the
conduction of nerve impulses (Fig. 2.5) and in muscle
contraction.

22 SECTION I Pathophysiology: Background and Overview
Na+
ICF K+ K+
Protein
Cell membraneECF
Na+
K+ K+
K+
STIMULUS
Na+
Na+
K+
Na+
K+
IMPULSE
Na+
K+ K+
K+
Na+
K+
(eq. 70 mv)
(+35 mv)
(+10 mv)
( 70 mv)
1. Polarization
Resting state of
semipermeable membrane
2. Depolarization
Stimulus opens Na+
channels, Na+ moves
into cell.
3. Repolarization
As impulse moves along
membrane, Na+ channels
close and K+ channels open,
allowing K+ to move outward.
4. Return to Resting State
Channels close.
Sodium-potassium pump
returns Na+ outside cell
and K+ inside cell.
IMPULSE
FIG. 2.5 Role of sodium and potassium ions in the
conduction of an impulse.
TABLE 2.4 Distribution of Major Electrolytes
Ions Intracellular (mEq/L) Blood (mEq/L)
Cations
Sodium (Na) 10 142
Potassium (K) 160 4
Calcium (Ca) Variable 5
Magnesium (Mg) 35 3
Anions
Bicarbonate (HCO3−) 8 27
Chloride (Cl−) 2 103
Phosphate (HPO4−) 140 2
Note: There are variations in “normal” values among individuals.
The concentration of electrolytes in plasma varies slightly from that in the
interstitial fluid or other types of extracellular fluids.
The number of anions, including those present in small quantities, is
equivalent to the concentration of cations in the intracellular compartment
(or the plasma) so as to maintain electrical neutrality (equal negative and
positive charges) in any compartment.
It is important to note the relative changes of electro-
lytes and fluids associated with the individual’s specific
problem to put the actual serum value in perspective.
For example, excessive sweating may result in a low
serum sodium level if proportionately more sodium is
lost than water or if only water is used to replace the
loss. If an individual loses more water than sodium in
perspiration, the serum sodium level may be high.
Hyponatremia
Normal blood sodium levels are presented on the inside
back cover. Hyponatremia refers to a serum sodium
concentration below 3.8 to 5 mmol per liter or 135 mil-
liequivalent (mEq) per liter.
Causes of Hyponatremia
A sodium deficit can result from direct loss of sodium
from the body or from an excess of water in the extracel-
lular compartment, resulting in dilution of sodium.
Common causes of low serum sodium levels include the
following:
1. Losses from excessive sweating, vomiting, and diarrhea

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 23
2. Use of certain diuretic drugs combined with low-salt
diets
3. Hormonal imbalances such as insufficient aldosterone,
adrenal insufficiency, and excess ADH secretion
(SIADH or syndrome of inappropriate antidiuretic
hormone secretion)
4. Early chronic renal failure
5. Excessive water intake
Effects of Hyponatremia
• Low sodium levels impair nerve conduction and
result in fluid imbalances in the compartments.
Manifestations include fatigue, muscle cramps, and
abdominal discomfort or cramps with nausea and
vomiting (Table 2.5).
THINK ABOUT 2.10
a. A high fever is likely to cause deep, rapid respirations,
excessive perspiration, and higher metabolic rate. How
would this affect the fluid and electrolyte balance in the
body?
b. List several reasons why drinking a fluid containing water,
glucose, and electrolytes would be better than drinking
tap water after vomiting.
TABLE 2.5 Signs of Sodium Imbalance
Hyponatremia Hypernatremia
Anorexia, nausea, cramps Thirst; tongue and mucosa
are dry and sticky
Fatigue, lethargy, muscle
weakness
Weakness, lethargy,
agitation
Headache, confusion, seizures Edema
Decreased blood pressure Elevated blood pressure
• Decreased osmotic pressure in the extracellular
compartment may cause a fluid shift into cells, resulting
in hypovolemia and decreased blood pressure (Fig. 2.6).
• The brain cells may swell, causing confusion, headache,
weakness, or seizures.
Hypernatremia
Hypernatremia is an excessive sodium level in the blood
and extracellular fluids (more than 145 mEq per liter).
Causes of Hypernatremia
Excess sodium results from ingestion of large amounts
of sodium without proportionate water intake or a loss
of water from the body that is faster than the loss of
sodium.
Na+
Venule
Water
Na+
Na+
High
osmotic pressure
K+
K+
K+
K+
Cell Water excess
K+
K+
K+
Cell swells
and ruptures
Interstitial fluid
3. Water shifts
out of blood
2. Low osmotic
pressure in
extracellular
fluids
1. Low sodium
concentration
in blood
Low sodium concentration
Low osmotic pressure in ISF
Capillary
Blood in arteriole
4. More water shifts
into cell (from
low to high
osmotic pressure)
in cell
5. Cell swells, function decreases,
and then cell ruptures
FIG. 2.6 Hyponatremia and fluid shift into cells.

24 SECTION I Pathophysiology: Background and Overview
Specific causes include the following:
1. Insufficient ADH, which results in a large volume of
dilute urine (diabetes insipidus)
2. Loss of the thirst mechanism
3. Watery diarrhea
4. Prolonged periods of rapid respiration
THINK ABOUT 2.12
a. Compare the effects of aldosterone with those of ADH on
serum sodium levels.
b. List the signs and symptoms common to both
hyponatremia and hypernatremia and also any signs that
differentiate the two states.
c. Explain how sodium imbalances affect cardiac function.
THINK ABOUT 2.11
Hypernatremia accompanied by an elevated hematocrit value
indicates what fact about body fluids?
Effects of Hypernatremia
The major effect of hypernatremia is a fluid shift out of
the cells owing to the increased osmotic pressure of
interstitial or extracellular fluid; this effect is manifested
by the following:
• Weakness, agitation
• Firm subcutaneous tissues (see Table 2.5)
• Increased thirst, with dry, rough mucous membranes
• Decreased urine output because ADH is secreted
Note that the manifestations can change depending on
the cause of the problem. If the cause of hypernatremia
is fluid loss caused by lack of ADH, urine output is high.
these hydrogen ions move into the cell, they displace
potassium out of the cell to maintain electrochemical
neutrality. Then the excess potassium ions in the interstitial
fluid diffuse into the blood, leading to hyperkalemia.
The reverse process occurs with alkalosis. Acidosis also
promotes hydrogen ion excretion by the kidneys and
retention of potassium in the body. Potassium assists
in the regulation of intracellular fluid volume and has
a role in many metabolic processes in the cell. It is also
important in nerve conduction and contraction of all
muscle types, determining the membrane potential (see
Fig. 2.5). Most important, abnormal potassium levels,
both high and low, have a significant and serious effect
on the contractions of cardiac muscle causing changes
in the electrocardiogram (ECG) and ultimately cardiac
arrest or standstill.
Hypokalemia
In hypokalemia the serum level of potassium is less than
2 mmol per liter or 3.5 mEq per liter.
Causes of Hypokalemia
Low serum potassium levels may result from the
following:
1. Excessive losses from the body due to diarrhea
2. Diuresis associated with certain diuretic drugs; patients
with heart disease who are being treated with certain
diuretic drugs such as furosemide may have to increase
their intake of potassium in food or take a potassium
supplement because hypokalemia may increase the
toxicity of heart medications such as digitalis
3. The presence of excessive aldosterone or glucocorticoids
in the body (in Cushing syndrome, in which gluco-
corticoids have some mineralocorticoid activity,
retaining sodium and excreting potassium)
4. Decreased dietary intake, which may occur with
alcoholism, eating disorders, or starvation
5. Treatment of diabetic ketoacidosis with insulin
Effects of Hypokalemia
• Cardiac dysrhythmias are serious, showing typical
ECG pattern changes (Fig. 2.8) that indicate prolonged
repolarization, and eventually may lead to cardiac
arrest (see Chapter 12).
• Hypokalemia interferes with neuromuscular function,
and the muscles become less responsive to stimuli, as
shown by fatigue and muscle weakness commencing
in the legs (Table 2.6).
• Paresthesias (abnormal touch sensations) such as “pins
and needles” develop.
• Decreased digestive tract motility causes decreased
appetite (anorexia) and nausea.
• In people with severe potassium deficits, the respiratory
muscles become weak, leading to shallow respirations.
• In severe cases, renal function is impaired, leading to
failure to concentrate the urine, and increased urine
output (polyuria) results.
Potassium Imbalance
Review of Potassium
Potassium (K+) is a major intracellular cation, and therefore
serum levels are very low (3.5–5 mEq per liter or
3.5–5 mmol per liter) compared with the intracellular
concentration that is about 160 mEq per liter (see Table
2.4). It is difficult to assess total body potassium by
measuring the serum level. Potassium is ingested in foods
and is excreted primarily in the urine under the influence
of the hormone aldosterone. Foods high in potassium
include bananas, citrus fruits, tomatoes, and lentils;
potassium chloride tablets may be taken as a supplement.
The hormone insulin also promotes movement of potas-
sium into cells (see Chapter 16).
Potassium levels are also influenced by the acid-base
balance in the body; acidosis tends to shift potassium
ions out of the cells into the extracellular fluids, and
alkalosis tends to move more potassium into the cells
(Fig. 2.7). With acidosis, many hydrogen ions diffuse
from the blood into the interstitial fluid because of the
high hydrogen ion concentration in the blood. When

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 25
Hyperkalemia
In hyperkalemia the serum level of potassium is greater
than 2.6 mmol per liter or 5 mEq per liter.
Causes of Hyperkalemia
Causes of high serum potassium levels include the
following:
1. Renal failure
2. Deficit of aldosterone
3. Use of “potassium-sparing” diuretic drugs, which
prevent potassium from being excreted in adequate
amounts
4. Leakage of intracellular potassium into the extracellular
fluids in patients with extensive tissue damage such
as traumatic crush injuries or burns
5. Displacement of potassium from cells by prolonged
or severe acidosis (see Fig. 2.7)
Venule
Capillary
Arteriole
H+
ACIDOSIS
More H+
HYPERKALEMIA
H+
H+
K+
K+
K+
K+
More
H+
H+
2. More H+
enter ISF
Interstitial fluid
H+
H+
H+
H+
H+
H+
K+H
+
K+ H
+
K+
H+
K+
K+
K+
K+
K+
K+
K+
K+
H+
H+
H+
H+
Cell
3. More enter cell
and displace
from cell
K+
H+
5. High K+ concentration
in blood
4. More
diffuse
into blood
K+
1. High H+ concentration
in blood
FIG. 2.7 Relationship of hydrogen and potassium ions.
TABLE 2.6 Signs of Potassium Imbalance
Hypokalemia Hyperkalemia
Cardiac arrhythmias, cardiac
arrest
Arrhythmias, cardiac arrest
Anorexia, nausea, constipation Nausea, diarrhea
Fatigue, muscle twitch,
weakness, leg cramps
Muscle weakness, paralysis
beginning in legs
Shallow respirations,
paresthesias
Paresthesias—fingers, toes,
face, tongue
Postural hypotension,
polyuria, and nocturia
Oliguria
Serum pH elevated—7.45
(alkalosis)
Serum pH decreased—7.35
(acidosis)

26 SECTION I Pathophysiology: Background and Overview
and feces. Calcium balance is controlled by parathyroid
hormone (PTH) and calcitonin (see Chapter 16), but it
is also influenced by vitamin D and phosphate ion levels.
For example, low blood calcium levels stimulate the
secretion of PTH, which (1) increases the bone resorption
causing the release of calcium and phosphate into circula-
tion; (2) increases the formation of 1,25 dihydroxycho-
lecalciferol in the kidneys to increase the absorption of
calcium and phosphate by the intestine; and (3) decreases
calcium excretion and increases phosphate excretion by
the kidneys.
Vitamin D may be ingested or synthesized in the skin
in the presence of ultraviolet rays, but then it must be
activated in the kidneys. It promotes calcium movement
from the bone and intestines into blood. Most people
living in northern climates have reduced vitamin D
because of lack of exposure of the skin to the sun; dietary
supplements are recommended to ensure adequate levels
during cold weather. Sun blocking agents with an SPF
greater than 15 appear to reduce vitamin D synthesis.
There is also increasing evidence that vitamin D deficits
may contribute to the development of multiple sclerosis
and certain cancers (Box 2.1).
Calcium and phosphate ions in the extracellular fluid
have a reciprocal relationship. For example, if calcium
levels are high, phosphate is low. The product of calcium
and phosphate concentrations should be a constant value.
If levels of both calcium and phosphate rise, crystals of
calcium phosphate precipitate in soft tissue. The measured
or biologically active form of calcium is the ionized form,
which is not attached to plasma protein or bonded to
other ions such as citrate. Alkalosis can decrease the
number of free calcium ions, causing hypocalcemia.
Calcium has many important functions:
• It provides the structural strength essential for bones
and teeth.
• Calcium ions maintain the stability of nerve mem-
branes, controlling the permeability and excitability
needed for nerve conduction.
• Calcium ions are required for muscle contractions.
• Calcium ions are necessary for many metabolic
processes and enzyme reactions such as those involved
in blood clotting.
Effects of Hyperkalemia
• The ECG shows typical cardiac dysrhythmias (see Fig.
2.8), which may progress to cardiac arrest.
• Muscle weakness is common, progressing to paralysis
as hyperkalemia advances and impairs neuromuscular
activity (see Table 2.6).
• Fatigue, nausea, and paresthesias are also common.
Normokalemia
Hypokalemia
Hyperkalemia
Normal
PR interval
Normal
P wave
Normal
QRS
Rounded,
normal-size
T wave
U wave shallow
if present
ST depression
Prominent
U waveShallow
T wave
Slightly
prolonged
PR interval
Decreased
R wave
amplitude
Tall, peaked
T wave
Depressed
ST segment
Widened QRS
Wide, flat
P wave
Prolonged
PR interval
Slightly
peaked
P wave
FIG. 2.8 Electrocardiogram changes with potassium imbalance.
(From McCance KL, et al: Pathophysiology: The Biologic Basis for
Disease in Adults and Children, ed 6, St. Louis, 2010, Mosby.)
THINK ABOUT 2.13
a. Compare the manifestations of hyponatremia and
hypokalemia.
b. Why is any small change in potassium level considered a
serious problem?
As of 2013, the Vitamin D/Calcium Polyp Prevention Study being
conducted by the Dartmouth-Hitchcock Medical Center had
recruited approximately 2200 participants to determine if
vitamin D supplements helped prevent the development of
adenomas in patients where an adenoma had been removed.
So far the data are inconclusive. The Vitamin D and Omega 3
Trial (VITAL) is also examining whether vitamin D supplements
can prevent a variety of cancers in the elderly. This trial expects
to recruit 20,000 participants with an estimated completion
date of the study in December 2017.
BOX 2.1 Vitamin D: Cancer Preventative?
Calcium Imbalance
Review of Calcium
Calcium (Ca++) is an important extracellular cation.
Calcium is ingested in food, especially milk products,
stored in bone, and excreted from the body in the urine

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 27
THINK ABOUT 2.14
When nerve membranes become more permeable, is the nerve
more or less easily stimulated?
Hypocalcemia
In hypocalcemia, the serum calcium level is less than
2.2 mmol per liter or below 4 mEq per liter.
Causes of Hypocalcemia
Causes of hypocalcemia include the following:
1. Hypoparathyroidism—decreased parathyroid hormone
results in decreased intestinal calcium absorption
2. Malabsorption syndrome—resulting in decreased
intestinal absorption of vitamin D or calcium
3. Deficient serum albumin
4. Increased serum pH—resulting in alkalosis
In renal failure, hypocalcemia results from retention of
phosphate ion, which causes loss of calcium; also, vitamin
D is not activated, thereby decreasing the intestinal
absorption of calcium.
Effects of Hypocalcemia
• The increase in the permeability and excitability of
nerve membranes leads to spontaneous stimulation
of skeletal muscle. This leads to muscle twitching,
carpopedal spasm (atypical contraction of the fingers),
and hyperactive reflexes (Table 2.7). The Chvostek
sign, spasm of the lip or face when the face is tapped
in front of the ear, and the Trousseau sign, carpopedal
spasm when a blood pressure cuff blocks circulation
to the hand, both indicate low serum calcium and
tetany (skeletal muscle spasms causing prolonged
contraction and/or cramps). Severe calcium deficits
may cause laryngospasm, which obstructs the airway.
Paresthesias are common, as are abdominal cramps.
• Heart contractions become weak owing to insufficient
calcium for muscle action, conduction is delayed,
arrhythmias develop, and blood pressure drops.
Note that the effects of hypocalcemia on skeletal muscle
and cardiac muscle differ. Skeletal muscle spasms result
from the increased irritability of the nerves associated
with the muscle fibers, whereas the weaker contraction
TABLE 2.7 Signs of Calcium Imbalance
Hypocalcemia Hypercalcemia
Tetany—involuntary skeletal
muscle spasm, carpopedal
spasm, laryngospasm
Tingling fingers
Mental confusion, irritability
Arrhythmias, weak heart
contractions
Apathy, lethargy
Anorexia, nausea,
constipation
Polyuria, thirst
Kidney stones
Arrhythmias, prolonged
strong cardiac contractions,
increased blood pressure
Note: Effects on bone depend on the cause of the calcium imbalance.
of cardiac muscle (which lacks nerves) is directly related
to the calcium deficit. Also, adequate calcium is stored
in the skeletal muscle cells to provide for contractions,
whereas contraction of cardiac muscle relies on available
extracellular calcium ions passing through the calcium
channels. This is the basis for action of one group of
cardiac drugs.
THINK ABOUT 2.15
Explain the different effects of low serum calcium on skeletal
muscle and cardiac muscle.
Hypercalcemia
In hypercalcemia the serum calcium is greater than 5 mEq
per liter or greater than 2.5 mmol per liter.
Causes of Hypercalcemia
Excessive serum levels of calcium frequently result from
the following:
1. Uncontrolled release of calcium ions from the bones
due to neoplasms; malignant bone tumors may directly
destroy the bone, and some tumors, such as broncho-
genic carcinoma, may secrete PTH in excess of body
needs
2. Hyperparathyroidism
3. Immobility, which may decrease stress on the bone,
leading to demineralization
4. Increased intake of calcium due either to excessive
vitamin D or to excess dietary calcium
5. Milk-alkali syndrome, associated with increased milk
and antacid intake, which may also elevate serum
calcium levels
Effects of Hypercalcemia
• High serum calcium levels depress neuromuscular
activity, leading to muscle weakness, loss of muscle
tone, lethargy, and stupor, often with personality
changes, anorexia, and nausea (see Table 2.7).
• High calcium levels interfere with the function of ADH
in the kidneys, resulting in less absorption of water
and in polyuria. If hypercalcemia is severe, blood
volume drops, renal function decreases, nitrogen wastes
accumulate, and cardiac arrest may ensue.
• Cardiac contractions increase in strength, and dys-
rhythmias may develop.
• Effects on bone vary with the cause of hypercalcemia.
If excess PTH is the cause, bone density will be
decreased, and spontaneous (pathologic) fractures may
occur, particularly in the weight-bearing areas, causing
bone pain. If intake of calcium is high, PTH levels will
be low, and more calcium will be stored in the bone,
maintaining bone strength.
• May contribute to the formation of kidney stones in
the urinary system.

28 SECTION I Pathophysiology: Background and Overview
• As an integral part of the cell membrane
• In its reciprocal relationship with serum calcium
Causes of Hypophosphatemia
• Malabsorption syndromes
• Diarrhea
• Excessive use of antacids
• Alkalosis
• Hyperparathyroidism
Effects of Hypophosphatemia
• Tremors
• Weak reflexes (hyporeflexia)
• Paresthesias
• Confusion and stupor
• Anorexia
• Difficulty in swallowing (dysphagia)
• Blood cells function less effectively—oxygen transport
decreases, and clotting and phagocytosis decrease
Other Electrolytes
Magnesium
Magnesium (Mg++) is an intracellular ion that has a normal
serum level of 0.7 to 1.1 mmol per liter. About 50% of
total body magnesium is stored in bone. Serum levels
are linked to both potassium and calcium levels. Mag-
nesium is found in green vegetables and is important in
many enzyme reactions as well as in protein and DNA
synthesis. Magnesium imbalances are rare.
Hypomagnesemia
Hypomagnesemia results from malabsorption or mal-
nutrition, often associated with chronic alcoholism.
Causes of Hypomagnesemia
• Use of diuretics
• Diabetic ketoacidosis
• Hyperparathyroidism
• Hyperaldosteronism
Effects of Hypomagnesemia
• Neuromuscular hyperirritability
• Tremors or chorea (involuntary repetitive movements)
• Insomnia
• Personality changes
• Increased heart rate with arrhythmias
Hypermagnesemia
Cause of Hypermagnesemia
• Usually occurs with renal failure
Effects of Hypermagnesemia
• Depressed neuromuscular function
• Decreased reflexes
• Lethargy
• Cardiac arrhythmias
Phosphate
Phosphate ions (HPO4−− and H2PO4−) are located primarily
in the bone but circulate in both the intracellular and
extracellular fluids. The serum level is normally 0.85 to
1.45 mmol per liter. Phosphate is important in a variety
of circumstances:
• In bone and tooth mineralization
• In many metabolic processes, particularly those involv-
ing the cellular energy source, adenosine triphosphate
(ATP)
• As the phosphate buffer system for acid-base balance,
and it has a role in the removal of hydrogen ions from
the body through the kidneys
THINK ABOUT 2.16
Describe the effect of each of the following conditions on serum
calcium levels and on bone density: (1) hyperparathyroidism,
(2) renal failure, and (3) a large intake of vitamin D.
THINK ABOUT 2.17
Explain how serum calcium levels are affected by low phosphate
levels.
Causes of Hyperphosphatemia
• Often results from renal failure. Dialysis patients often
take phosphate binders with meals to control their
serum phosphate levels.
• Tissue damage or cancer chemotherapy may cause
the release of intracellular phosphate.
Effects of Hyperphosphatemia
• The manifestations of hyperphosphatemia are the same
as those of hypocalcemia.
Chloride
Chloride ion (Cl−) is the major extracellular anion with
a normal serum level of 98 to 106 mmol per liter. Chloride
ions tend to follow sodium because of the attraction
between the electrical charge on the ions, therefore high
sodium levels usually lead to high chloride levels.
Chloride and bicarbonate ions, both negatively charged,
can exchange places as the blood circulates through the
body to assist in maintaining acid-base balance (see
Acid-Base Imbalance). As bicarbonate ions are used up
in binding with metabolic acids, chloride ions diffuse
out of the red blood cells into the serum to maintain the
same number of negative ions in the blood (Fig. 2.9). The
reverse situation can also occur when serum chloride
levels decrease, and bicarbonate ions leave the erythrocytes
to maintain electrical neutrality. Thus, low serum chloride
leads to high serum bicarbonate, or alkalosis. This situ-
ation is referred to as a chloride shift.
Causes of Hypochloremia
• Associated with alkalosis in the early stages of vomiting
when hydrochloric acid is lost from the stomach.

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 29
Blood in capillary
Blood
ISF
ISF
Cl–
Erythrocyte
HYPOCHLOREMIC ALKALOSIS
Cl–
Cl–
Cl– Shifts from
plasma to ISF
Stomach
1. Vomiting —
Lose HCl
Cl–2. Low
Cl– Moves from
ISF to gastric
secretions
3.
4.
moves out of
erythrocyte
to replace lost Cl–
Bicarbonate ion5.
Increased
in blood leads
to alkalosis
6.
= CHLORIDE ION
= BICARBONATE ION
= INTERSTITIAL FLUID
HCO3
–
HCO3
–
HCO3
–
HCO3
–
HCO3
–
HCO3
–
HCO3
–
HCO3
–
HCO3
–
HCO3
–
FIG. 2.9 Schematic representation of chloride-bicarbonate shift with vomiting.
• Excessive perspiration associated with fever or strenu-
ous labor on a hot day can lead to loss of sodium
chloride, resulting in hyponatremia and hypochloremia,
and ultimately, dehydration.
Effects of Hypochloremia
• Nausea
• Vomiting
• Diarrhea
• Muscle twitching
• Confusion, sleepiness
Causes of Hyperchloremia
• Excessive intake of sodium chloride, orally or
intravenously
• Hypernatremia due to other causes
Effects of Hyperchloremia
• Edema
• Weight gain
THINK ABOUT 2.18
a. State one cause of hypomagnesemia.
b. State one cause of hyperphosphatemia.
c. List and describe two signs of hypophosphatemia.
Acid-Base Imbalance
Review of Concepts and Processes
Acid-base balance is essential to homeostasis because
cell enzymes can function only within a narrow pH range.
The normal serum pH range is 7.35 to 7.45. Death usually
results if serum pH is below 6.8 or above 7.8 (Fig. 2.10).
For example, a pH of less than 7.35 depresses central
nervous system function and decreases all cell enzyme
activity.
When serum pH is less than 7.4, more hydrogen ions
(H+) are present, and acidosis results. A serum pH of
greater than 7.4 is more basic, indicating alkalosis or the
Serum pH
7.4
NORMAL RANGE
7.35 7.45
Acidosis Alkalosis
Increased H+ Decreased H+
7.86.8
Death Death
FIG. 2.10 The hydrogen ion and pH scale.

30 SECTION I Pathophysiology: Background and Overview
presence of fewer hydrogen ions. The body normally
has a tendency toward acidosis, or a lower pH, because
cell metabolism is constantly producing carbon dioxide
(CO2) or carbonic acid (H2CO3) and nonvolatile metabolic
acids such as lactic acid, ketoacids, sulfates, or phosphates.
Lactic acid results from the anaerobic (without oxygen)
metabolism of glucose, ketoacids result from incomplete
oxidation of fatty acids, and protein metabolism may
produce sulfates or phosphates.
THINK ABOUT 2.20
How does the respiratory rate change when more hydrogen
ions enter the blood, and how does this change affect acid levels
in the body?
APPLY YOUR KNOWLEDGE 2.2
Predict three ways by which control of serum pH could be
impaired.
THINK ABOUT 2.19
a. When hydrogen ions are decreased, is the pH higher or
lower?
b. State the optimal range of serum pH and effects on
normal cell function if serum pH is not in the optimal
range.
Control of Serum pH
As the blood circulates through the body, nutrients diffuse
from the blood into the cells, various metabolic processes
take place in the cells using these nutrients, and metabolic
wastes, including acids, diffuse from the cells into the
blood (Fig. 2.11).
Three mechanisms control or compensate for pH:
1. The buffer pairs circulating in the blood respond to
pH changes immediately.
2. The respiratory system can alter carbon dioxide levels
(carbonic acid) in the body by changing the respiratory
rate (see Chapter 13).
3. The kidneys can modify the excretion rate of acids
and the production and absorption of bicarbonate ion
(see Chapter 18).
Note that the lungs can change only the amount of
carbon dioxide (equivalent to the amount of carbonic
acid) in the body. The kidneys are slow to compensate
for a change in pH but are the most effective mechanism
because they can excrete all types of acids (volatile or
gaseous and nonvolatile) and can also adjust serum
bicarbonate levels.
Buffer Systems
To control serum pH, several buffer systems are present
in the blood. A buffer is a combination of a weak acid
and its alkaline salt. The components react with any acids
or alkali added to the blood, neutralizing them and
thereby maintaining a relatively constant pH.
The body has four major buffer pairs:
1. The sodium bicarbonate–carbonic acid system
2. The phosphate system
3. The hemoglobin system
4. The protein system
The bicarbonate system is the major extracellular fluid
buffer and is used clinically to assess a client’s acid-base
status. The principles of acid-base balance are discussed
here using the bicarbonate pair. Specific values are not
used because the emphasis is on understanding basic
concepts and recognizing trends. Laboratory tests will
report the specific values and state the implications of
those values.
Bicarbonate–Carbonic Acid Buffer System and
Maintenance of Serum pH
The bicarbonate buffer system is composed of carbonic
acid, which arises from the combination of carbon dioxide
with water, and bicarbonate ion, which is present as
sodium bicarbonate. The balance of bicarbonate ion
(HCO3−), a base, and carbonic acid (H2CO3) levels is
controlled by the respiratory system and the kidneys
(see Fig. 2.11). Cell metabolism produces carbon dioxide,
which diffuses into the interstitial fluid and blood, where
it reacts with water to form carbonic acid, which then
dissociates immediately under the influence of the enzyme
carbonic anhydrase to form three hydrogen ions and one
bicarbonate ion per molecule of carbonic acid. This
enzyme is present in many sites, including the lungs and
the kidneys. In the lungs, this reaction can be reversed
to form carbon dioxide, which is then expired along with
water, thus reducing the total amount of carbonic acid
or acid in the body. In the kidneys, the reaction needed
to form more hydrogen ions is promoted by enzymes;
the resultant hydrogen ions are excreted in the urine,
and the bicarbonate ions are returned to the blood to
restore the buffer levels.
To maintain serum pH within the normal range, 7.35
to 7.45, the ratio of bicarbonate ion to carbonic acid (or
carbon dioxide) must be 20 : 1. A 1 : 1 ratio will not maintain
a pH of 7.4! The ratio is always stated with the H+
component as 1.
As one component of the ratio changes, the other
component must change proportionately to maintain the
20 : 1 ratio and thus serum pH. For instance, if respiration
is impaired, causing an increase in carbon dioxide in the
blood, the kidneys must increase serum bicarbonate levels
to compensate for the change. The actual concentrations
are not critical as long as the proportions are sustained.
It may help to remember that the bicarbonate part or
alkali part of the buffer ratio is 20, the higher figure,
because more bicarbonate base is required to neutralize
the acids constantly being produced by the body cells.

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 31
Respiratory System
When serum carbon dioxide or hydrogen ion levels
increase, chemoreceptors stimulate the respiratory control
center to increase the respiratory rate, thus removing
more carbon dioxide or acid from the body. When
alkalosis develops, the respiratory rate decreases, thus
retaining more carbon dioxide and increasing acid levels in
the body.
Renal System
The kidneys can also reduce the acid content of the
body by exchanging hydrogen for sodium ions under
the influence of aldosterone and can remove H+ by
combining them with ammonia and other chemicals. The
kidneys also provide the bicarbonate ion for the buffer
THINK ABOUT 2.21
If bicarbonate ion is lost from the body, how will carbonic acid
levels change?
3. H+ binds
to HCO3
in buffer
HCO3Acids
L
R
L
R
HEART
CO2 expired
LUNGS
Blood—
Less H2CO3
CIRCULATING BLOOD
KIDNEYS
CELLS
CO2Other H+
H+
H+ in urine
CO2
CELL
2. Blood
CO2 + H2O H2CO3
1. Cell metabolism
produces acids
5. Blood has
less H+
more HCO3
6. BUFFER ACTION
CO2 + H2O H2CO37.8. More acids in
blood and less
bicarbonate
buffer
LUNGS
H2CO3 CO2 + H2O
9.
10.
11.
4. KIDNEYS
H2CO3
HCO3
+ H+

–
–
–
–
FIG. 2.11 Changes in acids, bicarbonate ion, and serum pH in circulating blood.
pair as needed. Urine pH may range from 4.5 to 8 as the
kidneys compensate for metabolic conditions and dietary
intake:
lungs CO H O H CO H HCO kidneys: :2 2 2 3 3+ ↔ ↔ ++ −
THINK ABOUT 2.22
a. Reduced blood flow through the kidneys for a long time
will have what effect on serum pH? Why?
b. How would the lungs and kidneys respond to the
ingestion of large quantities of antacids?
c. How is the kidney more effective in maintaining serum pH
than the lungs?
lungs carbon dioxide water carbonic acid
hydrogen ions bic
: + ↔ ↔
+ aarbonate ions kidneys:
A number of laboratory tests can determine acid-base
balance. These tests include arterial blood gases (ABGs),

32 SECTION I Pathophysiology: Background and Overview
Compensation
The cause of the imbalance determines the first change
in the ratio (Figs. 2.12–2.15). Respiratory disorders are
always represented by an initial change in carbon dioxide.
All other problems are metabolic and result from an initial
change in bicarbonate ions.
The compensation is assessed by the subsequent change
in the second part of the ratio (Table 2.9) and requires
function by body systems not involved in the cause. For
example, if a patient has a respiratory disorder causing
acidosis, the lungs cannot compensate effectively, but the
kidneys can. As long as the ratio of bicarbonate to carbonic
acid is maintained at 20 : 1 and serum pH is normal, the
imbalance is considered to be compensated. Compensation
is limited, and the patient must be monitored carefully
if there is an ongoing threat to homeostasis.
Decompensation
If the kidneys and lungs cannot compensate adequately,
the ratio changes, and serum pH moves out of the normal
range, thus affecting cell metabolism and function.
TABLE 2.8 Acid-Base Imbalances
Acidosis Alkalosis
Respiratory
Causes Slow shallow respirations (eg, drugs) Hyperventilation (anxiety, aspirin overdose)
Respiratory congestion
Effect Increased PCO2 Decreased PCO2
Compensation Kidneys excrete more hydrogen ion and reabsorb
more bicarbonate
Kidneys excrete less hydrogen ion and reabsorb less
bicarbonate
Laboratory Elevated PCO2 Low PCO2
Elevated serum bicarbonate Low serum bicarbonate
Compensated—serum pH = 7.35 to 7.4 Compensated—serum pH = 7.4 to 7.45
Decompensated—serum pH < 7.35 Decompensated—serum pH > 7.45
Metabolic
Causes Shock Vomiting (early stage)
Diabetic ketoacidosis Excessive antacid intake
Renal failure
Diarrhea
Effect Decreased serum bicarbonate ion Increased serum bicarbonate ion
Compensation Rapid, deep respirations Slow, shallow respirations
Kidneys excrete more acid and increase
bicarbonate absorption
Kidneys excrete less acid and decrease bicarbonate
absorption
Laboratory Low serum bicarbonate Elevated serum bicarbonate
Low PCO2 Elevated PCO2
Compensated—serum pH = 7.35 to 7.4 Compensated—serum pH = 7.4 to 7.45
Decompensated—serum pH < 7.35 Decompensated—serum pH > 7.45
THINK ABOUT 2.23
Name or state the category of the imbalance resulting from
each of the following: (1) increased respiratory rate, (2) renal
failure, and (3) excessive intake of bicarbonate, and state the
resulting change in the 20 : 1 ratio.
base excess or deficit, or anion gap, and details about
them may be found in various clinical laboratory manuals.
Some normal values are listed inside the front cover of
this book.
Acid-Base Imbalance
An increase in hydrogen ions or a decrease in serum pH
results in acidosis, whereas alkalosis refers to an increase
in serum pH or decreased hydrogen ions.
There are four basic types of acid-base imbalance (Table
2.8):
1. Respiratory acidosis, which can result from an increase
in carbon dioxide levels (acid) due to respiratory
problems
2. Metabolic acidosis, which can result from a decrease
in bicarbonate ions (base) because of metabolic or renal
problems
3. Respiratory alkalosis, which can result when increased
respirations cause a decrease in carbon dioxide (less
acid)
4. Metabolic alkalosis, which can result from the loss of
hydrogen ions through the kidneys or the gastro-
intestinal tract
Imbalances may be acute or chronic. In some situations,
combinations of imbalances may occur; for example,
metabolic acidosis and respiratory alkalosis can occur
simultaneously.

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 33

:
:
:
:
201
HCO�3H2CO3
HCO
�
3
H2C
O3
1 10
CO2 + H2O
H2CO3
HCO
�
3
0.75 10
Acidic
urine
HCO�3 + H+
LactateHCO�3H2CO3
201
Metabolic balance
before onset of
acidosis
Body’s compensation
Hyperactive breathing to
“blow off” CO2
Kidneys conserve HCO�3
and eliminate H+ ions in
acidic urine
H2CO3: Carbonic acid
HCO�3 : Bicarbonate ion
(Na+ • HCO�3 )
(K+ • HCO�3 )
(Mg++ • HCO�3 )
(Ca++ • HCO�3 )
CO2
HCO�3
+
H+
Therapy required
to restore metabolic
balance
Lactate-
containing
solution
Lactate solution used
in therapy is converted
to bicarbonate ions
in the liver
Metabolic acidosis
HCO�3 decreases
because of excess
presence of ketones,
chloride, or organic
acid ions
4
3
2
1
FIG. 2.12 Metabolic acidosis. (From Patton KT, Thibodeau GA:
Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby.)
THINK ABOUT 2.24
a. In an individual with very low blood pressure or
circulatory shock, blood flow to the cells is very poor,
resulting in increased lactic acid. Briefly describe the
compensations that will take place.
b. What changes in the bicarbonate ratio and serum pH
indicate that decompensation has occurred?
At this point, the imbalance is termed decompensa-
tion. Intervention is essential if homeostasis is to be
regained. Examples of acid-base imbalance are given in
Table 2.8.
Acidosis
Causes of Acidosis
Respiratory acidosis, in which there is an increase in carbon
dioxide levels, may occur under several conditions:
• Acute problems such as pneumonia, airway obstruction
(aspiration or asthma), or chest injuries, and in those
taking drugs such as opiates, which depress the
respiratory control center
• Chronic respiratory acidosis, common in people with
chronic obstructive pulmonary disease (COPD) such
as emphysema
• Decompensated respiratory acidosis, which may
develop if the impairment becomes severe or if, for

34 SECTION I Pathophysiology: Background and Overview
:
:
:
:
Metabolic balance
before onset of
alkalosis
HCO�3
1
1 40
20
H2CO3: Carbonic acid
HCO�3 : Bicarbonate ion
(Na+ • HCO�3 )
(K+• HCO�3 )
(Mg++ • HCO�3 )
(Ca++ • HCO�3 )
Metabolic alkalosis
HCO�3 increases
because of loss
of chloride ions
or excess ingestion
of sodium
bicarbonate
H
2CO
3 HCO �
3
H2CO3
Body’s compensation
Therapy required
to restore
metabolic balance
Breathing suppressed
to hold CO2
Kidneys conserve
H+ ions and
eliminate HCO�3
in alkaline urine
HCO�3 ions
replaced
by Cl� ions
Chloride-
containing
solution
Cl�
1.25 30
1 20
H2CO3 HCO�3
HCO�3
H+ + HCO�3
H2CO3
CO2
CO2
CO2 + H2O
H+
+
HCO�3
Alkaline
urine
1
2
3
4
FIG. 2.13 Metabolic alkalosis. (From Patton KT, Thibodeau GA:
Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby.)
example, a patient with a chronic problem develops
an additional infection
Metabolic acidosis is associated with a decrease in serum
bicarbonate resulting from the following:
• Excessive loss of bicarbonate ions—for example, from
diarrhea and loss of bicarbonate in the intestinal
secretions.
• Increased utilization of serum bicarbonate to buffer
increased acids, when large amounts of acids are
produced in the body because the buffer bicarbonate
binds with such acids until they can be removed by
the kidneys. For example, lactic acid may accumulate
if blood pressure decreases and insufficient oxygen is
available to the cells, or diabetic patients may produce
large amounts of ketoacid that use up bicarbonate
ions (see Chapter 16)
• Renal disease or failure, in which both decreased
excretion of acids and decreased production of bicar-
bonate ion occur (see Chapter 18). In people with renal
failure, compensation by the lungs is inadequate
because the lungs can only remove carbon dioxide,
not other acids, nor can they produce bicarbonate;
therefore a treatment such as dialysis is required to
maintain serum pH.
• Decompensated metabolic acidosis, which may develop
when an additional factor interferes with compensation.

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 35
:
:
:
:
1
2
3
4
Metabolic balance
before onset of
acidosis
Body’s compensation
Therapy required to
restore metabolic
balance
Kidneys conserve
HCO�3 ions and
eliminate H+ ions
in acidic urine
Lactate solution used
in therapy is converted
to bicarbonate ions
in the liver
Lactate-
containing
solution
Lactate
Respiratory acidosis
Breathing is suppressed,
holding CO2 in body
HCO�3
Acidic
urine23 0
1
22 0
20
CO2
CO2
CO2
H2CO3
H2CO3
H2C
O3
H2CO3
H2CO3
HCO
�
3
HCO3�
HCO
�
3 HCO�3
+
H+
HCO�3
2 20
H2CO3: Carbonic acid
HCO�3 : Bicarbonate ion
(Na+ • HCO�3 )
(K+• HCO�3 )
(Mg++ • HCO�3 )
(Ca++ • HCO�3 )
FIG. 2.14 Respiratory acidosis. (From Patton KT, Thibodeau
GA: Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby.)
For example, a person with severe diarrhea may
become so dehydrated that the kidneys receive little
blood and cannot function adequately, causing decom-
pensation. The same result is seen with cardiac arrest.
Effects of Acidosis
The direct effects of acidosis are manifested by the nervous
system, in which function is impaired, leading to inad-
equate responses. Headache, lethargy, weakness, and
confusion develop, leading eventually to coma and death.
Compensations are manifested by deep, rapid breathing
(Kussmaul respirations) and secretion of urine with a
low pH (eg, 5).
Alkalosis
Alkalosis does not occur as frequently as acidosis.
Respiratory alkalosis results from hyperventilation, usually
caused by anxiety, high fever, or an overdose of aspirin
(ASA). Head injuries or brain stem tumors may lead to
hyperventilation. Stress-related alkalosis may develop
rapidly. If the individual cannot quickly be calmed enough
to hold his or her breath repeatedly, then it is best treated
by rebreathing exhaled air containing excreted carbon
dioxide from a paper bag placed over the face. Even if
renal compensation is not impaired, it is slow to take place.
Metabolic alkalosis, in which there is an increase in serum
bicarbonate ion, commonly follows loss of hydrochloric

36 SECTION I Pathophysiology: Background and Overview
measures such as fluid/electrolyte replacement or
removal.
• Deficits can be reversed by adding fluid or the par-
ticular electrolyte to the body fluids. Excess amounts
of either fluid or electrolytes must be removed. For
example, a fluid deficit is returned to normal by the
increased intake of fluid. Excess fluid is removed,
perhaps by taking diuretic drugs to increase the excre-
tion of fluid through the kidneys.
• Caution is required when adjusting fluid levels, to
ensure that electrolyte balance is maintained. For
example, when adding fluid to the body, it is necessary
to check electrolyte levels and perhaps add sodium
or other electrolytes to achieve normal levels of all
components.
acid from the stomach either in the early stages of vomit-
ing or with drainage from the stomach. Other potential
causes are hypokalemia (see Electrolyte Imbalances) and
excessive ingestion of antacids.
Effects of Alkalosis
Alkalosis increases the irritability of the nervous system,
causing restlessness, muscle twitching, tingling and
numbness of the fingers, and eventually tetany, seizures,
and coma.
Treatment of Imbalances
The underlying cause of the imbalance must be diagnosed
and treated in addition to more immediate corrective
Metabolic balance
before onset of
alkalosis
Body’s compensation
Chloride-
containing
solution
Respiratory alkalosis
Hyperactive breathing
“blows off” CO2
15
Kidneys conserve H+ ions
and eliminate HCO�3
in alkaline urine
Therapy required
to restore metabolic
balance
105
HCO�3 ions are replaced
by Cl� ions
1
1 20
H2CO3
0.5
0.5
20
H
2CO
3
CO2
CO2 + H2O
H2CO3
Alkaline
urine
Cl�
H2CO3
0.
HCO�3
HCO �
3
HCO�3
HCO�3
HCO�3
2
3
4
:
:
H2CO3: Carbonic acid
HCO�3 : Bicarbonate ion
(Na+ • HCO�3 )
(K+• HCO�3 )
(Mg++ • HCO�3 )
(Ca++ • HCO�3 )
FIG. 2.15 Respiratory alkalosis. (From Patton KT, Thibodeau
GA: Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby.)

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 37
• The addition of bicarbonate to the blood will reverse
acidosis; levels of bicarbonate need to be monitored
because excess bicarbonate levels may occur.
• In some cases, diet may be modified to maintain better
electrolyte balance.
• Other factors such as respiratory or kidney disorders
and hormonal imbalances can have dramatic effects
on the fluid/electrolyte balance.
TABLE 2.9 Examples of Acidosis
Respiratory Acidosis—Individual With Emphysema Retaining CO2
Stage 1: Kidneys compensate for slight increase in PCO2 by increasing excretion of acids and
production of bicarbonate.
No change in serum levels
Stage 2: Increased retention of CO2. Respiratory acidosis. Elevated PCO2
Stage 3: Compensation. Kidneys reabsorb more bicarbonate. Elevated serum ions.
bicarbonate
Stage 4: Compensated respiratory acidosis: Abnormal serum values indicate problem and
compensation adequate to maintain ratio and normal serum pH.
Serum pH = 7.35
Stage 5: Decompensated respiratory acidosis: Patient acquires pneumonia, and much more CO2 is
retained. Also, kidneys cannot maintain compensation. Ratio is no longer normal, CNS
depression, coma, and serum pH drops below the normal range.
Serum pH = 7.31
Metabolic Acidosis—Individual With Diabetic Ketoacidosis Owing to Insulin Deficit
Stage 1: Slight increase in production of ketoacids.
Kidneys increase excretion of acids.
No change in serum values
Stage 2: Metabolic acidosis: More ketoacids produced than kidneys can excrete quickly, and acids
bind with or “use up” buffer bicarbonate.
Low serum bicarbonate
Stage 3: Respirations become rapid and deep to remove CO2. Kidneys compensate by excreting
more acids and reabsorbing more bicarbonate but cannot keep up with the increasing
ketoacids added to the blood.
Low PCO2
Stage 4: Compensated metabolic acidosis: Abnormal serum values indicate the problem and
compensation adequate to maintain ratio and normal serum pH.
Serum pH = 7.35
Stage 5: Decompensated metabolic acidosis: Ketoacids continue to increase in the blood at a faster
rate, and the kidneys have decreased function owing to dehydration. Therefore the
problem becomes more severe and compensation is inadequate. The ratio is not
maintained, and serum pH drops below the normal range.
Serum pH = 7.31
THINK ABOUT 2.25
a. For each of the following situations, list the kind of
acid-base imbalance likely to occur: (1) chest injury with
fractured ribs, (2) infection with high fever, (3) diarrhea.
b. Describe the effect of metabolic acidosis on respiration
and on the central nervous system.
c. In an elderly person with respiratory acidosis due to
chronic respiratory congestion, why would decreased
kidney function be so dangerous?
d. If serum pH decreases to 7.1 because of severe renal
disease, explain the change that has occurred in the buffer
pair and the effect of this change on the central nervous
system.
CASE STUDY A
Vomiting
Mr. K.B. is age 81 and has had gastritis with severe vomiting for 3
days. He has a history of heart problems and is presently feeling
dizzy and lethargic. His eyes appear sunken, his mouth is dry, he
walks unsteadily, and he complains of muscle aching, particularly
in the abdomen. He is thirsty but is unable to retain food or
fluid. A neighbor has brought Mr. K.B. to the hospital, where
examination shows that his blood pressure is low, and his pulse
and respirations are rapid. Laboratory tests demonstrate elevated
hematocrit, hypernatremia, decreased serum bicarbonate, serum
pH 7.35, and urine of high specific gravity (highly concentrated).
This case study illustrates a combination of fluid, electrolyte,
and acid-base imbalances. Specific laboratory values are not
given so as to focus on the basic concepts. For clarity, this case
study is discussed in three parts, the early stage, middle stage,
and advanced stage of the imbalances. Further information about
the specific problems involved is given in each part and is followed
by a series of questions.
Part A: Day 1
Initially, Mr. K.B. lost water, sodium in the mucus content, and
hydrogen and chloride ions in the hydrochloric acid portion of
the gastric secretions.
Alkalosis develops for two reasons, the first being the direct
loss of hydrogen ions and the second being the effects of chloride

38 SECTION I Pathophysiology: Background and Overview
C H A P T E R S U M M A R Y
Water, electrolytes, and acids are constantly moving
between compartments in the body, depending on intake,
output, and variations in cell metabolism. Numerous
mechanisms work to maintain a constant internal
environment:
• Edema, local or general, results from excess fluid in
the interstitial compartment due to increased capillary
hydrostatic pressure, increased sodium ion concentra-
tion in ECF, decreased plasma osmotic pressure related
to decreased plasma proteins, obstructed lymphatic
circulation, or increased capillary permeability.
• Dehydration or fluid deficit in the body may be caused
by decreased intake or excessive loss of water. Infants
and elderly persons exhibit the greatest risk for
dehydration.
• The signs of dehydration include thirst, dry oral
mucous membrane and decreased skin turgor, fatigue,
decreased urine output, and low blood pressure with
rapid, weak pulse.
• Third-spacing refers to the movement of fluid out of
the vascular compartment into a body cavity or tissue
where it cannot circulate.
• Hyponatremia impairs the conduction of nerve
impulses, muscle contraction, and distribution of body
fluids.
• Hypernatremia causes fluid to shift out of cells, affect-
ing cell function.
• Both hyperkalemia and hypokalemia lead to cardiac
arrhythmias and possible cardiac arrest.
• Calcium ion levels in the blood are affected by para-
thyroid hormone, calcitonin, vitamin D, phosphate
ion levels, diet, digestive tract, and renal function.
ion loss. When chloride ion is lost in the gastric secretions, it is
replaced by chloride from the serum (see Fig. 2.9). To maintain
equal numbers of cations and anions in the serum, chloride ion
and bicarbonate ion can exchange places when needed. Therefore
more bicarbonate ions shift into the serum from storage sites
in the erythrocytes to replace the lost chloride ions. More
bicarbonate ions in the serum raise serum pH, and the result is
hypochloremic alkalosis.
1. Which compartments are likely to be affected in this case
by early fluid loss?
2. Explain how a loss of sodium ions contributes to
dehydration.
3. Describe the early signs of dehydration in Mr. K.B.
4. What serum pH could be expected in Mr. K.B. after this
early vomiting?
5. Describe the compensations for the losses of fluid and
electrolytes that should be occurring in Mr. K.B.
6. Explain why Mr. K.B. may not be able to compensate for
losses as well as a younger adult.
Part B: Days 2 to 3
As Mr. K.B. continues to vomit and is still unable to eat or drink
any significant amounts, loss of the duodenal contents, which
include intestinal, pancreatic, and biliary secretions, occurs. No
digestion and absorption of any nutrients occurs.
Losses at this stage include water, sodium ions, potassium
ions, and bicarbonate ions. Also, intake of glucose and other
nutrients is minimal. Mr. K.B. shows elevated serum sodium levels.
7. Explain why serum sodium levels appear to be high in
this case.
8. Explain how high serum sodium levels might affect the
intracellular fluid.
9. Using your knowledge of normal physiology, explain how
continued fluid loss is likely to affect the following:
a. Blood volume
b. Cell function
c. Kidney function
10. Given Mr. K.B.’s history, why might potassium imbalance
have more serious effects on him?
Part C: Day 3: Admission to the Hospital
After a prolonged period of vomiting, metabolic acidosis develops.
This change results from a number of factors:
• Loss of bicarbonate ions in duodenal secretions
• Lack of nutrients leading to catabolism of stored fats and
protein with production of excessive amounts of ketoacids
• Dehydration and decreased blood volume leading to
decreased excretion of acids by the kidney
• Decreased blood volume leading to decreased tissue
perfusion, less oxygen to cells, and increased anaerobic
metabolism with increased lactic acid
• Increased muscle activity and stress leading to increased
metabolic acid production
These factors lead to an increased amount of acids in the
blood, which bind with bicarbonate buffer and result in decreased
serum bicarbonate and decreased serum pH or metabolic
acidosis.
11. List several reasons why Mr. K.B. is lethargic and weak.
12. Predict the serum level of carbon dioxide or carbonic
acid in this case.
13. If Mr. K.B. continues to lose body fluid, why might serum
pH decrease below 7.35?
CASE STUDY B
Diarrhea
Baby C., 3 months old, has had severe watery diarrhea accom-
panied by fever for 24 hours. She is apathetic and responds
weakly to stimulation. The condition has been diagnosed as
viral gastroenteritis.
1. List the major losses resulting from diarrhea and fever.
2. List other signs or data that would provide helpful
information.
3. Explain several reasons why infants become dehydrated
quickly.
14. If serum pH drops below 7.35, what signs would be
observed in Mr. K.B.?
15. Describe the effect of acidosis on serum potassium
levels.
16. Mr. K.B. will be given replacement fluid therapy. Why is it
important that sodium and potassium be given as well as
water?

CHAPTER 2 Fluid, Electrolyte, and Acid-Base Imbalances 39
• Hypocalcemia causes muscle twitching and tetany
related to increased permeability and excitability of
nerve fibers, but it also leads to weaker cardiac muscle
contractions.
• Excessive parathyroid hormone leads to hypercalcemia
and bone demineralization that may cause spontaneous
fractures.
• Chloride and bicarbonate ions are important in acid-
base balance.
• The buffer ratio of 20 parts bicarbonate ion (base) to
1 part CO2 (carbonic acid) is essential to maintain serum
pH in the normal range of 7.35 to 7.45.
• Respiratory acidosis or alkalosis is caused by respira-
tory impairment increasing Pco2, or hyperventilation
decreasing Pco2, respectively. The kidneys compensate
by altering bicarbonate ion levels to maintain the
required ratio.
• Metabolic acidosis results from a deficit of bicarbonate
ion, either due to excessive loss of acids (eg, from
diarrhea) or to excessive accumulated acids (eg, diabetic
ketoacidosis). Metabolic alkalosis is caused by increased
bicarbonate ion levels, perhaps from increased antacid
ingestion. The respiratory and renal systems compen-
sate for these changes.
• Decompensation develops when serum pH moves
outside the normal range, preventing the cell enzymes
from functioning. This can happen when the kidneys
are damaged or when dehydration prevents adequate
kidney function.
• Initially, vomiting causes loss of hydrochloric acid from
the stomach and metabolic alkalosis. If vomiting is
prolonged and severe, dehydration and metabolic
acidosis develop.
• Diarrhea causes loss of fluid and bicarbonate ions,
leading to metabolic acidosis.
• Generalized edema results from low levels of
plasma proteins related to kidney or liver disease or
malnutrition.
S T U D Y Q U E S T I O N S
1. Describe the locations of intracellular and
extracellular fluids.
2. Which makes up the higher proportion of body
fluid, intracellular fluid or extracellular fluid?
3. How does the proportion of fluid in the body
change with age?
4. Why does dehydration affect cell function?
5. What is the function of sodium ion in the body?
6. Describe the effect of hypernatremia on
extracellular fluid volume and on intracellular
fluid volume.
7. State the primary location (compartment) of
potassium.
8. How are sodium and potassium levels controlled
in the body?
9. Describe the signs and symptoms of hypocalcemia.
10. Describe how a deficit of vitamin D would affect
the following:
a. bones
b. serum calcium level
11. Explain how hypochloremia affects acid-base
balance.
12. State the normal range of pH for the following:
a. blood
b. urine
13. Describe how very slow, shallow respirations are
likely to affect the following:
a. Pco2
b. serum pH
14. State three possible causes of metabolic acidosis.
15. A diabetic client is producing excess amounts of
ketoacids.
a. Describe the effects of this excess on serum
bicarbonate levels and serum pH.
b. Explain the possible compensations for this
imbalance.
c. Describe the signs of this compensation.
16. The respirations that accompany metabolic
acidosis are frequently called Kussmaul
respirations or “air hunger.” What is the purpose
of such respirations?
17. A person is found unconscious. He is wearing a
Medic-Alert bracelet for diabetes, and his breath
has the typical odor of acetone (ketoacids).
a. Predict his serum pH and the rationale for this
prediction.
b. Predict his serum potassium level.
18. How does insulin administration affect serum
potassium?
19. A person will probably become very dehydrated
as ketoacidosis develops. What heart rate and
pulse characteristics would you expect to be
present in this dehydrated condition?
20. Prolonged strenuous exercise usually leads to an
increase in lactic acid. Given your knowledge of
normal circulation, explain why it is helpful to
have a cool-down period with mild exercise rather
than total rest immediately after strenuous
exercise.
21. General anesthetics, the presence of pain, and
narcotic analgesics for pain often lead to slow,
shallow respirations after surgery, circulation is
frequently slow, and oxygen levels are somewhat
reduced. Predict the effects on the partial pressure
of carbon dioxide and how this would affect
serum pH.

40
Pharmacology
Basic Principles
Drug Effects
Administration and Distribution of
Drugs
Drug Mechanisms and Receptors
Responses
Dose Effects
Time Effects
Variability
Toxicity
Drug Classifications and Prescriptions
Traditional Forms of Therapy
Physiotherapy
Occupational Therapy
Speech/Language Therapy
Nutrition/Diet
Registered Massage Therapy
Osteopathy
Chiropractic
Complementary or Alternative Therapies
Noncontact Therapeutic Touch
Naturopathy
Homeopathy
Herbal Medicine
Aromatherapy
Asian Concepts of Disease and Healing
Acupuncture
Shiatsu
Yoga
Reflexology
Craniosacral Therapy
Ayurveda
Case Study
Chapter Summary
Study Questions
C H A P T E R O U T L I N E
After studying this chapter, the student is expected to:
1. Define common terms used in pharmacology.
2. Differentiate the types of adverse reactions.
3. Explain the factors that determine blood levels of a drug.
4. Compare the methods of drug administration.
5. Describe the difference between the terms dose and
dosage.
6. Describe the role of receptor sites in drug action.
7. Differentiate a generic name from a trade name.
8. Explain the basis for the various legal restrictions on the
sale of drugs listed in different schedules.
9. Describe the roles of specified members of the health care
team, traditional and alternative.
10. Describe the basic concepts of Asian medicine.
L E A R N I N G O B J E C T I V E S
antagonism
compliance
contraindications
dosage
dose
holistic
idiosyncratic
meridians
parenteral
placebo
potentiation
synergism
synthesized
therapeutic
K E Y T E R M S
C H A P T E R 3
Introduction to Basic Pharmacology
and Other Common Therapies
Pharmacology
Health professionals are required to record and maintain
medical profiles for each patient that includes all medica-
tions as well as over-the-counter drugs. An example of
a general/simple medical history can be found in Ready
Reference 6 at the back of the book. This chapter provides
a brief overview of the basic principles of pharmacology
and therapeutics.
Basic Principles
Pharmacology is an integrated medical science involving
chemistry, biochemistry, anatomy, physiology, microbiol-
ogy, and others. Pharmacology is the study of drugs,
their actions, dosage, therapeutic uses (indications), and
adverse effects. Drug therapy is directly linked to the
pathophysiology of a particular disease. It is helpful for
students to understand the common terminology and

CHAPTER 3 Introduction to Basic Pharmacology and Other Common Therapies 41
regulatory bodies. Listed contraindications are circum-
stances under which the drug usually should not be taken.
Generally drugs have more than one effect on the
body, some of which are undesirable, even at recom-
mended doses.
• Side effects are unwanted actions and are generally mild.
For example, antihistamines frequently lead to a dry
mouth and drowsiness, but these effects are tolerated
because the drug reduces the allergic response. On
occasion, a side effect is used as the primary goal; for
example, promethazine (Phenergan) has been used as
an antiemetic or a sedative as well as an antihistamine.
• Adverse or toxic are side effects that are dangerous, cause
tissue damage, or are life threatening (e.g., excessive
bleeding). In such cases, the drug is discontinued or
a lower dose ordered. In some cases, such as cancer
chemotherapy, a choice about the benefits compared
with the risks of the recommended treatment is neces-
sary. Unfortunately, a long period of time may elapse
before sufficient reports of toxic effects are compiled
to warrant warnings about a specific drug, and in
some cases its withdrawal from the marketplace. It is
important to realize that undesirable and toxic effects
can occur with over-the-counter (OTC) items, as well as
prescription drugs. OTC drugs are available without a
prescription, such as aspirin, acetaminophen, antacids,
and some cold medications and are considered safe for
open sale. However, megadoses of some vitamins are
very toxic, and excessive amounts of acetaminophen
can cause kidney and liver damage. In late 2000, some
cough and cold preparations, as well as appetite sup-
pressants containing phenylpropanolamine (PPA), were
removed from the market because of a risk of hemor-
rhagic strokes in young women. Research continues
into the development of “ideal” drugs with improved
or more selective therapeutic effects, fewer (or no) side
effects, and no toxic effects.
Several specific forms of adverse effects should be
noted:
• Hypersensitivity or allergic reactions to drugs such as
penicillin and local anesthetics are common. The
reaction may be mild (eg, a rash) or can result in
anaphylaxis. The patient should stop taking the medica-
tion immediately and notify the physician. Generally
a person is allergic to other structurally similar drugs
and should avoid that group in the future.
• Idiosyncratic (also called paradoxic) reactions are
unexpected or unusual responses to drugs—for
example, excessive excitement after taking a sedative
(sleep-inducing drug). These reactions occur in some
elderly individuals. Some idiosyncratic reactions are
used therapeutically; stimulants are used in attention-
deficit/hyperactivity disorder (ADHD) to reduce
distraction and increase concentration.
• Iatrogenic refers to a negative effect on the body caused
by a medication error, drug overdose, or unusual
response.
concepts used in drug therapy to enable them to look
up and comprehend information on a specific drug.
Medications frequently have an impact on patient care
and have a part in emergency situations/care. It is
important to recognize the difference between expected
manifestations of a disease and the effects of a drug.
A drug is a substance that alters biologic activity in a
person. Drugs may come from natural sources such as
plants, animals, and microorganisms such as fungi, or
they may be synthesized. Many manufactured drugs
originated as plant or animal substances. In time the
active ingredient was isolated and refined in a laboratory
and finally mass produced as a specific synthesized
chemical or biologic compound.
Drugs may be prescribed for many reasons, including
the following:
• To promote healing (eg, an anti-inflammatory
glucocorticoid)
• To cure disease (eg, an antibacterial drug)
• To control or slow progress of a disease (eg, cancer
chemotherapy)
• To prevent disease (eg, a vaccine)
• To decrease the risk of complications (eg, an
anticoagulant)
• To increase comfort levels (eg, an analgesic for pain)
• As replacement therapy (eg, insulin)
• To reduce excessive activity in the body (eg, a sedative
or antianxiety drug)
Pharmacology is organized into separate disciplines
that deal with actions of drugs:
• Pharmacodynamics. Drug-induced responses of physi-
ologic and biochemical systems
• Pharmacokinetics. Drug amounts at different sites after
administration
• Pharmacotherapeutics. Choice and drug application for
disease prevention, treatment, or diagnosis
• Toxicology. Study of the body’s response to drugs,
harmful effects, mechanisms of actions, symptoms,
treatment, and identification
• Pharmacy. Preparation, compounding, dispensing, and
record keeping of therapeutic drugs
Drug Effects
A drug may exert its therapeutic or desired action by
stimulating or inhibiting cell function. Some drugs, such
as antihistamines, block the effects of biochemical agents
(like histamine) in the tissues. Other drugs have a physical
or mechanical action; for example, some laxatives provide
bulk and increase movement through the gut. Drugs are
classified or grouped by their primary pharmacologic
action and effect, such as antimicrobial or antiinflamma-
tory. The indications listed for a specific drug in a drug
manual provide the approved uses or diseases for which
the drug has been proved effective. Off-label uses are
those for which the drug has shown some effectiveness,
but not the use for which the drug was approved by

42 SECTION I Pathophysiology: Background and Overview
microbes as soon as possible. It is equally important not
to increase the prescribed dose over a period of time (the
“if one tablet is good, two or three are better” concept),
nor to increase the frequency, because these changes could
result in toxic blood levels of the drug.
The frequency of dosing is important in maintaining
effective blood levels of the drug without toxicity, and
directions regarding timing should be carefully followed
(Fig. 3.1). Optimum dosing schedules are established for
each drug based on factors such as absorption (rate it
leaves the site and arrives at site of action), transport in
the blood (distribution), half-life of the particular drug,
and biotransformation. Drugs usually should be taken
at regular intervals over the 24-hour day, such as every
6 hours. Directions regarding timing related to meals or
other daily events are intentional and should be observed.
For example, insulin intake must match food intake.
Sometimes the drug is intended to assist with food intake
and digestion and hence should be taken before meals.
In other cases, food may inactivate some of the drug or
interfere with absorption, reducing the amount reaching
the blood; therefore the drug must be taken well before
a meal or certain foods must be avoided. Alternatively,
it may be best to take the drug with or after the meal to
prevent gastric irritation. A sleep-inducing drug is more
effective if taken a half hour before going to bed, rather
than when getting into bed with the expectation that one
will fall asleep immediately.
A drug enters the body by a chosen route, travels in
the blood around the body, and eventually arrives at the
site of action (e.g., the heart), exerts its effect, and then
is metabolized and excreted from the body. For example,
a drug taken orally is broken down and absorbed from
the gastrointestinal tract into the blood (rather like ingest-
ing food and drink). Sometimes a drug is administered
directly into an organ or tissue where it is expected to
act. Another exception is the application of creams on
skin lesions, where minimal absorption is expected.
Actual blood levels of a drug are also dependent on
such factors as the individual’s
• Circulation and cardiovascular function
• Age
• Body weight and proportion of fatty tissue
• Activity level/exercise
• Ability to absorb, metabolize, and excrete drugs (liver
and kidney function)
• Food and fluid intake
• Genetic factors
• Health status, or presence of disease—chronic or acute
Therefore drug dosage and administration may have to be
modified for some individuals, particularly young children
and elderly people. A child’s dose is best calculated using
the child’s weight, not age. A proper measuring device
should be used when giving medication because general
household spoons and cups vary considerably in size.
It is sometimes difficult to determine exactly how much
drug actually is effective at the site. A laboratory analysis
• Teratogenic or harmful effects on the fetus, leading to
developmental defects, have been associated with some
drugs. Fetal cells are particularly vulnerable in the
first 3 months (see the discussion of congenital defects
in Chapter 21). This is an area in which research cannot
be totally effective in screening drugs. It is recom-
mended that pregnant women or those planning
pregnancy avoid all medications.
• Interactions occur when a drug’s effect is modified by
combining it with another drug, food, herbal com-
pounds, or other material. Interactions commonly occur
with nonprescription drugs such as aspirin, antacids,
or herbal compounds, as well as with alcohol. Even
a healthy food such as grapefruit juice can cause
changes in drug absorption. Interactions are a particular
concern for elderly patients, who often take many
drugs and consult several physicians.
The effect of the combination may be increased much
more than expected (synergism) or greatly decreased
(antagonism). Synergistic action can be life threatening—
for example, causing hemorrhage or coma. It has been
documented that the majority of drug overdose cases
and fatalities in hospital emergency departments result
from drug-drug or drug-alcohol combinations.
Alternatively, when synergism is established, it may
be used beneficially to reduce the dose of each drug to
achieve the same or more beneficial effects with reduced
side effects. For example, this is an intentional advanta-
geous action when combining drugs to treat pain.
The presence of an antagonist prevents the patient
from receiving the beneficial action of a drug. In a patient
with heart disease or a serious infection, this would be
hazardous. On the other hand, antagonistic action is
effectively used when an antidote is required for an
accidental poisoning or overdose.
One other form of interaction involves potentiation,
whereby one drug enhances the effect of a second drug.
For example, the inclusion of epinephrine with local
anesthetics is intended to prolong the effects of the local
anesthetic, without increasing the dose. It causes vaso-
constriction in the area, which decreases blood flow and
thereby helps keep the anesthetic in the area longer
because it will not be absorbed as quickly.
Administration and Distribution of Drugs
The first consideration with administration is the amount
of the medication and the frequency it is given. Dose
refers to the amount of a drug given at a single time,
whereas dosage refers to the total amount of the drug
given over a period of time.
In some circumstances, a larger dose may be admin-
istered initially, or the first dose may be given by injection,
to achieve effective drug levels quickly. This “loading
dose” principle is frequently applied to antimicrobial
drugs, in which case it is desirable to have sufficient
drug in the body to begin destruction of the infecting

CHAPTER 3 Introduction to Basic Pharmacology and Other Common Therapies 43
(suppository) inhalation, subcutaneous or intramus-
cular injection, intravenous injection, and intrathecal
(injection through the sheath meninges around the
spinal cord into the subarachnoid space).
The major routes for administration of drugs are oral
and parenteral (injection). Table 3.1 provides a comparison
of some common routes, with regard to convenience,
approximate time required to reach the blood and the
site of action, and the amount of drug lost. The common
abbreviations for various routes may be found in Ready
Reference 4. Drugs may also be administered by inhalation
can determine actual blood levels for many drugs. This
may be requested if toxicity is suspected.
Drugs can be administered for acting locally or having
a systemic action:
• Local administration includes topical application
to the skin, application to the mucous membranes,
orally, inhalation for selected respiratory conditions,
and iontophoretically, which is administered to treat
a local inflammation.
• Systemic administration transdermal therapeutic
systems, orally, sublingual, transdermal, rectal
B
LO
O
D
L
E
V
E
L
O
F
D
R
U
G
Toxic
Unsafe
EFFECTIVE
Too low
1st
dose
2nd 3rd 4th 5th 6th 7th 8th 9th 10th11th12th13th
Reach effective
blood levels quickly
Regular intake, normal distribution and excretion
TIME AND DOSING OF DRUG
Maintain
desirable
blood level
B
LO
O
D
L
E
V
E
L
O
F
D
R
U
G
Toxic
Unsafe
EFFECTIVE
Too low
1st
dose
2nd 3rd 4th 5th 6th 7th 8th 9th 10th 11th 12th 13th
Slow onset
Factors: taking drug at irregular intervals, missing doses
TIME AND DOSING OF DRUG
Blood level
changeable and ineffective
B
LO
O
D
L
E
V
E
L
O
F
D
R
U
G
Toxic
Unsafe
EFFECTIVE
Too low
1st
dose
2nd 3rd 4th 5th 6th 7th 8th 9th 10th11th12th 13th
Factors: taking double dose or too frequently; kidney
or liver damage
TIME AND DOSING OF DRUG
Blood level
dangerously high
FIG. 3.1 Factors affecting blood levels of drugs—amount of
drug taken into the body, frequency of intake, and amount of
drug excreted.

44 SECTION I Pathophysiology: Background and Overview
tablets, various types of injection, skin creams, and eye
drops.
Oral medications are absorbed from the stomach or
intestine, transported to the liver, and then released into
the general circulation. This process takes time, and
considerable drug may be lost in transit through the
digestive tract and liver. Drugs injected intramuscularly
are gradually absorbed into the blood, depending on the
status of the circulation. For example, absorption could
be delayed for a person in shock, but it could occur more
rapidly if the person is exercising.
The circulating blood picks up drugs and transports
them, often bound to plasma proteins. Some of the drug
may follow different pathways, branching off into different
organs or tissues (Fig. 3.2). Depending on the specific
characteristics of a drug, some may be lost temporarily
in storage areas such as fatty tissue (eg, anesthetics) or
may be quickly metabolized. At some point during this
movement through the body, the drug reaches the tissue
or organ where it acts, passes into the interstitial fluid,
and exerts its effect. Most drugs are gradually metabolized
and inactivated in the liver and then excreted by the
kidneys. A few drugs are excreted in bile or feces. Some
anesthetics are expired through the lungs.
into the lungs (either for local effect[eg, a bronchodilator]
or for absorption into blood [eg, an anesthetic]), via topical
application through the skin or mucous membranes, and
rectally, using a suppository for local effect or absorption
into the blood. The transdermal (patch) method provides
for long-term continuous absorption of drugs such as
nicotine, hormones, or nitroglycerin through the skin
into the blood. Variations on these methods are possible,
particularly for oral medications. Time-release or long-
acting forms are available (eg, for cough and cold medica-
tions), which may contain three doses to be released over
a 12-hour period. Less frequent administration may be
more efficient and increase patient compliance (adherence
to directions) because of the convenience. Enteric-coated
tablets (a special coating that prevents breakdown until
the tablet is in the intestine) are prepared for drugs such
as aspirin to prevent gastric ulcers or bleeding in persons
who take large doses of this antiinflammatory drug over
prolonged periods of time.
Some drugs can only be taken by one route. However,
insulin, which had to be injected in the past, can be
given orally now (Generex Oral-lyn). A few drugs,
such as glucocorticoids (eg, cortisol or prednisone),
can be administered in many ways, such as via oral
TABLE 3.1 Various Routes for Drug Administration
Route Characteristics
Time to Onset and Drug
Loss Advantages Disadvantages
Oral tablet, capsule,
liquid ingested
Simple
administration,
easily portable
Long time to onset(eg,
30–60 min); more loss
in digestive system
Tablets stable, cost
varies, safe
Taste and swallowing
problems; gastric
irritation; uncertain
absorption
Sublingual (eg,
nitroglycerin)
Very simple to use,
portable
Immediate, directly into
blood, little loss of drug
Convenient, rapid
action
Tablets soft and
unstable
Subcutaneous injection
(eg, insulin)
Requires syringe,
self-administer,
portable
Slow absorption into
blood; some loss of drug
Simplest injection; only
small doses can be
given
Requires asepsis and
equipment; can be
irritating
Intramuscular injection
(eg, penicillin)
Requires syringe and
technique (deltoid
or gluteal muscle)
Good absorption into
blood; some time lag
and drug loss until
absorption
Use when patient
unconscious or
nauseated; rapid,
prolonged effect
Requires asepsis and
equipment; short
shelf life; discomfort,
especially for elderly
Intravenous injection Requires equipment
and technique
(directly into vein)
Immediate onset and no
drug loss
Immediate effect,
predictable drug level;
use when patient
unconscious
Costly, skill required;
no recovery of drug;
irritation at site
Inhalation (into
respiratory tract)
Portable inhaler
(puffer) or machine
and technique
required
Rapid onset, little loss of
drug.
Local effect or absorb
into alveolar
capillaries; rapid
effect; good for
anesthesia
Requires effective
technique
Topical (skin or mucous
membranes) gel, cream,
ointment, patch, spray,
liquid, or suppository
Local application,
portable; also eye,
ear, vaginal, rectal
application
Onset rapid; some loss;
absorption varies
Easy to apply; few
systemic effects;
useful local anesthetic
Can be messy;
sometimes difficult
application (eg, eye)
Intraperitoneal pump Requires surgery Excellent control of blood
glucose levels
Immediate onset Costly and may
become infected

CHAPTER 3 Introduction to Basic Pharmacology and Other Common Therapies 45
or gamma-aminobutyric acid [GABA]), or electrolytes
(eg, calcium ions). The drug classification may be named
as such—for example, calcium-blocking drugs. Many
medications act at these distinct receptor sites in cells
or on cell membranes, either stimulating the receptor
directly or blocking normal stimulating chemicals in
the body (Fig. 3.3). Depending on the uniqueness of the
receptors, some drugs have very specific effects; others
have a broad range of activity. The drug binds to one
type of receptor and stimulates the same activity as the
natural substance (an agonist). A different drug may bind
to the same receptor, not stimulate it, but block entry of a
natural substance and thus prevent the normal stimulus
and inhibit the activity (an antagonist or blocking agent).
For example, beta-adrenergic blocking agents bind to
beta receptors (sympathetic nervous system) in the heart,
preventing epinephrine from stimulating the heart to
contract at a faster rate and increasing blood pressure.
Similarly as different receptors have been identified, many
drugs have been designed to stimulate or block certain
activities in diverse areas of the body, including the brain
and digestive tract. Research is focused on identifying
particular receptors and synthesizing drugs that act only
at those specific receptors in order to reduce the risk of
side effects.
Some barriers to drug passage exist. Many drugs cannot
pass the blood-brain barrier, a protection provided by
tight junctions between cells surrounding the brain.
However, at times, drugs are required in the brain—for
example, anesthetics or antimicrobial drugs—and only
a select few are able to pass through the blood-brain
barrier. Likewise, the placental barrier protects the fetus.
ORAL
INGESTION
OF DRUG
Digestion
GRADUAL
ABSORPTION
To the
liver
Drug moves gradually
into general circulation
DRUG
METABOLISM
in liver
To digestive
system
INTRAVENOUS
INJECTION
Urine
To fatty tissue –
storage
SOME BLOOD
TO KIDNEYS FOR
EXCRETION
INTRAMUSCULAR
INJECTION
From muscle
To muscle
To brain
Through
heart
FIG. 3.2 Drug absorption, distribution, and excretion.
Drug Mechanisms and Receptors
Drugs possess different mechanisms for their actions.
A common pharmacologic action is the drug-receptor
interaction. Numerous receptors are present on or within
cells in the body, responding to natural substances
such as enzymes, natural hormones (eg, estrogen),
neurotransmitters (eg, acetylcholine, norepinephrine,
THINK ABOUT 3.1
a. Explain why sublingual administration is faster than oral
administration.
b. How would severe kidney or liver damage affect blood
levels of a drug?
c. Describe three types of adverse reactions.

46 SECTION I Pathophysiology: Background and Overview
Variability
Many variables influence the biotransformation and
eventual elimination of the drug from the system. These
variables include (but are not limited to) the
following:
• Chemical properties
• Toxic effects
• Liver and kidney disease
• Age
• Genetics
• Gender
• Metabolic cycles
• Overall health
Toxicity
A toxic effect is simply an effect that is harmful to a
biologic system. A study of the toxicity of a drug includes
the following characteristics:
• Physiochemical properties
• Routes and rates of administration
• Rates of absorption, biotransformation, and
excretion
The specific determination of drug toxicity is based on
comparisons with other drugs to measure relative safety
levels.
Drug Classifications and Prescriptions
A prescription is a signed legal document that must
include the patient’s name, address, and age if significant
(eg, the patient is a child); the prescriber’s name, address,
and identification; the date; the name and amount of the
drug; the dosage, route, and directions for taking the
drug; and permission for additional quantities. Abbrevia-
tions, taken from Latin words, are frequently used on
prescriptions and physicians’ orders in the hospital. Lists
of common abbreviations and equivalent measures are
found in Ready Reference 3 at the end of this book. The
apothecary system of measurement (eg, grains or drams)
has largely been replaced by the metric system of mg
and mL.
Chemical names for drugs tend to be complex and
difficult to remember and are therefore limited primarily
to scientific or manufacturing groups. Each drug can be
identified by two additional names. One is the generic
name, a unique, official, simple name for a specific drug.
This name is considered easy to remember accurately
and is used in many circumstances. The other name is
the trade, proprietary, or brand name, a trademark name
assigned by a single manufacturer, and it is to be used
only by that manufacturer. Many trade names may apply
to one generic name, and they are considered equivalent.
With the increase in new drugs, some trade names sound
similar and this can lead to drug error. See Table 3.2 for
examples of drug trade names.
Often members of a family of drugs with similar actions
can be identified by the similarities in their generic names.
Responses
Once a drug is administered to the human body it will
produce a series of responses, which can be divided into
four categories:
1. Dose effects
2. Time effects
3. Variability
4. Toxicity
Dose Effects
All drugs are considered potential poisons depending
on a number of factors, not the least of which are dose
and dosage. In determining the correct dose or overall
dosage level, the amount necessary to produce a thera-
peutic effect must be balanced with the level that may
produce a toxic effect. The establishment of a minimal
effective dose should produce the desired positive effects
and minimize the potential toxic effects. This will vary
somewhat from patient to patient based on factors such
as age, gender, and genetic profile.
Time Effects
Time is a major factor that will affect the magnitude of
the response to the dose given. The time response itself
measures the following:
• Time of administration
• Onset of response
• Cessation of effect
• Peak effect
• Duration of action
• Latency to effect
• Threshold level
DRUG #1
Tissue
receptor
site
Interstitial
fluid
Interstitial
fluid
Drug receptor
binds to tissue receptor
DRUG #1 STIMULATES INCREASED ACTIVITY
DRUG #2
Tissue
receptor
site
Drug receptor
binds to tissue receptor,
but no stimulus
DRUG #2 DECREASES ACTIVITY
Drug blocks
entry of natural
stimulator
substance in body
FIG. 3.3 Receptors and drug action. Drugs may stimulate natural
receptors, increasing activity, or block receptors, decreasing
activity.

CHAPTER 3 Introduction to Basic Pharmacology and Other Common Therapies 47
involve a few selected patients; if successful, the trial
group is greatly expanded. Researchers form a hypothesis
and develop questions for their study based on the
particular drug and trial requirements. A project design
frequently involves dividing the patients randomly and
anonymously into two groups—one to receive the
standard drug therapy the other group to receive the
new therapy—in an effort to assess the effectiveness and
safety of the new drug. Generally one group is given a
placebo, a “sugar” pill lacking any active ingredient, to
form a comparison for the new drug. A placebo may
also be used for its psychological impact on certain
patients.
For example, drugs classified as benzodiazepines, used
as antianxiety agents, include diazepam, clonazepam,
lorazepam, and oxazepam.
Trade names are always used for combinations of drugs
in a single tablet or liquid. An exception to this pattern
occurs with a few drugs that have been identified for
many years by a common name, such as aspirin.
Many drug names are similar in appearance and sound.
This can lead to serious errors. It is important to match
the drug name and its action with the patient’s disease
to prevent errors.
Legally, the Food and Drug Administration (FDA) in
the United States regulates the production, labeling,
distribution, and other aspects of drug control. Similar
agencies assume this responsibility in other countries.
When taking a drug history, it is wise to ask the patient
specifically about OTC medications and any herbal
products because individuals may feel they are not
significant and not volunteer this information. However,
for example, a drug such as aspirin may be important
because it is likely to cause excessive bleeding. To prevent
possible complications, it is recommended that a health
professional avoid giving a patient any OTC drug for any
reason, unless a physician or dentist so directs.
Other drugs, considered a greater risk, are classified
by the FDA in official schedules according to their effects
and potential for adverse effects, abuse, or dependency
(Table 3.3) Their sale is restricted, and prescription
requirements are set accordingly. For example, certain
narcotics such as morphine are under tighter control,
requiring a written, signed prescription (not by telephone)
without refill privileges. Another schedule contains drugs
that require a prescription but can be ordered by tele-
phone. One schedule is very limited, listing drugs that
can only be used for research. Drugs may be added or
moved between schedules at any time. The Centers for
Disease Control and Prevention (CDC) maintains a stock
of drugs for rare infections. These drugs can only be
obtained through consultation with the CDC.
Clinical research or trials of promising new drugs may
be encountered in practice. The clinical research phase
follows preliminary studies into efficacy and safety. Rules
for this research have been established by government
agencies, and committees oversee projects. Trials encom-
pass a prolonged period of time. It usually takes 10 to
15 years for the development of a new drug. Early trials
TABLE 3.2 Examples of Drug Nomenclature
Generic Name (Nonproprietary) Trade Name (Proprietary) Chemical Name
Diazepam Valium, Vivol, Apo-Diazepam,
Diastat
7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-
one
Ibuprofen Advil, Motrin, Ibren 2-(p-isobutyl phenyl)propionic acid
Hydrochlorothiazide Hydro DIURIL, Esidrix,
Hydro-Par, Oretic
6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide
1,1-dioxide
TABLE 3.3 Schedules of Controlled Substances
Schedule I High probability for
abuse, no
therapeutic use,
lack of safety
controls
Examples: heroin, LSD.
mescaline
Schedule II High probability of
abuse, therapeutic
use or accepted for
therapy under
close restrictions
Examples: raw opium,
cocaine, morphine,
methadone,
amphetamines,
barbiturates
Schedule III Less potential for
abuse than I and II,
therapeutic uses
accepted for
treatment in the
US, low potential
for physical or
psychological
dependence
Examples: barbiturates
with reduced
concentrations of
morphine, codeine
or nalorphine
Schedule IV Less potential for
abuse than III,
reduced potential
for physical/
psychological
dependency than
III
Examples: chloral
hydrate, diazepam,
pentazocine
Schedule V Less potential for
abuse or physical/
psychological
dependency than
schedule IV
Examples: codeine,
dihydrocodeine,
atropinics

48 SECTION I Pathophysiology: Background and Overview
evaluation of motor, cognitive, and visual-spatial ability.
Whereas the physiotherapist focuses on functional
mobility and relief of pain, the occupational therapist
integrates remediation of motor control, cognition, and
visual-spatial perception, which is essential for client
safety and productivity.
In addition to remediation of functional capacities,
the OT has expertise in teaching the client to use adapta-
tions in meeting his or her needs. This includes assessment
of technologies available in the marketplace, their effective
use, and appropriateness for the particular client. In many
cases, OTs work directly with technicians in the production
of aids such as wheelchairs or walkers, as well as adaptive
devices for food preparation, feeding, and personal
hygiene. In the workplace setting, OTs work along with
occupational health personnel to assess the workplace
and essential tasks, identify appropriate accommodation,
and instruct clients in the effective and safe use of sup-
portive technologies.
Speech/Language Therapy
The speech/language pathologist is a specialist in the
assessment and treatment of those with communica-
tion or swallowing problems. The patient could be
an infant with swallowing and feeding problems, a
child with a hearing deficit who is mute, an adult with
aphasia after a stroke, or someone requiring a hearing
assessment.
Nutrition/Diet
As an expert in foods and the nutritional needs of the
body in health and illness, a nutritionist or dietitian offers
advice to individuals or groups on the nutritional demands
and food management best suited to a specific diagnosis—
for example, diabetes. Dietitians supervise food services
in hospitals and other health care institutions and may
be consulted regarding the dangers of extreme diets or
eating disorders such as anorexia nervosa.
Registered Massage Therapy
Registered massage therapists (RMTs) use a variety of
techniques to increase circulation, reduce pain, and
increase flexibility for clients experiencing join pain or
problems with body alignment. Registered massage
therapists may also use soothing aromatics, acupuncture,
or other modalities during therapy.
Osteopathy
Osteopaths are medical doctors who use all the traditional
treatment methods such as surgery and drugs, but in addi-
tion they promote the body’s natural healing processes
by incorporating manipulations of the musculoskeletal
system in both diagnosis and treatment.
Traditional Forms of Therapy
Many health professionals may be involved either directly
or indirectly in the team approach to care of a patient
who may be a hospital inpatient, an outpatient, or
someone in the community. Therapies must address the
pathophysiologic changes if a return to health is to result
or function is to improve with minimal complications.
Physiotherapy
A physiotherapist assesses physical function and works
to restore any deficit and prevent further physical dysfunc-
tion. Physiotherapy involves individualized treatment
and rehabilitation as well as reduction in pain resulting
from disease, surgery, or injury. Physiotherapy may
include appropriate exercises, the use of ultrasound,
transcutaneous electrical nerve stimulation (TENS), or
other methods to alleviate pain and increase joint flexibility
and mobility. Physiotherapists work with patients with
acute neurologic, musculoskeletal, and cardiopulmonary
disorders. Infants with congenital defects or children with
injuries affecting mobility require therapy as soon as
possible to promote appropriate development.
Other major areas for physiotherapy are rehabilitation
and long-term care, in which the focus is on maximizing
mobility and functional independence. Rehabilitation
and long-term care involve working with amputees and
those with acquired brain injury, spinal cord injuries, or
strokes, as well as with group cardiac and respiratory
rehabilitation programs. Chest therapy to mobilize excess
secretions and aid lung function is useful for postoperative
patients or those with chronic obstructive pulmonary
disease (COPD) or bronchiectasis and cystic fibrosis. The
benefits of appropriate physiotherapy to cancer patients
undergoing chemotherapy and radiation are now being
appreciated. Educating patients and families to assist
with and maintain their individual programs is an
important aspect of treatment. Physiotherapy aides or
assistants may take on some responsibilities under the
supervision of a registered physiotherapist.
Occupational Therapy
Occupational therapists (OTs) provide a functional assess-
ment of patient capabilities related to normal activities
of daily living (ADLs). This assessment includes an
THINK ABOUT 3.2
a. Explain why drugs are classified legally into different
schedules.
b. What is the effect on patients when a breakthrough in
scientific research is announced in the media?

CHAPTER 3 Introduction to Basic Pharmacology and Other Common Therapies 49
Naturopathy
Naturopathic treatment is based on promoting natural
foods, massage, exercise, and fresh air as a way of life,
thus enhancing health and preventing disease. Acupunc-
ture, herbal medicines, nutrition, massage, and physical
manipulations may be included as part of this form of
treatment. Many alternative therapies are age-old home
remedies that have stood the test of time to bring relief
from human health complaints or promote good health.
Naturopaths do not recommend any traditional drugs.
Homeopathy
Homeopathy has the goal of stimulating the immune
system and natural healing power in the body through
the use of plant, animal, and mineral products. A toxin
or offending substance is identified for each disease state
and following dilution by several thousand-fold, the toxin
is administered to treat the problem.
Herbal Medicine
Medicinal herbs were first documented in ancient Egypt.
Numerous groups throughout the world use herbs and
plants for medicinal purposes, and they are now freely
available in many stores. There has been much publicity
about the benefits of garlic in cardiovascular disease and
other conditions. Echinacea is found in many cold
remedies and used for prophylaxis. St. John’s wort
contains compounds similar to standard antidepressant
medications. Efforts are now being focused on providing
standardized content, proving efficacy, and improving
the purity of herbal compounds. As with other medica-
tions, it is important to consult with a knowledgeable
professional about safe dosage and interactions with other
medications.
Aromatherapy
Aromatherapy is enjoying increased popularity. Essential
oils that have therapeutic effects when rubbed on the
skin or inhaled are extracted from plants. One oil can
contain many substances. Oils may be absorbed through
the skin into the general circulation, when bathing or
with a massage, to exert a systemic effect. When inhaled,
the essence influences physiologic functions through the
olfactory system. For example, chamomile is used for its
calming and sleep-inducing effect, lavender and pep-
permint oil soothe headache, and rosemary relieves muscle
and joint disorders.
Asian Concepts of Disease and Healing
Asian therapies are based on the balance or imbalance
of life energy called qi in Chinese medicine (also called
ch’i or chi, pronounced chee) or ki in Japanese medicine.
Chiropractic
Chiropractic medicine is based on the concept that one’s
health status is dependent on the state of the nervous
system, which regulates all body functions to maintain
homeostasis. Practice frequently involves manipulation
of the vertebral column. Although no drugs or surgery
are included in chiropractic therapy, acupuncture may
be used.
Complementary or Alternative Therapies
Alternative therapies are therapeutic practices considered
to be outside the range of traditional Western medicine
that also focus on alleviating disease and suffering.
Included on the list of alternative therapies are acupunc-
ture, aromatherapy, shiatsu, reflexology, and herbal
medicine. Many of these therapies have roots in Asia,
where emphasis is placed on preserving a healthy lifestyle.
The approach to disease and healing is generally holistic,
a more comprehensive approach recognizing the inter-
relationships of body, mind, and spirit.
Until recently, these therapies were viewed by some
in the Western world to be “quackery” and by others
simply to have a placebo effect, or at times even to be
dangerous. More recently these therapies have gained
some general acceptance and are termed complementary,
to be used in conjunction with Western medical therapy.
In some cases, alternative therapies have become a focus
of last resort for individuals when traditional medicine
could not achieve a cure. Current statistics show that
almost half of the population uses some form of alternative
therapy, and future trend predictions estimate this figure
will continue to rise. Chinese medicine is now considered
to be an independent system of thought and practice,
including clinical observation, testing, and diagnosis.
Practitioners in these areas have varying degrees of
training and professional regulation. As with traditional
medicine, a patient should investigate the therapy and
the individual practitioner to ensure safety and consistency
with other treatment modalities. A few examples are
described here.
Noncontact Therapeutic Touch
Many nurses, as well as other professionals, have trained
in therapeutic touch since the 1970s. Energy is exchanged
between people to relieve pain and anxiety and to promote
healing. The first step in delivering touch therapy is to
consciously form a positive intent to heal, a mindset
maintained both before and during the session. The
practitioner is able to locate problem areas in the body
by first scanning the body with the hands. Healing is
promoted by lightly touching the skin or moving the
hands just above the body surface. Imagery, light, or
colors may be incorporated as a means of transferring
healing energy to the patient, bringing comfort.

50 SECTION I Pathophysiology: Background and Overview
produce pure yang energy that penetrates deeply into
the body tissues to bring about relief. The heating medium
is Artemisia vulgaris, or common mugwort, whose dried
and purified leaves produce moxa wool.
Medical schools have begun to offer continuing educa-
tion in acupuncture for health care professionals. The
curricula include both traditional Chinese medicine
theories and practice, as well as acupuncture based on
allopathic knowledge of pain pathways. Such practice
is often termed medical acupuncture and is offered by a
variety of regulated practitioners.
Shiatsu
Shiatsu (Japanese: finger pressure) is the Japanese refined
version of Chinese anma massage, or acupuncture without
needles. There are two main forms of shiatsu: one uses
only thumbs, and the Zen shiatsu, the more traditional
form, uses fingers, thumbs, palms, elbows, and knees to
deliver slow, deep, but gentle pressure by a therapist to
access the tsubo, or acupoints. The patient remains clothed,
usually supine on a mat on the floor. This therapy provides
a whole-body treatment in which all meridians are treated,
from their beginning to their end, followed by the area
of complaint, and the process takes approximately 1 hour.
Initial assessment is performed by palpating the meridians
and the hara, the area below the ribs and above the pubic
bone. Shiatsu therapists give clients exercises or other
techniques that are self-administered at home between
treatment sessions.
Shiatsu is recommended for stress-related illness and
back pain because it provides relaxation. Zen shiatsu puts
an emphasis on the psychological/emotional causes of
disharmony. The therapist also adopts the “intent to heal”
attitude before and during the treatment, using the power
of touch.
Yoga
Yoga is an ancient Indian discipline of various forms that
combines physical activity in the form of body stretching
postures (asanas) with meditation. Practice with stretching,
meditation, and special breathing techniques improves
the flow of prana, the Indian equivalent to Chinese qi.
Prana circulates through the body via channels or nadis
to connect to seven chakras or energy centers running up
the midline. Regular practice opens these chakras; improves
flexibility, muscle tone, endurance, and overall health;
and reduces stress. Often a diet of simple (unrefined),
pure food, possibly vegetarian in nature, is recommended.
The practice relieves pain and anxiety in some individuals
with chronic disease.
Reflexology
Reflexology, a therapy from ancient China and Egypt,
relates points on the feet (mainly) and the hands to 10
longitudinal zones in the body. When the foot is stimulated
with massage, this can elicit changes in distant organs
or structures in the body through meridians similar to
Disease is caused by a deficit or excess of qi, whereas
healing restores the energy balance. Qi is derived from
three sources: inherited or ancestral factors, the food
ingested, and air breathed in. Imbalance or disharmony
between yin (lack of qi or cold) and yang (excess of qi or
heat) may be caused by changes in diet, stress, metabolism,
activity, or environment, leading to disease.
In the body, the life force, qi, flows along specific
channels called meridians, which join all organs and
body parts together. Meridians are not to be confused
with anatomic nerves or blood vessels. Each meridian
has a name and function, and it may be located some
distance from the organ for which it is named. For
example, the large intestine meridian begins on the surface
of the index finger, travels past the wrist and shoulder,
up the neck, and across the upper lip to the nose. Then
the meridian goes internally to the lung and finally to
the large intestine. All meridians are bilateral except for
one midline anterior (the conception vessel) and one
midline posterior (the governor vessel). Along the merid-
ians qi flows, and this flow may be accessed or altered
at particular acupoints, or tsubo (Japanese). Each acupoint
has specific actions or properties, such as moving the qi
or blood, pain reduction, heating, cooling, drying, or
calming the emotions. A pattern of disharmony may
involve a number of acupoints and meridians. The goal
is to connect with the points that will normalize the flow
of qi and restore the balance of yin and yang.
Acupuncture
Acupuncture is a Chinese therapeutic discipline over
3000 years old that involves inserting very fine needles
into the various meridian acupoints that have the potential
to balance the body energy. There are classically 365
acupoints, or tsubo (Japanese), but today the commonly
used points number only 150. Each point has a specific
and a more generalized therapeutic action, and the points
are often used in combinations. Acupuncture may be
performed on extra points not related to meridians, and
also on ashi or “ouch points” anywhere. Acupuncture
deals with pain relief and balancing energy to restore
health by using superficial meridian acupoints. Current
theory suggests that acupuncture decreases pain because
it causes the release of endorphins in the brain.
An acupuncture treatment on average uses 5 to 15
needles, which should be sterile, stainless steel, and
disposable. The needles may be rotated or connected to
low-level electric current or laser for a period of 30 to 45
minutes. The needle may only be laid on the acupoint on
the surface of the skin without actually being inserted,
but most often the needles are inserted into the skin to
depths ranging from 1 to 2 mm on the face and ears to
up to 3 inches in the heavily muscled buttocks. Instead
of needles, ultrasonic waves or laser may be used over
acupoints.
Moxibustion is a form of acupuncture that specifically
treats cold or deficiency patterns by burning moxa to

CHAPTER 3 Introduction to Basic Pharmacology and Other Common Therapies 51
C H A P T E R S U M M A R Y
Drug therapy as well as other therapeutic modalities
may have an impact on the course of a disease, patient
well-being, or patient care when prescribed by any
member of the health care team.
• Drugs may have mild side effects(such as nausea) or
serious toxic effects (such as bone marrow depression)
in the body in addition to the beneficial or therapeutic
effect. Other potential unwanted outcomes of drug
treatment include hypersensitivity reaction, idiosyn-
cratic response, or teratogenic effects.
• The route of administration, dosing schedule, distribu-
tion in the individual’s body, and timing of elimination
of the drug determine the effective blood level of the
drug.
• Drugs may be used to stimulate or block specific natural
receptor sites in the body so as to alter certain activities,
such as heart rate.
• Drug interactions with other drugs, foods, or alcohol
may result in synergistic or antagonistic effects.
• Physiotherapists assess physical functions and select
therapy to improve mobility or relieve pain. Occupa-
tional therapists assist patients with ADLs, maximizing
independent function.
• Alternative or complementary therapies may be
provided by alternative practitioners such as osteo-
paths, naturopaths, and homeopaths. Treatments may
be offered as replacements for or in conjunction with
traditional medicine.
• Asian healing is based on restoring the balance of life
energy in the body (qi in Chinese medicine or ki in
Japanese therapy) using specific points or meridians
in the body. Therapeutic measures include acupuncture,
shiatsu, and reflexology.
those of acupuncture. For example, areas of the great toe
represent head and brain activities, and the medial arch
(bilaterally) influences the vertebral column.
The practitioner applies varying degrees of pressure
to the standard rotating thumb massage technique and
may include slight vibration directed to various foot reflex
areas. The session may conclude with essential oils being
massaged into the feet. This therapy is designed to relieve
stress and muscle tension.
Craniosacral Therapy
Craniosacral therapy was first published as a scientific
research paper by Dr. W. Sutherland, an osteopathic
physician, in the 1930s. This system is used by a wide
variety of health care practitioners: physiotherapists,
occupational therapists, acupuncturists, chiropractors,
medical doctors, osteopathic physicians, and dentists.
The therapy deals with the characteristic ebb and flow
pulsing rhythm of the meninges and cerebrospinal fluid
around the brain and spinal cord. Gentle palpation and
manipulation of the skull bones and vertebrae are thought
to rebalance the system. Research as recent as 2012 has
not yet been able to substantiate any healing effects using
this therapy.
Ayurveda
This system of medicine originated in India and is still
practiced today. Its goal is to balance body dosas or factors
so that a healthy mind and body result. Special dietary
plans, yoga, and herbal remedies are commonly used in
ayurvedic medicine.
CASE STUDY A
Therapies for Pain
Where possible, the following case study should be considered from
the professional standards of your studies.
While providing her health history, Ms. Z. reports severe
pain in her lower back.
1. What questions would you include in your history taking
for Ms. Z.? Provide a rationale for each question.
Ms. Z. reports using herbal remedies to help her sleep and
herbal compresses during the day to reduce pain. Her
doctor has prescribed acetaminophen with codeine to
relieve pain. She thinks that she usually takes two
“extra-strong” acetaminophen tablets every 4 hours and a
Tylenol 3 tablet whenever the pain is severe.
2. What sources would you use to find information on herbal
compounds and drugs?
3. What should Ms. Z. understand about the dosage of
acetaminophen she is taking?
4. How can Tylenol 3 tablets assist Ms. Z to fall asleep?
5. How may the Tylenol 3 tablets interfere with sleep in
some individuals?
6. What other measures can Ms. Z. use to control her pain
and reduce her need for acetaminophen?
7. What therapeutic help can you provide to assist Ms. Z. in
controlling her pain? Does this therapy affect drug action?
THINK ABOUT 3.3
Describe three ways in which Asian medicine differs from the
Western medical practices.

52 SECTION I Pathophysiology: Background and Overview
S T U D Y Q U E S T I O N S
1. Compare a generic name with a trade name.
2. Explain why one drug is taken every 3 hours, but
another drug is taken once daily.
3. Compare the advantages and disadvantages of the
following:
a. oral administration
b. intravenous administration
4. Explain how synergism can be
a. dangerous
b. beneficial
5. Explain why some drug is lost following
administration and not used in the body.
6. Which group of therapists could best
a. assist with fitting a wheelchair?
b. assist a young child with a swallowing
problem?
7. Compare the therapies used by osteopathic
physicians and chiropractors.
8. Compare the similarities and differences between
acupuncture and shiatsu.

53
Etiology and Sources of Pain
Structures and Pain Pathways
Physiology of Pain and Pain Control
Characteristics of Pain
Signs and Symptoms
Young Children and Pain
Referred Pain
Phantom Pain
Pain Perception and Response
Basic Classifications of Pain
Acute Pain
Chronic Pain
Headache
Central Pain
Neuropathic Pain
Ischemic Pain
Cancer-Related Pain
Pain Control
Methods of Managing Pain
Anesthesia
Case Studies
Chapter Summary
Study Questions
C H A P T E R O U T L I N E
After studying this chapter, the student is expected to:
1. State the causes of pain.
2. Describe the pain pathway.
3. Relate the methods of pain control to the
gate-control theory.
4. Discuss the signs and symptoms of pain in adults and
young children.
5. Compare referred and phantom pain.
6. Explain the factors that may alter pain
perception.
7. Compare acute and chronic pain.
8. Discuss the types of headache.
9. Describe methods of pain management.
L E A R N I N G O B J E C T I V E S
afferent fibers
analgesic
bradykinin
cordotomy
dermatome
efferent
endorphins
histamine
intractable
ischemia
neurotransmitter
nociceptors
opioids
prostaglandin
reticular activating system
reticular formation
rhizotomy
sedatives
substance P
tachycardia
K E Y T E R M S
C H A P T E R 4
Pain
Pain is an unpleasant sensation, a feeling of discomfort
resulting from stimulation of pain receptors in the body
when tissue damage occurs or is about to occur. Pain is
a body defense mechanism and is a warning of a problem,
particularly when it is acute. It is difficult to define because
it can have many variable characteristics, and it is a
subjective feeling, impossible to accurately measure.
However, subjective scales have been developed to
compare pain levels over time. In cases of trauma, the
danger may be obvious, but in other situations the cause
may be hidden deep inside the body. Pain involves
complex mechanisms, many of which scientists and health
care workers do not totally understand.
Etiology and Sources of Pain
Pain stimuli may occur for many reasons. Pain may be
caused by infection, ischemia and tissue necrosis, stretch-
ing of tissue, chemicals, or burns. In skeletal muscle,
pain may result from ischemia or hemorrhage. Many
organs such as the liver, kidney, or brain are characterized
by pain receptors in the covering capsule, and pain is
felt when the capsule is stretched by inflammation.
Stretching of tendons, ligaments, and joint capsules also
elicits pain; these effects may occur secondary to inflam-
mation or muscle spasm to guard a joint or painful body
part. In the stomach and intestines, pain may result from

54 SECTION I Pathophysiology: Background and Overview
thermal, chemical, or mechanical/physical means.
Thermal means refer to extremes of temperature; chemical
means could include acids or compounds produced in
the body, such as bradykinin, histamine, or prostaglan-
din; and mechanical/physical means could refer to
pressure.
The pain threshold refers to the level of stimulation
required to activate the nerve ending sufficiently for the
individual to perceive pain. The associated nerve fibers
then transmit the pain signal to the spinal cord and brain.
The pain threshold is relatively constant over time and
among individuals. The ability to withstand pain or the
perception of its intensity is referred to as pain tolerance;
this varies considerably with past pain experience and
overall state of health.
Two types of afferent fibers conduct pain impulses:
the myelinated A delta fibers that transmit impulses
inflammation of the mucosa, ischemia, distention, or
muscle spasm.
Somatic pain may arise from the skin (cutaneous) or
from deeper structures such as bone or muscle, to be
conducted by sensory nerves. Visceral pain originates in
the organs and travels by sympathetic fibers. Depending
on the cause, pain may be sudden and short term, marked
primarily by a reflex withdrawal. For example, if one
touches a hot object, the hand is involuntarily jerked
away from the source of injury. Or pain may be relatively
continuous, as when infection or swelling is present.
Structures and Pain Pathways
Pain receptors or nociceptors are free sensory nerve
endings that are present in most tissues of the body
(Fig. 4.1). These sensory nerves may be stimulated by
Dorsal root
6. LATERAL
SPINOTHALAMIC
TRACT (pain)
9. SOMATOSENSORY
CORTEX—PARIETAL
LOBE — locate pain
8. THALAMUS —
sensory relay
center
7. RETICULAR FORMATION
in pons and medulla —
awareness, alert
Spinal cord
1. STIMULUS
5. SPINAL DECUSSATION
(cross-over)
2. NOCICEPTOR
(pain receptor)
3. PERIPHERAL NERVE—
afferent pain fiber
4. SYNAPSE
Dorsal ganglion
Brain
11. LIMBIC SYSTEM — emotional response
10. HYPOTHALAMUS — stress response
FIG. 4.1 Pain pathway.

CHAPTER 4 Pain 55
connections with the pituitary gland and sympathetic
nervous system. Response to pain usually involves a
stress response (see Chapter 26) as well as an emotional
response such as crying, moaning, or anger. There may
be a physical response, perhaps rigidity, nausea, vomiting
or guarding of an area of the body. The thalamus processes
many types of sensory stimuli as they enter the brain
and is important in the emotional response to pain through
the limbic system.
THINK ABOUT 4.1
Trace the pathway of a pain impulse originating from a stubbed
toe by drawing a simple diagram and labeling the parts.
THINK ABOUT 4.2
a. Describe your response to a sudden severe pain in your
own experience—for example, how did you respond to an
injury? Describe your physical response and your
emotional reactions.
b. Using your knowledge of normal physiology, list the
effects of increased sympathetic nervous system
stimulation on body function and muscle tone.
c. Suggest how monitoring for sympathetic nervous system
changes assists you in evaluating a person’s level of pain.
rapidly and the unmyelinated C fibers that transmit
impulses slowly. Acute pain—the sudden, sharp, localized
pain related to thermal and physical stimuli primarily
from skin and mucous membranes—is transmitted by
the A delta fibers, whereas chronic pain—often experi-
enced as a diffuse, dull, burning or aching sensation—is
transmitted by C fibers. C fibers receive thermal, physical,
and chemical stimuli from muscle, tendons, the myocar-
dium, and the digestive tract as well as from the skin.
The peripheral nerves transmit the afferent pain impulse
to the dorsal root ganglia and then into the spinal cord
through the dorsal horn or substantia gelatinosa (see
Chapter 14).
Each spinal nerve conducts impulses from a specific
area of the skin called a dermatome (see Fig. 14.22, which
illustrates the areas of the skin innervated by each spinal
nerve), and the somatosensory cortex is “mapped” to
correspond to areas of the body so that the brain can
interpret the source of the pain (see Fig. 14.3 for a map
of the brain). The dermatomes can be used to test for
areas of sensory loss or pain sensation and thus determine
the site of damage after spinal cord injuries.
At the spinal cord synapse, a reflex response to sudden
pain results in a motor, or efferent, impulse back to the
muscles that initiates an involuntary muscle contraction
to move the body away from the source of pain. After
the sensory impulse reaches the synapse, connecting
neurons also transmit it across the spinal cord to the
ascending tracts to the brain. There are two types of
tracts in the spinothalamic bundle: the fast impulses for
acute sharp pain travel in the neospinothalamic tract,
whereas the slower impulses for chronic or dull pain use
the paleospinothalamic tract. This double pathway
explains the two stages of pain one often experiences
with an injury to the skin, the initial sharp severe pain,
followed by a duller but persistent throbbing or aching
pain. These tracts connect with the reticular formation
in the brain stem, hypothalamus, thalamus, and other
structures as they ascend to the somatic sensory area in
the cerebral cortex of the parietal lobe of the brain. It is
here that the location and characteristics of the pain are
perceived. The many branching connections from the
ascending tracts provide information to other parts of
the brain, forming the basis for an integrated response
to pain.
The arousal state of the reticular activating system
(RAS) in the reticular formation in the pons and medulla
influences the brain’s awareness of the incoming pain
stimuli. In clinical practice, many drugs depress the RAS,
thereby decreasing the pain experienced. The hypothala-
mus plays a role in the response to pain through its
Physiology of Pain and Pain Control
Pain is a highly complex phenomenon that is not fully
understood. There are many variables in its source and
perception and in the response to it in a specific individual.
The gate-control theory has been modified as the complexity
of pain is better realized, but the simple model serves as
a useful tool and visual explanation of pain pathways
that can be related to many concepts of pain and pain
control. According to this theory, control systems, or
“gates,” are built into the normal pain pathways in the
body that can modify the entry of pain stimuli into the
spinal cord and brain. These gates at the nerve synapses
in the spinal cord and brain can be open, thus permitting
the pain impulses to pass from the peripheral nerves to
the spinothalamic tract and ascend to the brain (Fig. 4.2).
Or they may be closed, reducing or modifying the passage
of pain impulses. Gate closure can occur in response to
other sensory stimuli along competing nerve pathways
that may diminish the pain sensations by modulating or
inhibiting impulses from higher centers in the brain. For
example, the application of ice to a painful site may reduce
pain because one is more aware of the cold than the pain.
Transcutaneous electrical nerve stimulation (TENS) is a
therapeutic intervention that increases sensory stimulation
at a site, thus blocking pain transmission. Alternatively,
the brain can inhibit or modify incoming pain stimuli by
producing efferent or outgoing transmissions through the
reticular formation. Many factors can activate this built-in
control system, including prior conditioning, the emotional
state of the affected person, or distraction by other events.
This last phenomenon has been observed in many individu-
als who feel no pain when injured suddenly but do
experience a delayed onset of pain once they are no longer
distracted by the immediate emergency situation.

56 SECTION I Pathophysiology: Background and Overview
The key to this analgesia system, or the blocking of
pain impulses to the brain, is the release of a number of
opiate-like chemicals (opioids) secreted by interneurons
within the central nervous system. These substances block
the conduction of pain impulses into the central nervous
system. They resemble the drug morphine, which is
derived from opium and is used as an analgesic (a pain-
blocking or relieving medication), and are therefore called
5. Pain perceived
1. Painful stimulus
Brain
Spinal cord
(dorsal horn or
substantia
gelatinosa)
Interneuron
(inactive)
Nociceptor
Nociceptor
Spinal cord
Peripheral nerve
A-delta and C pain fibers
Afferent touch
a-beta thick fibers
Afferent
pain fiber
1. Painful stimulus
Other sites for
endorphin and
enkephalin release
A
B
Substance P
neurotransmitter
Enkephalin
6. Gate closed
transmission
blocked on
afferent tract
2. Interneuron activated by:

efferent impulses
from the brain
afferent impulses
from touch stimulusor
5. Substance P
not released
4. Opiate receptors
blocked by 3. Interneuron
releases
4. RAS alert
3. Pain stimulus
to brain
2. Substance P
released at synapse
FIG. 4.2 Pain control. A, Gate open—pain stimulus transmitted. B, Gate closed—pain stimulus
blocked.
APPLY YOUR KNOWLEDGE 4.1
1. Predict several factors that could reduce pain tolerance
and make pain more severe.
2. Suggest methods that might be used to distract a patient
and reduce pain.

CHAPTER 4 Pain 57
experience pain. It has now been established that a young
infant does perceive pain and responds to it physiologically,
with tachycardia and increased blood pressure as well as
characteristic facial expressions. Infants with their eyes
tightly closed, their eyebrows low and drawn together, and
their mouths open and square are probably in pain.
There is great variation in the developmental stages
and coping mechanisms of children. A range of behavior
that may not accurately reflect the severity of pain should
be expected. Older children may flail their legs and arms
and resist comfort measures, or they may become physi-
cally rigid. Children may find it difficult to describe their
pain verbally. However, children can use drawings of
happy or sad faces, mechanical scales, or multicolored
symbols to better describe their feelings. Withdrawal and
lack of communication are often the result of pain in
older children and teens.
Referred Pain
Sometimes the source of a pain stimulus can be localized
to a specific area. In other cases the pain is generalized, and
the source is difficult to determine. Sometimes the pain is
perceived at a site distant from the source. This is called
referred pain. Generalized and referred pains are characteristic
of visceral damage in the abdominal organs. In some condi-
tions, such as acute appendicitis, the characteristics of the
pain may change as pathologic changes occur.
Referred pain occurs when the sensations of pain are
identified in an area some distance from the actual source
(Fig. 4.3). Usually the pain originates in a deep organ or
muscle and is perceived on the surface of the body in a
different area. For example, pain in the left neck and arm
is characteristic of a heart attack or ischemia in the heart.
Pain in the shoulder may be due to stretching of the dia-
phragm. Multiple sensory fibers from different sources
connecting at a single level of the spinal cord make it difficult
for the brain to discern the actual origin of the pain.
Phantom Pain
Pain or another sensation such as itching or tingling
occurs in some individuals, usually adults, after an
amputation. This phantom pain is perceived by the person
as occurring in the lost limb and usually does not respond
to usual pain therapies. The pain may resolve within
weeks to months. Although the phenomenon is not fully
understood, it appears that the brain “understands” the
limb is still present when processing incoming stimuli.
Research suggests that a history of prolonged or severe
chronic pain before surgery increases the probability of
phantom pain developing.
Pain Perception and Response
Pain tolerance is the degree of pain, either its intensity
or its duration, which is endured before an individual
endorphins or endogenous morphine. Endorphins include
enkephalins, dynorphins, and beta-lipotropins. Fig. 4.2
illustrates how enkephalin is released in the spinal cord
and is attached to opiate receptors on the afferent neuron,
thus blocking the release of the neurotransmitter sub-
stance P at the synapse. This process prevents transmission
of the pain stimulus into the spinal cord. Serotonin is
another chemical released in the spinal cord that acts on
other neurons in the spinal cord to increase the release
of enkephalins. Clients with clinical depression often
report chronic pain due to a reduction in serotonin levels
in the brain. In addition, natural opiate receptors are found
in many areas of the brain, as are secretions of endorphins,
which can block pain impulses at that level. The body
has its own endogenous analgesic or pain control system
that explains some of the variables in pain perception
and can be used to assist in pain control.
THINK ABOUT 4.3
Briefly describe three methods of “closing the gate” and reducing
pain.
Characteristics of Pain
Signs and Symptoms
Pain is a real sensation but a subjective symptom perceived
by each individual. There are many variations in
the clinical picture of pain as well as the verbal reports
of pain.
Possible details that may be helpful in diagnosing the
severity and cause of pain include the following:
• The location of the pain
• The use of many descriptive terms, such as aching,
burning, sharp, throbbing, widespread, cramping, constant,
periodic, unbearable, or moderate
• The timing of the pain or its association with an activity
such as food intake or movement, or with pressure
applied at the site
• Physical evidence of pain, when the patient may
demonstrate a stress response with physical signs such
as pallor and sweating, high blood pressure, or
tachycardia
• Nausea and vomiting or fainting and dizziness, which
may occur with acute pain
• Anxiety and fear, which are frequently evident in
people with chest pain but may be present in other
situations as well
• Clenched fists or rigid faces; restless or constant motion,
or lack of movement; often protecting, or “guarding”
the affected area
Young Children and Pain
For many years it was thought that newborn infants, because
of their immature nervous systems, did not perceive or

58 SECTION I Pathophysiology: Background and Overview
would include loud crying and wailing. Prior unpleasant
experiences and anticipatory fear or anxiety can lower
pain tolerance, magnifying the extent of the pain and
the response.
An individual’s temperament and personality can
influence the response to pain, and the circumstances
existing at the time of the incident may affect perception
of it. Anxiety, fear, and stress can increase the severity
of pain because in these circumstances the central nervous
system is at a higher level of awareness. Fatigue, hunger,
and the presence of other pathologies or problems may
takes some action. Tolerance may be increased by endor-
phin release or reduced by other factors such as fatigue
or stress. Tolerance does not necessarily depend on the
severity of the pain. Rather, it varies among people and
different situations.
Pain perception and response are subjective and depend
on the individual. Factors such as age, culture, family
traditions, and prior experience with pain shape one’s
perception and response to pain. For example, in certain
groups it is customary to approach pain with stoic
acceptance, whereas in other groups the proper response
Pain pathway
to brain
Spinal cord
convergence
Skin of left arm
Brain interprets
source of pain
as left arm
Pain in heart
Sensory
fibers
B
Cardiac
ischemia
Biliary colic
Cholecystitis
Pancreatitis
Duodenal ulcer
Small
intestine pain
Appendicitis
A
Colon
pain
Ureteral colic
Pancreatitis
Perforated
duodenal
ulcer
Cholecystitis
Penetrating
duodenal
ulcer
Cholecystitis
Pancreatitis
Renal colicRenal colic
Rectal
lesions
FIG. 4.3 A, Locations of referred pain. B, Proposed mechanism for referred pain. (A From Copstead-
Kirkorn LC: Pathophysiology, ed 4, St. Louis, 2009, Mosby.)

CHAPTER 4 Pain 59
• Long-term pain usually reduces tolerance to any
additional injury or illness.
Table 4.1 provides a brief comparison of acute and
chronic pain.
magnify a person’s response. Likewise, the specific cause
of the pain and its implications with respect to body
image, family relationships, or employment responsibili-
ties might alter the person’s perception of pain and the
response to it.
THINK ABOUT 4.4
a. From your own experience, describe a sharp pain, an
aching pain, and a cramping pain.
b. List factors that often make pain seem more severe.
c. Differentiate pain threshold from pain tolerance.
Basic Classifications of Pain
Acute Pain
• Onset of acute pain is usually sudden and severe, but
short term.
• It indicates tissue damage and decreases once the cause
has been treated.
• It may be localized or generalized.
• Acute pain usually initiates a physiologic stress
response with increased blood pressure and heart rate;
cool, pale, moist skin; increased respiratory rate; and
increased skeletal muscle tension (see Chapter 26).
• Vomiting may occur.
• In addition, there may be a strong emotional response,
as indicated by facial or verbal expression and a high
anxiety level.
Chronic Pain
Long-term pain can lead to different and often negative
effects such as loss of employment or interference with
personal relationships.
• Chronic pain is usually more difficult to treat effectively
than acute pain, and the prognosis may be less certain.
• The patient often perceives chronic pain as being more
generalized, and it is difficult to discern an exact
location.
• Because a specific cause may be less apparent to the
person experiencing the pain, the pain is more difficult
to deal with and can be debilitating.
• It is impossible to sustain a stress response over a long
period of time, and the individual with chronic pain
frequently is fatigued, irritable, and depressed.
• Sleep disturbances are common, and appetite may be
affected, leading to weight gain or loss.
• Constant pain frequently affects daily activities and
may become a primary focus in the life of the indi-
vidual, thus complicating any measures to affect pain
control by medication or other methods.
• Periods of acute pain may accompany exacerbations
of chronic disease, making it more difficult for the
patient to participate effectively in a pain management
program.
TABLE 4.1 General Comparison of Acute and
Chronic Pain
Acute Pain Chronic Pain
Type
A warning: fast, localized Slow, diffuse,
prolonged
Stimuli
Injury: mechanical, thermal Existing, chemical
Pathway
Fast A-delta myelinated fibers Slow unmyelinated
C fibers
Neospinothalamic tract Paleospinothalamic
tract
Response
Sudden, short-term Long-term, disabling
Stress response; increased pulse
and blood pressure: cool,
moist skin; nausea/vomiting
Fatigue, depression,
irritability
Emotion
Anxiety Loss of hope,
depression, anger
Treatment
If cause is identified, treatment
is effective
Difficult to treat
effectively
THINK ABOUT 4.5
Compare the characteristics of acute and chronic pain.
Headache
Headache is a common type of pain. There are many
categories of headache associated with different causes,
and some have specific locations and characteristics.
• Headaches associated with congested sinuses, nasal
congestion, and eyestrain are located in the eye and
forehead areas. Sinus headaches can be severe. These
headaches are usually steady and relieved when the
cause is removed.
• Tension headaches associated with muscle spasm result
from emotional stress and cause the neck muscles to
contract to a greater degree, pulling on the scalp.
Sometimes when people work for long periods of time
in one position, contraction and spasm of the neck
muscles also result, causing a dull, constant ache
usually in the occipital area. Tension headaches tend
to persist for days or weeks.

60 SECTION I Pathophysiology: Background and Overview
• Dihydroergotamine (DHE 45, Migranal), and ergot
derivative seems more effective with fewer side effects
than ergotamine.
• Triptans are the drugs of choice for severe migraines.
They act on some 5-HT (5-hydroxytryptamine) recep-
tors to block the vasodilation and release of vasoactive
peptides in the brain. These drugs relieve the nausea
and light sensitivity as well as pain and nausea.
Commercial examples of this family of drugs are
almotriptan (Axert), rizatriptan (Maxalt), sumatriptan
(Imitrex), naratriptan (Amerge), zolmitriptan (Zomig),
frovatriptan (Frova), and eletriptan (Relpax). Side
effects include reactions at the injection site, nausea,
dizziness, and muscle weakness.
• Opiates such as codeine may be used in severe cases,
but due to the habit-forming nature of these narcotics,
they are considered a last resort.
Some patients may use preventive medication on a daily
basis or just before a known migraine trigger. These drugs
include several cardiovascular drug groups usually used
for hypertension, beta blockers and calcium channel block-
ers (see Chapter 12). The older tricyclic antidepressants
such as amitriptyline (Elavil) may be helpful because they
raise serotonin and norepinephrine levels. Migraine clinics
are researching the hereditary factors as well as individual
exacerbating factors.
• Intracranial headaches result from increased pressure
inside the skull. Any space-occupying mass stretches
the cerebral vascular walls or the meninges covering
the brain. Causes of increased pressure include trauma
with edema or hemorrhage, tumors, infections such
as meningitis, or inflammation resulting from toxins
such as alcohol. Headaches may be occipital or frontal
in location depending on the site of the problem.
Usually other indicators of increased intracranial
pressure accompany the headache (see Chapter 14).
• Headache in the temporal area is often associated with
temporomandibular joint (TMJ) syndrome, in which
the underlying cause is a malocclusion involving the
jaw or inflammation of the joint due to arthritis or
poor body alignment, which causes muscle tension
in the neck that is transferred to the jaw.
• Migraine headaches are related to abnormal changes
in blood flow and metabolism in the brain, but the
exact mechanism is not yet fully understood. Research
has suggested that migraines may be caused by the
following reactions:
a. Increased neural activity spreads over areas of the
brain initiating pain stimuli in the trigeminal system,
which are then conducted to the thalamus and pain
centers in the sensory cortex.
b. An accompanying reduction in serotonin is observed
during migraine headaches and may cause the
release of neuropeptides, which travel to the meninges
covering the brain.
c. These neuropeptides act on the smooth muscle of
the blood vessels in the meninges, causing stretching
and inflammation. The result is severe vascular pain.
There are also many precipitating factors, includ-
ing atmospheric changes, stress, menstruation,
dietary choices, and hunger, that may affect the
severity and duration of a headache.
The pain associated with a migraine is usually throb-
bing and severe and is often incapacitating. Character-
istically, migraine headaches begin unilaterally in the
temple area but often spread to involve the entire head.
The pain is often accompanied or preceded by visual
disturbances and dizziness, nausea and abdominal
discomfort, and fatigue. These headaches may last up
to 24 hours, and there is often a prolonged recovery
period. Mild migraine may be treated with nonsteroidal
antiinflammatory drugs (NSAIDs) such as ibuprofen
(Advil, Motrin, and others) and acetaminophen
(Tylenol and others). Moderate migraine pain often
responds to a combination of acetaminophen, codeine,
and caffeine, or acetaminophen, aspirin, and caffeine
(Excedrin migraine).
Treatment of severe migraine pain is difficult and includes:
• Aspirin or ibuprofen and acetaminophen may relieve
mild migraines. Acetaminophen may be helpful as
well.
• Drug combinations marked specifically for migraines
may ease moderate migraine pain but are ineffective
for severe migraines.
• Ergotamine can be effective if it is administered
immediately after the onset of the headache. Newer
forms of ergotamine are available in a soluble tablet
to be placed under the tongue, thus providing a more
readily available and rapid-acting form of the drug.
A combination of ergotamine and caffeine can also be
used. Ergotamine may worsen nausea and vomiting
related to migraines. The drugs may also lead to
medication overuse and related headaches.
Central Pain
Central pain is pain that is caused by dysfunction or
damage to the brain or spinal cord. A lesion such as
abscess, infarction, hemorrhage, tumor, or damage result-
ing from direct injury may cause central pain. This type
of pain can be localized or can involve a large area of
the body. It is persistent, irritating, and can cause consider-
able suffering over an extended period of time.
Neuropathic Pain
Neuropathic pain is caused by trauma or disease involving
the peripheral nerves. This type of pain can vary from
THINK ABOUT 4.6
Compare the signs of a migraine headache with those of a tension
headache.

CHAPTER 4 Pain 61
• Pain associated with the treatment of the disease
• Pain that is the result of a coexisting disease unrelated
to the cancer
The most common category encountered in cancer-related
pain is that caused by the advance of the disease. As the
tumors grow, they can cause infections and inflammation,
which in turn cause increased pressure on nerve endings,
stretching of tissues, or obstruction of vessels, ducts, or
the intestines. This type of pain may be characterized as
acute with sudden onset, intermittent, or chronic persist-
ing over a long period of time.
Pain Control
Methods of Managing Pain
Pain can be managed in a number of ways in addition
to removing the cause as soon as possible. The most
common method is the use of analgesic medications to
relieve pain. These drugs may be administered in a variety
of ways, including orally or parenterally (by injection)
or transdermal patch. New drugs are constantly being
developed to improve the efficacy of treatment and reduce
side effects. Analgesics are frequently classified by
their ability to relieve mild, moderate, or severe pain
(Table 4.2).
Mild pain is usually managed with acetaminophen
(Tylenol) or acetylsalicylic acid (ASA, aspirin), both of
which act primarily at the peripheral site. The latter is
particularly useful when inflammation is present, whereas
the former is popular because it has fewer side effects.
Acetylsalicylic acid also acts as a platelet inhibitor, reduc-
ing blood clotting. NSAIDs, such as naproxen and ibu-
profen, are widely used to treat both acute and chronic
pain, particularly when inflammation is present (see
a tingling to a burning or severe shooting pain. Movement
can stimulate this pain as well as injured nerves that can
become hyperexcitable and some neurons with low
thresholds for thermal, mechanical/physical, or chemical
stimuli may spontaneously fire. Neuralgias are examples
of extremely painful conditions that are a result of damage
to peripheral nerves caused by infection or disease.
Causalgia is a type of neuralgia that involves severe
burning pain that can be triggered by normally “non-
traumatic” stimuli such as a light touch, sound, or cold.
Ischemic Pain
Ischemic pain results from a profound, sudden loss of
blood flow to an organ or tissues in a specific area of
the body. The decreased blood supply results in hypoxia,
which leads to tissue damage and the release of inflam-
matory and pain-producing substances. The description
of the pain may vary from aching, burning, or prickling
to a strong shooting pain (particularly in an extremity).
The exact symptoms depend on the location of the hypoxic
tissue and can be characterized as either acute or chronic
pain. Atherosclerotic disorders that cause blocking
of arterial flow can cause ischemic pain, particularly in
the lower extremities. Improving blood flow and
preventing/reducing tissue hypoxia can do much to
manage ischemic pain.
Cancer-Related Pain
Cancer is often associated with pain, usually chronic
pain. This pain has been broken down into several
categories:
• Pain caused by the advance of the disease and resultant
damage to the body
TABLE 4.2 Analgesic Drugs
Use Name Action Adverse Effects
For Mild Pain
ASA
Acetaminophen
NSAIDs
Decreases pain at peripheral site; all are
antipyretic; ASA and NSAIDs are
antiinflammatory
ASA and NSAIDs have many adverse effects
(nausea, gastric ulcers, bleeding, allergies)
For Moderate Pain
Codeine
Oxycodone
Percocet
Vicodin
Acts on central nervous system and affects
perception
Narcotic (opium)—tolerance and addiction, often
combined with ASA/acetaminophen; high dose
may depress respiration
For Severe Pain
Morphine
Demerol
Methadone
Meperidine
Oxycodone
Acts on central nervous system; euphoria
and sedation
Narcotic—tolerance and addiction; high dose
depresses respiration; nausea, constipation
common
ASA, acetylsalicylic acid (aspirin); NSAIDs, nonsteroidal antiinflammatory drugs.

62 SECTION I Pathophysiology: Background and Overview
include stress reduction and relaxation therapy, distrac-
tion, applications of heat and cold, massage, physiotherapy
modalities, exercise, therapeutic touch, hypnosis imaging,
and acupuncture (see Chapter 3). These measures may
act in the spinal cord at the “gate” or may modify pain
perception and response in the brain. Many of these
strategies are believed to increase the levels of circulating
endorphins that elevate the pain tolerance. Also, main-
tenance of basic nutrition and activity levels as well as
adequate rest assists people in coping with pain. Special-
ized clinics deal with certain types of pain such as chronic
back pain or temporal mandibular joint pain.
For intractable pain that cannot be controlled with
medications, surgical intervention is a choice. Procedures
such as rhizotomy or cordotomy to sever the sensory
nerve pathway in the spinal nerve or cord may be done.
Injections can be given with similar effects. These pro-
cedures carry a risk of interference with other nerve fibers
and functions, particularly when the spinal cord is
involved.
Anesthesia
Local anesthesia may be injected or applied topically to
the skin or mucous membranes (Table 4.3). Local anesthet-
ics may be used to block transmission of pain stimuli
from a specific small area. For example, an injection of
lidocaine may be given before extracting a tooth, removing
a skin lesion, or performing a diagnostic procedure that
is likely to be painful. A long-acting, localized block may
be used to reduce pain after some surgeries.
Spinal or regional anesthesia may be administered to
block pain impulses from the legs or abdomen. Spinal
anesthesia involves administering a local anesthetic into
the epidural space or the cerebrospinal fluid in the
subarachnoid space at an appropriate level, blocking all
nerve conduction at and below that level.
General anesthesia involves administering a gas to be
inhaled such as nitrous oxide or injecting a barbiturate
such as sodium pentothal intravenously. Although effec-
tive, these particular anesthetics are no longer widely
used. The barbiturate anesthetics have been replaced with
a nonbarbiturate drug, propofol. The gas nitrous oxide
has been widely replaced by sevoflurane, which is dis-
placed from the lungs more rapidly, leading to a more
rapid emergence from the anesthetic effects. Loss of
consciousness usually accompanies the use of a general
anesthetic. Analgesics are often used in combination with
these drugs. Neuroleptanesthesia is a type of general
anesthesia in which the patient can respond to commands
but is relatively unaware of the procedure or of any
discomfort. For example, diazepam can be administered
intravenously in combination with a narcotic analgesic
such as meperidine or morphine. Droperidol (a neuro-
leptic) and fentanyl (a narcotic analgesic) form a popular
combination (eg, Innovar) that is administered by
intravenous or intramuscular injection.
Chapter 5 for more information on inflammation and
drugs). In addition, these drugs possess antipyretic action,
lowering body temperature in case of fever. Even in high
doses, this group of drugs is not effective for severe pain.
For moderate pain, codeine is commonly used, either
alone or, more frequently, in combination with acetamino-
phen or aspirin. Codeine is a narcotic, a morphine
derivative, acting at the opiate receptors in the central
nervous system. Codeine exhibits some adverse effects,
causing nausea, constipation, and, in high doses, respira-
tory depression. Taking the drug with food or milk reduces
gastric irritation. Another choice is oxycodone, a synthetic
narcotic combined with acetaminophen or aspirin (Per-
cocet or Percodan). This drug affects the perception of
pain and emotional response, promoting relaxation and
a sense of well-being, predisposing to dependency.
Oxycodone abuse has become a significant problem (see
Chapter 27).
For severe pain, morphine, hydromorphone, or other
narcotics are favored. These drugs block the pain path-
ways in the spinal cord and brain and also alter the
perception of pain in a positive manner. In long-term
use, tolerance often develops, requiring a higher dose to
be effective or an alternative drug. Narcotics have a
number of adverse effects, such as the potential for
addiction with long-term use. However, addiction does
not always develop, and in most cases it is more important
to ensure that pain is managed effectively. Meperidine
is helpful for short-term pain, but its brief duration of
action as well as continuous usage results in a buildup
of a toxic metabolite, which negates its effectiveness in
treating severe chronic pain.
Sedatives and antianxiety drugs (minor tranquilizers
such as lorazepam) are popular adjuncts to analgesic
therapy because they promote rest and relaxation and
reduce the dosage requirement for the analgesic. The
muscle relaxation that is a side effect of the medication
is also helpful in relieving or preventing muscle spasm
associated with pain.
In patients with chronic and increasing pain, such as
occurs in some cases of cancer, pain management requires
a judicious choice of drugs used in a stepwise fashion
to maximize the reduction of pain. Usually tolerance to
narcotic drugs develops in time, requiring an increase
in dosage to be effective. Eventually a new drug may be
required.
Many patients with severe pain administer their own
medications as needed, using patient-controlled analgesia
(PCA). Small pumps are attached to vascular access sites,
and the patient either receives a dose of analgesic such
as morphine when needed or maintains a continuous
infusion. This has been a highly successful approach and
has been found to lessen the overall consumption of
narcotics.
Other pain control methods may accompany the use
of medications. Pain management clinics offer a variety
of therapeutic modalities for the individual. Such measures

CHAPTER 4 Pain 63
TABLE 4.3 Anesthetics
Type Example Effects Purpose
1. Local anesthetic Lidocaine; injected or topical; may add
epinephrine
Blocks nerve conduction
(sensory) in a peripheral
nerve
Removal of a skin lesion; tooth
extraction
2. General anesthetic Intravenous—propofol, thiopental
sodium; inhalation (gas)—sevoflurane,
nitrous oxide
Affects brain—partial or
total loss of
consciousness
General surgery, no pain/
awareness when combined
with analgesic
3. Relative or
neuroleptanesthesia
Diazepam or droperidol Can respond to questions
or commands
Can allow surgeon to assess his
or her progress immediately
through the patient response
4. Spinal anesthesia Local anesthetic injected into
subarachnoid or epidural space
around lower spinal cord
Blocks nerve conduction
(sensation) at and below
level of injection
Surgery on lower part of body:
labor and delivery
CASE STUDY A
Acute Pain
L.Y. is a healthy 13-year-old who had all her wisdom teeth removed
6 hours ago and is experiencing significant pain. She has been
prescribed acetaminophen and codeine for pain relief and is at
home recovering. Her mother wants her to rest and stop text-
messaging her friends about her dental surgery.
1. How do acetaminophen and codeine act to reduce pain?
What is a side effect of high levels of each drug? Why has
the dentist prescribed only a limited supply of the
medication?
2. How does L.Y.’s text-messaging behavior affect her
perception of pain?
3. Does L.Y. need to rest in bed quietly to reduce pain?
4. L.Y. becomes increasingly irritated with her mother and
tells her to “get off my case.” How does L.Y.’s stress affect
pain perception?
CASE STUDY B
Chronic Pain
Ms. J. is a 30-year-old healthy single mother with two children.
She has worked as a paramedic in her community for 6 years.
She and her partner responded to a call involving a man who
had been drinking heavily at a family party and who was partially
conscious. When she and her partner attempted to transfer the
100-kg man to a stretcher, the man grabbed her neck, causing
her severe pain. Ms. J.’s doctor diagnosed a spinal injury and
completed papers that would permit Ms. J. to be absent from
work. He recommended rest and the application of heat and
cold to the neck. One week later, Ms. J. saw him again and
reported continuing pain. She was referred to a specialist who
told her she had a herniated disc in the cervical area of her neck
and would require ongoing care and rehabilitation. Ms. J. has
been on disability leave for 6 months, during which she has
continued to have severe neck, jaw, and back pain. She takes
acetaminophen with codeine as required and sees a physio-
therapist and a registered massage therapist routinely in an
attempt to control chronic pain. She is worried that her disability
benefits will cease before she can return to work and has incurred
debts during her leave. She also finds it difficult to care for her
two children and keep the house clean.
1. What factors are significant in Ms. J.’s perception of pain?
How might each be reduced?
2. Why has Ms. J.’s doctor not prescribed stronger narcotic
medication?
3. Why does Ms. J. experience pain in her jaw and lower back
when the injury was to her neck?
4. Where in the pain pathway do massage therapy and
physiotherapy act to alleviate pain?
5. Ms. J. is concerned about maintaining her physical fitness
and decides to attend exercise classes in her community
pool. She finds this gives her more energy and reduces her
pain. How does appropriate exercise affect pain
perception? What precautions does Ms. J. need to observe
when exercising?
6. Ms. J. hears about acupuncture as a help for back pain and
does some research on the Internet before making an
appointment for treatment. How could acupuncture act to
block impulses for pain?
7. After 8 months, Ms. J. is cleared to return to work on a
part-time basis, which she manages well. Why does she
not return to full-time work immediately?
8. What can Ms. J. expect in the future as a result of
this injury?
C H A P T E R S U M M A R Y
Pain serves as one of the body’s defense mechanisms,
resulting from stimulation of nociceptors by ischemia,
chemical mediators, or distention of tissue.
• The pain pathway may be interrupted at many points,
including the receptor site, a peripheral nerve, the
spinal cord, or the brain.
• The gate control theory recognizes the role of synapses
serving as open or closed gates at points in the pain
pathway in the central nervous system. These gates
may close under the influence of natural endorphins

64 SECTION I Pathophysiology: Background and Overview
person with chronic pain is often fatigued and
depressed.
• There are many types of headaches, among them
tension, sinus, and migraine, each with different
characteristics.
• Analgesics are rated for the severity of pain controlled
by the drug—for example, aspirin for mild pain and
morphine for severe pain.
• Anesthesia may be classified as local, spinal or regional,
or general.
or other stimuli, thus inhibiting the passage of pain
impulses to the brain.
• Descriptions of pain are subjective evaluations by an
individual.
• Referred pain occurs when an individual locates the
pain at a site other than the actual origin.
• An individual’s perception of and response to pain
depend on prior conditioning and experiences.
• Acute pain is usually sudden and severe but short
term. Chronic pain is milder but long lasting. The
S T U D Y Q U E S T I O N S
1. Describe the characteristics and role of each of the
following in the pain pathway:
a. nociceptor
b. C fibers
c. spinothalamic tract
d. parietal lobe
e. reticular formation
f. endorphins and enkephalins
2. Define and give an example of referred
pain.
3. Differentiate the characteristics of acute and
intractable pain.
4. List several factors that can alter the perception of
pain and the response to pain.
5. Briefly describe six possible methods of pain
control.

65
Inflammation and Healing
S E C T I O N II
Defense/Protective Mechanisms
Review of Body Defenses
Review of Normal Capillary Exchange
Physiology of Inflammation
Definition
Causes
Steps of Inflammation
Acute Inflammation
Pathophysiology and General
Characteristics
Local Effects
Systemic Effects
Diagnostic Tests
Potential Complications
Chronic Inflammation
Pathophysiology and General
Characteristics
Potential Complications
Treatment of Inflammation
Drugs
First Aid Measures
Other Therapies
Healing
Types of Healing
Healing Process
Factors Affecting Healing
Complications due to Scar Formation
Loss of Function
Contractures and Obstructions
Adhesions
Hypertrophic Scar Tissue
Ulceration
Example of Inflammation and Healing
Burns
Classifications of Burns
Effects of Burn Injury
Healing of Burns
Children and Burns
Case Studies
Chapter Summary
Study Questions
C H A P T E R O U T L I N E
After studying this chapter, the student is expected to:
1. Explain the role of normal defenses in preventing disease.
2. Describe how changes in capillary exchange affect the
tissues and the blood components.
3. Compare normal capillary exchange with exchange during
the inflammatory response.
4. Describe the local and systemic effects of inflammation.
5. Explain the effects of chronic inflammation.
6. Discuss the modes of treatment of inflammation.
7. Describe the types of healing and the disadvantages of
each.
8. List the factors, including a specific example for each, that
hasten healing.
9. Identify the classifications of burns, and describe the
effects of burns.
10. Describe the possible complications occurring in the first
few days after a burn.
11. Explain three reasons why the healing of a burn may be
difficult.
L E A R N I N G O B J E C T I V E S
C H A P T E R 5

66 SECTION II Defense/Protective Mechanisms
Skin and
mucous
membrane
PATHOGENS OR INJURIOUS AGENTS
NONSPECIFIC
DEFENSES
Fluids—tears,
saliva, mucus,
gastric acid
Barriers
SPECIFIC DEFENSES
ALL DEFENSES OVERCOME
Phagocytosis
Interferon
Inflammatory
response
Immune
response
Cell-mediated
and humoral
INJURY
OR
DISEASE
FIG. 5.1 Defense mechanisms in the body.
abscess
adhesions
angiogenesis
anorexia
chemical mediators
chemotaxis
collagen
contracture
diapedesis
erythrocyte sedimentation
rate
exudate
fibrinogen
fibrinous
fibroblast
glucocorticoids
granulation tissue
granuloma
hematocrit
hematopoiesis
hyperemia
interferons
intraarticular
isoenzymes
leukocyte
leukocytosis
macrophage
malaise
neutrophil
perforation
permeability
phagocytosis
purulent
pyrexia
pyrogens
regeneration
replacement
resolution
scar
serous
stenosis
ulcer
vasodilation
K E Y T E R M S
Review of Body Defenses
Defense mechanisms used by the body to protect itself
from any injurious agent may be specific or nonspecific.
These mechanisms of defenses are generally divided into
three successive lines of defense:
• First Line of Defense: One nonspecific or general defense
mechanism is a mechanical barrier such as skin or
mucous membrane that blocks entry of bacteria or
harmful substances into the tissues (Fig. 5.1). Associated
with these mechanical barriers are body secretions
such as saliva or tears that contain enzymes or chemi-
cals that inactivate or destroy potentially damaging
material.
• Second Line of Defense: This category includes the non-
specific processes of phagocytosis and inflammation.

CHAPTER 5 Inflammation and Healing 67
movement of fluid, carbon dioxide, and other wastes
into the blood. Excess fluid and any proteins are recovered
from the interstitial area by way of the lymphatic system
and eventually returned to the general circulation.
Physiology of Inflammation
The inflammatory response is a protective mechanism
and an important basic concept in pathophysiology.
Inflammation is a normal defense mechanism in the body
and is intended to localize and remove an injurious agent.
You have probably observed the inflammatory process
resulting from a cut, an allergic reaction, an insect bite,
an infection, or a small burn on the body. The general
signs and symptoms of inflammation serve as a warning
of a problem, which may be hidden within the body.
Inflammation is not the same as infection, although
infection is one cause of inflammation. With infection,
microorganisms present at the site cause the inflammation.
The microbe can be identified and appropriate treatment
instituted to reduce the infection, and the inflammation
will then subside. When inflammation is caused by an
allergy or a burn, no microbes are usually present unless
the burn results in an open lesion, which can then be
infected by microorganisms.
Definition
Inflammation is the body’s nonspecific response to tissue
injury, resulting in redness, swelling, warmth, pain, and
sometimes a loss of function. Disorders are named using
the ending -itis for inflammation. The root word is usually
a body part or tissue—for example, pancreatitis, appen-
dicitis, laryngitis, or ileitis.
Phagocytosis is the process by which neutrophils
(a leukocyte) and macrophages randomly engulf
and destroy bacteria, cell debris, or foreign matter
(Fig. 5.2). Inflammation involves a sequence of events
intended to limit the effects of injury or a dangerous
agent in the body. Interferons are nonspecific agents
that protect uninfected cells against viruses (see
Chapter 6).
• Third Line of Defense: This is the specific defense
mechanism in the body (see Chapter 7). It provides
protection by stimulating the production of unique
antibodies or sensitized lymphocytes following expo-
sure to specific substances. Much effort has been
expended on research on the immune system in an
effort to increase understanding of the process of the
immune response and to create ways to strengthen
this defense mechanism.
APPLY YOUR KNOWLEDGE 5.1
Predict three ways that the normal defense systems in the body
can fail.
APPLY YOUR KNOWLEDGE 5.2
Predict three factors that can change and interfere with normal
capillary exchange.
Review of Normal Capillary Exchange
Usually all capillaries are not open in a particular capillary
bed unless the cells’ metabolic needs are not being met
by the blood supply to the area, or an accumulation of
wastes (by-products of metabolism) occurs. Precapillary
sphincters composed of smooth muscle restrict blood
flow through some channels. Movement of fluid, elec-
trolytes, oxygen, and nutrients out of the capillary at the
arteriolar end is based on the net hydrostatic pressure.
See Chapter 2 and Fig. 2.1 for a detailed explanation of
fluid shifts between body compartments. The net hydro-
static pressure is based on the difference between the
hydrostatic pressure within the capillary (essentially
arterial pressure) as compared with the hydrostatic pres-
sure of the interstitial fluid in the tissues as well as the
relative osmotic pressures in the blood and interstitial
fluid (see Fig. 5.2). Differences in concentrations of dis-
solved substances in the blood and interstitial fluid
promote diffusion of electrolytes, glucose, oxygen, and
other nutrients across the capillary membrane. Blood
cells and plasma proteins (albumin, globulin, and fibrino-
gen) normally remain inside the capillary.
At the venous end of the capillary, hydrostatic pressure
is decreased due to the previous movement of fluid into
the interstitial fluid space, and osmotic pressure in the
vessels is relatively high because plasma proteins remain
within the capillaries. This arrangement facilitates the
THINK ABOUT 5.1
a. What term would indicate inflammation of the stomach?
The liver? The large intestine? A tendon?The heart muscle?
b. Explain the relationship between inflammation and
infection.
Causes
Inflammation is associated with many different types of
tissue injury. Causes include direct physical damage such
as cuts or sprains, caustic chemicals such as acids or
alkali, ischemia or infarction, allergic reactions, extremes
of heat or cold, foreign bodies such as splinters or glass,
and infection.
Steps of Inflammation
An injury to capillaries and tissue cells will result in the
following reactions (Fig. 5.5, presented later in the chapter).
• Bradykinin is released from the injured cells.
• Bradykinin activates pain receptors.

68 SECTION II Defense/Protective Mechanisms
INFLAMMATION
1. Injury
3. Vasodilation – increased blood flow
Leukocyte
Chemotaxis
5. Leukocytes move
to site of injury
6. Phagocytosis – removal of debris in
preparation for healing
4. Increased
capillary
permeability
Protein and water leave
capillary – form exudate
Water
F
A
G
G
A
FF
A
Water,
electrolytes,
and protein
Macrophage engulfs debris Phagocytosis
+
2. Cells release chemical mediators
H
B
H
B
PG
Precapillary sphincter
Open capillary
Closed capillary
NORMAL
Arteriole
Venule
3. Cells remain in blood
Protein remains in blood
Water, electrolytes,
glucose into
interstitial fluid
2. Normal fluid shift
F
A
A
G = Globulin
A = Albumin
= Blood Cell
F = Fibrinogen PG = Prostaglandin
H = Histamine
B = Bradykinin
G
1. Blood flow
A
FIG. 5.2 Comparison of normal capillary exchange and the inflammatory response.

CHAPTER 5 Inflammation and Healing 69
arachidonic acid in mast cells before release and, therefore,
are responsible for the later effects, prolonging the inflam-
mation. Many of these chemicals also intensify the effects
of other chemicals in the response. Many antiinflammatory
drugs and antihistamines reduce the effects of some of
these chemical mediators.
Although nerve reflexes at the site of injury cause
immediate transient vasoconstriction, the rapid release
of chemical mediators results in local vasodilation
(relaxation of smooth muscle causing an increase in the
diameter of arterioles), which causes hyperemia, increased
blood flow in the area. Capillary membrane permeability
also increases, allowing plasma proteins to move into
the interstitial space along with more fluid (see Fig. 5.2).
The increased fluid dilutes any toxic material at the site,
while the globulins serve as antibodies, and fibrinogen
forms a fibrin mesh around the area in an attempt to
localize the injurious agent. Any blood clotting will also
provide a fibrin mesh to wall off the area. Vasodilation
and increased capillary permeability make up the vascular
response to injury.
During the cellular response, leukocytes are attracted
by chemotaxis to the area of inflammation as damaged
cells release their contents. Several chemical mediators
at the site of injury act as potent stimuli to attract leu-
kocytes. Leukocytes and their functions are summarized
in Table 5.2. First neutrophils (polymorphonuclear leu-
kocytes [PMNs]) and later monocytes and macrophages
collect along the capillary wall and then migrate out
through wider separations in the wall into the interstitial
area. This movement of cells is termed diapedesis. There
the cells destroy and remove foreign material, microorgan-
isms, and cell debris by phagocytosis, thus preparing
the site for healing. When phagocytic cells die at the site,
lysosomal enzymes are released and damage the nearby
cells, prolonging inflammation. If an immune response
• Sensation of pain stimulates mast cells and basophils
to release histamine.
• Bradykinin and histamine cause capillary dilation.
• This results in an increase of blood flow and
increased capillary permeability.
• Break in skin allows bacteria to enter the tissue.
• This results in the migration of neutrophils and
monocytes to the site of injury.
• Neutrophils phagocytize bacteria.
• Macrophages leave the bloodstream and phagocytose
microbes.
Acute Inflammation
Pathophysiology and General Characteristics
The inflammatory process is basically the same regardless
of the cause. The timing varies with the specific cause.
Inflammation may develop immediately and last only a
short time, it may have a delayed onset (eg, a sunburn),
or it may be more severe and prolonged. The severity
of the inflammation varies with the specific cause and
duration of exposure.
When tissue injury occurs, the damaged mast cells
and platelets release chemical mediators including
histamine, serotonin, prostaglandins, and leukotrienes
into the interstitial fluid and blood (Table 5.1). These
chemicals affect blood vessels and nerves in the damaged
area. Cytokines serve as communicators in the tissue
fluids, sending messages to lymphocytes and macro-
phages, the immune system, or the hypothalamus to
induce fever.
Chemical mediators such as histamine are released
immediately from granules in mast cells and exert their
effects at once. Other chemical mediators such as leu-
kotrienes and prostaglandins must be synthesized from
TABLE 5.1 Chemical Mediators in the Inflammatory Response
Chemical Source Major Action
Histamine Mast cell granules Immediate vasodilation and increased capillary permeability to
form exudate
Chemotactic factors Mast cell granules For example, attract neutrophils to site
Platelet-activating
factor (PAF)
Cell membranes of platelets Activate neutrophils
Platelet aggregation
Cytokines (interleukins,
lymphokines)
T lymphocytes,
macrophages
Increase plasma proteins, erythrocyte sedimentation rate
Induce fever, chemotaxis, leukocytosis
Leukotrienes Synthesis from arachidonic
acid in mast cells
Later response: vasodilation and increased capillary permeability,
chemotaxis
Prostaglandins (PGs) Synthesis from arachidonic
acid in mast cells
Vasodilation, increased capillary permeability, pain, fever,
potentiate histamine effect
Kinins (eg, bradykinin) Activation of plasma protein
(kinogen)
Vasodilation and increased capillary permeability, pain,
chemotaxis
Complement system Activation of plasma protein
cascade
Vasodilation and increased capillary permeability, chemotaxis,
increased histamine release

70 SECTION II Defense/Protective Mechanisms
(see Chapter 7) or blood clotting occurs, these processes
also enhance the inflammatory response.
As excessive fluid and protein collects in the interstitial
compartment, blood flow in the area decreases as swelling
leads to increased pressure on the capillary bed, and
fluid shifts out of the capillary are reduced. Severely
reduced blood flow can decrease the nutrients available
to the undamaged cells in the area and prevent the
removal of wastes. This may cause additional damage
to the tissue.
There are numerous naturally occurring defense or
control mechanisms that inactivate chemical mediators
and prevent the unnecessary spread or prolongation
of inflammation. These include substances such as
resolvins, which are metabolites of polyunsaturated
omega-3 fatty acids, and lipoxins, which are derived from
arachidonic acid.
THINK ABOUT 5.2
a. List the local signs and symptoms of inflammation.
b. Consider the last time you experienced tissue injury.
Describe the cause of the injury and how inflammation
developed.
B
A
FIG. 5.3 A, Erysipelas (cellulitis). B, Erysipelas of the face caused
by group A Streptococcus. (A From Lookingbill D, Marks J: Principles
of Dermatology, ed 3, Philadelphia, 2000, WB Saunders. B From Mahon
CR, Lehman DC, Manuselis G: Textbook of Diagnostic Microbiology,
ed 3, St. Louis, 2007, Saunders.)
TABLE 5.2 Function of Cellular Elements in the
Inflammatory Response
Leukocytes Activity
Neutrophils Phagocytosis of microorganisms
Basophils Release of histamine leading to
inflammation
Eosinophils Numbers are increased in allergic
responses
Lymphocytes Activity
T lymphocytes Active in cell-mediated immune
response
B lymphocytes Produce antibodies
Monocytes Phagocytosis
Macrophages Active in phagocytosis; these are
mature monocytes that have
migrated into tissues from the blood
Local Effects
The cardinal signs of inflammation are redness (rubor or
erythema), heat, swelling, and pain:
• Redness and warmth are caused by increased blood
flow into the damaged area (Fig. 5.3).
• Swelling or edema is caused by the shift of protein
and fluid into the interstitial space.
• Pain results from the increased pressure of fluid on
the nerves, especially in enclosed areas, and by the
local irritation of nerves by chemical mediators such
as bradykinins.
• Loss of function may develop if the cells lack nutrients
or swelling interferes mechanically with function, as
happens in restricted joint movement.
Exudate refers to a collection of interstitial fluid formed
in the inflamed area. The characteristics of the exudate
vary with the cause of the trauma:
• Serous or watery exudates consist primarily of fluid
with small amounts of protein and white blood cells.
Common examples of serous exudates occur with
allergic reactions or burns.
• Fibrinous exudates are thick and sticky and have a
high cell and fibrin content. This type of exudate
increases the risk of scar tissue in the area.
• Purulent exudates are thick, yellow-green in color,
and contain more leukocytes and cell debris as well
as microorganisms. Typically, this type of exudate

CHAPTER 5 Inflammation and Healing 71
production mechanisms such as shivering are activated
to increase cell metabolism. Involuntary cutaneous
vasoconstriction characterized by pallor and cool skin
reduces heat loss from the body. Voluntary actions such
as curling up or covering the body conserve heat. These
mechanisms continue until the body temperature reaches
the new, higher setting. Following removal of the cause,
body temperature returns to normal by reversing the
mechanisms.
indicates bacterial infection, and the exudate is often
referred to as pus.
• An abscess is a localized pocket of purulent exudate
or pus in a solid tissue (eg, around a tooth or in the
brain).
• A hemorrhagic exudate may be present if blood vessels
have been damaged.
Systemic Effects
Other general manifestations of inflammation include
mild fever, malaise (feeling unwell), fatigue, headache,
and anorexia (loss of appetite).
Fever or pyrexia (low grade or mild) is common if
inflammation is extensive. If infection has caused the
inflammation, fever can be severe, depending on the
particular microorganism. However, high fever can be
beneficial if it impairs the growth and reproduction of
a pathogenic organism. Fever results from the release of
pyrogens, or fever-producing substances (eg, interleukin-1),
from white blood cells (WBCs), or from macrophages
(Fig. 5.4). Pyrogens circulate in the blood and cause
the body temperature control system (the thermostat) in
the hypothalamus to be reset at a higher level. Heat
B
O
D
Y
T
E
M
P
E
R
A
T
U
R
E
TEMPERATURE CONTROL IN HYPOTHALAMUS
BODY TEMPERATURE
TIME
Normal
Fever
3. Body responses
that increase
body temperature
• Shiver (chills)
• Vasoconstriction
in skin (pallor)
• Increased BMR
• Increased heart rate
• Curl up body
8. Body returns
to normal
temperature
2. Reset hypothalamic
control high
1. Release of pyrogens
in circulation
4. Body reaches new
high temperature
• Feel warm
7. Body
responses
that increase
heat loss
• Vasodilation
• Sweating
• Lethargy
• Extend body
5. Treatment to
remove pyrogens
6. Reset
hypothalamus
to normal
FIG. 5.4 The course of a fever.
THINK ABOUT 5.3
a. What physiologic changes occur when the cause of a fever
is removed?
b. Explain the differences among serous, fibrinous, and
purulent exudates.
Diagnostic Tests
Refer to the normal values shown on the inside front cover
of this book.
Leukocytosis (increased white blood cells in the blood),
elevated serum C-reactive protein (CRP), an elevated
erythrocyte sedimentation rate (ESR), and increased

72 SECTION II Defense/Protective Mechanisms
The amount of necrosis that occurs depends on the
specific cause of the trauma and the factors contributing
to the inflammatory response. Extensive necrosis may
lead to ulcers or erosion of tissue. For example, gingivitis
or stomatitis in the oral cavity often leads to painful
ulcerations in the mouth, and inflammation in the stomach
may result in peptic ulcers.
plasma proteins and cell enzymes in the serum are
nonspecific changes (Table 5.3); they do not indicate the
particular cause or site of inflammation. They provide
helpful screening and monitoring information when a
problem is suspected or during treatment. In patients
with leukocytosis, there is often an increase in immature
neutrophils, commonly referred to as “a shift to the left.”
A differential count (the proportion of each type of WBC)
may be helpful in distinguishing viral from bacterial
infection. Allergic reactions commonly produce eosino-
philia. Examination of a peripheral blood smear may
disclose significant numbers of abnormal cells, another
clue as to the cause of a problem. Increased circulating
plasma proteins (fibrinogen, prothrombin, and alpha-
antitrypsin) result from an increase in protein synthesis
by hepatocytes.
Specific enzymes may be elevated in the blood in the
presence of severe inflammation and necrosis. Some of
the enzymes are not tissue specific. For example, aspartate
aminotransferase (AST, formerly serum glutamic-
oxaloacetic transaminase [SGOT]) is elevated in liver
disease and in the acute stage of a myocardial infarction
(heart attack). However, the isoenzyme of creatine kinase
with myocardial component (CK-MB) is specific for
myocardial infarction. The enzyme alanine aminotrans-
ferase (ALT) is specific for the liver.
If the cause of the inflammatory response is a brief
exposure to a damaging agent—for instance, touching
a hot object—the response often subsides in approximately
48 hours. Vascular integrity is regained, and excess
fluid and protein are recovered by the lymphatic capil-
laries and returned to the general circulation. The mani-
festations of inflammation gradually decrease. Otherwise
inflammation persists until the causative agent is removed
(Fig. 5.5).
TABLE 5.3 Changes in the Blood With Inflammation
Leukocytosis Increased numbers of white blood
cells, especially neutrophils
Differential count Proportion of each type of white
blood cell altered, depending on the
cause
Plasma proteins Increased fibrinogen and prothrombin
C-reactive protein A protein not normally in the blood,
but appears with acute
inflammation and necrosis within
24–48 hours
Increased
erythrocyte
sedimentation
rate
Elevated plasma proteins increase the
rate at which red blood cells settle
in a sample
Cell enzymes Released from necrotic cells and
enter tissue fluids and blood: may
indicate the site of inflammation
THINK ABOUT 5.4
a. Describe three differences between acute and chronic
inflammation.
b. Describe three changes in the blood with acute
inflammation.
Potential Complications
Local complications depend on the site of inflammation.
For example, inflammation in the lungs may impair
the expansion of the lungs, decreasing the diffusion of
oxygen. Inflammation of a joint may affect its range of
movement.
Infection may develop in an inflamed tissue because
microorganisms can more easily penetrate when the skin
or mucosa is damaged and the blood supply is impaired
(see Fig. 5.14, presented later). Foreign bodies often
introduce microbes directly into the tissue. Some microbes
resist phagocytosis, and the inflammatory exudate itself
provides an excellent medium for microorganisms to
reproduce and colonize the inflamed area.
Skeletal muscle spasms or strong muscle contractions
may be initiated by inflammation resulting from
musculoskeletal injuries such as sprains, tendinitis, or
fractures. A spasm is likely to force the bones of a joint
out of normal alignment, thus causing additional pressure
on the nerves and increasing the pain.
Chronic Inflammation
Chronic inflammation may develop following an acute
episode of inflammation when the cause is not completely
eradicated. Or inflammation may develop insidiously
owing to chronic irritation such as smoking, certain
bacteria, or long-term abnormal immune responses.
Pathophysiology and General Characteristics
Characteristics of chronic inflammation include less
swelling and exudate but the presence of more lympho-
cytes, macrophages, and fibroblasts (connective tissue
cells) than in acute inflammation. Frequently more tissue
destruction occurs with chronic inflammation. More
collagen is produced in the area, resulting in more fibrous
scar tissue forming. A granuloma, a small mass of cells
with a necrotic center and covered by connective tissue,
may develop around a foreign object such as a splinter

CHAPTER 5 Inflammation and Healing 73
Treatment of Inflammation
Drugs
Acetylsalicylic acid (aspirin, ASA) has long been used
as an antiinflammatory agent, sometimes in very large
doses (Table 5.4). This drug decreases prostaglandin
synthesis at the site of inflammation, reducing the inflam-
matory response. Acetylsalicylic acid reduces pain
(analgesic effect) and fever (antipyretic effect), which are
often helpful. However, ASA is never recommended for
children with viral infections, because the combination
of ASA and a viral infection is believed to contribute to
the development of Reye syndrome, a serious complication
TISSUE
INJURY
VASODILATION
AND INCREASED
BLOOD FLOW
(hot, red)
INCREASED
CAPILLARY PERMEABILITY
(edema, pain)
RELEASE OF CHEMICAL MEDIATORS
(histamine, kinins, prostaglandins)
Clot and fibrin mesh
walls off area
REGENERATION
(replacement by
same type of cell)
SCAR TISSUE (fibrosis) RESOLUTION
(damaged cells
recover)
CHRONIC INFLAMMATION
PREPARATION FOR HEALING
Phagocytosis
(remove cause
and cell debris)
CHEMOTAXIS
(WBCs to area)
IRRITATION OF
NERVE ENDINGS
(pain)
HEALING
ACUTE
INFLAMMATION
If cause persists
FIG. 5.5 The course of inflammation and healing.
or as part of the immune response in some infections
such as tuberculosis.
Potential Complications
Disorders such as rheumatoid arthritis are characterized
by chronic inflammation with periodic exacerbations of
acute inflammation. Deep ulcers may result from severe
or prolonged inflammation because cell necrosis and lack
of cell regeneration cause erosion of tissue. This in turn
can lead to complications such as perforation (erosion
through the wall) of viscera or the development of
extensive scar tissue.

74 SECTION II Defense/Protective Mechanisms
required. Ibuprofen has been recommended for many
disorders, including menstrual pain and headache. The
side effects are similar to those of aspirin but are less
severe. These drugs are available as oral medications,
and some, such as ibuprofen, are available in small doses
without a prescription.
A newer type of NSAID is celecoxib (Celebrex), which
appears to be effective without unwanted effects on the
stomach. This group of drugs (cyclooxygenase-2 [COX-2]
inhibitors) is currently under further investigation fol-
lowing the withdrawal from the market of one drug in
this class (rofecoxib, Vioxx). This followed reports of
serious side effects such as an increased incidence of
heart attacks. This is an example of the necessity for
long-term data collection from a large population to
determine all the facts about new drugs or medical
procedures.
Corticosteroids or steroidal antiinflammatory drugs
are synthetic chemicals that are related to the naturally
occurring glucocorticoids (hydrocortisone), hormones
produced by the adrenal cortex gland in the body (see
Chapter 16). These drugs are extremely valuable in the
short-term treatment of many disorders, but they also
have significant undesirable effects that may affect health
care.
The beneficial antiinflammatory effects of glucocorti-
coids include the following:
• Decreasing capillary permeability and enhancing the
effectiveness of the hormones epinephrine and nor-
epinephrine in the system; thus, the vascular system
is stabilized
• Reducing the number of leukocytes and mast cells at
the site, decreasing the release of histamine and
prostaglandins
• Blocking the immune response, a common cause of
inflammation
involving the brain and liver, which may be fatal. Many
individuals are allergic to ASA and similar antiinflam-
matory drugs. For others, the drug may cause irritation
and ulcers in the stomach. An enteric-coated tablet (the
tablet coating does not dissolve until it reaches the small
intestine) is available, as are drugs to reduce acid secretion
in the stomach to reduce this risk. Antiinflammatory
drugs also interfere with blood clotting by reducing
platelet adhesion, and therefore they cannot be used in
all conditions. Also it is usually necessary to discontinue
taking ASAs for 7 to 14 days before any surgical procedure
to prevent excessive bleeding.
Acetaminophen (Tylenol or Paracetamol) decreases
fever and pain but does not diminish the inflammatory
response.
TABLE 5.4 Comparison of Drugs Used to Treat Inflammation
Actions ASA Acetaminophen NSAID Glucocorticoid COX-2
Antiinflammatory Yes No Yes Yes Yes
Analgesia Yes Yes Yes No Yes
Antipyretic Yes Yes Yes No No
Adverse Effects
Allergya Yes No Yes No Yes
Delays blood clotting Yes No Yes No No
Risk of infection No No No Yes No
Gastrointestinal distress Yes No Yes Yes May occur
Stomach ulceration Yes No Yes Yes May occur
Edema or increased blood pressure No No No Yes May occur
Myocardial infarction or cerebrovascular accident No No No No May occur
Liver damage No No No No May occur
aNote that allergic reactions may occur with the administration of any drug.
THINK ABOUT 5.5
a. Based on your knowledge of the normal physiology of the
stomach, explain why intake of food or milk with a drug
reduces the risk of nausea and irritation of the stomach.
b. Why might an individual taking large quantities of
ASA need to be monitored for the presence of blood in
the feces?
Nonsteroidal antiinflammatory drugs (NSAIDs) such
as ibuprofen (Advil or Motrin), piroxicam (Feldene) or
diclofenac sodium (Arthrotec) are now used extensively
to treat many types of inflammatory conditions. These
drugs have antiinflammatory, analgesic, and antipyretic
activities. They act by reducing production of prosta-
glandins. They are used to treat inflammation in the
musculoskeletal system, both acute injuries and long-term
problems such as rheumatoid arthritis. Also, they have
become the treatment of choice for many dental proce-
dures when an analgesic and antiinflammatory are

CHAPTER 5 Inflammation and Healing 75
The chemical structure of the drug has been altered
slightly to enhance its antiinflammatory action and reduce
the other, less desirable effects of the hormone. These
drugs can be administered as oral tablets, creams and
ointments for topical application, or injections, both local
and systemic. Examples include prednisone (oral), tri-
amcinolone (topical), methylprednisolone (intraarticular—
into joint), dexamethasone (intramuscular [IM] or
intravenous [IV] injections), and beclomethasonedipro-
pionate (Beclovent [inhaler]).
However, with long-term use and high dosages of
glucocorticoids, marked side effects occur similar to
Cushing disease (see Chapter 16). These side effects (or
adverse effects) should be considered when taking a
medical history from a patient because they may com-
plicate the individual’s care.
The adverse effects of glucocorticoids include the
following:
• Atrophy of lymphoid tissue and reduced numbers of
WBCs, leading to an increased risk of infection and a
decreased immune response
• Catabolic effects (increased tissue breakdown with
decreased protein synthesis and tissue regeneration),
including osteoporosis (bone demineralization), muscle
wasting, and a tendency toward thinning and break-
down of the skin and mucosa (eg, peptic ulcer)
• Delayed healing
• Delayed growth in children
• Retention of sodium and water, often leading to high
blood pressure and edema
• Increases gluconeogenesis causing a rise in blood
sugar
THINK ABOUT 5.6
Explain why healing could be delayed in individuals taking
glucocorticoids over a long period of time.
One additional consideration with the long-term use of
steroids involves the effect of an increased intake of
glucocorticoids on the normal feedback mechanism in
the body, leading to a reduction of the normal secretion
of the natural hormones and atrophy of the adrenal gland.
Therefore a sudden cessation of the administration of
glucocorticoid drugs or the presence of increased stress
may cause an adrenal crisis (similar to shock) because
insufficient glucocorticoids are available in the body.
To lessen the risk of serious side effects, it is best to
limit use of glucocorticoids to minimal dosages in the
treatment of acute episodes. Intermittent drug-free time
periods (drug holidays) are recommended during long-
term therapy. Whenever the drug is discontinued, the
dosage should be gradually decreased over a period of
days to allow the body’s natural hormone secretions to
increase to normal levels. Adrenocorticotropic hormone
(ACTH) therapy is used for long-term therapy in some
patients because it stimulates the patient’s glands to
produce more cortisol. The risk of adrenal shock is less
because glandular atrophy does not occur.
A brief comparison of drugs used to treat inflammation
is shown in Table 5.4. Other drugs, such as analgesics
for pain, antihistamines, and antibiotics to prevent second-
ary infection may be required, depending on the cause
of the inflammation.
First Aid Measures
First aid directives for injury-related inflammation fre-
quently recommend the RICE approach:
• Rest
• Ice
• Compression
• Elevation
Cold applications are useful in the early stage of acute
inflammation. Application of cold causes local vasocon-
striction, thereby decreasing edema and pain. The use
of hot or cold applications during long-term therapy and
recovery periods depends on the particular situation. In
some instances, for example, acute rheumatoid arthritis,
heat, and moderate activity may improve the circulation
in the affected area, thereby removing excess fluid, pain-
causing chemical mediators, and waste metabolites, as
well as promoting healing.
Other Therapies
It is often helpful to keep an inflamed limb elevated to
improve fluid flow away from the damaged area. Com-
pression using elastic stockings or other supports may
reduce the accumulation of fluid.
Mild-to-moderate exercise is useful in cases of many
chronic inflammatory conditions in which improved blood
and fluid flow is beneficial and mobility could be
improved. Other treatment measures, including physio-
therapy or occupational therapy, may be necessary to
maintain joint mobility and reduce pain, although splints
may be required during acute episodes to prevent con-
tractures and fixed abnormal joint positions. Rest and
adequate nutrition and hydration are also important.
Healing
Types of Healing
Healing of a wound area can be accomplished in several
ways.
• Resolution is the process that occurs when there is
minimal tissue damage. The damaged cells recover,
and the tissue returns to normal within a short period
of time—for example, after a mild sunburn.
• Regeneration is the healing process that occurs in
damaged tissue in which the cells are capable of
mitosis. Some types of cells (eg, epithelial cells) are
constantly replicating, whereas other cells such as

76 SECTION II Defense/Protective Mechanisms
hepatocytes in the liver are able to undergo mitosis
when necessary. The damaged tissue is thus replaced
by identical tissue from the proliferation of nearby
cells. This type of healing may be limited if the orga-
nization of a complex tissue is altered. For instance,
sometimes fibrous tissue develops in the liver, distort-
ing the orderly arrangement of cells, ducts, and blood
vessels. Although nodules of new cells form, they do
not contribute to the overall function of the liver.
THINK ABOUT 5.7
a. Which types of cells can regenerate? Name three types
that cannot regenerate.
b. Explain why it is often advisable to elevate an
inflamed limb.
• Replacement by connective tissue (scar or fibrous tissue
formation) takes place when there is extensive tissue
damage or the cells are incapable of mitosis—for
example, the brain or myocardium. The wound area
must be filled in and covered by some form of tissue.
Chronic inflammation or complications such as infec-
tion result in more fibrous material.
Healing by first intention refers to the process involved
when the wound is clean, free of foreign material and
necrotic tissue, and the edges are held close together,
creating a minimal gap between the edges. This type of
healing is seen in some surgical incisions. Healing by
second intention refers to a situation in which there is a
large break in the tissue and consequently more inflam-
mation, a longer healing period, and formation of more
scar tissue. A compound fracture would heal in this
manner.
Healing Process
The process of tissue repair begins following injury when
a blood clot forms and seals the area. Inflammation
develops in the surrounding area (Fig. 5.6). After 3 to 4
days, foreign material and cell debris have been removed
by phagocytes, monocytes, and macrophages, and then
granulation tissue grows into the gap from nearby con-
nective tissue.
Granulation tissue is highly vascular and appears moist
and pink or red in color. It contains many new capillary
buds from the surrounding tissue. This tissue is fragile
and is easily broken down by microorganisms or stress
on the tissue (Fig. 5.7).
THINK ABOUT 5.8
What often happens if you pull a scab off a wound too early?
Describe the appearance of the tissue.
At the same time as the wound cavity is being filled
in, nearby epithelial cells undergo mitosis, extending across
the wound from the outside edges inward. Shortly,
fibroblasts and connective tissue cells enter the area and
produce collagen, a protein that is the basic component
of scar tissue and provides strength for the new repair.
Fibroblasts and macrophages produce growth factors
(cytokines) in the local area for the purpose of attracting
more fibroblasts, which act as mitogens to stimulate
epithelial cell proliferation and migration, and promote
development of new blood vessels (angiogenesis) in the
healing tissue.
Gradually cross-linking and shortening of the collagen
fibers promote formation of a tight, strong scar. The
capillaries in the area decrease, and the color of the scar
gradually fades. It is important to remember that scar
tissue is not normal, functional tissue, nor does it contain
any specialized structures such as hair follicles or glands.
It merely fills the defect or gap in the tissue. As scar
tissue matures over time, it gains strength, but it may
also contract, causing increased tension on normal tissues.
THINK ABOUT 5.9
a. Which would heal more rapidly, a surgical incision in
which the edges have been stapled closely together
or a large, jagged tear in the skin and subcutaneous
tissue? Why?
b. Even after a long period of healing, explain how the scar
tissue from a wound will be different from the surrounding
undamaged tissue.
One area of current research is tissue engineering, the
search for new methods of replacing damaged tissue
where regeneration is not possible—for example, extensive
burns, deep ulcers, or cardiac muscle death. Cells used
to populate the engineered tissue may be from a person’s
own stem cells, cord blood that has been stored, or a
stem cell line maintained by the laboratory. Research is
progressing, but no solid organs have yet been produced
and used in clinical practice to replace a damaged
organ. Ethical concerns regarding cost and access to
commercially produced organs are important and need
to be addressed before commencing therapies with this
technology.
Factors Affecting Healing
A small gap in the tissue results in complete healing
within a short period of time and with minimal
scar tissue formation. A large or deep area of tissue
damage requires a prolonged healing time and results
in a large scar.
Many factors can promote healing or delay the process
(Boxes 5.1 and 5.2).

CHAPTER 5 Inflammation and Healing 77
HEALING BY SECOND INTENTIONHEALING OF INCISED WOUND
BY FIRST INTENTION
1. Injury and
inflammation
2. Granulation tissue
and epithelial growth
3. Small scar
remains
Scab
Suture holds edges together
Blood clot
Inflammation
Neutrophils
Epithelial regeneration
Inflammation
Granulation tissue
begins to form
New capillaries
Macrophage
Fibroblast
Scar (fibrous)
tissue
1. Injury and
inflammation
2. Granulation tissue
and epithelial growth
3. Large scar
remains
Scab
Blood clot
Inflammation
Epithelial regeneration
Inflammation
Granulation tissue
and collagen
New capillary
Fibrous tissue contracts
Macrophage
Scar
A B
FIG. 5.6 The healing process.
• Advanced age, reduced mitosis
• Poor nutrition, dehydration
• Anemia (low hemoglobin)
• Circulatory problems
• Certain chronic diseases
• Presence of other disorders such as diabetes or cancer
• Irritation, bleeding, or excessive mobility
• Infection, foreign material, or exposure to radiation
• Chemotherapy treatment
• Prolonged use of glucocorticoids
BOX 5.2 Factors Delaying Healing
• Youth
• Good nutrition: protein, vitamins A and C
• Adequate hemoglobin
• Effective circulation
• Clean, undisturbed wound
• No infection or further trauma to the site
BOX 5.1 Factors Promoting Healing

78 SECTION II Defense/Protective Mechanisms
structures and may eventually cause distortion or twisting
of the tissue.
Hypertrophic Scar Tissue
An overgrowth of fibrous tissue consisting of excessive
collagen deposits may develop, leading to hard ridges
of scar tissue or keloid formation (Fig. 5.9). These masses
are disfiguring and frequently cause more severe con-
tractures. Skin and the underlying tissue may be pulled
out of the normal position by the shortening of the scar
tissue.
Ulceration
Blood supply may be impaired around the scar, resulting
in further tissue breakdown and possible ulceration. This
may occur when scar tissue develops in the stomach
following surgery or healing of an ulcer. This scar tissue
interferes with blood flow in nearby arteries.FIG. 5.7 An example of granulation tissue in a burn wound.
(Courtesy of Judy Knighton, clinical nurse specialist, Ross Tilley Burn
Center, Sunnybrook and Women’s College Health Center, Toronto,
Ontario, Canada.)
Complications Due to Scar Formation
Loss of Function
Loss of function results from the loss of normal cells and
the lack of specialized structures or normal organization
in scar tissue. For example, if scar tissue replaces normal
skin, that area will lack hair follicles, glands, and sensory
nerve endings. In a highly organized organ such as the
kidney, it is unlikely that the new tissue will fit the pattern
of blood vessels, tubules, and ducts of the normal kidney;
therefore the replacement tissue will not provide normal
function.
Contractures and Obstructions
Scar tissue is nonelastic and tends to shrink over time.
This process may restrict the range of movement of a
joint and eventually may result in fixation and deformity
of the joint, a condition known as contracture. Fibrous
tissue may also limit movement of the mouth or eyelids.
Physiotherapy or surgery may be necessary to break
down the fibrous tissue and improve mobility. Shrinkage
of the scar tissue may also cause shortening or narrowing
(stenosis) of structures, particularly tubes or ducts. For
example, if the esophagus is shortened, malposition of
the stomach (hiatal hernia) or a narrowed esophagus
causing obstruction during swallowing (Fig. 5.8) can
result.
Adhesions
Adhesions are bands of scar tissue joining two surfaces
that are normally separated. Common examples are
adhesions between loops of intestine (see Fig. 5.8B)
or between the pleural membranes. Such adhesions
usually result from inflammation or infection in the body
cavities. Adhesions prevent normal movement of the
THINK ABOUT 5.10
a. Describe three ways scar tissue on the thumb can
interfere with normal function.
b. Explain how the characteristics of scar tissue can actually
lead to new potential infections in the affected area.
Example of Inflammation and Healing
Burns
A burn is a thermal (heat) or nonthermal (electrical or
chemical) injury to the body, causing acute inflammation
and tissue destruction. Burns may be mild or cover only a
small area of the body, or they may be severe and life
threatening, as when an extensive area is involved. Burns
may be caused by direct contact with a heat source, such
as flames or hot water (a scald), or by chemicals, radiation,
electricity, light, or friction. Any burn injury causes an acute
inflammatory response and release of chemical mediators,
resulting in a major fluid shift, edema, and decreased blood
volume. Major burns constitute a medical emergency
requiring specialized care as quickly as possible.
The severity of the burn depends on the cause of the
burn, and the temperature, duration of the contact, as
well as the extent of the burn surface and the site of the
injury. The elderly have thinner skin; therefore they can
suffer much deeper burn injuries than younger adults.
Skin thickness varies over the body, with facial skin being
much thinner than the skin on the palms and soles. Thus,
facial burns are often more damaging than burns to the
soles of the feet.
THINK ABOUT 5.11
From your own experience and the information just given,
describe the appearance and sensation over time of a thermal
burn (eg, a burn resulting from touching a hot object).

CHAPTER 5 Inflammation and Healing 79
causing additional tissue destruction and scar tissue
formation.
• Third-degree burns (also known as full-thickness burns)
result in destruction of all skin layers and in cases of
fourth-degree burns, often underlying tissues as well
(Fig. 5.11, C). The burn wound area is coagulated or
charred and therefore is hard and dry on the surface.
This damaged tissue (eschar) shrinks, causing pressure
on the edematous tissue beneath it. If the entire cir-
cumference of a limb is involved, treatment (escha-
rotomy – surgical cuts through this crust) may be
necessary to release the pressure and allow better
circulation to the area. This procedure may also be
required when a large area of the chest is covered by
eschar, impairing lung expansion. Initially the burn
area may be painless because of the destruction of the
nerves, but it becomes very painful as adjacent tissue
becomes inflamed due to chemical mediators released
by the damaged tissues. Full-thickness burns require
skin grafts for healing because there are no cells avail-
able for the production of new skin. Many burn injuries
Classifications of Burns
Burns are classified by the depth of skin damage and
the percentage of body surface area involved (Fig. 5.10):
• First-degree burns (also known as superficial burns)
damage the epidermis and may involve the upper
dermis. They usually appear red and painful but heal
readily without scar tissue. Examples include sunburn
or a mild scald.
• Second-degree burns (also known as partial-thickness
burns) involve the destruction of the epidermis and
part of the dermis (Fig. 5.11). The area is red, edema-
tous, blistered, and often hypersensitive and painful
during the inflammatory stage. In severe cases, the
skin appears waxy with a reddened margin. The dead
skin gradually sloughs off, and healing occurs by
regeneration from the edges of the blistered areas and
from epithelium lining the hair follicles and glands.
If the area is extensive, healing may be difficult, and
complications occur. Grafts may be necessary to cover
larger areas. These burns easily become infected,
NORMALA
B NORMAL
Esophagus
Diaphragm
Stomach
Scar tissue
Stenosis/narrowing
Diaphragm
Hiatal hernia—
stomach pulled
above diaphragm
Scar tissue binds
loops of intestines
together
Intestine twisted
back to colon
FIG. 5.8 Effects of scar tissue. A, Esophageal scarring and obstruction. B, Adhesions and twisting
of the intestines.

80 SECTION II Defense/Protective Mechanisms
are mixed burns, consisting of areas of partial burns
mixed with full-thickness burns.
The percentage of body surface area (BSA) burned
provides a guideline for fluid replacement needs as well
as other therapeutic interventions. Complicated charts
are provided in burn treatment centers for the accurate
assessment of BSA. The rule of nines (Fig. 5.12) is a method
for rapid calculation. In this estimate, body parts are
assigned a value of nine or a multiple of nine. The head
and each arm are estimated at 9%. Each leg is calculated
at 18%. The anterior surface of the trunk is given a value
of 18%, and the posterior surface is also 18%. The groin
area at 1% brings the total BSA to 100%. The parts can
be subdivided also; for example, the distal part of the
arm (elbow to hand) accounts for 4.5% of the BSA. These
figures are approximations and can be revised; for
example, because a young child has a larger head and
shorter limbs than an adult, an adjustment is required.
The Lund and Browder chart provides a more detailed
calculation for children.
Minor burns to a small area can be treated in a physi-
cian’s office. Major burns, as classified by the American
Burn Association, are best treated in a center specializing
in burn wound care. Major burns include burns involving
a large surface area, young children, or the elderly;
burns to hands, feet, face, ears, or genitalia; inhalation
injury; chemical burns; or cases in which other injuries
or complications are present. Electrical injuries are
always considered serious because there is immediate
interference with the normal conduction of electrical
impulses in the body, often causing cardiac arrest, and
extensive unseen damage to blood vessels and organs.
(An electric current travels on the path of least resistance,
such as along the blood vessels, coagulating and obstruct-
ing blood supply.)
A
B
FIG. 5.9 Complications of scar tissue. A, Example of scar tissue
that may shrink and distort facial features in time. B, Example of
a keloid. (From Callen J, Greer K, Hood A, et al: Color Atlas of Dermatol-
ogy, Philadelphia, 1993, WB Saunders.)
Superficial burn
Redness
Partial-thickness burn
Blister
Full-thickness burn
FIG. 5.10 Depth of burns. The extent of involvement of skin layers. (From Frazier M, Dzymkowski
J: Essentials of Human Disease and Conditions, ed 6, St. Louis, 2016, Elsevier.)

CHAPTER 5 Inflammation and Healing 81
BA
C
FIG. 5.11 Examples of burns. A, Deep partial-thickness burn (note the blisters). B, Deep partial-
thickness burn (note the edema). C, Full-thickness burn (note the dark color). (All photos courtesy
of Judy Knighton, clinical nurse specialist, Ross Tilley Burn Center, Sunnybrook and Women’s College
Health Center, Toronto, Ontario, Canada.)

82 SECTION II Defense/Protective Mechanisms
Effects of Burn Injury
Serious burns have many effects, both local and systemic,
in addition to the obvious damage to the skin. The burn
wound is débrided during treatment, removing all foreign
material and damaged tissue, in preparation for healing.
A temporary covering is then applied.
Following is a brief description of additional effects,
to be expanded upon in subsequent chapters.
Shock
No bleeding occurs with a burn injury (tissue and blood
are coagulated or solidified by the heat). Under the burn
surface, an inflammatory response occurs. Where the
burn area is large, the inflammatory response results in
a massive shift of water, protein, and electrolytes into
the tissues, causing fluid excess or edema (see Chapter
2) (Fig. 5.13). Loss of water and protein from the blood
leads to decreased circulating blood volume, low blood
pressure, and hypovolemic shock (see Chapter 12), as
well as an increased hematocrit (the percentage of red
blood cells in a volume of blood) due to hemoconcentra-
tion. The fluid imbalance is aggravated by the protein
shift out of the capillaries and the resulting lower osmotic
pressure in the blood, making it difficult to maintain
blood volume until the inflammation subsides. Prolonged
or recurrent shock may cause kidney failure or damage
to other organs. Fluid and electrolytes as well as plasma
expanders (a substitute for lost protein) are replaced
intravenously using formulas designed to treat burn
patients. In some cases of severe shock, particularly with
extensive full-thickness burns, acute renal failure may
develop (see Chapter 18).
4.5%
4.5%
9%
9%
9%
1%
4.5%
4.5%
4.5%
4.5%
18%
9%
9%
BODY SURFACE AREA (BSA)
Anterior body surface Posterior body surface
Total head — 9%
Two arms — 18%
Trunk — 36%
Perineum — 1%
Two legs — 36%
Total — 100%
FIG. 5.12 Assessment of burn area using the rule of nines.
THINK ABOUT 5.12
a. Using the rule of nines, calculate the approximate area of
partial-thickness burn in an adult with burns to the right
arm and chest area.
b. State two reasons why full-thickness burns are considered
more serious than partial-thickness burns.
c. Why does sunburn usually heal readily?
THINK ABOUT 5.13
a. Explain how an increased hematocrit indicates a
fluid shift.
b. How do reduced protein levels in the blood affect tissue
metabolism and healing?
c. How does the reduction in blood flow through the burn
promote infection and make an infection harder to treat
should one develop?
Respiratory Problems
An immediate concern in the case of a burn patient is
the inhalation of toxic or irritating fumes. Inspiration of
carbon monoxide is dangerous because this gas prefer-
entially binds to hemoglobin, taking the place of needed
oxygen. The increasing presence of synthetic materials
in the environment has increased the risk of exposure to
toxic gases such as cyanide during a fire. These gases
are particularly dangerous when an individual has been
trapped in an enclosed space, such as a room or an
automobile. High levels of oxygen are administered and
the patient is observed for signs of respiratory impairment
following such a burn.
EMERGENCY TREATMENT FOR BURNS
Stop, Drop, and Roll!
When clothes are on fire, do the following:
• Stop what you are doing.
• Drop to the floor, cover up if possible.
• Roll to extinguish flames.
• Call emergency services (9-1-1) if the burn appears to be
extensive or a major burn.
• Ensure that electrical power is off before caring for an
electrical burn injury!
• Cool the burned area by soaking it with cool or tepid
water. Remove nonsticking clothing if possible, and
continue with cool water. Do not apply lotions, fats, or
lubricants!
• Cover loosely with a clean cloth (eg, the inside of a folded
sheet) or sterile gauze.
• For a chemical burn, remove any affected clothing and
flush the burn area well with cool water, then cover with a
clean cloth.

CHAPTER 5 Inflammation and Healing 83
FIG. 5.13 Direction of fluid and electrolyte shifts associated with burn shock. During burn shock,
K+ is moving out of the cell, and Na+ and H2O are moving in. After burn shock, K+ moves in, and
Na+ and H2O move out. (From Copstead-Kirkorn LC: Pathophysiology, ed 4, St. Louis, 2009, Mosby.)
If flame, hot air, steam, or irritating chemicals have
been inhaled, damage to the mucosal lining of the trachea
and bronchi may occur, and patients are observed for
indications of inflammation and obstruction developing
in the airway. Facial burns may be present, as well as
wheezing and coughing up sputum containing black
particles. Ventilation may be limited by eschar or pain.
Pneumonia, a lung infection, is a threat, because of
inflammation in the respiratory tract and immobility (see
Chapter 13).
Pain
Burns are very painful injuries throughout the treatment
process until healing is complete. The original injury,
body movements, and application of grafts and other
treatments contribute to pain. Analgesics (pain killers)
are required.
Infection
Infection is a major concern in patients with burns.
Infection of burn injuries increases tissue loss in the area,
often converting a partial-thickness burn to a full-thickness
burn. Because microbes are normally present deep in
glands and hair follicles (see Chapter 8), there is a ready-
made source of infection in the injured area. Also,
opportunistic bacteria and fungi (see Chapter 6) are
waiting to invade open areas, when defensive barriers
and blood flow are reduced. Common microbes involved
in burn injury infections include Pseudomonas aeruginosa,
Staphylococcus aureus (including drug-resistant strains),
Klebsiella, and Candida (Fig. 5.14). Antimicrobial drugs
are usually administered only after specific microorgan-
isms from the wound have been cultured and identified.
Excessive or incorrect use of antimicrobial drugs increases
the risk of the emergence of drug-resistant microorganisms
(see Chapter 6). When serious infection develops, there
is risk of microorganisms or toxins spreading throughout
the body, causing septic shock and other complications.
Treatment involves rapid excision or removal of the
damaged and infected tissue, application of antimicrobial
drugs, and replacement with skin grafts or a substitute
covering.
THINK ABOUT 5.14
a. Suggest three potential sources of infection in a
burn patient.
b. Other than skin damage, explain what other dangerous
effects can result from burns.
Metabolic Needs
Hypermetabolism occurs during the healing period after
a burn injury, and increased dietary intake of protein
and carbohydrates is required. There is considerable heat
loss from the body until the skin is restored; the patient
with burns tends to feel chilled and is sensitive to air
movement. Therefore the ongoing need to produce more
body heat and replace tissue demands increased nutrients.
Also, protein continues to be lost in exudate from the
burn site until healing is complete. The stress response
contributes to an increased metabolic rate and demand
for nutrients. Anemia or a low hemoglobin concentration
in the blood develops because many erythrocytes are
destroyed or damaged by the burn injury, and often bone
marrow functioning is depressed by compounds released
from damaged tissues, reducing hematopoiesis (the
production of blood cells in bone marrow). Hypoalbu-
minemia is common in burn patients and is associated
with complications related to increased extravascular
fluid, including edema, abnormal healing, and susceptibil-
ity to sepsis.

84 SECTION II Defense/Protective Mechanisms
A B
FIG. 5.14 Infections in a burn wound. A, Purulent exudate (to be cultured to identify microbes).
B, Blue-green color indicates infection by Pseudomonas aeruginosa. (Courtesy of Judy Knighton,
clinical nurse specialist, Ross Tilley Burn Center, Sunnybrook and Women’s College Health Center,
Toronto, Ontario, Canada.)
Healing of Burns
An immediate covering of a clean wound is needed to
protect the burned area and prevent infection. Nonstick
dressings are satisfactory for small areas or superficial
burns. When a piece of skin is to be grafted over the
burn wound, it may be “stretched” as a mesh to cover a
greater area (Fig. 5.15A). In some cases, a small section
of skin from the patient is cultured, producing a large
piece of skin in several weeks. Alternative protection for
the burn area may involve temporary substitute coverings,
such as pigskin or cadaver skin, which will be rejected
in time. In most serious burn cases, few epithelial cells
are available in the burn area for healing.
Large burn centers are now using forms of synthetic
and/or biosynthetic skin substitutes. At present, there
is no ideal substitute available. Skin substitutes are divided
into two main classes: biologic and synthetic substitutes.
The biologic skin substitutes have an intact extracellular
matrix structure, whereas synthetic skin substitutes can
be synthesized and modified for specific purposes. Each
class has its advantages and disadvantages. Biologic skin
substitutes allow the construction of a more natural new
dermis and allow excellent regrowth of epithelial cells
due to the presence of a basement membrane. Synthetic
skin substitutes have the advantage of increased control
over scaffold composition and structure. The ultimate
goal with any synthetic or biosynthetic skin substitute
is to achieve a substitute that provides an effective and
scar-free wound healing (Fig. 5.15B). Some examples of
synthetic skin substitutes are Tegaderm, Opsite, Matri-
derm, Integra, and Biobrane. Examples of biosynthetic
substitutes are Dermagraft, Apligraf, Orcel, and Hyalo-
matrix. The basic structure of the biosynthetics usually
involves a matrix, often a collagen structure, that is seeded
with fibroblasts.
Healing is more rapid, the number of surgical proce-
dures and grafts are reduced, there is less risk of infection,
and scarring is decreased when stable coverage of the
burn wound can be quickly accomplished. In a major
burn, healing is a prolonged process, taking perhaps
months. Scar tissue occurs even with skin grafting and
impairs function as well as appearance. Hypertrophic
scar tissue is common. Long-term use of elasticized
garments and splints may be necessary to control scarring.
In Fig. 5.16, a burn survivor is being measured for an
elastic pressure sleeve, a process that may be repeated
many times.
Physiotherapy and occupational therapy are often
necessary to reduce the effects of scar tissue and increase
functional use of the area. In some cases, surgery may
be necessary to release restrictive scar tissue or contrac-
tures. Severe burns require long-term team treatment
because complications are frequent. The length of treat-
ment has a major impact on a burn survivor, considering
the psychological and practical effects on physical
appearance and function, family, and job.

CHAPTER 5 Inflammation and Healing 85
A B
FIG. 5.15 A, Example of a mesh skin graft. B, Biosynthetic covering (TransCyte). Top: A temporary
dermal substitute “skin” is placed on a clean, partial-thickness burn wound. Bottom: The covering
is removed after new epithelial tissue has formed. (A, Courtesy of Judy Knighton, clinical nurse
specialist, Ross Tilley Burn Center, Sunnybrook and Women’s College Health Center, Toronto, Ontario,
Canada. B From Advanced Healing, Inc.)
A B
FIG. 5.16 A, Measurement for an elastic garment to control scar tissue from a burn. B, The
custom-fitted antiscar support garment modeled here effectively provides pressure therapy over
wounds, which helps to minimize the development of hypertrophic scarring. (A, Courtesy of Judy
Knighton, clinical nurse specialist, Ross Tilley Burn Center, Sunnybrook and Women’s College Health
Center, Toronto, Ontario, Canada. B, From Black JM, Matassarin-Jacobs E, editors: Medical-Surgical
Nursing: Clinical Management for Positive Outcomes, ed 7, Philadelphia, 2005, Saunders Courtesy
Medical Z, San Antonio, Texas.)

86 SECTION II Defense/Protective Mechanisms
Children and Burns
The growth of children is often affected during the acute
phase of burn recovery, when metabolic needs are
compromised and stress is great. Young children with
their thin skin frequently receive severe burns from
immersion in excessively hot water in a bathtub. The
increase in inflammatory mediators can cause renal
problems, although the kidneys are usually not perma-
nently damaged. Often at a later time, additional surgery
or grafts may be required to accommodate growth and
ease the effects of scarring.
THINK ABOUT 5.15
a. Explain why healing is a particularly slow process in burn
patients.
b. Explain what particular problems a child would encounter
after suffering an injury that has resulted in a considerable
amount of scar tissue.
CASE STUDY A
Trauma
M.H., age 6, fell while running down stairs and hurt his wrist
and elbow. His arm was scraped and bleeding slightly, and the
elbow became red, swollen, and painful. Normal movement was
possible, although painful.
1. Explain why the elbow is red and swollen.
2. Suggest several reasons why movement is painful.
3. State two reasons why healing may be slow in the scraped
area on the arm, and identify two factors that encourage
healing in this boy.
(1) the barriers—skin, mucous membrane, and secretions
such as tears and saliva; (2) phagocytosis; and (3) the
specific defense, the immune response:
• The inflammatory response is the response to any cell
or tissue injury by any agent.
• The acute inflammatory response consists of a sequence
of events: the release of chemical mediators from
damaged mast cells and platelets, local vasodilation
and increased capillary permeability, formation of
exudate, movement of leukocytes to the site, and
phagocytosis for removal of the offending agent and
debris.
• The signs of acute inflammation are redness, warmth,
swelling, pain, and, frequently, loss of function.
• With extensive inflammation, systemic signs may
present, including mild fever, headache, fatigue, and
leukocytosis.
• Chronic inflammation results in formation of fibrotic
or scar tissue.
• Antiinflammatory drugs include aspirin (ASA) and
the nonsteroidal antiinflammatory drugs (NSAIDs),
which block prostaglandin production at the site.
These drugs also have antipyretic and analgesic
activity. The glucocorticoids such as hydrocortisone
are effective antiinflammatory and antiallergenic
agents, but significant adverse effects develop with
long-term use.
• Healing may take place by regeneration, if
cells are capable of mitosis and the damaged area is
small.
• Fibrotic or scar tissue, consisting primarily of collagen
fibers, replaces normal tissue when damage is extensive
or cells are incapable of mitosis. Scar tissue lacks normal
function and is nonelastic, tending to shrink over time,
possibly causing contractures, deformity, or strictures
at a later time.
• Factors promoting healing include youth, good
circulation and nutrition, and lack of infection or other
disease.
• Burns, an example of inflammation and healing, are
classified by the percentage of body surface area
damaged and the depth of the skin damage in
the burn area. Partial-thickness burns involve the
epidermis and part of the dermis. Full-thickness burns
destroy all skin layers, thus a skin graft is required
for healing. In some cases, eschar restricts circulation
or ventilation.
• Following severe burns, shock frequently occurs
because of fluid and protein loss from the burn wound.
Infection is a threat because the protective skin barrier
has been lost. Inhalation of toxic or irritating fumes
may cause respiratory impairment. Hypermetabolism
and the increased demand for nutrients for healing
require dietary supplements.
• Healing of burns is a prolonged process, and multiple
skin grafts may be required. Biosynthetic wound
coverings have promoted healing in many cases.
CASE STUDY B
Burns
While P.J., age 28, was trying to light a barbecue, the propane
tank exploded, burning his face, arms, and chest. He had mixed
burns to most areas except for his hands and face, which were
full-thickness burns.
1. Why would this be considered a major burn?
2. Describe the process taking place in the burned area
during the first hours after the injury.
3. P.J. was wheezing, coughing up mucus, and short of
breath. Explain why this has likely developed.
4. P.J. developed a bacterial infection on his right hand.
Explain three predisposing factors to this infection.
5. How will this burn injury affect P.J.’s ability to work? What
are some of the social needs in this case?
C H A P T E R S U M M A R Y
The inflammatory response is one of the nonspecific
defense mechanisms in the body. Other defenses include

CHAPTER 5 Inflammation and Healing 87
S T U D Y Q U E S T I O N S
In answering these questions, the student is expected to
use knowledge of normal anatomy and physiology.
Inflammation
1. a. Explain why a cast placed around a fractured
leg in which extensive tissue damage has
occurred might be too tight after 24 hours.
b. Explain why such a cast might become loose in
3 weeks.
2. List specific reasons why the inflammatory
response is considered a body defense
mechanism.
3. a. Explain the rationale for each of the following
with acute inflammation: (i) warmth, (ii) fever.
b. State three systemic signs of inflammation.
4. Explain why leukocytosis, a differential count, and
elevated ESR are useful data but are of limited
value.
5. a. Explain how acute inflammation predisposes to
the development of infection.
b. Classify each as inflammation or infection: (i)
sunburn, (ii) skin rash under adhesive tape, (iii)
common cold, (iv) red, swollen eye with
purulent exudate.
6. How does the presence of thick, cloudy, yellowish
fluid in the peritoneal cavity differ from the
normal state?
7. If a large volume of fluid has shifted from the
blood into the peritoneal cavity, how would this
affect blood volume and hematocrit?
8. Explain how acute inflammation impairs
movement of a joint.
9. Explain two mechanisms used to increase body
temperature as a fever develops.
10. Why might a client be advised to avoid taking
ASA a few days before extensive oral surgery
(eg, multiple tooth extractions)?
11. Explain why a young child taking prednisone
(glucocorticoid) for chronic kidney inflammation is
at high risk for infection and might need
prophylactic antibiotics.
Healing
12. a. When part of the heart muscle dies, how does it
heal?
b. How would the new tissue affect the strength of
the heart contraction?
13. Suggest several reasons why healing is slow in the
elderly.
14. Explain how scar tissue could affect the function
of the following:
a. small intestine
b. brain
c. cornea of the eye
d. mouth
e. lungs (try to find more than one point!)
Burns
15. a. Explain the reason for pain and redness
accompanying a burn.
b. Explain three reasons why protein levels in the
body are low after a major burn.
16. a. Explain why immediate neutralization or
removal of a chemical spilled on the hand
minimizes burn injury.
b. Describe some of the factors that would
promote rapid healing of this burn.
17. Describe three potential complications of a full-
thickness burn covering 30% of the body,
including the legs and back.
18. If the face receives a full-thickness burn, describe
three ways function could be impaired after
healing.

88
Review of Microbiology
Microorganisms
Types of Microorganisms
Bacteria
Viruses
Chlamydiae, Rickettsiae, and
Mycoplasmas
Fungi
Protozoa
Other Agents of Disease
Helminths
Prions
Algae
Resident Flora (Indigenous or Normal
Flora, Resident Microbiota)
Principles of Infection
Transmission of Infectious Agents
Host Resistance
Virulence and Pathogenicity of
Microorganisms
New Issues Affecting Infections and
Transmission
Control of Transmission and Infection
Physiology of Infection
Onset and Development
Patterns of Infection
Signs and Symptoms
Local Signs
Systemic Signs
Methods of Diagnosis
Treatment and Antimicrobial Drugs
Guidelines for Use
Classification
Mode of Action
Example of Infection: Influenza (Flu)
Case Studies
Chapter Summary
Study Questions
C H A P T E R O U T L I N E
After studying this chapter, the student is expected to:
1. Describe the basic characteristics of bacteria, viruses,
chlamydiae, rickettsiae, mycoplasmas, fungi, prions, and
helminths.
2. Discuss the locations, advantages, and disadvantages of
resident (normal) flora.
3. Describe the modes of transmission of microbes.
4. Describe the factors determining host resistance.
5. Explain the factors contributing to pathogenicity and
virulence of microbes.
6. Discuss methods of preventing and controlling infection.
7. Describe the stages in the development and course of an
infection.
8. Describe typical, local, and systemic signs of infection.
9. State the common diagnostic tests for infection and the
purpose of each.
10. Describe the mechanisms of action of common
antimicrobial drugs.
11. Explain the basic guidelines for use of antimicrobial drugs.
12. Describe the respiratory infection influenza, including the
cause, transmission, immunization, incidence,
manifestations, and possible complications.
L E A R N I N G O B J E C T I V E S
algae
antiseptics
autoclaving
culture
disinfectants
endemic
endospore
epidemics
fimbriae
hyphae
infection
leukocytosis
leukopenia
lymphadenopathy
monocytosis
mutation
neutropenia
nosocomial
obligate
opportunistic
parasite
pathogens
pili
prions
seizures
septicemia
sterilization
toxins
unicellular
K E Y T E R M S
C H A P T E R 6
Infection

CHAPTER 6 Infection 89
in higher plants and animals, including humans. They
lack cell walls (except in plants) but their DNA is enclosed
in a nuclear membrane and the cell membrane has a
complex structure.
Many microorganisms are classified as nonpathogenic
because they do not usually cause disease; in fact, they
are often beneficial. Pathogens are the disease-causing
microbes often referred to as “germs.” Infectious diseases
result from invasion of the body by microbes and mul-
tiplication of these microbes, followed by damage to the
body. These agents and their ability to cause disease vary
widely. In the 18th and 19th centuries, scientists experi-
mented on fermentation and spoilage of foods. This
resulted in the concept of the “germ theory of disease”
as well as explanations of how wine and other foods
became unfit for consumption. The transmission of
pathogens and infection through hands, surfaces, water,
Review of Microbiology
Microorganisms
Microbiology refers to the study of microorganisms or
microbes, very small living forms that are visible only
with a microscope. Microorganisms include bacteria,
fungi, protozoa, and viruses (Fig. 6.1 and Table 6.1).
Detailed classifications of organisms with their proper
names are available in microbiology references (eg, Bergey’s
Manual). Selected examples of microorganisms are
examined briefly here.
Bacteria are classified as prokaryotic cells because they
are simple in structure—lacking even a nuclear
membrane—but they function metabolically and repro-
duce. They also have a complex cell wall structure. By
comparison, eukaryotic cells are nucleated cells found
Coccus Bacillus Vibrio Spirilla
Spirochete Diplo- Staph(ylo)- Strep(to)- TetradPalisades
Pleiomorphic
Glycoprotein
Envelope
Capsomer
Nucleic Acid
Capsid
Core Protein
B
Nucleocapsid
Chlamydospore
BlastosporeC
A
FIG. 6.1 A, Bacterial cell morphology. B, Virus. C, Fungus. (A From VanMeter K, Hubert R:
Microbiology for the Healthcare Professional, St. Louis, 2010, Mosby.)
TABLE 6.1 Comparison of Common Microorganisms
Bacteria Virus Fungi Protozoa Mycoplasma
Cell wall Yes No Yes No No
Obligate intracellular
parasite
No Yes No Some No
DNA and RNA Yes No Yes Yes Yes
Reproduction Binary fission Use host cell to replicate
components and for assembly
Budding and spores
and extend hyphae
Varies Binary fission
Drug used to treat Antibacterial Antiviral Antifungal Selective Selective

90 SECTION II Defense/Protective Mechanisms
Types of Microorganisms
Bacteria
Bacteria are unicellular (single cell) organisms that do
not require living tissue to survive. They vary in size,
shape, and arrangement and are classified and named
accordingly (see Fig. 6.1). These obvious characteristics
may assist in rapid identification of microbes.
The major groups of bacteria based on cellular shape
are as follows:
• Bacilli, or rod-shaped organisms, which include vibrio
(curved rods) and pleomorphic (variable or indistinct
shape).
• Spirals, which include spirochetes and spirilla, display-
ing a coiled shape or “wavy line” appearance. These
two classifications of bacterial shape differ in that the
spirochete contains a structure called an axial filament,
whereas the spirilla have flagella. Both of these struc-
tures facilitate cell movement.
• Cocci, or spherical forms.
Bacterial cells can further be categorized by their char-
acteristic groupings or arrangement:
• Diplo- prefix, indicating pairs
• Strep(to)- prefix, indicating chains
• Staph(ylo)- prefix, indicating irregular, grapelike
clusters
• Tetrads refers to cells grouped in a packet or square
of four cells
• Palisade refers to cells lying together with the long
sides parallel
The basic structure of bacteria includes the following:
1. An outer rigid cell wall protects the bacteria, provides
a specific shape, and contributes to its pathogenicity
(Fig. 6.3). A bacterium has one of two types of cell
walls, gram-positive or gram-negative, which differ
primarily in the thickness of the peptidoglycan in the
wall (Fig. 6.4). Peptidoglycan is a mixed polymer of
hexose sugars cross-linked by peptide fragments. This
difference can be determined in the laboratory using
a Gram stain and provides a means of identifying and
classifying bacteria. This classification is useful for
selecting appropriate antimicrobial therapy; for
instance, penicillin acts on the cell wall of gram-positive
bacteria. Targeting cell wall structure and function is
important because human cells do not have cell walls.
A drug such as penicillin thus does not damage human
cells but is effective against gram-positive bacteria.
2. A cell membrane is located inside the bacterial cell wall
in gram-positive organisms and on both sides of the
cell wall in gram-negative organisms This semiper-
meable membrane selectively controls movement of
nutrients and other materials in and out of the cell.
Some metabolic processes also take place in the cell
membrane.
3. An external capsule or a slime layer is found on some,
but not all, bacteria. The capsule is found outside the
cell wall in gram-positive bacteria and outside the
and the air was documented, and the practices of asepsis
were begun.
Microorganisms vary widely in their growth needs,
and their specific requirements often form the basis for
identification tests. Many microbes can be grown in a
laboratory using an appropriate environment and a
suitable culture medium in a Petri dish (Fig. 6.2A) or a
test tube. The culture medium provides the required
nutrients for specific microbial groups. The culture base
may be synthetic or a broth base with additives. The
need for oxygen, carbohydrates, a specific pH or tem-
perature, or a living host depends on the needs of the
particular microbe. Microbes that require living cells in
which to survive are particularly difficult to identify
without specialized laboratory techniques such as cell
culture, molecular diagnostic techniques, immunoassays,
or electron microscopy. The specific growth factors play
a role in determining the site of infection in the human
body. For example, the organism causing tetanus is an
anaerobic bacterium that thrives in the absence of oxygen
and therefore can easily cause infection deep in the tissue.
FIG. 6.2 A, Culture plate growing Staphylococcus aureus. B, Culture
plate with hemolytic streptococcus destroying erythrocytes (colorless
area). (A From Stepp CA, Woods M: Laboratory Procedures for Medical
Office Personnel, Philadelphia, 1998, WB Saunders. B From De la
Maza LM, Pezzlo MT, Baron EJ: Color Atlas of Diagnostic Microbiology,
St. Louis, 1997, Mosby.)

CHAPTER 6 Infection 91
Capsule or slime
layer may be present
Ribosomes
DNA strand
Cytoplasm
Fimbriae or pili
(for adhesion)
Flagellum
(may be none or more
than one for motility)
Cell membrane
4. Cell membrane damage
(e.g., polymyxin)
3. Interference with chromosome/DNA
and protein synthesis
(e.g., tetracycline-bacteriostatic)
2. Metabolic interference
(e.g., sulfonamides)
1. Bacterial cell wall –
defective synthesis
(e.g., penicillin-bactericidal)
FIG. 6.3 Structure of a bacterium and mode of action
of antibacterial drugs.
outer membrane in gram negatives, offering additional
protection to the organism as well as adhesion to
surfaces. It also interferes with the phagocytosis by
macrophages and other white blood cells in the human
body. The slime layer has similar functions but is less
chemically organized than a capsule and can be easily
washed off of the cell.
4. One or more rotating flagella attached to the cell wall
provide motility for some species.
5. Pili and fimbriae are tiny hairlike projections found on
some bacteria, usually the gram-negatives. Fimbriae
assist in attachment of the bacterium to tissue and also
allow some organisms to “drag” themselves across
surfaces. Pili are a specialized kind of fimbriae that
facilitate the transfer of genetic material between some
bacterial cells, thus leading to greater genetic variation.
6. Bacteria contain cytoplasm, which contains the chromo-
some (composed of one long strand of DNA), ribosomes
and RNA, and plasmids, which are circular DNA
fragments that are important in the exchange of genetic
information with other bacteria. Plasmids commonly
contain genetic information conveying drug resistance;
thus such resistance can be shared with many other
types of bacteria. The cellular components provide
for the metabolism, growth, reproduction, and unique
characteristics of the bacterium. Drugs often target a
particular pathway in bacterial metabolism.
7. Some bacteria secrete toxic substances, toxins, and
enzymes. Toxins consist of two types, exotoxins and
endotoxins:
• Exotoxins are usually produced by gram-positive
bacteria and diffuse through body fluids. They have
a variety of effects, often interfering with nerve
conduction, such as the neurotoxin from the tetanus
bacillus. Other toxins termed enterotoxins may
stimulate the vomiting center and cause gastro-
intestinal distress. Exotoxins stimulate antibody or
antitoxin production, which, after being processed
to reduce the toxic effect, can be used as toxoids to
induce an immune response (see Chapter 7).
• Endotoxins are present in the cell wall of gram-
negative organisms and are released after the
bacterium dies. Endotoxins may cause fever and
general weakness, or they may have serious effects
on the circulatory system, causing increased capillary
permeability, loss of vascular fluid, and endotoxic
shock.
• Enzymes are produced by some bacteria and can be
a source of damage to the host tissues or cells. For
example, hemolysin is produced by bacteria called
hemolytic streptococcus. This enzyme destroys red
blood cells, as seen on a culture medium containing
red blood cells (see Fig. 6.2B). Other enzymes assist
the bacteria to invade tissue by breaking down tissue
components. For example, the enzyme collagenase
breaks down collagen, which is a protein found in
muscles, bone, and other connective tissue, and the
enzyme streptokinase helps dissolve blood clots.
8. Several species can form endospores, a latent form of
the bacterium with a coating that is highly resistant

92 SECTION II Defense/Protective Mechanisms
Lipoteichoic
acid
Peptidoglycan
Wall teichoic acid
Cell wall
Plasma
membrane
Protein
Lipoprotein
Phospholipid
Lipopolysaccharide
Outer
membrane
Peptidoglycan
Periplasm
Cell wall
Plasma
membrane
ProteinA
B
FIG. 6.4 Bacterial cell wall. These illustrations show the location of the peptidoglycan layer in
gram-positive and gram-negative cell walls along with other features unique to their structure.
A, Gram-negative cell was. B, Gram-positive cell wall.
to heat and other adverse conditions (Fig. 6.5). These
bacteria can survive long periods in the spore state,
but they cannot reproduce when in spore form. Later,
when conditions improve, the bacteria resume a
vegetative state and reproduce. Tetanus and botulism
are two examples of dangerous infections caused by
spores in the soil entering the body, where they return
to the vegetative state and reproduce.
Bacteria duplicate by a simple process called binary
fission (see Fig. 6.6), a division of the cell that produces
two daughter cells identical to the parent bacterium. The
rate of replication varies from a few minutes to many
hours, depending on the particular microbe. If binary
fission occurs rapidly, a large colony of bacteria can
develop quickly, and this leads to the rapid onset of
infection. Factors affecting bacterial growth include
insufficient nutrients and oxygen, the effects of increased
metabolic wastes in the area, and changes in pH or
temperature. These factors cause the population growth
to slow down and reach a stationary stage where the
number of new organisms will equal the number dying.
At some point in time the effects of the growth factors
will become so pronounced that the population will begin
to “die off,” which marks the beginning of the death
phase of the growth curve and the eventual destruction
of the entire population.

CHAPTER 6 Infection 93
FIG. 6.5 Bacterial endospores. This is a micrograph of a Schaeffer-
Fulton endospore stain of a Bacillus species. The pink bacilli are
vegetative cells and the green ovals, both inside and outside of the
cells, are the endospores. (From VanMeter K, Hubert R: Microbiology
for the Health Care Professional, ed 2, St. Louis, 2015, Elsevier.)
APPLY YOUR KNOWLEDGE 6.1
1. Describe three similarities and three differences between
bacteria and human cells.
2. Explain how some bacterial cells may be just as dangerous
when they are dead as when they are alive.
TABLE 6.2 Common Viral Diseases
Type of Virus
RNA or
DNA Example of Disease
Orthomyxoviruses RNA Influenza A, B, and C
Paramyxoviruses RNA Mumps, measles
Togavirus RNA Rubella virus (German
measles), hepatitis C virus
Herpesvirus DNA Herpes simplex, infectious
mononucleosis, varicella
(chickenpox)
Flaviviruses RNA West Nile virus, encephalitis
Picornaviruses RNA Poliovirus, hepatitis A virus
Hepadnaviruses DNA Hepatitis B virus
Papovaviruses DNA Warts, cancer (human
papillomavirus [HPV])
Retrovirus RNA Human immunodeficiency
viruses
Viruses
There are several types of viruses, many of which include
numerous subtypes. Table 6.2 lists some types of viruses
and common pathogens causing disease in humans. A
virus is a very small obligate intracellular parasite that
requires a living host cell for replication. The need for
living tissue complicates any laboratory procedure to
grow or test viruses. When it is extracellular, a virus
particle is called a virion. It consists of a protein coat, or
capsid, and a core of either DNA or RNA (see Fig. 6.1B).
The protein coat comes in many shapes and sizes and
undergoes change relatively quickly in the evolution of
the virions. The nucleic acid content and its form provide
methods of classification of viruses. A retrovirus such as
the human immunodeficiency virus (HIV) contains RNA
only, plus an enzyme to convert RNA into DNA, a process
activated when the virus enters the host cell. Most viruses
contain DNA. Some viruses have an additional outer
protective envelope.
When a virus infects a person, it attaches to a host
cell, and the viral genetic material enters the cell. Viral
DNA or RNA takes over control of the host cell, using
the host’s capacity for cell metabolism to synthesize
protein, producing many new viral components (Fig.
6.7). The new viruses are assembled, then released by
lysis of the host cell or by budding from the host cell
membrane (see Fig. 7.14 and Fig. 6.7D)—usually with
destruction of the host cell—and the new viruses in turn
infect nearby cells.
Some viruses remain in a latent stage; they enter host
cells and replicate slowly or not at all until sometime
later. Viruses can also insert their capsid proteins into
the cell membrane of the host cells; these cells are then
recognized as viral invaders and are attacked by the
body’s immune system.
Frequently one type of virus exists in many similar
forms or strains, and viruses tend to mutate, or change
slightly, during replication (eg, the cold or influenza
viruses). Some viruses such as the influenza virus are
composed of nucleic acids from differing viral strains in
animals and humans. Influenza H1N1 has components
from both swine influenza and human influenza; these
mixtures can change rapidly, leading to new combinations.
These factors make it difficult for a host to develop
adequate immunity to a virus, either by effective antibod-
ies or by vaccines. Because of their unique characteristics,
viruses are difficult to control. They can hide inside human
cells, and they lack their own metabolic processes or
structures that might be attacked by drugs.
Certain intracellular viruses may also alter host cell
chromosomes, thus leading to the development of
malignant cells or cancer. Several strains of the human
papillomavirus (HPV) have been shown to be a major
cause of cervical cancer. A vaccine is now available for
this common cancer and is approved for use in females
entering puberty to prevent later cancer.
THINK ABOUT 6.1
a. Compare three characteristics of a bacterium and a virus.
b. Why are viruses so hard to control?

94 SECTION II Defense/Protective Mechanisms
• Rickettsiae are tiny gram-negative bacteria that live
inside a host cell (obligate intracellular parasites). They
are transmitted by insect vectors, such as lice or ticks,
and cause diseases such as typhus fever and Rocky
Mountain spotted fever. They attack blood vessel walls,
causing a typical rash and small hemorrhages.
• Mycoplasma infection is a common cause of pneumonia
(Fig. 6.8B) (see Chapter 13). These microbes lack cell
walls—therefore are not affected by many antimicrobial
drugs—and they can appear in many shapes. They
are the smallest cellular microbes.
Fungi
Fungi are found everywhere, on animals, plants, humans,
and foods. Growth of various types of fungi can be
observed easily on cheese, fruit, or bread. They are often
found on dead organic material such as plants.
Fungal or mycotic infection results from single-celled
yeasts or multicellular molds. These organisms are clas-
sified as eukaryotic and consist of single cells or chains
of cells, which can form a variety of structures (see Fig.
Chlamydiae, Rickettsiae, and Mycoplasmas
These three groups of microorganisms have some similari-
ties to both bacteria and viruses. They replicate by binary
fission, but they lack some basic component; therefore
they require the presence of living cells for reproduction.
• Chlamydiae are considered primitive forms related to
bacteria that lack many enzymes for metabolic
processes. They exist in two forms. One, the elementary
body (EB) is infectious, possessing a cell wall and the
ability to bind to epithelial cells. The other form, the
reticulate body (RB) is noninfectious but uses the host
cell to make adenosine triphosphate (ATP) and repro-
duce as an obligate intracellular organism (Fig. 6.8A).
After large numbers of new microbes are produced
inside the host cells, the new RBs change into EBs,
rupturing the host cells’ membranes and dispersing
to infect more cells. Chlamydial infection is a common
sexually transmitted disease that causes pelvic inflam-
matory disease and sterility in women. Infants born
to infected mothers may develop eye infections or
pneumonia.
REPRODUCTION BY BINARY FISSION
VEGETATIVE FORM
A
B
SPORE FORMATION BY SOME GRAM-POSITIVE BACTERIA (eg, CLOSTRIDIUM TETANI )
VEGETATIVE FORM
Adverse conditions
RETURN TO VEGETATIVE FORM OF BACTERIUM
DNA
duplicates
DNA duplicates
and cell membrane
grows inward to seal it off
Multiple resistant layers
form strong coat around DNA
Old cell wall breaks down
Spore released
Under adverse conditions,
the spore remains viable in
a dormant state for months
Favorable environment (eg, in body)
Spore sheds resistant coat
Begins reproducing
by binary fission process
Cell
divides
2 identical
daughter cells
Each daughter cell
continues to divide
FIG. 6.6 Bacteria—binary fission and spore formation.

Envelope
Protein coat (capsid)A
B
DNA or RNA
Host cell
Viral nucleic acid –
either DNA
or RNA
Nucleus
Virus1. Attachment
to host cell
and penetration
2.
Release of many
new viruses and
host cell lysis
6.
Host cell
synthesizes
viral components
4.
Uncoating – viral DNA
or RNA enters host cell
nucleus and takes control
of host cell DNA
3.
Assemble
new
viruses
5.
C D
FIG. 6.7 A, Different shapes of viruses. B, Viral replication. C, D, Herpesvirus particles and
budding. Herpes simplex virus (HSV) using electron microscopy; HSV consists of a core containing
DNA in an icosahedral capsid surrounded by a granular zone, within an external envelope. The
particles form in the host cell nucleus (see Fig. 6.6C), but the envelope is acquired during budding
through the host cell membrane (see Fig. 6.6D). (C, D From De la Maza LM, Pezzlo MT, Baron EJ:
Color Atlas of Diagnostic Microbiology, St. Louis, 1997, Mosby.)

96 SECTION II Defense/Protective Mechanisms
EB
Host cell
EB
EB enters host cell
EB
EB reorganizes into RB
8-12 hrs
Binary fission
Division of RB
RB
Inclusion grows
containing RBs and EBs
12-36 hrs
Condensation stage
36-72 hrs
Inclusion bursts, releasing EBs
48-96 hrs
A
FIG. 6.8 A, Developmental cycle of Chlamydia. EB, elementary body; RB, reticulate body.
B, Mycoplasma. Mycoplasma hominis colonies viewed through a light microscope. Mycoplasmas
are the smallest free-living organisms. Unlike bacteria, they lack a cell wall and behave as parasites
on the surface of host cells but are not intracellular. Complex media and tissue culture techniques
are used for their isolation. (A From Stepp CA, Woods M: Laboratory Procedures for Medical Office
Personnel, Philadelphia, 1998, WB Saunders. B From De la Maza LM, Pezzlo MT, Baron EJ: Color Atlas
of Diagnostic Microbiology, St. Louis, 1997, Mosby.)

CHAPTER 6 Infection 97
A
FIG. 6.9 Thrush. A, Micrograph of the fungus Candida albicans in
the yeast form (this fungus can also form filamentous mycelia) that
is responsible for an oral infection called thrush. Candida albicans
can also cause vaginal infections in women. B, Oral candidiasis
illustrating the white plaques. (A From VanMeter K, Hubert R:
Microbiology for the Healthcare Professional, St. Louis, 2010, Mosby.
B From Zitelli BJ, Davis HW: Atlas of Pediatric Physical Diagnosis,
ed 4, St. Louis, 2002, Mosby.)
(see Fig. 17.5B), called thrush in infants, and is a common
cause of vaginal infections. In immunodeficient individu-
als, Candida frequently becomes opportunistic, causing
extensive chronic infection (see Fig. 7.17C) and perhaps
spreading to cause serious systemic infection. Histoplasma
is a fungus causing a lung infection that may become
disseminated through the body in immunosuppressed
patients. Histoplasmosis is transmitted by inhaling
contaminated dust or soil particles.
It is not always easy to clearly classify microorganisms
because microbes may demonstrate characteristics of more
than one group. For example, Pneumocystis carinii, an
opportunist causing pneumonia, has some characteristics
of fungi and some of protozoa. It was once considered a
fungus, then a protozoon, but now it may be classified
as a fungus again (see Fig. 7.17A).
Protozoa
Protozoa are more complex eukaryotic organisms. They
are unicellular, usually motile, and lack a cell wall, but
they occur in a number of shapes, sometimes within the
life cycle of a single type. Many live independently, some
live on dead organic matter, and others are parasites
living in or on another living host. As in other microbial
classifications, protozoa are divided into a number of
subcategories.
The pathogens are usually parasites. Some diseases
caused by protozoan infection include trichomoniasis,
malaria, and amebic dysentery.
Trichomonas vaginalis is distinguished by its flagella
(Fig. 6.10A). It causes a sexually transmitted infection of
the reproductive tracts of men and women, attaching to
the mucous membranes and causing inflammation (see
Chapter 19).
The causative agents for malaria, the Plasmodium
species, belong to a group of nonmotile protozoa called
sporozoa. Plasmodium vivax is found in temperate climates
such as the southern United States (Fig. 6.10B). Clinically
these microbes are found in the red blood cells, where
they undergo several stages in their life cycle. The red
blood cells become large and eventually rupture and
release new microbes and toxins into the blood, causing
acute illness. The microbe is transmitted by a blood-
sucking insect, the female Anopheles mosquito. One form
of malarial parasite, Plasmodium falciparum, is extremely
virulent and has become resistant to almost all antimalarial
drugs. It is expected that global warming will put more
of the world’s population at risk of malaria in the future
as the Anopheles mosquito extends its range and infects
nonimmune individuals.
The amebas are a motile group of protozoa, moving
by extending part of their cytoplasm and flowing forward
(ameboid movement). They engulf food in the same
manner. The important pathogen in this group is Ent-
amoeba histolytica, a parasite in the large intestine that
causes amebic dysentery, a severe form of diarrhea, and
liver abscesses if it penetrates into the portal circulation
6.1). Fungi can grow on a wide range of environmental
conditions, which makes them common contaminants
found on surfaces and in foods. Fungi are frequently
considered beneficial because they are important in the
production of yogurt, beer, and other foods, as well as
serving as a source of antibiotic drugs.
The long filaments or strands of a fungus are hyphae,
which intertwine to form a mass called the mycelium,
the visible mass. Fungi reproduce by budding, extension
of the hyphae, or producing various types of spores.
Spores can spread easily through the air and are resistant
to temperature change and chemicals. Inhaled spores
can stimulate an allergic reaction in humans.
Only a few fungi are pathogenic, causing infection on
the skin or mucous membranes. Infections such as tinea
pedis (athlete’s foot) result from the fungus invading the
superficial layers of the skin. Tinea pedis infection is often
transmitted in public pools, showers, or gymnasiums.
Candida is normally a harmless fungus present on the
skin (Fig. 6.9). However, when there are imbalances in
the normal flora, it may cause infection in the oral cavity

98 SECTION II Defense/Protective Mechanisms
A genus of flagellated protozoans that are responsible
for gastrointestinal infections in humans is Giardia.
Most giardiasis cases are caused by the consumption of
contaminated food or water and in some cases, person-
to-person contact. Giardia is a cyst-forming organism that
is excreted in feces and can survive in the environment
for a considerable period of time before it is ingested
by a new host.
(Fig. 6.10C). These organisms exist in two forms. One
form is actively pathogenic and is termed the trophozoite.
Trophozoites secrete proteolytic enzymes, which break
down the intestinal mucosa, causing flask-shaped ulcers.
Trophozoites may invade blood vessels and spread to
other organs, such as the liver. The organism also forms
cysts, which are resistant to environmental conditions
and are excreted in feces. Entamoeba histolytica infection
is spread by the fecal-oral route. Although the infection
is more common in less developed areas of the world,
people may become infected and transmit the infection
to family members and associates if proper handwashing
is not employed. Simple treatment of water with chlorine
or other halogens does not destroy the cysts; filtration
or boiling of water is necessary to prevent infection when
water has been fecally contaminated.
A B
C D
FIG. 6.10 A, Trichomonas. B, Trypanosoma in a blood sample. C, Entamoeba histolytica. D,
Pinworm ova in a fecal smear. (A From De la Maza LM, Pezzlo MT, Baron EJ: Color Atlas of Diagnostic
Microbiology, St. Louis, 1997, Mosby. B From VanMeter K, Hubert R: Microbiology for the Healthcare
Professional, St. Louis, 2010, Mosby. C From Mahon C, et al: Textbook of Diagnostic Microbiology,
ed 5, St. Louis, 2015, Elsevier. D From Stepp CA, Woods M: Laboratory Procedures for Medical Office
Personnel, Philadelphia, 1998, WB Saunders.)
THINK ABOUT 6.2
a. Explain why parasites do not usually kill their host.
b. Explain how routine laboratory tests might not show the
presence of mycoplasma, rickettsia, or protozoans in the
body.

CHAPTER 6 Infection 99
folding and change of shape. This renders the protein
molecule nonfunctional and causes degenerative disease
of the nervous system. Prion diseases in humans include
Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob
disease (see Chapter 14). These are rapidly progressive
and fatal. It is thought that variant Creutzfeldt-Jakob
disease is caused by the consumption of meat that has
been contaminated with nervous tissue from an infected
animal such as beef cattle. In areas where bovine spongi-
form encephalopathy (BSE), the animal prion infection,
is prevalent, consumption of ground meats, sausages, or
offal should be avoided.
Algae
Algae are eukaryotic microorganisms widespread in
fresh and marine waters; they are a main component
of plankton and are usually not a concern for human
disease. Medical concerns involving algae include human
consumption of marine animals that have fed on algae
and accumulated toxins produced by the algae. Some fish
kills have been attributed to the algae Pfiesteria piscicida.
Resident Flora (Indigenous Normal Flora,
Resident Microbiota)
Many areas of the body, such as the skin, nasal cavity,
and mouth, have a resident population of mixed microor-
ganisms, primarily bacteria. Different sites host different
species (Table 6.3). Some areas of the body, such as the
lungs, brain, blood, bladder, and kidneys, lack resident
flora or are sterile under normal circumstances, and
properly obtained specimens from these areas should
not contain microorganisms.
Certain microbes in the intestinal tract are of great
benefit to the host in the synthesis of vitamin K and in
some digestive processes. These microbes are not patho-
genic under normal circumstances but may cause disease
Other Agents of Disease
Helminths
Helminths or worms are not microorganisms but are
often included with microbes because they are parasites
and cause infections in humans throughout the world.
They are multicellular, eukaryotic organisms that are
divided into many subgroups, depending on their physical
characteristics. They may be very small, barely visible,
or up to 1 meter in length. Their life cycle consists of
at least three stages, ovum (egg), larva, and adult. The
ova or larvae may be ingested in contaminated food or
water or may enter through the skin or be transmitted
by infected insects. They are often found in the intestine
but can inhabit the lung or blood vessels during parts
of their life cycle.
Helminths are usually diagnosed by observation of
ova or eggs in stool specimens (Fig. 6.10D). Helminth
infections are more commonly found in young children,
and in North America they include pinworms (Fig. 6.11),
hookworms, tapeworms (Fig. 6.12), and Ascaris or giant
roundworms. When large numbers of worms are present
in the body, systemic effects may develop, such as severe
anemia.
Prions
Prions are protein-like agents that are transmitted by
consumption of contaminated tissues such as muscle or
the use of donor tissues contaminated with the protein.
There is a great deal that is not known about prion
disorders, and some researchers question whether prions
are actually the agent of diseases. The following informa-
tion is from publications of the Centers for Disease Control
and Prevention (CDC).
A prion is an abnormal molecule that is transmissible in
tissues or blood of animals or humans. It induces proteins
within the brain of the recipient to undergo abnormal
FIG. 6.11 Pinworm. This micrograph shows the mouth structure
of the pinworm Enterobius vermicularis, which causes the disease
enterobiasis. (From VanMeter K, Hubert R: Microbiology for the
Healthcare Professional, St. Louis, 2010, Mosby.)
FIG. 6.12 Tapeworm. Two main features of the tapeworm are the
scolex, which has muscular suckers surrounded by hooks for attach-
ment, and the individual body segments called proglottids. (From
VanMeter K, Hubert R: Microbiology for the Healthcare Professional,
St. Louis, 2010, Mosby.)

100 SECTION II Defense/Protective Mechanisms
• Direct contact with no intermediary, such as touching
an infectious lesion or sexual intercourse. Microbes
may be in the blood, body secretions, or a lesion. Not
all microorganisms can cross the blood-brain barrier
or placental barriers. However, some microbes that
can cross the placenta have serious effects on fetal
development and health. Treponema pallidum, the cause
of syphilis, can lead to multiple defects or death in
the fetus, and Toxoplasma gondii, the cause of toxoplas-
mosis, results in many neurologic deficits.
• Indirect contact involving an intermediary such as a
contaminated hand or food, or a fomite, an inanimate
object such as instruments or bed linen that carries
organisms. In some cases, there are several stages in
transmission. For example, shellfish can be contami-
nated by human feces in the water. The microorganisms
in the shellfish are then ingested and cause infection
in another human.
• Droplet transmission (oral or respiratory) occurring
when respiratory or salivary secretions containing
pathogens such as tuberculosis bacteria are expelled
from the body. The organisms from these secretions
may be inhaled directly by another person close by
or fall on nearby objects to be transmitted indirectly.
• Aerosol transmission involving small particles from
the respiratory tract that remain suspended in the air
and travel on air currents, infecting any new host who
inhales the particles.
• Vector-borne, when an insect or animal serves as an
intermediary host in a disease such as malaria.
Lack of proper hand sanitation is considered a major
culprit in spreading infection from many sources, in health
care facilities, the home, office, or school. Frequent, proper
handwashing is essential in infection control and has
been shown to be the most commonly ignored procedure
in maintaining personal and public health.
Nosocomial infections are infections that occur in
health care facilities, including hospitals, nursing homes,
doctors’ offices, and dental offices. The CDC estimates that
10% to 15% of patients acquire an infection in the hospital.
Reasons for these infections include the presence of many
microorganisms in these settings, patients with contagious
diseases, overcrowding, use of contaminated instruments,
immunocompromised and weakened patients, the chain
of transmission through staff, diagnostic procedures, and
equipment, therapeutic aids, and food trays. Also, many
microbes in health care settings are resistant to several
drugs.
The CDC has identified the most frequently occurring
nosocomial infections in US acute care facilities (2011 data):
Estimated Cases
Pneumonia 157,500
Gastrointestinal 123,100
Urinary tract 93,300
Bloodstream 71,900
Post surgical 157,500
Other 118,500
if they are transferred to another location in the body, if
the balance among the species is not maintained (eg, one
variety becomes dominant), or if the body’s defenses are
impaired (eg, in immunodeficiency states). Such infections
are termed opportunistic.
A resident flora is usually helpful in preventing other
organisms from establishing a colony. For example, some
antibacterial drugs intended to treat infection elsewhere
in the body will destroy part of the normal flora in the
intestine, thus allowing for an imbalance in growth there
or invasion by other microbes, causing opportunistic
infection and diarrhea.
Principles of Infection
An infection occurs when a microbe or parasite is able
to reproduce in or on the body’s tissues. Infectious diseases
may occur sporadically in single individuals, localized
groups, and epidemics or worldwide pandemics. Certain
infections are consistently occurring in that population
and are referred to as being endemic to an area. Others
may occur outside their normal geographic range or in
higher than expected numbers; these infections are
referred to as epidemics. Knowledge of the modes of
transmission of microorganisms and methods of control
is essential for the prevention and control of infection
within the community.
Transmission of Infectious Agents
A chain of events occurs during the transmission of infect-
ing organisms from one person or organism to another (Fig.
6.13). The reservoir, or source of infection, may be a person
with an obvious active infection in an acute stage or a
person who is asymptomatic and shows no clinical signs or
symptoms. The latter may be in the early incubation stage
of infection, or the person may be a carrier of the organism
and never develop infection. Hepatitis B is an example of
an infection that is often transmitted by unknown carriers
or persons who have a subclinical form of infection that is
very mild, with few or no manifestations. The reservoir
also may be an animal or contaminated water, soil, food, or
equipment.
The mode of transmission from the reservoir to the
new host may be as follows:
TABLE 6.3 Location of Resident Flora
Resident Flora Present Sterile Area
Skin Blood, cerebrospinal fluid
Nose, pharynx Lungs
Mouth, colon, rectum
Vagina Uterus, fallopian tubes,
ovary
Distal urethra and perineum Bladder and kidney

CHAPTER 6 Infection 101
Inhalation
Direct access–
blood
Animals
Poultry
Contaminated water/soil
Egg
Sexual intercourse
Oral/nasal
secretions
SOURCE
Ingestion
INFECTIOUS
DISEASE
Needle
Injury
Bites,
stings,
worms
FIG. 6.13 Transmission of infectious agents.
Most infections in health care facilities are spread by
direct contact between persons or contaminated objects.
There have been several outbreaks of infection in hospitals
by a more dangerous strain of the bacterium, Clostridium
difficile (c-diff), particularly in intensive care units where
most individuals are taking antimicrobial drugs. The
resulting disruption of normal flora allows C. difficile to
multiply and cause severe diarrhea and many deaths.
Methicillin-resistant Staphylococcus aureus (MRSA) infec-
tions are also increasingly seen as a source of nosocomial
infection that is challenging to treat (this is in the com-
munity, not just the hospital). The importance of obtaining
a complete and accurate health history with respect to
hospitalization and prior infections cannot be overstated.
Host Resistance
The healthy individual is quite resistant to infection. With
some infections, such as tuberculosis, host resistance is
a primary factor in determining the risk of active infection
following exposure (Box 6.1).
Interferons are proteins produced by human host cells
in response to viral invasion of the cell. These interferons
then influence the activity of nearby host cells, increasing
their resistance to viral invasion and interfering with
viral replication. Interferons also stimulate the immune
system and are used in cancer treatment for this reason.
Host Resistance Increased Microbial Virulence
Intact skin and mucous
membrane
Production of exotoxins and
endotoxins
Body secretions—stomach
acid, tears
Production of destructive
enzymes
Nonspecific phagocytosis Spore formation
Effective inflammatory
response
Entry of large number of
organisms into body
Absence of disease Presence of bacterial capsule
and pili
Effective immune system
Interferon production (virus)
BOX 6.1 Host Resistance and Microbial Virulence

102 SECTION II Defense/Protective Mechanisms
Microorganisms undergo frequent mutation. Slight
changes in the organism may occur spontaneously or
in response to environmental conditions, including
the presence of drugs. When bacteria or viruses mutate,
antibodies that matched the earlier form are no longer
effective, so the individual is no longer protected.
Vaccines or drugs are unlikely to be effective against
the new form. This is why a new influenza vaccine
must be developed and administered each year.
Virulence is often expressed in the case fatality rate, the
percentage of deaths occurring in the number of persons
who develop the disease. In parasitic infections, host
resistance and the ability of a microbe to cause disease
often coexist in a delicate balance.
New Issues Affecting Infections
and Transmission
There has been increasing concern and fear about new
emerging diseases and “superbugs,” microbes that have
caused serious illness in otherwise healthy individuals
or do not respond to any drugs. Emerging infectious
diseases are identified by a new or unique set of signs or
symptoms or by increased spread. Careful monitoring and
collection of data are essential to identify new threats so
that preventive measures may be put in place. The 2003
severe acute respiratory syndrome (SARS) epidemic in
the Toronto area was well established before information
about cases occurring in travelers from Southeast Asia was
received. In some cases the incubation period is so short
that it is difficult to prevent an epidemic even if health
statistics are collected—for example, in cholera infections.
In such situations the focus must be on preventing the
spread of infection to the wider community. Increased
global travel, changing environments and global weather
patterns, and changes in food and water supplies are
some of the factors leading to altered disease patterns.
Epidemiologists at the CDC, World Health Organization
(WHO), as well as a greater number of local agencies
collect and analyze reports on new diseases and other
trends. They also update the list of notifiable diseases,
approximately 60 diseases that must be reported to
public health agencies. The CDC reports are published
in Morbidity and Mortality Weekly Report. The United
Nations (UN) has also assumed a role in a number of
global issues related to infectious diseases such as AIDS,
tuberculosis, and malaria.
Following the SARS threat (see Chapter 13) in 2003,
these agencies cooperated to quickly identify a previously
unknown microbe, a coronavirus, and work on controlling
the spread of the infection. As more deaths occurred and
a second wave of infection developed, they were able to
identify factors in the transmission of the virus.
The CDC and WHO have published guidelines for
health care facilities to manage the screening procedures,
rapid containment, and treatment of serious infectious
diseases that may lead to a pandemic. These measures
Unfortunately, they have not proved to be as beneficial
in the widespread treatment of cancer or other immune-
based diseases as expected.
Factors that decrease host resistance include the
following:
• Age (infants and the elderly)
• Genetic susceptibility
• Immunodeficiency of any type
• Malnutrition
• Chronic disease, including cardiovascular disease,
cancer, and diabetes
• Severe physical or emotional stress
• Inflammation or trauma affecting the integrity of the
skin or mucosa, including burns, lack of protective
secretions, bladder catheters, or other invasive proce-
dures. Sometimes infection occurs easily because of
a very small break in the skin or mucous membrane
or in an area of inflammation. As discussed in Chapter
5, the loss of skin and other defenses in a burn patient
often results in secondary infection at the site.
• Impaired inflammatory response—for example, long-
term glucocorticoid medication
Severe or multiple infections are common in home-
less individuals, in whom multiple factors decrease host
resistance. For example, poor nutrition, open lesions,
inadequate hygiene, fatigue, lack of access to health
care, and possible drug or alcohol abuse combine to
create a high risk of infections such as tuberculosis.
Prophylactic antimicrobial medication may be required
by any individuals with low resistance before exposure
to possible infecting microbes—for example, before an
invasive procedure.
Virulence and Pathogenicity of Microorganisms
Pathogenicity refers to the capacity of microbes to cause
disease. Nonpathogens can become pathogens. When a
member of the resident flora is introduced into another
area of the body, it may become an opportunistic patho-
gen. For example, if Escherichia coli from the colon enter
the urinary tract, they will cause infection. (This microbe
is the most common cause of cystitis.)
Virulence is the degree of pathogenicity of a specific
microbe, based on the following:
• Invasive qualities, allowing it to directly damage host
cells and tissues and spread.
• Toxic qualities, including production of enzymes,
exotoxins, and endotoxins that damage host cells or
interfere with a host function such as nerve conduction.
• Adherence to tissue by pili, fimbriae, capsules, or
specific membrane receptor sites. Certain organisms
tend to establish infection in particular areas of the
body considered hospitable to that microbe; for
example, streptococci are common in respiratory and
ear infections.
• Ability to avoid host defenses (eg, the presence of a
capsule or mutation with altered antigenicity).

CHAPTER 6 Infection 103
jurisdictions now offer reimmunization with the measles,
mumps, and rubella (MMR) vaccine in the teen years. The
recommended immunization schedules for children 0 to
6 and 7 to 18 as well as a catch-up schedule are updated
regularly and approved by the American Academy of
Pediatrics, the Advisory Committee on Immunization
Practices of the CDC, and the American Academy of
Family Physicians.
The other issue to be addressed is the increasing
number of microbes that are resistant to several drug
groups, thus making infection control much more difficult.
The multidrug-resistant microbes include strains of
Mycobacterium tuberculosis, Plasmodium falciparum, Strep-
tococcus pneumoniae, Haemophilus influenzae, Staphylococcus
aureus, and Neisseria gonorrhoeae. Currently there is much
more emphasis on the reduced use of antibacterial drugs
to treat minor infections or as prophylactics to lessen the
problem. It is important for health care workers to remain
up to date on current recommendations about infection
control measures in their scope of practice.
Control of Transmission and Infection
Isolation of infected persons is rarely carried out on a
large scale, and there are fewer diseases that must be
reported to government bodies. It is not feasible to test
every client or patient for the presence of infection before
initiating care. Therefore infection control, understanding
the transmission, and breaking the chain of infection (Fig.
6.14) become much more important, particularly to health
have proved effective in several recent outbreaks, such
as the influenza A H1N1 outbreak in Mexico in 2009.
Precautions were instituted in several countries, and at
the time of this writing these precautions appear to have
been successful in preventing a full-blown pandemic.
Health care workers in all settings were required to screen
clients and put respiratory precautions in place for those
who were symptomatic.
In some cases, organisms such as the Ebola virus are
spreading, have become highly virulent, and have the
power to cause serious infection, even in a healthy host.
At this time, no drugs are available to control this and
related viral infections. Certain strains of a common
microorganism, such as E. coli, a normal part of resident
intestinal flora, have suddenly developed new strains
that have caused life-threatening infections. The so-called
flesh-eating bacteria are specific strains of a beta-hemolytic
streptococcus that are highly invasive, secreting proteases,
enzymes that break down tissue, resulting in the life-
threatening disease necrotizing fasciitis. These bacteria
also produce a toxin, causing shock.
The effectiveness of immunizations over long time
periods is difficult to assess. It appears that some vaccines
are losing their protective qualities over time. The increas-
ing incidence of pertussis (whooping cough), mumps,
and measles appears related to decreasing immunity from
vaccines given in childhood. This indicates a need for
booster immunization and the importance of continued
monitoring of all infectious diseases, including those
in which routine immunizations are in place. Many
Breaking the chain
SOURCE
Person, animal,
insect, environment,
in the home,
workplace, or
community (bus, store)
RESERVOIR
SUSCEPTIBLE HOST
Incubation period
(asymptomatic)
Health status, point of entry,
number of microbes
Current
immunization
ENTRY
Mouth, nose,
broken skin, vagina
INFECTIOUS
DISEASE
CARRIER
Mouth, skin,
intestine
EXIT
DIRECT
Saliva, blood,
feces, semen,
exudates from skin
INDIRECT
Respiratory droplet
on hands or surfaces,
insect bites (vectors),
contaminated food
and water
TRANSMISSION
Barriers
(Gloves, glasses, gown)
Safe waste disposal
Reduce the
numbers Barriers
HAND-WASHING
disinfect, sterilize,
food handling and cooking,
water treatment
FIG. 6.14 Infection cycle and breaking the chain.

104 SECTION II Defense/Protective Mechanisms
sneezing when the infected person is in close contact
with other people. However, it is now evident that
contaminated oral and nasal secretions are more
dangerous when they are on the hands or on tissues
than when they are airborne, so proper disposal of
contaminated items is essential. It is advisable for
anyone with or without an infection to use general
universal precautions to prevent transmission by body
fluids.
• Knowledge of the mode (droplet, fecal-oral) or modes
of transmission of specific infections is essential to
block transmission. Precautions must be undertaken
in a prescribed manner; for example, the use of
appropriate condoms following recommended guide-
lines is essential to prevent the spread of sexually
transmitted disease during intimate sexual activity.
Using disposable equipment, proper sterilization and
cleaning, good ventilation, and frequent handwashing
are some ways to reduce transmission:
• Portals of entry and exit should be blocked by
covering the nose and mouth with a mask and
placing barriers over breaks in the skin or mucous
membranes.
• Host susceptibility (increase host resistance) can be
reduced by maintaining immunizations and boosters
according to guidelines. Proper nutrition to maintain
skin and mucous membranes is also essential to
reduce host susceptibility.
Additional techniques to reduce transmission include
the following:
1. Adequate cleaning of surroundings and clothing.
2. Sterilization (the complete destruction/removal of all
microorganisms) of fomites by exposure to heat using
several methods, such as autoclaving. Time, packaging,
and temperature are critical to success. Moist heat is
preferable, because it penetrates more efficiently and
can destroy microbes at lower temperatures. Incinera-
tion (burning) and autoclaving are also effective
methods of destroying microbes in waste.
3. Disinfectants are chemical solutions, designed to be
used on nonliving surfaces, that are known to destroy
microorganisms or their toxins on inanimate objects.
The literature on these solutions must be carefully
checked to determine the limitations of the specific
chemicals as well as the instructions for use. For
example, few chemicals destroy spores. Adequate
exposure time and concentration of the chemical are
required to kill some viruses, such as hepatitis B. Other
potential problems include inactivation of some
chemicals by soap or protein (mucus, blood) or damage
to metals or latex materials on instruments by the
disinfectant. One of the more effective disinfectants
at present is glutaraldehyde. Flushing certain equipment
and tubing (eg, in a dental office) with disinfectant
and water is a recommended daily activity.
4. Antiseptics are antimicrobial chemicals designed to
be used on living tissue such as isopropyl alcohol–70%,
professionals, who must protect themselves, their families,
and the community as well as their patients.
Universal precautions provide the basic guidelines by
which all blood, body fluids, and wastes are considered
“infected” in any client regardless of the client’s appar-
ent condition. There are two levels: one general for all
individuals and one specific to known infections at
specific sites in the body, such as the intestines. Gloves
and appropriate protective apparel are then used to reduce
the transmission of organisms in either direction—that is,
from patient to caregiver and from caregiver to patient.
Guidelines have been established for the disposal of such
potentially dangerous items as needles, tissue, and waste
materials. The CDC can be consulted for appropriate and
up-to-date information.
To break the cycle and minimize the risk of infection,
the following must be considered:
• The reservoir or sources of infection must be located
and removed. Sources and contacts must be identified in
some situations, especially when asymptomatic carriers
may be involved or when travelers may be infected:
• Contaminated food or water or carrier food handlers
should be identified to prevent continued transmis-
sion or epidemics of infectious disease. As a precau-
tion, some institutions test stool specimens from
food handlers so as to identify carriers. Some
intestinal pathogens can survive in feces outside
the body for long periods of time and increase the
risk of contaminating food or water.
• In some cases, infection can be transmitted before
clinical signs are evident in the infected person,
and this permits widespread contamination if the
incubation period is prolonged. For example, there
is a prolonged window of time before hepatitis or
human immunodeficiency virus (HIV) infection can
be identified in persons. In institutions, infection
such as hepatitis A can spread rapidly, particu-
larly when the patient’s health status is already
compromised.
• Infected travelers should refrain from travel to
prevent spreading infectious diseases into new areas,
and travelers who become ill should seek prompt
health care and share their specific travel history
with health care workers. In the spring of 2016, a
number of press personnel and athletes decided
not to participate in the 2016 Olympic games in
Rio de Janeiro, Brazil, due to the occurrence of the
Zika virus. Some health groups and doctors called
for the cancellation of the games, as they feared it
could spread the virus worldwide. Both the WHO
and CDC agreed that the potential for an epidemic
occurring or worldwide spread of the virus was
extremely low and did not endorse the cancellation
requests.
• The portal of exit (secretions, eg, blood, saliva, urine)
of microbes from the reservoir should be blocked. This
includes minimizing the effects of coughing and

CHAPTER 6 Infection 105
Only if the host defenses are insufficient to destroy all
the pathogens during this process will infection be
established.
The incubation period refers to the time the body is
exposed to the organism and the appearance of clinical
signs of the disease. Incubation periods vary considerably,
depending on the characteristics of the organism, and
may last for days or months. During this time the organ-
isms reproduce until there are sufficient numbers to cause
adverse effects in the body.
The prodromal period is the early symptoms stage when
the infected person may feel fatigued, lose appetite, or
have a headache and usually senses that “I am coming
down with something.”
Next comes the acute period, when the infectious disease
develops fully and the clinical manifestations reach a
peak. The onset of a specific infection may be insidious,
with a prolonged or gradual prodromal period, or sudden
or acute, with the clinical signs appearing quickly with
severe manifestations.
The length of the acute period depends on the virulence
of the particular pathogen and host resistance. In many
cases the acute period ends when host resistance, perhaps
the immune system, becomes effective at destroying the
which is the active ingredient in hand sanitizers.
Antiseptics reduce the number of organisms in an
area but often do not destroy all of them. Also, they
may be diluted or removed quickly by body secretions.
Some antiseptics, such as iodine compounds, may
cause allergic reactions in some individuals.
THINK ABOUT 6.3
a. Explain why, when using an antiseptic, killing all the
bacteria may not be the desired result.
b. Given that every client cannot be fully screened for
infections, what precautions are essential to limit the
transmission of microbes that are agents of disease?
Relate your answer to your specific scope of practice.
N
U
M
B
E
R
O
F
O
R
G
A
N
IS
M
S
TIME
Septicemia—death
Overwhelming infection
Chronic infection
mild signs but
destructive
3. Pathogen reproduces rapidly
4. Prodromal signs
may appear
2. Pathogen colonizes
appropriate site
1. Pathogen
enters host
5. Acute signs
present
6. Decreased
reproduction and
death of pathogens
• Host defenses
take effect
• Nutrient supply
decreases
• Wastes and
cell debris increase
• Antibacterial drug
7. Recovery—signs subside
8. Total recovery
FIG. 6.15 Onset and possible courses of infection.
Physiology of Infection
Onset and Development
Infectious agents can be present in the body for some
time before any clinical signs are apparent. The micro-
organisms must gain entry to the body, choose a hospitable
site, establish a colony, and begin reproducing (Fig. 6.15).

106 SECTION II Defense/Protective Mechanisms
exudate, or pus, is usually present, whereas a viral infec-
tion results in serous, clear exudates. The color and other
characteristics of the exudates and tissue may help to
identify the microorganism. Fig. 5.13 illustrates infection
of a burn wound by two different microorganisms. Tissue
necrosis at the site is likely as well. Lymphadenopathy
typically occurs and is manifest by swollen and tender
lymph nodes (Table 6.4).
Other local signs depend on the site of infection. For
instance, in the respiratory tract, local signs probably
include coughing or sneezing and difficulty in breathing.
In the digestive tract, local signs might include vomiting
or diarrhea.
Systemic Signs
Systemic signs include signs and symptoms common
to significant infections in any area of the body. Fever,
fatigue and weakness, headache, and nausea are all com-
monly associated with infection. The characteristics of
fever (pyrexia) may vary with the causative organism.
The body temperature may be very high or spiking
and may be accompanied by chills (see Chapter 5), or it
may be elevated only slightly. In some viral infections
the temperature is subnormal. With severe infection the
nervous system may be affected, resulting in confusion
or disorientation, seizures (convulsions), or loss of
consciousness.
pathogen. It may end when sufficient nutrients for the
numbers of microbes decline or when they are affected
by wastes from dead organisms and necrotic tissue, thus
decreasing their reproductive rate. The acute phase is
followed by the recovery or convalescent period, when
signs subside and body processes return to normal.
Patterns of Infection
Infections have varied patterns as defined by their
characteristics or location:
• Local infections—organism enters the body and remains
confined to a specific location
• Focal infections—pathogen spreads from a local infec-
tion to other tissues
• Systemic infections—infection spreads to several sites
and tissue fluids, typically through the circulatory
system
• Septicemia—caused by multiplication of pathogenic
organisms in the blood and the cause of sepsis, a
toxic inflammatory condition arising from the spread
of microbes
• Bacteremia—presence of bacteria in the blood
• Toxemia—presence of toxins in the blood
• Viremia—presence of viruses in the blood
• Mixed infections—several infectious agents concur-
rently establish themselves at the same site
• Acute infections—appear rapidly with severe symp-
toms but are short lived
• Chronic infections—less severe symptoms than acute
but persist for a long period
• Primary infections—initial or first time exposure/
infection
• Secondary infections—follow a primary infection and
are caused by a microbe other than that causing the
primary infection; opportunistic pathogens are often
the cause of a secondary infection
• Subclinical infections—do not cause apparent signs
or symptoms, although they may persist over long
periods of time
FIG. 6.16 Staphylococcus abscess. (From Braverman IM: Skin Signs
of Systemic Disease, ed 3, Philadelphia, 1998, Saunders.)
TABLE 6.4 Local and Systemic Signs of Bacterial
Infection
Local Signs Systemic Signs
Swelling Fever
Erythema (redness) Leukocytosis
Pain and tenderness Elevated erythrocyte
sedimentation rate
Lymphadenopathy Fatigue, weakness, anorexia
Exudate, purulent Headache, arthralgia
THINK ABOUT 6.4
a. Compare the prodromal period with the acute period of
infection, using your own experience as an example
(perhaps the last time you had a cold).
b. Compare subclinical infection and chronic infection.
c. Explain three reasons why infection may not occur after
microbes enter the body.
Signs and Symptoms of Infection
Local Signs
The local signs of infection are usually those of inflam-
mation: pain or tenderness, swelling, redness, and warmth
(Fig. 6.16). If the infection is caused by bacteria, a purulent

CHAPTER 6 Infection 107
localized in one lobe (consolidation) usually indicates
pneumococcal pneumonia.
Treatment and Antimicrobial Drugs
Guidelines for Use
It is not always necessary to use drugs to treat an infection
because the body’s normal defenses are often adequate
to limit the infection. Also the usual growth pattern of
the microbes is self-limiting, as the colony uses up
nutrients and produces more wastes. Current guidelines
attempt to limit the use of antimicrobial drug so that the
development of drug resistance can be reduced.
Increased use of antimicrobials has resulted in resistance
of many organisms to certain drugs. Through mutations,
Methods of Diagnosis
Organisms can be identified by culture and staining
techniques, using specific specimens such as sputum in
patients in whom tuberculosis is suspected. It is important
that specimens be procured carefully and examined
quickly to achieve an accurate result. Many organisms
can be grown easily on specific culture media in the
laboratory, whereas other organisms such as viruses
require a living host. Blood cultures may be examined
to check the distribution or possible spread of the infecting
agent. Frequently drug sensitivity tests, such as the
Kirby-Bauer method (disc diffusion method) and the
minimum inhibitory concentration (MIC) method (Fig.
6.17), are also instituted. Drug therapy is often ordered
immediately based on preliminary data and knowledge
of the common infections occurring at the particular site,
but it is helpful to establish the most effective therapy
as soon as possible, particularly if there may be serious
consequences to continued infection. A test that calls for
a culture may require several days.
• Blood tests, particularly variations in the numbers of
leukocytes, are another general indicator of infection.
With bacterial infections, leukocytosis, or an increase in
white blood cells, is common, whereas viral infections
often cause leukopenia, a reduction in the number
of leukocytes in the blood. Changes in the distribu-
tion of types of leukocytes occur as well (differential
count), depending on the organism—for example,
monocytosis or neutropenia. Neutrophils tend to
increase with acute infections, but lymphocytes and
monocytes increase with chronic infection. C-reactive
protein and erythrocyte sedimentation rate are usually
elevated and are a general indicator of inflammation
(see Chapter 5). Blood tests also are useful for detecting
antibodies and confirming a diagnosis, particularly in
the case of viral infection. None of these factors by
themselves provides a diagnosis, but they contribute
to a final diagnosis. In hepatitis B infections, such tests
can also be used to monitor the course of the infection
because different antibodies form at various points in
the course of this infection.
• Rapid tests, both those based on metabolic character-
istics and those based on serologic characteristics of
the organisms, provide quick and accurate identifica-
tion of the pathogens. Latex agglutination tests have
been developed to specifically identify the presence
of methicillin-resistant Staphylococcus aureus (MRSA).
• In addition, radiologic examination may be used to
identify the site of the infection and may assist in the
identification of the agent. For example, lung congestion
THINK ABOUT 6.5
List three local signs of infection and three systemic signs, and
explain what is causing these signs.
Same inoculum size of bacteria added
Control
GrowthB No growth
Increasing drug concentration
A
FIG. 6.17 A, Disc diffusion (Kirby-Bauer method). The clear areas
surrounding the antibiotic discs are called the zones of inhibition.
The size of these zones can be used to determine the effectiveness
of the antibiotic against the selected bacterium. B, Minimum
inhibitory concentration. The minimum inhibitory concentration
(MIC) for a specific agent is indicated by the absence of growth in
the tube containing the lowest drug concentration. (From VanMeter
K, Hubert R: Microbiology for the Healthcare Professional, St. Louis,
2010, Mosby.)

108 SECTION II Defense/Protective Mechanisms
Classification
Antimicrobials may be grouped in many ways in addition
to their chemical classification. This section provides an
overview of their classification, but a pharmacology
reference should be consulted for details.
• Antibiotics are drugs or substances that can kill or
inhibit the growth of microorganisms. Originally
derived from organisms, such as penicillin from mold,
many drugs are now synthetic or semisynthetic.
• Antimicrobials may be classified by the type of microbe
against which the drug is active, such as antibacterials,
antivirals, and antifungals. These drugs are unique to
the type of organism and are not interchangeable.
• Bactericidal refers to drugs that kill organisms, whereas
bacteriostatic applies to drugs that inhibit reproduc-
tion and rely on the host’s defenses to destroy the
organisms.
• Broad spectrum refers to antibacterials that are effective
against both gram-negative and gram-positive organ-
isms; narrow-spectrum agents act against either gram-
negative or gram-positive organisms, but not both.
Narrow-spectrum drugs are often preferred because
they are less likely to upset the balance of resident
flora in the body, which may result in an overgrowth
of one organism and cause a new or secondary infec-
tion. This new infection that arises while treating
another infection typically involves a different organism
and one that is antibiotic resistant and is known as a
superinfection. For example, after a prolonged course
of tetracycline, clients may develop a fungal (Candida)
infection in the mouth, and women may develop
vaginal candidiasis.
• The terms first-generation and second-generation drug
now appear in texts, first generation referring to the
original drug class and second generation referring
to a later, improved version of the same drug group.
Mode of Action
Antibacterial drugs may act in one of five ways:
1. Interference with bacterial cell wall synthesis is a
bactericidal mechanism and is seen in drugs such as
penicillin and vancomycin (see Fig. 6.3). Large doses
of such drugs are usually safe in humans because
human cells lack cell walls and are not directly affected
by the drug.
2. A second mechanism is to increase the permeability
of the bacterial cell membrane, allowing leakage of
bacterial cell contents; this mechanism is exemplified
by polymyxin.
3. Some drugs, such as tetracycline, interfere with protein
synthesis. These can have significant effects on the
developing fetus and young child.
4. Other agents interfere with nucleic acid synthesis.
These agents include ciprofloxacin and rifampicin.
5. In addition to disruption of protein and nucleic acid
synthesis, some agents can disrupt other critical
metabolic processes such as crucial enzyme production/
drug resistance has developed in several ways as some
bacteria have had changes in their metabolism, allowing
them to block drug action.
Improper use of an antibiotic can allow resistant
organisms to dominate an infection that may have had
few resistant organisms at the onset. Improper use may
also result in an inadequate concentration of the drug
being in contact for too short a time to be effective. In
this case the weaker organisms will be killed, whereas
stronger organisms with resistance mutations will survive,
thrive, and eventually dominate the infection.
Antimicrobial drugs may be administered prophylacti-
cally, before any invasive procedure, in high-risk clients
(eg, immunosuppressed patients). Before major mouth
or dental surgery, a prophylactic antibiotic is sometimes
administered because of the diverse flora of the oral cavity
and the potential entrance into the bloodstream through
the highly vascular tissue of the cavity. In treating an
acute infection, frequently a loading or larger dose is
administered initially to achieve effective blood levels
quickly; this is often paired with a shorter duration of
treatment.
Guidelines for effective drug therapy include the
following:
1. The drug should be taken at regular, evenly spaced
intervals over 24 hours to maintain blood levels that
are adequate to control and destroy the organisms.
2. Antimicrobial drugs should be taken until the pre-
scribed medication is completely used, even if the
symptoms have subsided, to ensure that the infection
is completely eradicated and prevent the development
of resistant organisms.
3. It is important to follow directions for administration
with respect to food or fluid intake because drugs
may be inactivated or drug absorption impaired if
consumed with certain foods.
4. It is best to identify the specific organism and choose
the most effective antibiotic that has the least effect
on resident flora and human tissue.
5. Because many individuals have drug allergies, obtain-
ing a complete drug history is essential, keeping in
mind that an allergy usually includes all members of
the chemically related drug group.
6. In viral infections, antiviral agents do not destroy the
virus but merely inhibit its reproduction, providing
an opportunity for host defenses to remove the virus.
Antibacterial agents (antibiotics) are not effective
against viruses. Antibacterials block synthesis of a
bacterial cell wall or interfere with bacterial metabolism,
but because viruses lack these components, antibacteri-
als have no effect on them. Antibacterial drugs may
be given in viral infection to reduce the risk of second-
ary bacterial infection in particularly vulnerable clients,
but this is not a common practice. Use of an antimi-
crobial drug for a viral illness such as the common
cold usually makes the person feel worse without any
benefit.

CHAPTER 6 Infection 109
entry into a cell but typically cannot destroy the virus.
They control but do not cure infection. In some cases the
drugs are effective only against actively replicating
viruses, not against those in the latent stage. These drugs
may interfere with attachment of the virus to the host
cell, with the shedding or disruption of the envelope or
capsid, with the action of enzymes such as reverse
transcriptase required for synthesis of DNA and RNA,
or with protein synthesis (Fig. 6.18). The drugs may be
virus specific; for example, acyclovir is effective against
herpes simplex viruses. Antiviral drugs can have signifi-
cant adverse effects on the host because they sometimes
alter viral interaction within the host cell.
Genomics is the basis for several new types of antiviral
drugs as the search continues for drugs targeting hepatitis
B or C, enteroviruses, HIV, and other viral pathogens.
One type of drug is based on blocking segments of viral
DNA or RNA with antisense molecules, rendering the
nucleic acid incapable of expression or replication.
Ribozymes are enzymes that split DNA or RNA into
segments and inhibit replication of viral genes in the
cell. These new agents appear to be active against several
types of viruses; a few drugs are in clinical trials.
Antifungal agents may interfere with mitosis in fungi
(eg, griseofulvin), or they may increase fungal membrane
permeability. Because fungi are eukaryotic cells with
many similarities to animal/human cells, systemic
antifungal agents are often toxic to the animal/human
cells, and treatment with these agents usually requires
strict medical supervision. Most antifungal agents are
One drug, cefotaxime, is a third-generation cephalo-
sporin and is related to the penicillin family. It has been
developed to be more active against gram-negative
microbes and multidrug resistant organisms. This drug
can pass through the blood-brain barrier; thus it is more
effective in treating some forms of meningitis as well.
Antiviral agents can decrease the reproduction of
viruses inside the host cell or prevent its attachment/
THINK ABOUT 6.6
a. Describe two mechanisms by which antibacterial drugs act
on microorganisms.
b. Why do most antibacterial drugs not destroy human cells?
c. Explain the benefit of narrow-spectrum over broad-
spectrum drugs.
d. Explain why a drug may have to be changed if an infection
persists.
activity. These agents include the sulfonamides and
trimethoprim.
The common problems with antibacterial drugs are allergic
reactions, both mild and severe, and digestive tract
discomfort. Penicillin and its related compounds may
cause anaphylaxis. Digestive tract discomfort may result
from irritation of the stomach or the change in the
intestinal resident flora caused by the antibacterial action,
often leading to diarrhea. Secondary infections, particu-
larly fungal, may develop as the balance of resident flora
is disturbed.
Virus
Host cell
Pleconaril blocks
attachment and
uncoating of
picornaviruses
(hepatitis A
and poliovirus)
Amantadine blocks
uncoating of
influenza A virus
Ganciclovir inhibits
viral DNA binding with
host DNA and
synthesis (eg, CMV)
Acyclovir inhibits
viral DNA synthesis
(herpes simplex)
Interferons
inhibit assembly
Indinavir
(protease inhibitor)
inhibits assembly
Zidovidine (AZT)
inhibits conversion of
viral RNA to DNA by
reverse transcriptase
Retrovirus
(eg, HIV)
FIG. 6.18 Examples of antiviral agents.

110 SECTION II Defense/Protective Mechanisms
This process would permit more rapid production to
meet an increased demand for vaccines.
In the spring of 2009 a new variant of type A influenza
was identified in Mexico. This form of influenza was
subsequently named 2009 type A H1N1 influenza. It was
highly contagious and caused significant morbidity and
mortality in children younger than 18 years and pregnant
women. It is thought that those older than 65 may have
some immunity to the virus from earlier outbreaks of
similar viruses. The H1N1 influenza virus is genetically
and antigenically similar to the virus that caused the
Spanish flu pandemic in 1918. It contains genetic mate-
rial from avian, pig, and human influenza types and is
expected to mutate rapidly. The designation H1N1 refers to
the specific type of antigens on the viral capsule (Fig. 6.19).
Some children developed severe acute respiratory
syndrome and died quickly from the infection in 2009.
At the time of writing it is unclear how the H1N1 virus
causes this response in young children and teens, par-
ticularly because most had no other health problems at
the time of infection. Possible explanations being
researched include formation of pulmonary emboli or
altered capillary exchange in the alveoli of the lung. H1N1
flu reemerged in North America and Europe in late
September of 2009. Immunization programs specific for
H1N1 were begun, but vaccine shortages and public
resistance to vaccines may lead to high rates of morbidity
and mortality in at-risk populations. In August of 2010
the WHO declared the H1N1 virus to have moved into
the post-pandemic period but cautioned that localized
outbreaks were still likely to continue.
The constituents of each multivalent vaccine, currently
three in number, are specifically designated each year.
The WHO monitors the incidence and movement of
the infection worldwide. Most new strains evolve in
Southeast Asia. World Health Organization scientists
collect and analyze specimens worldwide, then they check
the incidence of each strain so as to determine the most
effective vaccine components. For example, one antigen
might be called A/New Caledonia/20/99, which indicates
the type (A), the geographic origin (New Caledonia), the
strain number (20), and the year of isolation (1999) for a
particular viral strain.
The vaccine may be administered as an intranasal
spray (live vaccine) or intramuscular injection (inactivated
or killed). It is now recommended that all individuals
be immunized annually between November and February.
For many health care providers, immunization is a condi-
tion of employment. The vaccine that remains effective
from 2 to 4 months reduces the severity of the infection
in cases in which it does not provide total prevention.
The influenza virus was first isolated and identified
in 1933. It is transmitted directly by respiratory droplet
or indirectly by contact with a contaminated object. The
virus can survive at room temperature as long as 2 weeks.
It is destroyed by heat and some disinfectants such as
ethanol and detergents.
administered topically to skin or mucous membranes.
Amphotericin B may be administered intravenously for
systemic infections.
Antiprotozoal agents have a similar characteristic to
the antifungal agents in that the targets are eukaryotic
cells and can be toxic to human cells. Many pathogenic
protozoa also have several stages in their life cycles that
require treatment with different agents at different stages.
With the exception of quinine, most antiprotozoal agents
are synthetic, such as metronidazole and pyrimethamine.
Antihelminthic agents have a variety of modes of action.
These agents share the same drawback as the antifungal
and antiprotozoal agents, as they are attacking eukaryotic
organisms. Some are designed to suppress a metabolic
process that is more important to the helminth than the
host, whereas others inhibit the movement of the worm
or prevent it from remaining in the specific organ. Some
examples of these agents are piperazine (paralyzes muscles
in the worm’s body wall), niclosamide (prevents ATP
formation), and ivermectin (blocks nerve transmission).
Example of Infection: Influenza (Flu)
Influenza is a viral infection that may affect both the upper
and the lower respiratory tracts. Annually on average 5%
to 20% of the population is affected in North America.
Although the influenza infection itself may be mild, it is
frequently complicated by secondary bacterial infections
such as pneumonia. The mortality rate from complications
can be high, particularly in those older than 65 years
and those with chronic cardiovascular or respiratory
disease. Influenza may occur sporadically, in epidemics
or pandemics, usually during colder weather. Serious
pandemics occurred in 1918 to 1919 (Spanish flu) with
a very high mortality rate, again in 1957 (Asian flu), and
in 1968 (Hong Kong flu). In 1997 there was an outbreak
in Hong Kong of an avian flu transmitted from chickens
to humans, and this potential crossover to a new species
host is being closely monitored. Epidemiologists predict
that serious pandemics will occur in the future.
The influenza viruses are classified as RNA viruses
of the myxovirus group. There are three subgroups of
the influenza virus: type A, the most prevalent pathogen,
type B, and type C. Types A and B cause epidemics and
pandemics that tend to occur in cycles. The influenza
virus, particularly type A, is difficult to control because
it undergoes frequent mutations leading to antigenic shifts
or variations. This limits the ability of individuals to
develop long-term immunity to the virus and requires
the preparation of new vaccines annually to match the
predicted new strains of the virus for the coming year.
Unfortunately, new strains may emerge during the winter
months, creating a slightly different infection. Some years
the epidemic has occurred at an earlier time and individu-
als have not yet received their immunization. Technology
to produce a new type of vaccine using viruses grown
in a cell culture rather than in eggs is being developed.

CHAPTER 6 Infection 111
congestion. The infection is often self-limiting, although
fatigue may persist for several weeks afterward. Contin-
ued fever or other signs usually indicate complications,
such as the development of bacterial pneumonia.
Treatment is symptomatic and supportive unless
bacterial infection or respiratory complications occur.
Certain antiviral drugs such as oseltamivir (Tamiflu),
if given promptly, may reduce the symptoms in some
cases. The CDC recommended the use of oseltamivir or
zanamivir (Relenza) for the 2008 to 2009 flu season. In
2010 the WHO reported that 99.6% of the strains of H1N1
were resistant to oseltamivir. Other antiviral treatment
has been tried, but adverse effects have occurred.
The virus enters the cells in the respiratory mucosa,
replicates, and causes inflammation and necrosis of the
tissue as well as shedding of the virus into the secretions
and adjacent cells. The inflammation may also involve the
sinuses, pharynx, and auditory tube, causing congestion
and obstruction. The widespread necrosis of the respira-
tory mucosa typical of influenza leaves the area vulnerable
to secondary infection by bacteria, which are often resident
flora of the upper respiratory tract. The virus may extend
into the lungs and cause viral pneumonia.
Influenza usually has a sudden, acute onset with fever
and chills, marked malaise, headache, general muscle
aching, sore throat, unproductive or dry cough, and nasal
The genetic change that enables a flu strain to jump from
one animal species to another, including humans, is called “ANTIGENIC SHIFT.”
Antigenic shift can happen in three ways: The new strain
may further
evolve to
spread from
person to
person. If so,
a flu pandemic
could arise.
B
Bird influenza A strain
Bird host
HA
antigen
HA
antigen
NA
antigen
NA
antigen
Human influenza A strain Human
host
Intermediate
host (pig)
Intermediate
host cell
Link Studio for NIAID
Genetic mixing
Viral entry
iintermediate host cell
New influenza
strain
C
A-1
Without
undergoing
genetic change,
a bird strain of
influenza A
can jump
directly from a
duck or other
aquatic bird to
humans.
A duck or other
aquatic bird passes a bird
strain of influenza A to
an intermediate host
such as a chicken or a pig.
Without
undergoing
genetic
change,
a bird strain of
influenza A
can jump
directly from a
duck or other
aquatic bird
to an
intermediate
animal host
and then to
humans.
A person passes
a human strain of
influenza A to the
same chicken or pig. (Note that reassortment can
occur in a person who is infected with two flu strains.)
When the viruses infect the same cell,
the genes from the bird strain mix
with genes from the human
strain to yield a new strain.
The new
strain can
spread
from the
intermediate
host to
humans.
A-2
A-3
A-4
FIG. 6.19 History of the 2009 Type A H1N1 influenza
virus showing antigenic shift. (From the National
Institute of Allergy and Infectious Disease [NIAID].)

112 SECTION II Defense/Protective Mechanisms
C H A P T E R S U M M A R Y
• Infections are caused by pathogenic microorganisms.
They may be classified and identified by their char-
acteristics, such as size, shape, component parts, and
requirements for growth and reproduction.
• Bacteria are single-cell organisms enclosed within a
cell wall and sometimes an outer capsule. They
reproduce by binary fission. They may secrete exo-
toxins, endotoxins, or enzymes that damage the human
host cells.
• A virus is an intracellular parasite requiring a living
host cell for reproduction. Each viral particle contains
either DNA or RNA. They cause disease by destroying
human cells during replication or by altering human
cell DNA.
• Only a few fungi are pathogenic; Candida is an example
of an opportunistic member of resident flora in the
human body.
• Helminths are parasitic worms that can infect the gut,
liver, bloodstream, or lungs.
• Prions are protein-like molecules that cause deforma-
tion of proteins within the central nervous system.
Their mode of action is not well understood. Prions
are transmitted by ingestion of undercooked meat
contaminated with prions or by organ donation from
an infected donor.
• Resident or normal flora refers to the large variety of
nonpathogenic microbes normally present in diverse
sites in the body, such as skin, mouth, nose and
pharynx, intestines, and vagina.
• The degree of virulence of a specific pathogen deter-
mines the severity of the resulting infection.
• Transmission of pathogens may occur by direct or
indirect contact, including oral or respiratory droplet,
sexual contact, fomite, or vector.
• The infection cycle may be broken by reducing the
reservoir of microbes, blocking transmission, or increas-
ing host resistance.
• Universal precautions, as outlined by the CDC, assume
that blood and body fluids from any person may be
a source of infection; therefore appropriate preventive
measures must be taken with all individuals.
• Signs of infection are not apparent until sufficient
numbers of microorganisms are established and
reproducing in the body. Local signs of infection include
inflammation and necrosis of tissue. Systemic signs
include fever, headache, fatigue, anorexia, and malaise.
THINK ABOUT 6.7
a. Explain why influenza continues to be a common infection
in North America.
b. State three ways the incidence might be reduced.
c. Explain why secondary bacterial infection is common in
persons with influenza.
CASE STUDY A
Viral Gastroenteritis
G.B., 15 months old, had severe vomiting and diarrhea for 12
hours and no intake of fluid or food. She began vomiting blood
and was quite dehydrated and lethargic. She was taken to the
hospital, admitted, and treated with intravenous fluid, electro-
lytes, and glucose. A fecal specimen was submitted to the labora-
tory for diagnosis.
The report indicated an infection with rotavirus, an RNA
virus and member of the reovirus class. This virus causes gas-
troenteritis. The incubation period is 1 to 2 days, and the virus
is transmitted by the fecal-oral route, probably at G.B.’s nursery
school, where several children have been ill. The virus replicates
in the epithelial cells at the tip of villi in the small intestine.
This cell damage results in lack of absorption of fluid and
nutrients.
1. Explain, using pathophysiology, how the virus could cause
bleeding.
2. Using your knowledge of normal physiology, explain how
the vomiting and diarrhea as well as the lack of intake
could affect the child physiologically.
3. Describe several factors probably contributing to
transmission in this case. How long before the vomiting
began was the child probably exposed to the virus?
4. What does the classification “RNA virus” mean?
5. Why is it necessary to determine the specific cause of the
vomiting and diarrhea? Is any other treatment for
rotavirus infection indicated?
CASE STUDY B
Upper Respiratory Infection
K.W., age 9, suddenly developed a fever with very sore throat,
headache, and malaise. When examined, her pharynx was red
and her tonsils enlarged with pus on the surface and in the
crypts. Her cervical lymph nodes were also enlarged. The physi-
cian suspected a bacterial infection and therefore took a throat
swab for examination and prescribed a course of penicillin so
as to prevent complications.
Laboratory examination confirmed streptococcal infection
and continued treatment with penicillin. This microbe is gram
positive, and it adheres to epithelial cells in the pharynx. It
produces several exotoxins and resists phagocytosis. It is spread
by oral droplet.
1. Suggest several precautions to prevent further
transmission in this case.
2. What factor indicated this was a bacterial infection rather
than viral?
3. Describe the typical appearance of Streptococcus under a
microscope.
4. Explain the meaning of gram positive and how this
classification is helpful.
5. K.W. wanted to stop her medication several days later
when the headache and fever disappeared. State two
reasons why this is not advisable.

CHAPTER 6 Infection 113
• Antiviral drugs limit viral replication, thus reducing
the active stage, but do not kill the virus or cure the
infection.
• Influenza is a respiratory infection caused by a virus
that frequently mutates, preventing long-term immu-
nity by vaccination or experiencing the infection.
Epidemics are common. Secondary bacterial infections
such as pneumonia are common, particularly in the
elderly.
• Infection may be eradicated without drug treatment
when the microbial colony becomes limited in growth,
perhaps because of insufficient nutrients, or when host
defenses destroy the invader.
• Antibacterial drugs are classified by their activity
(bactericidal or bacteriostatic, narrow or broad spec-
trum) and mechanism (eg, interference with protein
or cell wall synthesis).
• Adverse effects of antibacterial agents are allergic
reactions, secondary infections, and increasing numbers
of drug-resistant microbes.
S T U D Y Q U E S T I O N S
1. Explain how each of the following contributes to
the virulence of bacteria:
a. production of endotoxin
b. spore formation
c. presence of a capsule
2. Predict how each of the following could reduce
host resistance to infection:
a. bone marrow damage
b. circulatory impairment
c. puncture wound
3. Explain two benefits of resident flora.
4. Differentiate infection from inflammation.
5. Describe three ways of reducing transmission of a
respiratory infection.
6. Explain each of the following:
a. why the clinical signs of infection are not
present immediately after the microorganism
enters the body
b. why infection can often be cured without drug
treatment
c. why antibacterial agents might be prescribed
for an infection
7. Explain why it is important to take the complete
course of antimicrobial medication prescribed.
8. Explain why viral infections are difficult to treat.
9. State two local and two systemic signs of
influenza.
10. Explain why a new influenza vaccine is prepared
each year and consists of several components.

114
Review of the Immune System
Components of the Immune
System
Elements of the Immune System
Antigens
Cells
Antibodies or Immunoglobulins
Complement System
Chemical Mediators
Immune Response
Diagnostic Tests
Process of Acquiring Immunity
Outcome of Infectious Disease
Emerging and Reemerging Infectious
Diseases and Immunity
Bioterrorism
Tissue and Organ Transplant Rejection
Rejection Process
Treatment and Prevention
Hypersensitivity Reactions
Type I: Allergic Reactions
Causative Mechanism
Clinical Signs and Symptoms
Anaphylaxis or Anaphylactic
Shock
Type II: Cytotoxic Hypersensitivity
Type III: Immune Complex
Hypersensitivity
Type IV: Cell-Mediated or Delayed
Hypersensitivity
Autoimmune Disorders
Mechanism
Example: Systemic Lupus
Erythematosus
Immunodeficiency
Causes of Immunodeficiency
Effects of Immunodeficiency
Acquired Immunodeficiency Syndrome
History
Agent
Transmission
Women With AIDS
Children With AIDS
People Over 50 With HIV/AIDS
Case Studies
Chapter Summary
Study Questions
C H A P T E R O U T L I N E
After studying this chapter, the student is expected to:
1. Describe the normal immune response.
2. List the components of the immune system and the
purpose of each.
3. Explain the four methods of acquiring immunity.
4. Discuss tissue transplant rejection and how it is treated.
5. Describe the mechanism and clinical effects of each of the
four types of hypersensitivity reactions.
6. Explain the effects of anaphylaxis.
7. Discuss the mechanism of autoimmune disorders.
8. Describe the disorder systemic lupus erythematosus, its
pathophysiology, clinical manifestations, diagnostic tests,
and treatment.
9. Explain the causes and effects of immunodeficiency.
10. Describe the cause, modes of transmission, and
implications for health professionals of acquired
immunodeficiency syndrome.
11. Describe the course, effects, and complications of HIV/
AIDS.
L E A R N I N G O B J E C T I V E S
acquired immunodeficiency
syndrome
allergen
anaphylaxis
antibiotics
antimicrobial
antiviral
autoantibodies
bronchoconstriction
colostrum
complement
cytotoxic
encephalopathy
erythema
fetus
glycoprotein
hypogammaglobulinemia
hypoproteinemia
mast cells
monocytes
mononuclear phagocytic
system
mutate
placenta
polymerase chain reaction
prophylactic
pruritic
replication
retrovirus
splenectomy
stem cells
thymus
titer
vesicles
K E Y T E R M S
C H A P T E R 7
Immunity

CHAPTER 7 Immunity 115
of the cells. The thymus is significant during fetal
development in that it programs the immune system
to ignore self-antigens. When this process is faulty, the
body may attack its own tissues as nonself, causing
some of the autoimmune disorders. The blood and
circulatory system provide a major transportation and
communication network for the immune system.
• Chemical mediators include chemicals such as hista-
mines and interleukins that can play a major role in
the body’s immune reaction.
• The major components of the immune system and
their functions are summarized in Table 7.1.
Elements of the Immune System
Antigens
Antigens (or immunogens) are either foreign substances
or human cell surface molecules that are unique (except
in identical twins) in each individual. They are usually
composed of complex proteins or polysaccharides, or a
combination of molecules such as glycoproteins. Antigens
activate the immune system to produce specific antibodies.
These specific antibodies are produced by B lymphocytes.
The antigens representing self are present on an
individual’s plasma membranes. These antigen molecules
are coded by a group of genes inherited from the parents,
called major histocompatibility complex (MHC), located
on chromosome 6. Owing to the large number of possible
combinations of genes that may be inherited from the
parents, it is unlikely that two individuals would ever
have the same antigens, with the exception of identical
twins. The MHC has an essential role in the activation
and regulation of the immune response as well as intercel-
lular communications. MHC molecules are useful in
detecting changes in cell membranes altered by viruses
or cancerous changes and alerting the immune system
to their presence. Human MHC is also known as human
leukocyte antigen (HLA), because it was first detected
on the cell membranes of leukocytes. These antigens are
also used to provide the close match for a tissue transplant;
the immune system will be activated by the presence of
cells with different MHC molecules. The immune system
generally tolerates self-antigens on its cells, thus no
immune response is initiated against its own cells.
Autoimmune diseases are an exception in which the
immune system no longer recognizes self from nonself
and begins to attack its own cells/structures or organs.
Cells
The macrophage is critical in the initiation of the immune
response. Macrophages develop from monocytes (see
Chapter 10), part of the mononuclear phagocytic system
that was formerly known as the reticuloendothelial
system. Macrophages occur throughout the body in such
tissues as the liver, lungs, and lymph nodes. They are
large phagocytic cells that intercept and engulf foreign
material and then process and display the antigens from
Review of the Immune System
The immune system is responsible for the body’s defenses.
The system has a nonspecific response as shown in
Chapter 5 and a specific response mechanism discussed
in this chapter. In specific defense the immune system
is responding to particular substances, cells, toxins, or
proteins, which are perceived as foreign to the body and
therefore unwanted or potentially dangerous. The specific
immune response is intended to recognize and remove
undesirable material from cells, tissues, and organs.
Components of the Immune System
The immune system consists of lymphoid structures,
immune cells, tissues concerned with immune cell
development, and chemical mediators:
• The lymphoid structures, including the lymph nodes, the
spleen and tonsils, the intestinal lymphoid tissue, and
the lymphatic circulation, form the basic structure within
which the immune response can function (Fig. 7.1).
• The immune cells, or lymphocytes, as well as macro-
phages provide the specific mechanism for the
identification and removal of foreign material.
• Tissues involving immune cell production and develop-
ment include the bone marrow and the thymus. All
immune cells originate in the bone marrow, and the
bone marrow and thymus have roles in the maturation
Lymph nodes—
inguinal
Lymph nodes—
intestinal
Spleen
Palatine tonsil
Lymph nodes—cervical
Lymphatic vessels
Lymph nodes—
axillary
Pharyngeal tonsil
(adenoid)
Thymus
Bone marrow
FIG. 7.1 Structures in the immune system.

116 SECTION II Defense/Protective Mechanisms
special function of recognizing and reacting with antigens
in the body. The two groups of lymphocytes, B lympho-
cytes and T lymphocytes, determine which type of
immunity will be initiated, either cell-mediated immunity
or humoral immunity, respectively.
T lymphocytes (T cells) arise from stem cells, which are
incompletely differentiated cells held in reserve in the bone
marrow and then travel to the thymus for further dif-
ferentiation and development of cell membrane receptors.
Cell-mediated immunity develops when T lymphocytes with
protein receptors on the cell surface recognize antigens on
the foreign material on their cell membranes; the lym-
phocytes respond to this display, thus initiating the
immune response (Fig. 7.2). Macrophages also secrete
chemicals such as monokines and interleukins (see Table
7.1) that play a role in the activation of additional lym-
phocytes and in the inflammatory response, which
accompanies a secondary immune response.
The primary cell in the immune response is the lym-
phocyte, one of the leukocytes or white blood cells produced
by the bone marrow (see Chapter 11). Mature lymphocytes
are termed immunocompetent cells—cells that have the
TABLE 7.1 Major Components of the Immune System and Their Functions
Antigen Foreign substance, microbes, or component of cell that stimulates immune response
Antibody Specific protein produced in humoral response to bind with antigen
Autoantibody Antibodies against self-antigen; attacks body’s own tissues
Thymus Gland located in the mediastinum, large in children, decreasing size in adults; site of maturation
and proliferation of T lymphocytes
Lymphatic tissue and organs Contain many lymphocytes; filter body fluids, remove foreign matter, immune response
Bone marrow Source of stem cells, leukocytes, and maturation of B lymphocytes
Cells
Neutrophils White blood cells for phagocytosis; nonspecific defense; active in inflammatory process
Basophils White blood cells: bind IgE, release histamine in anaphylaxis
Eosinophils White blood cells: participate in allergic responses and defense against parasites
Monocytes White blood cells: migrate from the blood into tissues to become macrophages
Macrophages Phagocytosis; process and present antigens to lymphocytes for the immune response
Mast cells Release chemical mediators such as histamine in connective tissue
B lymphocytes Humoral immunity–activated cell becomes an antibody-producing plasma cell or a B memory cell
Plasma cells Develop from B lymphocytes to produce and secrete specific antibodies
T lymphocytes White blood cells: cell-mediated immunity
Cytotoxic or killer T cells Destroy antigens, cancer cells, virus-infected cells
Memory T cells Remember antigen and quickly stimulate immune response on reexposure
Helper T cells Activate B and T cells; control or limit specific immune response
NK lymphocytes Natural killer cells destroy foreign cells, virus-infected cells, and cancer cells
Chemical Mediators
Complement Group of inactive proteins in the circulation that, when activated, stimulate the release of other
chemical mediators, promoting inflammation, chemotaxis, and phagocytosis
Histamine Released from mast cells and basophils, particularly in allergic reactions; causes vasodilation and
increased vascular permeability or edema, also contraction of bronchiolar smooth muscle, and
pruritus
Kinins (eg, bradykinin) Cause vasodilation, increased permeability (edema), and pain
Prostaglandins Group of lipids with varying effects; some cause inflammation, vasodilation and increased
permeability, and pain
Leukotrienes Group of lipids, derived from mast cells and basophils, which cause contraction of bronchiolar
smooth muscle and have a role in development of inflammation
Cytokines (messengers) Includes lymphokines, monokines, interferons, and interleukins; produced by macrophages and
activated T lymphocytes; stimulate activation and proliferation of B and T cells, communication
between cells; involved in inflammation, fever, and leukocytosis
Tumor necrosis factor (TNF) A cytokine active in the inflammatory and immune responses; stimulates fever, chemotaxis,
mediator of tissue wasting, stimulates T cells, mediator in septic shock (decreasing blood
pressure), stimulates necrosis in some tumors
Chemotactic factors Attract phagocytes to area of inflammation

CHAPTER 7 Immunity 117
cells destroy the target cell by binding to the antigen
and releasing damaging enzymes or chemicals, such as
monokines and lymphokines, which may destroy foreign
cell membranes or cause an inflammatory response, attract
macrophages to the site, stimulate the proliferation of more
lymphocytes, and stimulate hematopoiesis. Phagocytic
cells then clean up the debris. The helper CD4 positive T cell
facilitates the immune response. A subgroup, the memory
T cells, remains in the lymph nodes for years, ready to
activate the response again if the same invader returns.
the surface of target cells and directly destroy the invading
antigens (see Fig. 7.2). These specially programmed T cells
then reproduce, creating an “army” to battle the invader,
and they also activate other T and B lymphocytes. T cells
are primarily effective against virus-infected cells, fungal
and protozoal infections, cancer cells, and foreign cells
such as transplants. There are a number of subgroups of
T cells, marked by different surface receptor molecules,
each of which has a specialized function in the immune
response (see Table 7.1). The cytotoxic CD8 positive T-killer
1. Lymphoblasts—
bone marrow stem cells
2. Bone marrow
Plasma cells
Memory B cells
Variable
region
6. Antibody
5. Antigen stimulation
Antibody in circulation
Macrophage
Constant
region
Binding sites
for specific antigen
Foreign substance
Presence
required
HUMORAL OR
ANTIBODY-
MEDIATED
IMMUNITY
CELL-
MEDIATED
IMMUNITY
Processed
antigen
4. Migrate to lymph nodes4. Migrate to lymph nodes
6. Various types of
sensitized T cells
in circulation
• Helper T cell
• Memory T cell
• Suppressor T cell
• Cytotoxic T cell
2. Thymus
MATURATION
3. T cells 3. B cells
FIG. 7.2 Development of cellular and humoral immunities.

118 SECTION II Defense/Protective Mechanisms
Complement involves a group of inactive proteins,
numbered C1 to C9, circulating in the blood. When an
antigen-antibody complex binds to the first complement
component, C1, a sequence of activating steps occurs
(similar to a blood clotting cascade). Eventually this
activation of the complement system results in the destruc-
tion of the antigen by lysis when the cell membrane is
damaged, or some complement fragment may attach to a
microorganism, marking it for phagocytosis. Complement
activation also initiates an inflammatory response.
Chemical Mediators
A number of chemical mediators such as histamine or
interleukins may be involved in an immune reaction,
depending on the particular circumstances. These chemi-
cals have a variety of functions, such as signaling a cellular
response or causing cellular damage (see Chapter 5). A
brief summary is provided in Table 7.1.
Immune Response
Because of unique antigens, often a protein, on the surface
of an individual’s cells, that person’s immune system
can distinguish self from nonself (foreign) and can thus
detect and destroy unknown material. Normally the
immune system ignores “self” cells, demonstrating toler-
ance. When the immune system recognizes a specific
nonself-antigen as foreign, it develops a specific response
to that particular antigen and stores that particular
response in its memory cells for future reference if the
antigen reappears in the body. It is similar to a surveillance
system warning of attack and the subsequent mobilization
of an army for defense. For example, lymphoid tissue in
the pharynx, such as tonsils and adenoids, can capture
antigens in material that is inhaled or ingested and process
the immune response. Note that a person must have
been exposed to the specific foreign antigen and must
have developed specific immunity to it (such as antibod-
ies) before this defense is effective. This response is usually
repeated each time the person is exposed to a particular
substance (antigen) because the immune system has
memory cells. Immune responses that occur after the
first introduction of the antigen are usually more rapid
and intense than the initial response. In destroying foreign
material, the immune system is assisted by nonspecific
defense mechanisms such as phagocytosis and the inflam-
matory response. By removing the foreign material, the
immune system also plays a role in preparing injured
tissue for healing.
Two subgroups of T cells have gained prominence as
markers in patients with acquired immunodeficiency
syndrome (AIDS). T-helper cells have “CD4” molecules
as receptors on the cell membrane, and the killer T cells
have “CD8” molecules. These receptors are important
in T-cell activation. Although the CD8+ killer cells are
primarily cytotoxic, CD4+ T cells regulate all the cells in
the immune system, the B and T lymphocytes, macro-
phages, and natural killer (NK) cells, by secreting the
“messenger” cytokines. The human immunodeficiency
virus (HIV) destroys the CD4 cells, thus crippling the
entire immune system. The ratio of CD4 to CD8 T cells
(normal ratio, 2 : 1) is closely monitored in people infected
with HIV as a reflection of the progress of the infection,
using a technique known as flow cytometry.
The B lymphocytes or B cells are responsible for humoral
immunity through the production of antibodies or immu-
noglobulins. B cells are thought to mature in the bone
marrow and then proceed to the spleen and lymphoid
tissue. After exposure to antigens, and with the assistance
of T lymphocytes, they become antibody-producing
plasma cells (see Fig. 7.2). B lymphocytes act primarily
against bacteria and viruses that are outside body cells.
B-memory cells that provide for repeated production of
antibodies also form in humoral immune responses.
Natural killer cells are lymphocytes distinct from the
T and B lymphocytes. They destroy, without any prior
exposure and sensitization, tumor cells and cells infected
with viruses.
Antibodies or Immunoglobulins
Antibodies are a specific class of proteins termed immu-
noglobulins, and are present in different body fluids. Each
has a unique sequence of amino acids (variable portion,
which binds to antigen) attached to a common base
(constant region that attaches to macrophages). Antibodies
bind to the specific matching antigen, destroying it. This
specificity of antigen for antibody, similar to a key opening
a lock, is a significant factor in the development of
immunity to various diseases. Antibodies are found in
the general circulation, forming the gamma region of the
plasma proteins, as well as in lymphoid structures.
Immunoglobulins are divided into five classes, each of
which has a special structure and function (Table 7.2).
Specific immunoglobulins may be administered to treat
diseases such as Guillain-Barré syndrome, an autoimmune
disease that attacks the peripheral nervous system and
can cause progressive paralysis.
Complement System
The complement system is frequently activated during an
immune reaction with IgG or IgM class immunoglobulins.
APPLY YOUR KNOWLEDGE 7.1
Predict three reasons why the immune system might not respond
correctly to foreign material in the body.
THINK ABOUT 7.1
a. Describe two differences between B and T lymphocytes.
b. Where is IgG found in the body?
c. Which lymphocyte has a role in both cell-mediated and
humoral immunity?
d. Describe the development of antibodies to a specific
antigen.

CHAPTER 7 Immunity 119
Diagnostic Tests
Many new and improved diagnostic techniques are
emerging, and more details on these techniques may
be found in reference works on serology or diagnostic
methods. Tests may assess the levels and functional quality
(qualitative and quantitative) of serum immunoglobulins
or the titer (measure) of specific antibodies. Identifica-
tion of antibodies may be required for such purposes
as detecting Rh blood incompatibility (indirect Coombs
test) or screening for HIV infection (by enzyme-linked
immunosorbent assay [ELISA]). Pregnant women are
checked for levels of antibodies, particularly for German
measles, to establish their potential for complications if
they are exposed to this disease during pregnancy, which
could result in fetal death. During hepatitis B infection,
changes in the levels of antigens and antibodies take place,
and these changes can be used to monitor the course of
the infection and level of immunity (see Chapter 17).
The number and characteristics of the lymphocytes in
the circulation can be examined as well. Extensive HLA
(MHC) typing is required to complete tissue matching
before transplant procedures.
When the plasma membrane of malignant neoplastic
cells is abnormal, the immune system may be able to
identify these cells as “foreign” and remove them, thus
playing an important role in the prevention of cancer
(see Chapter 20). It has been noted that individuals
frequently develop cancer when the immune system is
depressed as with an infection or increased stress.
However, not all cancer cells are identifiable as foreign;
therefore the immune system may not remove them. The
immune system directs the response to an antigen, but
it also has built-in controls to prevent excessive response.
Two limiting factors are the removal of the causative
antigen during the response and the short life span of
the chemical messengers. Tolerance to self-antigens
prevents improper responses.
TABLE 7.2 Immunoglobulins and Their Functions
Characteristic Structure Function
IgG
Monomer
Most common antibody in the blood; produced in both primary and secondary immune
responses; activates complement; includes antibacterial, antiviral, and antitoxin
antibodies; crosses placenta, creates passive immunity in newborn
IgM
Pentamer
Bound to B lymphocytes in circulation and is usually the first to increase in the immune
response; activates complement; forms natural antibodies; is involved in blood ABO
type incompatibility reaction
IgA
Monomer,
dimer
Found in secretions such as tears and saliva, in mucous membranes, and in colostrum to
provide protection for newborn child
IgE
Monomer
Binds to mast cells in skin and mucous membranes; when linked to allergen, causes
release of histamine and other chemicals, resulting in inflammation
IgD
Monomer
Attached to B cells; activates B cells
THINK ABOUT 7.2
a. Explain why the immune system is considered a specific
defense.
b. Explain why the immune system must distinguish between
self and nonself.

120 SECTION II Defense/Protective Mechanisms
in the memory. Young children are subject to many
infections until they establish a pool of antibodies. As
one ages, the number of infections declines. However,
when there are many strains of bacteria or viruses causing
a disease—for example, the common cold (which has
more than 200 causative organisms, each with slightly
different antigens)—an individual never develops antibod-
ies to all the organisms, and therefore he or she has
recurrent colds. The influenza virus, which affects the
respiratory tract, has several antigenic forms—for example,
type A and type B. These viruses have various strains
that mutate or change slightly over time. For this reason,
a new influenza vaccine is manufactured each year, its
composition based on the current antigenic forms of the
virus most likely to cause an epidemic of the infection.
Immunity is acquired four ways (Table 7.3). Active
immunity develops when the person’s own body develops
antibodies or T cells in response to a specific antigen
introduced into the body. This process takes a few weeks,
but the result usually lasts for years because memory B
and T cells are retained in the body.
• Active natural immunity may be acquired by direct
exposure to an antigen—for example, when a person
has an infection and then develops antibodies.
• Active artificial immunity develops when a specific
antigen is purposefully introduced into the body,
stimulating the production of antibodies. For example,
a vaccine is a solution containing dead or weakened
(attenuated) organisms that stimulate the immune
system to produce antibodies but does not result in
the disease itself. Work continues on the development
of vaccines using antigenic fragments of microbes or
genetically altered forms. A long list of vaccines is
available, including those for protection against polio,
diphtheria, measles, and chickenpox. Infants begin a
regular schedule of immunizations/vaccines shortly
Process of Acquiring Immunity
Natural immunity is species specific. For example, humans
are not usually susceptible to infections common to many
other animals. Innate immunity is gene specific and is
related to ethnicity, as evident from the increased sus-
ceptibility of North American aboriginal people to
tuberculosis.
The immune response consists of two steps:
• A primary response occurs when a person is first
exposed to an antigen. During exposure the antigen
is recognized and processed, and subsequent develop-
ment of antibodies or sensitized T lymphocytes is
initiated (Fig. 7.3). This process usually takes 1 to 2
weeks and can be monitored by testing serum antibody
titer. Following the initial rise in seroconversion the
level of antibody falls.
• A secondary response results when a repeat exposure
to the same antigen occurs. This response is much
more rapid and results in higher antibody levels than
the primary response. Even years later the memory
cells quickly stimulate production of large numbers
of the matching antibodies or T cells.
When a single strain of bacteria or virus causes a
disease, the affected person usually has only one episode
of the disease because the specific antibody is retained
Secondary
anti-A response
121086420
S
er
um
a
nt
ib
od
y
tit
er
Primary
anti-A response
Antigen A
Weeks
Antigen A
FIG. 7.3 Graph illustrating primary and secondary immune
responses. (Adapted from Abbas AK, Lichtman AH: Cellular and
Molecular Immunology, ed 5, Philadelphia, 2003, Saunders.)
THINK ABOUT 7.3
a. Predict why a person usually has chickenpox only once in
a lifetime but may have influenza many times.
b. Explain how the secondary response to an antigen is
faster and greater than the primary response.
TABLE 7.3 Types of Acquired Immunity
Type Mechanism Memory Example
Natural active Pathogens enter body and cause illness; antibodies form
in host
Yes Person has chickenpox once
Artificial active Vaccine (live or attenuated organisms) is injected into
person; no illness results, but antibodies form
Yes Person has measles vaccine and gains
immunity
Natural passive Antibodies passed directly from mother to child to
provide temporary protection
No Placental passage during pregnancy or
ingestion of breast milk
Artificial passive Antibodies injected into person (antiserum) to provide
temporary protection or minimize severity of infection
No Gammaglobulin if recent exposure to
microbe

CHAPTER 7 Immunity 121
Emerging and Reemerging Infectious Diseases
and Immunity
Emerging infectious diseases are those newly identified
in a population. Reemerging infectious diseases were
previously under control, but unfortunately not all
individuals participate in immunization programs;
therefore infectious disease outbreaks persist. An example
is the reemergence of measles in the United States. In
2000 the CDC declared that the measles virus had been
eliminated in the United States. Due to the importation
of the virus from other countries and a decrease in vac-
cinations, in 2014, the CDC reported 592 cases in 18
outbreaks. These infectious diseases are on the rise due
to globalization, drug resistance, and many other factors.
Bioterrorism
Biologic warfare and bioterrorism use biologic agents to
attack civilians or military personnel. Concern continues
about the possibility of bioterrorism using altered anti-
genic forms of common viruses or bacteria. Such bio-
weapons would have widespread impact on populations
because current immunizations do not protect against
them. It is important to recognize that large outbreaks
of diseases formerly controlled by vaccines may represent
acts of bioterrorism. Such outbreaks should be reported
to the local authorities as soon as they are recognized.
Tissue and Organ Transplant Rejection
Replacement of damaged organs or tissues by healthy
tissues from donors is occurring more frequently as the
success of such transplants improves. Skin, corneas, bone,
kidneys, lungs, hearts, and bone marrow are among the
more common transplants. Transplants differ according
to donor characteristics, as indicated in Table 7.4. In most
cases transplants, or grafts, involve the introduction of
foreign tissue from one human, the donor, into the body
of the human recipient (allograft). Because the genetic
after birth to reduce the risk of serious infections and
in hopes of eradicating some infectious diseases. The
Centers for Disease Control and Prevention (CDC)
publishes immunization recommendations for all age
groups. A toxoid is an altered or weakened bacterial
toxin that acts as an antigen in a similar manner. A
booster is an additional immunization given perhaps
5 or 10 years after initial immunization that “reminds”
the immune system of the antigen and promotes a
more rapid and effective secondary response. Booster
immunizations are currently used for tetanus.
Passive immunity occurs when antibodies are transferred
from one person to another. These are effective immedi-
ately, but offer only temporary protection because memory
has not been established in the recipient, and the antibod-
ies are gradually removed from the circulation. There
are also two forms of passive immunity:
• Passive natural immunity occurs when IgG is transferred
from mother to fetus across the placenta. Breast milk
also supplies maternal antibodies. These antibodies
protect the infant for the first few months of life.
• Passive artificial immunity results from the injection of
antibodies from a person or animal into a second
person. An example is the administration of rabies
antiserum or snake antivenom. Sometimes immuno-
globulins are administered to an individual who has
been exposed to an organism but has not been immu-
nized to reduce the effects of the infection (for example,
hepatitis B).
Outcome of Infectious Disease
The occurrence of many infectious diseases, such as polio
and measles, has declined where vaccination rates have
been high, creating “herd immunity”—a phenomenon
in which a high percentage of a population is vaccinated
or has experienced a prior infection of the disease, thus
decreasing chances of acquiring and spreading an infec-
tious disease. Believing smallpox (variola) had been
eradicated in many countries by the mid-1950s, the United
States discontinued the smallpox vaccine in 1972. The
World Health Organization (WHO) worked toward
worldwide eradication, and the last case of naturally
occurring smallpox was recorded in 1977.
Polio vaccination was implemented in 1954, and cases
are a rare occurrence today in developed areas of the
world. Recent outbreaks of measles and mumps in North
America are the result of inadequate revaccination of
teens.
The search continues for additional vaccines against
AIDS and malaria, tuberculosis, and other widespread
infections. Research is also continuing on genetic vac-
cines, in which only a strand of bacterial DNA forms
the vaccine, thus reducing risks from injection of the
microorganism itself. Immunotherapy is an expanding
area of cancer research in the search for new and more
specific therapies.
THINK ABOUT 7.4
a. Explain why a newborn infant is protected from infection
by the measles virus immediately after birth but later will
be given the measles vaccine.
b. Explain the differences between active artificial immunity
and passive natural immunity.
APPLY YOUR KNOWLEDGE
a. Predict reasons why antibodies might not form in
response to an antigen.
b. Suggest reasons why individuals might not want
vaccinations.
7.2

122 SECTION II Defense/Protective Mechanisms
makeup of cells is the same only in identical twins, the
obstacle to complete success of transplantation has been
that the immune system of the recipient responds to the
HLAs (MHCs) in foreign tissue, rejecting and destroying
the graft tissue.
Rejection Process
Rejection is a complex process, primarily involving a
type IV cell-mediated hypersensitivity reaction (see the
Hypersensitivity Reactions section), but also involving
a humoral response, both of which cause inflammation
and tissue necrosis. The rejection process eventually
destroys the organ, so that transplanted organs often
must be replaced. Survival time of a transplant is increased
when the HLA match is excellent, the donor is living
(less risk of damage to donor tissue), and immunosup-
pressive drugs are taken on a regular basis. Corneas
and cartilage lack a blood supply; therefore rejection
is less of a problem with these transplanted tissues;
however, rejections can occur. With improved surgical
techniques and better drug therapy, transplants are now
lasting a longer time and significantly prolonging the
recipient’s life.
It now appears that neonates and young infants can
receive heart transplants from donors without a good
tissue match. Rejection does not occur because the infant’s
immune system is not yet mature and does not respond
to the foreign tissue. The long-term effects are not known,
but the results to date are encouraging. Because heart
transplants in infants are limited by organ size as well
as organ availability, the removal of the HLA restrictions
would make more heart transplants available when
needed and more donor hearts could be used rather than
wasted.
One type of rejection occurs when the host’s, or recipi-
ent’s, immune system rejects the graft (host-versus-graft
disease [HVGD]), a possibility with kidney transplants.
The other type of rejection that occurs is when the graft
tissue contains T cells that attack the host cells (graft-
versus-host disease [GVHD]), as may occur in bone
TABLE 7.4 Types of Tissue or Organ Transplants
Allograft (homograft) Tissue transferred between members
of the same species but may differ
genetically (eg, one human to
another human)
Isograft Tissue transferred between two
genetically identical bodies (eg,
identical twins)
Autograft Tissue transferred from one part of
the body to another part on the
same individual (eg, skin or bone)
Xenograft
(heterograft)
Tissue transferred from a member of
one species to a different species
(eg, pig to human)
THINK ABOUT 7.5
Explain why immunosuppressive drugs should be taken on a
regular and permanent basis following a transplant.
marrow transplants or in transfused blood products with
viable T-lymphocytes (TA-GVHD transfusion-associated
graft versus host disease).
Rejection may occur at any time:
• Hyperacute rejection occurs immediately after trans-
plantation as circulation to the site is reestablished.
This is a greater risk in patients who have preexisting
antibodies, perhaps from prior blood transfusions. The
blood vessels are affected, resulting in lack of blood
flow to the transplanted tissue.
• Acute rejection develops after several weeks when
unmatched antigens cause a reaction.
• Chronic or late rejection occurs after months or years,
with gradual degeneration of the blood vessels.
Treatment and Prevention
Immunosuppression techniques are used to reduce the
immune response and prevent rejection. The common
treatment involves drugs such as cyclosporine, azathio-
prine (Imuran), and prednisone, a glucocorticoid (see
Chapter 5). The drugs must be taken on a continuous
basis and the patient monitored for signs of rejection.
The use of cyclosporine has been very successful in
reducing the risk of rejection, but the dosage must be
carefully checked to prevent kidney damage. Many new
drugs are also under investigation in clinical trials. The
major concern with any immunosuppressive drug is the
high risk of infection, because the normal body defenses
are now limited. Infections are often caused by oppor-
tunistic microorganisms, microbes that usually are
harmless in healthy individuals (see Chapter 6). Persons
with diabetes frequently require transplants of kidneys
and other tissues, and this group of patients is already
at risk for infection because of vascular problems (see
Chapter 16). Loss of the surveillance and defense functions
of the immune system has also led to increased risk of
lymphomas, skin cancers, cervical cancer, and colon cancer
in those taking antirejection drugs. Dental professionals
should be aware of the high incidence of gingival hyper-
plasia in patients taking cyclosporine. (See Fig. 14.27 for
a photograph of gingival hyperplasia.)
Hypersensitivity Reactions
Hypersensitivity or allergic reactions are unusual and
sometimes harmful immune responses to normally
harmless substances. These reactions stimulate an inflam-
matory response. There are four basic types of hyper-
sensitivities (Table 7.5), which differ in the mechanism
causing tissue injury. The World Allergy Organization
has developed a standard nomenclature to identify allergic

CHAPTER 7 Immunity 123
mast cells (see Table 7.1). These chemical mediators cause
an inflammatory reaction involving vasodilation and
increased capillary permeability at the site (eg, the nasal
mucosa), resulting in swelling and redness of the tissues.
This initial release of histamine also irritates the nerve
endings, causing itching or mild pain.
Other chemical mediators, including prostaglandins
and leukotrienes, are released at the site in a second
phase of the reaction, and these cause similar effects. If
the sensitized mast cells are located in the nasal mucosa,
the antigen-antibody reaction causes the typical signs of
hay fever. If sensitization occurs in the respiratory mucosa
in the lungs, the chemical mediators also cause bron-
choconstriction (contraction of the bronchiolar smooth
muscle and narrowing of the airway) and a release of
mucus in the airways, resulting in obstruction of the
airways, or asthma.
Clinical Signs and Symptoms
The signs and symptoms of an allergic reaction occur on
the second or any subsequent exposure to the specific
allergen because the first exposure to the allergen causes
only the formation of antibodies and sensitized mast
cells. The target area becomes red and swollen, there
may be vesicles or blisters present, and usually the area
is highly pruritic or itchy.
Hay Fever or Allergic Rhinitis
An allergic reaction in the nasal mucosa causes frequent
sneezing, copious watery secretions from the nose, and
itching. Because the nasal mucosa is continuous with the
mucosa of the sinuses and the conjunctiva of the eyelid,
the eyes are frequently red, watery, and pruritic as well.
Hay fever, or allergic rhinitis, is usually seasonal because
it is related to plant pollens in the air, but some people
are susceptible to multiple allergens such as molds or
dusts and can exhibit signs at any time of year.
Food Allergies
Food allergies may be manifested in several ways. When
an inflammatory reaction occurs in the mucosa of the
digestive tract it results in nausea, vomiting, or diarrhea.
In some cases, food allergies may cause a rash on the
skin called hives, which are large, hard, raised red masses
problems and differentiate them from similar conditions—
for example, allergic rhinitis, allergic asthma, and allergic
contact dermatitis.
Type I: Allergic Reactions
Allergies are common and appear to be increasing in
incidence and severity, particularly in young children.
Allergic reactions take many forms, including skin rashes,
hay fever, vomiting, and anaphylaxis. A tendency toward
allergic conditions is inherited, and the manifestation of
such an allergy in a family is referred to as an atopic
hypersensitivity reaction. The antigen causing the reaction
is often called an allergen. The specific allergen may be
a food, a chemical, pollen from a plant, or a drug. One
person may be allergic to a number of substances, and
these may change over time. Common allergenic foods
include shellfish, nuts, and strawberries. Hypersensitivi-
ties occur frequently with drugs such as acetylsalicylic
acid (ASA;aspirin), penicillin, sulfa, and local anesthetics.
Cross-allergies are common; therefore an allergy to one
form of penicillin means that an individual is likely allergic
to all drugs in the penicillin family.
There has been a significant increase in the number
of children who experience severe type I hypersensitivity
reactions. Most of these reactions occur when the child
is exposed to a particular food, such as peanuts or other
members of the legume family. The reactions may be
severe enough to result in anaphylaxis. Once diagnosed,
the child carries an emergency injector or EpiPen, which
can be administered to prevent severe anaphylaxis result-
ing in bronchospasm and hypovolemia.
Causative Mechanism
Type I hypersensitivity begins when an individual is
exposed to a specific allergen and for some reason
develops IgE antibodies from B lymphocytes. These
antibodies attach to mast cells in specific locations (Fig.
7.4), creating sensitized mast cells. Mast cells are connective
tissue cells that are present in large numbers in the mucosa
of the respiratory and digestive tracts. On reexposure to
the same allergen, the allergen attaches to the IgE antibody
on the mast cell, stimulating the release of chemical
mediators such as histamine from granules within the
TABLE 7.5 Types of Hypersensitivities
Type Example Mechanism Effects
I Hay fever; anaphylaxis IgE bound to mast cells; release of histamine
and chemical mediators
Immediate inflammation and
pruritus
II ABO blood incompatibility IgG or IgM reacts with antigen on cell–
complement activated
Cell lysis and phagocytosis
III Autoimmune disorders: systemic lupus
erythematosus, glomerulonephritis
Antigen–antibody complex deposits in
tissue–complement activated
Inflammation, vasculitis
IV Contact dermatitis: transplant rejection Antigen binds to T lymphocyte; sensitized
lymphocyte releases lymphokines
Delayed inflammation

124 SECTION II Defense/Protective Mechanisms
trunk, or extremities (see Chapter 8). It is associated with
ingested foods, irritating fabrics, and a dry atmosphere.
There may be remissions as the child develops, but the
condition may recur in adulthood.
Asthma
A lung disorder, asthma may result from an allergic
response in the bronchial mucosa that interferes with
airflow. Asthma is covered in more detail in Chapter 13.
that are highly pruritic. In severe cases, hives also occur
on the pharyngeal mucosa and may obstruct airflow;
therefore it is important to watch for respiratory difficulty
associated with any allergenic skin rash.
Atopic Dermatitis or Eczema
Eczema or atopic dermatitis is a chronic skin condition,
often with a genetic component, common in infants and
young children. The skin rash may occur on the face,
1. First exposure
Allergen
Immune system
Mast cells and basophils
in tissues2. IgE forms
Second exposure
Allergen
5. Inflammation
Edema, redness,
and pruritus
Vasodilation and
increased permeability
of blood vessels
3. Sensitized mast
cells and basophils
4. Release of
mediators
(histamine)
FIG. 7.4 Type I hypersensitivity, allergic reaction.

CHAPTER 7 Immunity 125
THINK ABOUT 7.6
Explain three reasons why anaphylaxis is a serious problem.
EMERGENCY TREATMENT FOR
ANAPHYLAXIS
• Inject epinephrine immediately if it is available. Persons
who have experienced acute allergic or anaphylactic
reactions often carry an injectable epinephrine (EpiPen)
with them because there are only seconds or minutes
between the exposure to the allergen and the body’s
collapse. Epinephrine acts to increase blood pressure by
stimulating the sympathetic nervous system; it causes
vasoconstriction and increases the rate and strength of
the heartbeat. This drug also relaxes the bronchial smooth
muscle, opening the airway.
• If available, oxygen should be administered immediately
along with an injectable antihistamine.
• Seek emergency help as soon as possible by dialing 9-1-1.
• Treat for shock, keeping the person warm.
• Cardiopulmonary resuscitation (CPR) should be initiated if
necessary.
TABLE 7.6 Signs and Symptoms of Anaphylaxis
Manifestation Rationale
Skin: pruritus, tingling,
warmth, hives
Histamine and chemical mediators
irritate sensory nerves
Respiration: difficulty
in breathing, cough,
wheezing, tight
feeling
Chemical mediators cause
contraction of smooth muscle
in bronchioles, edema, and
increased secretions, leading to
narrow airways and lack of
oxygen
Cardiovascular:
decreased blood
pressure
Chemical mediators cause general
vasodilation, with rapid, weak
pulse, perhaps irregular leading
to low blood pressure;
sympathetic nervous system
responds by increasing rate
Central nervous
system: anxiety and
fear (early); weakness,
dizziness, and loss of
consciousness
Early, sympathetic response; later,
lack of oxygen to the brain
because of low blood pressure
and respiratory obstruction
THINK ABOUT 7.7
a. Explain the importance of determining the specific causes
of allergic reactions.
b. Explain the purpose of including allergies in a health
history.
Frequently a triad of atopic conditions including hay
fever, eczema, and asthma occurs in family histories.
Anaphylaxis or Anaphylactic Shock
Anaphylaxis is a severe, life-threatening, systemic
hypersensitivity reaction resulting in decreased blood
pressure, airway obstruction, and severe hypoxia. Com-
monly caused by exposure to latex materials such as
gloves, insect stings, ingestion of nuts or shellfish,
administration of penicillin, or local anesthetic injections,
the reaction usually occurs within minutes of the
exposure.
■ Pathophysiology
Large amounts of chemical mediators are released from
mast cells into the general circulation quickly, resulting
in two serious problems. General or systemic vasodilation
occurs with a sudden, severe decrease in blood pressure.
In the lungs, edema of the mucosa and constriction of
the bronchi and bronchioles occur, obstructing airflow
(Fig. 7.5). The marked lack of oxygen that results from
both respiratory and circulatory impairment causes loss
of consciousness within minutes.
■ Signs and Symptoms
The initial manifestations of anaphylaxis include a general-
ized itching or tingling sensation over the body, coughing,
and difficulty in breathing. This is quickly followed by
feelings of weakness, dizziness or fainting, and a sense
of fear and panic (Table 7.6). Edema may be observed
around the eyes, lips, tongue, hands, and feet. Hives, or
urticaria, may appear on the skin. General collapse soon
follows with loss of consciousness, usually within minutes.
■ Treatment
It is essential that an epinephrine injection be administered
immediately. This acts in the same way as the natural
hormone epinephrine.
Antihistamine drugs (diphenhydramine [Benadryl] or
chlorpheniramine [Chlor-Trimeton]) are useful in the
early stages of an allergic reaction because they block
the response of the tissues to the released histamine
(blocking histamine-1 receptors on cells). Glucocorticoids
or cortisone derivatives may be used for severe or pro-
longed reactions because they reduce the immune
response and stabilize the vascular system. Glucocorticoids
can be administered by injection or by mouth, or they
can be applied topically to the skin (see Chapter 5).
Skin tests can be performed to determine the specific
cause of an allergy. This procedure involves scratching
the skin and dropping a small amount of purified antigen
on the scratch. The site is observed for erythema or
redness, which indicates a positive skin reaction. In many
cases, the person with an allergy can determine the
contributing factors by observation and keep a log of
daily exposure to foods, pollens, and other allergens.
Avoidance of the suspected antigen will keep the person
symptom free. Desensitization treatments involving
repeated injections of small amounts of antigen to create
a blocking antibody may reduce the allergic response.

126 SECTION II Defense/Protective Mechanisms
or by releasing cytolytic enzymes related to complement
activation. An example of this reaction is the response
to an incompatible blood transfusion (see Chapter 10).
A person with type A blood has A antigens on the red
blood cells and anti-B antibodies in the blood. A person
with type B blood has anti-A antibodies. If type B blood
from a donor is added to the recipient’s type A blood,
Type II: Cytotoxic Hypersensitivity
In type II hypersensitivity, often called cytotoxic hyper-
sensitivity, the antigen is present on the cell membrane
(Fig. 7.6). The antigen may be a normal body component
or foreign. Circulating IgG antibodies react with the
antigen, causing destruction of the cell by phagocytosis
Antigen in body
IgE antibody
Mast cell
SKIN
Itching
CARDIOVASCULAR
All blood vessels
Nerve endings
irritated
Decreased blood pressure,
faint, weak
5. Severe oxygen
deficit to the
brain
Airways obstructed;
cough, dyspnea
Smooth
muscle
contracts
Edema
Mucus
4. Vasodilation and
increased capillary
permeability
3. Mast cell releases
large amount of histamine
into general circulation
1. Second or subsequent
exposure to antigen
2. Antigen binds
with IgE antibodies
Constriction of bronchioles;
release of mucus
LUNGS
FIG. 7.5 The effects of anaphylaxis (type I hypersensitivity reaction).

CHAPTER 7 Immunity 127
deposits occur in many tissues. With reduced use of
animal serum for passive immunization, serum sickness
is much less common today. An Arthus reaction is a
localized inflammatory and tissue necrosis that results
when an immune complex lodges in the blood vessel
wall, causing vasculitis. One example is “farmer’s lung,”
a reaction to molds inhaled when an individual handles
moldy plant matter.
Type IV: Cell-Mediated or
Delayed Hypersensitivity
This type of hypersensitivity is a delayed response by
sensitized T lymphocytes to antigens, resulting in release
of lymphokines or other chemical mediators that cause
an inflammatory response and destruction of the antigen
(Fig. 7.8). The tuberculin test (eg, the Mantoux skin test)
uses this mechanism to check for prior exposure to the
organism causing tuberculosis. Once in the body, this
mycobacterium has the unusual characteristic of causing
a hypersensitivity reaction in the lungs, even when an
active infection does not develop (see Chapter 13). When
a small amount of antigen is injected into the skin of a
previously sensitized person, an area of inflammation
develops at the injection site, indicating a positive test.
This positive reaction does not necessarily indicate active
infection, but it does indicate exposure of the body to
the tuberculosis organism at some prior time. An x-ray
and sputum culture will determine the absence or presence
of active tuberculosis. As mentioned previously in this
chapter, organ transplant rejection belongs in this
category.
Contact dermatitis, or an allergic skin rash, is caused
by a type IV reaction to direct contact with a chemical.
Such chemicals include cosmetics, dyes, soaps, and metals.
Other examples include skin reactions to plant toxins
such as poison ivy. These skin reactions usually do not
occur immediately after contact; these reactions usually
take more than 24 hours.
Of importance to health care workers is the high
frequency of sensitivity to rubber and latex products,
particularly with the increased use of latex gloves. Latex
sensitivity may result from type I or type IV reactions.
In most cases, a type IV reaction causes a rash, 48 to 96
hours after contact. The type I response is more rare but
also more serious, manifested as asthma, hives, or
anaphylaxis. Contact with latex proteins may occur
through skin or mucous membranes, by inhalation, or
by internal routes. More severe reactions often occur when
mucous membranes are involved, such as the mouth or
vagina of latex-sensitive individuals. Also metals such
as nickel, which are frequently found in instruments or
equipment used by health care professionals, can trigger
an immune response. Such sensitivities are usually
indicated by the location of the rash. The skin is red and
pruritic, and vesicles and a serous exudate may be present
at the site.
RBC-A destroyed
RBC-type A
Surface antigen A
4. Lysis of
cell wall
of RBC—
type A
1. Anti-A antibodies
in type B blood mix
with type A blood
and attach to
2. Target cell with
surface antigen
3. Complement
activated
5. Phagocytosis
FIG. 7.6 Type II hypersensitivity, cytotoxic reaction.
the antigen-antibody reaction will destroy the red blood
cells (hemolysis) in the type A blood (see Fig. 7.6). Another
type of blood incompatibility involves the Rh factor, which
is discussed in Chapter 22.
Type III: Immune Complex Hypersensitivity
In this type of reaction, the antigen combines with the
antibody, forming a complex, which is then deposited
in tissue, often in blood vessel walls, and also activates
complement (Fig. 7.7). This process causes inflammation
and tissue destruction. A number of diseases are now
thought to be caused by immune complexes, including
glomerulonephritis (see Chapter 18) and rheumatoid
arthritis (see Chapter 9). Serum sickness refers to the
systemic reaction that occurs when immune complex

128 SECTION II Defense/Protective Mechanisms
When self-tolerance is lost, the immune system is unable
to differentiate self from foreign material. The autoantibod-
ies then trigger an immune reaction leading to inflam-
mation and necrosis of tissue. Some individuals may
lose their immune tolerance following tissue destruction
and subsequent formation of antibodies to the damaged
cell components. Aging may lead to loss of tolerance to
self-antigens. A genetic factor also appears to be involved
in autoimmune diseases, as evidenced by increased
familial incidence.
Example: Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is a chronic inflam-
matory disease that affects a number of systems; therefore
it can be difficult to diagnose and treat. The name of this
systemic disorder is derived from the characteristic facial
rash, which is erythematous and occurs across the nose
and cheeks, resembling the markings of a wolf (lupus)
(Fig. 7.10). The rash is now often referred to as a “butterfly
rash,” reflecting its distribution. The condition is becoming
better known and more cases are identified in the early
stages, improving the prognosis. Certain drugs may cause
a lupus-like syndrome, which usually disappears when
the drug is discontinued. Discoid lupus erythematosus is
a less serious version of the disease affecting only the
skin.
Occurrence is uncertain because many cases are prob-
ably not diagnosed in the early stages. Systemic lupus
erythematosus affects primarily women and becomes
Autoimmune Disorders
Autoimmune disorders occur when the immune system
cannot distinguish between self and nonself antigens.
The exact causes of autoimmune diseases/disorders are
still unknown.
Mechanism
Autoimmune disorders occur when individuals develop
antibodies to their own cells or cellular material, and
these antibodies then attack the individual’s tissues (Fig.
7.9). The term autoantibodies refers to antibodies formed
against self-antigens. There is greater recognition as well
as better diagnosis and treatment of autoimmune disorders
now due to advances in diagnostic procedures. Some of
these disorders affect single organs or tissues (eg, Hashi-
moto thyroiditis) and some are generalized (eg, systemic
lupus erythematosus). Other examples are rheumatic
fever, myasthenia gravis, scleroderma, pernicious anemia,
and hyperthyroidism (Graves disease).
Self-antigens are usually tolerated by the immune
system, and there is no reaction to one’s own antigens.
BLOOD
Antibody
Antigen
Neutrophils
3. Complexes
deposit in
blood
vessels
or tissues
4. Activation of
complement
1. Antibody
binds
to antigen
2. Immune
complexes form
in circulation
5. Inflammatory
response at
site of deposit
6. Release of lysosomal
enzymes and chemical
mediators
7. Tissue
damage
FIG. 7.7 Type III hypersensitivity, immune complex reaction.
THINK ABOUT 7.8
Differentiate between the hypersensitivity reactions involving
an incompatible blood transfusion and that involved in a
tuberculin test for tuberculosis.

CHAPTER 7 Immunity 129
normal apoptosis and removal of damaged cells, leaving
cell contents such as nucleic acids in the tissues.
■ Pathophysiology
Systemic lupus erythematosus is characterized by the
presence of large numbers of circulating autoantibodies
against DNA, platelets, erythrocytes, various nucleic
acids, and other nuclear materials (antinuclear antibodies
[ANAs]). Immune complexes, especially those with
anti-DNA antibody, are deposited in connective tissues
anywhere in the body, activating complement and causing
inflammation and necrosis. Vasculitis, or inflammation
of the blood vessels, develops in many organs, impairing
blood supply to the tissue. The resulting ischemia (inad-
equate oxygen for the cells) leads to further inflammation
and destruction of the tissue. This process usually takes
place in several organs or tissues. Common sites include
the kidneys, lungs, heart, brain, skin, joints, and digestive
tract. Diagnosis is based on the presence of multiple
system involvement (a minimum of four areas) and
laboratory data showing the presence of autoantibodies.
These autoantibodies may be present for many years
before the first symptoms appear.
■ Clinical Signs and Symptoms
The clinical presentation of SLE varies greatly because
different combinations of effects develop in each indi-
vidual, often making it difficult to diagnose the disorder.
Many persons present initially with skin rash or joint
inflammation, which progresses to lung or kidney involve-
ment. Common signs and symptoms are listed in Table
7.7. The course is progressive and is marked by remissions
and exacerbations.
■ Diagnostic Tests
The presence of numerous ANAs, especially anti-DNA,
as well as other antibodies in the serum is indicative of
SLE. Lupus erythematosus (LE) cells, mature neutrophils
containing nuclear material (Fig. 7.11) in the blood, are
a positive sign. Complement levels are typically low, and
the erythrocyte sedimentation rate (ESR) is high, indicating
the inflammatory response. Frequently counts of
erythrocytes, leukocytes, lymphocytes, and platelets are
low. Additional immunologic tests for various antibodies
may be required to confirm the diagnosis. Also, all organs
and systems need to be examined for inflammation and
damage.
■ Treatment
Systemic lupus erythematosus is usually treated by a
rheumatologist, and the specific treatment often depends
on the severity and symptoms of the disease. Frequently
prednisone, a glucocorticoid, is the drug used to reduce
the immune response and subsequent inflammation (see
Chapter 5). High doses may be taken during an exacerba-
tion or periods of stress, but the dose should be reduced
when the patient is in remission to minimize the side
manifest between the ages of 10 and 50 years. The
incidence is higher in African Americans, Asians, Hispan-
ics, and Native Americans.
The specific cause has not been established, but it
appears to be multifactorial and includes genetic, hor-
monal (estrogen levels), and environmental (ultraviolet
light exposure) factors. A single lupus gene has not been
identified, but genes increasing susceptibility to auto-
immune disorders have been identified. A number of
research projects are in process, including studies of the
complement system and immune systems in affected
individuals and their families. Another focus concerns
identification of a possible genetic defect interfering with
Host T lymphocyte
5. Tissue
destruction
2. Sensitization of
T lymphocyte
Antigen
1. Macrophage presents antigen
3. Release of
lymphokines
4. Inflammation and
lysis of antigen-
bearing cells of
the tissue
FIG. 7.8 Type IV hypersensitivity, cell-mediated delayed
hypersensitivity.

130 SECTION II Defense/Protective Mechanisms
NORMAL IMMUNE RESPONSE
AUTOIMMUNE DISEASE
1. Invaders
(antigen)
FIRST EXPOSURE SECOND EXPOSURE
DNA
RNA
Autoantibody
2. Antibodies
form
3. Antibodies remove
invading antigens
1. Immune system
forms antibody to
self-antigens
2. Autoantibodies
attack self-antigens
and immune
complexes deposit
3. Inflammation and
tissue damage
occur
4. Antibody remains
for future protection
FIG. 7.9 The autoimmune process.
FIG. 7.10 “Butterfly rash” with distribution on the cheeks and
over the nose associated with systemic lupus erythematosus.
(Courtesy of Dr. M. McKenzie, Toronto, Ontario, Canada.)
FIG. 7.11 An LE cell present with systemic lupus erythematosus.
Note the large LE mass that has been phagocytized by the neutrophil
(arrow) and is taking up most of the cytoplasm of the cell. The cell
nucleus has been pushed to the side. (From Stevens ML: Fundamentals
of Clinical Hematology, Philadelphia, 1997, Saunders.)

CHAPTER 7 Immunity 131
TABLE 7.7 Common Manifestations of Systemic Lupus Erythematosus
Joints Polyarthritis, with swollen, painful joints, without damage; arthralgia
Skin Butterfly rash with erythema on cheeks and over nose or rash on body; photosensitivity—exacerbation
with sun exposure; ulcerations in oral mucosa; hair loss
Kidneys Glomerulonephritis with antigen–antibody deposit in glomerulus, causing inflammation with marked
proteinuria and progressive renal damage
Lungs Pleurisy—inflammation of the pleural membranes, causing chest pain
Heart Carditis—inflammation of any layer of the heart, commonly pericarditis
Blood vessels Raynaud phenomenon—periodic vasospasm in fingers and toes, accompanied by pain
Central nervous system Psychoses, depression, mood changes, seizures
Bone marrow Anemia, leukopenia, thrombocytopenia
THINK ABOUT 7.9
a. Define the term and describe the autoantibodies present
in SLE.
b. Explain why it is important to reduce the number of
exacerbations.
c. Explain why SLE may be difficult to diagnose and treat.
TABLE 7.8 Examples of Immunodeficiency Disorders
Deficit/ Defect Primary Disorder Secondary
B cell (humoral) Hypogammaglobulinemia (congenital) Kidney disease with loss of globulins
T cell (cell mediated) Thymic aplasia Hodgkin disease (cancer of the lymph nodes)
DiGeorge syndrome AIDS (HIV infection); temporary with some viruses
B and T cell Inherited combined immunodeficiency syndrome
(CIDS)
Radiation, immunosuppressive drugs, cytotoxic drugs
(cancer chemotherapy)
Phagocytes Inherited chronic granulomatous diseases (CGDs) Immunosuppression (glucocorticoid drugs,
neutropenia); diabetes (decreased chemotaxis)
Complement Inherited deficit of one or more systems Malnutrition (decreased synthesis), components of
liver disease—cirrhosis
Immunodeficiency
Immunity is the body’s capacity to fight foreign sub-
stances. Immunodeficiency results in a compromised or
a lack of an immune response.
Causes of Immunodeficiency
Immunodeficiency results from a loss of function, partial
or total, of one or more components of the immune system
leading to increased risk of infection and cancer. Examples
are presented in Table 7.8. The problem may be acute
and short term or chronic. Deficits may be classified by
etiology or component.
Primary deficiencies involve a basic developmental
failure somewhere in the system (eg, in the bone marrow’s
production of stem cells), the thymus, or the synthesis
of antibodies. Many defects result from a genetic or
congenital abnormality and are first noticed in infants
and children. There may be associated problems that
affect other organs and systems in the body. Examples
include an inherited X-linked hypogammaglobulinemia
(low antibody levels because of a B-cell defect) or a
developmental defect known as DiGeorge syndrome
(hypoplasia of the thymus).
Secondary or acquired immunodeficiency refers to loss
of the immune response resulting from specific causes
effects of the drug. Nonsteroidal antiinflammatory drugs
are also useful. The antimalarial drug, hydroxychloro-
quine, appears to reduce exacerbations. Additional therapy
may be required for specific system involvement. Limiting
damage to vital organs improves quality of life. One
research effort continues to seek drugs that block only
the B-lymphocyte response to antigens, reducing antibody
formation.
Minimizing exacerbations by avoiding aggravating
factors and by promptly treating acute episodes is a major
goal. Avoidance of sun exposure and excessive fatigue
assists in preventing flare-ups. Warning signs of exacerba-
tions include increasing fatigue, rash, pain, fever, and
headache.
The prognosis for SLE is much improved now with
early diagnosis and careful treatment, providing most
individuals with an active life and normal life span.

132 SECTION II Defense/Protective Mechanisms
Acquired Immunodeficiency Syndrome
Acquired immunodeficiency syndrome (AIDS) is a
chronic infectious disease caused by the human immu-
nodeficiency virus (HIV), which destroys helper T lym-
phocytes, causing loss of the immune response and
increased susceptibility to secondary infections and cancer.
It is characterized by a prolonged latent period followed
by a period of active infection (Fig. 7.12). An individual
is considered HIV-positive when the virus is known to be
present in the body but few if any clinical signs have
developed. Acquired immunodeficiency syndrome is the
stage of active infection, with marked clinical manifesta-
tions and multiple complications. An individual may be
HIV positive for many years before he or she develops
AIDS.
Current therapy has extended the time before develop-
ment of symptomatic AIDS; however, eventually the
active stage develops. The infection may not be diagnosed
in the early stages because of this latent asymptomatic
period; this contributes to greater spread of the disease.
If a patient presents with an unusual infection such as
Pneumocystis carinii pneumonia or a cancer such as Kaposi
sarcoma (termed an AIDS indicator disease) and no other
pathology, this often marks the presence of active HIV
infection and signals the need for HIV testing.
History
The first case of AIDS was recognized in 1981, although
there is evidence that there were earlier, sporadic cases.
Acquired immunodeficiency syndrome is now considered
a worldwide pandemic, and cases still are multiplying,
particularly in sub-Saharan Africa and Asia. Many cases
are not diagnosed or recorded; therefore the estimates
may not reflect the true extent of the infection. It is no
longer a disease of homosexual men; more women and
children are now infected. In 1995, AIDS was the leading
cause of death in the 25- to 40-year-old group; now, with
treatment, the life span has been greatly extended from
the original 6 months to many years, and AIDS is con-
sidered to be a chronic disease.
The CDC reports that as of 2012 there were 1.2 million
cases in the United States. In 2014, more than 44,000 new
cases were identified. Race/ethnicity of persons newly
diagnosed in the United States in 2014 shows the
following:
• 44% African American (black)
• 27% Caucasian (white)
• 23% Hispanic (Latino)
• 2% Asian or Pacific Islander
• 1% American Indian or Alaskan indigenous
and may occur at any time during the lifespan. Loss of
the immune response can occur with infection, particularly
viral infection, splenectomy (removal of the spleen),
malnutrition or liver disease (hypoproteinemia—low
serum protein level), use of immunosuppressive drugs in
clients with organ transplants, and radiation and che-
motherapy for cancer treatment. Immunodeficiency
associated with cancer is a result of malnutrition and
blood loss as well as the effects of treatment, all of which
depress bone marrow production of leukocytes (see
Chapter 20). Glucocorticoid drugs such as prednisone,
a common long-term treatment for chronic inflammatory
diseases as well as for cancer, cause decreased leukocyte
production, atrophy of lymph nodes, and suppression
of the immune response (see Chapter 5). Also it is thought
that severe stress, physical or emotional, may cause a
temporary immunodeficiency state owing to high levels
of glucocorticoid secretion in the body. Another well-
known cause of secondary immunodeficiency is AIDS
or HIV infection, affecting T-helper cells, discussed later
in this chapter.
Effects of Immunodeficiency
Immunodeficiency predisposes patients to the develop-
ment of opportunistic infections by normally harmless
microorganisms. This may involve multiple organisms
and be quite severe. These infections are difficult to
treat successfully. They often arise from resident flora
of the body—for example, fungal or candidal infec-
tion in the mouth (referred to as thrush) of someone
whose normal defenses are impaired. Sometimes
severe, life-threatening infections result from unusual
organisms that are normally not pathogenic or disease-
causing in healthy individuals, such as Pneumocystis
carinii.
It is essential that prophylactic antimicrobial drugs
(preventive antibiotics) be administered to anyone in
an immunodeficient state before undertaking an invasive
procedure that carries an increased risk of organisms
entering the body. The immune-compromised host is
vulnerable to microorganisms not usually considered
harmful (opportunistic infection). This includes any
procedure in which there is direct access to blood or
tissues (eg, a tooth extraction) and especially procedures
in areas in which normal flora are present (see Chapter
6). There also appears to be an increased incidence of
cancer in persons who have impaired immune systems,
probably related to the decrease in the body’s immune
surveillance and the failure of the immune system to
destroy malignant cells quickly.
■ Treatment
Replacement therapy for antibodies using gamma globulin
may be helpful. Depending on the cause, bone marrow
or thymus transplants are possible, but success with these
has been limited.
THINK ABOUT 7.10
Explain why a person whose blood test shows an abnormally
low leukocyte count should be given an antimicrobial drug before
a tooth extraction.

CHAPTER 7 Immunity 133
These numbers must be viewed with the knowledge
that in many areas reporting of new cases is sporadic or
absent, thus the numbers are likely much higher than
reported incidence of infection. In 2003 the UN launched
the 3 by 5 initiative to provide a combination of three
less expensive drugs along with educational materials
to 3 million infected persons living in African nations
and other countries lacking access to these materials.
The goal was to be achieved by 2005; in fact, the 2008
report on the global AIDS epidemic by the Joint United
Nations Programme on HIV/AIDS (UNAIDS) character-
izes progress on reducing the HIV epidemic as a “stable
rate of transmission at unacceptably high levels.” In
addition, 17.1 million of those infected worldwide are
unaware of their infections. Despite these facts, the annual
number of new HIV infections has remained relatively
stable.
Since the beginning of the epidemic in the United
States, an estimated 1,194,039 people have been diagnosed
with AIDS. An estimated 13,712 patients with AIDS died
in 2012 and an estimated 658,507 people with AIDS died
in the United States since the epidemic began (information
from the CDC). In addition, the number of persons aged
50 years and older infected with HIV or having AIDS
The same report shows the highest incidence of new
cases (67%) in adult males for 2014 occurred as a result
of male-to-male sexual transmission, with heterosexual
contact coming in second with 24% and injection drug
use coming in third with 6%. Newly diagnosed cases in
adult females related to high-risk heterosexual sex were
fourfold higher than those in women who injected drugs.
In 2014 it was also reported that 22% of the newly reported
cases were young people between 13 to 24 years old.
Within this group, gay and bisexual men accounted for
92% of the newly diagnosed cases. Children accounted
for <0.5% of new cases in 2014. Globally, reports from the United Nations (UN) for 2016 include about 36.7 million persons infected. Sub- Saharan Africa reports 25.8 million infected persons (more than 50% are women). Numbers of newly infected cases in Asia continue to rise, particularly in India and China. Statistics from the WHO showed that in 2014, 1.9 million worldwide were now receiving antiretroviral treatment, and 73% of all pregnant women worldwide living with HIV received medicines that prevented the transmission of the virus to their babies. The global mortality from AIDS was 1.2 million in 2014; this estimate includes both children and adults. B lo od le ve l Months Seroconversion Exposure HIV-positive AIDS Years 8 1210 6420 6 875 10 12119432 • Window period • Virus in blood • No antibodies • Mild symptoms • More antibodies form • Small amounts of virus in blood • Asymptomatic • Active infection • Decreasing CD4 count • AIDS indicator diseases CD4 cells Anti-HIV HIV Normal CD4 cells An tibo die s fo rm Viremia –opportunistic infections –lymphoma –wasting syndrome –dementia FIG. 7. 12 Typical stages in the development of AIDS. 134 SECTION II Defense/Protective Mechanisms than 10%, a two-stage testing protocol is used. The viral RNA or DNA can be identified in the blood and lym- phocytes in about 5 days using polymerase chain reaction (PCR) technology to rapidly replicate the genetic material in the laboratory. With this technology a small amount of the nucleic acids to be tested or analyzed is introduced has been increasing. This increase is partially due to the increased life expectancy resulting from active antiviral therapy and also due to increased public awareness and emphasis in HIV testing/diagnosis for persons over the age of 50. Agent Human immunodeficiency virus refers to human immuno- deficiency virus (type 1 or 2), a retrovirus, which contains RNA. (See Chapter 6 for general information on viruses and infections.) The virus is a member of a subfamily, lentivirus, so called because infection develops slowly. HIV-1 is the major cause of AIDS in the United States and Europe and appears to have originated in central Africa, although it now occurs worldwide. Human immunodeficiency virus-2 (HIV-2) is found primarily in central Africa. It is thought that the virus crossed from chimpanzees to humans as chimpanzees were hunted and prepared for food. New research has indicated that this likely happened between 1894 and 1924 in Central Africa. Initially the infection was sporadic, but with the development of industry and movement to crowded urban centers with workers migrating seasonally between village and city, the rate of infection increased dramatically. As indicated earlier in the chapter, the virus primarily infects the CD4 T-helper lymphocytes, leading to a decrease in function and number of these cells, which play an essential role in both humoral and cell-mediated immune responses. Also, HIV attacks macrophages and central nervous system cells. At an early stage, the virus invades and multiplies in lymphoid tissue, the lymph nodes, tonsils, and spleen, using these tissues as a reservoir for continued infection. The core of HIV contains two strands of RNA and the enzyme reverse transcriptase, and the coat is covered with a lipid envelope studded with “spikes” of glyco- proteins that the virus uses to attach to human cells (Fig. 7.13). Once inside the human host cell, the viral RNA must be converted by the viral enzyme into viral DNA, which is then integrated with the human DNA. The virus then controls the human cell and uses its resources to produce more virus particles, and subsequently the host cell dies. The new viruses can be seen “budding” out of the host cell in Fig. 7.14. A number of subtypes and recombinants have been identified. There is a delay or “eclipse” before the antibodies to the virus appear in the blood; the delay may be from 2 weeks to 6 months but averages 3 to 7 weeks. Antibodies form more rapidly following direct transmission into blood and more slowly from sexual transmission. This likely reflects a differing dose rate received through the differing routes. Antibodies form the basis for routine testing for the presence of HIV, and this delay creates difficulty in detecting the infection following exposure. In areas where infection is less than 10%, three-stage testing is required. In highly endemic areas with an infection rate greater HIV particle attaches to Receptors on helper-T4 lymphocyte (CD4) cell surface Viral RNA and reverse transcriptase enzyme enter helper-T4 cell Enzyme converts viral RNA to DNA Drug AZT blocks transcription Viral DNA joins helper-T4 cell DNA Replication of HIV— helper-T4 cell produces viral components Anti-HIV protease inhibitor drugs block Assemble new virus particles Infected helper-T4 cells shed many HIV particles to invade other helper-T4 cells and lymphoid tissue (viremia) Infected helper-T4 cells destroyed Initial infection usually in 3–6 weeks with mild, nonspecific “flu-like” symptoms Self-limiting—initially the immune response limits infection Antibodies form in 2–10 weeks (blood test) PHASE 1— LATENT—may last years—asymptomatic or lymphadenopathy may be present Helper-T4 cell count decreases and weaker immune response. Gradually move into active infection PHASE 2—L VERY LOW T4 CELL COUNT MULTIPLE SEVERE OPPORTUNISTIC INFECTIONS CANCERS WASTING SYNDROME CNS INVOLVEMENT PHASE 3—ACUTE— RNA HIV T4 cell Receptors bind AIDS—IMMUNODEFICIENCY TEST HIV POSITIVE FIG. 7. 13 The course of HIV/AIDS. CHAPTER 7 Immunity 135 Infected organ donors can also transmit the infection. Individuals who have a history of high-risk activities such as IV drug use, unprotected sex, or untreated sexually transmitted diseases are not accepted as organ or blood donors to reduce the possibility of transmitting the virus. Health care workers should assume there is a risk of some infection (there is a higher risk of transmitting other infections such as hepatitis B or C) from contact with body fluids from any individual and follow universal precautions (see Chapter 6). Patients infected with HIV are not isolated or labeled because such information may not include those infected and in the window period. All clients must be treated as though they may be infected if transmission by blood and body fluids is to be pre- vented. Where transmission is suspected, the health care worker should immediately seek counseling and post- exposure prophylaxis. Testing for HIV antibodies will be carried out using the three-stage testing procedure. In cases in which it is known that a client has HIV infection, appointments for invasive procedures may be scheduled at the end of the clinic day before daily disinfec- tion of the clinic. Judgment must be used to balance the needs of the immunocompromised client and others in the clinic. Special precautions may be required in prepar- ing the body of a patient who has died of AIDS to prevent transmission before cremation or burial. People who are high-risk sources of HIV include intravenous drug users (shared needles) and those with multiple sexual partners. Unprotected sexual intercourse with infected persons (heterosexual as well as homosexual) provides another mode of transmission, particularly in the presence of associated tissue trauma and other sexually transmitted infections that promote direct access to the blood. Currently the greatest increase in cases of HIV infection is occurring in women, either by heterosexual contact or intravenous drug use. Infected women may also transmit the virus to a fetus in the uterus, particularly if AIDS is advanced. Administration of azidothymidine (AZT, zidovudine) to pregnant women has greatly decreased the risk of infant infection. Many infants carry the mother’s antibodies for the first few months, appearing infected, but eventually they convert to test negative. The child may become infected during delivery through contact with secretions in the birth canal and should receive drug treatment after a vaginal birth. Delivery by cesarean section can reduce this risk. Also, breast milk can transmit the virus. In developing countries, this creates a dilemma, because breast milk protects infants from so many other potentially fatal infections, and infant formula is not readily available. Human immunodeficiency virus is not transmitted by casual contact (touching or kissing an infected person), sneezing and coughing, fomites such as toilet seats or eating utensils, or insect bites. Studies have shown the virus may survive up to 15 days at room temperature, but is inactivated at into a solution of enzymes and nucleotides in the presence of heat; the result is thousands of copies of the nucleic acid that can then be compared with a reference sample. In developed areas of the world with medical labo- ratories, diagnosis of AIDS is based on the absolute number of CD4 T-helper cells. Infection is shown when the CD4 T-helper lymphocyte count is less than 200 cells per cubic milliliter of blood. Where a suitable equipped laboratory is not available, the WHO recommends a modified case definition based on the presence of oppor- tunistic infections, tumors such as Kaposi sarcoma, weight loss, or Pneumocystis carinii pneumonia (PCP). Early in the infection, large numbers of viruses are produced, followed by a reduction as the antibody level rises. The failure of the antibodies to destroy all the viruses is not totally understood, but the factors include the following: • The virus is hidden safely inside host cells in the lymphoid tissue during the latent phase. • There appear to be frequent slight mutations in the viral envelope, making the antibodies less effective. • Progressive destruction of the T-helper cells and macrophages gradually cripples the entire immune system. Transmission When transmitted, the virus must find entry into the circulating blood of the recipient. The virus is transmitted in body fluids, such as blood, semen, and vaginal secre- tions. Blood contains the highest concentration of virus, with semen next. Human immunodeficiency virus may be present in small numbers in other secretions, such as saliva, but transmission in such cases has not been established. There is a slight risk that blood donated by newly infected persons will not test positive for antibodies during the “window” period; therefore blood products are now tested for the virus and treated when possible. This has reduced the risk for hemophiliacs and others who must have repeated treatment with blood products. FIG. 7. 14 HIV budding from a host cell surface. (From De la Maza LM, Pezzlo MT, Baron EJ: Color Atlas of Diagnostic Microbiology, St. Louis, 1997, Mosby.) 136 SECTION II Defense/Protective Mechanisms patients demonstrate no clinical signs, whereas some have a generalized lymphadenopathy or enlarged lymph nodes. It appears that viral replication is reduced during this time. The final acute stage, when immune deficiency is evident, is marked by numerous serious complications. The categories include general manifestations of HIV infection, gastrointestinal effects, neurologic effects, secondary infections, and malignancies. Secondary infec- tions and cancer are caused by the immunodeficiency. Each patient may demonstrate more effects in one or two categories as well as minor changes in the other systems (Fig. 7.15): • Generalized effects include lymphadenopathy, fatigue and weakness, headache, and arthralgia. Gastro- intestinal effects seem to be related primarily to opportunistic infections, including parasitic infections. The signs include chronic severe diarrhea, vomiting, and ulcers on the mucous membranes. Necrotizing periodontal disease is common, with inflammation, necrosis, and infection around the teeth in the oral cavity. Severe weight loss, malnutrition, and muscle wasting frequently develop. • Human immunodeficiency virus encephalopathy (general brain dysfunction), sometimes called AIDS dementia, refers to the direct infection of brain cells by HIV. This is often aggravated by malignant tumors, particularly lymphomas, and by opportunistic infec- tions such as herpesvirus, various fungi, and toxo- plasmosis in the brain. Nutritional deficits, particularly of vitamins, are a contributing factor. Encephalopathy is reflected by confusion, progressive cognitive impair- ment, including memory loss, loss of coordination and balance, and depression. Eventually the person cannot talk or move, and seizures or coma may develop. • Secondary infections are common with AIDS and are the primary cause of death. They are frequently multiple, and they are more extensive and severe than usual. Drug treatment of the secondary infection is often ineffective. In the lungs, Pneumocystis carinii, now considered a fungus, is a common cause of severe pneumonia (see Chapter 13) and is frequently the cause of death (Fig. 7.16A). Herpes simplex, a virus causing cold sores, is common (see Fig. 8.9), and Candida, a fungus, involves the mouth and often extends into the esophagus (see Fig. 37.17C). The incidence of tuberculosis in AIDS patients is quite high and climbing rapidly. • There is an increased incidence of all cancers in persons with AIDS, but unusual cancers are a marker for AIDS. Kaposi sarcoma affects the skin, mucous membranes, and internal organs (see Fig. 7.16B). Skin lesions of Kaposi sarcoma appear purple or brown and are nonpruritic (not itchy), painless patches that eventually become nodular. Non-Hodgkin’s lymphomas are another frequent form of malignancy in AIDS patients (see Chapter 11). temperatures greater than 60°C. It is inactivated by 2% glutaraldehyde disinfectants, autoclaving, and many disinfectants, such as alcohol and hypochlorite (household bleach). ■ Diagnostic Tests The presence of HIV infection can be determined by using a blood test for HIV antibodies, using HIV antigen from recombinant HIV or ELISA for the primary test. The procedure in primary use today is a three-stage process; each stage involves specific immunoassay tests to deter- mine the following: 1. Presence of HIV-1/2 antigen/antibody 2. Differentiation/identification between HIV-1 and HIV-2 antibodies 3. A nucleic acid test is used to confirm HIV-1 positive and eliminate a false negative Tests for the virus itself, both RNA and DNA, include PCR typing of viral RNA and DNA from the blood. Polymerase chain reaction typing is used to check the status of a newborn child who may carry the mother’s antibodies but not be infected. It is essential for testing blood donations and to monitor the viral load in the blood as the disease progresses. A new rapid, noninvasive test (20 minutes) using saliva is now available, but the more complex testing is necessary to confirm a positive result. The ease of this new test may facilitate diagnosis in more individuals. A diagnosis of AIDS depends on a major decrease in CD4+ T-helper lymphocytes in the blood (see Fig. 7.13) and a change in the CD4+ to CD8+ ratio in the presence of opportunistic infection or certain cancers. B lympho- cytes remain normal, and IgG is increased. Additional tests depend on the particular effects of AIDS in the individual. The CDC has established case definition criteria using the indicator diseases, opportunistic infec- tions, and unusual cancers, and it has provided a clas- sification for the phases of the infection. ■ Clinical Signs and Symptoms The clinical effects of HIV infection vary among individu- als, and differences are also apparent among men, women, and children. During the first phase, a few weeks after exposure, viral replication is rapid and there may be mild, generalized flulike symptoms such as low fever, fatigue, arthralgia, and sore throat. These symptoms disappear without treatment. Many persons are asymp- tomatic. In the prolonged second, or latent, phase, many THINK ABOUT 7.11 a. Explain the problem when a virus attacks T-helper cells. b. Why are the infections and cancers that accompany AIDS significant? c. Differentiate among HIV exposure, HIV infection, and AIDS. CHAPTER 7 Immunity 137 the cause of death in children, and prophylactic antimi- crobial drugs are often prescribed. People Over 50 With HIV/AIDS Persons over the age of 50 have more of the risk factors for HIV infections than the younger population. The challenges for prevention in this age group include but are not limited to the following: • Older persons are sexually active but may not practice safe sex • Drug injections or smoking of crack cocaine may occur • Late testing because of stigma • Misdiagnosis because of normal symptoms of aging ■ Treatment Antiviral drugs can reduce the replication of viruses, but they do not kill the virus, and thus are not a cure. There also are significant side effects, especially with higher drug dosages. The virus mutates as well, becoming resistant to the drug, particularly when single drugs are administered. HIV drugs are grouped into six classes according to how they fight against HIV: Women With AIDS Although AIDS in women is clinically similar to the disease in men in many ways, Kaposi sarcoma is much rarer in women than in men. It appears that women with AIDS have a higher incidence of severe and resistant vaginal infections and pelvic inflammatory disease (PID) than women without AIDS (see Chapter 19), as well as more oral Candida and herpes infections. Sexually trans- mitted diseases are more severe in women with AIDS than in unaffected women, and infected women show a high incidence of cervical cancer. Children With AIDS Two positive PCR tests are required to confirm HIV infection in young children. Some children are seriously ill and die within the first or second year. In others, the effects develop gradually over some years. Infants born with AIDS are usually smaller in size and exhibit failure to thrive, developmental delays, and neurologic impair- ment such as spastic paralysis early in life. Seizures and poor motor skills are common. Malignancies are rare in children. The life and health care of an infected child are frequently complicated by the illness and perhaps death of the parents. Pneumocystis carinii pneumonia is often Mouth, esophagus Candidiasis Herpes simplex Lymphadenopathy Generalized Lungs Pneumocystis carinii pneumonia Tuberculosis Gastrointestinal Chronic diarrhea, infections Wasting Anorexia Skin Dermatitis, infections Kaposi sarcoma Brain Memory loss, confusion, dementia Infections (e.g., toxoplasmosis, herpes) Lymphoma Blood Viremia-HIV Decreasing count of helper T-lymphocytes FIG. 7.15 The common effects of AIDS. 138 SECTION II Defense/Protective Mechanisms virus from several points (see Fig. 6.16). The drugs must be taken continually on a rigid schedule. A “one pill daily” combination of three drugs (Atripla) is available to improve patient adherence to their drug protocol. Currently highly active antiretrovirus (HAART) therapy has been very effective at controlling the virus, reducing the viral load in the blood, and returning CD4 cell counts to near-normal levels. A primary focus of treatment is on minimizing the effects of complications, such as infections or malignancy, by prophylactic medications and immediate treatment. Tuberculosis is reactivated in 50% of HIV+ patients and is often a systemic form requiring intensive drug treat- ment. In many cases tuberculosis (TB) is resistant to drugs that have been used in the past. Antidiarrheal medication may also be required on a long-term basis. Even though safer and more effective drugs are available in many parts of the world, there continues to be an uneven distribution of such drugs. Concerns continue with respect • Non-nucleoside reverse transcriptase inhibitors (NNRTIs) • Nucleoside reverse transcriptase inhibitors (NRTIs) • Protease inhibitors (PIs) • Fusion inhibitors • CCR5 antagonists (CCR5s) (also called entry inhibitors) • Integrase strand transfer inhibitors (INSTIs) Azidothymidine (AZT) is probably the best-known single drug being used in the fight against HIV; however, combinations of three to five drugs in a “cocktail” are being used successfully to prolong the latent phase as well as reduce the viral load during the final phase. This use of multiple drugs is referred to as antiretroviral therapy (ART). For example, two viral reverse transcrip- tase inhibitors, such as zidovudine and lamivudine, plus a protease inhibitor such as indinavir form one such combination. This approach reduces drug-resistant muta- tions of the virus, and the drugs are chosen to attack the A BB DC FIG. 7.16 Complications of AIDS. A, Silver stain of Pneumocystis carinii ( jiroveci) in a sputum sample. B, Kaposi sarcoma. C, Candida esophagitis. The thick greenish membrane is composed of Candida hyphae and purulent exudate. D, Necrotizing periodontal disease with inflammation, necrosis, and infection around the teeth. (A From Murray P, et al: Medical Microbiology, ed 5, St. Louis, 2005, Elsevier. B From Goodman C, Fuller K: Pathology for the Physical Therapy Assistant, St. Louis, 2012, Elsevier. C From Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology, ed 3, Sydney, 2004, Churchill Livingstone. D Courtesy of Evie Jesin, RRDH, BSc, George Brown College, Toronto, Ontario, Canada.) CHAPTER 7 Immunity 139 to the toxicity of drugs, particularly for pregnant women, and the development of drug resistance in various strains of HIV. The prognosis at the present time is much improved because persons with HIV infection are living longer with improved drug treatment. Without treatment, death occurs within several years as opposed to decades. Treatment should start when the following have occurred: • Severe symptoms • CD4 count is under 500 • Pregnancy • HIV-related kidney disease • When one is being treated for hepatitis B CASE STUDY A Hypersensitivity M.C., a 23-year-old woman, has developed a skin rash as well as nausea and vomiting, after taking an antimicrobial drug for a short time. The skin rash is red and quite itchy and is spreading over her entire body. The physician stops the medication because of this allergic reaction. The patient has a history of skin rashes, both eczema and contact dermatitis, since infancy. She has had hay fever during the summer and fall for the past few years. 1. Why would the physician consider this an allergic reaction to a drug? 2. What kind of hypersensitivity is hay fever, and what are the signs of it? CASE STUDY B Anaphylaxis Mr. J.A., age 32, with no prior history of allergies, was mowing grass around the noon hour when he felt a sharp pain in his lower right leg. It was later determined that the lawn mower hit a hornets’ nest in the ground. He continued cutting the grass for a moment, and then felt itchy all over his body. It was a very hot day and the air was heavy with dust and grass fragments. He jumped in the swimming pool to cool off, but he immediately felt exhausted and climbed out. He lay down, feeling faint, and tried to call for help. However, he could not talk clearly and was having difficulty breathing. Shortly, a family member appeared and called 9-1-1. At this time he could not swallow and was feeling nauseated. When emergency services arrived, J.A. could not talk or provide information to assist with a diagnosis. Finally one paramedic could detect a mark on his leg, but no swelling at the site. He was losing consciousness and had cold, moist skin. His blood pressure was falling, so anaphylaxis was suspected. He was given an epinephrine injection and oxygen, then was transported to the hospital. There he was given intravenous glucocorticoids. He recovered consciousness and was able to talk. The diagnosis was anaphylaxis resulting from multiple insect stings. 1. Describe the type of hypersensitivity reaction involved here. 2. Is it likely that J.A. had experienced a sting at some previous time? 3. Explain the rationale for (a) pruritus (itchy skin), (b) difficulty talking and breathing, and (c) feeling faint. 4. Why was this condition difficult for emergency personnel to diagnose? 5. Explain how epinephrine and glucocorticoids would reduce the manifestations of anaphylaxis. J.A. was expecting to be discharged from the hospital that evening. However, the doctor noted a rash developing on his back. This continued to spread over his entire body and his neck was swollen; therefore he remained in the hospital. Intravenous glucocorticoids were continued as well as the antihistamine diphenhydramine (Benadryl). The rash began to subside in 48 hours. By the third day, the area where the stings occurred on the leg had turned a dark purple color. 6. What likely caused this rash to develop? J.A. was finally discharged from the hospital and directed to continue the medications oral prednisone and diphenhydramine for a week. He returned for testing, which indicated an allergy to hornets and honeybees. He continues to take desensitizing injections. Each of these causes swelling, itchiness, and pain on the arm. He also carries an EpiPen and Benadryl with him at all times, and he avoids situations in which a sting could occur. 7. Why is it important for this patient to carry an EpiPen with him and wear a Medic-Alert bracelet? Suggest several situations to avoid, thus reducing the risk of future stings. CASE STUDY C Systemic Lupus Erythematosus Ms. A.S., age 31, has been diagnosed with systemic lupus ery- thematosus. She had her first signs and symptoms 2 years ago. At this time she is having an exacerbation, which includes a facial rash, joint pains, and chest pain. She also has protein in her urine, indicating a kidney abnormality. 1. Explain the basic pathophysiology of this disease. 2. Describe three factors that would assist in making the diagnosis. 3. Describe the typical rash Ms. A.S. would have at this time. 4. Her chest pain is due to inflammation of the pleural membranes. Explain why this pain would be more severe during inspiration. 5. Her dose of prednisone, a glucocorticoid, has been increased. Briefly explain why she will return to a lower dose after the exacerbation ends. 6. Explain why moderate exercise would be helpful. CASE STUDY D HIV and AIDS Ms. C.W. is a college student with an active social life. She is in a relationship with a fellow classmate who says that he has not had many relationships before theirs. After a party, they engage in unprotected sex, although they usually use a condom. She believes she will be safe because he shows no signs of AIDS and comes from a nice home. Several weeks later her friend tells her he has just tested HIV+. She immediately seeks advice and 140 SECTION II Defense/Protective Mechanisms sensitized T lymphocytes (cell-mediated immunity) form, which then can destroy the matching foreign antigen. Specialized memory cells ensure immediate recognition and destruction of that antigen during future exposures. • Active immunity is acquired by exposure to the antigen—for example, infectious bacteria or intentional immunization before exposure. • Passive immunity provides only temporary protection. • Hypersensitivity reactions are abnormal immune responses to harmless substances. • Type I hypersensitivity (allergies) refers to responses to allergens, ingested, inhaled, or by direct contact, with subsequent development of IgE antibodies. • Anaphylaxis is a severe, systemic, life-threatening allergic reaction characterized by rapidly decreasing blood pressure and respiratory obstruction. • Type II, cytotoxic hypersensitivity involves a reaction with IgG and cell antigens, such as occurs with incompatible blood transfusion. • Type III, immune complex, hypersensitivity occurs when antigen–antibody complexes are deposited in tissues, causing inflammation, the basis of some diseases such as glomerulonephritis. • Type IV, cell-mediated hypersensitivity involves a delayed response by sensitized T lymphocytes, as may be seen with a tuberculin skin test. • Autoimmune diseases develop when antibodies form in response to self-antigens, elements of the person’s cells or tissues. Systemic lupus erythematosus is an example, in which antibodies to nuclear material such as DNA form, causing inflammatory responses in various organs and tissues. • Immunodeficiency occurs in many forms, resulting from a deficit of any component of the immune response. • Acquired immunodeficiency syndrome is an example in which the human immunodeficiency virus (HIV) destroys T-helper lymphocytes, preventing both humoral and cell-mediated immunity. A diagnosis of HIV+ means the virus and its antibodies are present in the blood. A diagnosis of AIDS means active disease is present, with frequent opportunistic infections, malignant tumors, or AIDS encephalopathy. More women and children are now affected by HIV. Life expectancy has been prolonged by the administration of HAART, using combinations of drugs, and by prophylactic antimicrobial drugs. Women and children present a different clinical picture than men. • Human immunodeficiency virus is transmitted by blood, tissues, or sexual contact, not by casual contact. It also may be transmitted by infected mothers to infants before, during, or after birth. C H A P T E R S U M M A R Y The immune response is a specific defense mechanism in the body. When a foreign antigen enters the body, specific matching antibodies (humoral immunity) or testing from the campus health center and is told that three tests over several months will be done. She is offered azidothy- midine (AZT) as a preventive medication that may reduce infectivity. 1. Why does the health care center recommend more than one test for HIV antibody status? 2. What is the action of AZT in preventing infection with HIV? Ms. C.W.’s second test shows presence of HIV antibodies and she is diagnosed as HIV+. Although this is a great shock to her, her physician and counselor help her to accept the fact that she is HIV+ and can most likely live several years if she takes a combination of antiretroviral drugs. Ms. C.W.’s CD4 helper cell count rises and remains in a healthy range. She pursues a career and meets a man whom she marries. 3. What is the risk of transmission of HIV to men versus women? What are considered very high-risk sexual practices? 4. What factors might the couple consider in deciding whether to have a child? Mrs. C.W. becomes pregnant and seeks information from her specialist about the risks of transmitting HIV to her unborn child. 5. What is the risk of transmitting HIV during pregnancy and labor and delivery? 6. How can the risk of infection be reduced before birth, during delivery, and after birth? 7. Why is blood testing of her newborn daughter for HIV not done until 3 to 6 months after birth? 8. Ms. C.W. wants to breast-feed her daughter, but her doctor tells her that she should not do so. Why should she not breast-feed? Ms. C.W.’s daughter is not infected and grows into a healthy toddler. Six years later, Ms. C.W. develops a chronic cough, overwhelming fatigue, recurrent diarrhea, and a sore mouth. Her physician diagnoses AIDS with PCP pneumonia, oral thrush, and infectious diarrhea. Blood tests show a significant reduction in CD4 helper T cells. Ms. C.W. is admitted to hospital for treatment. 9. There is no notice on Ms. C.W.’s room that she is HIV+. Why is this not done to reduce the likelihood of a staff member becoming infected with HIV? 10. What is the significance of a reduction in CD4 helper T cells? 11. Ms. C.W. remains antibody positive for HIV. Why don’t the antibodies reduce viral load? 12. What is the cause of her pneumonia and oral infection? 13. What is the prognosis for Ms. C.W. if these infections cannot be controlled and if her CD4 helper T cell count does not return to more normal levels? CHAPTER 7 Immunity 141 S T U D Y Q U E S T I O N S 1. Describe the role of the macrophage in the immune response. 2. State the origin and purpose of lymphocytes. 3. Compare active natural immunity and passive artificial immunity, describing the causative mechanism and giving an example. 4. What is the purpose of a booster vaccination? 5. Describe the purpose of gamma globulins. 6. Where is IgA found in the body? 7. Describe how type III hypersensitivity develops. 8. Explain the process by which an attack of hay fever follows exposure to pollen. 9. Explain why anaphylaxis is considered life threatening. 10. Describe the pathophysiology of a type III hypersensitivity reaction. 11. Define an autoimmune disease, and explain how the causative mechanism differs from a normal defense. 12. Describe two factors that promote a successful organ transplant. 13. Differentiate between a diagnosis of being HIV+ and a diagnosis of having AIDS. 14. Why are opportunistic infections common with AIDS? 15. State three methods of transmitting HIV and three methods by which the virus is not transmitted. 16. Describe two common complications associated with AIDS. 142 S E C T I O N III Pathophysiology of Body Systems Review of the Skin Resident Microbial Flora Skin Lesions Skin Inflammatory Disorders Contact Dermatitis Urticaria (Hives) Atopic Dermatitis Psoriasis Pemphigus Scleroderma Skin Infections Bacterial Infections Cellulitis Furuncles Impetigo Acute Necrotizing Fasciitis Leprosy Viral Infections Herpes Simplex Verrucae Fungal Infections Tinea Other Infections Scabies Pediculosis Skin Tumors Keratoses Squamous Cell Carcinoma Malignant Melanoma Kaposi Sarcoma Case Studies Chapter Summary Study Questions Chapter Outline After studying this chapter, the student is expected to: 1. Describe common skin lesions. 2. Describe the causes, typical lesions, and location of contact dermatitis, urticaria, and atopic dermatitis. 3. Describe the cause and lesions associated with the inflammatory conditions psoriasis erythematosus, pemphigus, and scleroderma. 4. Distinguish between the bacterial infections impetigo and furuncles. 5. Describe the effects of Streptococcus pyogenes on connective tissue in acute necrotizing fasciitis. 6. Describe the effects and treatment of leprosy. 7. Describe the viral infections herpes simplex and warts. 8. Describe the forms of tinea, a fungal infection. 9. Describe the agent, the infection, and manifestations of scabies and pediculosis. 10. Compare the skin cancers, describing the lesion, predisposing factors, and spread of squamous cell carcinoma, malignant melanoma, and Kaposi sarcoma. L E A R N I N G O B J E C T I V E S C H A P T E R 8 Skin Disorders abscess albinism atopic autoinoculation denuded eosinophilia excoriations keratin larvae lichenification macules pruritus sebum K E Y T E R M S CHAPTER 8 Skin Disorders 143 stratum basale (the only layer of the epidermis where mitosis occurs), and one of each pair of cells then moves upward. • The stratum spinosum (spiny layer) is the layer located above or outward of the stratum basale. This layer is composed of irregularly shaped cells with intercellular connections called desmosomes. These cells are rich in RNA and are capable of contributing to the protein synthesis required to produce keratin. • The stratum granulosum (granular layer) is the layer where the process of surface keratin formation begins. Keratin is a protein found in skin, hair, and nails that prevents both loss of body fluid through the skin and entry of excessive water into the body, as when swim- ming. Although there is important biochemical activity occurring in this layer, generally the cells, at this stage called keratinocytes, are starting to die and break down, making this layer sometimes hard to identify as a distinct layer of the epidermis. • The stratum lucidum (clear layer) is a layer composed of the degenerating keratinocytes that are flattened, closely packed with indistinct cell margins. The cells are filled with eleidin, which is later transformed to keratin. This layer is usually not found in thin skin but is apparent in thicker skin (skin on soles of feet). • The stratum corneum (horny layer) is the outermost layer of the epidermis. It is primarily composed of flat, dead cells that are constantly being shred and replaced from the underlying layers. The interior of these cells is filled with a dense network of keratin fibers formed from the eleidin, making them a strong, waterproof barrier. This process of the cells forming in the stratum basale and moving upward and filling with keratin to eventually end up on the surface is called keratinization. The entire process, from the formation of the cells to their sloughing from the surface, usually takes a few weeks. The epidermis also contains melanocytes, specialized pigment-producing cells. The amount of melanin, or dark pigment, produced by these cells determines skin color. Melanin production depends on multiple genes as well as environmental factors such as sun exposure (ultraviolet light). Dark skinned people rarely develop skin cancer as a result of ultraviolet light exposure because of increased melanin in the skin, which acts as a protection from the sun’s rays. Albinism is a recessive trait congenital disorder in which the body lacks production of melanin. A person with this trait has white skin and hair and lacks pigment in the iris of the eye. This individual must avoid exposure to the sun. Vitiligo refers to small areas of hypopigmenta- tion that may gradually spread to involve larger areas. Melasma, or chloasma, refers to patches of darker skin, often on the face, that may develop during pregnancy. An additional pigment, carotene, gives a yellow color to the skin. Pink tones in the skin are increased with addi- tional vascularity or blood flow in the dermis. Review of the Skin As the largest organ in the body, the skin plays significant roles in both the function of the body physically and how we are perceived in society. Skin has many functions: • When unbroken, it provides the first line of defense against invasion by microorganisms and other foreign material. The sebaceous glands produce sebum, which is acidic and inhibits bacterial growth. The resident flora of the skin is a deterrent to invading organisms. • Skin prevents excessive fluid loss. • It is important in controlling body temperature, using two mechanisms: cutaneous vasodilation, which increases peripheral blood flow, and increased secretion and evaporation of sweat—both have a cooling effect on the body. • Sensory perception provided by the skin is important as a defense against environmental hazards, as a learning tool, and as a means of communicating emotions. • Another important function of the skin is the synthesis and activation of vitamin D on exposure to small amounts of ultraviolet light. The skin, or integument, consists of two main layers, the epidermis and the underlying dermis, along with their associated appendages, such as hair follicles and glands (Fig. 8.1). The epidermis consists of five layers, which vary in thickness at different areas of the body. For example, facial skin is relatively thin, but the soles are protected by a thick layer of skin (primarily stratum corneum). There are no blood vessels or nerves in the epidermis. Nutrients and fluid diffuse into it from blood vessels located in the dermis. There are five basic layers of the epidermis: • The stratum basale (base layer) is the innermost layer of the epidermis, located on the basement membrane. New squamous epithelial cells form by mitosis in the Hair Capillaries Vein Artery Adipose tissue Stratum corneum Stratum basale Sensory receptor E P ID E R M IS D E R M IS S U B C U TA N E O U S T IS S U E Sebaceous gland Smooth muscle Nerve fiberHair follicle Eccrine gland Melanocyte FIG. 8.1 Diagram of the skin. 144 SECTION III Pathophysiology of Body Systems The dermis is a thick layer of connective tissue varying in thickness over the body that lies below the epidermis and includes elastic and collagen fibers. These constituents provide both flexibility and strength in the skin and support for the nerves and blood vessels passing through the dermis. Many sensory receptors for pressure or texture, pain, heat, or cold are found in the dermis. The junction of the dermis with the epidermis is marked by papillae, irregular projections of dermis into the epidermal region. More capillaries are located in the papillae to facilitate diffusion of nutrients into the epidermis. Blood flow is controlled by the sympathetic nervous system. Embedded in the skin are the appendages, or accessory structures such as the hair follicles, sweat and sebaceous glands, and nails: • The hair follicles are lined by epidermis that is continu- ous with the surface, the stratum basale producing the hair. Each hair follicle has smooth muscle attached to it, the arrector pili, controlled by sympathetic nerves. These may be stimulated by emotion or exposure to cold, causing the hairs to stand upright (“on end”) or creating small elevations on the skin (“goose bumps”). • Sebaceous glands may be associated with hair follicles or may open directly onto the skin. These glands produce an oily secretion, sebum, which keeps the hair and skin soft and hinders fluid loss from the skin. Secretions of sebum increase at puberty under the influence of the sex hormones. • There are two types of sweat glands: • Eccrine, or merocrine, glands are located all over the body and secrete sweat through pores onto the skin in response to increased heat or emotional stress (SNS control). • Apocrine sweat glands are located in the axillae, scalp, face, and external genitalia, and the ducts of these glands open into the hair follicles. The secretion, sweat or perspiration, is odorless when formed, but bacterial action by normal flora on the constituents of sweat often causes odor to develop. Beneath the dermis is the subcutaneous tissue or hypo- dermis, which consists of connective tissue, fat cells, macrophages, fibroblasts, blood vessels, nerves, and the base of many of the appendages. APPLY YOUR KNOWLEDGE 8.1 Explain how excessive handwashing may in some cases increase the potential for a bacterial skin infection. THINK ABOUT 8.1 a. Describe three ways in which the dermis differs from the epidermis. b. Explain how the basal layer of the epidermis is nourished. c. Describe the role of sebaceous glands and eccrine glands. d. Explain three ways the skin acts as a defense mechanism. primarily bacteria and fungi, are also present deep in the hair follicles and glands of the skin and may be a source of opportunistic infections when there is injury such as burns (see section on burns in Chapter 5) or other inflammatory lesion. Infection may spread systemically from skin lesions. Skin damage can also occur as a result of toxins produced by opportunistic microorganisms. The balance of the normal flora on skin can change rapidly and dramatically as external environmental conditions change. A change as simple as the drying of the skin in the winter due to outside exposure or interior dry heating, can dramatically change the normal microbial populations leading to conditions like surface rashes. The skin is prone to damage as it is in constant contact with the external environment, which includes such threats as toxic chemicals, direct trauma, or animal bites/stings. Systemic disorders additionally may affect the skin. Also, the skin changes with aging, showing loss of elasticity, thinning, and loss of subcutaneous tissue (see Chapter 24). Minor abrasions or cuts of the skin heal quickly with mitosis of the epithelial cells (see Chapter 5 to explore the healing process). When large areas of the skin are damaged, appendages may be lost, function impaired, and fibrous scar tissue forms, often restricting mobility of joints. See the discussion on burns in Chapter 5 for information on biosynthetic wound coverings or “artificial skin,” useful when large areas of skin are damaged. Resident Microbial Flora A complex mix of resident (normal) flora is present on the skin, and the components differ in various body areas (see Chapter 6). Microbes residing under the fingernails may infect inflammatory lesions or breaks in the skin, particularly when one scratches the skin. Microbes, Skin Lesions The characteristics of skin lesions are frequently helpful in making a diagnosis. Skin lesions may be caused by systemic disorders such as liver disease, systemic infec- tions such as chickenpox (typical rash), or allergies to ingested food or drugs, as well as by localized factors such as exposure to toxins. Common types of lesions are illustrated in Fig. 8.2 and defined in Table 8.1. The location, length of time the lesion has been present, and any changes occurring over time are significant. Physical appearance (including color, elevation, texture), type of exudate, and the presence of pain or pruritus (itching) are also important considerations. Some lesions, such as tumors, usually are neither painful nor pruritic and therefore may not be noticed. A few skin disorders, such as herpes, cause painful lesions. Pruritus is associated with allergic responses, chemical irritation due to insect bites, or infestations by parasites CHAPTER 8 Skin Disorders 145 microbes on the fingers (under the nails) or on the sur- rounding skin to invade the area. Infection may then produce scar tissue in the area and under certain condi- tions can become systemic, affecting other areas of the body. ■ Diagnostic Tests Bacterial infections may require culture and staining of specimens for identification. Skin scrapings for microscopic such as scabies mites. The mechanisms producing pruritus are not totally understood. It is known that release of histamine in a hypersensitivity response causes marked pruritus (see Chapter 7). Pruritus also may result from mild stimulation of pain receptors by irritants. The most common manifestations include redness and itchiness. Scratching a pruritic area usually increases the inflam- mation and may lead to secondary infection. Infection results from breaking the skin barrier, thus allowing Macule Nodule Macule: flat, circumscribed A B C D E F G H Nodule: firm, raised, deep Papule Papule: small, solid elevation Pustule: raised, often with a “head,” filled with exudate or “pus” Vesicle Ulcer Pustule Plaque Fissure Vesicle or blister: thin wall, raised, fluid filled Ulcer: cavity in tissue Fissure: crack in tissue Plaque: Slightly elevated, flat, “scale”-like lesion FIG. 8.2 Common skin lesions. 146 SECTION III Pathophysiology of Body Systems Precancerous lesions may be removed by surgery, laser therapy, electrodesiccation (heat), or cryosurgery (eg, freezing by liquid nitrogen). There are a large number of skin disorders. Only a small number of representative dermatologic conditions are included here. Skin Inflammatory Disorders Burns cause an acute inflammatory response. This topic is covered in Chapter 5 along with the processes of healing. Contact Dermatitis Contact dermatitis may be caused by exposure to an allergen or by direct chemical or mechanical irritation of the skin. Allergic dermatitis may result from exposure to any of a multitude of substances, including metals, cosmetics, soaps, chemicals, and plants. ■ Pathophysiology Sensitization occurs on the first exposure (type IV cell- mediated hypersensitivity—see Chapter 7), and on subsequent exposures, manifestations such as a pruritic rash develop at the site a few hours after exposure to that allergen. The location of the lesions is usually a clue to the identity of the allergen (Fig. 8.3). For example, poison ivy may cause lesions, often linear, on the ankles or hands, or a necklace may cause a rash around the neck. ■ Signs and Symptoms Typical allergic dermatitis manifestations include the following: • Pruritic area • Erythematous (reddened) area • Edematous (swollen) area • Area often covered with small vesicles Direct chemical irritation does not involve an immune response but is an inflammatory response caused by direct exposure to substances such as soaps and cleaning materials, acids, or insecticides. Manifestations usually include the following: • Edematous area • Erythematous area • May be pruritic or painful examination, sample culturing, direct observation of the infected area, and other specific procedures (eg, ultraviolet light, Wood’s lamp) are necessary to detect fungal or parasitic infections. Biopsy is an important procedure in the detection of malignant changes in tissue and provides a safeguard prior to or following removal of any skin lesion. Blood tests may be helpful in the diagnosis of condi- tions due to allergy or abnormal immune reactions. Patch or scratch tests are used to screen for allergens and may be followed by diet restrictions to identify specific food allergens. Drug reactions are assessed utilizing specific antigen-antibody testing. ■ General Treatment Measures Pruritus may be treated by antihistamines or glucocorti- coids, administered topically or orally. Identification and avoidance of allergens reduce the risk of recurrence. With many skin disorders, extremes of heat or cold and contact with certain rough materials such as wool aggravate the skin lesions. Soaks or compresses using solutions such as Burow solution (aluminum acetate) or colloidal oatmeal (Aveeno) may cool the skin and reduce itching. Some topical skin preparations contain a local anesthetic to reduce itching and burning sensations. Infections may require appropriate topical antimicrobial treatment. If the infection is severe, systemic medication may be preferred. TABLE 8.1 Description of Some Skin Lesions Macule Small, flat, circumscribed lesion of a different color than the normal skin Papule Small, firm, elevated lesion Nodule Palpable, elevated lesion; varies in size Pustule Elevated, erythematous lesion, usually containing purulent exudate Vesicle Elevated, thin-walled lesion containing clear fluid (blister) Plaque Large, slightly elevated lesion with flat surface, often topped by scale Crust Dry, rough surface or dried exudate or blood Lichenification Thick, dry, rough surface (leatherlike) Keloid Raised, irregular, and increasing mass of collagen resulting from excessive scar tissue formation Fissure Small, deep, linear crack or tear in skin Ulcer Cavity with loss of tissue from the epidermis and dermis, often weeping or bleeding Erosion Shallow, moist cavity in epidermis Comedone Mass of sebum, keratin, and debris blocking the opening of a hair follicle THINK ABOUT 8.2 a. Describe each of the following: (1) macule; (2) vesicle; and (3) pustule. b. Explain two causes of pruritus. c. List four potential causes of skin lesions. d. Explain why cellular components of all resected skin lesions should be evaluated by a pathologist. CHAPTER 8 Skin Disorders 147 severe cases. For chronic cases, a biologic drug, omali- zumab (Xolair), may be prescribed for patients 12 and older. Atopic Dermatitis Atopic dermatitis (eczema) is a common problem in infancy and may persist into adulthood in some persons. Atopic refers to an inherited tendency toward allergic conditions. Frequently the family history includes indi- viduals with eczema, allergic rhinitis or hay fever, and asthma, indicating a genetic component. Areas affected include the flexor surfaces of the arms and legs (eg, antecubital areas) and the hands and feet. ■ Pathophysiology Chronic inflammation results from the response to allergens (Fig. 8.5). Eosinophilia (a high level of the white blood cells called eosinophils in the blood) and increased serum IgE levels indicate the allergenic basis for atopic dermatitis (type I hypersensitivity). Potential complica- tions include secondary infections due to scratching and disseminated viral infections such as herpes. Affected areas also become more sensitive to many irritants such as soaps and certain fabrics. Marked changes in tem- perature and humidity tend to aggravate the dermatitis, leading to more exacerbations in patients living in areas with dry winter months or hot, humid summers. ■ Signs and Symptoms In infants the manifestations include the following: • Pruritic lesions may appear. • Lesions are moist, red, vesicular, and covered with crusts. • Involved areas are usually located symmetrically on the face, neck, extensor surfaces of the arms and legs, and buttocks. In adults the manifestations include the following: • Skin appears dry and scaling. • Thick and leathery patches called lichenification are present. • Skin folds may be moist and red. • Pruritus is common. ■ Treatment Removal of the irritant as soon as possible and reduction of the inflammation with topical glucocorticoids are usually an effective treatment. Urticaria (Hives) ■ Pathophysiology Urticaria results from a type I hypersensitivity reaction, commonly caused by ingested substances such as shellfish or certain fruits or drugs. ■ Signs and Symptoms The subsequent release of histamine causes manifestations that include the following: • Eruption of hard, raised erythematous lesions on the skin, often scattered all over the body (Fig. 8.4) • Highly pruritic lesions Occasionally, hives also develop in the pharyngeal mucosa and may obstruct the airway, causing difficulty with breathing. In this case, medical assistance should be sought as quickly as possible. ■ Treatment Treatment with over-the-counter antihistamines often proves effective. In more serious cases where inflammation of the airways occurs, prescription corticosteroids taken orally can be effective but are usually only used in more FIG. 8.3 Contact dermatitis resulting from adhesive tape. Note how the location and shape of the rash indicate the causative agent. (Courtesy of Dr. M. McKenzie, Toronto, Canada.) FIG. 8.4 Urticaria (hives). (From Dorland’s Illustrated Medical Dictionary, ed 32, St. Louis, 2012, Saunders.) 148 SECTION III Pathophysiology of Body Systems in severity and psoriatic arthritis is associated with psoriasis in some cases. Psoriasis results from the abnor- mal activation of T cells and an associated increase in cytokines in affected tissues. These immunologic changes then lead to excessive proliferation of keratinocytes and the symptoms of the disease. Animal studies have shown that a reduction in T-cell activity leads to regression of skin changes in a short period of time. The rate of cellular proliferation is greatly increased, leading to thickening of the dermis and epidermis. Epidermal shedding may occur in 1 day rather than the normal 2-week turnover period. The lesion begins as a small red papule that enlarges. A silvery plaque forms while the base remains erythematous because of inflam- mation and vasodilation. (Fig. 8.6 illustrates the acute inflammatory stage and the chronic lesion.) If the plaque is removed, small bleeding points are apparent. Lesions are commonly found on the face, scalp, elbows, and knees and may be accompanied by an itching or burning sensation. The fingernails may be thickened, pitted or ridged. ■ Treatment Identification and elimination of the aggravating agents and the use of topical glucocorticoids are helpful. Anti- histamines may reduce pruritus, and avoidance of skin irritants such as strong detergents or wool, a change to a hypoallergenic diet, and adequate moisturizing of the skin may reduce the inflammation. In severe cases, topical glucocorticoids may be used when severe pruritus interferes with sleeping and eating, particularly in infants, when the condition further exacerbates irritability and stress. Psoriasis Psoriasis is a chronic inflammatory skin disorder that affects 1% to 3% of the population and is considered to be genetic in origin following research studies in mice. ■ Pathophysiology Onset usually occurs in the teen years, and the course is marked by remissions and exacerbations. Cases vary A CB FIG. 8.5 Atopic dermatitis—an extremely pruritic condition. A, Multiple excoriations, vesiculation, and marked lichenification are seen in this patient. B, Minute excoriations with marked lichenification in the antecubital fossa. C, Atopic dermatitis. Characteristic lesions with crusting from irritation and scratching over knees and around ankles. (B From Callen JP, et al: Color Atlas of Dermatology, Philadelphia, 1993, Saunders. C From McCance KL, et al: Pathophysiology, ed 6, St. Louis, 2010, Mosby. Courtesy Department of Dermatology, School of Medicine, University of Utah.) CHAPTER 8 Skin Disorders 149 ■ Pathophysiology The autoantibodies disrupt the cohesion between the epidermal cells, causing blisters to form. In the most common form, pemphigus vulgaris, the epidermis sepa- rates above the basal layer. Blisters form initially in the oral mucosa or scalp and then spread over the face and trunk during the ensuing months. The vesicles become large and tend to rupture, leaving large denuded areas of skin covered with crusts. ■ Signs and Symptoms For pemphigus vulgaris the manifestations include the following: • Blisters in mouth • Blisters spreading to the skin • Blisters are painful but not pruritic • Breathing difficulty due to swollen mouth and throat Manifestations for pemphigus foliaceus are similar to vulgaris except there are usually no mouth blisters and the blisters are typically not painful. ■ Treatment Systemic glucocorticoids such as prednisone and other immunosuppressants are used to treat pemphigus. Scleroderma Scleroderma may occur as a skin disorder, or it may be systemic, affecting the viscera. The primary cause is not known, but increased collagen deposition is observed in all cases. ■ Pathophysiology Collagen deposition in the arterioles and capillaries reduces blood flow to the skin or internal organs. Collagen deposits, inflammation, and fibrosis with decreased capillary networks develop in the skin. ■ Signs and Symptoms • Hard, shiny, tight, immovable areas of skin are present. • Fingertips are narrowed and shortened, and the Raynaud phenomenon may be present, further pre- disposing the individual to ulceration and atrophy in the fingers. • The facial expression is lost as the skin tightens, and movement of the mouth and eyes may be impaired (Fig. 8.7). • The cutaneous form may also affect the microcirculation of various organs, eventually causing renal failure, intestinal obstruction, or respiratory failure due to pulmonary hypertension. ■ Treatment Because of the diversity in the types of scleroderma cases, medications vary dramatically based on the specific manifestations, the degree of the disorder, and the individual patient. For cases primarily involving serious ■ Signs and Symptoms Manifestations include the following: • Red patches of skin covered with silvery scales • Small scaling spots (commonly seen in children) • Dry, cracked skin that may bleed • Itching, burning, or soreness • Thickened, pitted, or ridged nails • Swollen and stiff joints ■ Treatment Treatments that reduce cell proliferation include glu- cocorticoids, tar preparations, and, in severe cases, the antimetabolite methotrexate. Exposure to ultraviolet light is frequently part of the treatment regimen. Research on new treatments related to immunologic changes in psoriasis is underway. Pemphigus Pemphigus is an autoimmune (see Chapter 7) disorder that comes in mainly two forms: pemphigus vulgaris and pemphigus foliaceus. The severity of the disease varies among individuals. B A FIG. 8.6 A, Psoriasis—acute inflammatory stage. B, Psoriasis. (A Courtesy of Dr. M. McKenzie, Toronto, Canada. B From Lookingbill DP, Marks JG: Principles of Dermatology, ed 3, Philadelphia, 2000, Saunders.) 150 SECTION III Pathophysiology of Body Systems inflammation, traditional antiinflammatory drugs such as nonsteroidal antiinflammatory agents (NSAIDs) or corticosteroids have proved somewhat effective, as well as immunosuppressive therapies. Vascular disease caused by scleroderma has been treated with vasodilator therapies including use of calcium channel blocking drugs such as nifedipine. Some research continues involving use of antifibrotic agents that reduce collagen production, but results have not yet been conclusive. FIG. 8.7 Scleroderma. (From Odom RB, James WD, Berger TG: Andrews’ Diseases of the Skin, ed 9, Philadelphia, 2000, Saunders.) THINK ABOUT 8.3 a. Describe the typical lesions of atopic dermatitis in the infant and adult in terms of their location and characteristics. b. Explain the pathologic changes in the skin that occur with psoriasis. c. Describe the development of the skin lesions of pemphigus vulgaris. d. Explain how the deposition of collagen in scleroderma may lead to tissue/organ damage. e. Name two findings in the evaluation of a blood sample that would indicate the allergenic basis for atopic dermatitis. be secondary, developing in wounds or pruritic lesions. Some infections are superficial; others can involve deeper tissues. Deeper infections can cause the formation of a mass of pus in the tissue, which is referred to as an abscess. Pus consists of both living and dead white blood cells and bacteria, along with tissue debris and serum. Acne, a staphylococcal infection common in young adults, is covered in Chapter 23 (see Fig. 23.5). ■ Pathophysiology Bacterial infections involve the same basic pathophysiol- ogy. A pathogenic organism establishes a population either on the surface of the skin or below in the underlying layers. As the organisms multiply, an inflammatory/ immune reaction will occur either as a result of the pres- ence of the organism itself or as a reaction to a toxin or metabolic product produced by the pathogens. The severity and effect in tissue will depend of factors such as location of infection and the infectious organism itself. Cellulitis Cellulitis (erysipelas) is an infection of the dermis and subcutaneous tissue, usually arising secondary to an injury, a furuncle (boil), or an ulcer (see Fig. 5.3). The causative organism is usually Staphylococcus aureus (S.aureus), or occasionally Streptococcus spp. It frequently occurs in the lower trunk and legs, particularly in indi- viduals with restricted circulation in the extremities or those who are immunocompromised. ■ Signs and Symptoms Manifestations include the following: • Reddened area • Edematous (swollen) • Pain • Red streaks running along the lymph vessels proximal to the infected area may develop ■ Treatment Systemic antibiotics are usually necessary to treat the infection along with analgesics for pain. Furuncles A furuncle (boil) is an infection, usually by S. aureus, which begins in a hair follicle (folliculitis) and spreads into the surrounding dermis (Fig. 8.8A). Common loca- tions are the face, neck, and back. ■ Signs and Symptoms Manifestations include the following: • Firm, red lesion • Painful nodule, which develops into a large, painful mass called an abscess • Abscess produces large amounts of purulent exudate (pus) composed of leukocytes, cellular debris from Skin Infections Infections occur frequently in the skin. They may be caused by bacteria, viruses, fungi, or other types of microorganisms as well as parasites. Pathogens or opportunistic microbes may penetrate the skin through minor abrasions or cuts as well as through inflamed areas. When serious infections develop, it is essential to culture the exudate to identify the causative organism and determine appropriate treatment. Bacterial Infections Bacterial infections of the skin are common. They may be primary, often caused by resident flora, or they may CHAPTER 8 Skin Disorders 151 ■ Treatment Warm compresses will promote drainage of the furuncles/ carbuncles. Analgesics such as ibuprofen or acetamino- phen can provide pain relief from inflammation. If drainage doesn’t occur in a few days, a physician should be called to cut and drain the abscess and may, if necessary, prescribe an antibiotic. Impetigo Impetigo is a common infection in infants and children but can also occur in adults. As it is a highly contagious infection, impetigo is a significant threat to neonates in nurseries due to their immature or compromised immune system and close contact with potentially infected caregiv- ers or equipment. ■ Pathophysiology In older children, infection results primarily from S. aureus but, alternatively, may be caused by group A beta- hemolytic streptococci. The infection is easily spread by direct contact with the hands, eating utensils, equipment, or towels. Activities involving close physical contact or contact with infected fomites can cause a rapid spread of this infection. Impetigo is commonly spread among team members of full-contact sports in which mats or equipment (fomites) serve to spread the infection from one person to the next. ■ Signs and Symptoms Lesions commonly occur on the face, and manifestations include the following: • Small red vesicles are present, which rapidly enlarge. • Vesicles will rupture to form yellowish-brown crusty masses (see Fig. 8.8B). Underneath this characteristic crust, the lesion is red and moist and exudes a honey- colored liquid. • Additional vesicles develop around the primary site by autoinoculation with hands, towels, or clothes. • Pruritus is common, leading to scratching and further spread of infection. ■ Treatment Topical antibiotics may be used in the early stages, but systemic administration of these drugs is necessary if the lesions are extensive. Unfortunately, the number of antibiotic-resistant strains of S. aureus is increas- ing, resulting in local outbreaks of infection. Another concern with impetigo due to certain strains of strep- tococci or staphylococci is glomerulonephritis, which can develop if treatment is not instituted promptly (see Chapter 18). Acute Necrotizing Fasciitis Acute necrotizing fasciitis has been termed flesh-eating disease because of the extremely rapid tissue invasion resulting from reduced blood supply to the tissues FIG. 8.8 A, Furuncle. B, Impetigo. Note the yellowish pustules with brownish crust, the inflammation, and the spreading lesions on the face. (A From Lookingbill D, Marks J: Principles of Dermatology, ed 2, Philadelphia, 1993, Saunders. B Courtesy of Dr. M. McKenzie, Toronto, Canada.) dead blood cells and bacteria, and a thin protein-rich fluid component Squeezing boils can result in the spread of infection by autoinoculation (transfer, of microbes from one site of infection on the body to another site most likely by fingers) to other areas of the skin, can cause cellulitis, or can force the bacteria in the abscess deeper into the dermis or subcutaneous tissue. Also, compression of furuncles in the nasal area may lead to thrombi or infection that spreads to the brain if the infected material reaches the cavernous sinus (a collecting point for venous blood from the face and brain) in the facial bones. Carbuncles are a collection of furuncles that coalesce to form a large infected mass, which may drain through several sinuses or develop into a single large abscess. 152 SECTION III Pathophysiology of Body Systems problem in parts of Africa, Asia, the South Pacific, and some areas of South America. The organism is not highly contagious, and extended contact with a source is required for transmission. The actual mechanism of pathogenic- ity of Mycobacterium leprae is largely unknown because this organism cannot easily be grown in culture media, which makes laboratory studies difficult. The disease is classified into two groups based on the treatments required: • Paucibacillary—limited disease with fewer, less widespread lesions • Multibacillary—disease much more widespread with significant lesions and tissue damage The clinical signs and symptoms vary but generally affect the skin, mucous membranes, and peripheral nerves. Manifestations typically include the following: • Formation of characteristic skin lesions or macules, which are flat skin lesions that may or may not have distinct borders • Loss of feeling due to nerve damage results in a situ- ation where the person may damage or destroy tissue through injury but not know it immediately; this damage can lead to the loss of limbs or other extremities due to irreparable damage or infection and eventual tissue necrosis The method of diagnosis involves microscopic examina- tion of a skin biopsy to identify the presence of the bacterium. ■ Treatment Treatment of leprosy primarily involves the use of antibiotics to control the causative organism as well as treat any secondary infections, rehabilitation, and edu- cation. The WHO has recommended antibiotics, which include rifampicin, minocycline (Minocin), or ofloxacin (Floxin). Viral Infections Herpes Simplex Herpes simplex (cold sores) virus type 1 (HSV-1) is the most common cause of cold sores or fever blisters, which occur on or near the lips. Herpes simplex type 2 (genital herpes) is considered in Chapter 19, herpes zoster or shingles is presented in Chapter 14, and herpetic stomatitis is covered in Chapter 17. Both types of herpes simplex virus cause similar effects and type 2 may cause oral as well as genital lesions. ■ Pathophysiology The primary infection may be asymptomatic, but the virus remains in a latent stage in the sensory nerve ganglion of the trigeminal nerve, from which it may be reactivated, causing the skin lesion (Fig. 8.9). Recurrence may be triggered by infection such as a common cold, sun exposure, or stress. The virus is spread by direct contact with fluid from the lesion. Viral particles may and the secretion of protease enzymes that destroy tissue. ■ Pathophysiology Although a mixture of aerobic and anaerobic microbes is frequently present at the site, the fulminant course with severe inflammation and tissue necrosis appears primarily to result from the actions of a highly viru- lent strain of gram-positive, group A, beta-hemolytic Streptococcus (S. pyogenes, also responsible for “strep throat”). This strain also produces a toxin causing toxic shock (see Chapter 12). Although relatively rare, there has been an increase in cases during the past few years, and the cases seem to increase in frequency in the cold months. There is often a history of minor trauma or infection in the skin and subcutaneous tissue of an extremity. The superficial fascia in the subcutaneous tissue and fascia surrounding the skeletal muscle, as well as other soft tissues, become edematous and necrotic, with occlusion of small blood vessels leading to gangrene. ■ Signs and Symptoms Manifestations include the following: • Infected area appears markedly inflamed • Very painful • Infected area rapidly increases in size • Dermal gangrene is apparent Systemic toxicity rapidly develops and produces further manifestations: • Fever • Tachycardia • Hypotension • Mental confusion and disorientation • Possible organ failure Diagnosis during the early stages of this infection is sometimes difficult as the signs/symptoms can be similar to cellulitis. This delay in diagnosis and subsequent treatment is extremely dangerous as this infection pro- gresses so rapidly. ■ Treatment Treatment includes aggressive antimicrobial therapy, fluid replacement, excision of all infected tissue, treat- ment with high oxygen flow in hyperbaric chambers, and possibly amputation to prevent further spread of infection. Delays in treatment result in greater tissue loss, potential amputation, and higher probability of mortality. Case fatality rates are estimated by the CDC to be 20% to 30%. Leprosy Leprosy (Hansen disease) is caused by the bacterium Mycobacterium leprae and in the past has affected millions of people worldwide. According to data from the World Health Organization (WHO), the global number of new cases has decreased dramatically although it is still a CHAPTER 8 Skin Disorders 153 1. Herpes simplex virus (HSV) enters human cell. 3. Viral replication causes necrosis and vesicle formation. 4. Defenses control infection. Virus migrates along trigeminal nerve to sensory ganglion and remains in latent state. Lesion heals. 5. Recurrence – HSV activated and migrates back along nerve to mucocutaneous site, replicates, and new lesion develops. 2. Virus replicates inside human cell and spreads to adjacent cells. Vesicle Lips Sensory ganglion Cranial nerve HSV A FIG. 8.9 Herpes simplex. A, Recurrent infection by herpes simplex virus. B, Herpes simplex on the face. (Courtesy of Dr. M. McKenzie, Toronto, Canada.) 154 SECTION III Pathophysiology of Body Systems be present in the saliva for some weeks following healing of the lesion and therefore can spread the infection to others or to the fingers—for example, if there is a break in the skin. A potential complication is spread of the virus to the eyes, causing keratitis (infection and ulceration of the cornea). Another complication is herpetic whitlow, a painful infection of the fingers, which can pose a risk for dental personnel (see Fig. 17.6). ■ Signs and Symptoms Reactivation is usually indicated by manifestations that include the following: • A preliminary burning or tingling sensation along the nerve and at the site on the lips • Development of painful vesicles, which then rupture and form a crust; spontaneous healing occurs in 2 to 3 weeks ■ Treatment The acute stage and viral shedding and spreading may be reduced by the topical application of antivi- ral drugs such as acyclovir (Zovirax) or valcyclovir (Valtrex). Verrucae (Warts) Verrucae are caused by human papillomaviruses (HPVs). There are many types of these viruses, associated with a variety of diseases. Common plantar warts, discussed here, are caused by HPV types 1 through 4. They fre- quently develop in children and young adults and are annoying but relatively harmless. Genital warts (HPV types 6 and 11) are described in Chapter 19, as is cervical cancer, associated with HPV types 16 and 18. ■Pathophysiology Plantar warts are common, occurring on the soles, with a similar variety affecting the hands or fingers (dorsal surface) and face. The infection spreads by viral shedding of the surface skin. Warts tend to persist even with treat- ment. Sometimes they resolve spontaneously within several years. ■ Signs and Symptoms Manifestations include the following: • A papule, which is a solid, raised lesion with distinct margins • Papules will develop a rough surface (Fig. 8.10), white or tan in color, and often are multiple • May be painful if pressure is applied, especially on the feet ■ Treatment A variety of local treatments are available, including laser, freezing with liquid nitrogen, and topical medications with ASA compounds. FIG. 8.10 Plantar warts on sole of foot. (Courtesy of Dr. M. McKenzie, Toronto, Canada.) Fungal Infections Fungal infections (mycoses) are diagnosed from scrap- ings of the skin processed with potassium hydroxide to accentuate the spores and hyphae (filaments) of the fungal growth, which then becomes fluorescent in ultraviolet light. Microscopic examination and culturing of samples can also be used to aid in identification. Most fungal infections are superficial, because the fungi live off the dead, keratinized cells of the epidermis (dermatophytes). Specific antifungal agents are required to treat these infections. Candidal infections are discussed in Chapter 17 (see Fig. 17.5, oral candida or thrush) and in Chapter 19 (vaginal infection). Candida also occurs frequently in patients with diabetes (see Fig. 16.8B). Tinea Tinea may cause several types of superficial skin infections (dermatophytoses or ringworm), depending on the area of the body affected. ■ Pathophysiology Tinea capitis is an infection of the scalp that is common in school-aged children (Fig. 8.11A). The infection may result from Microsporum canis, transmitted by cats and dogs, or by Trichophyton tonsurans, transmitted by humans. ■ Signs and Symptoms Manifestations include the following: • Circular bald patch is observed as hair is broken off above the scalp. • Erythema or scaling may be apparent. CHAPTER 8 Skin Disorders 155 A B C FIG. 8.11 A, Tinea corporis. Annular scaly plaques in superficial basal cell epithelioma. B, Tinea capitis, localized patch. C, Tinea pedis. (From Callen JP, et al: Color Atlas of Dermatology, Philadelphia, 1993, Saunders.) The manifestations include the following: • Skin between the toes becomes inflamed and macerated. • Painful and pruritic fissures (Fig. 8.11C) appear. • Feet may have a foul odor. Secondary bacterial infection is common, adding to the inflammation and necrosis. Topical tolnaftate is usually effective. Tinea unguium, or onychomycosis, is an infection of the nails, particularly the toenails. Infection begins at the tip of one or two nails, the nail turning first white and then brown. The nail then thickens and cracks, and the infection tends to spread to other nails. Other Infections Scabies Scabies is the result of an invasion by a mite, Sarcoptes scabiei. ■ Pathophysiology The female mite burrows into the epidermis, laying eggs over a period of several weeks as she moves along in the stratum corneum (Fig. 8.12). The male dies after fertilizing the female, and the female dies after laying the eggs. The larvae emerging from the eggs migrate to ■ Treatment Oral antifungal agents such as griseofulvin are recommended. Tinea corporis is a fungal infection of the body, particu- larly the nonhairy parts (Fig. 8.11B). ■ Signs and Symptoms The manifestations include the following: • A round, erythematous ring of vesicles or papules appears, with a clear center (ringworm) scattered over the body. • Pruritus or a burning sensation may be present. ■ Treatment Topical antifungal medications such as tolnaftate or ketoconazole are effective. Tinea pedis, or athlete’s foot, involves the feet, particu- larly the toes. Either Trichophyton mentagrophytes or Trichophyton rubrum is the usual causative organism. This condition may be associated with swimming pools and gymnasia if appropriate precautions are not in place (eg, wearing sandals, changing to clean, dry socks). The organisms may be normal flora that become opportunists or that spread easily from lesions under conditions of excessive warmth and moisture. 156 SECTION III Pathophysiology of Body Systems A B FIG. 8.13 A, Pediculus humanus capitis (head louse). B, Lice in hair. (A, From Frazier M, Dzymkowski J: Essentials of Human Disease and Conditions, ed 6, St. Louis, 2016, Elsevier. B, From Callen J, et al: Color atlas of dermatology, ed 1, Philadelphia, 1993, Saunders.) louse (cooties). Lice are small, brownish parasites that feed off human blood (humans are hosts only to human lice, not to animal lice) and cannot survive for long without the human host. ■ Pathophysiology Female lice lay eggs on hair shafts, cementing the egg firmly to the hair close to the scalp (Fig. 8.13). The egg, or nit, appears as a small, whitish shell attached to a hair. After hatching, the louse bites the human host, sucking blood for its survival. ■ Signs and Symptoms The manifestations include the following: • A macule or papule forms. • Macule is highly pruritic owing to mite saliva. The excoriations that result from scratching and the visible nits provide evidence of infestation; the adult lice usually are not visible. ■ Treatment Topical permethrin, malathion, or pyrethrin is used to treat lice, although resistance to these drugs is widespread. the skin surface and then burrow into the skin in search of nutrients. As the larvae mature into adults, the cycle is repeated. ■ Signs and Symptoms Manifestations include the following: • Burrows appear on the skin as tiny, light brown lines • Often with small vesicles • Erythema • Inflammation and pruritus caused by the damage done to the skin by the burrowing and the presence of mite fecal material in the burrow Common sites include the areas between the fingers, the wrists, the inner surfaces of the elbow, and the waistline. ■ Treatment Topical treatment with lindane (gamma-hexachlorocy- clohexane) is effective. Mites can survive for only a short time away from the human host and are usually spread only by close contact. Pediculosis Pediculosis (lice) can take three forms in humans. Pediculus humanus corporis is the body louse, Pediculus pubis is the pubic louse, and Pediculus humanus capitis is the head A B FIG. 8.12 Scabies. A, Scabies mite, as seen clinically when removed from its burrow. B, Characteristic scabies bites. (From McCance KL, et al: Pathophysiology, ed 6, St. Louis, 2010, Mosby. Courtesy of the Department of Dermatology, School of Medicine, University of Utah.) CHAPTER 8 Skin Disorders 157 THINK ABOUT 8.4 a. Distinguish between tinea pedis and tinea capitis by location and lesion. b. State one significant identifying feature of the lesions of (1) impetigo and (2) herpes simplex. c. State the causative organism of (1) scabies, (2) ringworm, and (3) pediculosis. d. Explain why herpes simplex tends to recur. Squamous Cell Carcinoma Skin cancer is easy to detect, accessible for treatment, and when identified in the early stages should have a good prognosis. Squamous cell carcinoma is similar to the common basal cell carcinoma in many respects (see Chapter 20 and Fig. 20.11). Both of these malignant tumors have an excellent prognosis when the lesion is removed within a reasonable time. ■ Pathophysiology Squamous cell carcinoma is a painless, malignant tumor of the epidermis; sun exposure is a major contributing factor. The lesions are found most frequently on exposed areas of the skin, such as the face and neck (Fig. 8.14). Smokers also have a higher incidence of squamous cell carcinoma in the lower lip region and mucous membranes of the mouth. Scar tissue is also a source of carcinoma, particularly in the African-American population. Actinic keratoses predispose to in situ or intraepidermal squa- mous cell carcinoma, which usually remains limited to the epidermis for a long time. The invasive type of squamous cell carcinoma arises from premalignant condi- tions such as leukoplakia. ■ Signs and Symptoms The manifestations of this carcinoma include the following: • Development of a scaly, slightly elevated, reddish lesion • Irregular border around the lesion • Central ulceration The tumor grows relatively slowly in all directions, invading surrounding tissues, and then spreads to the regional lymph nodes. It rarely metastasizes to distant sites. Malignant Melanoma Malignant melanoma, a much more serious form of skin cancer, develops from melanocytes and is increasing in incidence. The development of malignant melanoma A fine-toothed comb can be used to remove empty nits from the hair. Clothing, linen, and the surrounding area need to be carefully cleaned to prevent reinfection. Skin Tumors Keratoses Keratoses are benign lesions that are usually associated with aging or skin damage. Seborrheic keratoses result from proliferation of basal cells, leading to an oval elevation that may be smooth or rough and is often dark in color. This type of keratosis is often found on the face or upper trunk. Actinic keratoses occur on skin exposed to ultraviolet radiation and commonly arise in fair-skinned persons. The lesion appears as a pigmented, scaly patch. Actinic keratoses may develop into squamous cell carcinoma. There is increasing concern regarding the continued rise in skin lesions related to sun exposure. Estimates indicate that one in seven persons will develop skin cancer. Skin cancers currently represent 50% of all cancers diagnosed in the United States. Increased exposure to harmful ultraviolet rays is a result of more participation in outdoor sports, clothes that expose more skin along with the desire to have a fashionable tan, and increased use of tanning salons, as well as depletion of the protective ozone layer around the earth. The danger is evidenced by the increased incidence of tumors in those who have experienced severe sunburns, those who work or spend considerable time outdoors in the sun, or those who have blond hair and light-colored skin containing less melanin. Guidelines to reduce the risk of skin cancers have been developed. They include the following: • Reducing sun exposure at midday and early afternoon • Covering up with clothing, remaining in shade, and wearing broad-brimmed hats to protect face and neck • Applying sunscreen or sunblock, minimum SPF-15 (sun protection factor), broad spectrum, to protect from UVA and UVB rays • Protecting infants and children from exposure and sun damage to skin that may lead to skin cancer (see Chapter 20) WARNING SIGNS OF SKIN CANCER • A sore that does not heal • A change in shape, size, color, or texture of a lesion, especially an expanding, irregular circumference or surface • New moles or odd-shaped lesions that develop • A skin lesion that bleeds repeatedly, oozes fluid, or itches It is recommended that individuals routinely check skin, particularly exposed areas, moles, lesions resulting from sun damage, dark spots, or keratoses. Photodynamic therapy for keratoses and skin cancer involves a light-sensitive drug in a cream that is absorbed by the tumor cells. A laser then destroys the cells containing the chemical. 158 SECTION III Pathophysiology of Body Systems depends on genetic factors, exposure to ultraviolet radiation, and hormonal influences. ■ Pathophysiology Melanomas arise from melanocytes in the basal layer of the epidermis or from a nevus (mole), a collection of melanocytes. There are many types of nevi, most of which do not become malignant. Nevi that grow; change shape, color, size, or texture; or bleed are to be suspected of malignancy (Box 8.1). Malignant melanomas often appear as multicolored lesions with an irregular border (Fig. 8.15). Melanomas grow quickly, extending down into the tissues, then metastasize quickly to the regional lymph nodes and then to other organs, leading to a poor prognosis in many cases. FIG. 8.15 Malignant melanoma. (From McCance KL, et al: Patho- physiology, ed 6, St. Louis, 2010, Mosby. (Courtesy of Dr. M. McKenzie, Toronto, Canada.) Area of the mole is increased. Border is irregular. Color is changed in mole. Diameter of the mole is increased. BOX 8.1 “ABCD” Signs That a Mole or Nevus May Be a Melanoma B A FIG. 8.14 Squamous cell carcinoma. A, Skin. B, Squamous cell carcinoma on a sun-exposed ear. (A From Callen JP, et al: Color Atlas of Dermatology, Philadelphia, 1993, Saunders. B From McCance KL et al: Pathophysiology, ed 6, St. Louis, 2010, Mosby.) ■ Treatment When malignant melanomas are surgically removed, an extensive amount of tissue around and below the lesion is excised as well to ensure that all the malignant cells are removed. Additional radiation and chemotherapy now provides a 5-year survival rate of approximately 99% in cases of localized tumors and 7% to 70% in cases in which the tumor has invaded or metastasized, depending on what tissues have been invaded and the extent of the metastasis. In the United States 80% of melanomas are identified in the localized stage. Kaposi Sarcoma This formerly rare type of skin cancer has come into promi- nence because of its association with human immunodefi- ciency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) (see Chapter 7). Kaposi sarcoma was a relatively rare cancer that occurred in older men originat- ing from Eastern Europe or the Mediterranean area before the HIV pandemic. The disease is also endemic in Africa and affects younger individuals. Cases are still seen in individuals who are not HIV positive. ■ Pathophysiology In immunosuppressed patients, Kaposi’s sarcoma is common and may affect the viscera as well as the skin. Herpesvirus 8 (KSHV) forms part of the etiology of these tumors. The malignant cells arise from the endothelium in small blood vessels. CHAPTER 8 Skin Disorders 159 THINK ABOUT 8.5 a. Explain why squamous cell carcinoma has a better prognosis than malignant melanoma. b. List skin disorders to which exposure to sunlight is a predisposing factor. c. List the signs of possible malignant changes in a skin lesion. d. Compare the characteristics of the typical lesion of squamous cell carcinoma, melanoma, and Kaposi sarcoma. e. List the four warning signs of skin cancer. CASE STUDY A Atopic Dermatitis J.W., at age 5 months, had a moist, erythematous rash on the cheeks, chest, and extensor surfaces of the arms, caused by atopic dermatitis. She had a secondary bacterial infection on one cheek. 1. State the factors in the family history that may support a genetic predisposition to atopic dermatitis in this infant. 2. Explain why a secondary bacterial infection has probably developed. 3. List four factors that tend to aggravate atopic dermatitis. 4. Explain two ways in which administration of an antihistamine could help J.W. sleep. Two years later, eczema has persisted, although controlled partially by the use of moisturizers and hydrocortisone cream. The skin in some areas is thick and rough in texture. 5. Explain how hydrocortisone cream may reduce the inflammation and skin damage. ■ Signs and Symptoms The multiple skin lesions commence as purplish macules, often on the face, scalp, oral mucosa, or lower extremities. As macules develop, manifestations include the following: • Nonpruritic lesions • Nonpainful • Lesions progress to form large, irregularly shaped plaques or nodules, which may be darker in color, purplish or brownish (see Fig. 7.17B) • In immunocompromised patients, lesions develop rapidly over the upper body and may become painful ■ Treatment A combination of radiation, chemotherapy, surgery, and biologic therapy constitutes the common treatment. CASE STUDY B Malignant Melanoma Mr. P.X. age 45, had been swimming and was sitting on the beach when a friend commented on a dark reddish black “pimple” with a rough surface on it on his upper back. Mr. P.X. said he had C H A P T E R S U M M A R Y The skin or integument has many important functions, particularly in protecting the body from the environment. Secondary effects of many skin lesions include infection or scar tissue. Skin lesions may be distinguished by their physical characteristics, location, exudate if any, and the presence of pruritus or pain. • Contact dermatitis may be caused by an irritant or an allergen, often identifiable by the location of the lesion. • Urticaria (hives) results from a type I hypersensitivity to ingested food or drugs. • Atopic dermatitis (eczema) is a familial hypersensitivity beginning in infancy and often associated with hay fever and asthma. • Psoriasis is a chronic inflammatory disorder character- ized by accelerated cell proliferation. The typical lesion is a silvery plaque covering an erythematous base. • Staphylococcus aureus is a common cause of skin infec- tions, including cellulitis (in the legs and lower trunk), furunculosis (in hair follicles), and impetigo (on the faces of young children). • Acute necrotizing fasciitis is characterized by bacterial invasion with rapid tissue destruction and septic shock. • Herpes simplex virus type 1 (cold sores) causes recurrent painful vesicles around the mouth. It may be transmit- ted in the exudate or the saliva. Between exacerbations the virus remains in a latent form in a nearby sensory ganglion. • Mycoses are fungal infections such as tinea, which may affect the feet (athlete’s foot), the scalp, or the body. • Pediculosis (lice) may infect the scalp or body, thriving on human blood. • There is increasing evidence of sun damage to skin predisposing patients to malignant tumors. • Squamous cell carcinoma is a slow-growing tumor common to exposed areas. • Malignant melanoma, arising from a nevus, grows quickly and metastasizes early. numerous moles on his body and it was not of concern. However, later he thought about the comment and saw his physician, who thought the lesion was suspicious and should be checked. The border and surface of the mass were irregular, and it appeared to be quite thick. A similar small lesion was located nearby. The lesion was diagnosed as a superficial spreading malignant melanoma, and surgery was scheduled. Surgery revealed that the melanoma had penetrated through the dermis and had spread to the regional lymph nodes. 1. Explain the factors that make this lesion suspicious for cancer. 2. List the possible predisposing factors in this patient. 3. Predict the prognosis and the reasons for it in this case. 160 SECTION III Pathophysiology of Body Systems S T U D Y Q U E S T I O N S 1. Describe the structure of a hair follicle, including any gland associated with it. 2. Describe the location of resident or normal flora related to the skin and its appendages. 3. State the location of nerves and blood vessels in the skin. 4. List the functions of the skin. 5. Define the terms papule, ulcer, and fissure. 6. Explain how glucocorticoids may reduce pruritus, and give examples of conditions for which these drugs may be helpful. 7. Compare the mechanisms and possible causes of allergic and irritant contact dermatitis. 8. Describe the manifestations of each of the following and state the causative agents for each: a. shingles b. boils c. scabies d. scleroderma 9. Prepare a list of contagious skin disorders. 10. Suggest a preventive measure that could reduce the risk of skin cancer. 11. Explain why allergic responses tend to recur. 12. Compare the characteristics of the exudate found in a furuncle and in herpes simplex. 13. Explain why Kaposi sarcoma is more common in immunocompromised patients. 14. Explain the specific cause of pruritus with the following: a. scabies b. pediculosis c. contact dermatitis 161 Review of the Musculoskeletal System Bone Skeletal Muscle Joints Diagnostic Tests Trauma Fractures Factors Affecting the Healing of Bone Dislocations Sprains and Strains Other Injuries Muscle Tears Repetitive Strain Injury Bone Disorders Osteoporosis Rickets and Osteomalacia Paget Disease (Osteitis Deformans) Osteomyelitis Abnormal Curvatures of the Spine Bone Tumors Disorders of Muscle, Tendons, and Ligaments Muscular Dystrophy Primary Fibromyalgia Syndrome Joint Disorders Osteoarthritis Rheumatoid Arthritis Juvenile Rheumatoid Arthritis Infectious (Septic) Arthritis Gout (Gouty Arthritis) Ankylosing Spondylitis Other Inflammatory Joint Disorders Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Describe the general structure and function of bone and joints. 2. Describe the general structure and function of skeletal muscle. 3. Describe the types of fractures, the healing process in bone, and potential complications. 4. Compare dislocations, sprains, and strains. 5. Describe the pathophysiology of osteoporosis, the predisposing factors, and possible complications. 6. Compare the causes and effects of rickets, osteomalacia, and Paget disease. 7. Describe the common bone tumors. 8. Describe the characteristics of Duchenne muscular dystrophy. 9. Describe the effects of fibromyalgia. 10. Compare osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis with regard to pathophysiology, etiology, manifestations, and possible complications. 11. Describe the distinguishing features of infectious (septic) arthritis. 12. State the etiology and common signs of gout. 13. Describe the differences between the joint inflammatory disorders: bursitis, synovitis, and tendinitis. L E A R N I N G O B J E C T I V E S anabolic steroids ankylosis arthroscopy articulation crepitus diaphysis electromyograms endosteum epiphysis fascia hyperuricemia kyphosis lordosis medullary cavity metaphysis motor unit neuromuscular junction osteoblasts osteoclast osteocytes osteoporosis periosteum pseudohypertrophic scoliosis uveitis K E Y T E R M S C H A P T E R 9 Musculoskeletal System Disorders 162 SECTION III Pathophysiology of Body Systems • Osteoprogenitor cells are derived from embryonic mesenchymal cells and differentiate into osteoblasts. • Osteoblasts are responsible for secreting the matrix of bone. • Osteoclasts are derivatives of macrophage progenitor cells, and their function is the resorption of bone tissue. • Osteoblast and osteoclast activity depend on two hormones: calcitonin and parathyroid hormone. • Calcitonin stimulates osteoblasts. • Parathyroid hormone stimulates osteoclasts. Bone tissue consists of two types, which differ in density. Compact bone is formed when many Haversian systems are tightly packed together, producing a strong, rigid structure that forms the outer covering of bones. Cancellous or spongy bone is less dense and forms the interior structure of bones. Spongy bone lacks Haversian systems but is made up of plates of bone bordering cavities that contain marrow. A typical long bone consists of the diaphysis, a thin shaft, between two larger ends or epiphyses (see Fig. 9.1B). The diaphysis is formed of compact bone sur- rounding a medullary cavity containing marrow. The metaphysis is the area where the shaft broadens into the epiphysis. The epiphysis is made up of spongy bone covered by compact bone. The end of each epiphysis is covered by hyaline cartilage (articular cartilage), which facilitates movement at points of articulation between bones. The epiphyseal cartilage or plate (“growth” plate) is the site of longitudinal bone growth in children and adolescents, such growth being promoted by growth hormone and sex hormones. Longitudinal bone growth ceases when the epiphyseal plate ossifies during adoles- cence or early adulthood depending on the specific bone. The epiphyseal plate is referred to as the epiphyseal line following ossification or closure; no bone growth in length occurs after this phase. Changes in bone density or thickness can occur at any time under the influence of hormones such as growth hormone, parathyroid hormone, or cortisol. The stress (weight-bearing or muscle tension) placed on the bone also affects the balance between osteoblastic and osteoclastic activity. With aging, bone loss is accentu- ated, resulting in decreased bone mass and density. Osteoporosis, loss of bone density due to loss of calcium salts, is common in older people, particularly women (see Chapter 24). Except for the surface of the bone covered by articular cartilage, the bone is covered by periosteum, a fibrous connective tissue. The periosteum contains osteoblasts, blood vessels, nerves, and lym- phatics, some of which penetrate into the canals in the bone. When the periosteum is stretched or torn, severe pain results. The medullary cavity is lined with endosteum, also containing osteoblasts. These osteoblasts are required for bone repair and remodeling as needed. At birth the medullary cavity in most bones contains red bone marrow Review of the Musculoskeletal System The musculoskeletal system is composed of the bones of the skeletal system, the skeletal muscles, joints, cartilage, tendons, ligaments and other connective tissues that bind and support other structures of the body. Bone Bones form the skeletal system and provide rigid support and protection for the body, particularly when it is in an upright position or in motion. The skeletal system provides rigid support and protection for the body, particularly when it is in an upright position or is in motion. The skeletal framework determines the basic size and proportions of the body. Protection is provided for the viscera, such as the heart and lungs, and for fragile structures such as the spinal cord and brain. Bone also has important metabolic functions related to calcium metabolism and storage and the bone marrow, which serves as the area where new blood cells are produced by a process called hematopoiesis. Bones may be classified by shape: • Long bones, such as the humerus and femur, consist of a long, hollow shaft with two bulbous ends. • Short bones are generally square-like in shape and are found in the wrist and ankle. • Flat bones occur in the skull and are relatively thin and often curved. • Irregular bones, which have many projections and vary in shape, are represented by the vertebrae and the mandible. Individual bones have unique markings, which may be lines, ridges, processes, or holes. Such landmarks provide for attachment of tendons or passage of nerves and blood vessels. Bone is special connective tissue consisting of an inter- cellular matrix and bone cells. The matrix is organized in microscopic structural units called Haversian systems or osteons, in which rings of matrix (lamellae) surround a Haversian canal containing blood vessels (Fig. 9.1). The matrix is composed of collagen fibers and calcium phosphate salts (eg, hydroxyapatite crystals), which provide a strong and rigid structure. Mature bone cells, or osteocytes, lie between the rings of matrix in spaces called lacunae. Small passages termed canaliculi provide communication between the Haversian canals and the lacunae. The following communication processes occur in the canaliculi passages: • A dynamic equilibrium is maintained between new bone, which is constantly being produced by osteo- blasts, and the resorption of bone by osteoclast activity, in accordance with the various hormonal levels and the degree of stress imposed on the bone substance. Osteoblast and osteoclast activity provide the homeo- stasis of bone. CHAPTER 9 Musculoskeletal System Disorders 163 Volkmann’s canal Haversian canal Haversian canal Trabeculae of spongy bone Osteon of compact bone Lamellae Lacunae containing osteocytes Canaliculi Osteon Periosteum Epiphysis Epiphysis Diaphysis Articular cartilage Periosteum Endosteum Nutrient foramen Medullary cavity Compact bone Spongy bone Epiphyseal line Articular cartilage A B FIG. 9.1 A, Structure of a bone. B, Structure of a long bone. (From Applegate EJ: The Anatomy and Physiology Learning System, Philadelphia, 2000, Saunders.) THINK ABOUT 9.1 a. Describe the functions of bone. b. Differentiate compact bone from cancellous bone in terms of structure and function. c. Describe the characteristics of the (1) periosteum, (2) epiphyseal plate, and (3) metaphysis. in which hematopoiesis takes place. Gradually, yellow (fatty) bone marrow replaces red bone marrow in the long bones. In adults, red bone marrow is found in the cranium, bodies of the vertebrae, ribs, sternum, and ilia, the last two being the usual sites of bone marrow aspira- tion used in the diagnosis and monitoring of leukemias and blood dyscrasias. 164 SECTION III Pathophysiology of Body Systems neuromuscular junction, where the synapse between the end of the motor nerve and the receptor site in the muscle fiber is located, the chemical transmitter acetyl- choline is released (Fig. 9.2). Following its release and the subsequent muscle contraction, acetylcholine is inactivated by the enzyme acetylcholinesterase (AChE). Skeletal muscle-relaxing drugs may act by blocking acetylcholine at the muscle receptor sites, whereas muscle activity may be promoted by drugs that interfere with cholinesterase activity. Each muscle cell contains myofibrils, which in turn are made up of smaller myofilaments consisting of the proteins actin and myosin. Actin and myosin filaments are the contractile elements of the muscle fiber. The mechanism of muscle contraction starts at the neuromuscular junction and ends with the actual contrac- tion of the skeletal muscle fibers: • An action potential from the motor neuron arrives at the presynaptic terminal. • The arrival of the action potential results in the depo- larization of the presynaptic terminal. • The depolarization is followed by a calcium influx into the presynaptic terminal. • The calcium influx results in the exocytosis of the neurotransmitter (ACh) into the synaptic cleft. • Diffusion of the neurotransmitter to the postsynaptic receptor results in a muscle action potential. • The muscle action potential travels down the t-tubules to cause a second messenger activation. • Calcium is released from the sarcoplasmic reticulum and causes the power stroke—contraction of the muscle fiber. • During muscle relaxation, calcium is transported back into the sarcoplasmic reticulum. • Both muscle contraction and relaxation require cellular energy (adenosine triphosphate [ATP]). Skeletal Muscle Skeletal muscle has four basic functions: 1. To facilitate body movement by muscle contraction 2. To maintain body position by continuing muscle tone 3. To stabilize the joints and prevent excessive movement 4. To maintain body temperature by producing heat through muscle contraction Skeletal muscle is considered to be under voluntary control, although some muscle activities occur without deliberate intent, such as respiratory movements, postural reflexes, blinking, shivering, or certain facial expressions. Skeletal muscle is striated muscle that consists of bundles of muscle fibers (cells) covered by connective tissue. The striated or striped appearance results from the arrangement of the actin and myosin filaments within the muscle fibers. Connective tissue coverings of skeletal muscles are as follows: • Epimysium—surrounding the entire muscle • Perimysium—surrounding the fascicles (a small bundle of muscle fibers) • Endomysium—surrounding the individual muscle fibers (cells) Muscle tissue is well supplied with nerves and blood vessels, necessary to fulfill its function. Each muscle fiber is an elongated muscle multinucleated cell containing many mitochondria that supply energy for the contraction process. A muscle is stimulated to contract when an efferent impulse is conducted along a motor neuron to a muscle. The axon of the motor nerve branches as it penetrates a muscle so that each muscle fiber in the muscle receives a stimulus to contract at the same time. The motor neuron of the spinal cord and all the muscle fibers it stimulates are referred to as the motor unit. At the Capillary Muscle fiber Axon Axon terminal Nerve impulse Synaptic vesicles – contain ACh Synaptic cleft Folded sarcolemma Receptor sites— bind with ACh FIG. 9.2 The neuromuscular junction. A nerve impulse (action potential) travels down the axon terminal. The impulse causes the release of acetylcholine. The neurotransmitter diffuses across the synaptic cleft and stimulates the muscle fiber. (From Applegate EJ: The anatomy and Physiology Learning System, ed 4, St. Louis, 2011, Elsevier.) CHAPTER 9 Musculoskeletal System Disorders 165 or replace damaged muscle. However, muscle cells may undergo hypertrophy (increased size of the muscle cell) when the demands are increased, such as with regular exercise. Aerobic or endurance exercise, such as swimming or running, increases the muscle’s capacity to work for a longer time without causing marked hypertrophy of the muscle. Such exercise increases the capillaries and blood flow in a muscle as well as the mitochondria and myoglobin content, thus improving efficiency and endur- ance. This type of exercise also promotes general respira- tory and cardiovascular function. Anaerobic or resistance exercise, such as weight lifting or bodybuilding, focuses on increasing muscle strength by increasing muscle mass (hypertrophy). It is helpful for those persons interested in developing strong muscles to incorporate some aerobic exercise into the training program to improve cardiopul- monary fitness as well as strength. Anabolic steroids are synthetic hormones similar to testosterone, the male sex hormone. They are used by some athletes, bodybuilders, and others interested in changing the body image to build up muscle strength and mass. Speed and endurance do not appear to be affected. These synthetic hormones (eg, methenolone [Primobolan]) have been developed to increase the anabolic effects, or protein synthesis, and decrease the androgenic or male characteristics produced by these chemicals. Serious and sometimes life-threatening side effects are associated with the use of these substances, such as liver damage, cardiovascular disease, personality changes, emotional lability, and sterility. Unfortunately, many adolescents and young adults abuse this type of steroid, including those involved in sports, those with eating disorders, and those with psychological problems related to body image and poor self-esteem. Many organizations have banned the use of anabolic steroids by participants in athletic competition. Skeletal muscle also may atrophy, in which muscle cell size is decreased when the muscle is not used (see Chapter 1). Atrophied muscle becomes weak and flaccid. Atrophy may occur within a short period of time when a fractured limb is placed in a cast or the pain of arthritis limits movement. Such disuse atrophy is also associated with immobilization and chronic illness (see Chapter 25). Atrophy may be secondary to nerve injury, with resultant flaccid paralysis. Also, nutritional deficiencies, particularly protein, secondary to disorders such as anorexia or Crohn disease, lead to atrophy. Skeletal muscle may also become weak owing to degenerative changes involving accumula- tions of fatty or fibrous tissue. Muscle mass decreases with aging, owing to both a decrease in number of muscle cells and a decrease in size (diameter) of the fibers. Muscle strength generally diminishes as well, although this may vary with the individual’s degree of activity and general health status. Muscle twitch or tetany usually results from increased irritability of the motor nerves supplying the muscle. For example, hypocalcemia causes increased permeability During exercise, the blood vessels in the muscles are dilated to promote greater blood flow into the muscle, thus increasing the supply of oxygen and nutrients (glucose and fatty acids) to provide energy for the contraction and remove metabolic wastes. Limited amounts of oxygen can be bound to myoglobin and stored in muscle fibers. Myoglobin is a red oxygen-binding protein, similar in structure to hemoglobin, which is present in muscle cells. Glycogen, a stored form of glucose, is also stored in muscle. Aerobic respiration to produce ATP can be maintained in muscle fibers as long as adequate oxygen is made available from the myoglobin and the circulating blood. If the supply of oxygen does not meet the demand, the process of anaerobic respiration begins, using glucose as the primary energy source and incurring an oxygen debt (the amount of oxygen required to restore the muscle cell to its normal resting state, including converting lactic acid to pyruvic acid, glucose, or glycogen and replenishing stores of ATP). Anaerobic respiration produces lactic acid rather than carbon dioxide, and smaller amounts of ATP. This state of acidosis leads to the increased respirations commonly observed during exercise. These respirations operate as a compensatory mechanism to reduce acidosis by decreasing carbon dioxide levels in the blood (see Chapter 2). The accumulated lactic acid may cause local muscle pain and cramping during and immediately after exercise. A muscle cramp is pain resulting from a strong muscle contraction or spasm, usually caused by local irritation from metabolic wastes. Muscle spasm reduces blood flow, thus leading to ischemic pain. Muscle soreness and pain that appear a day or so after strenuous exercise are often due to minor damage to muscle cells and subsequent inflammation. Also, during periods of strenuous physical activity and anaerobic metabolism, excessive lactic acid diffuses into the blood, lowering serum pH and causing metabolic acidosis (see Chapter 2). A muscle may be attached directly to the periosteum of a bone, but more often the connective tissue covering the muscle (perimysium) extends to form a cordlike structure or tendon, which attaches each end of the muscle to the two bones that articulate at a joint. At a joint, one bone remains fixed, forming the origin of the muscle. The other bone attached to the same muscle is moved by the muscle contraction and is called the insertion. Ligaments form a direct attachment between two bones. Muscles may work singly or in groups to perform a specific movement. Also, muscles at a site may be des- ignated as antagonists because one muscle opposes the action of another, allowing movement in either direction. For example, at the elbow, the triceps brachii muscle functions as an extensor muscle, whereas the biceps brachii is a flexor muscle. Antagonistic muscles prevent excessive movement and provide better control of movements. Skeletal muscle cells do not undergo mitosis; therefore that process cannot be used to enhance muscle activity 166 SECTION III Pathophysiology of Body Systems The joint cavity or space between the articulating ends of the bones is filled with a small amount of synovial fluid, which facilitates movement. The synovial fluid prevents the articular cartilage on the two surfaces from damaging each other and also provides nutrients to the articular cartilage. The synovial fluid is produced by the synovial membrane (synovium), which lines the joint capsule to the edge of the articular cartilages. The synovial membrane is well supplied with blood vessels. The articular capsule is composed of the synovial membrane and its outer covering, the fibrous capsule, a tough protective material that extends into the periosteum of each articulating bone (Sharpey fibers). The capsule is reinforced by ligaments, straps across the joint that link the two bones, which support the joint and prevent excessive movement of the bones. There are some variations in joint structure. The knee has additional moon-shaped fibrocartilage pads, termed lateral and medial menisci, which act to stabilize the joint. Bursae are fluid-filled sacs composed of synovial mem- brane and located between structures such as tendons and ligaments; they act as additional cushions in the joint. The TMJ (temporomandibular joint), the only movable joint in the skull and face, has two synovial cavities and a central articular cartilage of dense collagen tissue. of the nerve membrane and therefore increased or spontaneous stimulation of the skeletal muscle fibers, causing a contraction or spasm of the muscle. Note that sufficient calcium is stored and returned to storage in the skeletal muscle cell following contraction, and therefore hypocalcemia does not directly affect skeletal muscle function, but rather its innervation. THINK ABOUT 9.2 a. Explain why skeletal muscle cells contain many mitochondria. b. Explain the purpose of shivering when one is cold. c. What electrolyte is required for skeletal muscle contraction, and what is its source? d. Differentiate muscle hypertrophy from atrophy, and give a cause of each. e. Explain how an anticholinesterase drug affects skeletal muscle function. f. When does anaerobic metabolism occur in skeletal muscle, and what are its effects? APPLY YOUR KNOWLEDGE 9.1 Explain how blood doping—taking extra concentrated doses of red blood cells—can help an athlete. THINK ABOUT 9.3 a. Name and describe the type of joint found in the skull. b. Describe two structures in a joint that facilitate movement. c. Describe the location and purpose of the synovial membrane. Joints The function of joints or articulations between bones is accomplished by tendons and ligaments, which are composed of collagen fibers arranged in bundles, a structure that can withstand considerable stress. At the insertion point of tendons or ligaments there is a gradual transition from the connective tissue to the bone or cartilage. Tendons and ligaments have little blood supply; therefore healing of these structures is difficult and slow. Joints vary in the degree of movement allowed: • Synarthroses, represented by the sutures in the skull, are immovable joints. • Amphiarthroses, slightly movable joints, are joints in which the bones are connected by fibrocartilage or hyaline cartilage. Examples of this type of joint include the junction of the ribs and sternum and the symphysis pubis. • Diarthroses or synovial joints are freely movable joints and are the most common type of joint in the body. Different types of diarthroses allow a variety of move- ments. For example, a hinge joint, providing flexion and extension, is found at the elbow, whereas a ball-and-socket joint at the shoulder provides a wide range of motion, including rotation. Both hinge and gliding movements are found in the temporomandibular joint (TMJ), control- ling the opening of the mouth. Common body movements are illustrated in Ready Reference 1 (see Fig. RR 1.6). In a synovial joint, the ends of the bone are covered with articular (hyaline) cartilage, providing a smooth surface and a slight cushion during movement (see Fig. 9.13A, presented later). With aging, the cartilage in joints tends to degenerate and become thin, leading to difficulty with movement and potential changes in the alignment of bones. The nerves supplying a joint are those supplying the muscles controlling the joint. These motor fibers are accompanied by sensory fibers from proprioceptors in the tendons and ligaments that respond to the chang- ing tensions related to movement and posture. The joint capsule and ligaments are supplied with pain receptors. Diagnostic Tests In persons in whom trauma, tumors, or metabolic disease are suspected, bone abnormalities may be evaluated using x-rays (radiographs) and bone scans. Electromyograms (EMGs) measure the electrical charge associated with muscle contraction and are helpful in differentiating muscle disorders from neurologic disease. Also, the strength of individual muscle groups can be CHAPTER 9 Musculoskeletal System Disorders 167 • Open-closed. An open or compound fracture results when the skin is broken (Fig. 9.4). The bone fragments may be angled and protrude through the skin. In open fractures there is more damage to soft tissue, including the blood vessels and nerves, and there is also a much higher risk of infection. In a closed fracture the skin is not broken at the fracture site. • Number of fracture lines: • Simple fracture, a single break in the bone in which the bone ends maintain their alignment and position • Segmental fracture, a bone break in which several large bone fragments separate from the main body of a fractured bone • Comminuted fracture, in which there are multiple fracture lines and bone fragments • Compression fracture, common in the vertebrae, occurring when a bone is crushed or collapses into small pieces • Other types are as follows: • Impacted fracture occurs when one end of the bone is forced or telescoped into the adjacent bone; for example, the neck of the femur is crushed against the pelvis. • Pathologic fracture results from a weakness in the bone structure due to conditions such as a tumor or osteoporosis. The break occurs spontaneously or with very little stress on the bone. • Stress fractures (fatigue fractures) result from repeated excessive stress, commonly in the tibia, femur, or second and third metatarsals. • Depressed fracture occurs in the skull when the broken section is forced inward on the brain. • Transverse fracture is a fracture across the bone. • Linear fracture is a break along the axis of the bone. • Oblique fracture is a break at an angle to the diaphysis of the bone. • Spiral fracture is a break that angles around the bone, usually due to a twisting injury. Unique names for certain specific types of fractures include the following: • Colles fracture is a break in the distal radius at the wrist, commonly occurring when a person attempts to break a fall by extending the arm and open hand. Sometimes the ulna is also damaged. • Pott fracture refers to a fracture of the lower fibula due to excessive stress on the ankle, such as occurs when stepping down with force. The tibia may be damaged as well. ■ Pathophysiology When a bone breaks, bleeding occurs from the blood vessels in the bone and periosteum. Bleeding and inflam- mation also develop around the bone because of soft tissue damage. This hematoma or clot forms in the medul- lary canal, under the periosteum, and between the ends of the bone fragments (Fig. 9.5). Necrosis occurs at the determined. Muscle biopsy is required to confirm the presence of some muscular disorders, such as muscular dystrophy. Joints may be visualized by arthroscopy (insertion of a lens directly into the joint) or by magnetic resonance imaging (MRI), a noninvasive imaging pro- cedure. Synovial fluid may be aspirated and analyzed to ascertain whether inflammation, bleeding, or infection is present. Serum calcium, phosphate, and parathyroid hormone levels may indicate metabolic changes, perhaps secondary to renal disease or parathyroid hormone imbalance. Muscle disorders may be checked by determining levels of components such as serum creatine kinase (CK), which is elevated in persons with many muscle diseases. Creatine kinase, an enzyme with an essential role in energy storage, leaks out of damaged muscle cells into body fluids. Trauma Fractures A fracture is a break in the rigid structure and continuity of a bone (Fig. 9.3). Fractures can be classified in several ways: • Complete-incomplete. A complete fracture occurs when the bone is broken to form two or more separate pieces, whereas in an incomplete fracture the bone is only partially broken. An example of the latter is a greenstick fracture, common in the softer bones of children, in which the shaft of the bone is bent, tearing the cortical bone (outer layer of compact bone) on one side but not extending all the way through the bone. FIG. 9.3 Fracture of the midshaft of the humerus. (Courtesy of Dr. Mercer Rang, The Hospital for Sick Children, Toronto, Ontario, Canada.) 168 SECTION III Pathophysiology of Body Systems repaired bone is remodeled by osteoblastic and osteoclastic activity in response to mechanical stresses on the bone. The excessive bone in the callus is removed, more compact bone is laid down, and eventually the bone assumes a normal appearance. To summarize, the five stages of bone healing are hematoma, granulation tissue, procallus (fibrocartilage), bony callus, and remodeling. Factors Affecting the Healing of Bone Many factors affect the healing process in bone. In children, fractures usually heal in approximately 1 month; in adults, the process requires 2 or more months. A fracture in an elderly person may require many months to heal. Addi- tional factors include: • The amount of local damage done to the bone and soft tissue is a major determining factor. Prolonged inflammation or extensive damage to the periosteum or blood vessels impairs healing. ends of the broken bone because the torn blood vessels are unable to continue delivery of nutrients. An inflam- matory response develops as a reaction to the trauma and the presence of debris at the site. At fracture sites, the hematoma serves as the basis for a fibrin network into which granulation tissue grows. Many new capillaries extend into this tissue, and phagocytic cells (for removing debris) and fibroblasts (for laying down new collagen fibers) migrate to it. Also, chondroblasts begin to form cartilage. Thus the two bone ends become splinted together by a procallus or fibrocartilaginous callus (collar). This structure is not strong enough to bear weight, but it constitutes the preliminary bridge repair in the bone. Osteoblasts from the periosteum and endosteum begin to generate new bone to fill in the gap. Gradually the fibrocartilaginous callus is replaced by bone through extensive osteogenic activity, which forms a bony callus. Note that damaged bone is repaired by new bone forma- tion, not by scar tissue. During subsequent months the Oblique Comminuted Open Pathologic Segmented Spiral Transverse Greenstick Bending of softer bone in child Impacted Colles fracture (wrist-distal radius) Potts fracture (ankle-distal fibula) Compression fracture of vertebra Bone tumor A B C D E F G H I J K L FIG. 9.4 Types of fractures. CHAPTER 9 Musculoskeletal System Disorders 169 deficits as well as in those taking drugs such as glu- cocorticoids (see Chapter 5). Complications may affect healing in patients who sustain severe injuries: 1. Muscle spasm may occur as local pain and irritation cause strong muscle contractions at the fracture site. This muscle spasm pulls the bone fragments further out of position, causing angulation (deformity), rotation of a bone, or overriding of the bone pieces. Such abnormal movement of the bone causes more soft tissue damage, bleeding, and inflammation. 2. Infections such as tetanus or osteomyelitis (see Chapters 6 and 23) are a threat in persons with compound fractures or when surgical intervention is required. In such cases, precautions include wound débridement, application of a windowed cast, tetanus booster shots, and prophylactic antimicrobial therapy. 3. Ischemia is a complication that develops in a limb fol- lowing cast treatment as edema increases during the first 48 hours after the trauma and the limb is com- pressed by the cast. If the peripheral area (eg, the toes or fingers) becomes pale or cold and numb or if the peripheral pulse has decreased or is absent, it is likely that the cast has become too tight and is compromising the circulation in the limb. The cast must be released quickly to prevent secondary tissue damage. During the later stages of healing it is also important that the cast not become too loose as edema decreases and muscle atrophies because the newly formed procallus may break down if there is any bone movement. 4. Compartment syndrome may develop shortly after the fracture occurs when there is more extensive inflam- mation, such as with crush injuries. Increased pressure of fluid within the fascia, the nonelastic covering of the muscle, compresses the nerves and blood vessels, causing severe pain and ischemia or necrosis of the muscle. The pressure effects may be aggravated by a cast. 5. Fat emboli are a risk when fatty marrow escapes from the bone marrow into a vein within the first week after injury. Fat emboli are more common in patients with fractures of the pelvis or long bones such as the femur, particularly when the fracture site has not been well immobilized during transportation immediately after the injury. Fat emboli travel to the lungs (see Chapter 13), where they cause obstruction, extensive inflammation, and respiratory distress syndrome, and they may disseminate into the systemic circulation as well. Frequently the first indications of a fat embolus are behavioral changes, confusion, and disorientation associated with cerebral emboli, in combination with respiratory distress and severe hypoxia. 6. Nerve damage may occur with severe trauma or tearing of the periosteum. 7. Failure to heal (nonunion) or healing with deformity (malunion) may result if the bone is not stabilized with ends closely approximated and aligned. • The more closely approximated the ends of the bone are, the smaller the gap to be filled and the faster the healing process. When necessary to promote healing and prevent deformity, the bones must be realigned (reduced) in the proper position before healing can begin. It is most important to maintain immobilization of the bones to prevent disturbance or damage to the developing fragile bridge of tissue. • Any secondary problem such as foreign material or infection at the site delays healing. • Numerous systemic factors also affect the healing process in bone. For example, fracture repair is delayed in older persons and individuals with circulatory problems, anemias, diabetes mellitus, or nutritional Healed bone Endosteum Fracture Remodeling bone Clot retracting Increased chondroblasts and osteoblasts Medullary (marrow) cavity Necrotic bone resorbed Fibrin mesh and granulation tissue Periosteum Bleeding— hematoma forms Calcification Bony callus forms Procallus or fibrocartilage “collar” forms Osteogenic activity fills gap in bone A B C D E F FIG. 9.5 Healing of a fracture. 170 SECTION III Pathophysiology of Body Systems Dislocations A dislocation is the separation of two bones at a joint with loss of contact between the articulating bone surfaces (Fig. 9.6). Usually one bone is out of position, whereas the other remains in its normal location. For example, the humerus is displaced from the shoulder joint. If the bone is only partially displaced, with partial loss of contact between the surfaces, the injury is termed subluxation. Trauma, such as a fall, is usually the cause of disloca- tions. In some cases, a fracture is associated with a disloca- tion, whereas in others, an underlying disorder such as a muscular disease or rheumatoid arthritis, or other damage such as torn ligaments, may predispose the individual to dislocation. Dislocations cause considerable soft tissue damage, including damage to the ligaments, nerves, and blood vessels as the bone is pulled away from the joint. Severe pain, swelling, and tenderness develop; bleeding and inflammation may result. Deformity and limited move- ment are usually evident. The diagnosis is confirmed by x-rays. Treatment consists of reduction to return the dislocated bone to its normal position, immobilization during healing, and therapy to maintain joint mobility. Healing is slow if the ligaments and soft tissue are extensively damaged. Sprains and Strains A sprain is a tear in a ligament, and a strain is a tear in a tendon. Ligaments and tendons support the bones in a joint and can easily be torn when excessive force is exerted on a joint. In some cases, the ligaments or tendons can be completely separated from their bony attachments, a problem known as avulsion. Sprains and strains are painful 8. Fractures in or near the joint may have long-term residual effects, such as osteoarthritis or stunted growth if the epiphyseal plate is damaged in a child. ■ Signs and Symptoms In some cases a fracture is clearly present, as in patients with compound fractures or an obvious deformity. Swell- ing, tenderness at the site, or altered sensation is present but may occur with any type of injury. Inability to move the broken limb is apparent. Crepitus, a grating, creaking, cracking or popping sound, may be heard if the ends of the bone fragments move over each other. (The broken limb should not be moved to test for this!) Pain usually occurs immediately after the injury. In some cases, particularly with compound or multiple fractures, pain is delayed when nerve function at the site is lost temporarily. Pain results from direct damage to the nerves by the trauma and from pressure and irritation due to the accumulated blood and inflammatory response. Severe pain may cause shock with pallor, diaphoresis, hypotension, and tachycardia. Nausea and vomiting sometimes occur. ■ Diagnostic Tests X-ray films are used to confirm the presence of a fracture. ■ Treatment Immediate splinting and immobilization of the fracture site is essential to minimize the risk of complications. If necessary, reduction of the fracture is performed to restore the bones to their normal position. Closed reduction is accomplished by exerting pressure and traction; open reduction requires surgery. During surgery, devices such as pins, plates, rods, or screws may be placed to fix the fragments in position; any necrotic or foreign material is removed, and the bone ends are aligned and closely approximated. Immobilization is attained by applying a cast or splints or by using traction. Traction involves the application of a force or weight pulling on a limb that is opposed by body weight. This force maintains the alignment of the bones, prevents muscle spasm, and immobilizes the limb. During the healing period, exercises are helpful to limit muscle atrophy in the immobilized area, maintain good circula- tion, and minimize joint stiffness or contractures. EMERGENCY TREATMENT FOR FRACTURES 1. Cover open wounds with sterile or clean dressing material. 2. Splint for support and immobilize for transport, including joints above and below the fracture. 3. Elevate the limb slightly and apply cold if possible. Check pulse and sensory function distal to the fracture. 4. Keep patient warm. Check for signs of shock. Bone displaced out of joint Clavicle Humerus Scapula FIG. 9.6 Dislocation. CHAPTER 9 Musculoskeletal System Disorders 171 be elevated. In third-degree tears, surgery may be neces- sary to repair the tear. An example of a third-degree tear requiring surgery may be tearing of the gastrocnemius (the “hamstring”). In all cases, any scar tissue that forms will reduce the flexibility and strength of the muscle. Repeated injuries eventually result in fibrous scar tissue replacing normal structures, hindering mobility, as well as permanent joint damage and the development of osteoarthritis. For example, repeated tears in the knee ligaments appear to cause early development of osteo- arthritis. Shoulder pain and damage to the rotator cuff can result from excessive swinging motions, particularly with force (as occurs in golf, tennis, or hockey and when painting walls and ceilings), leading to tendinitis. Repetitive Strain Injury Repetitive strain injury (RSI) refers to disorders affecting muscles, tendons, and nerves that develop over a period of time. The cause seems to be repeated forceful or preci- sion movements, many of which are associated with work-related activities, although sports such as golf and certain exercises are also common causes. It appears that rapid repetition of certain movements interferes with circulation to the area and damages soft tissues, with cumulative effects. Most injuries affect the upper body. Higher stress levels increase the risk. Those affected are primarily in the 30-to-50-year age range, and the incidence is increasing. Work-related activities such as repetitive lifting of merchandise, pivoting on an assembly line, or retrieving and shelving library materials are associated with a higher risk of RSI. The result is pain, weakness, and numbness, causing disability and interference with sleep. Examples include tendinitis, inflammation or injury of the tendon and sheath, or compression of a peripheral nerve, seen in carpal tunnel syndrome. In the latter, the median nerve is compressed at the wrist between tendons and the transverse carpal ligament. Diagnosis requires a history, x-rays, and perhaps arthroscopic examination. Common treatment includes rest, applications of cold or heat, use of nonsteroidal antiinflammatory drugs, and physiotherapy. Occupational therapy is helpful in identifying ergonomic changes in work that will lessen damage or reduce strain and pain. Surgery may be required to repair tears, remove damaged tissue, or replace joints. Sports medicine clinics can provide evaluation, education and preventive measures, assistive devices, and rehabilitation programs. and are accompanied by tenderness, marked swelling, and often discoloration due to hematoma formation. Bleeding into the joint capsule delays healing. Strength and range of movement in the joint are limited. Diagnosis requires x-rays and other tests to rule out the presence of a fracture and determine the extent of the damage. After a tear occurs, inflammation and then granulation tissue develop at the site. Collagen fibers are formed that create links with the remaining tendon or ligament, and eventually the healing mass is bound together with fibrous tissue. A tendon or ligament requires approximately 6 weeks before it is strong again. Stress on a tendon in the early stage will reopen the tear and lead to the develop- ment of excessive fibrous tissue in the tendon and thus less strength, shortening, and decreased flexibility at the joint. With severe damage to the tendons and ligaments, surgical repair may be necessary. Other Injuries The number of traumatic and overuse injuries has been increasing with the rising numbers of adults and children participating in fitness and recreational activities. Some of the predisposing factors include inappropriate or inadequate equipment, training, or warm-up techniques; more aggressive approaches to sports (eg, skiing); and failure to allow minor injuries to heal completely before resuming activity. Minor injuries resulting from excessive use or abuse, particularly of joints, are also increasing—for example, tennis elbow, in which inflammation develops at the junction of the forearm muscles with the humerus. Muscle tears are more common, leading to hematoma and scar tissue formation. Muscle Tears Muscle tears are tears along the muscle itself or at points of attachment. They can occur as a result of a direct trauma or overexertion/overstressing of the muscle. There are three degrees of muscle tears: • First degree—usually involves only a small percent- age of the muscle. Pain is usually mild and does not result in any appreciable loss in strength or range of motion. • Second degree—a larger tear that involves much of the muscle but stops short of being a complete tear. Pain is usually severe and the muscle can be partially contracted with a substantial loss of strength and range of motion. • Third degree—a complete tear across the width of the muscle. The muscle will be unable to contract, there will be a great deal of internal bleeding, and surgery may be required for proper healing. As soon as a tear occurs, activity involving the use of the muscle should stop, cold should be applied to help reduce internal bleeding, a compression bandage should be applied, and the limb or affected area should THINK ABOUT 9.4 a. Define each type of fracture: (1) compound, (2) comminuted, and (3) transverse. b. List the three degrees of muscle tears and the steps in the treatment of a third-degree tear. c. Differentiate a dislocation from a sprain. 172 SECTION III Pathophysiology of Body Systems • One limb or area of the body may be affected by osteoporosis when it is immobilized because of conditions such as a fracture (disuse osteoporosis). • Hormonal factors such as hyperparathyroidism, Cushing syndrome, or continued intake of catabolic glucocorticoids such as prednisone • Deficits of calcium, vitamin D, or protein related to diet or history of deficits in childhood or malabsorption disorders • Cigarette smoking • Small, light bone structure, as in Asian and Caucasian persons • Excessive caffeine intake ■ Signs and Symptoms Compression fractures of the vertebrae have several obvious effects. Back pain is a common sign of osteopo- rosis, associated with the altered vertebrae causing pressure on the nerves. Kyphosis and scoliosis, abnormal curvatures of the spine with accompanying loss of height, are characteristic of the spinal changes seen with osteo- porosis (see Figs. 23.2 and 23.3). Spontaneous fractures involving the head of the femur or pelvis are frequent occurrences. Healing of the fractures is slow. ■ Treatment Usually bone cannot be restored to normal structural levels, but therapy can retard further bone loss. In addition to treating any underlying problem, therapeutic measures may include the following: • Dietary supplements of calcium and vitamin D or protein. It is currently recommended that premeno- pausal women need at least 1000 mg of calcium, whereas postmenopausal women require more than 1500 mg. Intake of vitamin D should be 400 to 800 IU daily. • Fluoride supplements to promote bone deposition. • Bisphosphonates such as alendronate (Fosamax) can be used as a short-term option to inhibit osteoclast activity and bone resorption. • Calcitonin (Miacalcin nasal spray). • Injected human parathyroid hormone to decrease bone resorption (helpful for some individuals). • Regular weight-bearing exercise program such as walking or weight lifting. • Raloxifene (Evista) or tamoxifen, classed as selective estrogen receptor modulator drugs; recommended in specific cases because there is less effect on uterine and breast tissue (the use of estrogen replacement therapy for osteoporosis has been questioned because of the possible risk of cancer). • Other newer medications under investigation, including strontium ranelate that appears to decrease bone resorption and increase bone formation as well as antibody preparations that bind to osteoclasts, prevent- ing bone resorption. • Surgery to reduce kyphosis and realign the vertebral column. Bone Disorders Osteoporosis Osteoporosis is a common metabolic bone disorder characterized by a decrease in bone mass and density, combined with loss of bone matrix and mineralization (see Fig. 24.1). Estimates for prevalence run as high as 10 million in the United States, with many more having low bone mass, and therefore increased risk. Although women have a higher risk of osteoporosis, a significant number of men also have been diagnosed. Osteoporosis is a factor in an estimated 1.5 million fractures annu- ally, of which 300,000 involve the hip. Regular bone mass density tests are recommended for all individuals older than 50 years of age. This procedure requires resting on the scanner table for 10 to 15 minutes and is noninvasive. Osteoporosis occurs in two forms: primary, which includes postmenopausal, senile, or idiopathic osteopo- rosis, and secondary, which affects men and women and follows a specific primary disorder such as Cushing syndrome. ■ Pathophysiology During the continuous bone remodeling process, bone resorption exceeds bone formation, leading to thin, fragile bones that are subject to spontaneous fracture, particularly in the vertebrae (see Fig. 24.2). Although bone density and mass are reduced, the remaining bones are normal. Osteoporosis affects the bones consisting of higher propor- tions of cancellous bone, such as the vertebrae and femoral neck. The early stages of the condition are asymptomatic but can be diagnosed using various bone density scans and x-rays to demonstrate the bone changes. ■ Etiology Bone mass normally peaks in young adults, and then gradually declines, depending on genetic factors (such as vitamin D receptors), nutrition, weight-bearing activity, and hormonal levels. It appears that calcium intake in the child and young adult is critical to maintenance of bone mass later in life. A number of factors predispose people to osteoporosis. These include the following: • Aging: • Osteoporosis is common in older individuals, particularly postmenopausal women with estrogen deficiency (see Chapter 24). • Osteoblastic activity is less effective with advancing age. • Decreased mobility or a sedentary lifestyle: • Mechanical stress on bone by muscle activity is essential for osteoblastic activity. Decreased mobility is a factor with aging, but it can also occur if a patient is on bed rest for a prolonged time with a chronic illness or has limited activity due to rheu- matoid arthritis. CHAPTER 9 Musculoskeletal System Disorders 173 ■ Treatment As with other infections, antibiotics are the primary treatment used to eliminate the infection. If the infection is prolonged and significant damage has occurred in the bone tissue, surgery may be required to remove and repair the damaged tissue. If an insert or mechanical implant is involved, surgery may also be necessary to remove the device. Abnormal Curvatures of the Spine The curves formed by the vertebrae help the spine absorb the stress of body movement and the action of gravity. When abnormalities occur, the curves may become misaligned or exaggerated, resulting in three main types of curvature disorders: lordosis, kyphosis, and scoliosis (Fig. 9.7). ■ Pathophysiology and Etiology The three types of abnormal curvature share some common causes such as osteoporosis or arthritis, but other causes are specific to the disorder. These abnormali- ties can also develop during adolescence and are covered in Chapter 23. Lordosis, also referred to as swayback, is characterized by the spine curving significantly inward at the lower back. Some of the specific causes of lordosis include the following: • Achondroplasia • Obesity • Discitis • Slipping forward of the vertebrae Kyphosis, also referred to as hunchback or humpback, is characterized by an abnormally rounded upper back. Some specific causes of kyphosis include the following: • Poor posture • Spina bifida • Congenital defects • Spinal tumors or infections • Scheuermann disease Scoliosis is characterized by either an S- or C-shaped sideways curve to the spine. The specific causes of the most common form of this abnormality are gener- ally not known; however, scoliosis tends to run in families, and some more general causes such as disease, trauma, or congenital defects are also believed to be implicated. ■ Treatment Treatments may vary depending on the specific disorder and its severity but may include the following: • Medication for pain and inflammation • Weight loss • Wearing a brace • Exercises and physical therapy • Surgery Research continues into new methods to stabilize bones and prevent fractures. Rickets and Osteomalacia These conditions result from a deficit of vitamin D and phosphates required for bone mineralization. They occur with dietary deficits, malabsorption, prolonged intake of phenobarbital (for seizures), or lack of sun exposure. The result is soft bone and rickets in children. Vitamin D is required for the absorption of calcium, and the lack of calcification of the cartilage forming at the epiphyseal plate leads to weak bones, often deformities, and the typical “bow legs” (rickets). The child’s height is usually below normal. Osteomalacia occurs in adults in whom poor absorption of vitamin D or sometimes calcium causes soft bones and resulting compression fractures. “Renal rickets” refers to osteomalacia associated with severe renal disease (see Chapter 18). Paget Disease (Osteitis Deformans) Paget disease is a progressive bone disease that occurs in adults older than 40 years. The cause has not yet been established; however, childhood infection with a virus has been implicated and there is evidence of a genetic factor. Excessive bone destruction occurs, with replace- ment of bone by fibrous tissue and abnormal bone. Structural abnormalities, evident on x-rays, and enlarge- ment (or thickening) are apparent in the long bones, vertebrae, pelvis, and skull. In some cases, the disease is asymptomatic. Pathologic fractures are common. When the vertebrae are affected, compression fractures and kyphosis result. Skull involvement leads to signs of increased pressure such as headache and compression of cranial nerves. Paget disease also causes cardiovascular disease and heart failure. Treatment goals are to reduce the risk of fractures and deformity. Osteomyelitis ■ Pathophysiology and Etiology Osteomyelitis is a bone infection usually caused by bacteria and sometimes fungi. The microorganisms can enter the blood from an infection anywhere in the body and spread to the bones. An infection can also occur as a result of surgery, particularly when a pin or structural insert is involved. ■ Signs and Symptoms As with most infections, there can be both local and systemic manifestations. These may include the following: • Local inflammation and bone pain • Fever and excessive sweating • Chills • General malaise 174 SECTION III Pathophysiology of Body Systems Both types of tumor grow quickly and metastasize to the lungs in the early stages of tumor development. Sometimes the tumor is revealed by pathologic fracture. Bone pain is the common symptom, a constant steady pain at rest as well as with activity that gradually increases in severity. An individual often feels the increased pain at night. Treatment involves surgical amputation or excision of the tumor, followed by chemotherapy. Some clinics have used adjuvant chemotherapy before localized surgery without the need for amputation. Adjuvant chemotherapy appears to increase the survival rates in most patients. Survival rates vary greatly depending on the stage of the cancer and the histologic features of the tumor. Tumors localized to the bone at the time of diagnosis have a survival rate of 70%. Many bone tumors have already metastasized at diagnosis, leading to a poorer prognosis, with approximately 30% survival rates. Newer surgical methods have been successful in removing secondary tumors from the lung and preserving lung tissue. Chondrosarcomas arise from cartilage cells and are more common in adults older than 30 years. These tumors develop more gradually in the pelvic bone or shoulder girdle at the points of muscle attachment and eventu- ally metastasize to the lung. Pain does not develop until late, and the tumors may remain silent until they are well advanced. Surgery is the primary treatment for chondrosarcomas. Various nontraditional forms of treatment such as chi- ropractic treatment, nutritional therapy, and acupuncture are also used. Bone Tumors A majority of primary bone tumors are malignant. Bone is also a common site of secondary tumors, particularly in the spine and pelvis. Metastatic bone tumors usually are secondary to malignant tumors in the breast, lung, or prostate. Osteosarcoma (osteogenic sarcoma) is a primary malig- nant neoplasm that usually develops in the metaphysis of the femur, tibia, or fibula in children or young adults, particularly males (Fig. 9.8). Ewing sarcoma is another malignant neoplasm common in adolescents that occurs in the diaphysis of long bones. FIG. 9.8 Gross appearance of osteosarcoma. (From Damjanov I: Pathology for the Health Professions, ed 4, St. Louis, 2012, Elsevier.) THINK ABOUT 9.5 a. Describe four contributing factors to osteoporosis in older women. b. Explain how osteoporosis leads to loss of height. Kyphosis Normal spine position B A Lordosis Normal spine position FIG. 9.7 Kyphosis (A) and lordosis (B) in relation to normal spinal curvature. (From Frazier M, Drzymkowski J: Essentials of Human Disease and Conditions, St. Louis, 2013, Elsevier.) CHAPTER 9 Musculoskeletal System Disorders 175 TABLE 9.1 Types of Muscular Dystrophy Type Inheritance Age of Onset Distribution Progress Duchenne (variant- Becker type) X-linked recessive (affects males) 2–3 years Hips, legs, shoulder girdle (ascending) Rapid Fascioscapulohumeral (Landouzy) Autosomal dominant Before age 20 Shoulder, neck, face Slow to moderate Myotonic Autosomal dominant (chromosome 19) Birth to 50 years Face, hands Slow Limb girdle Autosomal recessive All ages Shoulders, pelvis Varies A B C FIG. 9.9 A, Gower maneuver. B, Electrocardiogram in Duchenne muscular dystrophy. C, Calf hypertrophy in Becker muscular dys- trophy. (From Perkin GD: Mosby’s Color Atlas and Text of Neurology, ed 2, London, 2002, Mosby.) Disorders of Muscle, Tendons, and Ligaments Muscular Dystrophy Muscular dystrophy (MD) is a group of inherited disorders characterized by degeneration of skeletal muscle. The disorders differ in type of inheritance, area affected, age at onset, and rate of progression. Common types are summarized in Table 9.1. Duchenne or pseudohypertrophic muscular dystrophy is the most common type, affecting young boys, with a prevalence of about 3/100,000 males. X-linked inheritance has been demonstrated in most cases of Duchenne muscular dystrophy. Some cases appear to be spontaneous gene mutations. Serum CK is elevated in many but not all carriers of the abnormal gene and appears before the first signs. ■ Pathophysiology The basic pathophysiology is the same in all types of muscular dystrophy. A metabolic defect, a deficit of dystrophin (a muscle cell membrane protein), leads to degeneration and necrosis of the cell. Skeletal muscle fibers are replaced by fat and fibrous connective tissue (leading to the hypertrophic appearance of the muscle; Fig. 9.9). Muscle function is gradually lost. Cardiomy- opathy is common. ■ Signs and Symptoms With the Duchenne type of muscular dystrophy, early signs appear at around 3 years of age, when motor weakness and regression become apparent in the child. Initial weakness in the pelvic girdle causes a waddling gait and difficulty with climbing stairs or attaining an upright position. The “Gower maneuver,” in which the child pushes to an erect position by using the hands to climb up the legs, is a typical manifestation (see Fig. 9.9). The weakness spreads to other muscle groups and eventu- ally to the shoulder girdle. Tendon reflexes are reduced. Vertebral deformities such as kyphoscoliosis and various contractures develop. Respiratory insufficiency and infections are common. The majority of patients with muscular dystrophy develop cardiac abnormalities and mental retardation. ■ Diagnostic Tests Diagnosis is based on identification of common genetic abnormalities, elevated creatine kinase levels (which are raised before clinical signs appear), electromyography, and muscle biopsy. Female carriers in a family can be identified by the presence of defective dystrophin in the 176 SECTION III Pathophysiology of Body Systems Men tend to have localized fibromyalgia, including jaw pain or headache. ■ Treatment Treatment includes stress reduction, regular early morning exercise, rest as needed, local applications of heat or massage as needed, and low doses of antidepres- sants, such as the tricyclic antidepressants or selective serotonin-norepinephrine reuptake inhibitors (SNRIs). A new drug, Lyrica (pregabalin), has been approved for fibromyalgia and mediates the pain pathway. Nonsteroidal antiinflammatory drugs (NSAIDs) have been helpful to some individuals. Massage therapy is helpful as is occupa- tional therapy to identify strategies to deal with pain and fatigue. Joint Disorders Arthritis occurs in many forms that impair joint function, leading to various types of disability in all age groups. Osteoarthritis Osteoarthritis (OA) may be called a degenerative, or “wear and tear,” joint disease. The incidence of osteoar- thritis is increasing. It is estimated that one in three adults in the United States has some degree of osteoarthritis. Men are affected more often than women. It is a major cause of disability and absence from the workplace. ■ Pathophysiology In this condition the progression is as follows: 1. The articular cartilage, of weight-bearing joints in particular (eg, hips, knees), is damaged and lost through structural fissures and erosion resulting from excessive mechanical stress (Fig. 9.10), or breaks down for unknown reasons. 2. The surface of the cartilage becomes rough and worn, interfering with easy joint movement. 3. Tissue damage appears to cause release of enzymes from the cells, which accelerates the disintegration of the cartilage. 4. Eventually the subchondral bone may be exposed and damaged, and cysts and osteophytes or new bone spurs develop around the margin of the bone. 5. Pieces of the osteophytes and cartilage break off into the synovial cavity, causing further irritation. 6. The joint space becomes narrower (easily seen on x-rays). 7. There may be secondary inflammation of the surround- ing tissues in response to altered movement and stress on the joint. No systemic effects are present with osteoarthritis. ■ Etiology The primary form of osteoarthritis is associated with obesity and aging, whereas the secondary type follows blood. Chorionic villus testing can be performed on the fetus at 12 weeks’ gestation. ■ Treatment Because no specific treatment is available, the goal is to maintain motor function as much as possible with moder- ate exercise and the use of supportive appliances. Occupational therapists play a significant role in support, assessment, and provision of appropriate assistive devices as the client’s status and needs change. Death usually results by age 20 from respiratory or cardiac failure. If the patient chooses to use a ventilator in the event of respiratory failure, the life span can be prolonged sub- stantially. Research on muscular dystrophy in mice has identified genetic therapies that alter the expression of MD genes and prevent dystrophic changes in young mice. This research is promising, but human applications will not be available until at least the mid-2020s. THINK ABOUT 9.6 a. Describe the pathophysiologic changes in muscular dystrophy. b. Explain how vertebral deformities develop in muscular dystrophy. Primary Fibromyalgia Syndrome Primary fibromyalgia syndrome is a group of disorders characterized by pain and stiffness affecting muscles, tendons, and surrounding soft tissues (not joints). ■ Pathophysiology There are no obvious signs of inflammation or degenera- tion in the tissues. The cause is not known, but it appears to be related to altered central neurotransmission, resulting in increased soft tissue sensitivity to substance P, a neurotransmitter involved in pain sensation. The incidence is higher in women 20 to 50 years of age. There is often a history of prior trauma or osteoarthritis. Aggravating factors include sleep deprivation, stress, and fatigue. ■ Diagnosis Eighteen specific tender or trigger points, where pain and tenderness may be stimulated, have been identified in tendons and ligaments in the neck and shoulder area, trunk, and limbs, and these trigger points may be used in diagnosis. ■ Signs and Symptoms Manifestations may include the following: • Generalized aching pain • Marked fatigue • Sleep disturbances • Depression • In some individuals, irritable bowel syndrome or urinary symptoms due to interstitial cystitis CHAPTER 9 Musculoskeletal System Disorders 177 joints are affected as the individual exerts more stress on normal joints to protect the damaged joints. Osteoarthritis is not a systemic disorder; therefore there are no systemic signs or changes in serum levels. Diagnosis is based on exclusion of other disorders and radiographic evidence of joint changes consistent with the clinical signs. Radiographic evidence often shows lesser progression of joint changes than the clinical effects of disease. ■ Treatment Any undue stress on the joint should be minimized and adequate rest and additional support provided to facilitate movement. Ambulatory aids such as canes or walkers are helpful. Orthotic inserts in the shoes reduce the risk of deformity and help to maintain function. Physiotherapy and massage therapy help to reduce spasm in adjacent muscles due to pain. This results in maintenance of joint function and muscle strength. Occupational therapy is important in providing assistive devices such as joint splints and teaching alternate practices to reduce pain and deal with stiffness. Individuals with early OA may injury or abuse. Genetic changes in joint cartilage have been identified in research studies now underway. These genetic changes result in accelerated breakdown of articular cartilage. Osteoarthritis often develops in specific joints because of injury or excessive wear and tear on a joint. This is a common consequence of participation in sports and certain occupations. Congenital anomalies of the musculoskeletal system may also predispose a patient to osteoarthritis. Once the cartilage is damaged, joint alignment or the frictionless surface of the articular cartilage is lost. A vicious cycle ensues, because uneven mechanical stress is then applied to other parts of the joint and to other joints. The large weight-bearing joints (eg, the knees and hips) that are subject to injury or occupational stress are frequently affected. ■ Signs and Symptoms The pain of osteoarthritis, which is often mild and insidi- ous initially, is an aching that occurs with weight bearing and movement. Pain becomes more severe as the degen- erative process advances. It may be unilateral in some cases. Joint movement is limited. Frequently the joint appears enlarged and hard as osteophytes develop. Walking becomes difficult if the joint is unstable, and the muscles atrophy, causing a predisposition to falls, particularly in older individuals. When the temporomandibular joint is involved, mastication becomes difficult, there is dif- ficulty opening the mouth to speak or yawn, and pre- auricular pain may be severe. In some cases, the hands are involved, with bony enlargement of the distal interphalangeal joints (Heberden nodes; Fig. 9.11). Usually little soft tissue swelling is seen. Crepitus may be heard as the cartilages become irregular, grating against each other. In some cases, other Osteophyte or bone spur Cyst in bone Cartilage fragments Narrow joint space Erosion of cartilage and bone FIG. 9.10 Pathologic changes with osteoarthritis. FIG. 9.11 Heberden node. (From Lemmi FO, Lemmi CAE: Physical Assessment Findings CD-ROM, Philadelphia, 2000, Saunders.) 178 SECTION III Pathophysiology of Body Systems FIG. 9.12 Hip arthroplasty. Radiograph shows hip after Charnley total hip arthroplasty (replacement of the femoral head and acetabu- lum with prosthesis cemented into bone). (From Petty W: Total Joint Replacement, Philadelphia, 1991, Saunders.) find pain relief and improved flexibility with the use of glucosamine-chondroitin compounds. Research studies on the use of static magnets to reduce pain have not shown significant results in rigorous double-blinded studies. Intraarticular injection of synthetic synovial fluid may reduce pain and facilitate movement. Glucocorticoids may be helpful. Analgesics or NSAIDs may be required for pain. Surgery is available to repair or replace joints such as the knee or hip with prostheses (Fig. 9.12). Success of such arthroplasty also depends on full participation in a rehabilitation program following surgery. Rheumatoid Arthritis Rheumatoid arthritis (RA) is considered an autoimmune disorder causing chronic systemic inflammatory disease. It affects more than 1% of the population and is a major cause of disability. Rheumatoid arthritis has a higher incidence in women than men and increases in older individuals. ■ Pathophysiology Remissions and exacerbations lead to progressive damage to the joints. The disease often commences insidiously with symmetric involvement of the small joints such as the fingers, followed by inflammation and destruction of additional joints (eg, wrists, elbows, knees). Many individuals also have involvement of the upper cervical vertebrae and TMJ. The severity of the condition varies from mild to severe, reflecting the number of joints affected, the degree of inflammation, and the rapidity of progression. In the affected joints, the first step in the development of rheumatoid arthritis is an abnormal immune response, causing inflammation of the synovial membrane with vasodilation, increased permeability, and formation of exudate, causing the typical red, swollen, and painful joint. This synovitis appears to result from the immune abnormality. Rheumatoid factor (RF), an antibody against immunoglobulin G, as well as other immunologic factors, is present in the blood in the majority of persons with rheumatoid arthritis. Rheumatoid factor is also present in synovial fluid. After the first period of acute inflam- mation, the joint may appear to recover completely. During subsequent exacerbations, the process continues: 1. Synovitis. Inflammation recurs, synovial cells proliferate. 2. Pannus formation. Granulation tissue from the synovium spreads over the articular cartilage. This granulation tissue, called pannus, releases enzymes and inflamma- tory mediators, destroying the cartilage (Fig. 9.13). 3. Cartilage erosion. Cartilage is eroded by enzymes from the pannus, and in addition, nutrients that are normally supplied by the synovial fluid to the cartilage are cut off by the pannus. Erosion of the cartilage creates an unstable joint. 4. Fibrosis. In time, the pannus between the bone ends becomes fibrotic, limiting movement. This calcifies and the joint space is obliterated. 5. Ankylosis. Joint fixation and deformity develop. During each exacerbation or acute period, inflammation and further damage occur in joints previously affected, and additional joints become affected by synovitis. During this process, other changes frequently occur around the joint: • The acute inflammation leads to disuse atrophy of the muscles and stretching of the tendons and ligaments, thus decreasing the supportive structures in the unstable joint. • The alignment of the bones in the joint shifts, depending on how much cartilage has been eroded and the balance achieved between muscles. • Inflammation and pain may cause muscle spasm, further drawing the bones out of normal alignment. • Contractures and deformity with subluxation develop. Various contractures and deformities, such as ulnar deviation, swan neck deformity, or boutonniere defor- mity, may occur in the hands (Fig. 9.14), depending on the degree of flexion and hyperextension in the joints. Mobility is greatly impaired as the various joints become damaged and deformed. Walking becomes very difficult when the knees or ankles are affected. CHAPTER 9 Musculoskeletal System Disorders 179 Pathologic Changes in Rheumatoid Arthritis 3. Loss of cartilage 2. Pannus Normal Synovial Joint Joint cavity Synovial membrane Epiphyseal plate Synovial fluid Articular cartilage Joint capsule Bone 4. Fibrous tissue (ankylosis) Pannus-filled erosion 1. Inflamed synovium A B FIG. 9.13 Pathologic changes with rheumatoid arthritis. Ulna Ulnar drift Deformity and ankylosis of joint Boutonniere deformity FIG. 9.14 Typical deformity in a hand with rheumatoid arthritis. The inflammatory process has other effects on the body. Rheumatoid or subcutaneous nodules may form on the extensor surfaces of the ulna. Nodules also may form on the pleura, heart valves, or eyes. These are small granu- lomas on blood vessels. Systemic effects are thought to arise from the circulating immune factors, causing marked fatigue, depression and malaise, anorexia, and low-grade fever. Iron deficiency anemia with low serum iron levels is common; when it results from rheumatoid arthritis, this anemia is resistant to iron therapy. ■ Etiology Although rheumatoid arthritis is considered an auto- immune disorder, the exact nature of the abnormality has not been fully determined. A genetic factor is present, with familial predisposition. The abnormality seems to be linked to several viral infections. Rheumatoid factor is not present in all patients with rheumatoid arthritis, yet it may be present in certain other disorders as well. Rheumatoid arthritis is more common in women than men, and the incidence increases with aging. ■ Signs and Symptoms Rheumatoid arthritis is insidious at onset, often becoming manifest as mild general aching and stiffness. Other more specific manifestations may include the following: • Inflammation may be apparent first in the fingers or wrists. It affects joints in a symmetric (bilateral) fashion, and usually more than one pair of joints is involved. • The joints appear red and swollen and often are sensi- tive to touch as well as painful. • Joint stiffness occurs following rest, which then eases with mild activity as circulation through the joint improves. • Joint movement is impaired by the swelling and pain. Frequently, daily activities become difficult, including dressing, food preparation, and oral hygiene. • Malocclusion of the teeth may develop from TMJ involvement as the condyle is damaged. • Systemic signs are marked during exacerbations and include fatigue, anorexia, mild fever, generalized lymphadenopathy, and generalized aching. With each exacerbation of disease, the function of the affected joints is further impaired as joint damage pro- gresses. Eventually the joint is no longer inflamed but is fixed and deformed (“burned out”). The College of Rheumatology has established criteria for diagnosis based on four out of seven of the manifesta- tions on their list—for example, swelling of three joints for a minimum of 6 weeks. 180 SECTION III Pathophysiology of Body Systems Most individuals are subject to periodic exacerbations. If the number and severity of recurrences can be mini- mized, mobility can be maintained. About 10% of indi- viduals incur severe disability. Juvenile Rheumatoid Arthritis Juvenile rheumatoid arthritis (JRA) occurs in several different types. In some respects, JRA differs from the adult form of rheumatoid arthritis (see Chapter 23). For example, the onset is usually more acute than the adult form. Systemic effects are more marked, but rheumatoid nodules are absent. The large joints are frequently affected. Rheumatoid factor is not usually present, but other abnormal antibodies such as antinuclear antibodies (ANAs) may be present. The systemic form, sometimes referred to as Still disease, develops with fever, rash, lymphadenopathy, and hepatomegaly as well as joint involvement. A second form of JRA causes polyarticular inflammation similar to that seen in the adult form. A third form of JRA involves four or fewer joints but causes uveitis, inflammation of the iris, ciliary body, and choroid (uveal tract) in the eye. Infectious (Septic) Arthritis Infectious or septic arthritis usually develops in a single joint. The joint is red, swollen, and painful, with decreased range of movement. The synovium is swollen, and a purulent exudate forms. Aspiration of synovial fluid followed by culture and sensitivity tests confirms the diagnosis. Blood-borne bacteria such as gonococcus or staphylococcus are the source of infection in many cases, although anaerobic bacteria are becoming increasingly common. In some cases there is a history of trauma, surgery, or spread from a nearby infection such as osteomyelitis (see Chapter 23). Lyme disease, caused by a spirochete and transmitted by ticks, is characterized by a migratory arthritis and rash developing several weeks to months after the tick bite. The knee and other large joints are most often involved. A vaccine for Lyme disease is now available. In cases of infectious arthritis, immediate, aggressive antimicrobial treatment is necessary to prevent excessive cartilage destruction and fibrosis of the joint. Gout (Gouty Arthritis) This form of joint disease is common in men older than 40 years. Gout results from deposits of uric acid and urate crystals in the joint that then cause an acute inflammatory response (Fig. 9.15). Uric acid is a waste product of purine metabolism, normally excreted through the kidneys. Hyperuricemia may develop if renal excre- tion is not adequate or a metabolic abnormality, often a genetic factor such as a deficit of the enzyme uricase, leading to elevated levels of uric acid (primary gout), is present. ■ Diagnostic Tests Synovial fluid analysis demonstrates the inflammatory process. Rheumatoid factor may be present in serum but is not specific for diagnosis. ■ Treatment • A balance between rest and moderate activity is sug- gested to maintain mobility and muscle strength while preventing additional damage to the joints. Physical therapy and occupational therapy are important parts of any treatment regimen. Both assist in reducing pain and maintaining function. Occupational therapy also teaches adaptive practices to reduce effort and fatigue. • For pain control, relatively high doses of the antiinflam- matory analgesic aspirin (ASA) or NSAIDs may be required (see Chapter 4). In more severe cases, gluco- corticoids may be prescribed, and administered either orally or as intraarticular injections. Patients like the effects of glucocorticoids because the drug does promote a feeling of well-being and improves the appetite. However, there are a number of potential complications with long-term use of these drugs, so they should be used only during acute episodes or taken on alternate days at the lowest effective dose (see Chapter 4). Other drugs, such as gold compounds and immunosuppressants (methotrexate), are used in more resistant cases. A newer group of NSAIDs, the cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex), act to inhibit prostaglandins during inflammation. They appear to be quite effective in rheumatoid arthritis; at this time they are under further investigation because of the increased incidence of heart attacks and strokes associated with their use. Disease-modifying antirheumatic drugs (DMARDs), including gold salts, methotrexate, and hydroxychloro- quine, have proved useful in some cases. Newer biologic response-modifying agents (such as infliximab [Remicade]) block tumor necrosis factor, an inflammatory cytokine present in RA. Beta cell–depleting agents (rituximab [Rituxan]) and interleukin-1 antagonists (anakinra [Kineret]) seem to be effective in cases of severe pain and improving joint function. • The use of heat and cold modalities can be very effective when they are used correctly. • During acute episodes, joints may require splinting to prevent excessive movement and maintain align- ment. Appropriate body positioning and body mechan- ics when walking or moving also help to maintain function. • Assistive devices such as wrist supports or padded handles with straps are available to help the patient cope with daily activities and reduce contractures. • Surgical intervention to remove pannus, replace damaged tendons, reduce contractures, or replace joints may be necessary to improve function. This is particularly important in the treatment of RA in the hands. CHAPTER 9 Musculoskeletal System Disorders 181 ■ Pathophysiology The following will be noted in patients with ankylosing spondylitis: 1. The vertebral joints first become inflamed. 2. Fibrosis and calcification or fusion of the joints follows. The result is ankylosis or fixation of the joints and loss of mobility (Fig. 9.16). 3. Inflammation begins in the lower back at the sacroiliac joints and progresses up the spine, eventually causing a typical “poker back.” 4. Kyphosis develops as a result of postural changes necessitated by the rigidity and loss of the normal spinal curvature. 5. Osteoporosis is common and may contribute to kyphosis because of pathologic compression fractures of the vertebrae. 6. Lung expansion may be limited at this stage, as cal- cification of the costovertebral joints reduces rib movement. ■ Signs and Symptoms • Initially low back pain and morning stiffness are evident. Pain is often more marked when lying down and may radiate to the legs similar to sciatic pain. The discomfort is relieved by walking or mild exercise. A sudden increase in serum uric acid levels usually precipitates an attack of gout. Gout often affects a single joint, such as in the big toe. When acute inflammation develops from uric acid deposits, the articular cartilage is damaged. The inflammation causes redness and swell- ing of the joint and severe pain. Attacks occur intermit- tently. Diagnosis is confirmed by examination of synovial fluid and blood tests. A tophus is a large, hard nodule consisting of urate crystals that have been precipitated in soft tissue or bone, causing a local inflammatory reaction. Tophi usually occur a few years after the first attack of gout and may develop at joint bursae, on the extensor surfaces of the forearm, or on the pinnae of the ear. Treatment consists of reducing serum uric acid levels by drugs and dietary changes, depending on the underly- ing cause. Increasing fluid intake and increasing the pH of the urine promote excretion of excess uric acid. Col- chicine may be used during an acute episode, and allopurinol is used as a preventive maintenance treatment. Normalization of serum uric acid levels is important because uric acid kidney stones are a threat in anyone with chronic hyperuricemia. Also, the inflammation and pain associated with acute attacks by NSAIDs should be relieved as soon as possible. Ankylosing Spondylitis Ankylosing spondylitis is a chronic progressive inflam- matory condition that affects the sacroiliac joints, intervertebral spaces, and costovertebral joints of the axial skeleton. Women tend to have peripheral joint involvement to a greater extent than men, although the disorder is more common in men. It usually develops in persons 20 to 30 years of age and varies in severity. Remissions and exacerbations mark the course. The cause has not been fully determined, but it is deemed an autoimmune disorder with a genetic basis, given the presence of HLA-B27 antigen in the serum of most patients. FIG. 9.15 Gout. Urate crystals in synovial fluid cause inflammation in the joint. (From Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, 1997, Saunders.) Ossification of disks, joints, and ligaments of spinal column Bilateral sacroiliitis FIG. 9.16 Characteristic posture and sites of ankylosing spondylitis. (From Mourad L: Orthopedic Disorders, St. Louis, 1991, Mosby.) 182 SECTION III Pathophysiology of Body Systems • As calcification develops, the spine becomes more rigid, and flexion, extension, and rotation of the spine are impaired. • Some individuals (about one-third of patients) develop systemic signs such as fatigue, fever, and weight loss. • Uveitis, particularly iritis (inflammation in the eye), is a common additional problem. ■ Treatment Treatment is directed at relief of pain and maintenance of mobility. Sleeping in a supine position reduces the tendency to flexion, and an appropriate daily exercise program promotes muscle support and proper posture. Antiinflammatory drugs, as described, are useful during exacerbations of disease. • Tendinitis is the irritation or inflammation of the tendon. It is usually characterized by a dull ache at the site of tendon attachment, tenderness, and mild swelling. Although tendinitis can be caused by a single, sudden trauma, it is more likely the result of repetitive motions/ actions. Diagnosis is done by physical examination. The first line of treatment involves rest, application of ice, and pain relievers. If the condition persists or worsens, treatments include antiinflammatory drugs and physical therapy. In cases in which there has been significant injury to the tendon, surgery may be required. CASE STUDY A Fracture J.R., age 17, has a compound fracture of the femur and is undergo- ing surgical repair. 1. Describe a compound fracture. 2. Give several reasons why it is important in this case to have immobilized the femur well before transporting J.R. to the hospital. 3. Explain why there is an increased risk of osteomyelitis in this case. 4. Explain why there is severe pain with this type of fracture. The day after surgery J.R.’s toes are numb and cold. 5. Explain the possible causes of the cold, numb toes. 6. Explain why appropriate exercise is important during healing of the fracture. 7. List four factors that would promote healing of this fracture. 8. Explain why the leg should be elevated during recovery. 9. Explain why, following the removal of the cast, J.R. can expect to feel some weakness and stiffness in the leg. CASE STUDY B Rheumatoid Arthritis Ms. W.P. is 42 years old and has had rheumatoid arthritis for 6 years. Her fingers are stiff and show slight ulnar deviation. She is now experiencing an exacerbation, and her wrists are red and swollen. She finds it to be painful when something such as clothing touches the skin over her wrists. Her elbows and knees are also stiff and painful, especially after she has been resting. She is feeling extremely tired and depressed and has not been eating well. 1. Explain the reasons for the appearance and the pain occurring at her wrists. 2. Describe the factors contributing to the stiff, deformed fingers. 3. Explain why some activity relieves the pain and stiffness of rheumatoid arthritis. 4. Describe several factors contributing to the systemic symptoms noted in Ms. W.P. 5. Explain how each of the following drugs acts in the treatment of rheumatoid arthritis (see Chapter 5): (a) NSAIDs, (b) glucocorticoids, (c) disease-modifying agents, and (d) biologic agents. 6. Predict the possible course of this disease in Ms. W.P. THINK ABOUT 9.7 a. Compare osteoarthritis and rheumatoid arthritis with respect to pathophysiology, common joints affected, and characteristics of pain. b. Describe two unique characteristics of septic arthritis. c. Explain how the pathophysiologic changes in ankylosing spondylitis differ from those of rheumatoid arthritis. Other Inflammatory Joint Disorders • Bursitis is an inflammation of the bursae associated with bones, muscles, tendons, and ligaments of various joints. The bursae are small fluid-filled sacs that act as cushions at or near the structures of the joint. The most common causes of this inflammation are repetitive motions or positions that physically irritate the bursae at a specific joint. These include actions such as throw- ing a baseball repeatedly or washing floors frequently on hands and knees. Bursitis is primarily diagnosed by physical examination in which the joint appears swollen, red, achy, or stiff and pain with joint motion. Other methods for diagnosis may include imaging such as ultrasound or MRI and analysis of the fluid in the bursae to detect underlying problems such as an infection. The first step in treatment involves rest, application of cold compresses, and pain relievers. If the condition persists or worsens, treatments include antiinflammatory drugs, physical therapy, antibiotics in cases in which an infection is a cause, and in severe cases the bursae can be surgically drained. • Synovitis is an inflammation of the synovial membrane lining the joint. Movement of the joint is restricted and painful due to swelling as the synovial sac fills with fluid. The joint becomes swollen, red, and warm and can also be diagnosed by analyzing the synovial fluid for signs of infection or crystals indicating gout. Treatment includes use of antiinflammatory drugs and treatment for underlying causes such as in cases of infection. CHAPTER 9 Musculoskeletal System Disorders 183 • Primary fibromyalgia syndrome causes generalized aching pain, severe fatigue, and depression. • Osteoarthritis is a progressive degenerative disorder often affecting the large weight-bearing joints. Pain increases with movement and weight bearing. • Rheumatoid arthritis is a progressive systemic inflam- matory disease that usually affects the small joints initially and progresses symmetrically. The pathologic process in an affected joint includes synovitis, pannus formation, cartilage erosion, fibrosis, and ankylosis, leading to contractures and loss of function. • Infectious or septic arthritis usually involves a single joint. Early treatment is required to prevent permanent damage. • Gout is a form of inflammatory arthritis caused by deposits of uric acid and urates in a joint. • Ankylosing spondylitis is a progressive inflammatory disorder of the vertebral joints that leads to a rigid spine. • Bursitis, synovitis, and tendinitis are three common joint inflammation disorders. C H A P T E R S U M M A R Y Muscles, bones, joints, tendons, and ligaments form the framework of the body, providing support and protection as well as a mechanism for movement. Any damage to the parts of this system is likely to impair mobility. • The type of fracture, such as open, closed, or com- minuted, is defined by the characteristics of the bone fragments. • Fractures heal in four stages: the hematoma, fibrocar- tilaginous callus, bony callus, and remodeling. • Dislocations, sprains, and strains cause soft tissue damage at joints. • Osteoporosis is a common disorder in which decreased bone mass and density predispose patients to fractures. • Rickets and osteomalacia are caused by deficits of vitamin D and phosphate. • Osteosarcoma and Ewing sarcoma are malignant tumors, commonly occurring in the long bones of young adults. Constant bone pain is typical. • Duchenne muscular dystrophy is one of a group of progressive degenerative muscle disorders, often inherited as an X-linked recessive trait, affecting boys. S T U D Y Q U E S T I O N S 1. Describe each of the following structures in a bone: a. endosteum b. medullary cavity c. diaphysis of a long bone 2. Define an irregular bone and give an example. 3. Where is red bone marrow found in adults? What is the purpose of red marrow? 4. a. Describe the sources of energy for skeletal muscle contraction. b. Explain the effect of a cholinergic blocking agent on skeletal muscle contraction (see Chapter 14). c. Explain how anabolic steroid drugs affect skeletal muscle. d. Describe the purpose and structure of a tendon. e. Describe the outcome after part of a muscle has died. 5. a. Describe the structures that stabilize and support a joint. b. What type of joint is needed for the articulation between the ribs and sternum? What kind of mobility does it have? c. Explain the meaning of the term origin as related to muscles at a joint. 6. a. Describe each type of fracture: (1) compression fracture, (2) pathologic fracture, and (3) spiral fracture. b. Differentiate the procallus from the bony callus in the healing of a fracture. 7. Compare the changes and effects of a strain and a subluxation. 8. Compare the pathophysiology of osteoporosis, osteomalacia, and Paget disease. 9. a. Explain why the muscles of the legs of a child with Duchenne muscular dystrophy appear large. b. Explain why only boys are affected by Duchenne muscular dystrophy. c. Explain why a child with muscular dystrophy pulls himself up a flight of stairs. 10. Describe the characteristics of synovial fluid in the following: a. rheumatoid arthritis b. gout c. septic arthritis d. osteoarthritis 11. Explain why eating and coughing may be difficult in a person with severe ankylosing spondylitis. 184 Review of the Circulatory System and Blood Anatomy, Structures, and Components Blood Vessels Blood Composition of Blood Blood Cells and Hematopoiesis Hemostasis Blood Clotting Antigenic Blood Types Diagnostic Tests Blood Therapies Blood Dyscrasias Anemias Iron-Deficiency Anemia Pernicious Anemia–Vitamin B12 Deficiency (Megaloblastic Anemia) Aplastic Anemia Hemolytic Anemias Blood-Clotting Disorders Hemophilia A von Willebrand Disease Disseminated Intravascular Coagulation Thrombophilia Myelodysplastic Syndrome Neoplastic Blood Disorders Polycythemia Leukemias Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Define the terms describing abnormalities in the blood. 2. Describe and compare the pathophysiology, etiology, manifestations, diagnostic tests, and treatment for each of the selected anemias: iron-deficiency, pernicious, aplastic, sickle cell, and thalassemia. 3. Differentiate between primary and secondary polycythemia, and describe the effects on the blood and circulation. 4. Describe hemophilia A: its pathophysiology, signs, and treatment. 5. Discuss the disorder disseminated intravascular coagulation: its pathophysiology, etiology, manifestations, and treatment. 6. Discuss the myelodysplastic syndrome and its relationship to other blood disorders. 7. Compare acute and chronic leukemia: the incidence, onset and course, pathophysiology, signs, diagnostic tests, and treatment. L E A R N I N G O B J E C T I V E S achlorhydria agglutination ataxia autoregulation bilirubin cyanotic demyelination deoxyhemoglobin diapedesis dyscrasia dyspnea ecchymoses erythrocytosis erythropoietin ferritin gastrectomy glossitis hemarthrosis hematocrit hematopoiesis hemolysis hemoptysis hemosiderin hemostasis hepatomegaly hypochromic interleukin leukocytosis leukopenia leukopoiesis macrocytes macrophages malabsorption megaloblasts microcytic morphology myelodysplastic myelotoxins neutropenia oxyhemoglobin pallor pancytopenia petechiae phlebotomy plasma plethoric reticulocyte serum splenomegaly stomatitis syncope tachycardia thrombocytopenia K E Y T E R M S C H A P T E R 10 Blood and Circulatory System Disorders CHAPTER 10 Blood and Circulatory System Disorders 185 capillaries, depending on the metabolic needs of the tissues. • Small venules conduct blood from the capillary beds toward the heart. • Larger veins collect blood draining from the venules. Normally a high percentage of the blood (approxi- mately 70%) is located in the veins at any one time; hence, the veins are called capacitance vessels. Blood flow in the veins depends on skeletal muscle action, respiratory movements, and gravity. Valves in the larger veins in the arms and legs have an important role in keeping the blood flowing toward the heart. Respira- tory movements assist the movement of blood through the trunk. The walls of arteries and veins are made up of three layers: 1. The tunica intima, an endothelial layer, is the inner layer. 2. The tunica media, a layer of smooth muscle that controls the diameter and lumen size (diameter) of the blood vessel, is the middle layer. 3. The tunica adventitia, or externa, is the outer con- nective tissue layer and contains elastic and collagen fibers. The vasa vasorum consists of tiny blood vessels that supply blood to the tissues of the wall itself. Normally the large arteries are highly elastic in order to adjust to the changes in blood volume that occur during the cardiac cycle. For example, the aorta must expand during systole to prevent systolic pressure from rising too high, and during diastole the walls must recoil to maintain adequate diastolic pressure. Veins have thinner walls than arteries and less smooth muscle (Fig. 10.3). Localized vasodilation or vasoconstriction in arterioles is controlled by autoregulation, a reflex adjustment in a small area of a tissue or an organ, which varies depending on the needs of the cells in the area. For example, a decrease in pH, an increase in carbon dioxide, or a decrease in oxygen will lead to local vasodilation. Release of chemical mediators such as histamine or an increase in temperature at a specific area can also cause vasodi- lation. These local changes do not affect the systemic blood pressure. Norepinephrine and epinephrine increase systemic vasoconstriction by stimulating alpha1-adrenergic recep- tors in the arteriolar walls. Angiotensin is another powerful systemic vasoconstrictor. Vascular or vasomotor tone is maintained at all times by constant input from the sympathetic nervous system (SNS), which results in partial vasoconstriction throughout the body to ensure continued circulation of blood. Capillary walls consist of a single endothelial layer to facilitate the exchange of fluid, oxygen, carbon dioxide, electrolytes, glucose and other nutrients, as well as wastes between the blood and the interstitial fluid. Capillary exchange and abnormal electrolyte shifts are discussed in Chapter 2. Review of the Circulatory System and Blood Anatomy, Structures, and Components Although distinct in their specific structures and functions, all the systems of the human body are intricately inter- related and constantly interact in order to maintain balance and the proper functioning of the body. One component on which all systems depend is blood. Blood circulates through the body and functions to: • Transport oxygen and nutrients to all tissues • Remove waste products of cellular metabolism • Play a critical role in the body’s defenses/ immune system, and serve in maintaining body homeostasis Blood and lymph, another essential body fluid, are transported throughout the body via a complex system of vessels and the pumping action of the heart. Due to the complexity and distinct features involved in the production and circulation of blood and lymph, this chapter examines blood itself along with a basic review of the vessels involved in the distribution of blood throughout the body and the associated blood disorders. Chapter 11 presents an examination of the lymphatic system and associated disorders. Chapter 12 presents a detailed examination of the cardiovascular system with specific emphasis on the heart and associ- ated disorders, along with disorders of the blood vessels themselves. Blood Vessels The arteries, capillaries, and veins constitute a closed system for the distribution of blood throughout the body. Major blood vessels, most of which are paired left and right, are shown in Figs. 10.1 and 10.2. The following considerations should be kept in mind when reviewing the components of the circulatory system: • There are two separate circulations—the pulmonary circulation allows the exchange of oxygen and carbon dioxide in the lungs, and the systemic cir- culation provides for the exchange of nutrients and wastes between the blood and the cells throughout the body. • Arteries transport blood away from the heart into the lungs or to body tissues. • Arterioles are the smaller branches of arteries that control the amount of blood flowing into the capillaries in specific areas through the degree of contraction of smooth muscle in the vessel walls (vasoconstriction or dilation). • Capillaries are very small vessels organized in numerous networks that form the microcircula- tion. Blood flows slowly through capillaries, and precapillary sphincters determine the amount of blood flowing from the arterioles into the individual 186 SECTION III Pathophysiology of Body Systems Anterior cerebral Middle cerebral Basilar Vertebral Celiac Splenic Renal Superior mesenteric Aorta Inferior mesenteric External iliac Internal iliac (hypogastric) Common femoral Deep femoral (profunda femoris) Superficial femoral Peroneal Posterior tibial Dorsalis pedis Internal carotid External carotid Common carotid Subclavian Axillary Innominate Brachial Radial Interosseous Ulnar Deep palmar arch Superficial palmar arch Popliteal Anterior tibial FIG. 10.1 Anatomy of major arteries. (From Fahey VA: Vascular Nursing, ed 4, Philadelphia, 2004, Saunders.) THINK ABOUT 10.1 a. Explain why a high elastic content is required in the wall of the aorta. b. Explain the function of smooth muscle in the arterioles. c. Predict those organs that would be expected to have a large capillary network. What criteria did you use in making this prediction? d. Explain how venous return increases with exercise and the purpose of such action. Blood Blood provides the major transport system of the body for essentials such as oxygen, glucose and other nutrients, hormones, electrolytes, and cell wastes. It also serves as a critical part of the body’s defenses, carrying antibodies and white blood cells for the rapid removal of any foreign material. As a vehicle promoting homeostasis, blood provides a mechanism for controlling body temperature by distributing core heat throughout the peripheral tissues. Blood is the medium through which body fluid levels and blood pressure are measured and adjusted by various CHAPTER 10 Blood and Circulatory System Disorders 187 42% to 52%, than females, 37% to 48%. An elevated hematocrit could indicate dehydration (loss of fluid) or excess red blood cells. A low hematocrit might result from blood loss or anemia. • Plasma is the clear yellowish fluid remaining after the cells have been removed • Serum refers to the fluid and solutes remaining after the cells and fibrinogen have been removed from the plasma. The plasma proteins include albumin, which maintains osmotic pressure in the blood; globulins or antibodies; and fibrinogen, which is essential for the formation of blood clots. The components of blood and their functions are sum- marized in Fig. 10.4. Normal values for blood components are found inside the front cover of this book. controls, such as hormones. Clotting factors in the circulat- ing blood are readily available for hemostasis. Buffer systems in the blood maintain a stable pH of 7.35 to 7.45 (see the discussion of acid-base balance in Chapter 2). Composition of Blood The adult body contains approximately 5 liters of blood. Blood consists of water and its dissolved solutes, which make up about 55% of the whole blood volume; the remaining 45% is composed of the cells or formed liquid elements, the erythrocytes, along with leukocytes, and thrombocytes or platelets: • Hematocrit refers to the proportion of cells (essentially the erythrocytes) in blood and indicates the viscosity of the blood. Males have a higher hematocrit, average Internal jugular External jugular Right innominate Left innominate Superior vena cava Inferior vena cava Cephalic Basilic Median cubital Common iliac Internal iliac (hypogastric) Greater saphenous SUPERFICIAL LEG VEINS SUPERFICIAL ARM VEINS DEEP ARM VEINS DEEP LEG VEINS Lesser saphenous Hepatic Renal Subclavian Axillary Profunda brachial Brachial Radial (paired) Interosseous (paired) Ulnar (paired) External iliac Common femoral Profunda femoris Superficial femoral Popliteal Anterior tibial (paired) Posterior tibial (paired) Peroneal (paired) FIG. 10.2 Anatomy of major veins. (From Fahey VA: Vascular Nursing, ed 4, Philadelphia, 2004, Saunders.) 188 SECTION III Pathophysiology of Body Systems Erythrocytes or red blood cells (RBCs) are biconcave, flexible discs (like doughnuts but with thin centers rather than holes) that are non-nucleated when mature and contain hemoglobin (Fig. 10.6). The size and structure are essential for easy passage through small capillaries. The hormone erythropoietin, originating from the kidney, stimulates erythrocyte production in the red bone marrow in response to tissue hypoxia, or insufficient oxygen available to cells. Normally RBCs (4.2 to 6.2 million/mm3) constitute most of the cell volume in blood. Adequate RBC produc- tion and maturation depend on the availability of many raw materials, including amino acids, iron, vitamin B12, vitamin B6, and folic acid. Hemoglobin consists of the globin portion, two pairs of amino acid chains, and four heme groups, each contain- ing a ferrous iron atom, to which the oxygen molecule Blood Cells and Hematopoiesis All blood cells originate from the red bone marrow. In the adult, red bone marrow is found in the flat and irregular bones, ribs, vertebrae, sternum, and pelvis. The iliac crest in the pelvic bone is a common site for a bone marrow aspiration for biopsy. The various blood cells develop from a single stem cell (pluripotential hematopoietic stem cell) during the process of hemopoiesis or hematopoiesis (Fig. 10.5). From this basic cell, the differentiation process forms committed stem cells for each type of blood cell. These cells then proliferate and mature, providing the specialized functional cells needed by the body. A pathologic condition of the blood that usually refers to disorders involving the cellular components of blood is called dyscrasia. A number of specific blood dyscrasias are addressed later in the chapter. ARTERY VEIN Endothelium (tunica intima) Valve Elastic membrane (thinner in veins) Smooth muscle layer (tunica media) (thinner in veins) A Connective tissue (tunica adventitia) (in artery, thinner than tunica media; in vein, thickest layer) Vein Artery B C FIG. 10.3 Structural comparison of arteries and veins. (From Salvo S: Mosby’s Pathology for Massage Therapists, ed 2, St. Louis, 2009, Elsevier.) CHAPTER 10 Blood and Circulatory System Disorders 189 Only a small proportion of the carbon dioxide (CO2) in blood is carried by hemoglobin (carbaminohemoglobin) attached to nitrogen in an amino acid group at a different site from that for oxygen. Most carbon dioxide is trans- ported in blood as bicarbonate ion (in the buffer pair). Oxygen can easily be displaced from hemoglobin by carbon monoxide, which binds tightly to the iron, thus causing a fatal hypoxia (deficit of oxygen). Carbon monoxide poisoning can be recognized by the bright cherry-red color in the lips and face. (O2) can attach (see Fig. 10.16A, presented later in the chapter). Heme provides the red color associated with hemoglobin. Normally hemoglobin becomes fully satu- rated with oxygen in the lungs. Oxyhemoglobin is a bright red color, which distinguishes arterial blood from venous blood. As the blood circulates through the body, oxygen dissociates from hemoglobin, depending on local metabolism (see Fig. 13.6). Deoxygenated hemoglobin (deoxyhemoglobin or reduced hemoglobin) is dark or bluish red in color and is found in venous blood. Amino acids Carbohydrates Lipids Vitamins Hormones Enzymes Electrolytes Wastes Cells (formed elements) 45% Blood Cells Cellular components Functions Plasma 55% Leukocytes Erythrocytes Thrombocytes Proteins Fluid/chemical components Water Other Albumin Globulins Fibrinogen Other Blood clotting Osmotic pressure of blood Antibodies Cell metabolism Hemoglobin transports oxygen Transport and exchange of body fluids and secretions Release histamine and heparin - inflammatory response Neutrophils Eosinophils Basophils Lymphocytes Monocytes Granulocytes Agranulocytes Phagocytosis Phagocytosis Allergic response Cell-mediated and humoral immunity Blood clotting FIG. 10.4 Components of blood and their functions. 190 SECTION III Pathophysiology of Body Systems The life span of a normal RBC is approximately 120 days. As it ages, the cell becomes rigid and fragile and finally succumbs to phagocytosis in the spleen or liver and is broken down into globin and heme (Fig. 10.7). Globin is broken down into amino acids, which can be recycled in the amino acid pool, and the iron can be returned to the bone marrow and liver to be reused in the synthesis of more hemoglobin. Excess iron can be stored as ferritin or hemosiderin in the liver, blood, and other body tissues. A genetic disorder, hemochromatosis, otherwise known as iron overload, results in large amounts of hemosiderin accumulating in the liver, heart, and other organs, causing serious organ damage. The balance of the heme component is converted to bilirubin and transported by the blood to the liver, where it is conjugated (or combined) with glucuronide to make it more soluble, and then excreted in the bile. Excessive Myeloblast MonocyteLymphocyteNeutrophil Lymphoblast Eosinophil Monoblast Basophil Megakaryoblast Erythrocytes Megakaryocyte Reticulocyte Megakaryocyte breakup Granulocytes Platelets Agranulocytes Leukocytes Basophilic erythroblast Basophilic myelocyte Eosinophilic myelocyte Neutrophilic myelocyte Polychromatic erythroblast Basophilic band cell Eosinophilic band cell Neutrophilic band cell Progranulocyte Hemocytoblast Proerythroblast FIG. 10.5 Hematopoiesis. (From Shiland BJ: Medical Terminology and Anatomy for ICD-10 Coding, St. Louis, 2012, Mosby.) FIG. 10.6 Normal biconcave non-nucleated red blood cells. (From Rodak BR: Hematology: Clinical Principles and Applications, ed 2, Philadelphia, 2002, Saunders.) CHAPTER 10 Blood and Circulatory System Disorders 191 phagocytosis. An immature neutrophil is called a band or stab, and these increase in number by bacterial infection. The laboratory reports note this as a “shift to the left” in the pattern of leucocytes seen. • Basophils appear to migrate from the blood and enter tissue to become mast cells that release histamine and heparin. They may be fixed in tissues or wandering. • Eosinophils tend to combat the effects of histamine. They are increased by allergic reactions and parasitic infections. HEMOLYSIS OF ERYTHROCYTE HEMOGLOBIN GLOBIN HEME BILIRUBIN — UNCONJUGATED BLOOD LIVER — Conjugated with glucuronic acid BILIRUBIN — CONJUGATED BILE Amino acids recycled Transported bound to serum albumin (Spleen and liver remove old [120 days] or damaged cells) IRON recycled to bone marrow or stored Hematopoiesis FIG. 10.7 Breakdown of hemoglobin. FIG. 10.8 Normal blood cells. Note the many erythrocytes, discs with concave (faded) centers; the leukocytes, larger size with nuclei; stained purple, various types; and thrombocytes, the small dark pieces. (From Stepp C, Woods M: Laboratory Procedures for Medical Office Personnel, Philadelphia, 1998, Saunders.) hemolysis or destruction of RBCs may cause elevated serum bilirubin levels, which result in jaundice, the yellow color in the sclera of the eye and of the skin. Hematopoiesis Leukocytes, which number 4500–10,500/mm3, make up only about 1% of blood volume. They are subdivided into three types of granulocytes and two types of agranu- locytes. All types develop and differentiate from the original stem cell in bone marrow (see Fig. 10.5). Leu- kopoiesis, or production of white blood cells (WBCs), is stimulated by colony-stimulating factors (CSFs) pro- duced by cells such as macrophages and T lymphocytes. For example, granulocyte CSF or multi-CSF (interleukin-3 [IL-3]) may be produced to increase certain types of WBCs during an inflammatory response (see Chapter 5). White blood cells may leave the capillaries and enter the tissues by diapedesis or ameboid action (movement through an intact capillary wall) when they are needed for defensive purposes. The five types of leukocytes vary in physical charac- teristics and functions (see Fig. 10.4). Some examples of WBCs are visible as large, nucleated cells (purple stain) in the blood smear in Fig. 10.8. • Lymphocytes make up 30% to 40% of the WBCs. The roles of B and T lymphocytes in the immune response are reviewed in Chapter 7. Some T cells are designated natural killer cells and are significant in immunity. • Neutrophils (also called polys, segs, or PMNs) are the most common leukocyte, comprising 50% to 60% of WBCs, but they survive only 4 days. They are the first to respond to any tissue damage and commence 192 SECTION III Pathophysiology of Body Systems Hemostasis, the process of stopping bleeding, consists of three steps: • First, the immediate response of a blood vessel to injury is vasoconstriction or vascular spasm. In small blood vessels, this decreases blood flow and may allow a platelet plug to form. • Second, thrombocytes tend to adhere to the underlying tissue at the site of injury and, if the blood vessel is small, can form a platelet plug in the vessel. • Third, the blood-clotting or coagulation mechanism is required in larger vessels, by which the clotting factors that are present in inactive forms in the circulating blood are activated through a sequence of reactions (see Fig. 10.9). Evidence indicates additional overlap • Monocytes can enter the tissue to become macrophages, which act as phagocytes when tissue damage occurs. A differential count indicates the proportions of specific types of WBCs in the blood and frequently assists in making a diagnosis. For example, a bacterial infection or inflammatory condition stimulates an increase in neutrophils, whereas allergic reactions or parasitic infec- tions increase the eosinophil count. Thrombocytes, also called platelets, are an essential part of the blood-clotting process or hemostasis (Fig. 10.9). Thrombocytes are not cells; rather, they are very small, irregularly shaped, non-nucleated fragments from large megakaryocytes (see Fig. 10.8). Platelets stick to damaged tissue as well as to each other to form a platelet plug that seals small breaks in blood vessels, or they can adhere to rough surfaces and foreign material. The common drug acetylsalicylic acid (ASA), or aspirin, reduces this adhesion and can lead to an increased bleeding tendency. Thrombocytes can also initiate the coagulation process. Ca required 2+ INTRINSIC PATHWAY (Activated by endothelial injury in blood vessel) EXTRINSIC PATHWAY (Activated by tissue and platelet injury) XII (Hageman factor) XIIa III (Tissue thromboplastin) IIIa XI IX IXa VIII VII X V Platelet phospholipid Prothrombin Thrombin Prothrombin Activator Fibrinogen Fibrin XIII Platelets Vitamin K required for synthesis Insoluble fibrin clot XIa VIIIa Xa VIIa ORAL ANTICOAGULANTS (WARFARINS) block synthesis of prothrombin THROMBOLYTICS (TPA) or “clot-busters” (e.g., streptokinase) ASA blocks platelet aggregation HEPARIN blocks sequence here Natural fibrinolytics Antithrombin III Protein C Plasmin FIG. 10.9 Hemostasis and anticoagulant drugs. APPLY YOUR KNOWLEDGE 10.1 Predict three possible problems that could arise in the production of blood and blood cells, and explain the cause of each. CHAPTER 10 Blood and Circulatory System Disorders 193 individuals tend to form clots readily; others are predis- posed to excessive bleeding. To prevent inappropriate thrombus formation, coagulation inhibitors such as antithrombin III circulate in the blood. Through thrombin, a prostaglandin is released to prevent platelets sticking to nearby undamaged tissue. Thrombin also binds to thrombomodulin, an endothelial cell receptor protein, which triggers a series of reactions leading to fibrinolysis. Heparin, an anticoagulant, is released from basophils or mast cells in the tissues and exerts its major action by blocking thrombin. The drug form of Heparin may be administered intravenously to patients at risk for throm- bus formation. It does not dissolve clots but will prevent further growth of the thrombus. Also, there is a natural fibrinolytic process that can break down newly formed clots. Inactive plasminogen circulates in the blood. Following injury it can be con- verted, by tissue plasminogen activator (tPA) and streptokinase through a sequence of reactions, into plasmin. The product, plasmin, then breaks down fibrin and fibrinogen. This fibrinolysis is a localized event only, because plasmin is quickly inactivated by plasmin inhibi- tor. These numerous checks and balances are essential in the regulation of defense mechanisms. Application of this mechanism with “clot-buster” drugs such as strep- tokinase (Streptase) is proving successful in minimizing the tissue damage resulting from blood clots causing strokes (cardiovascular accidents [CVAs]) and heart attacks (myocardial infarctions [MIs]). However, constant moni- toring of blood-clotting times and careful administration technique are essential to prevent excessive bleeding or hematoma formation. New protocols for anticoagulant medications are under development in the United States to ensure greater safety for patients. Antigenic Blood Types An individual’s blood type (eg, ABO and Rh groups) is determined by the presence of specific antigens on the cell membranes of that person’s erythrocytes. ABO groups are an inherited characteristic that depends on the pres- ence of type A or B antigens or agglutinogens (Table 10.1). Shortly after birth, antibodies that react with different antigens on another person’s RBCs are formed in the blood of the newborn infant. Such an antigen-antibody reaction would also occur with an incompatible blood transfusion, resulting in agglutination (clumping) and hemolysis of the recipient’s RBCs (Fig. 10.11). Blood types of both donor and recipient are carefully checked before transfusion. Persons with type O blood lack A and B antigens and therefore are considered in factor activity between the intrinsic and extrinsic pathways, but the cascade of reactions is the basis for coagulation. Blood Clotting Clot formation (coagulation) requires a sequence or cascade of events as summarized: 1. Damaged tissue and platelets release factors that stimulate a series of reactions involving numerous clotting factors, finally producing prothrombin activator (PTA). 2. Prothrombin or factor II (inactive in the plasma) is converted into thrombin. Thrombin is a multifunctional molecule that functions as both a procoagulant and an anticoagulant. 3. Fibrinogen (factor I) is converted into fibrin threads through the action of the thrombin. 4. A fibrin mesh forms to trap cells, making up a solid clot, or thrombus, and stopping the flow of blood (Fig. 10.10). 5. The clot gradually shrinks or retracts, pulling the edges of damaged tissue closer together and sealing the site. The circulating clotting factors are produced primarily in the liver. Their numbers relate to the order of their discovery, not to the step in the clotting process. Vitamin K, a fat-soluble vitamin, is required for the synthesis of most clotting factors. Calcium ions are also essential for many steps in the clotting process. A person can use other measures to facilitate this clotting process. For example, applying pressure and cold (a vasoconstrictor) to the site reduces blood flow in the area, or thrombin solution can be applied directly to speed up clotting. Fibrinolysis A delicate balance is always necessary between the tendency to clot to prevent blood loss and the tendency to form clots unnecessarily and cause infarctions. Some FIG. 10.10 A blood clot or thrombus, showing blood cells trapped by fibrin strands (scanning electron microscope photograph). (From Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, 1997, Saunders.) APPLY YOUR KNOWLEDGE 10.2 Predict three ways that normal blood clotting could be impaired. Predict three ways that inappropriate blood clotting could be promoted. 194 SECTION III Pathophysiology of Body Systems Diagnostic Tests The basic diagnostic test for blood is the complete blood count (CBC), which includes total RBCs, WBCs, platelet counts, cell morphology (size and shape), a differential count for WBCs, amount/concentration of hemoglobin, and hematocrit values (see normal values inside the front cover of this book). These tests are useful screening tools. For example, leukocytosis, an increase in WBCs in the circulation, is often associated with inflammation or infection. Leukopenia, a decrease in leukocytes, occurs with some viral infections as well as with radia- tion and chemotherapy. An increase in eosinophils is common with allergic responses. The characteristics of the individual cells observed in a blood smear, includ- ing size and shape, uniformity, maturity, and amount of hemoglobin, are very important. Different types of anemia are distinguished by the characteristic size and shape of the cell as well as the presence of a nucleus in the RBC. More specialized tests are available. A summary of the most common diagnostic tests is provided in Ready Reference 5. The hematocrit shows the percentage of blood volume composed of RBCs and indicates fluid and cell content. A low RBC count may be an indicator of anemia. Hemo- globin is measured, and the amount of hemoglobin per cell is shown by the mean cellular hemoglobin (MCH). MCH indicates the oxygen-carrying capacity of the blood. universal donors. Persons with type AB blood are universal recipients. Signs of a transfusion reaction include a feeling of warmth in the involved vein, flushed face, headache, fever and chills, pain in the chest and abdomen, decreased blood pressure, and rapid pulse. Another inherited factor in blood is the Rh factor, which may cause blood incompatibility if the mother is Rh- negative and the fetus is Rh-positive. This condition/ disorder is referred to as erythroblastosis fetalis (see Fig. 22.2). Rh blood incompatibility between maternal and fetal blood is reviewed in Chapter 22. Plasma or colloidal volume-expanding solutions can be administered without risk of a reaction because they are free of antigens and antibodies. TABLE 10.1 ABO Blood Groups and Transfusion Compatibilities Blood Group Red Blood Cell Antigens Antibodies in Plasma For Transfusion, Can Receive Donor Blood Group O None Anti-A and anti-B O A A Anti-B O or A B B Anti-A O or B AB A and B None O, A, B, or AB Recipient’s blood Reactions with donor’s blood Donor type O Donor type A Donor type B Donor type AB RBC antigens Plasma antibodies None (type O) A (type A) B (type B) AB (type AB) Anti-A Anti-B Anti-B Anti-A (None) Normal blood Agglutinated blood FIG. 10.11 Results of (cross-matching) different combinations (types) of donor and recipient blood. The left columns show the antigen and antibody characteristics that define the recipient’s blood type, and the top row shows the donor’s blood type. Cross-matching identifies either a compatible combination of donor-recipient blood (no agglutination) or an incompatible combination (agglutinated blood). Inset shows drops of blood showing appearance of agglutinated and nonag- glutinated red blood cells. (From Belcher AE: Blood Disorders, St. Louis, 1993, Mosby.) CHAPTER 10 Blood and Circulatory System Disorders 195 pelvic bone, filtered, and infused into the recipient’s vein. Normal cells should appear in several weeks. In cases of malignant disease, pretreatment with chemotherapy or radiation is required to destroy tumor cells before the transplant. • For patients suffering from a lack of blood clotting capability, there are drugs available to aid in the clotting process. The USFDA has approved Nplate to directly stimulate platelet production by the bone marrow. NovoSeven is a drug developed primarily to treat hemophiliacs, but it has been adapted for use in treating combat trauma. Although these drugs are in use today, unintentional clots that may form during their use continue to be a dangerous problem that must be closely monitored. Blood Dyscrasias Anemias Anemias reduce oxygen transport in the blood due to a decrease in hemoglobin content. The low hemoglo- bin level may result from declining production of the protein, a decrease in the number of erythrocytes, or a combination of these factors. Anemias may be classified by typical cell characteristics such as size and shape (morphology) or by etiology—for example, the hemolytic anemias. The oxygen deficit leads to a sequence of events: • Less energy is produced in all cells; cell metabolism and reproduction are diminished. • Compensation mechanisms to improve the oxygen supply include tachycardia and peripheral vasoconstriction. • These changes lead to the general signs of anemia, which include fatigue (excessive tiredness), pallor (pale face), dyspnea (increased effort to breathe), and tachy- cardia (rapid heart rate). • Decreased regeneration of epithelial cells causes the digestive tract to become inflamed and ulcerated, leading to stomatitis (ulcers in the oral mucosa), inflamed and cracked lips, and dysphagia (difficulty swallowing); the hair and skin may show degenerative changes. • Severe anemia may lead to angina (chest pain) during stressful situations if the oxygen supply to the heart is sufficiently reduced. Chronic severe anemia may cause congestive heart failure. Bone marrow function can be assessed by the reticu- locyte (immature non-nucleated RBC) count, plus a bone marrow aspiration and biopsy. Chemical analysis of the blood can determine the serum levels of such components as iron, vitamin B12 and folic acid, cholesterol, urea, glucose, and bilirubin. The results can indicate metabolic disorders and disorders within various other body systems. Blood-clotting disorders can be differentiated by tests such as bleeding time (measures platelet function—the time to plug a small puncture wound); prothrombin time or International Normalized Ratio (INR, which measures the extrinsic pathway); and partial thromboplastin time (PTT—intrinsic pathway), which measure the function of various factors in the coagulation process. They are also used to monitor anticoagulant therapy. The reference values for these tests are best established for individual patients based on their health history. Blood Therapies • Whole blood, packed red blood cells, or packed platelets may be administered when severe anemia or throm- bocytopenia develops. • Plasma or colloidal volume-expanding solutions can be administered without risk of a reaction because they are free of antigens and antibodies. These can help in balancing osmotic and hydrostatic pressures. • Artificial blood products are available, but none can perform all the complex functions of normal whole blood. They are compatible with all blood types. Hemolink is made from human hemoglobin, whereas Hemopure is made from cow hemoglobin. Oxygent is a synthetic, genetically engineered blood substitute. Other agents, such as MP4, which is undergoing clinical trials, is combined with blood to improve the oxygen transfer from RBCs to tissues. Various companies are also testing polyethylene glycol (PEG) to bind and stabilize hemoglobin molecules, thus decreasing the problem of the disassociation of hemoglobin that occurs in storage. Although promising, none of these artificial blood products have yet received approval from the United States Food and Drug Administration (USFDA). • Epoetin alfa (Procrit, Eprex) is a form of erythropoietin produced through the use of recombinant DNA technol- ogy. It may be administered by injection to stimulate production of red blood cells before certain surgical procedures (eg, hip replacement) and for patients with anemia related to cancer or chronic renal failure. This reduces the risks of infection or immune reaction associated with multiple blood transfusions. • Bone marrow or stem cell transplants are used to treat some cancers, severe immune deficiency, or severe blood cell diseases. A close match in tissue or human leukocyte antigen (HLA) type is required for success. The marrow stem cells are extracted from the donor’s THINK ABOUT 10.2 a. State the function of each type of cell in the blood. b. State three major functions of plasma proteins, and list the component responsible for each. c. What is the normal pH range of blood? Why is it important to maintain this pH? d. Describe the three stages of hemostasis. 196 SECTION III Pathophysiology of Body Systems • Duodenal absorption of iron may be impaired by many disorders, including malabsorption syndromes such as regional ileitis and achlorhydria (lack of hydrochloric acid in the stomach). • Severe liver disease may affect both iron absorption and iron storage. An associated protein deficit would further impede hemoglobin synthesis. • In the form of iron deficiency anemia associated with some infections and cancers, iron is present but is not properly used, leading to low hemoglobin levels but high iron storage levels. ■ Signs and Symptoms Mild anemias are frequently asymptomatic. As the hemoglobin value drops, the general signs of anemia become apparent: • Pallor of the skin and mucous membranes related to cutaneous vasoconstriction • Fatigue, lethargy, and cold intolerance as cell metabo- lism decreases • Irritability, a central nervous system response to hypoxia • Degenerative changes, such as brittle hair, spoon- shaped (concave) and ridged nails • Stomatitis and glossitis, inflammation in the oral mucosa and tongue, respectively • Menstrual irregularities • Delayed healing • Tachycardia, heart palpitations, dyspnea, and perhaps syncope (fainting) as the anemia becomes more severe ■ Diagnostic Tests Laboratory tests demonstrate low values for hemoglobin, hematocrit, mean corpuscular volume and mean corpus- cular hemoglobin, serum ferritin and serum iron, and transferrin saturation. On microscopic examination the erythrocytes appear hypochromic and microcytic. ■ Treatment The underlying cause must be identified and resolved if possible. The treatment and prognosis depend on the cause. Iron-rich foods or iron supplements in the least irritating and most easily absorbable forms for the individual may be administered. It is advisable to take iron with food to reduce gastric irritation and nausea. Iron supplements usually lead to constipation. Liquid iron mixtures stain teeth and dentures, and therefore a straw should be used to drink the medication. Anemias may also occur when there is a deficiency of a required nutrient, bone marrow function is impaired, or blood loss/excessive destruction of erythrocytes occurs. This section of the chapter covers a few examples of different types of anemias. Iron Deficiency Anemia ■ Pathophysiology Insufficient iron impedes the synthesis of hemoglobin, thereby reducing the amount of oxygen transported in the blood (see Fig. 10.16A, presented later in the chapter, for a diagram showing four heme groups). This results in microcytic (small cell), hypochromic (less color) erythrocytes owing to a low concentration of hemoglobin in each cell (Fig. 10.12). Iron deficiency anemia is common; it ranges from mild to severe and occurs in all age groups. An estimated one in five women is affected, and the proportion increases for pregnant women. Because iron deficiency anemia is frequently a sign of an underlying problem, it is important to determine the specific cause of the deficit. There is also a reduction in stored iron, as indicated by decreased serum ferritin, decreased hemo- siderin, and decreased iron-containing histiocytes in the bone marrow. ■ Etiology An iron deficit can occur for many reasons: • Dietary intake of iron-containing vegetables or meat may be below the minimum requirement, particularly during the adolescent growth spurt or during pregnancy and breastfeeding, when needs increase. Normally, only 5% to 10% of ingested iron is absorbed, but this can increase to 20% when there is a deficit. • Chronic blood loss from a bleeding ulcer, hemorrhoids, cancer, or excessive menstrual flow is a common cause of iron deficiency. Continuous blood loss, even small amounts of blood, means that less iron is recycled to maintain an adequate production of hemoglobin (Fig. 10.13). FIG. 10.12 Iron deficiency anemia shown in a blood smear. (From Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, 1997, Saunders.) THINK ABOUT 10.3 a. Explain how chronic bleeding leads to iron deficiency anemia. b. Explain the signs of anemia that indicate compensation for hypoxia is occurring. c. Explain how the destruction of acid-producing cells in the stomach can lead to iron deficiency anemia. CHAPTER 10 Blood and Circulatory System Disorders 197 the glands of the gastric mucosa (Fig. 10.14). Intrinsic factor must bind with vitamin B12 to enable absorption of the vitamin in the lower ileum. An additional problem occurs with the atrophy of the mucosa because the parietal cells can no longer produce hydrochloric acid, resulting in a low level or absence of acid in the gastric secretions referred to as achlorhydria. Achlorhydria interferes with the early digestion of protein in the stomach and with the absorption of iron; thus an iron deficiency anemia may be present as well. A deficit of vitamin B12 leads to impaired maturation of erythrocytes owing to interference with DNA synthesis. The RBCs are very large (megaloblasts or macrocytes) and contain nuclei (Fig. 10.15). These large erythrocytes are destroyed prematurely, resulting in a low erythrocyte count, or anemia. The hemoglobin in the RBCs is normal and is capable of transporting oxygen. Often the matura- tion of granulocytes is also affected, resulting in develop- ment of abnormally large hypersegmented neutrophils. Thrombocyte levels may be low. In addition, lack of vitamin B12 is a direct cause of demyelination of the Pernicious Anemia–Vitamin B12 Deficiency (Megaloblastic Anemia) Megaloblastic anemias, as the name implies, are character- ized by very large, immature, nucleated erythrocytes. This type of anemia usually results from a deficit of folic acid (vitamin B9) or vitamin B12 (cyanocobalamin). Vitamin deficiencies usually develop gradually. There is an increased interest in the folic acid deficiency that may occur during the first 2 months of pregnancy, resulting in an increased risk of spina bifida and other spinal abnormalities in the child. It is recommended that women in the childbearing years take folic acid supplements. Folic acid deficits are usually diet related. The prototype of megaloblastic anemia in this chapter is pernicious anemia, a vitamin B12 deficiency. ■ Pathophysiology Pernicious anemia is the common form of megaloblastic anemia that is caused by the malabsorption of vitamin B12 owing to a lack of intrinsic factor (IF) produced in HEMOGLOBIN PRODUCTION ERYTHROCYTE PRODUCTION CIRCULATING BLOOD CHRONIC BLEEDING (e.g., peptic ulcer, tumor) Loss of hemoglobin from the body Decreased iron for recycling Decreased transferrin and ferritin storage DECREASED HEMOGLOBIN PRODUCTION RBC with DECREASED HEMOGLOBIN (microcytic, hypochromic RBC) Normal lifespan 120 days HEMOLYSIS of old RBC Release HEMOGLOBIN HEME GLOBIN (recycled) IRON RECYCLED BILIRUBIN (to liver) IRON in diet ABSORPTION (only 10–15%) BLOOD (transferrin) LIVER STORAGE (ferritin or hemosiderin) BONE MARROW FIG. 10.13 Iron deficiency anemia related to blood loss. 198 SECTION III Pathophysiology of Body Systems Vitamin B ( ) ingested in food 12 1. Parietal cells in gastric glands secrete intrinsic factor ( ) into stomach 2. Vitamin B binds with intrinsic factor in stomach 3. Vitamin B intrinsic factor complex ( ) absorbed from ileum and B transported to bone marrow 4. Ileum Vitamin B promotes maturation of erythrocytes 5. Normal erythrocytes in circulating blood 6. Vitamin B ingested in food 1. Antibody reaction causes atrophy of gastric mucosa— no intrinsic factor in stomach 2. Ileum Lack of vitamin B causes bone marrow to produce megaloblastic erythrocytes 5. No absorption of vitamin B in ileum 3. Vitamin B excreted 4. Normal Erythropoiesis A B 12 12 12 12 12 12 Vitamin B Deficit12 12 12 FIG. 10.14 Development of pernicious anemia. CHAPTER 10 Blood and Circulatory System Disorders 199 • The bone marrow is hyperactive, with increased numbers of megaloblasts. Granulocytes are hyperseg- mented and are decreased in number. • The vitamin B12 level in the serum is below normal. In the Schilling test, an oral dose of radioactive vitamin B12 is used to measure absorption. • The presence of hypochlorhydria or achlorhydria confirms the presence of gastric atrophy. ■ Treatment Oral supplements are recommended as prophylaxis for pregnant women and vegetarians. Vitamin B12 is admin- istered by injection as replacement therapy for people with pernicious anemia. Prompt diagnosis and treatment of pernicious anemia prevents cardiac stress and neuro- logic damage. Aplastic Anemia ■ Pathophysiology Aplastic anemia results from impairment or failure of bone marrow, leading to loss of stem cells and pancyto- penia, the decreased numbers of erythrocytes, leukocytes, and platelets in the blood. These deficits lead to many serious complications. In addition, the bone marrow exhibits reduced cell components and increased fatty tissue. ■ Etiology Aplastic anemia may be a temporary or permanent condition depending on the cause: • In approximately half the cases, the patients are middle- aged, and the cause is unknown or idiopathic (primary type). • Myelotoxins, such as radiation, industrial chemicals (eg, benzene), and drugs (eg, chloramphenicol, gold salts, phenylbutazone, phenytoin, and antineoplastic drugs) may damage the bone marrow. In these cases it is important to detect and remove the causative factor quickly to allow the marrow to recover. When severe aplastic anemia due to cancer treatment is a risk, the patient’s stem cells may be harvested before treatment and then transfused later when needed. • Viruses, particularly hepatitis C, may cause aplastic anemia. • Autoimmune disease such as systemic lupus erythe- matosus (SLE) may affect the bone marrow. FIG. 10.15 Vitamin B12 deficiency with macrocytes and a neutrophil with hypersegmented nucleus in a peripheral blood smear. (From Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, 1997, Saunders.) THINK ABOUT 10.4 a. Explain why individuals with pernicious anemia have a low hemoglobin level. b. Explain how pernicious anemia can cause a neurologic effect such as a tingling sensation in extremities or loss of coordination. c. Why is oral administration of vitamin B12 not effective as a treatment for pernicious anemia? peripheral nerves and eventually of the spinal cord. Loss of myelin interferes with conduction of nerve impulses and may be irreversible. Sensory fibers are affected first, followed by motor fibers. ■ Etiology • Dietary insufficiency is rarely a cause of this anemia because very small amounts of vitamin B12 are required. Because the source of the vitamin is animal foods (protein, fats, dairy), vegetarians and vegans must ensure they include a fortified source in their daily intake. • The most common cause of vitamin B12 deficiency is malabsorption, which may result from an autoimmune reaction, particularly in older individuals; from chronic gastritis, which is common in alcoholics and causes atrophy of the gastric mucosa; or from inflammatory conditions such as regional ileitis. • The condition may also be an outcome of such surgical procedures as gastrectomy (removal or resection of part of the stomach), in which the parietal cells are removed, or resection of the ileum, which is the site of absorption. ■ Signs and Symptoms The basic manifestations of anemia are listed earlier. In addition, pernicious anemia has the following distinctive signs: • The tongue is typically enlarged, red, sore, and shiny. • The decrease in gastric acid leads to digestive discom- fort, often with nausea and diarrhea. • The neurologic effects include tingling or burning sensations (paresthesia) in the extremities or loss of muscle control/coordination, referred to as ataxia. ■ Diagnostic Tests • The erythrocytes appear macrocytic or megaloblastic and nucleated on microscopic examination and are reduced in number in the peripheral blood. 200 SECTION III Pathophysiology of Body Systems Hemolytic Anemias Hemolytic anemias result from excessive destruction of RBCs, or hemolysis, leading to a low erythrocyte count and low total hemoglobin. They have many causes, including genetic defects affecting structure, immune reactions, changes in blood chemistry, the presence of toxins in the blood, infections such as malaria, transfusion reactions, and blood incompatibility in the neonate (erythroblastosis fetalis). Two examples follow: sickle cell anemia and thalassemia. Sickle Cell Anemia ■ Pathophysiology Sickle cell anemia is representative of a large number of similar hemoglobinopathies. In this anemia, an inherited characteristic leads to the formation of abnormal hemo- globin, hemoglobin S (HbS). In HbS, one amino acid in the pair of beta-globin chains has been changed from the normal glutamic acid to valine (Fig. 10.16). When this altered hemoglobin is deoxygenated, it crystallizes and changes the shape of the RBC from a disc to a crescent or “sickle” shape. The cell membrane is damaged, leading to hemolysis, and the cells have a much shorter life span than normal, perhaps only 20 days, instead of the normal 120 days. Initially the sickling may be reversible when increased oxygen is available, but after several episodes, the damage to the RBC is irreversible and hemolysis occurs. Hemoglobin S can transport oxygen in the normal fashion, but the erythrocyte count is very low, resulting in a low hemoglobin level in the blood. A major problem resulting from the sickling process is the obstruction of the small blood vessels by the elongated and rigid RBCs, resulting in thrombus formation and repeated multiple infarctions, or areas of tissue necrosis, throughout the body (Fig. 10.17). The deoxygenation of hemoglobin may occur in the peripheral circulation as the oxygen content of the blood is gradually reduced, leading to repeated minor infarctions. A serious crisis may occur in individuals with lung infection or dehydration when basic oxygen levels are reduced. During a sickling crisis, many larger blood vessels may be involved, and multiple infarctions occur throughout the body, affecting the brain, bones, or organs. In time, significant damage and loss of function occur in many organ systems. In addition to the basic anemia, the high rate of hemolysis leads to hyperbilirubinemia, jaundice, and gallstones (see Fig. 10.7 and Chapter 17). ■ Etiology The gene for HbS is recessive and is common in individu- als from Africa and the Middle East. In homozygotes, most of the normal hemoglobin (hemoglobin A [HbA]) is replaced by HbS, resulting in clinical signs of sickle cell anemia (Fig. 10.18). Individuals vary greatly in the severity of the anemia and the number of sickling crises. In heterozygotes, less than half the hemoglobin is the abnormal HbS; therefore clinical signs occur only with • Genetic abnormalities such as myelodysplastic syn- drome or Fanconi anemia may also affect bone marrow function. ■ Signs and Symptoms In a majority of cases, the onset is insidious. Because the entire bone marrow is affected, manifestations include the following: • Anemia (pallor, weakness, and dyspnea) • Leukopenia, such as recurrent or multiple infections • Thrombocytopenia (petechiae—flat, red, pinpoint hemorrhages on the skin [Fig. 10.19, presented later in the chapter]—and a tendency to bleed excessively, particularly in the mouth) As blood counts diminish, particularly WBCs and platelets, uncontrollable infection and hemorrhage are likely. ■ Diagnostic Tests Blood counts indicate pancytopenia. A bone marrow biopsy may be required to confirm the cause of the pancytopenia. The erythrocytes are often normal in appearance. ■ Treatment Prompt treatment of the underlying cause and removal of any bone marrow suppressants are essential to recovery of the bone marrow. Blood transfusion may be necessary if stem cell levels are very low. Bone marrow transplantation may be helpful in younger patients; its success depends on the accuracy of the tissue match using human leukocyte antigen (HLA). Chemotherapy and radiation are used to prepare the recipient’s bone marrow for transplantation of stem cells (taken from the marrow of the pelvic bone of a suitable donor). Newer techniques allow harvesting of stem cells from the peripheral blood, not the marrow. The donor stem cells are infused intravenously into the blood of the recipient; they migrate to the bone marrow and provide a new source of blood cells after several weeks. Antirejection drugs are required for a year, but unlike the situation with other transplants, these drugs can then be discontinued. Common complications include damage to the digestive tract from the preparatory treatment, infection resulting from immune suppression, and rejec- tion reactions. THINK ABOUT 10.5 a. Explain why bone marrow damage can result in multiple, recurring infections. b. Explain why excessive bleeding occurs with aplastic anemia. c. Explain why it is necessary to treat the bone marrow recipient with chemotherapy and radiation before transplant. CHAPTER 10 Blood and Circulatory System Disorders 201 • Vascular occlusions and infarctions lead to periodic painful crises and permanent damage to organs and tissues. Such damage may be manifested as ulcers on the legs and feet, areas of necrosis in the bones or kidneys, or seizures or hemiplegia resulting from cerebral infarctions (strokes). Pain can be intense. • In the lungs, occlusions and infection cause acute chest syndrome with pain and fever. It can be diagnosed by x-ray. It is a frequent cause of death. • Occlusions in the smaller blood vessels of the hands or feet cause hand-foot syndrome. Pain and swelling are often early signs in children. • Growth and development are delayed. Late puberty is common. Tooth eruption is late, and hypoplasia is common. Intellectual development is usually impaired. • Congestive heart failure may develop owing to constant efforts to improve the supply of oxygen and the increased peripheral resistance caused by the obstructions. • Frequent infections occur because of the decreased defenses when the damaged spleen can no longer adequately filter the blood, the presence of necrotic tissues, and poor healing capabilities. Pneumonia is a common cause of death in children. Infections severe hypoxia under unusual circumstances, for example, pneumonia or at high altitudes; this condition is termed the sickle cell trait. It is estimated that 1 in 12 African Americans have the trait and about 1 in 500 have sickle cell anemia. It is interesting that the carrier population in Africa is very high, evidently owing to a decreased incidence of malaria in those with HbS. ■ Signs and Symptoms Clinical signs of sickle cell anemia do not appear until the child is about 12 months of age, when fetal hemoglobin (HbF) has been replaced by HbS. The proportion of HbS in the erythrocytes determines the severity of the condition. • Severe anemia causes pallor, weakness, tachycardia, and dyspnea. • Hyperbilirubinemia is indicated by jaundice, the yel- lowish color being most obvious in the sclerae of the eyes. The high bilirubin concentration in the bile may cause the development of gallstones (see Chapter 17). • Splenomegaly, enlargement of the spleen, is common in young people because sickled cells cause congestion, but in adults the spleen is usually small and fibrotic owing to recurrent infarction. β2 β1 α2 α1 O2 In sickle cell anemia, one amino acid, valine, replaces glutamic acid on the beta chain. CO2 is attached to nitrogen in amino acids in globin Globin chain (polypeptide) 4 heme contain iron (Fe) to which O2 attaches N Fe A B C FIG. 10.16 A, Structure of hemoglobin. B, An oxygenated sickle cell erythrocyte. C, A deoxygenated sickle cell erythrocyte. (B, C Courtesy of Dr. James White.) 202 SECTION III Pathophysiology of Body Systems RBCs containing HbS in presence of oxygen are flexible discs. When O2 level is low, RBCs sickle, becoming elongated and rigid. As the blood circulates through the body, the oxygen levels may decrease. Erythrocytes sickle and are unable to pass easily through small arteries. Cell membrane is damaged and RBC has short life span. INCREASED HEMOLYSIS of RBC in spleen Decreased RBC Severe ANEMIA HYPERBILIRUBINEMIA Jaundice OCCLUSION OF SMALL ARTERIES Tissue damage and multiple infarctions Pain Loss of function Heart Sickling Circulating blood Occlusion of artery FIG. 10.17 Sickle cell anemia—the effects of sickling. a a sa sa as aa aa PARENT WITH SICKLE CELL TRAIT A B C 50% for child with sickle cell trait normal normaltrait trait NORMAL PARENT Probability PARENT WITH SICKLE CELL TRAIT s a sa ss as sa aa PARENT WITH SICKLE CELL TRAIT 25% normal 25% with sickle cell anemia 50% with sickle cell trait anemia trait normal trait Probability NORMAL PARENT a a sa sa ss sa sa PARENT WITH SICKLE CELL ANEMIA 100% with sickle cell trait trait trait trait trait Probability KEY aa � normal: HbA ss � sickle cell anemia: HbS sa � sickle cell trait: mixed HbA and HbS FIG. 10.18 Inheritance of sickle cell anemia. tend to cause more sickling, and a vicious cycle develops. ■ Diagnostic Tests Carriers of the defective gene can be detected by a simple blood test (hemoglobin electrophoresis). This identification is useful in alerting those with sickle cell trait to avoid severe hypoxia and sickling episodes (eg, with severe anemia, surgery, or at high altitudes), as well as in assisting prospective parents in decision making about the risk of having an affected child (see Chapter 21). Prenatal diagnosis can be checked by DNA analysis of the fetal blood. In children older than 1 year of age, the diagnosis can be confirmed by the presence of sickled cells in peripheral blood and the presence of HbS. The bone marrow is hyperplastic, and more reticulocytes (immature RBCs) are released into the circulation. ■ Treatment The search continues for more effective drugs to reduce sickling. The use of hydroxyurea (Hydrea, Droxia) has reduced the frequency of crises and prolonged the life span for many, but it is not effective for all patients. Dietary supplementation with folic acid (folate) is recom- mended even during asymptomatic periods. Avoidance of strenuous activity or high altitudes is helpful. Other supportive measures are utilized to prevent dehydration, acidosis, infection, or exposure to cold, all of which increase the sickling tendency and painful crises. Children should be immunized against pneumonia, influenza, and meningitis. Continued prophylactic penicillin may be necessary for two groups, young children and adults CHAPTER 10 Blood and Circulatory System Disorders 203 ■ Etiology Thalassemia is the most common genetic disorder in the world, and it occurs in two common forms. Thalassemia beta (autosomal dominant inheritance) occurs frequently in people from Mediterranean countries such as Greece or Italy, and it is the more common form. The alpha form is found in those of Indian, Chinese, or Southeast Asian descent. Because more than one gene is involved, there are many possible gene mutations with varied effects on hemoglobin synthesis and the severity of the resultant anemia. ■ Signs and Symptoms The usual signs of anemia and increased hemolysis are present as described earlier: • The child’s growth and development are impaired directly by the hypoxia and indirectly by the fatigue and inactivity. • Hyperactivity in the bone marrow leads to invasion of bone and impairs normal skeletal development. • Heart failure develops as a result of the compensation mechanism increasing cardiac workload. ■ Diagnostic Tests Red blood cells are microcytic, often varying in size, and hypochromic (low hemoglobin). There is an increase in erythropoietin levels. Often an iron overload exists. Prenatal diagnosis can be done by chorionic villus assay at 12 weeks or by amniocentesis at 16 weeks. ■ Treatment Blood transfusions are the only treatment available at this time. Iron chelation therapy may be necessary to remove the excess iron from numerous transfusions. Administration of folate is also recommended. Bone marrow transplants have been curative in some children and are in clinical research trials. Patients with mild forms of the disease have a normal life span, and those with moderate to severe disease live into their 30s with transfu- sions and chelation therapy. Those with very severe anemia may die in childhood. Characteristics of the selected anemias are compared in Table 10.2. with severe cases. Gene therapy is under investigation. Bone marrow transplant is effective, but because of the limited number of African-American potential donors on bone marrow registries, it may be difficult to find a match. In the past, patients rarely lived past their 20s, but improvements in care have extended the life span into middle age for many patients. Thalassemia ■ Pathophysiology This anemia results from a genetic defect in which one or more genes for hemoglobin are missing or variant. When two genes are involved, thalassemia is moderate to severe. This abnormality interferes with the produc- tion of the globin chains, and therefore the amount of hemoglobin synthesized and the number of RBCs are reduced. Hemoglobin is normally composed of four globin chains, two alpha and two beta (see structure in Fig. 10.16A). Thalassemia alpha refers to a reduction in or lack of alpha chains. Thalassemia beta refers to a decrease or lack of beta chains. In either case, less normal hemoglobin can be made. In addition to missing chains, there is an accumulation of the other available chains, damaging the RBCs. For example, when a beta chain is missing, the extra alpha chains collect in RBCs and damage the cell membrane, leading to hemolysis and anemia. Homozygotes have thalassemia major (Cooley anemia), a severe form of the anemia; heterozygotes have thalassemia minor and exhibit mild signs of anemia. In severe cases, increased hemolysis of RBCs aggravates the anemia and causes splenomegaly, hepatomegaly, and hyperbilirubinemia. The bone marrow is hyperactive, trying to compensate. THINK ABOUT 10.6 a. Explain why vascular occlusions are common in patients with sickle cell disease. b. Compare sickle cell trait and sickle cell anemia in terms of the genetic factor involved, the amount of HbS present, and the presence of clinical signs. TABLE 10.2 Comparison of Selected Anemias Anemia Characteristic Red Blood Cells Etiology Additional Effects Iron deficiency anemia Microcytic, hypochromic Decreased hemoglobin production Decreased dietary intake, malabsorption, blood loss Only effects of anemia Pernicious anemia Megaloblasts (immature nucleated cells) Short life span Deficit of intrinsic factor owing to immune reaction Neurologic damage Achlorhydria Aplastic anemia Often normal cells Pancytopenia Bone marrow damage or failure Excessive bleeding and multiple infections Sickle cell anemia Red blood cell elongates and hardens in a sickle shape when O2 levels are low—short life span Recessive inheritance Painful crises with multiple infarctions Hyperbilirubinemia 204 SECTION III Pathophysiology of Body Systems primarily in adults, especially in young women when antibodies destroy thrombocytes. Human immunodefi- ciency virus infection, hepatomegaly and splenomegaly, and certain drugs also lead to thrombocytopenia. • Chemotherapy, radiation treatments, and cancers such as leukemia also reduce platelet counts, causing bleeding. • Defective platelet function is associated with uremia (end-stage kidney failure) and ingestion of aspirin (ASA). Anyone with a bleeding disorder should avoid ASA or ASA-containing drugs, as well as nonsteroidal antiinflammatory drugs, because all these interfere with platelet adhesion. • Vitamin K deficiency may cause a decrease in pro- thrombin and fibrinogen levels. Vitamin K is a fat- soluble vitamin produced by the intestinal bacteria and is present in some foods as well. A deficiency of vitamin K may occur in patients with liver disease, accompanied by a decrease in bile production, and in those with malabsorption problems. However, vitamin K is a useful antidote when an excess of warfarin (Coumadin), an oral anticoagulant, causes bleeding. • Liver disease reduces the available proteins and vitamin K and thus interferes with the production of clotting factors in the liver and reduces the available proteins and vitamin K. • Inherited defects cause bleeding disorders resulting from a deficiency of one of the clotting factors. Serum factor analysis and more specific tests are useful here. These include PT to measure the extrinsic pathway, activated partial thromboplastin time (APTT) to measure the intrinsic pathway, and thrombin time for the final stage, fibrinogen to fibrin. Blood-Clotting Disorders Spontaneous bleeding or excessive bleeding following minor tissue trauma often indicates a blood-clotting disorder. Note that the following warning signs may also be caused by other factors, such as infections and damaged or fragile blood vessels (eg, vitamin C deficit). Excessive bleeding has many causes: • Thrombocytopenia may be caused by acute viral infections in children (usually resolves in 6 months) or autoimmune reactions in adults (chronic idiopathic thrombocytopenic purpura). The chronic form occurs WARNING SIGNS OF EXCESSIVE BLEEDING AND POSSIBLE BLOOD-CLOTTING DISORDERS • Persistent bleeding from the gums (around the teeth) or repeated nosebleeds • Petechiae—pinpoint flat red spots on skin or mucous membranes (like a rash); result from bleeding from a capillary or small arteriole (see Fig. 10.19B) • Frequent purpura and ecchymoses—large, purplish red or greenish areas on the skin (bruises) (see Fig. 10.19A) • More persistent bleeding than warranted by a trauma • Bleeding into a joint—hemarthroses—swollen, red, and painful • Coughing up blood—hemoptysis—bright red flecks in sputum • Vomiting blood—hematemesis—often coarse brown particles (coffee grounds); may be red • Blood in feces—often black (tarry) or occult (hidden) • Anemia • Feeling faint and anxious, low blood pressure, rapid pulse A B FIG. 10.19 A, Facial ecchymoses. B, Petechiae. (From Young NS: Bone Marrow Failure Syndromes, Philadelphia, 2000, Saunders.) CHAPTER 10 Blood and Circulatory System Disorders 205 on the amount of the factor present in the blood. In mild forms (more than 5% factor VIII activity), excessive bleeding occurs only after trauma, whereas frequent spontaneous bleeding is common in people with severe deficiencies (less than 1% factor VIII activity). About 70% of affected individuals have the severe form. ■ Signs and Symptoms • Prolonged or severe hemorrhage occurs following minor tissue trauma. • Persistent oozing of blood after minor injuries and hematomas is common. • Spontaneous hemorrhage into joints (hemarthrosis) may occur, eventually causing painful and crippling deformities resulting from recurrent inflammation. • Blood may appear in the urine (hematuria) or feces because of bleeding in the kidneys or digestive tract. ■ Diagnostic Tests Bleeding time and PT are normal, but the PTT, APTT, and coagulation time are prolonged. Serum levels of factor VIII are low. Thromboplastin generation time differentiates between deficits of factor VIII and factor IX. ■ Treatment All precautions mentioned earlier should be followed. Treatment with desmopressin (DDAVP) may raise clot- ting factor levels in some clients. This drug stimulates the endothelium lining blood vessels to release stored factor VIII. Replacement therapy for factor VIII is avail- able for intravenous administration at regular intervals and especially before any surgical or dental procedure. Unfortunately, hepatitis and HIV have been transmitted through blood products. Although blood is now treated to destroy known viruses, a risk remains that some unknown infection may be acquired by such treatment. Some individuals have developed immune reactions to repeated replacement therapy. A newer recombinant DNA product (Advate), produced through genetic engineering, does not contain any material such as protein from human or animal blood, therefore reducing the risk of immune responses. A new drug Nplate has been approved by the USFDA that stimulates platelet production in bone marrow. Research continues into gene therapy. X Xh XhXh XXh YXh XY YXh AFFECTED FATHERB For female child 50% carrier 50% affected For male child 50% normal 50% affectedaffected normalcarrier affected CARRIER MOTHER Probability CARRIER MOTHER X Xh XXh XX YX XY YXh NORMAL FATHERA For female child 50% carrier 50% normal For male child 50% affected 50% normal normal carrier affected normal Probability FIG. 10.20 Inheritance of hemophilia A. • Hemorrhagic fever viruses such as Ebola virus cause excessive bleeding and acute illness, affecting many organs. • Anticoagulant drugs such as warfarin (Coumadin) are often prescribed on a long-term basis and the patient’s hemostatic ability requires close monitoring (see Fig. 10.6 for site of action of anticoagulant drugs). The difference between a helpful therapeutic drug level and a blood level that causes bleeding is very small. Also, many foods, drugs, and herbal compounds can alter the effects of anticoagulant drugs, creating a dangerous situation. When a patient with any bleeding disorder is at risk for hemorrhage because of an invasive procedure, it is best to be prepared by using laboratory tests to check the current blood-clotting status and to administer prophylactic medications if needed. Personnel should be ready and supplies should be available for any emergency, including the application of pressure, cold dressings, and absorbable hemostatic packing agents such as Gelfoam or Oxycel and styptics. Hemophilia A ■ Pathophysiology Hemophilia A, or classic hemophilia, is a deficit or abnormality of clotting factor VIII (see Fig. 10.9) and is the most common inherited clotting disorder. Ninety percent of hemophiliac patients have type A. The defect causing hemophilia A is transmitted as an X-linked recessive trait (Fig. 10.20); therefore it is manifest in men but is carried by women, who are asymptomatic (see Chapter 21). With improved treatment and a longer life span for men, this pattern could change. An affected man and a carrier woman could produce a female child who inherits the gene from both parents. Hemophilia B (Christmas disease) is similar and involves a deficit of factor IX; hemophilia C (Rosenthal’s hemophilia) is a milder form resulting from a decrease in factor XI. Some cases of hemophilia result from a spontaneous gene mutation in a person with no previous family history of the disease. There are approximately 18,000 to 20,000 cases of hemophilia in the United States and an estimated 400 infants are born each year with hemophilia. There are varying degrees of severity of hemophilia, depending 206 SECTION III Pathophysiology of Body Systems relatively mild, treatment may only be required in cases such as surgery, tooth extraction, or accident trauma. The manmade hormone desmopressin can be used to treat milder cases. The injection or nasal spray of this hormone causes increased release of von Willebrand factor and factor VIII into the bloodstream. These factors can also be directly injected into a vein as a replacement therapy and are used in the more severe types of the disease. Antifibrinolytic drugs that help prevent the breakdown of blood clots are often used after minor surgery or injury. In addition, women with an abnormal menstrual flow caused by this disease can be treated with birth control pills, as these also cause an increase in release of the clotting factors. Disseminated Intravascular Coagulation ■ Pathophysiology Disseminated intravascular coagulation (DIC) is a condi- tion, often life threatening, that involves both excessive bleeding and excessive clotting. It occurs as a complication of numerous primary problems, which activate the clotting process in the microcirculation throughout the body (Fig. 10.21). Clotting may be induced by the release of tissue thromboplastin or by injury to the endothelial cells, causing platelet adhesion. The process causes multiple thromboses and infarctions but also consumes the avail- able clotting factors and platelets and stimulates the fibrinolytic process. The resulting consumption of clotting factors and fibrinolysis then leads to hemorrhage and eventually to hypotension or shock. von Willebrand Disease ■ Pathophysiology This is the most common hereditary blood clotting/ bleeding disorder. This disease is caused by a deficiency of the von Willebrand factor, a clotting factor that helps platelets clump and stick to the walls of blood vessels where damage has occurred. There are three major types of this disease which have signs/symptoms similar to, but much milder than hemophilia. ■ Signs and Symptoms Depending on the type of the disease, signs and symptoms typically include the following: • Skin rashes • Frequent nosebleeds • Easy bruising • Bleeding of the gums • Abnormal menstrual bleeding ■ Diagnostic Tests Although sometimes hard to diagnose due to nonspecific signs and symptoms, the tests that may be done to diagnose this disease include bleeding time, blood typing, factor VIII levels, platelet count and aggregation test, ristocetin cofactor test, and von Willebrand factor specific tests. ■ Treatment Treatment is based on the type of von Willebrand disease and its severity. Because most cases of this disease are A primary condition such as septicemia, obstetric complication, severe burns, or trauma causes orEXTENSIVE ENDOTHELIAL DAMAGE ISCHEMIA AND MULTIPLE INFARCTIONS INITIATE THE CLOTTING PROCESSINITIATE THE CLOTTING PROCESS ORGAN FAILURE FIBRINOLYSIS stimulated RELEASE OF TISSUE THROMBOPLASTINRELEASE OF TISSUE THROMBOPLASTIN EXCESSIVE BLEEDING AND HEMORRHAGE Many thrombi form Activate plasmin Platelets collect Throughout the microcirculation Use up clotting factors DECREASED SERUM FIBRINOGEN THROMBOCYTOPENIA FIG. 10.21 Disseminated intravascular coagulation. CHAPTER 10 Blood and Circulatory System Disorders 207 Thrombophilia ■ Pathophysiology Thrombophilia refers to a group of inherited or acquired disorders that increase the risk of developing abnormal clots in the veins or arteries. Abnormal clotting events can result in conditions such as deep venous thrombosis, pulmonary embolism, or peripheral vascular disease. Inherited thrombophilias are a result of mutations among the genes responsible for producing the coagula- tion proteins in the blood. Acquired thrombophilias commonly occur during events such as surgery, injury, or other medical conditions that allow for an increase of the amount of clotting factors in the blood or an accumula- tion of antibodies. ■ Signs and Symptoms The signs and symptoms of an abnormal clotting event are not specific and can affect any organ or system in which the clot may lodge and cut off the blood supply. In cases in which the clot lodges in the heart or vessels of the lung, the result can be a myocardial infarction or an acute stroke. ■ Diagnosis Tests to diagnose thrombophilia involve blood testing for clotting factor levels and abnormal antibody levels. ■ Treatment In cases in which the disorder has been provoked by another underlying medical condition, the causative condition should be treated to decrease the potential of acquired thrombophilia. When the disorder is not pro- voked by another condition, anticoagulants such as warfarin (Coumadin) may be prescribed to reduce the risk of abnormal clot formation. The use of these types of medication must be weighed with the risks for excessive bleeding due to the interruption of the normal coagulation capability of the blood. Myelodysplastic Syndrome Myelodysplastic syndrome (MDS) is the term used for diseases that involve inadequate production of cells by the bone marrow. It excludes disorders such as aplastic anemias and deficiency dyscrasias. Myelodysplastic diseases may be idiopathic or can often occur follow- ing chemotherapy or radiation treatment for other Chronic DIC is a milder form and may be difficult to diagnose, as blood counts may be normal or abnormal. It is usually caused by chronic infection, and thrombo- embolism is the dominant feature. ■ Etiology A variety of disorders can initiate DIC. It may result from an obstetric complication such as toxemia, amniotic fluid embolus, or abruptio placentae, in which tissue throm- boplastin is released from the placenta (see Chapter 22). Infection, particularly gram-negative infection, leads to endotoxins that cause endothelial damage or stimulate the release of thromboplastin from monocytes. Many carcinomas release substances that trigger coagulation. Major trauma, such as burns or crush injuries, and widespread deposits of antigen-antibody complexes result in endothelial damage, releasing thromboplastin and initiating the process. ■ Signs and Symptoms Whether hemorrhage or thrombosis dominates, the clinical effects depend somewhat on the underlying cause. Obstetric patients usually manifest increased bleeding, whereas cancer patients tend to have more thromboses. More often, hemorrhage is the critical problem, which is manifested as follows: • A low plasma fibrinogen level is present. • Thrombocytopenia occurs. • Prolonged bleeding time, PT, APTT, and thrombin time are noted. • Accompanying the hemorrhage are the effects of low blood pressure or shock. • Multiple bleeding sites are common. • Petechiae or ecchymoses may be present on the skin or mucosa. • Mucosal bleeding is common, and hematuria may develop (see Fig. 10.19). • Vascular occlusions are frequently present in small blood vessels but occasionally affect the large vessels as well, causing infarcts in the brain or other organs. • Respiratory impairment is evident as difficulty in breathing and cyanosis. • Neurologic effects include seizures and decreased responsiveness. • Acute renal failure with oliguria often accompanies shock. ■ Treatment A fine balance is required to treat the coagulation imbal- ance, particularly in life-threatening cases. Treatment is difficult and depends on whether hemorrhages or thromboses are dominant. The underlying cause, such as infection, must be treated successfully, as well as the major current problem, whether it is excessive clotting or hemorrhage. The prognosis depends on the severity of the primary problem. THINK ABOUT 10.7 a. State the probability that a child with a carrier mother will have hemophilia A. b. Describe briefly three causes of excessive bleeding other than hemophilia. c. Explain how a deep vein thrombosis in a large vein in the leg can result in a life-threatening condition such as a stroke or myocardial infarction. 208 SECTION III Pathophysiology of Body Systems disease or from living at high altitudes. Some cases result from erythropoietin-secreting tumors such as renal carcinoma. ■ Signs and Symptoms Manifestations include the following: • Patient appears plethoric and cyanotic, with the deep bluish red tone of the skin and mucosa resulting from the engorged blood vessels and sluggish blood flow. • Hepatomegaly, an enlarged liver, and splenomegaly are present. • Pruritus is common. • Blood pressure increases, and the pulse is full and bounding, • Dyspnea, headaches, or visual disturbances are common. • Thromboses and infarctions may affect the extremities, liver, or kidneys as well as the brain or the heart. • Congestive heart failure frequently develops because of the increased workload resulting from the increased volume and viscosity of blood. • High levels of uric acid resulting from cell destruction lead to severe joint pain. ■ Diagnostic Tests Cell counts are increased, as are hemoglobin values, and hematocrit is elevated. In polycythemia vera, the malig- nant or abnormal cell is the erythrocyte. Bone marrow is hypercellular, with the red marrow replacing some fatty marrow. Hyperuricemia is present because of the high cell-destruction rate. ■ Treatment Drugs or radiation may be used to suppress the activity of the bone marrow. There is significant risk that fibrosis or leukemia may develop with these methods. Periodic phlebotomy, or removal of blood, may be used to mini- mize the possibility of thromboses or hemorrhages. Leukemias The leukemias are a group of neoplastic disorders involv- ing the white blood cells. The estimated number of new cases of leukemia each year is 31,000, including 2500 children. Of these cases, 11,000 are lymphoid, 15,000 are myelogenous, and 5000 fall into other categories. Although some types of leukemia respond well to chemotherapy, overall survival is about 45%, with much higher survival rates seen in lymphoid types in children. cancers. Several different types are described, including anemias and pancytopenias in which all cell types are reduced. Diagnosis is based on the patient’s history, standard blood tests, and bone marrow biopsy. Treat- ment measures depend on the type of deficiency and include transfusion replacements, chelation therapy to reduce iron levels, and supportive therapies to prevent complications. Low-level chemotherapy may be used with growth factors to stimulate more normal bone marrow function. Bone marrow transplants are curative, but often the patient’s health will not allow this treatment. The prognosis for patients with MDS is dependent on age of onset, past treatment with chemotherapy or radiation, and response to treatment. Myelodysplastic syndrome may progress to chronic or acute leukemia in some cases if treatment is not effective in normalizing the blood picture. Neoplastic Blood Disorders Polycythemia ■ Pathophysiology Primary polycythemia, or polycythemia vera, is a condi- tion in which there is an increased production of erythrocytes and other cells in the bone marrow. It is considered a neoplastic disorder. Serum erythropoietin levels are low. Secondary polycythemia, or erythrocytosis, is an increase in RBCs that occurs in response to prolonged hypoxia and increased erythropoietin secretion. Usually the increase in RBCs is not as marked in secondary polycythemia, and more reticulocytes appear in the peripheral blood. In polycythemia vera, there is a marked increase in erythrocytes and often in granulocytes and thrombo- cytes as well, resulting in increased blood volume and viscosity. Blood vessels are distended and blood flow is sluggish, leading to frequent thromboses and infarc- tions throughout the body, especially when platelet counts are high. Blood pressure is elevated and the heart hypertrophied. Hemorrhage is frequent in places where the blood vessels are distended. The spleen and liver are congested and enlarged, and the bone marrow is hypercellular. In some patients, the bone marrow eventually becomes fibrotic, hematopoiesis develops in the spleen, and anemia follows. In a few patients, acute myeloblastic leukemia develops in the later stages, especially if treatment has involved chemotherapy. ■ Etiology Primary polycythemia is a neoplastic disorder of unknown origin that commonly develops between the ages of 40 and 60 years, although younger individu- als can be affected. Secondary polycythemia may be a compensation mechanism intended to increase oxygen transport in the presence of chronic lung disease or heart THINK ABOUT 10.8 Compare the general effects of anemia and polycythemia in terms of hemoglobin level, hematocrit, general appearance, and possible complications. CHAPTER 10 Blood and Circulatory System Disorders 209 to anemia, thrombocytopenia, and a lack of normal functional leukocytes (Fig. 10.23). The rapid turnover of cells leads to hyperuricemia and a risk of kidney stones and kidney failure, especially in patients who are receiving chemotherapy. The crowding of the bone marrow causes severe bone pain resulting from pressure on the nerves in the rigid bone and the stretching of the periosteum. As the malignancy progresses, the increased numbers of leukemic cells cause congestion and enlargement of lymphoid tissue, lymphadenopathy, splenomegaly, and hepatomegaly. Death usually results from a complication such as overwhelming infection or hemorrhage. ■ Etiology Chronic leukemias are more common in older people, whereas acute leukemias occur primarily in children and younger adults. ALL, the most common childhood cancer, usually begins between the ages of 2 and 5 years and constitutes 80% of childhood leukemia cases. The cause in children has not been established. AML is common in adults. A number of factors have been shown to be associated with leukemia in adults, including exposure to radiation, chemicals such as benzene, and certain viruses. It may develop years after a course of chemo- therapy, particularly those protocols incorporating alkylating agents. There also appears to be an association of leukemia, particularly ALL, with chromosomal abnormalities, particularly translocations; this factor is evident in the increased incidence of leukemia in children with Down syndrome. Of interest is the fact that many adults with chronic myeloblastic leukemia have the Philadelphia chromosome (#22), a specific abnormal chromosomal translocation that serves as a marker in the diagnosis of chronic myeloblastic leukemia. ■ Pathophysiology One or more of the leukocyte types are present as undif- ferentiated, immature, nonfunctional cells that multiply uncontrollably in the bone marrow, and large quantities are released as such into the general circulation (Fig. 10.22). As the numbers of leukemic cells increase, they infiltrate the lymph nodes, spleen, liver, brain, and other organs. Acute leukemias are characterized by a high proportion of very immature, nonfunctional cells (blast cells) in the bone marrow and peripheral circulation; the onset usually is abrupt, with marked signs and complica- tions. Chronic leukemias have a higher proportion of mature cells (although they may have reduced function), with an insidious onset, mild signs, and thus a better prognosis. Depending on the particular stem cell affected, both acute and chronic leukemias can be further differenti- ated according to the cell type involved—for example, lymphocytic leukemia. The four major types are acute lym- phocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML). Most cases of ALL involve the precursors to B lymphocytes. Myelogenous leukemia affects one or more of the granulocytes. The neoplastic stem cell may, in some cases of myelogenous leukemia, involve all blood cells. The major groups are then further differentiated—for example, acute monoblastic leukemia, which is a type of myelogenous leukemia. In some severe forms of acute leukemias, only undifferentiated stem cells can be identified. When the cells are primitive, the term blast may be used in the name. Several detailed classifications for the leukemias are available. A brief summary can be found in Table 10.3. The proliferation of leukemic cells in the bone marrow suppresses the production of other normal cells, leading FIG. 10.22 Acute lymphocytic leukemia, common in young children. Blood smear shows small lymphocytes and normocytic anemia. (From Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, 1997, Saunders.) TABLE 10.3 Types of Leukemias Type Malignant Cell Primary Age Group Acute lymphocytic leukemia (ALL) B lymphocytes Young children Acute myelogenous (or myelocytic) leukemia (AML) Granulocytic stem cells Adults Chronic lymphocytic leukemia B lymphocytes Adults older than 50 years Chronic myelogenous leukemia (CML) Granulocytic stem cells Adults 30–50 Acute monocytic leukemia Monocytes Adults Hairy cell leukemia B lymphocytes Males older than 50 years 210 SECTION III Pathophysiology of Body Systems immature and appear abnormal. Numbers of RBCs and platelets are decreased. Bone marrow biopsy confirms the diagnosis. ■ Treatment Chemotherapy is administered (see Chapter 20). Some types of leukemia, such as ALL in young children, respond well to drugs, and the prognosis is excellent, with many children enjoying a cure. The best prog- nosis is found in children between 1 and 9 years of age; infants and adolescents respond less positively to chemotherapy. The more rapid the response to drugs, the more positive is the outlook. Chemotherapy is less successful in adults with AML, although remissions may be achieved. Biologic therapy, such as interferon, to stimulate the immune system has been used in cases of CML. Even with treatment, the course of CML may accelerate in some cases to an acute stage. Individuals with chronic leukemia may live up to 10 years with treat- ment. The prognosis is often related to the WBC count and the proportion of blast cells present at the time of diagnosis. It is important to try to maintain the proper level of nutrition and hydration, particularly if high uric acid levels develop. Alkalinizing the urine by ingesting ant- acids may help prevent the formation of uric acid kidney stones. Chemotherapy may have to be temporarily discontinued if the blood cell counts drop too low—for example, in marked thrombocytopenia or neutropenia (a reduction in circulating neutrophils). Transfusions of platelets or blood cells may be required. ■ Signs and Symptoms The onset of acute leukemia is usually marked by the following: • Infection occurs that is unresponsive to treatment. • Multiple infections often develop because of the nonfunctional WBCs. • Severe hemorrhage (in the brain or digestive tract) occurs because of thrombocytopenia. • Signs of anemia develop as the erythrocyte count drops. • Bone pain is severe and steady, continuing during rest. • Weight loss and fatigue result from the hypermetabo- lism associated with neoplastic growth, from anorexia caused by infection, from pain, and from the effects of chemotherapy. • Fever may result from hypermetabolism or infection. • The lymph nodes, spleen, and liver are often enlarged and may cause discomfort. • If leukemic cells infiltrate the central nervous system, headache, visual disturbances, drowsiness, or vomiting follows. Chronic leukemia tends to have a more insidious onset, with milder signs, and may be diagnosed during a routine blood check. Early signs include fatigue, weakness, and frequent infections. ■ Diagnostic Tests Peripheral blood smears show the immature leukocytes and the altered numbers of WBCs, which are usually greatly increased. A high percentage of the WBCs are ACUTE LYMPHOCYTIC LEUKEMIA INCREASED NUMBER OF IMMATURE, NONFUNCTIONAL LYMPHOCYTES IN BONE MARROW INCREASED PRESSURE EXPANSION OF BONE MARROW Severe bone pain and tenderness High percentage lymphoblasts in blood CROWDS OUT OTHER CELLS AND REDUCES PRODUCTION DECREASED RBCs ANEMIA – fatigue, poor healing DECREASED PLATELETS THROMBOCYTOPENIA – Spontaneous bleeding HEMORRHAGE Multiple resistant INFECTIONS FIG. 10.23 Effects of acute lymphocytic leukemia. CHAPTER 10 Blood and Circulatory System Disorders 211 C H A P T E R S U M M A R Y Blood serves many purposes in the body. Abnormalities involving blood cells, plasma proteins, or blood clotting factors frequently have widespread and possibly life- threatening effects on the body. When lymphatic disorders interfere with the immune response, serious consequences may result. • Anemias may be caused by many factors, including dietary deficits, malabsorption syndromes, genetic defects, damage to the bone marrow, or blood loss. • Chronic blood loss causes iron-deficiency anemia with the production of hypochromic, microcytic RBCs. • Pernicious anemia is a megaloblastic anemia resulting from a deficit of intrinsic factor required for the absorp- tion of vitamin B12. Peripheral nerve degeneration and hypochlorhydria accompany the anemia. • Pancytopenia characterizes aplastic anemia, with impaired production of all blood cells. • Sickle cell anemia and thalassemia are caused by inherited defects in hemoglobin synthesis. These result in excessive hemolysis and a low erythrocyte count. • Polycythemia may occur as a primary or secondary problem. Increased RBCs cause vascular congestion. • Hemophilia A is a genetic blood-clotting disorder related to a deficit of factor VIII. Replacement therapy is now available. Infections such as hepatitis B and HIV have been transmitted through transfusions to many of these patients. • When DIC develops as a complication of trauma, infection, or other primary problems, generalized blood clotting occurs, using up available blood clotting factors, and subsequently causing hemorrhage. The balance between coagulation and hemorrhage varies with the individual patient, the underlying problem, and the difficulty in treating the combination of problems. • Myelodysplastic syndrome comprises a number of conditions in which the bone marrow does not produce adequate cellular elements for the blood. It may be related to prior history of chemotherapy or radiation. • Leukemias may be acute or chronic. They are named by the specific neoplastic cell that is proliferating excessively in the bone marrow. The malignant cells are immature and nonfunctional, increasing the risk of infection. Thrombocytopenia and anemia are also present. THINK ABOUT 10.9 a. Compare and contrast the characteristics of acute and chronic leukemias, including the age groups involved, onset, and typical blood cell characteristics. b. Why are multiple opportunistic infections common in patients with leukemia? c. Explain why it is best to defer (if possible) any invasive procedures in leukemic patients, including dental treatment, until the blood counts become normal. d. The mouth and mucosa of the digestive tract are usually inflamed and ulcerated because of anemia, the effects of chemotherapy, and the presence of infections, such as candidiasis. Explain how this situation would affect food and fluid intake and list some possible subsequent effects on the patient with leukemia. CASE STUDY A Acute Lymphocytic Leukemia P.M., aged 4 years, has returned to the family physician because of a recurrent sore throat and cough. Her mother mentions unusual listlessness and anorexia. The physician notices several bruises on her legs and arms and one on her back. The physician orders blood tests and a course of antibacterial drugs. Test results indicate a low hemoglobin level, thrombocytopenia, and a high lymphocyte count, with abnormally high numbers of blast cells. Following a bone marrow aspiration, a diagnosis of ALL is confirmed. 1. Describe the pathophysiology of ALL. 2. State the rationale for each of P.M.’s signs. 3. Explain the significance of blast cells in the peripheral blood. 4. Describe the effects of hypermetabolism in leukemia. 5. Explain how chemotherapy aggravates the effects of leukemia (refer to Chapter 20). 6. Describe the possible effects if leukemic cells infiltrate the brain. 7. Describe the pain associated with leukemia, and explain the reason for it. Bone marrow transplantation may be tried when chemotherapy is ineffective. Any tumor cells must be eradicated in the recipient’s bone marrow, and a suitable donor must be located before transplantation is attempted (see earlier section, Aplastic Anemia). 212 SECTION III Pathophysiology of Body Systems S T U D Y Q U E S T I O N S 1. Name six substances that are transported in the blood and the function of each. 2. Explain the importance/function for each of the following: a. High elastic fiber content in the aorta b. Smooth muscle in the arterioles c. Extensive capillaries in the liver and lungs d. Valves in the leg veins 3. Explain the cause of incompatible blood transfusion. 4. List three types of clotting problems. 5. Explain how pernicious anemia may develop from chronic gastritis. 6. For which conditions could secondary polycythemia develop as compensation: Ventricular septal defect, congestive heart failure, chronic lung disease, aplastic anemia, multiple myeloma? 7. Explain how DIC develops, and state two signs of its development. 8. Explain why severe bone pain occurs with leukemia. 213 Review of the Lymphatic System Structures and Function Composition and Production of Lymph Lymphatic Circulation Lymphatic Disorders Lymphomas Hodgkin Disease/Hodgkin Lymphoma Non-Hodgkin Lymphomas Multiple Myeloma or Plasma Cell Myeloma Lymphedema Elephantiasis (Filariasis) Castleman Disease Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Identify the structures that constitute the lymphatic system and their general functions. 2. Differentiate between the vessels of the lymphatic system and blood vessels based on structure, function, and general circulation. 3. Compare and contrast Hodgkin and non-Hodgkin lymphomas based on pathophysiology, signs and symptoms, diagnosis, and treatment. 4. Describe the pathophysiology, signs and symptoms, and treatment of multiple myeloma. 5. Identify and describe the disorders resulting from obstruction of the flow of lymph in the lymphatic circulation. 6. Describe the pathophysiology, signs and symptoms, and treatment of Castleman disease. L E A R N I N G O B J E C T I V E S Ann Arbor staging system Castleman disease fascia filaria hydrocele lymph lymphedema lymphoma myeloma Reed-Sternberg cell spleen thymus gland tonsils K E Y T E R M S C H A P T E R 11 Lymphatic System Disorders Review of the Lymphatic System Structures and Function The lymphatic system consists of lymphatic vessels, lymphoid tissue, which includes the palatine and pha- ryngeal tonsils, lymph nodes, the spleen, and the thymus gland (Fig. 11.1). The system functions to return excess interstitial fluid and protein to the blood, to filter and destroy unwanted material from the body fluids, and to initiate an immune response. Lymphatic vessels originate as microscopic capillaries that are in direct contact with tissue cells and the inter- stitial fluid surrounding the cells (Fig. 11.2). These capillaries in turn form branches, then trunks, and finally ducts. These ducts empty into the left and right subclavian veins. Although similar in structure to veins, lymphatic vessels have thinner walls, more valves, and contain nodes at certain intervals. The thinner walls allow an increased degree of permeability allowing large molecules and some particulate matter to be removed from the interstitial spaces. Proteins that accumulate in the inter- stitial fluids can only be returned to the blood system through the lymphatic vessels. Any condition that might affect normal return from lymphatic vessels to the blood vessels could have a dramatic effect on blood protein concentration and osmotic pressure with serious or fatal results. Lymph capillaries in the villi of the small intestines 214 SECTION III Pathophysiology of Body Systems Right lymphatic duct Right subclavian vein Axillary lymph nodes Thymus Thoracic duct Spleen Tonsil Left subclavian vein Bone marrow Inguinal lymph nodes Blood capillaryTissue cells Venule Arteriole Lymph capillaries FIG. 11.1 Lymph capillaries in tissue spaces. (From VanMeter K, Hubert R: Microbiology for the Healthcare Professional, St. Louis, 2010, Elsevier.) Tissue spaces Arteriole Tissue cells Lymphatic vessel Capillary Venule Lymph capillary FIG. 11.2 Lymph capillaries in tissue spaces. (From Applegate E: The Anatomy and Physiology Learning System, ed 4, St. Louis, 2011, Elsevier.) CHAPTER 11 Lymphatic System Disorders 215 The thymus gland consists of two lobes and is located in the mediastinum, lying in front of the top half of the heart and extending up the neck to the bottom of the thyroid gland. The thymus is covered by a fibrous capsule that extends inward to subdivide the lobes into small lobules (Fig. 11.3). The thymus plays a critical role as part of the immunity mechanism against infections. In this role it has at least two primary functions: the final site of lymphocyte development before birth and the secretion of hormones after birth, which enable lymphocytes to develop into mature T cells (Fig. 11.4). Because of the T cell’s functions in attacking foreign or abnormal cells and as regulators of immune function, the role of the thymus is extremely important as part of the immune mechanism of the body. Composition and Production of Lymph Lymph is the clear, watery, isotonic fluid that is circu- lated in the lymphatic vessels. Lymph and interstitial fluid (see Chapter 2) are almost chemically identical when taken from the same part of the body. Both also closely resemble blood plasma; however, they usually contain a lower protein percentage than plasma except in the thoracic duct. In the thoracic duct, the lymph is protein rich as a result of the outflow into the duct from the liver and small intestine. Interstitial fluid that is not absorbed by the cells or the capillaries tends to accumulate in the interstitial spaces and as this fluid builds it will drain into the lymphatic vessels and become lymph. Lymphatic Circulation The lymphatic circulation functions as follows: 1. It begins with blind-ending capillaries containing one-way minivalves at the terminus, into which excess interstitial fluid flows as pressure builds up in the tissues (Fig. 11.5). 2. The lymphatic capillaries join to form larger vessels with valves to ensure a one-way flow of fluid, similar to the network of veins. Flow depends on pressure arising from movement of surrounding skeletal muscle and organs (Fig. 11.6). 3. Lymphatic vessels are interrupted periodically by lymph nodes, at which point the lymph is filtered and more lymphocytes may enter the lymph en route to the general circulation. 4. The vessels of the upper right quadrant of the body empty into the right lymphatic duct, which returns the lymph into the general circulation via the right subclavian vein. 5. The remainder of the lymphatic vessels drain into the thoracic duct in the upper abdomen and thoracic cavity. This duct drains into the left subclavian vein. 6. Lymphatic capillaries in the intestinal villi absorb and transport most lipids as chylomicrons. are called lacteals and have an important function in the absorption of fats and other nutrients that are produced as a result of digestion. The lymph nodes and lymphoid tissue act as a defense system, removing foreign or unwanted material from the lymph fluid before it enters the general circulation. When infection is present, the regional lymph nodes are often swollen and tender; for example, upper respiratory infection causes enlarged nodes in the neck area. Lymph nodes containing many lymphocytes and macrophages are situated along all lymphatic and blood vessels, ensur- ing constant filtration and surveillance of body fluids. Notably, the lymph nodes are essential to the immune response and the sensitization of B and T lymphocytes (see Chapter 7). The palatine and pharyngeal tonsils are composed of lymphoid tissue and are located in a ring under the mucous membrane of the mouth and at the back of the throat. These tonsils protect against bacterial infection in the area of the openings between the nasal and oral cavities. The tonsils are truly the first line of defense from invasion by external organisms and are therefore often subject to infections such as tonsillitis. Recurrent infections may require surgical removal of the tonsils; however, this treatment is a controversial topic due to the important immunological role that is played by lymphoid tissue. The spleen is located on the left side of the abdomi- nopelvic cavity directly below the diaphragm. As with other lymphoid organs, the spleen is surrounded by a fibrous capsule and internally it is divided into compart- ments (see Fig. 11.2). The spleen has many functions: defense, hematopoiesis, and red blood cell (RBC) and platelet destruction, as well as serving as a reservoir for blood. As part of the body’s defense, the blood passes through the spleen, where macrophages remove microorganisms from the blood and destroy them through phagocytosis. During hematopoiesis, monocytes and lymphocytes mature and become activated in the spleen. Erythrocytes are formed in the spleen prior to birth; however, after birth the spleen is responsible for red blood cell formation only in extreme cases of hemolytic anemia. The function of red blood cell and platelet destruction is carried out by macrophages that destroy old blood cells and platelets through phagocytosis. These cells also break down the hemoglobin molecules from the destroyed RBCs and salvage the iron and globin portion of the hemoglobin, where they are then returned to the blood circulation for storage in the liver and bone marrow. As a blood reservoir the spleen contains a large amount of blood in the pulp and venous sinuses. This blood can be quickly returned to the circulatory system needed. This large reservoir of blood can damage the spleen, in the form of severe trauma, a serious problem that can result in rapid death—for instance, if a rib punctures the spleen. 216 SECTION III Pathophysiology of Body Systems TrabeculaCapsule The thymus consists of several incomplete lobules. Each lobule contains an independent outer cortical region, but the central medullary region is shared by adjacent lobules. Trabeculae, extensions of the capsule down the corticomedullary region, form the boundary of each lobule. The cortex consists of stromal cells and developing T cells (thymocytes), macrophages, and thymic cortical Histologic organization of the thymus Blood vesselHassall’s corpuscle Medulla Cortex Cortex epithelial cells. MHC classes I and II molecules are present on the surface of the cortical epithelial cells. The characteristic deep-blue nuclear staining of the cortex in histologic preparations reflects the predominant population of T cells as compared with the less basophilic medulla containing a lower number of thymocytes. Hassall’s corpuscles are a characteristic component of the medulla. Hassall’s corpuscles are not seen in the cortex. FIG. 11.3 Microscopic structure of the thymus showing several lobules, each with a cortex and a medulla. (From Kierszenbaum A, Tres L: Histology and Cell Biology: An Introduction to Pathology, ed 3, St. Louis, 2012, Saunders, Elsevier.) Bone marrow Thymus Periphery Stem cell Double-negative “DN” cell Double-positive “DP” cell Pathway to α:β cells Pathway to γ:δ cells T-cell progenitor Subcapsular zone Cortex Medulla Periphery Mature naive T cell CD4+ Effector cell CD8+ Effector cell Single-positive “SP” cell FIG. 11.4 Overview of the pathway for T-cell maturation. (From Nairn R, Helbert M: Immunology for Medical Students, ed 2, Philadelphia, 2007, Elsevier.) CHAPTER 11 Lymphatic System Disorders 217 Lymphatic Disorders Infectious mononucleosis is a common infection involving the lymphatic system. It is discussed in Chapter 23. Lymphomas Lymphomas are malignant neoplasms involving lymphocyte proliferation in the lymph nodes. The two main disorders, Hodgkin lymphoma and non- Hodgkin lymphoma, actually a group of lymphomas, are differentiated by lymph node biopsy. Many research projects have focused on characterizing new types of lymphoma and determining a classification system. One component of the latter relates to how rapidly growing or aggressive the tumor is. Specific causes of lymphomas have not been identified, but there is a higher incidence in adults who received radiation treatments during childhood. Hodgkin Disease/Hodgkin Lymphoma Hodgkin’s disease is a type of lymphoma starting in lymphocytes. The disease can start almost anywhere, but most often it originates in lymph nodes in the upper part of the body. While Hodgkin’s disease can occur in both children and adults, the onset of the disease occurs primarily in adults 20 to 40 years of age. The estimates from the American Cancer Society in the United States for 2017 are: • About 8260 new cases: 3610 in females and 4650 in males • About 1070 deaths: 440 females and 630 males. Due to advanced treatment, survival rates have improved significantly in the past few decades. The 1-year survival of all patients diagnosed is about 92%. Factors such as the stage of the disease and a person’s age can affect this rate. ■ Pathophysiology The malignancy initially involves a single lymph node, frequently in the neck area (Fig. 11.7). Later the cancer spreads to adjacent nodes and then to organs via the lymphatics. The T lymphocytes appear to be defective, and the lymphocyte count is decreased. The atypical cell used as a marker for diagnosis of Hodgkin lym- phoma is the Reed-Sternberg cell, a giant cell present in the lymph node (Fig. 11.8). Hodgkin disease can be Direction of flow Interstitial fluid (IF) entering lymphatic capillary Overlapping endothelial cells Valve open Valve closed Anchoring fibers FIG. 11.5 Structure of a typical lymphatic capillary. Notice that interstitial fluid enters through clefts between overlapping endo- thelial cells that form the wall of the vessel. Valves ensure one-way flow of lymph out of the tissue. Small fibers anchor the wall of the lymphatic capillary to the surrounding extracellular matrix and cells, thus holding it open to allow entry of fluids and small particles. (From Patton KT, Thibodeau GA: Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby.) Tonsils and adenoids Lymph nodes Spleen Appendix Peyer patches in intestinal wall Lymphatic vessels Thymus gland Bone marrow FIG. 11.6 Principal organs of the lymphatic system. (From Copstead L, Banasik L: Pathophysiology, ed 5, St. Louis, 2013, Saunders, Elsevier.) THINK ABOUT 11.1 a. Explain two purposes of the lymphatic system. b. Predict the result of destruction of the lymph nodes in a specific region. c. Under what circumstances might lymph nodes be surgically removed? 218 SECTION III Pathophysiology of Body Systems involvement such as bone, lung, or liver. Extensive testing is required to stage lymphomas accurately. ■ Signs and Symptoms • The first indicator is usually an enlarged lymph node, often cervical, that is painless, and nontender. • Later splenomegaly and enlarged lymph nodes at other locations may cause pressure effects; for example, enlarged mediastinal nodes may compress the esophagus. • General signs of cancer, such as weight loss, anemia, low-grade fever and night sweats, and fatigue, may develop. subdivided into four subtypes based on the cells found at biopsy. Various staging systems are used to determine the extent that cancer has manifested. A common system used for Hodgkin’s lymphoma is the Ann Arbor staging system, which uses the diaphragm as the differential landmark (Fig. 11.9). The Ann Arbor staging system generally defines a stage I cancer as affecting a single lymph node or region and stage II as affecting two or more lymph node regions on the same side of the dia- phragm or in a relatively localized area. Stage III cancer involves nodes on both sides of the diaphragm and the spleen. Stage IV represents diffuse extralymphatic S L IR Lymphatic capillary Anchoring fibers Lymphatic fluid Interstitial fluid (IF) Tissue cell Afferent lymphatic vessel Lymph flow Lymph flow Blood flow Sinus Valve Systemic capillary network Lymphatic capillaries Lymphatic capillaries Lymph node Pulmonary capillary network Lymphatic vessels Interstitial fluid (IF) Nodule Efferent lymphatic vessel Blood capillary FIG. 11.7 Circulation plan of lymphatic fluid. This diagram outlines the general scheme for lymphatic circulation. Fluids from the systemic and pulmonary capillaries leave the bloodstream and enter the interstitial space, thus becoming part of the interstitial fluid (IF). The IF also exchanges materials with the surrounding tissues. Often because less fluid is returned to the blood capillary than had left it, IF pressure increases, causing IF to flow into the lymphatic capillary. The fluid is then called lymph (lymphatic fluid) and is carried through one or more lymph nodes and finally to large lymphatic ducts. The lymph enters a subclavian vein, where it is returned to the systemic blood plasma. Thus fluid circulates through blood vessels, tissues, and lymphatic vessels in a sort of “open circulation.” (From Patton KT, Thibodeau GA: Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby.) CHAPTER 11 Lymphatic System Disorders 219 • Generalized pruritus is common. • Recurrent infection is common because the abnormal lymphocytes interfere with the immune response. ■ Treatment Radiation, chemotherapy, and surgery are used with much greater success now than previously. Although many newer drugs and combinations have been tried, one of the most effective remains the ABVD (Adriamy- cin, Bleomycin, Vinblastine, Dacarbzine) combination illustrated in Fig. 20.10. For a patient in stage II, three courses of chemotherapy at 4-week intervals would be suggested, and then the patient’s status evaluated. In the advanced stages, remissions are common, although secondary cancers have occurred in some patients despite extensive treatment. FIG. 11.8 A Reed-Sternberg cell (arrow) diagnostic for Hodgkin lymphoma. This lymphocyte is large with an irregular nucleus. (From Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, 1997, Saunders.) Stage II Multiple regions on same side of diaphragm Stage III Lymph node regions on both sides of diaphragm Stage IV Widespread Liver, spleen Stage I Single lymph node or region FIG. 11.9 The typical spread of Hodgkin lymphoma. 220 SECTION III Pathophysiology of Body Systems ■ Signs and Symptoms The onset is usually insidious and the malignancy well advanced before diagnosis. • Frequent infections may be the initial sign related to impaired production of antibodies. • Pain, related to bone involvement, is common and is present at rest. • Pathologic fractures may occur as bone is weakened. • Anemia and bleeding tendencies are common because blood cell production is affected. • Kidney function, particularly the tubules, is affected, leading to proteinuria and kidney failure. ■ Treatment Chemotherapy is used to encourage remission. Median survival is 3 years. Analgesics for bone pain and treatment for kidney impairment may be needed. Blood transfusions are required in the late stage. Non-Hodgkin Lymphomas Non-Hodgkin lymphomas are increasing in incidence, partly due to the numbers associated with HIV infec- tion. Non-Hodgkin lymphomas are similar to Hodgkin lymphoma only in some ways. About 80% of the cases involve B lymphocytes. The initial manifesta- tion is an enlarged, painless lymph node. The clinical signs, staging, and treatment are similar to Hodgkin lymphoma. Non-Hodgkin lymphoma is distinguished by multiple node involvement scattered throughout the body and a nonorganized pattern of widespread metastases, often present at diagnosis. Intestinal nodes and organs are frequently involved in the early stage. It is more difficult to treat when the tumors are not localized, but the survival rates have risen to 65% from the previous 30%. Multiple Myeloma or Plasma Cell Myeloma ■ Pathophysiology Multiple myeloma is a neoplastic disease of unknown etiology involving the plasma cells (mature B lymphocytes involved in production of antibodies). An increased number of malignant plasma cells replace the bone marrow and erode the bone (Fig. 11.10). Blood cell pro- duction is impaired, as well as production of antibodies. Multiple tumors with bone destruction develop in the vertebrae, ribs, pelvis, and skull. Pathologic or spontane- ous fractures at weakened sites in the bone are common. Hypercalcemia develops as bone is broken down. The tumor cells can spread throughout the body, into lymph nodes and infiltrating many organs. Extensive testing is required for the diagnosis. FIG. 11.10 Multiple myeloma. The radiograph shows lytic lesions. (From Abeloff M et al: Abeloff’s clinical oncology, ed 4, Philadelphia, 2008, Churchill Livingstone.) THINK ABOUT 11.2 a. Explain why infections occur frequently in patients with lymphomas. b. State the prognoses for a person with a stage I and stage IV Hodgkin lymphoma, and explain your reasoning. Lymphedema Lymphedema is a condition in which the tissues in the extremities swell due to an obstruction of the lymphatic vessels and the subsequent accumulation of lymph. ■ Physiology and Etiology The most common form of the disorder is congenital and may involve not only the vessels, but the lymph nodes as well. It is most often seen in women between the ages of 15 and 25 years. This condition can also be caused by blockage of the lymph vessels by infestation of parasitic worms. This specific form of lymphedema results in a condition called elephantiasis, which is addressed as a separate disorder. ■ Signs and Symptoms The extremities swell as the lymph accumulates. The swelling may initially be soft, but as the condition pro- gresses, the extremity affected may become firm, painful, and unresponsive to treatment. Chronic lymphedema may lead to frequent infections, resulting in high fever and chills ■ Treatment Treatments include the following: • Diuretics to reduce the swelling • Strict bed rest • Massage of the affected area • Elevation of the affected extremity If the edema is severe, infection has set in, or the patient’s mobility has been severely impaired, surgical CHAPTER 11 Lymphatic System Disorders 221 vessels, repeated streptococcal infections, and the removal of cancerous lymph nodes. ■ Signs and Symptoms Manifestations of this disorder include the following: • Extreme swelling of the legs, breasts, or genitalia • Thickening of the subcutaneous tissue • Frequent infections • Skin ulcerations • Fever ■ Diagnosis Positive diagnosis of lymphatic filariasis is by the detection and identification of the parasitic worms in the blood. Urine can also reveal the presence of the parasites as well as examination of hydrocele fluid. ■ Treatment The primary treatment for lymphatic filariasis is a medica- tion regimen to kill the parasite. In cases resulting in massive enlargement of the legs and resultant ulceration, surgery to perform a fluid-shunting procedure may be necessary. Castleman Disease Castleman disease is a rare illness that involves the overgrowth of lymphoid tissue. Although this disease is characterized by overgrowth of lymphatic cells, it is not considered a cancer but is associated with a higher risk of lymphoma. ■ Pathophysiology and Etiology Castleman disease is also known as giant lymph node hyperplasia and angiofollicular lymph node hyperplasia and is classified as a lymphoproliferative disorder. There are two types of Castleman disease: unicentric, which affects only a single lymph node, and multicentric, which affects multiple lymph nodes and tissue and may lead to a severe weakening of the immune system. ■ Signs and Symptoms Unicentric manifestations include: • Difficulty breathing or eating due to fullness or pressure in the chest or abdomen • A large lump in the neck, armpit, or groin • Unexplained weight loss and anorexia • Persistent cough Multicentric manifestations include: • Fever and night sweats • Nausea and vomiting leading to a loss of appetite and resulting in weight loss • Weakness and overall fatigue • Enlarged spleen, liver, or peripheral lymph nodes in the neck, groin, or armpits • Numbness or weakness in the hands and feet due to nerve damage removal of the affected tissue and surrounding fascia may be required. Other surgical options include implant- ing a shunt to drain lymph from the superficial to the deep lymphatic circulation. Elephantiasis (Filariasis) This is a type of lymphedema caused primarily by an infestation and blockage of the lymph vessels of the extremities by a parasitic worm called filaria. There is also a relatively rare, nonfilarial form of elephantiasis known as podoconiosis, which is difficult to treat and thought to be caused by skin irritation from contact with volcano ash. ■ Etiology The parasitic worms infest the small lymph vessels, blocking lymph flow and resulting in significant swelling of the affected extremity. In severe cases the swelling can be so pronounced that the extremity may resemble an elephant’s limb, giving this disorder its name (Fig. 11.11). The nonfilarial elephantiasis is caused by chemicals from volcanic ash entering the body through cuts on the feet. The chemicals in the ash irritate the lymph vessels, causing swelling, which in turn blocks the lymph vessels, causing excessive swelling of the affected area. There are other situations that can lead to this condition such as protozoal infection, birth defects in lymphatic S L I R FIG. 11.11 Elephantiasis. Prolonged infestation of the lymphatic system by filaria worms produces so much swelling (lymphedema) that the affected limbs begin to resemble those of an elephant. (From Damjanov I, Linder J: Pathology: A Color Atlas, St Louis, 2000, Elsevier.) 222 SECTION III Pathophysiology of Body Systems C H A P T E R S U M M A R Y Lymph and the associated vessels, structures, and organs function to return excess interstitial fluid and protein to the blood, to filter and destroy unwanted material from the body fluids, and to initiate an immune response. • Lymphatic vessels originate as microscopic capillaries that are in direct contact with tissue cells and the interstitial fluid surrounding the cells. • Lymph nodes containing many lymphocytes and macrophages are situated along all lymphatic and blood vessels, ensuring constant filtration and surveil- lance of body fluids. • The spleen has many functions: defense, hematopoiesis, and red blood cell and platelet destruction, as well as serving as a reservoir for blood. • The thymus gland plays a critical role as part of the immunity mechanism against infections. • Lymphomas are malignant neoplasms involving lymphocyte proliferation in the lymph nodes. • In Hodgkin lymphoma, the T lymphocytes appear to be defective, and the lymphocyte count is decreased. • Non-Hodgkin lymphoma is similar to Hodgkin lymphoma; however, about 80% of the cases involve B lymphocytes, which is not the case in Hodgkin lymphoma. • Multiple myeloma is a neoplastic disease of unknown etiology occurring in older adults and involving the plasma cells (mature B lymphocytes involved in the production of antibodies). • Lymphedema is a condition in which the tissues in the extremities swell due to an obstruction of the lymphatic vessels and the subsequent accumulation of lymph. • Castleman disease is a rare illness that involves the overgrowth of lymphoid tissue; however, it is not considered a cancer. ■ Diagnosis Diagnostic tests for Castleman disease include: • Physical examination of the lymph nodes • Blood and urine tests for anemia • Imaging techniques such as x-ray, computed tomog- raphy scans, or magnetic resonance imaging to detect the presence and number of any enlarged lymph nodes as well as the enlargement of organs such as the spleen or liver • Lymph node biopsy ■ Treatment The type of Castleman disease a patient has will determine the specific treatment: • For the unicentric form of the disease, surgical removal of the diseased and enlarged lymph node is the pre- ferred method of treatment. For cases in which surgical removal of the node may not be possible due to its location, medication such as corticosteroids or radiation treatment may be used to shrink or destroy the node. • For the multicentric form of the disease, the treatment is generally more difficult. Surgical removal of the affected nodes is not practical because of the number of nodes involved; however, the removal of an enlarged spleen can ease symptoms in some cases. The primary treatment is the use of medications to target the affected nodes or organs. These medications—such as corticosteroids, monoclonal antibodies, antiviral drugs, immune modulators, and some anticancer drugs—are being used with varying results. THINK ABOUT 11.3 Why might the absence of a parasitic nematode in the blood not be definitive proof that a patient is not suffering from elephantiasis? CASE STUDY A Hodgkin Disease J.R., age 32 years, noticed a lump on the side of his neck a few months ago. The lump is relatively large, painless, and not tender to the touch. A few days ago he experienced some difficulty swallowing as if there was something putting pressure on his esophagus. He has also noticed unexplained weight loss, fever, night sweats, and general fatigue over the past few weeks. A visit to his physician produced lab results showing a marked decrease in the lymphocyte count as well as the presence of a giant cell in the tissue of a biopsied lymph node, subsequently confirmed as a Reed-Sternberg cell. The lab results confirmed Hodgkin lymphoma. 1. Describe the pathophysiology of Hodgkin lymphoma. 2. Outline the conditions of the disease at each of the four stages as defined by the Ann Arbor staging system. 3. List some of the differences between Hodgkin and non-Hodgkin lymphoma. 4. List the methods currently available to treat this disease. S T U D Y Q U E S T I O N S 1. Describe the functions of the lymph nodes, the thymus gland, the tonsils, and the spleen. 2. Trace the basic path of the lymphatic circulation. 3. Compare and contrast Hodgkin and non-Hodgkin lymphomas based on pathophysiology, signs and symptoms, diagnosis, and treatments. 4. What are the two forms of Castleman disease, and what distinguishes one from the other? 223 Review of the Cardiovascular System Heart Anatomy Conduction System Control of the Heart Coronary Circulation Cardiac Cycle Blood Pressure Heart Disorders Diagnostic Tests for Cardiovascular Function General Treatment Measures for Cardiac Disorders Coronary Artery Disease, Ischemic Heart Disease, or Acute Coronary Syndrome Arteriosclerosis and Atherosclerosis Angina Pectoris Myocardial Infarction Cardiac Dysrhythmias (Arrhythmias) Sinus Node Abnormalities Atrial Conduction Abnormalities Atrioventricular Node Abnormalities: Heart Blocks Ventricular Conduction Abnormalities Treatment of Cardiac Dysrhythmias Cardiac Arrest or Standstill (Asystole) Congestive Heart Failure Young Children With Congestive Heart Failure Congenital Heart Defects Ventricular Septal Defect Valvular Defects Tetralogy of Fallot Inflammation and Infection in the Heart Rheumatic Fever and Rheumatic Heart Disease Infective Endocarditis Pericarditis Vascular Disorders Arterial Disorders Hypertension Peripheral Vascular Disease and Atherosclerosis Aortic Aneurysms Venous Disorders Varicose Veins Thrombophlebitis and Phlebothrombosis Shock Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Describe the common diagnostic tests for cardiovascular function. 2. Describe the dietary and lifestyle changes, and the common drug groups used, in the treatment of cardiovascular disease. 3. Explain the role of cholesterol and lipoproteins in the development of atheromas. 4. Explain the significance of metabolic syndrome in the development of cardiovascular disease. 5. State the factors predisposing to atherosclerosis. 6. Compare angina and myocardial infarction. 7. Describe the common arrhythmias and cardiac arrest. 8. Discuss the causes of congestive heart failure and the effects of left-sided and right-sided failure. 9. Explain the changes in blood flow and their effects in common congenital heart defects. 10. Discuss the development of rheumatic fever and rheumatic heart disease. 11. Describe the etiology and pathophysiology of infectious endocarditis and pericarditis. 12. Explain the development and possible effects of essential hypertension. 13. Compare the arterial peripheral vascular diseases atherosclerosis and aneurysms. 14. Describe the development and effects of the venous disorders varicose veins, phlebothrombosis, and thrombophlebitis. 15. Discuss the types of shock and the initial and progressive effects of shock on the body. L E A R N I N G O B J E C T I V E S C H A P T E R 12 Cardiovascular System Disorders 224 SECTION III Pathophysiology of Body Systems Review of the Cardiovascular System Heart Anatomy The heart functions as the pump for the circulating blood in both the pulmonary and systemic circulations. The path of a specific component of the blood, such as a red blood cell, through the heart and circulation is illustrated in Fig. 12.1. The heart is located in the mediastinum between the lungs and is enclosed in the double-walled pericardial sac (see Fig. 12.29, presented later in the chapter). The outer fibrous pericardium anchors the heart to the diaphragm. The visceral pericardium, also called the epicardium, consists of a serous membrane that provides a small amount of lubricating fluid within the pericardial cavity between the two pericardial membranes to facilitate heart movements. The middle layer of the heart is the myo- cardium, composed of specialized cardiac muscle cells that contract rhythmically and forcefully to pump blood throughout the organs. The left ventricular wall is thicker because it must eject blood into the extensive systemic circulation. The inner layer of the heart is the endocardium, which also forms the four heart valves that separate the chambers of the heart and ensure one-way flow of blood. The atrioventricular (AV) valves separate the atria from the ventricles; they comprise, on the right side, the tri- cuspid valve with three leaflets or cusps, and on the left side, the mitral or bicuspid valve with two leaflets. The semilunar valves, each with three cusps, include the aortic and pulmonary valves located at the exits to the large arteries from the ventricles. The septum separates the left and right sides of the heart. Conduction System Impulses to initiate cardiac contractions are conducted along specialized myocardial (cardiac muscle) fibers. No nerves are present within the cardiac muscle. The unique characteristics of cardiac muscle include the presence of intercalated discs at the junctions between fibers. These discs contain desmosomes, connections to prevent muscle cells from separating during contraction, and gap junc- tions, which permit ions to pass from cell to cell, facilitat- ing rapid transmission of impulses. These specialized structures ensure that all muscle fibers of the two atria normally contract together, followed shortly by the two ventricles. This coordinated effort results in a rhythmic Brain Digestive tract Skeletal muscle Skin Kidneys Erythrocyte takes one of these routes Lose O2 from Hemoglobin Add O2 to Hemoglobin Systemic Circulation Pulmonary Circulation Pulmonary artery Pulmonary (semilunar) valve Inferior vena cava Tricuspid valve Right ventricle Right atrium Left atrium Left ventricle Aortic (semilunar) valve Mitral (bicuspid) valve Pulmonary vein Lungs FIG. 12.1 Path of erythrocyte in the circulation. adrenergic anastomoses angioplasty Aschoff bodies auscultation autoregulation baroreceptors bradycardia cardiomegaly depolarization ectopic electrodes endarterectomy hemoptysis microcirculation murmurs orthopnea sulcus syncope synergistic tachycardia troponins verrucae K E Y T E R M S and efficient filling and emptying of the atria and ven- tricles that has sufficient force to sustain the flow of blood through the body. The pathway for impulses in the cardiac conduction system is as follows: • All cardiac muscle cells can initiate impulses, but normally the conduction pathway originates at the CHAPTER 12 Cardiovascular System Disorders 225 wave of depolarization in the ventricles (QRS). This wave masks the effect of atrial repolarization, but the third wave (T wave) represents the repolarization of the ventricles, or recovery phase. Abnormal variations in the ECG known as arrhythmias or dysrhythmias may indicate acute problems, such as an infarction, or systemic prob- lems, such as electrolyte imbalances (eg, potassium deficiency [see Fig. 2.8]). Control of the Heart Heart rate and force of contraction are controlled by the cardiac control center in the medulla of the brain. The baroreceptors in the walls of the aorta and internal carotid arteries detect changes in blood pressure and the cardiac center then responds through stimulation of the sympa- thetic nervous system (SNS) or the parasympathetic nervous system to alter the rate and force of cardiac contractions as required. Sympathetic innervation increases heart rate (tachycardia) and contractility, whereas parasympathetic stimulation by the vagus nerve slows the heart rate (bradycardia). The sympathetic or beta1-adrenergic receptors in the heart (see Chapter 14) are an important site of action for some drugs, such as beta blockers. Because beta blockers fit the receptors and prevent normal SNS stimulation, they are used to block any increases in rate and force of contractions after the heart has been damaged. sinoatrial (SA) node, often called the pacemaker, located in the wall of the right atrium. • The SA node automatically generates impulses at the basic rate, called the sinus rhythm (approximately 70 beats per minute), but this can be altered by autonomic nervous system fibers that innervate the SA node and by circulating hormones such as epinephrine. • From the SA node, impulses then spread through the atrial conduction pathways, resulting in contraction of both atria. • The impulses then arrive at the AV node, located in the floor of the right atrium near the septum. This is the only anatomic connection between the atrial and ventricular portions of the conduction system. • There is a slight delay in conduction at the AV node to allow for complete ventricular filling; then the impulses continue into the ventricle through the AV bundle (bundle of His), the right and left bundle branches, and the terminal Purkinje network of fibers, stimulating the simultaneous contraction of the two ventricles. Conduction of impulses produces a change in electrical activity that can be picked up by electrodes attached to the skin at various points on the body surface, producing the electrocardiogram (ECG) (Fig. 12.2). The atrial contrac- tion is represented by the depolarization in the P wave, and the ventricular contraction is shown by the large R P Q S T Pulmonary artery Atrial excitation Excitation of ventricles begins (initial downward deflection is a Q wave) Left ventricle Septum Right atrium Internodal pathways Right ventricle Left atrium Sinoatrial (SA) node Atrioventricular (AV) node AV bundle (bundle of His) FIG. 12.2 Schematic drawing of the conducting system of the heart. An impulse normally is generated in the sinus node and travels through the atria to the AV node, down the bundle of His and Purkinje fibers, and to the ventricular myocardium. Recording of the depolarizing and repolarizing currents in the heart with electrodes on the surface of the body produces characteristic waveforms. (From Copstead-Kirkhorn LE, Banasik JL: Pathophysiology, ed 4, Philadelphia, 2009, Saunders.) 226 SECTION III Pathophysiology of Body Systems or contraction as the contracting muscle compresses the arteries. Thus rapid or prolonged contractions can reduce the blood supply to the cardiac muscle cells. Anastomoses, or direct connections, exist between small branches of the left and right coronary arteries near the apex, as well as in other areas in which branches are nearby (see Fig. 12.3). These junctions have the potential to open up and provide another source of blood to an area. Collateral circulation (alternative source of blood and nutrients) is important if an artery becomes obstructed. When obstruction develops gradually, more capillaries from nearby arteries tend to enlarge or extend into adjacent tissues to meet the metabolic needs of the cells. Regular aerobic exercise contributes to cardiovascular fitness by stimulating the development of collateral channels. Any interference with blood flow will affect heart function, depending on the specific area supplied by that artery. Generally, the right coronary artery supplies the right side of the heart and the inferior portion of the left ventricle, as well as the posterior interventricular septum. The left anterior descending artery brings blood to the anterior wall of the ventricles, the anterior septum, and the bundle branches, and the circumflex artery nourishes the left atrium and the lateral and posterior walls of the left ventricle. The source of blood for the SA node depends on the specific position of the arteries, which varies in individuals. The SA node is supplied by the right coronary artery in slightly more than half the population and by the left circumflex artery in the remainder. The AV node is nourished primarily by the right coronary artery. This information implies that blockage of the right coronary Factors that increase heart rate include the following: • Elevated body temperature, such as in fever • Increased environmental temperatures, especially if humidity is high • Exertion or exercise, notably when beginning, followed by a leveling off • Smoking even one cigarette • Stress response • Pregnancy • Pain Any stimulation of the SNS, as with stress, increases the secretion of epinephrine, which in turn stimulates beta receptors and increases both the heart rate and contractility. THINK ABOUT 12.1 a. Where is the mitral valve located? Describe the direction and type of blood (oxygenated or nonoxygenated) that flows through this valve. b. List two functions of the AV node. c. Describe the control of heart rate during and after exercise. Circumflex branch Great cardiac vein Left coronary artery Right coronary artery Anterior interventricular branch FIG. 12.3 Coronary Arteries. (From Frazier M, Drzymowski J: Essentials of Human Disease and Conditions, ed 6, St. Louis, 2016, Elsevier.) Coronary Circulation Cardiac muscle requires a constant supply of oxygen and nutrients to conduct impulses and contract efficiently, but it has very little storage capacity for oxygen. The distribution of the major blood vessels in the coronary circulation is as follows: 1. Two major arteries, the right and left coronary arteries, branch off the aorta immediately above the aortic valve (Fig. 12.3). 2. The left coronary artery soon divides into the left anterior descending or interventricular artery, which follows the anterior interventricular sulcus or groove downward over the surface of the heart, and the left circumflex artery, which circles the exterior of the heart in the left atrioventricular sulcus. 3. Similarly, the right coronary artery follows the right atrioventricular sulcus on the posterior surface of the heart and branches into the right marginal artery and the posterior interventricular artery, and then descends in the posterior interventricular groove toward the apex of the heart, where it comes close to the terminal point of the left anterior descending artery. The passage of arteries over the surface of the heart in these grooves is helpful because it permits surgical replacement of obstructed arteries with “bypasses”—using sections of other veins or arteries (see Fig. 12.13, presented later in the chapter, for a diagram of a bypass). 4. Many small branches extend inward from these large arteries to supply the myocardium and endocardium. Blood flow through the myocardium is greatest during diastole or relaxation and is reduced during systole CHAPTER 12 Cardiovascular System Disorders 227 1. The cycle begins with the two atria relaxed and filling with blood (from the inferior and superior venae cavae into the right atrium, and from the pulmonary veins into the left atrium). 2. The AV valves open as the pressure of blood in the atria increases and the ventricles are relaxed. 3. Blood flows into the ventricles, almost emptying the atria. 4. The conduction system stimulates the atrial muscle to contract, forcing any remaining blood into the ventricles. 5. The atria relax. 6. The two ventricles begin to contract, and pressure increases in the ventricles. 7. The AV valves close. 8. For a brief moment, all valves are closed, and the ventricular myocardium continues to contract, build- ing up pressure in this isovolumetric phase (no change in blood volume in the ventricles). 9. Then the increasing pressure opens the semilunar valves; blood is forced into the pulmonary artery artery is more likely to result in conduction disturbances of the AV node (resulting in dysrhythmias), whereas interference with the blood supply to the left coronary artery will most likely impair the pumping capability of the left ventricle (potentially leading to congestive heart failure). The course of the coronary or cardiac veins generally parallels that of the arteries, with a majority of the blood returning to the coronary sinus and emptying directly into the right atrium. APPLY YOUR KNOWLEDGE 12.1 Predict three basic ways that cardiac function could be impaired. DIASTOLE • atria fill • all valves closed 1. DIASTOLE • increased atrial pressure opens AV valves • ventricles fill 2. SYSTOLE BEGINS • atria contract and empty • ventricles are full 3. SYSTOLE • ventricles begin contraction • pressure closes AV valves • atria relax 4.SYSTOLE • ventricles contract • increased pressure in ventricles • aortic and pulmonary valves open • blood ejected into aorta and pulmonary artery 5.DIASTOLE • ventricles empty • ventricles relax • aortic and pulmonary valves close 6. FIG. 12.4 Cardiac cycle. Cardiac Cycle The cardiac cycle refers to the alternating sequence of diastole, the relaxation phase of cardiac activity, and systole, or cardiac contraction, which is coordinated by the conduction system for maximum efficiency (Fig. 12.4): 228 SECTION III Pathophysiology of Body Systems and aorta. Note that the muscle contraction must be strong enough to overcome the opposing pressure in the artery to force the valve open. This is significant, particularly in the left ventricle, in which the pressure must be greater than the diastolic pressure in the aorta. Because the pulmonary circulation is a low- pressure system, the right ventricle does not have to exert as much pressure to pump blood into the pulmonary circulation. 10. At the end of the cycle, the atria have begun to fill again, the ventricles relax, the aortic and pulmonary valves close to prevent backflow of blood, and the cycle repeats. The same volume of blood is pumped from the right and left sides of the heart during each cycle. This is important to ensure that blood flow through the systemic and pulmonary circulations is consistently balanced. THINK ABOUT 12.2 a. Discuss the importance of collateral circulation, and explain how collateral circulation can be maximized. b. Why is there a pause after the atrial contraction and before the ventricular contraction? c. Predict the outcome if more blood is pumped into the pulmonary circulation than into the systemic circulation during each cardiac cycle. Facial artery Brachial artery Radial artery Popliteal artery (posterior knee) Temporal artery Axillary artery Femoral artery Dorsalis pedis artery Common carotid artery FIG. 12.5 Location of commonly used pulse points. Each pulse point is named after the artery associated with it. (From Applegate E: The Anatomy and Physiology Learning System, ed 4, St. Louis, 2011, Elsevier.) THINK ABOUT 12.3 a. What information does the ECG provide about heart function? b. Describe the function of the areas of the heart usually supplied by the left coronary artery. c. Describe the effect if the atria were to contract at the same time as the ventricles, or if the ventricles contracted slightly before the atria. The heart sounds, “lubb-dupp,” which can be heard with a stethoscope (referred to as mediate auscultation) result from vibrations due to closure of the valves. Closure of the AV valves at the beginning of ventricular systole causes a long, low “lubb” sound, followed by a “dupp” sound as the semilunar valves close with ventricular diastole. Defective valves that leak or do not open completely cause unusual turbulence in the blood flow, resulting in abnormal sounds, or murmurs. A hole in the heart septum resulting in abnormal blood flow would also cause a heart murmur. The pulse indicates the heart rate. The pulse can be felt by the fingers (not the thumb) placed over an artery that passes over bone or firm tissue, most commonly at the wrist (Fig. 12.5). During ventricular systole, the surge of blood expands the arteries. The characteristics of the pulse, such as weakness or irregularity in a peripheral pulse (eg, the radial pulse in the wrist), often indicate a problem. The apical pulse refers to the rate measured at the heart itself. A pulse deficit is a difference in rate between the apical pulse and the radial pulse. Cardiac function can be measured in a number of ways: • Cardiac output is the volume of blood ejected by a ventricle in one minute and depends on heart rate and stroke volume, the volume pumped from one ventricle in one contraction (Fig. 12.6). This means that at rest, the heart pumps into the system an amount equal to the total blood volume in the body every minute, which is a remarkable feat. When necessary, the normal heart can increase its usual output by four or five times the minimum volume. • Stroke volume varies with sympathetic stimulation and venous return. When an increased amount of blood returns to the heart, as during exercise, the heart is stretched more and the force of the contraction normally increases proportionately. During exercise, stress, or infection, cardiac output increases considerably. • Cardiac reserve refers to the ability of the heart to increase output in response to increased demand. • Preload refers to the mechanical state of the heart at the end of diastole with the ventricles at their maximum volume. • Afterload is the force required to eject blood from the ventricles and is determined by the peripheral resistance to the opening of the semilunar valves. For example, afterload is increased by a high diastolic pressure resulting from excessive vasoconstriction. CHAPTER 12 Cardiovascular System Disorders 229 Peripheral resistance is the force opposing blood flow, or the amount of friction with the vessel walls encountered by the blood. Decreasing the diameter (or lumen) of the blood vessel increases the resistance to blood flow. Normally peripheral resistance can be altered by the systemic constriction or dilation of the arterioles. Systemic or widespread vasoconstriction occurs in response to sympathetic stimulation and increases blood pressure. Systemic or general vasodilation that leads to decreased blood pressure results from reduced SNS stimulation. (There is no parasympathetic nervous system innervation in the blood vessels.) Any obstruction in the blood vessel also increases resistance. Local vasoconstriction or dilation does not affect the overall systemic blood pressure. Changes in blood pressure are detected by the baro- receptors and relayed to the vasomotor control center in the medulla, which adjusts the distribution of blood to maintain normal blood pressure. For example, when one rises from a supine position, blood pressure drops Blood Pressure Blood pressure refers to the pressure of blood against the systemic arterial walls. The distribution and structure of the various blood vessels is discussed in detail in Chapter 10. In adults, a normal pressure is commonly in the range of 120/70 mm Hg at rest. Systolic pressure, the higher number, is the pressure exerted by the blood when ejected from the left ventricle. Diastolic pressure, the lower value, is the pressure that is sustained when the ventricles are relaxed. The brachial artery in the arm is used to measure blood pressure with a sphygmoma- nometer and an inflatable blood pressure cuff. Pulse pressure is the difference between the systolic and diastolic pressures. Blood pressure depends on cardiac output and periph- eral resistance (Fig. 12.7). Specific variables include blood volume and viscosity, venous return, the rate and force of heart contractions, and the elasticity of the arteries. CARDIAC OUTPUT The amount of blood pumped by each ventricle in 1 minute HEART RATE The number of contractions of the ventricles each minute STROKE VOLUME The amount of blood ejected from each ventricle with each contraction AVERAGE 4900–5000 mL 70 70 mL = X = X FACTORS AFFECTING CARDIAC OUTPUT Sympathetic nervous system Epinephrine Venous return (preload) Blood volume Sympathetic nervous system (contractility) Peripheral resistance (afterload) = X CO = HR X SV FIG. 12.6 Cardiac output. BLOOD PRESSURE FOR EXAMPLE: 1. BP - no change = ↑ CO X ↓ PR 2. BP - elevated = CO - no change X ↑ PR 3. IF: ↑ heart rate (↑ CO) X systemic vasoconstriction (↑ PR) ------→ increased BP 4. IF: ↓ stroke volume (↓ CO) X systemic vasodilation (↓ PR) ------→ decreased BP CARDIAC OUTPUT PERIPHERAL RESISTANCE= X BP = CO X PR FIG. 12.7 Blood pressure. 230 SECTION III Pathophysiology of Body Systems Diagnostic Tests for Cardiovascular Function Because many of the same tests are used in the diagnosis and monitoring of a variety of cardiovascular disorders, a few of the basic tests are summarized here: • An ECG is useful in the initial diagnosis and monitoring of arrhythmias, myocardial infarction, infection, and pericarditis (see Fig. 12.17, presented later in the chapter). It is a noninvasive procedure and can illustrate the conduction activity of the heart as well as the effects of systemic abnormalities such as serum electrolyte imbalance. An individual may wear a portable Holter monitor to record ECG changes while he or she pursues daily activities. A log of activities is usually maintained to match with the changes in ECG. A normal baseline ECG recording is recommended for everyone; it can be used for comparison if cardiovascular disease ever develops. • Valvular abnormalities or abnormal shunts of blood cause murmurs that may be detected by auscultation of heart sounds by means of a stethoscope. A recording of heart sounds may be made with a phonocardiograph. In echocardiography, ultrasound (or reflected sound waves) is used to record the image of the heart and valve movements (see Fig. 12.25, presented later in the chapter). These tests provide useful information regarding valvular abnormalities, congenital defects, and changes in heart structure or function. • Exercise stress tests (bicycle, step, or treadmill) are useful for assessing general cardiovascular function and checking for exercise-induced problems such as arrhythmias. They may be used in fitness clubs before setting up an individualized exercise program or by insurance companies in the evaluation of an indi- vidual’s health risks, as well as in cardiac rehabilitation programs following heart attacks or cardiovascular surgery. • Chest x-ray films can be used to show the shape and size of the heart, as well as any evidence of pulmonary congestion associated with heart failure. • Nuclear imaging with radioactive substances such as thallium assesses the size of an infarct in the heart, the extent of myocardial perfusion, and the function of the ventricles. Tomographic studies, which illustrate various levels of a tissue mass, may be used when available. Nuclear medicine studies can identify dead or damaged areas of myocardial tissues and may be used to assess the extent of myocardial damage after a myocardial infarction. • Single-photon emission computed tomography (SPECT) is a specialized CAT scan that accurately assesses cardiac ischemia at rest. Therapeutic intervention is not possible during this procedure. (Compare with coronary angiography, discussed later.) • Cardiac catheterization—passing a catheter through an appropriate blood vessel, usually a large vein in the leg, into the ventricle—may also be utilized to visualize momentarily owing to gravitational forces until the reflex vasoconstriction mechanism in the body ensures that more blood flows to the brain. Blood pressure is elevated by increased SNS stimulation in two ways: 1. SNS and epinephrine act at the beta1-adrenergic recep- tors in the heart to increase both the rate and force of contraction. 2. SNS, epinephrine, and norepinephrine increase vaso- constriction by stimulating the alpha1 receptors in the arterioles of the skin and viscera. This reduces the capacity of the system and increases venous return. Other hormones also contribute to the control of blood pressure: • Antidiuretic hormone (ADH) increases water reabsorp- tion through the kidney, thus increasing blood volume. Antidiuretic hormone, also known as vasopressin, also causes vasoconstriction. • Aldosterone increases blood volume by increasing reabsorption of sodium ions and water. • The renin-angiotensin-aldosterone system in the kidneys is an important control and compensation mechanism that is initiated when there is any decrease in renal blood flow. This stimulates the release of renin, which in turn activates angiotensin (vasoconstrictor) and stimulates aldosterone secretion (see Chapter 18). THINK ABOUT 12.4 a. Explain four factors that can increase blood pressure. b. List the compensatory mechanisms (in the correct sequence) that can help return the blood pressure to normal levels following a slight drop, such as can occur when standing up too rapidly. c. List three ways that systemic circulation could be impaired. d. Describe the effect of a hot compress on the tissues to which it is applied. e. How does vasoconstriction in the skin and viscera result in increased venous return to the heart? Heart Disorders Heart disease is ranked as a major cause of morbidity and mortality in North America. Common heart diseases include congenital heart defects, hypertensive heart disease, angina and heart attacks, cardiac arrhythmias, and congestive heart failure. There is increasing emphasis on routine preventive measures for all individuals, with a focus on factors such as a healthy diet, regular exercise, moderation in alcohol intake, cessation of smoking, safe sexual practices, immunizations, monitoring body weight and blood pressure, and basic screening tests for choles- terol levels and the presence of cancer. CHAPTER 12 Cardiovascular System Disorders 231 Other specific tests are mentioned under the appropriate topic and in Ready Reference 5 at the back of the book. More specialized tests may be necessary. General Treatment Measures for Cardiac Disorders Because some treatment measures apply to many disor- ders, a number of common therapies are covered here. Additional specific treatment modalities are mentioned with the disorder to which they apply. 1. Dietary modifications usually include reducing total fat intake and intake of saturated (hydrogenated or animal) fat as well as “trans” fats, which are com- mercially hydrogenated plant oils used to stabilize convenience foods. General weight reduction may be recommended for some persons. Salt (sodium) intake is decreased as well in order to reduce blood pressure. The American Heart Association has current dietary guidelines. 2. A regular exercise program is suggested to improve overall cardiovascular function and circulation to all areas of the body. Exercise assists in lowering serum lipid levels, increasing high-density lipoprotein (HDL) levels, and reducing stress levels, which in turn lessen peripheral resistance and blood pressure. 3. Cessation of cigarette smoking decreases the risk of coronary disease. Smoking appears to increase vaso- constriction and the heart rate, thus increasing the workload on the heart. Smoking increases platelet adhesion and the risk of thrombus (clot) formation, and it increases serum lipid levels as well. Also, carbon monoxide, a product of smoking, displaces oxygen from hemoglobin. In a compromised patient, this decrease in oxygen can be dangerous. 4. Drug therapy is an important component in the maintenance of cardiac patients. Many individuals take several drugs. Common medications include the following: • Vasodilators, such as nitroglycerin or long-acting isosorbide, reduce peripheral resistance systemically and therefore the workload for the heart and also act as coronary vasodilators. These actions provide a better balance of oxygen supply and demand in the heart muscle. Vasodilators may cause a decrease in blood pressure, resulting in dizziness or syncope and a flushed face. A person should sit quietly for a few minutes after taking nitroglycerin sublingually. • Beta blockers such as metoprolol or atenolol are used to treat hypertension and dysrhythmias, as well as to reduce the number of angina attacks. These drugs block the beta1-adrenergic receptors in the heart and prevent the SNS from increasing heart activity. • Calcium channel blockers, which block the move- ment of calcium ions into the cardiac and smooth muscle fiber, make up another group of effective the inside of the heart, measure pressures, and assess valve and heart function. Determination of central venous pressure and pulmonary capillary wedge pressure, which indicate blood flow to and from the heart, can be made with a catheter. After contrast dye is injected into the ventricle, fluoroscopy can monitor blood movement continuously and check for abnormalities. There is some risk with this procedure, but it has proved beneficial in many instances. • Blood flow in the coronary arteries can be visualized with coronary angiography (Fig. 12.8). Current research using very tiny ultrasound instruments within the vessels has proved more effective in diagnosing obstructions. Obstructions can be assessed and then treated with the basic catheterization procedure, with injected thrombolytic agents or laser therapy to break down clots, or balloon angioplasty to open a narrow coronary artery mechanically. • Troponin blood test is used to measure the levels of blood proteins called troponins. These proteins are released when cardiac muscle has been damaged. The more damage to the heart, the higher the levels of the troponins. Very high levels of the proteins are an indication that a heart attack has occurred. • Blood flow in the peripheral vessels can be assessed with Doppler studies, in which essentially a microphone that records the sounds of blood flow or obstruction is placed over the blood vessel. • Blood tests are used to assess serum triglyceride and cholesterol levels and the levels of sodium, potassium, calcium, and other electrolytes. Hemoglobin, hemat- ocrit, blood cell counts, and the differential count for white cells are also routine aspects of blood tests. • Arterial blood gas determination is essential to check the current oxygen level and acid-base balance in patients with shock or myocardial infarction. FIG. 12.8 Coronary angiography shows stenosis (arrow) of left anterior descending coronary artery. (From Braunwald E: Heart Disease: A Textbook of Cardiovascular Medicine, ed 4, Philadelphia, 1992, Saunders.) 232 SECTION III Pathophysiology of Body Systems retention). The result is a decrease in preload and afterload. Angiotensin II receptor blocking agents such as losartan (Cozaar) and irbesartan (Avapro) prevent angiotensin from acting on blood vessels, and thus lower blood pressure. They do not appear to have side effects. • Diuretics remove excess sodium and water from the body through the kidneys by blocking the reabsorption of sodium or water (see Chapter 18). Patients often refer to them as “water pills.” They are useful drugs in the treatment of high blood pressure and congestive heart failure because they increase urine output, reducing blood volume and edema. Examples are hydrochlorothiazide, a mild diuretic, and furosemide, a more potent drug. These diuretics may also remove excessive potassium from the body, requiring supplements to prevent hypokalemia. Spironolactone is an example of a “potassium-sparing” diuretic. • Anticoagulants or “blood thinners” may be used to reduce the risk of blood clot formation in coronary or systemic arteries or on damaged or prosthetic heart valves. In many cases, a small daily dose of aspirin (acetylsalicylic acid [ASA]) is recommended to decrease platelet adhesion. Oral anticoagulants such as warfarin (Coumadin) may be taken by individuals in high-risk groups. These drugs block the coagulation process (Fig. 10.9). It is essential to monitor clotting ability, measuring prothrombin time or activated partial thromboplastin time closely in these patients to prevent hemorrhage and to observe patients for increased bleeding tendencies (see blood clotting in Chapter 10). There is a new group of blood-thinning drugs, including Apixaban (Eliquis), Dabigatran (Pradaxa), Edoxaban (Savaysa), and Rivaroxaban (Xarelto), that offer an alternative to warfarin. In addition to monitoring the actual clotting abilities, warfarin users must carefully monitor their vitamin K levels, and individuals must be cautious about taking other medication (including nonprescription drugs), drinking alcohol, and making dietary changes, and they should avoid potentially traumatic activities. With this new group of drugs, there are fewer drug interactions that could cause problems, and the vitamin K levels do not influence their effectiveness. Blood-thinning drugs, however, are not a “one size fits all” situation and the prescribing of a specific drug will be based on numerous factors as evaluated by a physician. • Cholesterol or lipid-lowering drugs are prescribed when diet and exercise are ineffective in reducing blood levels. These drugs, referred to as the statins, include simvastatin (Zocor) and atorvastatin (Lipitor). They reduce low-density lipoprotein (LDL) and cholesterol content of the blood by blocking synthesis in the liver. Current investigations are assessing their ability to lower C-reactive protein levels, which cardiovascular drugs. Members of the group may be used as agents to decrease cardiac contractility, as an antidysrhythmic particularly for excessive atrial activity, or as an antihypertensive and vasodilator. They also serve a prophylactic purpose for angina. Some drugs such as diltiazem are more selective for the myocardium and reduce both conduction and contractility. Verapamil slows the heart rate by depressing the action of the SA and AV nodes, preventing tachycardia and fibrillation. Others, like nifedipine, are more effective as peripheral vasodilators. Amlodipine (Norvasc) has been useful in lowering blood pressure. Note that these drugs do not affect skeletal muscle contraction because more calcium is stored in skeletal muscle cells. • Digoxin, a cardiac glycoside, has been used for many years as a treatment for heart failure and as an antiarrhythmic drug for atrial dysrhythmias. It slows conduction of impulses and heart rate. Digoxin improves the efficiency of the heart because it also is inotropic, increasing the contractility of the heart. The contractions are less frequent but stronger. Because the effective dose is close to the toxic dose, patients must be observed for signs of toxicity, and blood levels of the drug must be checked periodically. • Antihypertensive drugs may be used to lower blood pressure to more normal levels. There are a number of groups in this category, including the adrenergic or sympathetic-blocking agents, the calcium block- ers, the diuretics, the angiotensin-converting enzyme (ACE) inhibitors, and the angiotensin II receptor blocking agents. Combinations of drugs from various classifications are frequently prescribed to effectively lower blood pressure. Some of these drugs do cause orthostatic hypotension, a drop in blood pressure accompanied by dizziness, when arising from a recumbent position. These drugs may be used for treatment of essential hypertension or congestive heart failure or after myocardial infarction. Calcium blockers and beta-adrenergic blockers were dis- cussed previously. • Adrenergic-blocking drugs may act on the SNS cen- trally (brain), may block peripheral (arteriolar) alpha1-adrenergic receptors, or may act as direct vasodilators. • Angiotensin-converting enzyme inhibitors (ACE inhibi- tors) are currently preferred in the treatment of many patients with hypertension and congestive heart failure (CHF). They act by blocking the conver- sion of angiotensin I to angiotensin II, stimulated by the release of renin from the kidney (angiotensin II is a powerful vasoconstrictor). These drugs, such as enalapril (Vasotec), ramipril (Altace), captopril (Capoten), and perindopril (Coversyl), reduce both peripheral resistance (vasoconstriction) and aldos- terone secretion (thus decreasing sodium and water CHAPTER 12 Cardiovascular System Disorders 233 repeated heart attacks is 735,000 Americans. It is estimated that 27.6 million live with coronary artery disease in the United States. An additional 6 million are currently diagnosed with congestive heart failure (there is some overlap within these figures). The Centers for Disease Control and Prevention (CDC) reported that in 2013, high blood pressure was listed as a factor in 360,000 deaths and affects 68 million Americans. Males tend to develop heart disease at an earlier age than women, but women tend to have more complications, likely due to later diagnosis. The current statistics show a decrease in numbers of individuals being diagnosed with heart disease, which many attribute to prevention awareness programs. Arteriosclerosis and Atherosclerosis ■ Pathophysiology Arteriosclerosis can be used as a general term for all types of arterial changes. It is best applied to degenerative changes in the small arteries and arterioles, commonly occurring in individuals over age 50 and those with diabetes. Elasticity is lost, the walls become thick and hard, and the lumen gradually narrows and may become have a role in the inflammation associated with atheroma formation. Table 12.1 provides a summary of common cardiovascular drugs. A drug index may be found in Ready Reference 8 at the back of the book. Coronary Artery Disease, Ischemic Heart Disease, or Acute Coronary Syndrome Sometimes called coronary heart disease, coronary artery disease includes angina pectoris or temporary cardiac ischemia and myocardial infarction or heart attack. Myocardial infarction results in damage to part of the heart muscle because of obstruction in a coronary artery. The basic problem is insufficient oxygen for the needs of the heart muscle. A common cause of disability and death, coronary artery disease may ultimately lead to heart failure, serious dysrhythmias, or sudden death. It is the leading cause of death in men and women in the United States, causing approximately 365,000 deaths each year. Statistics for 2015 reveal that one in four deaths are the result of some form of heart disease, and the incidence for new or TABLE 12.1 Selected Cardiovascular Drugs Name Use Action Adverse Effects Nitroglycerin Angina attacks and prophylaxis Reduces cardiac workload, peripheral and coronary vasodilator Dizziness, headache Metoprolol (Lopressor) Hypertension, angina, antiarrhythmic Blocks beta-adrenergic receptors, slows heart rate Dizziness, fatigue Nifedipine (Adalat) Angina, hypertension, peripheral vasodilator, antiarrhythmic Calcium blockers, vasodilator Dizziness, fainting, headache Digoxin (Lanoxin) Congestive heart failure and atrial arrhythmias Slows conduction through AV node and increases force of contraction (cardiotonic) to increase efficiency Nausea, fatigue, headache, weakness Enalapril (Vasotec) Hypertension ACE inhibitor—blocks formation of angiotensin II and aldosterone Headache, dizziness, hypotension Furosemide (Lasix) hypertension Edema with CHF, hypertension Diuretic—increases excretion of water and sodium Nausea, diarrhea, dizziness Simvastatin (Zocor) Hypercholesteremia (CHD) Decreases cholesterol and LDL Digestive discomfort Warfarin (Coumadin) Prophylaxis and treatment of thromboemboli Anticoagulant—interferes with vitamin K in synthesis of clotting Excessive bleeding (antidote: vitamin K), interaction with other medications ASA (aspirin) Prophylaxis of thromboemboli Prevents platelet adhesion, antiinflammatory Gastric irritation, allergy Apixaban (Eliquis), Dabigatran (Pradaxa), Edoxaban (Savaysa) and Rivaroxaban (Xarelto) Blood-thinning drugs Anticoagulant Excessive bleeding, easy bruising, potential negative drug interactions CHD, coronary heart disease; CHF, congestive heart failure; LDL, low-density lipoprotein. 234 SECTION III Pathophysiology of Body Systems FIG. 12.9 Comparison of a normal aorta with its smooth lining and patent openings into branching arteries (top) with an athero- sclerotic aorta (bottom). Note the rough surface and blocked openings to branches. (Courtesy of Paul Emmerson and Seneca College of Applied Arts and Technology, Toronto, Canada.) Comparison of HDL and LDL LDL — “Bad” lipid Transport of lipids 1. Dietary intake of cholesterol and triglycerides Bile Intestine Liver HDL LDL Blood vessels 5. Liver synthesizes lipoproteins HDL —“Good” lipid Cholesterol A B Cholesterol Protein Protein Phospholipid Phospholipid Triglyceride Triglyceride 4. Remnants to liver 7. LDL attaches to LDL receptor in smooth muscle and endothelial tissue 6. LDL transports cholesterol to cells 2. Chylomicrons absorbed into blood and lymph 3. Lipid uptake by adipose and skeletal muscle cells 8. HDL transports cholesterol from cells to liver FIG. 12.10 Composition of lipoproteins and transport of lipoproteins in blood. obstructed. This leads to diffuse ischemia and necrosis in various tissues, such as the kidneys, brain, or heart. Atherosclerosis is differentiated by the presence of atheromas, plaques consisting of lipids, cells, fibrin, and cell debris, often with attached thrombi, which form inside the walls of large arteries. Note in Fig. 12.9 how the unaffected artery is smooth, and the openings to branch arteries are clearly defined. By comparison, the athero- sclerotic artery has a very rough, elevated surface, with loose pieces of plaque and thrombus, and the openings to branching arteries are blocked. Atheromas form primar- ily in the large arteries, such as the aorta and iliac arteries, the coronary arteries, and the carotid arteries, particularly at points of bifurcation, where turbulent blood flow may encourage the development of atheromas. Lipids or fats, which are usually transported in various combinations with proteins (lipoproteins), play a key role in this process (Fig. 12.10). Lipids, including cholesterol CHAPTER 12 Cardiovascular System Disorders 235 an irregular surface on which a thrombus easily forms. As the atheroma increases in size and the coronary arteries are partially obstructed, angina (temporary myocardial ischemia) may occur; a total obstruction leads to myo- cardial infarction. Atheromas are also a common cause of strokes, renal damage, and peripheral vascular disease, which affects the legs and feet (Fig. 12.12). ■ Etiology The cause of atherosclerosis appears to be multifactorial, and some of the factors are synergistic, enhancing the total effect. There are two groups of risk factors for atherosclerosis, one group that can be modified to some extent and one that cannot. The factors that cannot be changed (nonmodifiable) include the following: • Age, with atherosclerosis more common after age 40 years, particularly in men. • Gender—that is, women are protected by higher HDL levels until after menopause, when estrogen levels decrease. • Genetic or familial factors seem to have a strong influence on serum lipid levels, metabolism, and cell receptors for lipids; some conditions are inherited, such as familial hypercholesterolemia, but family lifestyle factors may also have a role. The other group of predisposing factors are modifiable. These include factors such as the following: • Obesity or diets high in cholesterol and animal fat, which elevate serum lipid levels, especially LDL. The significant increase in obesity in children is of great concern with regard to a relative increase in cardio- vascular disease in the coming years. The Centers for Disease Control and Prevention estimate that more than 12.5 million children and adolescents under age 19 in the United States are obese and at risk of metabolic syndrome. Data collected in the United States for 2011 also indicated that 35.7% of adult men and women were clinically obese. Obesity is the primary indicator of metabolic syndrome, which is directly linked with the development of coronary artery disease in adult- hood (see Chapter 23). • Cigarette smoking. The risk associated with smoking is directly related to the number of packs of cigarettes smoked per day. Smoking decreases HDL, increases LDL, promotes platelet adhesion, and increases fibrino- gen and clot formation as well as vasoconstriction. • Sedentary lifestyle, which predisposes to sluggish blood flow and obesity. Exercise also reduces blood pressure and stress level and increases HDL while lowering LDL and cholesterol. Increasing numbers of children and adults report declining levels of physical activity. • The presence of diabetes mellitus. In individuals with diabetes, especially those whose disease is not well controlled, serum lipid levels are increased and there is a tendency toward endothelial degeneration. The and triglycerides, are essential elements in the body and are synthesized in the liver; therefore they can never be totally eliminated from the body. Analysis of serum lipids includes assessment of all the subgroups (total cholesterol, triglycerides, low-density lipoproteins, and high-density lipoproteins) because the proportions indicate the risk factor for the individual. The serum lipids of particular importance follow: • Low-density lipoprotein, which has a high lipid content and transports cholesterol from the liver to cells, is the dangerous component of elevated serum levels of lipids and cholesterol. It is a major factor contributing to atheroma formation. Also, LDL binds to receptors— for example, on the membranes of vascular smooth muscle cells and enters them; it is considered the “bad” lipoprotein that promotes atheroma formation. • High-density lipoprotein is the “good” lipoprotein; it has a low lipid content and is used to transport cho- lesterol away from the peripheral cells to the liver, where it undergoes catabolism and excretion. The process occurs as follows: 1. Endothelial injury in the artery, often at a very young age. 2. Endothelial injury causes inflammation in the area, leading to elevated C-reactive protein (CRP) levels. 3. White blood cells, particularly monocytes and mac- rophages, and lipids accumulate in the intima, or inner lining, of the artery and in the media, or muscle layer. 4. Smooth muscle cells proliferate or multiply (Fig. 12.11). 5. Thus a plaque forms and inflammation persists. 6. Platelets adhere to the rough, damaged surface of the arterial wall, forming a thrombus and partial obstruc- tion of the artery. 7. Lipids continue to build up at the site of arterial injury, along with fibrous tissue. Platelets adhere and release prostaglandins, which precipitate inflammation and vasospasm. 8. This draws more platelets to aggregate at the site, enlarging the thrombus. Arterial flow becomes more turbulent, again promoting thrombus formation. A vicious cycle persists. Blood flow progressively decreases as the lumen narrows. At some point, the plaque may ulcerate and break open. This may pre- cipitate more inflammation or a thrombus may form at this site, resulting in total obstruction in a very short time. This may be the precipitating factor for myocardial infarction. The atheroma also damages the arterial wall, weaken- ing the structure and decreasing its elasticity. In time, atheromas may calcify, causing further rigidity of the wall. This process may lead to aneurysm, a bulge in the arterial wall (see Fig. 12.34, presented later in the chapter), or to rupture and hemorrhage of the vessel. Initially the atheroma manifests as a yellowish fatty streak on the wall. It becomes progressively larger, eventually becoming a large, firm, projecting mass with 236 SECTION III Pathophysiology of Body Systems A B C D Fatty streak Response to injury Damaged endothelium: Chronic endothelial injury Fibrous plaque Complicated lesion Hypertension Smoking Hyperlipidemia Hyperhomocysteinemia Hemodynamic factors Toxins Viruses Immune reactions _ _ _ _ _ _ _ _ Endothelium Tunica intima Tunica media Adventitia Lipids Foamy macrophage ingesting lipids Fibroblast Lipid pool Lipid accumulation Fibroblast Collagen cap (fibrous tissue) Fissure in plaque Thrombus Thinning collagen cap Lipid pool Platelets attach to endothelium Migration of smooth muscle into the intima Damaged endothelium Platelets Macrophage Monocyte FIG. 12.11 Progression of atherosclerosis. A, Damaged endothelium. B, Diagram of fatty streak and lipid core formation. C, Diagram of fibrous plaque. D, Diagram of completed lesion; thrombus is red; collagen is blue. Plaque is complicated by red thrombus deposition. (From McCance KL, et al: Pathophysiology, ed 6, St. Louis, 2010, Mosby.) CHAPTER 12 Cardiovascular System Disorders 237 substantial increase in incidence and earlier onset of type 2 diabetes has increased the incidence of cardio- vascular disease. • Poorly controlled hypertension, which causes endo- thelial damage. • Combination of some oral contraceptives and smoking. • The combination of high blood cholesterol and high blood pressure in an individual has been shown to increase the risk of atherosclerosis and coronary artery disease significantly. ■ Diagnostic Tests • Serum lipid levels, including those of LDL and HDL, should be checked to identify the patient’s risk and monitor the efficacy of treatment. Serum levels of high-sensitivity CRP indicate the presence of inflam- mation, indicating increased risk. However, CRP may be elevated due to other chronic inflammatory disease. Low CRP levels appear to indicate a low risk of developing cardiovascular disease. • Exercise stress testing can be used for screening or to assess the degree of obstruction in arteries. • Nuclear medicine studies can be used to determine the degree of tissue perfusion, the presence of collateral circulation, and the degree of local cell metabolism. To minimize risk and promote early diagnosis and treatment, the acceptable range for test results may be modified or lowered as new evidence becomes available. ATHEROSCLEROSISATHEROSCLEROSIS HEART Coronary arteries partial occlusion ANGINA PECTORIS (Ischemic heart disease) Total occlusion MYOCARDIAL INFARCTION–MI BRAIN Carotid or cerebral arteries partial occlusion TRANSIENT ISCHEMIC ATTACK Total occlusion CEREBROVASCULAR ACCIDENT (CVA) PERIPHERAL ARTERIES AORTA ANEURYSM – Occlusion – Rupture and hemorrhage LEGS Iliac arteries PERIPHERAL VASCULAR DISEASE – Gangrene and amputation Narrowing of large arteries by cholesterol plaque and thrombus Clear artery Partial obstruction Total obstruction FIG. 12.12 Possible consequences of atherosclerosis. APPLY YOUR KNOWLEDGE 12.2 Research is continuing to investigate the role of microbial infections in the damage of blood vessels. What are some portals of entry or potential sources from which bacteria may gain entry into the circulatory system and reach vessels such as the coronary arteries? What measures could be taken to prevent these types of infections and subsequent vessel damage? ■ Treatment Losing weight and maintaining weight at healthy levels reduce the onset of metabolic syndrome as well as hypertension and atherosclerosis. Waist measurements below 35 in/87.5 cm in females and below 40 in/100 cm in males are considered healthy benchmarks. • Lowering serum cholesterol and LDL levels by sub- stituting nonhydrogenated vegetable oils for trans fats and saturated fats has been well promoted as an effective means of slowing the progress of ath- erosclerosis. Vegetable oils containing linolenic acid and fish oils and other foods containing omega 3 fatty acids are considered particularly useful. High dietary fiber intake also appears to decrease LDL levels. General weight reduction decreases the workload on the heart. Lipid-reducing (cholesterol or LDL) drugs such as probucol, clofibrate, and lovastatin may help in resistant cases. These measures may slow the progress 238 SECTION III Pathophysiology of Body Systems Angina Pectoris ■ Pathophysiology Angina, or chest pain, occurs when there is a deficit of oxygen to the heart muscle. This can occur when the blood or oxygen supply to the myocardium is impaired, when the heart is working harder than usual and needs more oxygen, or when a combination of these factors is present (Fig. 12.14). Usually the heart can adapt its blood supply to its own needs by vasodilation (autoregulation) unless the vessel walls are damaged or cannot relax. The reduced blood supply may be due to partial obstruction by atherosclerosis or spasm in the coronary arteries. When the supply and demand for oxygen are marginally bal- anced, an increase in cardiac demand with any physical or emotional exertion can cause a relative deficit of oxygen to the myocardium. Chest pain may occur in a variety of patterns: classic or exertional angina; variant angina, in which vasospasm occurs at rest; and unstable angina, a more serious form. Unstable angina refers to prolonged pain at rest and of recent onset, perhaps the result of a break in an atheroma. This may precede a myocardial infarction. Most com- monly, an episode of anginal pain occurs when the demand for oxygen increases suddenly, with exertion. In most cases, no permanent damage to the myocardium results from angina unless the episodes are frequent, prolonged, and severe. ■ Etiology Insufficient myocardial blood supply is associated with atherosclerosis, arteriosclerosis, vasospasm (a localized contraction of arteriolar smooth muscle), and myocardial hypertrophy, in which the heart has outgrown its blood supply. Severe anemias and respiratory disease can also cause an oxygen deficit. Increased demands for oxygen can arise in circumstances such as tachycardia associated with hyperthyroidism or the increased force of contrac- tions associated with hypertension. Precipitating factors of angina attacks are related to activities that increase the demands on the heart, such as running upstairs, getting angry, respiratory infection with fever, exposure to weather extremes or pollution, or eating a large meal. of previously formed lesions and also prevent new ones. • Sodium intake should be minimized as well to control hypertension. • Control of primary disorders such as diabetes or hypertension is important. • Cease smoking. • Exercise appropriate for age and health status promotes collateral circulation and reduces LDL levels. • If thrombus formation is a concern, oral anticoagulant therapy may be required; this may include a small daily dose of ASA or warfarin (Coumadin) or other prescription blood-thinning drug. • When atheromas are advanced, surgical intervention (percutaneous transluminal coronary angioplasty) may be required to reduce obstruction by means of invasive procedures requiring cardiac catheteriza- tion. The catheter contains an inflatable balloon that flattens the atheroma. Newer techniques use laser angioplasty, a laser beam, and fiberoptic technology with a catheter. The high-energy laser causes the obstruction to disintegrate into microscopic particles that are removed by macrophages. There appears to be less risk of recurrence with this method. Stents, small tube-like structures, may be inserted into arteries after angioplasty, to maintain an opening. Surgery such as coronary artery bypass grafting (CABG) to reroute blood flow around the obstruction, using veins or the left internal mammary artery for a graft, appears to have an improved long-term prognosis (Fig. 12.13). A graft can also be placed around an obstructed aorta. Less invasive means of CABG are currently being used in some patients. Saphenous vein A B Saphenous vein Vein with directional valve rotated upside down Blocked right coronary artery Blocked left coronary artery Mammary artery FIG. 12.13 Coronary artery bypass graft (CABG) surgery. (From Shiland BJ: Medical Terminology and Anatomy for ICD-10 Coding, St. Louis, 2012, Mosby.) THINK ABOUT 12.5 a. Explain three ways of reducing the risk of atherosclerosis. b. Give three common locations of atheromas. c. Describe two ways in which an artery can become totally obstructed. CHAPTER 12 Cardiovascular System Disorders 239 ■ Treatment Anginal pain is usually quickly relieved by rest and the administration of coronary vasodilators, such as nitro- glycerin. The drug may relieve vasospasm in the coronary arteries but primarily acts to reduce systemic resistance, thus decreasing the demand for oxygen. Many patients carry nitroglycerin (in the correct dosage) with them at all times to be administered sublingually in an emergency (the tablet is not swallowed but dissolves under the tongue and enters the blood directly for instant effect). If chest pain persists following treatment, it is important to seek hospital care because the pain may indicate the presence of a myocardial infarction. It is important to determine the history of angina and the factors predisposing to attacks to minimize their frequency and severity. The avoidance of sudden physical exertion—especially in cold or hot weather, when there is marked fatigue, or during strong emotional incidents—is recommended. Antianxiety and stress reduction tech- niques may be necessary in certain situations. Some clients use nitroglycerin in the form of a topical ointment, a skin patch, a nasal spray, or oral tablets (isosorbide) on a regular basis to reduce the number of attacks. ■ Signs and Symptoms Angina occurs as recurrent, intermittent brief episodes of substernal chest pain, usually triggered by a physical or emotional stress that increases the demand by the heart for oxygen. Pain is described as a tightness or pressure in the chest and may radiate to the neck and left arm. Other manifestations may include the following: • Pallor • Diaphoresis (excessive sweating) • Nausea Attacks vary in severity and last a few seconds or minutes. O2 O2 O2 O2 Normal oxygen supply Decreased oxygen supply Normal/increased oxygen supply Increased activity Does not meet Decreased oxygen supply Decreased activity MYOCARDIAL ISCHEMIA Pain O2 Decreased oxygen supply Basic needs Does not meet MYOCARDIAL ISCHEMIA Pain Normal activity Normal activityA C B D E FIG. 12.14 Angina—an imbalance between oxygen supply and demand. EMERGENCY TREATMENT FOR ANGINA ATTACK 1. Let patient rest, stop activity. 2. Seat patient in an upright position. 3. Administer nitroglycerin sublingually (preferably patient’s own supply). 4. Check pulse and respiration. 5. Administer oxygen if necessary. 6. For a patient known to have angina, the American Heart Association recommends that a second dose of nitroglycerin be given if pain persists more than 5 minutes. After three doses within a 10-minute period and no pain relief, the pain should be treated as a heart attack. Call for assistance and emergency medical intervention. 7. For a patient without a history of angina, emergency medical aid should be sought after 2 minutes without pain relief. THINK ABOUT 12.6 Describe the characteristics of anginal pain. 240 SECTION III Pathophysiology of Body Systems At the point of obstruction the heart tissue becomes necrotic, and an area of injury, inflammation, and ischemia develops around the necrotic zone (see Fig. 12.15A). With cell destruction, specific enzymes are released from the myocardium into tissue fluid and blood; these enzymes appear in the blood and are diagnostic. The functions of myocardial contractility and conduction are lost quickly as oxygen supplies are depleted. If the blood supply can be restored in the first 20 to 30 minutes, irreversible damage may be prevented. After 48 hours, the inflammation begins to subside. If sufficient blood supply has been maintained in the outer area of inflammation, function can resume. On the other hand, if treatment has not been instituted quickly or is not effective, the area of infarction may increase. Because the myocardial fibers do not regener- ate, the area of necrosis is gradually replaced by fibrous (nonfunctional) tissue, beginning around the seventh day. It may take 6 to 8 weeks to form a scar, depending on the size of the infarcted area. The presence of collateral circulation may reduce the size of the infarct (see Review of the Cardiovascular System, presented earlier in this chapter). The effective- ness of collateral circulation depends on the location of the obstruction, the presence or absence of anastomoses, and whether collateral circulation was established before infarction in response to the gradual development of a partial occlusion. Also, if the atheroma has developed Myocardial Infarction A myocardial infarction (MI), also known as a heart attack, involves the death of myocardial tissue due to ischemia (deficiency of blood). For those who survive a myocardial infarction, there is notably greater risk of a second MI, congestive heart failure, or stroke occurring within a short time. ■ Pathophysiology An MI, or heart attack, occurs when a coronary artery is totally obstructed, leading to prolonged ischemia and cell death, or infarction, of the heart wall (Fig. 12.15). The most common cause is atherosclerosis, usually with thrombus attached (see previous discussion under Coro- nary Artery Disease). Infarction may develop in three ways: 1. The thrombus may build up to obstruct the artery. 2. Vasospasm may occur in the presence of a partial occlusion by an atheroma leading to total obstruction. 3. Part of the thrombus may break away, forming an embolus or emboli that flows through the coronary artery until lodging in a smaller branch, blocking that vessel (see Fig. 12.11). Most infarctions are transmural— that is, all three layers of the heart are involved. A majority involve the critical left ventricle. The size and location of the infarct determine the severity of the damage. Right coronary artery Right atrium Superior vena cava Posterior interventricular artery Right marginal artery Right ventricle Left ventricle Left atrium Aorta Pulmonary artery Circumflex artery AREA OF INFLAMMATION Left coronary artery Left anterior interventricular artery AREA OF NECROSIS OR INFARCTION THROMBUS CAUSES TOTAL OBSTRUCTION OF ARTERY A B C FIG. 12.15 A, Damage caused by myocardial infarction. B, C, Acute myocardial infarction. Microscopic section of an acute myocardial infarct at 48 hours showing coagulation necrosis and maximal neutrophilic infiltrate at low power (B) and high power (C). (A From Kumar V, Abbas AK, Fausto M: Robbins and Cotran Pathologic Basis of Disease, ed 7, Philadelphia, 2005, Saunders. B, C From King T: Elsevier’s Integrated Pathology, ed 1, St. Louis, 2007, Mosby.) CHAPTER 12 Cardiovascular System Disorders 241 12.16). The particular isoenzymes, LDH-1 and CK-MB, are more specific for heart tissue. 3. Serum levels of myosin and cardiac troponin are elevated a few hours after MI, providing for an earlier confirmation. A rise in cardiac troponin levels is considered most specific for myocardial tissue damage. 4. Serum electrolyte levels, particularly potassium and sodium, may be abnormal. 5. Leukocytosis and an elevated CRP and erythrocyte sedimentation rate are common, signifying inflamma- tion. There is evidence that high blood levels of CRP indicate a more marked inflammatory response, with plaques more inclined to rupture, thrombus to form, and ultimately a more severe heart attack. 6. Arterial blood gas measurements will be altered particularly if shock is pronounced. 7. Pulmonary artery pressure measurements are also helpful in determining ventricular function. ■ Complications The following are common occurrences immediately following the infarction and also at a later time: • Sudden death shortly after myocardial infarction occurs frequently (in about 25% of patients), usually owing to ventricular arrhythmias and fibrillation (see the next section, Cardiac Dysrhythmias [Arrhythmias]). This is the major cause of death in the first hour after an MI. One type of dysrhythmia, heart block, may occur when the conduction fibers in the infarcted area can no longer function. Second, an area of necrosis and inflammation outside the conduction pathway may stimulate additional spontaneous impulses at an ectopic site, causing, for example, premature ventricular contractions (PVCs) that lead to ventricular tachycardia or ventricular fibrillation. In some cases, dysrhythmias WARNING SIGNS OF HEART ATTACK (These signs may be intermittent initially.) 1. Feeling of pressure, heaviness, or burning in the chest, especially with increased activity 2. Sudden shortness of breath, sweating, weakness, fatigue 3. Nausea, indigestion 4. Anxiety and fear ■ Signs and Symptoms It is important to seek a diagnosis and medical care as soon as these signs occur to prevent permanent heart damage or death. If thrombolytic therapy is administered within 20 minutes of the onset, blood flow can be restored, and no permanent damage occurs in the heart. Many paramedic teams can now administer fibrinolytic drugs, saving many lives. Automated external defibrillators (AEDs) may be found in many public buildings to be used in event of cardiac arrest. As a myocardial infarction develops, the following manifestations become more evident: • Pain: Sudden substernal chest pain that radiates to the left arm, shoulder, jaw, or neck is the hallmark of myocardial infarction. The pain is usually described as severe, steady, and crushing, and no relief occurs with rest or vasodilators. In some cases, pain is not present (silent myocardial infarction) or is interpreted as gastric discomfort. Women often report a milder pain, more like indigestion. • Pallor • Diaphoresis • Nausea • Dizziness and weakness • Dyspnea • Marked anxiety and fear • Hypotension: Hypotension is common, and the pulse is rapid and weak as cardiac output decreases and shock develops. • Low-grade fever ■ Diagnostic Tests 1. Typical changes occur in the ECG during the course of a myocardial infarction, which confirm the diagnosis and assist in monitoring progress. 2. Serum enzymes and isoenzymes released from necrotic cells also follow a typical pattern, with elevations of lactic dehydrogenase (LDH-1), aspartate aminotrans- ferase (AST, formerly SGOT), and creatine phospho- kinase with M and B subunits (CK-MB or CPK-2) (Fig. INFARCTION 24 hours 48 hours 72 hours S er um le ve l Hours after INFARCTION AST CPK-MB LDH-1 FIG. 12.16 Serum enzymes and isoenzyme levels with myocardial infarction. AST, aspartate aminotransferase; CPK-MB, creatine phosphokinase containing M and B subunits; LDH-1, lactate dehydrogenase. gradually, there may have been several warning episodes of chest pain with exertion. If the infarction results from an embolus, there is no opportunity for collateral channels to develop, and therefore the infarcted area will usually be larger. Cardiac demand during the attack will also determine the effectiveness of collateral circulation. 242 SECTION III Pathophysiology of Body Systems and stress reduction are useful following recovery. A schedule for the resumption of normal activities, such as climbing stairs, returning to work, and resuming sexual activities, can be established. Appropriate medications to treat any predisposing condition, as well as those to minimize the effects of the MI, are prescribed. Frequently a low dose of ASA is recommended to reduce the risk of further thrombi. The American Heart Association has organized a hospital-based program “Get With the Guidelines” to provide optimum treatment to all patients and promote patient compliance after discharge, thus improving outcomes. The prognosis depends on the site and size of the infarct, the presence of collateral circulation, and the time elapsed before treatment. The mortality in the first year is 30% to 40% and results from complications or recurrences. occur later as inflammation spreads to the conduction pathways, leading to heart block. Conduction irregu- larities may also be precipitated by hypoxia, by increased potassium released from necrotic cells, acidosis, and drug toxicities. • Cocaine users may suffer fatal heart attacks, even at a young age, because cocaine interferes with cardiac conduction as well as causing vasospasm and occlusion. • Cardiogenic shock may develop if the pumping capabil- ity of the left ventricle is markedly impaired. This greatly reduces cardiac output, leading to significant hypoxia (see the topic of shock presented later in this chapter). • Congestive heart failure is a common occurrence when the contractility of the ventricle is reduced and stroke volume declines. This may occur a few days after the MI or much later as activity is resumed. (CHF is covered later in this chapter.) Less frequent complications include the following: • Rupture of the necrotic heart tissue, particularly in patients with a ventricular aneurysm or those with significant hypertension. This usually develops 3 to 7 days after the MI when the necrotic tissue is breaking down. • Thromboembolism may result from a thrombus that develops over the infarcted surface inside the heart (mural thrombus) and eventually breaks off. If originat- ing in the left side of the heart, the embolus will travel to the brain or elsewhere in the body, whereas if the source is the right ventricle, the result will be a pul- monary embolus. (A thrombus may form in the deep leg veins due to immobility and poor circulation and also cause a pulmonary embolus [see Chapter 13].) ■ Treatment As mentioned, paramedics in many areas are equipped to provide immediate lifesaving treatment: • Keeping the patient calm, oxygen therapy, and anal- gesics such as morphine for pain relief are the usual treatment modalities. • Anticoagulants such as heparin or warfarin may be used, or the newer thrombolytic agents, including streptokinase, urokinase, or tissue plasminogen activa- tor, may be administered immediately to reduce the clot in the first hours. • Depending on the individual circumstances, medication to reduce dysrhythmias, defibrillation, or a pacemaker (which may be temporary) may be required. Drugs, such as digoxin, support the heart function. • Specific measures may be required if shock or conges- tive heart failure develops. • Bypass surgery may be performed. • Other specific drugs are mentioned in the general treatment section. Cardiac rehabilitation programs that offer individual- ized plans for regular exercise, dietary modifications, THINK ABOUT 12.7 a. Compare the causes of the chest pain that occurs with angina to that which occurs with myocardial infarction. b. Explain why an embolus may cause a larger infarction than an atheroma with thrombus. c. List the tests that confirm a diagnosis of myocardial infarction. d. Explain why part of the myocardium is nonfunctional following myocardial infarction. e. Suggest several treatment measures that may minimize the area of infarction. Why is time a critical element in treatment of MI? Cardiac Dysrhythmias (Arrhythmias) Deviations from normal cardiac rate or rhythm may result from damage to the heart’s conduction system or systemic causes such as electrolyte abnormalities (see Chapter 2 for the effects of potassium imbalance), fever, hypoxia, stress, infection, or drug toxicity. Interference with the conduction system may result from inflammation or scar tissue associated with rheumatic fever or myocardial infarction. The ECG provides a method of monitoring the conduction system and detecting abnormalities (see Fig. 12.16). Holter monitors record the ECG over a prolonged period as a patient follows normal daily activities. Dysrhythmias reduce the efficiency of the heart’s pumping cycle. A slight increase in heart rate increases cardiac output, but a rapid heart rate prevents adequate filling during diastole, reducing cardiac output, and a very slow rate also reduces output to the tissues, including the brain and the heart itself. Irregular contractions are inefficient because they interfere with the normal filling and emptying cycle. Among the many types of abnormal conduction patterns that exist, only a few examples are considered here. CHAPTER 12 Cardiovascular System Disorders 243 response to sympathetic stimulation, exercise, fever, or stress, or it may be compensation for decreased blood volume. • Sick sinus syndrome is a heart condition marked by alternating bradycardia and tachycardia and often requires a mechanical pacemaker. Atrial Conduction Abnormalities Atrial conduction abnormalities are the most common dysrhythmias, (ie, clinical abnormalities of heart conduc- tion). Hospital admissions for paroxysmal atrial fibrillation Sinus Node Abnormalities The SA node is the pacemaker for the heart, and its rate can be altered. • Bradycardia refers to a regular but slow heart rate, less than 60 beats per minute (Fig. 12.17C); it often results from vagal nerve or parasympathetic nervous system stimulation. An exception occurs in athletes at rest, who may have a slow heart rate because they are conditioned to produce a large stroke volume. • Tachycardia is a regular rapid heart rate, 100 to 160 beats per minute (Fig. 12.17D). This may be a normal AV node block PAC NSR PAT Normal Bradycardia Tachycardia Premature atrial contraction (PAC) Atrial fibrillation Ventricular fibrillation V A B C D E F G FIG. 12.17 ECG strip chart recordings. A, Normal ECG. B, AV node block. Very slow ventricular contraction (25 to 45 beats/min at rest); P waves widely separated from peaks of QRS complexes. C, Bradycardia. Slow heart rhythm (less than 60 beats/min); no disruption of normal rhythm pattern. D, Tachycardia. Rapid heart rhythm (greater than 100 beats/min); no disruption of normal rhythm pattern. NSR, normal sinus rhythm; PAT, paroxysmal (sudden) atrial tachycardia. E, Premature atrial contraction (PAC). Unexpected, early P wave that differs from normal P waves; PR interval may be shorter or longer than normal; normal QRS complex; more than 6 PACs per minute may precede atrial fibrillation. F, Atrial fibrillation. Irregular, rapid atrial depolarizations; P wave rapid (greater than 300/min) with irregular QRS complexes (150 to 170 beats/min). G, Ventricular fibrillation. Complete disruption of normal heart rhythm. (From Patton KT, Thibodeau GA: Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby.) 244 SECTION III Pathophysiology of Body Systems 2. Second-degree, in which a longer delay leads periodi- cally to a missed ventricular contraction 3. Total, or third-degree, blocks occur when there is no transmission of impulses from the atria to the ventricles. The ventricles contract spontane- ously at a slow rate of 30 to 45 beats per minute, totally independent of the atrial contraction, which continues normally. In this case, cardiac output is greatly reduced, sometimes to the point of fainting (syncope), causing a Stokes-Adams attack or cardiac arrest. Ventricular Conduction Abnormalities 1. Bundle branch block refers to interference with conduc- tion in one of the bundle branches. This usually does not alter cardiac output but does appear on the ECG as a wide QRS wave. 2. Ventricular tachycardia is likely to reduce cardiac output because the filling time is reduced and the force of contraction is reduced. 3. In ventricular fibrillation the muscle fibers contract independently and rapidly (uncoordinated quiver- ing) and therefore are ineffective in ejecting blood (see Fig. 12.17G). The lack of cardiac output causes severe hypoxia in the myocardium, and contraction ceases. 4. Premature ventricular contractions (PVCs) are additional beats arising from a ventricular muscle cell or ectopic pacemaker. Occasional PVCs do not interfere with heart function, but increasing frequency, multiple ectopic sites, or paired beats are of concern because ventricular fibrillation can develop from these, leading to cardiac arrest. A summary of these abnormalities may be found in Table 12.2. have increased by 66% primarily due to aging of the population and an increase in the prevalence of coronary heart disease. Premature atrial contractions or beats (PAC/PAB) are extra contractions or ectopic beats of the atria that usually arise from a focus of irritable atrial muscle cells outside the conduction pathway. They tend to interfere with the timing of the next beat (Fig. 12.17E). Ectopic beats may also develop from reentry of an impulse that has been delayed in damaged tissue and then completes a circuit to reexcite the same area before the next regular stimulus arrives. Sometimes people feel palpitations, which are rapid or irregular heart contractions that often arise from excessive caffeine intake, smoking, or stress. Atrial flutter refers to an atrial heart rate of 160 to 350 beats per minute, and atrial fibrillation is a rate of more than 350 beats per minute (Fig. 12.17F). With flutter, the AV node delays conduction, and therefore the ventricular rate is slower. A pulse deficit may occur because a reduced stroke volume is not felt at the radial pulse. Atrial fibril- lation causes pooling of blood in the atria and is treated with anticoagulant medications to prevent clotting and potential cerebrovascular accident (stroke). Ventricular filling is not totally dependent on atrial contraction, and therefore these atrial arrhythmias are not always symp- tomatic unless they spread to the ventricular conduction pathways. Atrioventricular Node Abnormalities: Heart Blocks Heart block occurs when conduction is excessively delayed or stopped at the AV node or Bundle of His. Partial blocks may be as follows: 1. First-degree, in which the conduction delay prolongs the PR interval, the time between the atrial and ventricular contractions TABLE 12.2 Cardiac Dysrhythmias Name Conduction Change Effect Bradycardia Rate regular, slower than 60/minute Stroke volume increased Possibly reduced cardiac output Tachycardia Rate regular, fast, 100–160/minute Possibly reduced cardiac output Atrial flutter Rate 160–350/min Less filling time Often reduced cardiac output Fibrillation Rate over 300/min; uncoordinated muscle contractions No filling, no output—cardiac standstill Premature ventricular contractions Additional ectopic beats May induce fibrillation Bundle branch block Delayed conduction in one bundle branch, wide QRS wave No effect Heart block 1° (partial) Delays conduction in A-V node, prolongs PR interval No effect Heart block 2° (partial) Delays conduction in A-V node, gradually increasing PR until one contraction missed Periodic decrease in output Total heart block No conduction in A-V node, ventricles slowly contract independent of atrial contraction Marked decrease in output, causing syncope CHAPTER 12 Cardiovascular System Disorders 245 Cardiac Arrest or Standstill (Asystole) Cardiac arrest is the cessation of all activity in the heart. There is no conduction of impulses, and the ECG shows a flat line. Lack of contractions means that no cardiac output occurs, thus depriving the brain and heart itself of oxygen. Loss of consciousness takes place immediately, and respiration ceases. There is no pulse at any site, including the apical and carotid sites (see Fig. 12.17). Arrest may occur for many reasons; for example, excessive vagal nerve stimulation may slow the heart, drug toxicity may occur, or there may be insufficient oxygen to maintain the heart tissue due to severe shock or ventricular fibrillation. To resuscitate a person, blood flow to the heart and brain must be maintained. Electric defibrillators are often used to administer an electric pulse to “shock” the heart and restore its natural rhythm in cases of ventricular fibrillation. Automatic electric defibrillators (AEDs) have become simple to use, and an untrained individual that follows the instructions on the device can effectively use this lifesaving device. No longer found only in hospitals or ambulances, AEDs can be found in many public buildings and private facilities. Treatment of Cardiac Dysrhythmias The cause of the dysrhythmia should be determined and treated. Easily correctable problems include those caused by drugs, such as digitalis toxicity, bradycardia due to beta blockers, or potassium imbalance related to some diuretics. In these examples a change in dosage or drug may eliminate the dysrhythmia. Antiarrhythmic drugs are effective in many cases of heart damage. Beta1-adrenergic blockers and calcium channel blockers are discussed earlier in this chapter. Atrial dysrhythmias often respond to digoxin, which slows AV node conduction and strengthens the contrac- tion, thus increasing efficiency. Sinoatrial nodal problems or total heart block requires a pacemaker, either a temporary attachment or a device that is permanently implanted in the chest; such a device provides electrical stimulation through electrodes directly to the heart muscle (Fig. 12.18). Pacemakers may stimulate a heart contraction only as needed or take over total control of the heart rate. Caution is required with the use of some electronic equipment when certain types of pacemakers are in place. Serious life-threatening dys- rhythmias may require the use of defibrillators and cardioversion devices that transmit an electric shock to the heart to interrupt the disorganized electrical activity that occurs with fibrillation, for example, and then allows the SA node to take control again, returning the heart to sinus rhythm. These devices may be external or implanted internally. Newer devices have electronic memory, which can be downloaded to assess cardiac function and effi- ciency of the device. FIG. 12.18 Permanent pacemaker implanted in the chest. (From deWit S, Kumagai C: Medical-Surgical Nursing: Concepts and Practice, Philadelphia, 2013, Saunders.) THINK ABOUT 12.8 a. Compare PVCs, atrial flutter, atrial fibrillation, and total heart block. b. Using one type of dysrhythmia as an example, explain how cardiac output may be reduced. c. Explain the absence of peripheral pulses in ventricular fibrillation. EMERGENCY TREATMENT FOR CARDIAC ARREST 1. Call for emergency medical help and begin CPR. 2. Commence use of an automatic electrical defibrillator if one is available. (These are located in public buildings and marked with a red symbol showing an electrical flash through a heart. The letters “AED” appear on the cover [Fig. 12.19].) 3. Continue CPR if no AED device is available or if instructed to do so by the device. FIG. 12.19 The universal AED symbol indicates presence and location of automatic electrical defibrillator. Symbol may be red or green. Congestive Heart Failure ■ Pathophysiology Congestive heart failure occurs when the heart is unable to pump sufficient blood to meet the metabolic needs of the body. Usually CHF occurs as a complication of another condition. It may present as an acute episode but usually is a chronic condition. It may result from a problem in the heart itself, such as infarction or a valve defect; it 246 SECTION III Pathophysiology of Body Systems mechanisms often aggravate the condition instead of providing assistance: • The reduced blood flow into the systemic circulation and thus the kidneys leads to increased renin and aldosterone secretion. The resulting vasoconstric- tion (increased afterload) and increased blood volume (increased preload) add to the heart’s workload. • The SNS response also increases heart rate and periph- eral resistance. Increased heart rate may decrease the efficiency of the heart and impede filling, as well as increasing work for the heart. may arise from increased demands on the heart, such as those imposed by hypertension or lung disease; or it may involve a combination of factors. Depending on the cause, one side of the heart usually fails first, followed by the other side. For example, an infarction in the left ventricle or essential hypertension (high blood pressure) affects the left ventricle first, whereas pulmonary valve stenosis or pulmonary disease affects the right ventricle first. It is helpful in the early stages to refer to this problem as left-sided CHF or right-sided CHF. Initially various compensation mechanisms maintain cardiac output (Fig. 12.20, top part). Unfortunately, these EXAMPLE MYOCARDIAL INFARCTION LEFT VENTRICLE LOSS OF HEART MUSCLE DECREASED CARDIAC OUTPUT ACTIVATE COMPENSATION MECHANISMS STIMULATES SNS, LEADING TO Vasoconstriction and increased resistance for left ventricle Increased heart rate and force — increased work for heart STIMULATES RENIN SECRETION, LEADING TO Activation of angiotensin–vasoconstriction Stimulation of aldosterone secretion increased Na+ and water retention increased blood volume increased work for heart COMPENSATIONS MAINTAIN CARDIAC OUTPUT FOR A TIME HEART MUSCLE (LEFT VENTRICLE) WEAKENS PULMONARY CONGESTION LEFT VENTRICLE DOES NOT FULLY EMPTY BLOOD BACKS UP IN PULMONARY CIRCULATION DECREASED CARDIAC OUTPUT INCREASED RESISTANCE FOR RIGHT VENTRICLE RIGHT VENTRICLE WEAKENS AND CANNOT FULLY EMPTY RIGHT- SIDED CHF BLOOD BACKS UP IN SYSTEMIC CIRCULATION EDEMA IN LEGS AND DIGESTIVE SYSTEM TREATMENT TO BREAK CYCLE Alpha-adrenergic blockers Vasodilators Calcium blockers Beta blockers ACE inhibitors Diuretics Digoxin LEFT- SIDED CHF FIG. 12.20 Course of congestive heart failure. CHAPTER 12 Cardiovascular System Disorders 247 ■ Etiology Infarction that impairs the pumping ability or efficiency of the conducting system, valvular changes, or congenital heart defects may cause failure of the affected side. Pres- ently coronary artery disease is the leading cause of CHF. Increased demands on the heart cause heart failure that may take various forms, depending on the ventricle most adversely affected. For example, essential hypertension increases diastolic blood pressure, requiring the left ventricle to contract with more force to open the aortic valve and eject blood into the aorta. The left ventricle hypertrophies and eventually fails (Fig. 12.22A). Pulmo- nary disease, which damages the lung capillaries and increases pulmonary resistance, increases the workload for the right ventricle; the muscle hypertrophies and eventually fails. Right-sided CHF due to pulmonary disease is often referred to as cor pulmonale (see Fig. 12.22B and further discussion in Chapter 13). ■ Signs and Symptoms The signs and symptoms become more marked as the condition progresses. Drugs may be controlling the severity of the manifestations, but there is an increased risk of sudden death from CHF. 1. With failure of either side, the forward effects are similar: • Decreased blood supply to the tissues and general hypoxia • Fatigue and weakness • Dyspnea (breathlessness) and shortness of breath, especially with exertion • Exercise intolerance • Cold intolerance • Dizziness 2. Compensation mechanisms are indicated by tachycardia, pallor, and daytime oliguria. • The chambers of the heart tend to dilate (enlarge), and the cardiac muscle becomes hypertrophied (car- diomegaly), with the wall of the ventricle becoming thicker. This process demands increased blood supply to the myocardium itself, and eventually some myo- cardial cells die, to be replaced with fibrous tissue. There are two basic effects when the heart cannot maintain its pumping capability: 1. Cardiac output or stroke volume decreases, resulting in less blood reaching the various organs and tissues, a “forward” effect. This leads to decreased cell function, creating fatigue and lethargy. Mild acidosis develops, which is compensated for by increased respirations (see Chapter 2). Because the affected ventricle cannot pump its load adequately, the return of blood to that side of the heart is also impaired. 2. “Backup” congestion develops in the circulation behind the affected ventricle (Fig. 12.21). The output from the ventricle is less than the inflow of blood. For example, if the left ventricle cannot pump all of its blood into the systemic circulation, the normal volume of blood returning from the lungs cannot enter the left side of the heart. This eventually causes congestion in the pulmonary circulation, increased capillary pressure, and possible pulmonary edema, in which fluid is forced into the alveoli. This situation is termed left-sided CHF. In right-sided CHF, the right ventricle cannot maintain its output, so less blood proceeds to the left side of the heart and the systemic circulation (forward effect). The backup effect, or congestion, is apparent in the systemic circulation, as shown by increased blood volume and congestion in the legs and feet and eventually also in the portal circulation (liver and digestive tract) and neck veins. Right- and left-sided cardiac failures are compared in Table 12.3. TABLE 12.3 Congestive Heart Failure (CHF) Left-Sided CHF Right-Sided CHF Causes Infarction of left ventricle, aortic valve stenosis, hypertension, hyperthyroidism Infarction of right ventricle, pulmonary valve stenosis, pulmonary disease (cor pulmonale) Basic Effects Decreased cardiac output, pulmonary congestion Decreased cardiac output, systemic congestion, and edema of legs and abdomen Signs and Symptoms Forward effects (decreased output) Fatigue, weakness, dyspnea, exercise intolerance, cold intolerance Fatigue, weakness, dyspnea, exercise intolerance, cold intolerance Compensations Tachycardia and pallor, secondary polycythemia, daytime oliguria Tachycardia and pallor, secondary polycythemia, daytime oliguria Backup effects Orthopnea, cough producing white or pink-tinged phlegm, shortness of breath, paroxysmal nocturnal dyspnea, hemoptysis, rales Dependent edema in feet, hepatomegaly and splenomegaly, ascites, distended neck veins, headache, flushed face 248 SECTION III Pathophysiology of Body Systems this position as well, excess interstitial fluid returns to the blood, reducing edema but increasing blood volume and pooled fluid in the lungs. • Paroxysmal nocturnal dyspnea indicates the presence of acute pulmonary edema. This usually develops during sleep, when the increased blood volume in the lungs leads to increased fluid in the alveoli and interferes with oxygen diffusion and lung expansion. The individual awakes in a panic, struggling for 3. The backup effects of left-sided failure are related to pulmonary congestion and include the following: • Dyspnea and orthopnea, or difficulty in breath- ing when lying down, develop as increased fluid accumulates in the lungs in the recumbent position. • Cough is commonly associated with the fluid irritat- ing the respiratory passages. The lungs become a dependent area when the body is recumbent. In 2. Decreased cardiac output to system 3. Decreased renal blood flow stimulates renin-angiotensin and aldosterone secretion 3. Decreased renal blood flow stimulates renin-angiotensin and aldosterone secretion 5. High pressure in pulmonary capillaries leads to pulmonary congestion or edema Lung Lung Kidney Kidney Left-sided congestive heart failure Right-sided congestive heart failure 2. Decreased cardiac output to system 1. Left ventricle weakens and cannot empty 1. Right ventricle weakens and cannot empty 6. Very high venous pressure causes distended neck vein and cerebral edema 4. Backup of blood into systemic circulation (venae cavae) 5. Increased venous pressure results in edema in legs and liver and abdominal organs L L R R 4. Backup of blood into pulmonary vein Means less blood hereA B FIG. 12.21 Effects of congestive heart failure. CHAPTER 12 Cardiovascular System Disorders 249 secondary to congenital heart disease (see the next section, Congenital Heart Defects). Feeding difficulties are often the first sign, with failure of the child to gain weight or meet developmental guidelines. Sleep periods are short because the baby falls asleep while feeding and is irritable when awake. There may be a cough, rapid grunting respirations, flared nostrils, and wheezing. With right-sided failure, hepatomegaly and ascites are common. Often a third heart sound is present (gallop rhythm). ■ Diagnostic Tests • Radiographs show cardiomegaly and the presence or absence of fluid in the lungs. • Cardiac catheterization can be used to monitor the hemodynamics or pressures in the circulation. • Arterial blood gases are used to measure hypoxia. ■ Treatment The underlying problem should be treated if possible. Reducing the workload on the heart by avoiding exces- sive fatigue, stress, and sudden exertion is important in preventing acute episodes. Prophylactic measures such as influenza vaccine are important in preventing respiratory infections and added stress on the heart. Other common treatment measures have been outlined earlier in this chapter. Maintaining an appropriate diet with a low sodium intake, low cholesterol, adequate protein and iron, and sufficient fluids is essential. Antianxiety drugs or sedatives may be useful. Depending on the underlying problem, cardiac support is provided by drugs previously mentioned. Medications such as ACE inhibitors can reduce renin secretion and vasoconstriction, digoxin improves cardiac efficiency, antihypertensives and air and coughing, sometimes producing a frothy, blood-stained sputum (hemoptysis) if capillaries have ruptured with the pressure. Rusty-colored sputum may be present with recurrent pulmonary edema, indicating the presence of hemosiderin- containing macrophages in the lungs. Rales (bubbly sounds of fluid in the lungs) and a rapid, weak pulse together with cool, moist skin are usually present. Sleeping with the upper body elevated may prevent this complication. Excess fluid in the lungs frequently leads to infections such as pneumonia. 4. Signs of right-sided failure and systemic backup include the following: • Dependent edema in the feet or legs or areas such as the buttocks. • Hepatomegaly and splenomegaly, and eventually digestive disturbances as the wall of the digestive tract becomes edematous. • Ascites, a complication that occurs when fluid accumulates in the peritoneal cavity, leading to marked abdominal distention; hepatomegaly and ascites may impair respiration if upward pressure on the diaphragm impairs lung expansion. • Acute right-sided failure, indicated by increased pressure in the superior vena cava, resulting in flushed face, distended neck veins, headache, and visual disturbances; this condition requires prompt treatment to prevent brain damage due to reduced perfusion of brain tissue. Young Children With Congestive Heart Failure Infants and young children manifest heart failure somewhat differently than adults. Heart failure is often BA FIG. 12.22 A, Prominent concentric left ventricular hypertrophy. B, Chronic cor pulmonale showing dilated and enlarged right ventricle with thickened wall (left side). (A From Klatt E: Robbins and Cotran Atlas of Pathology, ed 3, Philadelphia, 2015, Elsevier. B From Kumar V, Abbas AK, Fausto M: Robbins and Cotran Pathologic Basis of Disease, ed 7, Philadelphia, 2005, Saunders.) 250 SECTION III Pathophysiology of Body Systems direction. For example, a left-to-right shunt means that blood from the left side of the heart is recycled to the right side and to the lungs, resulting in an increased volume in the pulmonary circulation, a decreased cardiac output, and an inefficient system. On the other hand, a right-to-left shunt means that unoxygenated blood from the right side of the heart bypasses the lungs directly and enters the left side of the heart. The direction and amount of the abnormal blood flow determine the effects on the individual. Acyanotic conditions are disorders in which systemic blood flow consists of oxygenated blood, although the amount may be reduced. In cyanotic disorders, venous blood mixes with arterial blood, permitting significant amounts of unoxygenated hemoglobin in the blood to bypass the lungs and enter the systemic circulation. The high proportion of unoxygenated blood produces a bluish color (characteristic of cyanosis) in the skin and mucous vasodilators reduce blood pressure, and diuretics decrease sodium and water accumulations. Because patients often take a number of medications on a long-term basis, it is important to check all of them for effectiveness, cumula- tive toxicities, and interactions. THINK ABOUT 12.9 a. Explain how cor pulmonale may develop. b. Explain two causes of left-sided heart failure, one related to the heart and one systemic. c. How should a patient with left-sided heart failure be positioned in a reclining chair or bed for treatment? 3. Decreased cardiac output 4. Incomplete atrial emptying 2. Left ventricular hypertrophy NORMAL VALVE STENOSIS INCOMPETENT VALVE EFFECT OF AORTIC STENOSIS Blood flows freely forward No backflow of blood Less blood flows through narrowed opening Blood flows freely forward A B C D Blood regurgitates backward through “leaky” valve No backflow of blood Narrowing of aortic valve limits blood leaving the ventricle 1. FIG. 12.23 Effects of heart valve defects. Congenital Heart Defects Cardiac anomalies are structural defects in the heart that develop during the first 8 weeks of embryonic life. A structure such as a valve may be altered or missing. Several specific examples are described following this introduction. It is estimated that in the United States, 8 of every 1000 infants (approximately 40,000 babies) per year are born with heart defects, the majority of which are mild. Heart defects are the major cause of death in the first year of life. Mortality rates have dropped considerably with improvements in surgical procedures. Both genetic and environmental factors contribute to the occurrence of congenital heart defects, and these defects often occur with other developmental problems. ■ Pathophysiology Congenital heart disease may include valvular defects that interfere with the normal flow of blood (Fig. 12.23), septal defects that allow mixing of oxygenated blood from the pulmonary circulation with unoxygenated blood from the systemic circulation, shunts or abnormalities in position or shape of the large vessels (aorta and pulmonary artery), or combinations of these (Fig. 12.24). Selected examples follow. Most defects can be detected by the presence of heart murmurs. All significant defects result in a decreased oxygen supply to the tissues unless adequate compensations are available. If untreated, the child may develop heart failure. Many variations and degrees of severity are possible with these defects, but if the basic cardiac cycle is under- stood, the effects of a change in blood flow in each situ- ation can be predicted. Different methods of classifying the defects are possible, using either the type of defect or the presence of cyanosis, a bluish color in the lips and oral mucosa. When an abnormal communication permits mixing of blood, the fluid always flows from a high-pressure area to a low-pressure area, and flow occurs only in one CHAPTER 12 Cardiovascular System Disorders 251 Postductal coarctation D PA Aorta C LV RV B LA RA A FIG. 12.24 A, Atrial septal defect. Blood flow through the defect is usually left to right and produces an acyanotic shunt. B, Ventricular septal defect. Blood flow through the defect is usually left to right and produces an acyanotic shunt. C, Patent ductus arteriosus. Blood flow through the ductus is usually from the aorta to the pulmonary artery and produces an acyanotic shut. D, Coarctation of the aorta. The arterial narrowing can produce a weaker pulse in lower extremities. Continued membranes, particularly the lips and nails. Death occurs in infancy in some severe cases, but many anomalies can be treated successfully shortly after birth. ■ Etiology Most defects appear to be multifactorial and reflect a combination of genetic and environmental influences. These defects are often associated with chromosomal abnormalities, such as Down syndrome. Environmental factors include viral infections such as rubella, mater- nal alcoholism (fetal alcohol syndrome), and maternal diabetes. ■ Compensation Mechanisms Through a sympathetic response, the heart increases its rate and force of contraction in an effort to increase cardiac output. This response increases the oxygen demand in the heart, restricts coronary perfusion, and increases peripheral resistance. The heart dilates and becomes hypertrophied. However, this response is ineffective because of the defect in the heart itself. Respiratory rate increases if the oxygen deficit results in acidosis due to increased lactic acid in the body, but oxygen levels must drop considerably before this factor influences the respira- tory rate (see Chapter 13). Secondary polycythemia 252 SECTION III Pathophysiology of Body Systems ■ Treatment Surgical repair is often needed to close abnormal openings or to replace valves or parts of vessels. Palliative surgery may take place immediately and then is followed up several years later by additional surgery. The timing of surgery depends on the individual situation, the severity of the defect, the ability of the individual to withstand surgery, and the impact of surgery on growth. In some cases, septal defects close spontaneously with time. Supportive measures and drug therapy are similar to those used for CHF. Prophylactic antimicrobial therapy may be administered before certain invasive procedures to prevent bacterial endocarditis (see Infective Endocar- ditis in this chapter). Ventricular Septal Defect Ventricular septal defect (VSD) is the most common congenital heart defect and is commonly called a “hole in the heart.” It is an opening in the interventricular septum, which may vary in size and location. (Septal defects may also occur in the atrial septum when the foramen ovale fails to close after birth.) Small defects do not affect cardiac function significantly but increase the risk of infective endocarditis. Large openings permit a left-to-right shunt of blood (see Fig. 12.24A). Blood can flow in only one direction, from the high-pressure area to the low-pressure area. In this case, the left ventricle is the high-pressure area, and therefore blood flows through the septal defect from the left ventricle to the right ventricle. The effect of this altered develops with chronic hypoxia as erythropoietin secretion increases as compensation. ■ Signs and Symptoms Small defects are asymptomatic other than the presence of a heart murmur. Large defects lead to the following: • Pallor and cyanosis • Tachycardia, with a rapid sleeping pulse and frequently a pulse deficit • Dyspnea on exertion and tachypnea, in which the signs of heart failure are often present • A squatting position, often seen in toddlers and older children, that appears to modify blood flow and be more comfortable for them • Clubbed fingers (thick, bulbous fingertips) developed in time • A marked intolerance for exercise and exposure to cold weather • Delayed growth and development ■ Diagnostic Tests Congenital defects, particularly severe ones, may be diagnosed at birth, but others may not be detected for some time. Many techniques and modalities, both invasive and noninvasive, can be used: • Cardiomegaly can be observed on radiography • Diagnostic imaging • Cardiac catheterization • Echocardiograms • ECG Pulmonary artery PDA ASD Aorta F Overriding aorta Pulmonary stenosis Ventricular septal defect Right ventricular hypertrophyE E, Tetralogy of Fallot showing the four characteristic abnormalities: pulmonary stenosis, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. Tetralogy of Fallot is a cyanotic defect. F, Transposition of the great arteries. Two separate circulations are formed, which is incompatible with life unless mixing blood occurs through other defects. (From Copstead LE, Banisik J: Pathophysiology, ed 5, St. Louis, 2013, Saunders.) FIG. 12.24, cont’d CHAPTER 12 Cardiovascular System Disorders 253 Figs. 12.23B and 12.24B). In time, that heart chamber will hypertrophy and may eventually fail. If a valve leaks and blood regurgitates backward, the heart must also increase its efforts to maintain cardiac output. Mitral stenosis and its effects are demonstrated in an echocardiogram in Fig. 12.25. Part B shows the normal valves and heart wall. In comparison, part C illustrates the thickened mitral valve leaflets and the narrow opening into the left ventricle. The left atrium is enlarged from the backup pressure and the increased workload has produced the thickened atrial wall. Treatment involves surgical replacement by mechanical, animal (porcine), or tissue engineered valves (Fig. 12.26). These prosthetic valves may last up to 10 years but are susceptible to thrombus formation, requiring patients to take daily ASA (see Fig. 12.26B). Also, infectious endo- carditis is a risk, so prophylactic antimicrobial drugs are suggested before any procedure that might cause bacteremia. flow is that less blood leaves the left ventricle, reducing stroke volume and cardiac output to the systemic circula- tion. More blood enters the pulmonary circulation, some of which is already oxygenated; this reduces the efficiency of the system and in time overloads and irreversibly damages the pulmonary blood vessels, causing pulmonary hypertension. This complication, which may occur in untreated VSD, would lead to an abnormally high pressure in the right ventricle and a reversal of the shunt to a right-to-left shunt, leading to cyanosis. Treatment typically involves both medications and surgical repair. The medications involved may be used to do the following: • Increase strength of contractions • Decrease amount of fluid in circulation • Keep a regular heartbeat Surgical methods include the following: • Direct open heart surgery to close the hole in the septum • Catheter procedure where a catheter is inserted into a blood vessel (typically in the groin) and is used to place a mesh patch in the hole • Hybrid procedure where a small incision is made in the heart and a catheter is inserted to place the patch in position to seal the hole THINK ABOUT 12.10 a. Describe the altered blood flow in the presence of an atrial septal defect. Include the direction of flow and the type of blood present in each circulation. b. Patent ductus arteriosus results when the ductus arteriosus, a vessel between the aorta and the pulmonary artery that is present during fetal development, fails to close after birth. Using your knowledge of normal anatomy, trace the abnormal pattern of blood flow, including the rationale for it. Would a heart murmur be present? Valvular Defects Malformations most commonly affect the aortic and pulmonary valves. Valve problems may be classified as stenosis, or narrowing of a valve, which restricts the forward flow of blood, or valvular incompetence, which is a failure of a valve to close completely, allowing blood to regurgitate or leak backward (see Fig. 12.23). Mitral valve prolapse is a common occurrence; it refers to abnor- mally enlarged and floppy valve leaflets that balloon backward with pressure or to posterior displacement of the cusp, which permits regurgitation of blood. An effect similar to stenosis arises from abnormalities of the large vessels near the heart—for example, in coarctation (constriction) of the aorta. Valvular defects reduce the efficiency of the heart “pump” and reduce stroke volume. If the opening is narrow, as in pulmonary stenosis, the myocardium must contract with more force to push the blood through (see THINK ABOUT 12.11 a. Explain why an incompetent valve reduces the efficiency of the heart contraction. b. Would symptomatic mitral valve prolapse cause a cyanotic or an acyanotic condition? Explain your reasoning. Tetralogy of Fallot Tetralogy of Fallot is the most common cyanotic congenital heart condition. It is more complex and more serious than the others described so far because it includes four (Greek tetra) abnormalities and is a cyanotic disorder (infants suffering from this condition are sometimes called “blue babies”). The four defects are pulmonary valve stenosis, VSD, dextroposition of the aorta (to the right over the VSD), and right ventricular hypertrophy (see Fig. 12.24C). This combination alters pressures within the heart and therefore alters blood flow. The pulmonary valve stenosis restricts outflow from the right ventricle, leading to right ventricular hypertro- phy and high pressure in the right ventricle. This pressure, now higher than the pressure in the left ventricle, leads to a right-to-left shunt of blood through the VSD. The flow of unoxygenated blood from the right ventricle directly into the systemic circulation is promoted by the position of the aorta, over the septum or VSD. The result is that the pulmonary circulation receives a small amount of unoxygenated blood from the right ventricle, and the systemic circulation receives a larger amount of blood consisting of mixed oxygenated and unoxygenated blood. The oxygen deficit is great; hence there are marked systemic effects and cyanosis. Surgery is the only effective treatment for the tetralogy of Fallot. The surgery is typically done during the first year after birth and involves a number of individual repairs: closing the VSD, repairing or replacing the 254 SECTION III Pathophysiology of Body Systems A B C FIG. 12.25 Echocardiograph showing mitral stenosis. LA, left atrium; LV, left ventricle; MS, mitral stenosis; MV, mitral valve; RA, right atrium; RV, right ventricle; TV, tricuspid valve. A, Position of the transducer at the apical window. B, A two-dimensional image of a normal heart from the apical window, showing the four chambers and atrioventricular valves. An ECG is taken at the same time. C, The heart of a patient with mitral stenosis, indicated by thickening of the mitral valve leaflets, hypertrophy of the atrial wall, and enlargement of the atrial chambers. Note the change in the ECG indicating the cardiac phase affected by the abnormality. (Courtesy of Helen Armstrong-Brown and Dr. P. Nihoyannopolous, Hammersmith Hospital, London, England.) BA FIG. 12.26 A, Porcine (pig) heart valve used to replace defective human valve. B, Patient after mitral valve replace- ment. Thrombosis obscures the underlying prosthetic valve. (A From deWit S, Kumagai C: Medical-Surgical Nursing: Concepts and Practice, Philadelphia, 2013, Saunders. B From Cross S: Underwood’s Pathology: A Clinical Approach, ed 6, London, 2013, Churchill Livingstone.) CHAPTER 12 Cardiovascular System Disorders 255 (see Fig. 12.28B). In some cases the chordae tendineae are involved in the inflammatory reaction, and fibrosis ensues, leading to shortened chordae and malfunction- ing valve. Recurrent inflammation is likely to cause more damage to the valves and increase risk for infective endocarditis. Other sites of inflammation in patients with rheumatic fever include the following: • Large joints, particularly in the legs, which may be involved with synovitis in a migratory polyarthritis (often multiple joints affected) • Skin, which may show a nonpruritic rash known as erythema marginatum (red macules or papules that enlarge and have white centers) • Wrists, elbows, knees, or ankles, where small, nontender subcutaneous nodules usually form on the extensor surfaces • Basal nuclei in the brain (more frequently in girls) causing involuntary jerky movements of the face, arms, and legs (Sydenham chorea or Saint Vitus dance) Not all signs and symptoms occur in a single individual. Diagnosis is based on the presence of several of the preceding criteria including general signs of inflamma- tory disease, as well as high levels of antistreptolysin O antibodies and a history of prior streptococcal infection. Rheumatic heart disease develops years later in some individuals, when scarred valves or arrhythmias Inflammation and Infection in the Heart Rheumatic Fever and Rheumatic Heart Disease ■ Pathophysiology Rheumatic fever is an acute systemic inflammatory condition that appears to result from an abnormal immune reaction occurring a few weeks after an untreated infec- tion, usually caused by certain strains of group A beta- hemolytic Streptococcus (see Figs. 6.1A and 6.2B). The inflammation involves the heart and other parts such as joints and skin. It usually occurs in children 5 to 15 years of age. Although rheumatic fever occurs less frequently now in many areas, it remains a threat because new strains of Streptococcus, the cause of the antecedent infection, continue to appear. Also the long-term effects, seen as rheumatic heart disease, may be complicated by infective endocarditis and heart failure in older adults. The antecedent or preceding infection commonly appears as an upper respiratory infection, tonsillitis, pharyngitis, or strep throat (awareness of the risk of rheumatic fever has led to increased use of rapid tests to quickly identify and treat a strep infection). Antibodies to the streptococcus organisms form as usual and then react with connective tissue (collagen) in the skin, joints, brain, and heart, causing inflammation (Fig. 12.27). The heart is the only site where scar tissue occurs, causing rheumatic heart disease. During the acute stage, the inflammation in the heart may involve one or more layers of the heart: • Pericarditis, inflammation of the outer layer, may include effusion (excessive fluid accumulation), which impairs filling. • Myocarditis, in which the inflammation develops as localized lesions in the heart muscle, called Aschoff bodies, may interfere with conduction. • Endocarditis, the most common problem, affects the valves, which become edematous, and verrucae form. Verrucae are rows of small, wartlike vegetations along the outer edge of the valve cusps (Fig. 12.28A). The mitral valve is affected most frequently. The inflam- mation disrupts the flow of blood and the effectiveness of the left ventricle. Eventually, the valve may be scarred, leading to stenosis if the cusps fuse together or to incompetence if fibrous tissue shrinks, or to a combination of these, ending in rheumatic heart disease THINK ABOUT 12.12 a. List the four defects present in the tetralogy of Fallot, and state the effect each has on blood flow. b. Describe the altered path of blood flow. c. How does cyanosis occur with the altered blood flow? d. Describe three signs of CHF in infants. ANTECEDENT INFECTION Group A beta-hemolytic streptococcus Recovery Antibodies formed Antibody-collagen reaction INFLAMMATION HEART MYOCARDITIS •Arrhythmias PERICARDITIS •Effusion ENDOCARDITIS •Valve damage SCAR TISSUE RHEUMATIC HEART DISEASE Loss of valve functions Arrhythmias — (and in joints, skin, brain) FIG. 12.27 Development of rheumatic fever and rheumatic heart disease. pulmonary valve, and widening the pulmonary arteries to increase flow. 256 SECTION III Pathophysiology of Body Systems may be necessary (see Fig. 12.26). The prognosis depends on the severity of heart damage and prevention of recurrences. When valve damage has occurred, precautionary measures such as prophylactic penicillin prior to invasive procedures or dental treatment marked by significant bleeding are recommended to prevent bacteremia and infective endocarditis (see the section on Infective Endocarditis). compromise heart function. Congestive heart failure may occur in either the acute or chronic stage. ■ Signs and Symptoms The general indications of a systemic inflammation are usually present in acute rheumatic fever: • Low-grade fever • Leukocytosis • Malaise • Anorexia and fatigue • Tachycardia, even at rest, is common • Heart murmurs that indicate the site of inflammation • Epistaxis and abdominal pain possible Acute heart failure may develop from the dysrhythmias or severe valve distortion. Recovery often requires a prolonged period of rest and treatment. ■ Diagnostic Tests Elevated serum antibody levels remain after the infection has been eradicated (antistreptolysin O titer). Leukocytosis and anemia are common. Heart function tests, as previ- ously mentioned, may be required. Characteristic ECG changes develop. ■ Treatment Antibacterial agents such as penicillin V may be admin- istered to eradicate any residual infection and prevent additional infection. Penicillin may be continued for some time to prevent recurrences, depending on previous attacks and the time lapse, the risk of infection, and the presence of cardiac damage. Any future streptococcal infection should be promptly treated. Antiinflammatory agents such as ASA or corticosteroids (prednisone) may be given. Specific treatment is required for dysrhythmias or heart failure, as previously described. Potential complications, such as heart failure resulting from severe valve damage, are similar to those mentioned earlier under congenital heart defects. Valve replacement A B FIG. 12.28 Rheumatic heart disease. A, Acute rheumatic mitral valvulitis. B, Mitral valve stenosis. Note the narrow valve opening. (A From Frazier M, Drzymkowski J: Essentials of Human Diseases and Conditions, ed 5, St. Louis, 2013, Elsevier. B From Klatt E: Robbins and Cotran Atlas of Pathology, ed 3, Philadelphia, 2015, Elsevier.) THINK ABOUT 12.13 a. Describe the stages of development of acute rheumatic fever. b. Explain how valvular damage due to rheumatic fever may be asymptomatic until increased exercise or pregnancy occurs. Infective Endocarditis ■ Pathophysiology Infective endocarditis, formerly called bacterial endocar- ditis, occurs in two forms: the subacute type, in which defective heart valves are invaded by organisms of low virulence such as Streptococcus viridans (part of the normal flora of the mouth); and the acute type, in which normal heart valves are attacked by highly virulent organisms such as Staphylococcus aureus, which tend to cause severe tissue damage and may be difficult to treat successfully. It is now recognized that many types of organisms can cause infective endocarditis, and it is important to identify and treat the specific organism promptly. The basic effects are the same, regardless of the causative organism. Microorganisms in the general circula- tion attach to the endocardium and invade the heart valves, causing inflammation and formation of vegetations on the cusps. Vegetations are large, fragile masses made up of fibrin strands, platelets and other blood cells, and microbes. In the acute stage, these may interfere with CHAPTER 12 Cardiovascular System Disorders 257 • Anorexia • Splenomegaly • Osler nodes (painful red nodules on the fingers) are often present. • Septic emboli from the vegetations that cause vascular occlusion or infection and abscesses in other areas of the body will result in additional manifestations depending on the location of the secondary problem • Release of bacteria into the blood may lead to intermit- tent increased fever. • Congestive heart failure develops in severe cases. Acute endocarditis has a sudden, marked onset: • With spiking fever • Chills • Drowsiness • Heart valves are badly damaged causing severe impair- ment of heart function As in the subacute form, septic emboli may cause infarc- tions or abscesses in organs, resulting in appropriate signs related to location. ■ Treatment Following a blood culture/rapid test to identify the causative agent, antimicrobial drugs are given, usually for a minimum of 4 weeks, to eradicate the infection completely. Other medication to support heart function is usually required. the opening and closing of the valves. Pieces may break away, forming infective or septic emboli that then cause infarction and infection in other tissues. This process causes additional destruction and scarring of the valve and the chordae tendineae. ■ Etiology A combination of factors predisposes to infection: the presence of abnormal tissue in the heart, the presence of microbes in the blood, and reduced host defenses. Abnormal valves associated with many predispos- ing conditions increase the risk of subacute infective endocarditis. These conditions include congenital defects, rheumatic fever, mitral prolapse, and artificial or replace- ment valves. Persons with septal defects, catheters, or other artificial implants are also susceptible to infection. Some individuals should be premedicated with penicil- lin or another antibacterial drug before any instrumenta- tion or invasive procedure such as scaling of the teeth, in which a transient bacteremia could occur. The American Heart Association and American Dental Association have issued specific recommendations regarding the conditions and procedures under which prophylactic medication should be given, the recommended drugs, and dosing. Medical conditions are classified with regard to the degree of risk for endocarditis. The drug of choice for prophylaxis is amoxicillin taken 1 hour before the procedure; the alternative in cases of allergy to penicillin is clindamycin or cephalexin. Abscesses or other sources of infection should be treated promptly. Intravenous drug users have an increased incidence of acute endocarditis. Anyone in whom the immune system is suppressed, such as those taking corticosteroids or those with acquired immuno- deficiency syndrome, is vulnerable. Endocarditis, both bacterial and fungal, is also a risk with open heart surgery. ■ Diagnostic Tests Various new heart murmurs are the common indicator, as well as other signs of impaired heart function. Initially it may be difficult to detect any change in the heart murmur from the predisposing condition, but the increas- ing impairment soon affects the sounds. Transesophageal echocardiogram may also be used to reveal the presence of vegetations. THINK ABOUT 12.14 Explain why a tooth extraction or scaling procedure could pose a special danger to an individual with an altered heart valve. ■ Signs and Symptoms Subacute infective endocarditis is frequently insidious in onset, manifesting only as an intermittent low-grade fever or fatigue. Other manifestations may include the following: THINK ABOUT 12.15 Describe the possible destination of an embolus from the mitral valve. Pericarditis ■ Pathophysiology Pericarditis may be acute or chronic and is usually second- ary to another condition in either the heart or the sur- rounding structures. Pericarditis can be classified by cause or by the type of exudate associated with the inflamma- tion. Acute pericarditis may involve a simple inflammation of the pericardium, in which the rough, swollen surfaces cause chest pain and a friction rub (a grating sound heard on the chest with a stethoscope). In some cases, an effusion may develop, with a large volume of fluid accumulating in the pericardial sac (Fig. 12.29). This fluid may be serous as with inflammation, may be fibrinous and purulent as with infection, or may contain blood (hemopericardium) as with trauma or cancer. Small volumes of fluid in the pericardium have little effect on heart function, but a large amount of fluid that accumulates rapidly may compress the heart and impair its expansion and filling, thus decreasing cardiac output (cardiac tamponade). The right side (low-pressure side) of the heart is affected first, causing increased pressure in the systemic veins and, if acute, distended neck veins. If fluid accumulates slowly, the heart adjusts, and a very 258 SECTION III Pathophysiology of Body Systems Vascular Disorders Arterial Disorders Hypertension ■ Pathophysiology Hypertension, or high blood pressure, in both its primary and secondary forms is a common problem. Estimates indicate one in three adults has high blood pressure. Within this group, one-third are undiagnosed, and some are not controlled. Men are more likely to have high blood pressure than women until age 55; after menopause the proportion of women exceeds that of men. Another third of the adult population are considered to have prehypertension, with blood pressure in the high normal range and not currently prescribed medication. African Americans have a higher prevalence of hypertension; the onset is earlier and the average blood pressure is higher. Because of the insidious onset and mild signs, hypertension is often undiagnosed until complications arise and has been called the “silent killer.” However, it is hoped that the availability of self-testing machines and other screening programs will aid in an early diag- nosis. Compliance with treatment measures may not occur until the problem is severe enough to interfere with function. Hypertension is classified in three major categories: 1. Primary or essential hypertension is idiopathic and is the form discussed in this section. 2. Secondary hypertension results from renal (eg, neph- rosclerosis) or endocrine (eg, hyperaldosteronism) disease, or pheochromocytoma, a benign tumor of the adrenal medulla or SNS chain of ganglia. In this type of hypertension, the underlying problem must be treated to reduce the blood pressure. 3. Malignant or resistant hypertension, the third type, is a hypertensive emergency with extremely high blood pressure. This condition usually results in organ damage, including the central nervous system and the renal system. Diastolic pressure is very high as well. Sometimes hypertension is classified as systolic or dia- stolic, depending on the measurement that is elevated. For example, elderly persons with loss of elasticity in the arteries frequently have a high systolic pressure and low diastolic value. Essential hypertension develops when the blood pressure is consistently above 140/90. This figure may be adjusted for the individual’s age. The diastolic pressure is important because it indicates the degree of peripheral large amount can build up before signs appear. A radio- graph would show the enlargement of the heart. Chronic pericarditis results in formation of adhesions between the pericardial membranes that may become constrictive, causing the pericardium to become a tight fibrous enclosure, thus limiting movement of the heart. ■ Etiology Acute pericarditis may be secondary to open heart surgery, myocardial infarction, rheumatic fever, systemic lupus erythematosus, cancer, renal failure, trauma, or viral infection. The fibrous tissue of chronic pericarditis often results from tuberculosis or radiation to the mediastinum. Inflammation or infection may develop from adjacent structures, for example, pleurisy or pneumonia in the lungs. Effusion may be secondary to hypoproteinemia resulting from liver or kidney disease. ■ Signs and Symptoms Signs vary with the underlying problem and its effects on the pericardium. Tachycardia is present, and chest pain, dyspnea, and cough are common signs. Electrocar- diogram changes and a friction rub may be present. Effusion and cardiac tamponade lead to distended neck veins, faint heart sounds, and pulsus paradoxus, in which systolic pressure drops 10 mm Hg during inspiration. Chronic pericarditis causes fatigue, weakness, and abdominal discomfort owing to systemic venous congestion. ■ Treatment The primary problem must be treated successfully. Fluid may be aspirated from the cavity (paracentesis) and analyzed to determine the cause. If effusion is severe, 4. Decreased blood flow to lungs 5. Decreased output to body 1. Fluid around heart compresses heart wall 2. Heart cannot expand to fill Aorta Myocardium Pericardial cavity Pericardium 3. Backup into systemic circulation FIG. 12.29 Effects of pericardial effusion. THINK ABOUT 12.16 Explain the process by which a large volume of fluid in the pericardial cavity decreases cardiac output. immediate aspiration of the excess fluid may be required to prevent tamponade and shock. CHAPTER 12 Cardiovascular System Disorders 259 controlled hypertension can be chronic renal failure, stroke due to hemorrhage, loss of vision, or congestive heart failure. Life span may be considerably shorter, particularly in men, when hypertension is not controlled. ■ Etiology Even in idiopathic hypertension, the form discussed here, many factors appear to predispose to the condition. The incidence increases with age, although hypertension does occur in children. Men are affected more frequently and more severely, but the incidence in women increases after middle age. Genetic factors are reflected by the fact that African Americans have a higher incidence than do Caucasians and experience a more severe form of hyper- tension. There are also familial trends, but these reflect lifestyle characteristics as well as heredity. Other factors implicated in the development of essential hypertension include high sodium intake, excessive alcohol intake (small amounts of alcohol appear to decrease blood pressure), obesity, and prolonged or recurrent stress. ■ Signs and Symptoms Hypertension is frequently asymptomatic in the early stages, and the initial signs are often vague and nonspe- cific. They include the following: • Fatigue • Malaise • Morning headache resistance and the increased workload of the left ventricle. The condition may be mild, moderate, or severe. In essential hypertension there is an increase in arteriolar vasoconstriction, which is attributed vari- ously to increased susceptibility to stimuli or increased stimulation or perhaps a combination of factors. A slight decrease in the diameter of the arterioles causes a major increase in peripheral resistance, reduces the capacity of the system, and increases the diastolic pressure or afterload substantially. Frequently, vasoconstriction leads to decreased blood flow through the kidneys, leading to increased renin, angiotensin, and aldosterone secretion. These substances increase vasoconstriction and blood volume, further increasing blood pressure (Fig. 12.30). If this cycle is not broken, blood pressure can continue to increase. Over a long period of time, the increased blood pressure causes damage to the arterial walls. They become hard and thick (sclerotic), narrowing the lumen. The wall may dilate or tear, forming an aneurysm, or encourage ath- eroma formation. Blood supply to the involved area is reduced, leading to ischemia and necrosis with loss of function. In many cases, the progressive changes are asymptomatic until well advanced. The areas most frequently damaged by elevated pres- sure are the kidneys, brain, and retina. One area that is easily checked through the pupil of the eye is the retina, where the blood vessels can easily be observed for sclerotic changes and rupture (Fig. 12.31). The result of poorly Systemic vasoconstriction Systemic vasoconstriction Aldosterone secretion Increased peripheral resistance Increased blood volume Decreased blood flow to kidney Damage to renal blood vessels Increased work for the heart causing left-sided CHF Damage to cerebral arteries causing stroke Damage to arterial walls leading to atherosclerosis Damage to retinal blood vessels causing blindness Increased renin secretion Increased blood pressure Nephrosclerosis Diabetic nephropathy FIG. 12.30 Development of hypertension. 260 SECTION III Pathophysiology of Body Systems alpha1 blockers cause vasodilation, calcium blockers reduce heart action and peripheral resistance, and beta blockers reduce heart action and sometimes renin release (see Table 12.1). Patient compliance can be difficult when no obvious signs of illness are present. However, it is important for the patient to continue to follow all the physician’s recom- mendations to prevent unseen damage and complications. Unfortunately, some of the drugs do have significant side effects, such as nausea, erectile dysfunction, and orthostatic hypotension. Orthostatic hypotension results from the lack of reflex vasoconstriction when rising from a supine position causing a decrease in blood flow to the brain. This results in dizziness and fainting and can result in falls. Rising slowly to a standing position and using support will decrease the risk of falls. Diuretics may cause increased urinary frequency in the morning and generalized weakness. Beta blockers may prevent the heart rate from increasing with exercise. This interfer- ence with normal responses can lead to misinterpretation of the results of exercise stress testing. Prognosis depends on treating any underlying prob- lems and maintaining constant control of blood pressure to prevent complications. • Consistently elevated blood pressure under various conditions is the key sign of hypertension; compli- cations are also asymptomatic until they are well advanced ■ Treatment Essential hypertension is usually treated in a sequence of steps, beginning with lifestyle changes, as needed, to reduce salt intake, reduce body weight and stress, and generally increase cardiovascular fitness. The recommendations and drugs selected are indi- vidualized. Mild diuretics such as the thiazide diuretics, which also have an antihypertensive action, are suggested for the next stage. Physicians recommend ACE inhibitors for many as the initial treatment. Subsequently, one or more drugs may be added to the regimen until blood pressure is reduced. Combinations of drugs with differ- ent actions are quite effective, and the adverse effects are minimal. The choice of drug also depends on the individual situation. For example, a patient with a high serum sodium level needs a stronger diuretic, such as furosemide, and a patient with high renin levels may take an ACE inhibitor. Other antihypertensive agents block the sympathetic stimulation in various ways: Eyes Retinopathy—arteriolar damage, with microaneurysms and rupture Heart Congestive heart failure Atherosclerosis Angina Myocardial infarction Brain Cerebral aneurysm Hemorrhagic CVA (stroke) Atherosclerosis Blood pressure Persistent elevation Kidney Nephrosclerosis Chronic renal failure FIG. 12.31 Effects of uncontrolled hypertension. CHAPTER 12 Cardiovascular System Disorders 261 • Reduction of serum cholesterol levels is recommended. • Thrombus formation can be reduced by platelet inhibi- tors or anticoagulant medications. • Cessation of smoking, which causes increased platelet adhesion, is highly recommended. • An exercise program can be helpful in preserving existing circulation. • Maintaining a dependent position for the legs can improve arterial perfusion. • Peripheral vasodilators such as calcium blockers may be helpful because they may enhance the collateral circulation. • Surgical procedures to restore blood flow include bypass grafts using a vein or synthetic material, angioplasty to reduce plaques, or endarterectomy (removal of the intima and obstructive material). • Care should be taken to avoid any skin trauma, and regular examination of the feet is important to avoid pressure from shoes, especially if there is sensory impairment. Specially fitted shoes may be required. • Gangrenous ulcers can be treated with antibiotics and débridement of dead tissue. • Amputation of a gangrenous toe or foot is often required to prevent spread of the infection into the systemic circulation and to relieve the severe pain of ischemia. In many cases, multiple amputations are required, beginning with a toe, then a foot, lower leg, and so on. Vascular disease is the primary reason for amputation. Healing is very slow because of the poor blood supply, and a prosthesis may be difficult to fit and maintain unless circulation can be improved. Peripheral Vascular Disease and Atherosclerosis ■ Pathophysiology Peripheral vascular disease refers to any abnormality in the arteries or veins outside the heart. The cause, develop- ment, and effects of atheromas have been discussed previously in this chapter (see Figs. 12.8 to 12.11). The most common sites of atheromas in the peripheral circula- tion are the abdominal aorta and the femoral and iliac arteries (see Fig. 10.1), where partial occlusions may impair both muscle activity and sensory function in the legs. Total occlusions may result from a thrombus obstructing the lumen or breaking off (an embolus) and eventually obstructing a smaller artery. Loss of blood supply in a limb leads to necrosis, ulcers, and gangrene, which is a bacterial infection of necrotic tissue. ■ Signs and Symptoms • Increasing fatigue and weakness in the legs develop as blood flow decreases. • Intermittent claudication, or leg pain associated with exercise due to muscle ischemia, is a key indicator. Initially pain subsides with rest. As the obstruction advances, pain becomes more severe and may be present at rest, particularly in the distal areas such as the feet and toes. • Sensory impairment may also be noted as paresthesias, or tingling, burning, and numbness. • Peripheral pulses distal to the occlusion (eg, the popliteal and pedal pulses) become weak or absent (see Fig. 12.4). • The appearance of the skin of the feet and legs changes, with marked pallor or cyanosis becoming evident when the legs are elevated and rubor or redness when they are dangling. The skin is dry and hairless, the toenails are thick and hard, and poorly perfused areas in the legs or feet feel cold. ■ Diagnostic Tests Blood flow can be assessed by Doppler studies (ultraso- nography) and arteriography. Plethysmography measures the size of limbs and blood volume in organs or tissues. ■ Treatment Treatment has several aspects, including slowing the progress of atherosclerosis, maintaining circulation in the leg, and treating complications: THINK ABOUT 12.17 a. State the cause of elevated blood pressure in essential hypertension. b. Describe the long-term effects of uncontrolled hypertension. c. Explain why orthostatic (postural) hypotension may occur with vasodilator drugs. d. Explain how compensation by the renin-angiotensin pathway aggravates hypertension. THINK ABOUT 12.18 a. What is the cause of weak peripheral pulses when the iliac artery is blocked? b. Why should the feet be carefully inspected on a daily basis in arterial peripheral vascular disease? c. How does gangrene develop in cases of arterial peripheral vascular disease, and why may healing following amputation to treat gangrene be reduced? Aortic Aneurysms ■ Pathophysiology An aneurysm is a localized dilatation and weakening of an arterial wall. The most common location is either the abdominal or thoracic aorta. The aneurysm may take different shapes: a saccular shape is a bulging wall on one side, whereas a fusiform shape is a circumferential dilatation along a section of artery (Fig. 12.32). Dissecting aneurysms develop when there is a tear in the intima, allowing blood to flow along the length of the vessel between the layers of the arterial wall. Aneurysms also occur in the cerebral circulation and are discussed in Chapter 14. The aneurysm develops from a defect in the medial layer, often associated with turbulent blood flow at the 262 SECTION III Pathophysiology of Body Systems ■ Signs and Symptoms Aneurysms are frequently asymptomatic for a long period of time until they become very large or rupture. Abdomi- nal aneurysms are sometimes detected as palpable pulsat- ing masses with bruits (abnormal sounds). In certain locations, earlier diagnosis may be achieved if a large aneurysm compresses the nearby structures, causing signs such as dysphagia from pressure on the esophagus or pain if a spinal nerve is compressed. Rupture occasionally leads to moderate bleeding but most often causes severe hemorrhage and death. Signs include severe pain and indications of shock. A dissecting aneurysm causes obstruction of the aorta and its branches as the intima peels back and blood flow is diverted between the layers. The dissection tends to progress down the aorta and sometimes back toward the heart as well. Dissection causes severe pain, loss of pulses, and organ dysfunction, as normal blood flow is lost. Many dissecting aneurysms ultimately rupture. ■ Diagnostic Tests Radiography, ultrasound, CT scans, or MRI confirm the problem. ■ Treatment Pending surgery, it is of critical importance to maintain blood pressure at a normal level, preventing sudden elevations due to exertion, stress, coughing, or constipa- tion. In some cases, small tears may occur before a major rupture; these need immediate surgical repair. Surgical repair with resection and replacement with a synthetic graft can prevent rupture. Venous Disorders Varicose Veins ■ Pathophysiology Varicosities are irregular dilated and tortuous areas of the superficial or deep veins (see Fig. 10.2). The most common location is the legs, but varicosities are also found in the esophagus (esophageal varices) and the rectum (hemorrhoids). Varicose veins in the legs may develop from a defect or weakness in the vein walls or in the valves (Fig. 12.33). Long periods of standing during which the pressure within the vein is greatly elevated can also lead to varicosi- ties. Superficial veins lack the muscle support of the deep veins. If a section of vein wall is weak, eventually the excessive hydrostatic pressure of blood under the influence of gravity causes the wall to stretch or dilate. The weight of blood then damages the valve below, leading to backflow of blood into the section distal to the starting point. If the basic problem is a defective valve, reflux of blood into the section of vein distal to the valve occurs, the overload distending and stretching the walls. The continued back pressure of blood in the leg veins leads to progressive damage down the vein. Some blood may site, from a bifurcation, or from an atheroma. Trauma such as a motor vehicle accident may result in tearing of tissues. Syphilis may also damage the tissues in the arterial wall. Over time the dilatation enlarges, particularly if hypertension develops. Frequently, a thrombus forms in the dilated area, obstructing branching arteries such as the renal arteries, or becoming a source of embolus. Many aneurysms eventually rupture, causing massive hemorrhage (see Fig. 12.32E). ■ Etiology Common causes are atherosclerosis, trauma (particularly car accidents), syphilis and other infections, as well as congenital defects. Hypertension is present in half the patients diagnosed with aortic aneurysms. Fusiform Saccular Dissecting Tear in intimaThrombus Blood flows between layers of wall A B C ED FIG. 12.32 A–C, Types of aortic aneurysms. D, Abdominal aorto- gram showing a saccular abdominal aneurysm (arrowhead). External view of abdominal aortic aneurysm with arrow marking rupture. (D From Kowalczyk, N: Radiographic Pathology for Technologists, ed 6, St. Louis, 2014, Elsevier.) CHAPTER 12 Cardiovascular System Disorders 263 the legs should be avoided. When standing or sitting for long periods, intermittent voluntary muscle contractions or position changes are helpful. For more severe varicosi- ties, sclerosing agents that obliterate the veins or surgical vein stripping may be tried, rerouting the blood to functional veins. be diverted into other veins, such as blood flowing from the deep veins through connecting veins into the super- ficial veins, further extending the damage. Varicosities can predispose to thrombus formation in the presence of other contributing factors such as immobility. ■ Etiology A familial tendency to varicose veins is probably related to an inherent weakness in the vein walls. The superficial leg veins are frequently involved because there is less muscle support for these veins. Valves may be damaged by trauma, intravenous administration of fluids, or thrombophlebitis. Many factors can increase pressure in the leg veins, such as standing for long periods of time, crossing the legs, wearing tight clothing, or pregnancy. ■ Signs and Symptoms Superficial varicosities on the legs appear as irregular, purplish, bulging structures. There may be edema in the feet as the venous return is reduced. Fatigue and aching are common as the increased interstitial fluid interferes with arterial flow and nutrient supply (see Chapter 2). Increased interstitial fluid or edema also leads to a shiny, pigmented, and hairless skin, and varicose ulcers may develop as arterial blood flow continues to diminish leading to skin breakdown. Healing is slow because of impaired blood flow. ■ Treatment Treatment is directed toward keeping the legs elevated and using support stockings to encourage venous return and relieve discomfort. Restrictive clothing and crossing S I P A BA Normal vein Normal venous valve Varicose vein Incompetent (leaky) venous valve FIG. 12.33 Varicose veins. A, Veins near the surface of the body—especially in the legs—may bulge and cause venous valves to leak. B, Varicose veins. (A From Patton KT, Thibodeau GA: Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby. B From Forbes C., Jackson W.: Color Atlas and Text of Clinical Medicine. Ed 3, St. Louis, Mosby.) Thrombophlebitis and Phlebothrombosis ■ Pathophysiology The terms thrombophlebitis and phlebothrombosis, as well as phlebitis and thromboembolic disease, are often used interchangeably. It can be difficult to differentiate the two conditions, but sometimes there is a significant difference in the predisposing factors, early signs, and risks of emboli. Thrombophlebitis refers to the development of a thrombus in a vein in which inflammation is present. The platelets adhere to the inflamed site, and a thrombus develops. In phlebothrombosis, a thrombus forms spon- taneously in a vein without prior inflammation, although inflammation may develop secondarily in response to thrombosis. The clot is less firmly attached in this case, and its development is asymptomatic or silent. THINK ABOUT 12.19 a. Compare the ideal position in a chair for a client with arterial obstruction with that for a client with varicose veins. b. Explain how leg ulcers may develop in people with varicose veins. 264 SECTION III Pathophysiology of Body Systems Shock Shock or hypotension results from a decreased circulating blood volume, leading to decreased tissue perfusion and general hypoxia. In most cases, cardiac output is low. There are several methods of classifying shock. Shock is most easily classified by the cause, which also indicates the basic pathophysiology and treatment (Table 12.4). Shock may be caused by a loss of circulating blood volume (hypovolemic shock), inability of the heart to pump the blood through the circulation (cardiogenic shock), and its subcategory, interference with blood flow through the heart (obstructive shock), or changes in peripheral resistance leading to pooling of blood in the periphery (distributive, vasogenic, neurogenic, septic, or anaphylactic shock). ■ Pathophysiology Blood pressure is determined by blood volume, heart contraction, and peripheral resistance. When one of these factors fails, blood pressure drops (Fig. 12.34). When blood volume is decreased, it is difficult to maintain pressure within the distribution system. If the force of the pump declines, blood flow slows, and venous return is reduced. The third factor, peripheral resistance, is altered by general vasodilation, which increases the capacity of the vascular system, leading to a lower pressure within the system and sluggish flow. Several factors usually predispose to thrombus development: • The first group of factors involves stasis of blood or sluggish blood flow, which is often present in people who are immobile or where blood flow is constricted by clothing or other devices. • Endothelial injury, which may have arisen from trauma, chemical injury, intravenous injection, or inflammation, is another factor. • The third factor involves increased blood coagulation, which may result from dehydration, cancer, pregnancy, or increased platelet adhesion. The critical problem is that venous thrombosis may lead to pulmonary embolism (see Chapter 13). A piece of thrombus (often the tail) breaks off, usually because of some activity, and flows in the venous blood returning to the heart. The first smaller blood vessels along the route are those of the lungs, where the clot lodges, obstructing the pulmonary circulation and causing both respiratory and cardiovascular complications. Sudden chest pain and shock are indicators of pulmonary embolus. TABLE 12.4 Types of Shock Type Mechanism Specific Causes Hypovolemic Loss of blood or plasma Hemorrhage, burns, dehydration, peritonitis, pancreatitis Cardiogenic Decreased pumping capability of the heart Myocardial infarction of left ventricle, cardiac arrhythmia, pulmonary embolus, cardiac tamponade Vasogenic (neurogenic or distributive) Vasodilation owing to loss of sympathetic and vasomotor tone Pain and fear, spinal cord injury, hypoglycemia (insulin shock) Anaphylactic Systemic vasodilation and increased permeability owing to severe allergic reaction Insect stings, drugs, nuts, shellfish Septic (endotoxic) Vasodilation owing to severe infection, often with gram- negative bacteria Virulent microorganisms (gram-negative bacteria) or multiple infections THINK ABOUT 12.20 Based on predisposing factors, explain why the elderly, immobile, or extremely obese individuals often experience thrombophlebitis or phlebothrombosis. ■ Signs and Symptoms Often thrombus formation is unnoticed until a pulmonary embolus occurs, with severe chest pain and shock. Thrombophlebitis in the superficial veins may present with the following characteristics: • Aching or burning and tenderness in the affected leg may be noted. • Leg may be warm and red in the area of the inflamed vein. • A thrombus in the deep veins may cause aching pain, tenderness, and edema in the affected leg as the blood pools distal to the obstructing thrombus. • A positive Homans sign (pain in the calf muscle when the foot is dorsiflexed) is common but not always reliable. • Systemic signs such as fever, malaise, and leukocytosis may be present. ■ Treatment Preventive measures, such as exercise, elevating the legs, and minimizing the effects of primary conditions, are important. Depending on the particular situation, treat- ments include the following: • Compression or elastic stockings • Exercise to reduce stasis • Anticoagulant therapy, including heparin • Fibrinolytic therapy • Surgical interventions such as thrombectomy, to reduce or remove the clot and prevent embolization CHAPTER 12 Cardiovascular System Disorders 265 • Increased secretion of ADH also promotes reabsorption of water from the kidneys to increase blood volume and acts as a vasoconstrictor. • Glucocorticoids are secreted that help stabilize the vascular system. • Acidosis stimulates respirations, increasing oxygen supplies and reducing carbon dioxide levels. Organs that are the source of the problem cannot com- pensate for the problem. Thus cardiogenic shock cannot be compensated for by increased cardiac output. If shock is prolonged, cell metabolism is diminished, and cell wastes are not removed, leading to lower pH, In patients with shock there is usually less cardiac output, and blood flow through the microcirculation is decreased, leading to reduced oxygen and nutrients for the cells. Less oxygen results in anaerobic metabolism and increased lactic acid production. Compensation mechanisms are initiated as soon as blood pressure decreases: • The SNS and adrenal medulla are stimulated to increase the heart rate, the force of contractions, and systemic vasoconstriction. • Renin is secreted to activate angiotensin, a vasoconstric- tor, and aldosterone to increase blood volume. Capillaries R L A. Normal circulation Capillaries R L C. Cardiogenic shock Capillaries R L D. Neurogenic or vascular shock Capillaries R L B. Hypovolemic shock Decreased blood flow Decreased venous return Decreased blood volume General vasodilation leads to increased capacity of system Decreased pumping force Heart damage To brain To brain To brain To brain FIG. 12.34 Causes of shock. 266 SECTION III Pathophysiology of Body Systems die. When organ damage occurs, shock may be irrevers- ible. Of concern is the occurrence of multiple organ failure after the patient appears stabilized. Decompensation causes complications of shock, such as the following: • Acute renal failure owing to tubular necrosis • Shock lung, or acute respiratory distress syndrome (ARDS), due to pooling of blood and alveolar damage • Hepatic failure due to cell necrosis • Paralytic ileus and stress or hemorrhagic ulcers • Infection or septicemia from digestive tract ischemia or from the primary problem; septic shock, primarily endotoxic shock, has a much higher mortality rate because the toxins cause depressed myocardial function or acidosis, which impairs cell enzyme function. Acidosis also tends to cause vasodilation and relaxes precapillary sphincters first, contributing further to the pooling of blood in the periphery and decreasing venous return to the heart (Fig. 12.35). If shock is not reversed quickly, it becomes even more difficult to reverse because the compensations and effects of shock tend to aggravate the problem. Vasoconstriction reduces arterial blood flow into tissues and organs, causing ischemia and eventually necrosis. Thrombi form in the microcirculation, further reducing venous return and cardiac output. Fluid shifts from the blood to the interstitial fluid as more cytokines are released from damaged cells. Organs and tissues can no longer function or undergo mitosis. Eventually the cells degenerate and COMPENSATIONS to maintain heart and brain functions STIMULATE SYMPATHETIC NERVOUS SYSTEM RENIN–ANGIOTENSIN–ALDOSTERONE INCREASED ADH SECRETION Thirst Anxiety, restlessness Tachycardia Vasoconstriction, pallor Vasoconstriction Retention of Na+ and water, oliguria Retention of water DIRECT EFFECTS OF DECREASED BLOOD PRESSURE VASODILATION AND DECREASED CELL FUNCTION Slow blood flow in microcirculation Thrombus forms Ischemia in organs Decreased function Necrosis (e.g., kidney) DECREASED VENOUS RETURN FURTHER DECREASE IN CARDIAC OUTPUT Severe acidosis CNS depression Organ damage (e.g., acute renal failure, lung damage) DECREASED BLOOD PRESSURE DECOMPENSATION Lethargy, weakness Anaerobic metabolism Metabolic acidosis FIG. 12.35 Progress of shock. CHAPTER 12 Cardiovascular System Disorders 267 • Tachycardia • Oliguria (Fig. 12.36); vasoconstriction shunts blood from the viscera and skin to the vital areas In cases of septic shock, the patient may experience “warm shock” with the following: • Fever • Warm, dry, flushed skin • Rapid, strong pulse • Hyperventilation • Evidence of infection Then the direct effects of a decrease in blood pressure and blood flow become manifest by the following: • Lethargy • Weakness • Dizziness • A weak, thready pulse • Initially hypoxemia and respiratory alkalosis as respira- tions increase • Acidosis or low serum pH due to anaerobic metabolism is compensated for by increased respirations (see Chapter 2) • As shock progresses, metabolic acidosis dominates (manifestations of shock with rationale are summarized in Table 12.5) If shock is prolonged, the body’s responsiveness decreases as oxygen supplies dwindle and wastes accu- mulate in the body. Compensated metabolic acidosis progresses to decompensated acidosis when serum pH drops below 7.35 (see Chapter 2). Decompensated acidosis leads to central nervous system depression, reduced cell metabolism, and diminished effectiveness of medications. Acute renal failure, indicated by increasing serum urea and creatinine due to tubular ischemia and necrosis, is a common occurrence in decompensated shock. When shock is severe and prolonged, monitoring may include the use of arterial catheters to assess blood pres- sure, ventricular filling, and cardiac output. Constant monitoring of arterial blood gases is essential to maintain acid-base balance. ■ Treatment The Emergency Treatment box that follows lists the treatment for shock. and acute respiratory distress syndrome (ARDS) and activate the coagulation process • Disseminated intravascular coagulation (DIC) as the clotting process is initiated • Depression of cardiac function by the oxygen deficit, acidosis, and hyperkalemia, and myocardial depressant factor released from the ischemic pancreas; eventually cardiac arrhythmias and ischemia develop, perhaps resulting in cardiac arrest • With multiorgan failure, shock becomes irreversible and death ensues ■ Etiology Shock has a multitude of causes. A few are mentioned here: • Hypovolemic shock results from loss of blood or loss of plasma from the circulating blood. In patients with burns (see Chapter 5), the inflammatory response leads to edema with shift of fluid and protein from the blood into surrounding tissues and continued loss from the burn wound area due to loss of skin. Peritonitis (see Chapter 17) causes hypovolemia when infection and inflammation in the peritoneal membranes cause a fluid shift out of the blood into another compartment, the peritoneal space, a condition termed third-spacing. Dehydration can reduce the circulating blood volume and blood pressure. • Cardiogenic shock is associated with cardiac impair- ment, such as acute infarction of the left ventricle, or arrhythmias. A subcategory, obstructive shock, is caused by cardiac tamponade or a pulmonary embolus that blocks blood flow through the heart. • The causes of vasogenic shock (it may be called distribu- tive shock, as the blood has been relocated within the system because of vasodilation) may be classified in a variety of ways. Neurogenic or vasogenic shock may develop from pain, fear, drugs, or loss of SNS stimuli with spinal cord injury. Metabolic dysfunction, such as hypoglycemia or insulin shock (see Chapter 16) or severe acidosis, may lead to this type of shock. • Anaphylactic shock results from rapid general vasodi- lation due to the release of large amounts of histamine in a severe allergic reaction (see Chapter 7). • Septic shock may develop in persons with severe infec- tion, particularly infections with gram-negative endotoxins, such as Escherichia coli, Klebsiella pneumoniae, and Pseudomonas. Initial circulatory changes vary with the causative organism, but eventually systemic vasodilation develops. In some cases, the organism affects the heart as well. ■ Signs and Symptoms Often missed, the first signs of shock are thirst and agita- tion or restlessness because the SNS is quickly stimulated by hypotension. This is followed by the characteristic signs of compensation: • Cool, moist, pale skin EMERGENCY TREATMENT FOR SHOCK 1. Place patient in supine position. 2. Cover and keep warm. 3. Call for assistance. 4. Administer oxygen if possible. 5. Determine underlying cause and treat if possible, such as using an EpiPen for anaphylaxis or applying pressure for bleeding. The primary problem must be treated as quickly as possible to prevent decompensation. In patients with hypovolemic shock, whole blood, plasma, or fluid with electrolytes and bicarbonate is required. When the cause 268 SECTION III Pathophysiology of Body Systems Dopamine and dobutamine increase heart function and, in low doses, dilate renal blood vessels, which may prevent acute renal failure. The prognosis is good in the early stages. However, the mortality rate increases as decompensated shock develops in conjunction with renal failure, ARDS, or DIC. is anaphylaxis, antihistamines and corticosteroids are given as well. Antimicrobials and glucocorticoids are necessary with septic shock. The oxygen supply should be maximized. The use of vasoconstrictors and vasodila- tors depends on the specific situation. Epinephrine acts both to reinforce heart action and constrict blood vessels. Lethargy, weakness Cool, moist, pale skin Low BP Tachycardia Weak, thready pulse Tachypnea Oliguria Metabolic acidosis 2. Progressive Anxiety, restlessness Thirst Tachycardia 1. Early Stupor, confusion Arrhythmias Weak, slow pulse Metabolic acidosis Acute respiratory distress syndrome Multiple thrombi Acute liver failure Acute renal failure Paralytic ileus Gastrointestinal hemorrhage 3. Decompensated FIG. 12.36 General effects of shock. TABLE 12.5 Manifestations of Shock Manifestations Causes Early signs Anxiety and restlessness Hypotension stimulates SNS Compensation Tachycardia SNS response stimulates heart Cool, pale, moist skin Peripheral vasoconstriction Oliguria Renal vasoconstriction and renin mechanism Thirst Osmoreceptors stimulated Rapid respirations Anaerobic metabolism increases lactic acid secretion, which leads to increased respiratory rate Progressive Lethargy, weakness, faintness Decreased blood flow and cardiac output Metabolic acidosis Anaerobic metabolism increases lactic acid Decreased renal excretion of acids and production of bicarbonate owing to decreased glomerular filtration rate SNS, sympathetic nervous system. CHAPTER 12 Cardiovascular System Disorders 269 THINK ABOUT 12.21 a. List and explain the signs indicating that compensation is occurring in patients with shock. b. Explain two reasons why acidosis develops in shock. c. State the expected changes in the arterial blood gas measurements with rationale for compensated acidosis with shock (see Chapter 2). d. Give several reasons why shock tends to become progressively more serious. e. Explain why septic shock could be referred to as “warm shock.” CASE STUDY A Myocardial Infarction Ms. X., aged 55 years, has been complaining of severe fatigue and “indigestion.” Her son is quite concerned and decides to take her to the emergency department. On arrival she appears very anxious, and her facial skin is cool and clammy; her blood pressure is 90/60, and the pulse is around 90, weak, and irregular. She is given oxygen, an intravenous line is opened, and leads for ECG are attached. Blood is taken for determination of serum enzymes and electrolytes. Tentative diagnosis is myocardial infarction involving the left ventricle. Her son provides informa- tion that indicates Ms. X is a long-time smoker, has a stressful job as a high school teacher, is recently separated after 20 years of marriage, and is fearful of losing the family home. She has also seemed to be more fatigued and stopped going to the gym about 18 months ago. She has begun to rely on “fast foods” like pizza and fried chicken and cooks infrequently. Her father had died of a heart attack at age 50. She had also noticed more fatigue and intermittent leg pain when walking or climbing stairs at work. Generalized atherosclerosis is suspected. 1. List the high-risk factors for atherosclerosis in this patient’s history. 2. Describe how atherosclerosis causes myocardial infarction. 3. It is suspected that the indigestion reported in the history was really angina. Explain how this pain may have occurred. 4. Explain each of the admitting signs. 5. What is “atypical” in Ms. X’s symptoms? How does this affect treatment and prognosis? 6. What information do serum enzyme and electrolyte levels provide? 7. What purpose does the ECG serve? It is determined that Ms. X. has a large infarct in the anterior left ventricle. 8. Ms. X. is showing increasing PVCs on the ECG. State the cause and describe the effect if these continue to increase in frequency. 9. On day 6 after admission Ms. X is preparing to go home with her son and they receive instructions on lifestyle modifications that are desirable if Ms. X is to avoid another MI. What measures should be included in such a discussion? CASE STUDY B Essential Hypertension Ms. J., aged 48 years, has essential hypertension, diagnosed 4 years ago. She has not been taking her medication during the past 6 months because she has been feeling fine. Now she has a new job and has been too busy to enjoy her usual swimming and golf. She has decided to have a checkup because she is feeling tired and dyspneic and has had several bouts of dizziness, blurred vision, and epistaxis (nosebleeds) lately. On examination, her blood pressure is found to be 190/120, some rales are present in the lungs, and the retinas of her eyes show some sclerosis and several arteriolar ruptures. The physician orders rest and medication to lower the blood pressure, as well as an appointment with a nutritionist and urinary tests to check kidney function. 1. Describe the pathophysiology of essential hypertension. 2. Explain the possible problems associated with the high diastolic pressure. 3. Explain the significance of the retinal changes. 4. The doctor suspects mild congestive heart failure. Explain how this can develop from hypertension. 5. Give two other possible signs of CHF. 6. List two medications that are helpful in treating hypertension, and describe their actions. Ms. X’s condition becomes less stable and she remains in the hospital. On the seventh day following admission, she is found unconscious on the floor of her bathroom. Her pulse is weak and elevated, and her skin is moist with pallor evident. Her BP is 50 systolic. A diagnosis of cardiogenic shock is made and resuscitation efforts are started. 10. Explain why Ms. X. has experienced cardiogenic shock at this time. 11. Describe the effects of cardiogenic shock on the organs of the body. 12. What problems will occur if decompensated shock occurs? How is compensation limited in this situation? 13. Ms. X dies shortly later. What is the cause of death in this case? C H A P T E R S U M M A R Y Heart function may be impaired by conduction system abnormalities, interference with the blood supply to the myocardium, or structural abnormalities. Arterial and venous disorders usually affect cardiac function as well. Multiple long-term factors usually predispose to heart dysfunction. Treatment of cardiovascular disorders fre- quently involves dietary changes, exercise programs, and cessation of cigarette smoking, as well as drug therapy and possibly surgery. • Arteriosclerosis refers to degeneration of small arteries with loss of elasticity; development of thick, hard walls and narrow lumens causing ischemia; and possibly local necrosis. • In atherosclerosis, cholesterol plaques and thrombi obstruct large arteries such as the aorta and the 270 SECTION III Pathophysiology of Body Systems coronary and carotid arteries. Obstructions may be partial or complete, and emboli are common. Factors such as genetic conditions, high cholesterol diet, elevated serum LDL levels, and elevated blood pressure predispose patients to the development of atheromas. • Angina pectoris attacks are precipitated when the demand for oxygen by the myocardium exceeds the supply. Chest pain is relieved by intake of the vasodila- tor nitroglycerin and decreasing demands on the heart. • MI results from total obstruction in a coronary artery, resulting in tissue necrosis and loss of function. Continuing chest pain, hypotension, and typical changes in the ECG are diagnostic. Arrhythmias are a common cause of death shortly after infarction occurs. • Cardiac arrhythmias may result from MI or systemic abnormalities such as electrolyte imbalance, infection, or drug toxicity. Arrhythmias include abnormally slow or rapid heart rates, intermittent additional heart contractions (extrasystoles), or missed contractions (heart blocks). • Depending on the cause, congestive heart failure may develop first in either the right or the left side of the heart, causing systemic backup and congestion or pulmonary congestion, respectively. In either case, cardiac output to the body is reduced, causing general fatigue and weakness, and stimulating the renin- angiotensin mechanism. • Congenital heart defects consist of a variety of single or multiple developmental abnormalities in the heart. These structural abnormalities may involve the heart valves, such as mitral stenosis; the septae, such as ventricular septal defect; the proximal great vessels; or a combination of structural defects The primary outcome is decreased oxygen to all cells in the body. • Cyanotic defects such as the tetralogy of Fallot refer to congenital defects where blood leaving the left ventricle consists of mixed oxygenated and unoxygen- ated blood, thereby delivering only small amounts of oxygen to all parts of the body. • Rheumatic fever is a systemic inflammatory condition caused by an abnormal immune response to certain strains of hemolytic streptococcus. Inflammation causes scar tissue on heart valves and in the myocardium, leading to rheumatic heart disease. • Infectious endocarditis causes destruction and per- manent damage to heart valves and chordae tendineae. Individuals with heart defects or damage should take prophylactic antibacterial drugs before invasive procedures in which bacteremia is a threat. • When pericarditis leads to a large volume of fluid accumulating in the pericardial cavity, filling of the heart is restricted, and cardiac output is reduced. • Essential or primary hypertension is idiopathic and marked by a persistent elevation of blood pressure above 140/90, related to increased systemic vasocon- striction. It is frequently asymptomatic, but if not monitored and controlled it may cause permanent damage to the kidneys, brain, and retinas as well as possible congestive heart failure. • Atherosclerosis in the abdominal aorta or iliac arteries may cause ischemia in the feet and legs, resulting in fatigue, intermittent claudication, sensory impairment, ulcers, and possibly gangrene and amputation. • Aortic aneurysms are frequently asymptomatic until they are very large or rupture occurs. • Varicose veins in the legs tend to be progressive. They cause fatigue, swelling, and possible ulcers in the skin. • Pulmonary emboli are a greater risk with phlebothrom- bosis, usually a silent problem, than with thrombo- phlebitis, in which inflammation is more apparent. • Circulatory shock may result from decreased blood volume, impaired cardiac function with reduced output, or generalized vasodilation, any of which reduce blood flow and available oxygen in the microcirculation. Compensation mechanisms include the sympathetic nervous system; renin mechanism; increased secre- tion of ADH, aldosterone, and cortisol; and increased respirations. Decompensated shock develops with complications such as organ failure or infection. S T U D Y Q U E S T I O N S 1. Name three mechanisms that can increase cardiac output. 2. Explain the effect on blood flow of mitral valve incompetence. 3. Explain the importance/function for each of the following: a. High elastic fiber content in the aorta b. Smooth muscle in the arterioles c. Extensive capillaries in the liver and lungs d. Valves in the leg veins 4. Differentiate angina from myocardial infarction with regard to its cause and the characteristics of pain associated with it. 5. If you had a client with persistent chest pain following rest and administration of nitroglycerin, what action would you take? 6. Explain why vasodilator drugs are of limited value in arterial disease. 7. List and explain briefly three possible causes of cardiac dysrhythmias. 8. Differentiate heart blocks from PVCs with regard to causes and effects on heart action. 9. Describe the stages in the development of an atheroma in an artery CHAPTER 12 Cardiovascular System Disorders 271 14. Describe three early signs of shock and the rationale for each. 15. Explain how neurogenic and hypovolemic shock may occur with major burns. 16. List four types of congenital heart defects, and briefly describe each. 10. Why would you recommend avoidance of prolonged stress for a patient with congenital heart disease? 11. Explain how aortic stenosis may develop following rheumatic fever. 12. Explain why untreated essential hypertension is dangerous. 13. Define and explain the term intermittent claudication. 272 Review of Structures of the Respiratory System Purpose and General Organization Structures in the Respiratory System Upper Respiratory Tract Lower Respiratory Tract Ventilation The Process of Inspiration and Expiration Pulmonary Volumes Control of Ventilation Gas Exchange Factors Affecting Diffusion of Gases Transport of Oxygen and Carbon Dioxide Diagnostic Tests General Manifestations of Respiratory Disease Common Treatment Measures for Respiratory Disorders Infectious Diseases Upper Respiratory Tract Infections Common Cold (Infectious Rhinitis) Sinusitis Epiglottitis Influenza (Flu) Scarlet Fever Lower Respiratory Tract Infections Bronchiolitis (Respiratory Syncytial Virus Infection) Pneumonia Severe Acute Respiratory Syndrome Tuberculosis Histoplasmosis Anthrax Obstructive Lung Diseases Cystic Fibrosis Lung Cancer Aspiration Obstructive Sleep Apnea Asthma Chronic Obstructive Pulmonary Disease Emphysema Chronic Bronchitis Bronchiectasis Restrictive Lung Disorders Pneumoconioses Vascular Disorders Pulmonary Edema Pulmonary Embolus Expansion Disorders Atelectasis Pleural Effusion Pneumothorax Flail Chest Infant Respiratory Distress Syndrome Adult or Acute Respiratory Distress Syndrome Acute Respiratory Failure Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E C H A P T E R 13 Respiratory System Disorders After studying this chapter, the student is expected to: 1. Describe the common upper respiratory tract infections. 2. Explain how secondary bacterial infections occur in the respiratory tract. 3. Compare the different types of pneumonia. 4. Differentiate the effects of primary from secondary tuberculosis. 5. Describe the pathophysiology and complications of cystic fibrosis. 6. Describe the etiology and pathophysiology of bronchogenic carcinoma. 7. Describe the possible outcomes of aspiration. 8. Compare the types of asthma and describe the pathophysiology and manifestations of an acute attack. 9. Compare emphysema and chronic bronchitis. 10. Explain how bronchiectasis develops as a secondary problem and also its manifestations. 11. Describe the causes of pulmonary edema, and explain how it affects oxygen levels. 12. Compare the effects of small, moderate, and large-sized pulmonary emboli. 13. Describe the causes of atelectasis and the resulting effects on ventilation and oxygen levels. 14. Explain the effects of pleural effusion on ventilation. 15. Compare the types of pneumothorax. 16. Explain how a flail chest injury affects ventilation, oxygen levels, and circulation. 17. Describe the pathophysiology and signs of infant respiratory distress syndrome. 18. Describe the possible causes of adult respiratory distress syndrome and the pathophysiology. 19. Describe the etiology and changes in blood gases with acute respiratory failure. 20. Explain the cause of sleep apnea, and describe the effects and complications of this disorder. L E A R N I N G O B J E C T I V E S CHAPTER 13 Respiratory System Disorders 273 Review of Structures of the Respiratory System Purpose and General Organization The respiratory system provides the mechanisms for transporting oxygen from the air into the blood and for removing carbon dioxide from the blood. Oxygen is essential for cell metabolism, and the respiratory system is the only means of acquiring oxygen. Carbon dioxide is a waste material resulting from cell metabolism, and it influences the acid-base balance in body fluids. The respiratory system consists of two anatomic areas. The upper respiratory tract is made up of the passageways that conduct air between the atmosphere and the lungs, and the lower respiratory tract consists of the trachea, bronchial tree, and the lungs, where gas exchange takes place. In addition, the pulmonary circulation, the muscles required for ventilation, and the nervous system, which plays a role in controlling respiratory function, are integral to the function of the respiratory system. Structures in the Respiratory System Upper Respiratory Tract When air is inhaled into the respiratory system, it first enters the nasal passages, passing over the conchae or turbinates, where it is warmed and moistened by the highly vascular mucosa. Foreign material is filtered out by the mucous secretions and hairs before the air enters the delicate lung tissue. Opening off the nasal cavity through small canals are four pairs of paranasal sinuses, which are small cavities in the skull bones (Fig. 13.1). The presence of the hollow sinuses reduces the weight of the facial bones and adds resonance to the voice. They are named according to the bones in which they are located—the frontal, ethmoid, sphenoid, and maxillary sinuses. The sinuses are lined by a continuation of the respira- tory mucosa. The respiratory mucosa consists of pseu- dostratified ciliated columnar epithelium, which includes mucus-secreting goblet cells. The resultant mucous blanket “traps” foreign particles, and the cilia “sweep” the mucus and debris up and out of the respiratory tract. This process is referred to as the “ciliary escalator.” Excessive amounts of mucus or particles stimulate a sneeze or a cough, which assists in expelling unwanted material away from the lungs. Smoking impairs the function of the cilia, and the irritation caused by smoke leads to replacement of ciliated epithelium by squamous cells, thereby removing this protective mechanism. The airflow continues through the nasopharynx and larynx into the trachea. On the posterior wall of the nasopharynx are located the pharyngeal tonsils or adenoids, which consist of lymphoid tissue, another defense against the inhalation of foreign material. If these tonsils become enlarged owing to infection, they can obstruct the flow of air through the nasopharynx, leading to mouth breath- ing. When air passes through the mouth directly into the respiratory tract, it is not warmed, moistened, and filtered properly before it reaches the delicate lung tissue. The tissues of the mouth become dry and irritated, and there is a risk of increased dental caries as normal salivary cleansing function is lost. The palatine tonsils, popularly called the tonsils, are lymphoid tissue located in the posterior portion of the oral cavity (see Fig. 17.2 in Chapter 17). Also opening off the nasopharynx are the two auditory (eustachian) tubes, which connect to the middle ear cavities. The continuation of the respiratory mucosa into the sinuses and middle ear creates a predisposition to the spread of infection from the upper respiratory tract. The upper respiratory tract has a resident flora, whereas the lungs are sterile, containing no microorganisms. The pharynx, where the nasopharynx joins the oropharynx, serves as a common passage for air and food and descends to the point of separation of the esophagus and trachea. When infection is present, the inflammation and swelling in the area causes sore throat and painful swallowing. In the airway, the cartilaginous epiglottis protects the opening into the larynx, or voice box, by flipping up or down during swallowing or ventilation. The larynx consists of various cartilages and their associated muscles. The largest is the thyroid cartilage, which forms the “Adam’s apple,” a structure that may protrude in the anterior neck area. There are two pairs of vocal cords, which are infoldings of the mucous membrane: the upper, or “false,” pair, and the lower pair, constituting the true vocal cords. The glottis refers to the true vocal cords and the space between them. When air is expired through the larynx, the true vocal cords vibrate, producing the sound of the voice. Other structures affect the characteristics of this sound, including the mouth, tongue, pharynx, and sinuses. The vocal cords, when approximated, prevent food from entering the trachea and lungs. apnea bifurcation bronchodilation caseation clubbing cohesion compliance empyema eupnea expectorant hemoptysis Hering-Breuer reflex hypercapnia hypoxemia orthopnea paroxysmal nocturnal dyspnea proteases pulsus paradoxus rales residual volume rhonchi sputum steatorrhea stridor surface tension vital capacity wheezing K E Y T E R M S 274 SECTION III Pathophysiology of Body Systems THINK ABOUT 13.1 a. Name and locate the lymphoid structures in the upper respiratory tract. b. Describe the structure and function of the paranasal sinuses. c. Describe how inhaled air may be altered as it passes through the nasal passages and pharynx. d. Explain how allergens such as pollen affect the upper respiratory tract. Pharyngeal tonsil Auditory tube opening Palatine tonsil Nasopharynx Oropharynx Laryngopharynx Vocal cords Secondary bronchus Esophagus Right lung Sphenoid sinus Nasal cavity Nose Epiglottis Larynx Trachea Bronchioles Mediastinum Primary bronchus Diaphragm Left lung Parietal pleura Visceral pleura Pleural cavity Respiratory bronchiole Alveolar duct Alveolar sac Alveolus Frontal sinus Hard palate FIG. 13.1 Anatomy of the respiratory system. As inspired air is tracked downward through the larynx, it flows into the trachea, or windpipe. The wall of the trachea contains 16 to 20 hyaline cartilage rings, fibroelastic tissue, and smooth muscle tissue. The trachea is flexible enough to allow bending and elongation. The cartilage rings prevent the collapse of the trachea and keep the airway open even with the pressure changes. The posterior wall of the trachea is not rigid, thus allowing the esophagus to expand as swallowed food moves through it. an inverted bronchial “tree.” As the bronchi become smaller, the cartilaginous rings are replaced by irregular plates of cartilage. As the bronchi divide into bronchioles, supportive cartilage is no longer present. The smooth muscle contracts or relaxes to adjust the diameter of the bronchioles. Bronchodilation results when sympathetic stimulation relaxes the smooth muscle, dilating or enlarg- ing the bronchioles. Many elastic fibers are present in the lung tissue, enabling the expansion and recoil of the lungs during ventilation. The respiratory mucosa thins and changes from pseudostratified columnar to simple columnar and then to simple cuboidal epithelium in the terminal and respiratory bronchioles. Air in the bronchioles then flows into the alveolar ducts and alveoli, or air sacs, which resemble a cluster of grapes. The alveoli are formed by a single layer of simple squa- mous epithelial tissue, which promotes the diffusion of gases into the blood, the end point for inspired air (see Fig. 13.5, presented later in the chapter). The respiratory membrane is the combined alveolar and capillary wall, a thin membrane, through which gas exchange takes place. There are millions of alveoli, and the capillaries of the pulmonary circulation are in close contact, provid- ing a large surface area for the diffusion of gases. The alveoli contain macrophages (alveolar macrophages), whose function is to remove any foreign material that penetrates to this level. However, some substances can escape any action by macrophages. The inside surfaces of the alveoli are coated with a small amount of fluid containing surfactant, produced by specialized cells in the alveolar wall. Surfactant has Lower Respiratory Tract At the lower end of the trachea, inhaled air proceeds into the right or left primary bronchus. The right bronchus is larger and straighter and therefore is the more likely destination for any aspirated material. The point at which the bronchus enters the lung is the hilum. Each major or primary bronchus then branches into many smaller (secondary) bronchi and then into bronchioles, forming CHAPTER 13 Respiratory System Disorders 275 high-pressure area to a low-pressure area (flow is one way only!). If atmospheric pressure is higher than air pressure inside the lungs, air will move from the atmosphere into the lungs (inspiration). For expiration to occur, pressure must be higher in the lungs than in the atmosphere. These pressure changes in the lungs result from alterations in the size of the thoracic cavity. As the size of the thoracic cavity decreases, the pressure inside the cavity increases (Boyle’s law). A sequence of events is responsible for the change in size of the thorax and the changes in airflow with inspira- tion and expiration: 1. Normal quiet inspiration begins with contraction of the diaphragm (the primary muscle of inspiration) and the external intercostal muscles. 2. The diaphragm flattens and descends, increasing the length of the thoracic cavity (Fig. 13.2). 3. The external intercostal muscles raise the ribs and sternum up and outward, increasing the transverse and anteroposterior diameters of the thorax. 4. The increased size of the thoracic cavity results in decreased pressure in the pleural cavity and in the alveoli and airways. 5. As the ribs and diaphragm move, the attached parietal pleura pulls the adhering visceral pleura and lungs along with it. 6. As the visceral pleura moves outward, the elastic lungs expand with it, resulting in a decrease in air pressure inside the lungs. 7. At this point, atmospheric pressure is greater than intraalveolar pressure, so air flows from the atmo- sphere down the airways into the alveoli. Note that the thorax and lungs must expand before more air can enter the lungs; it is not the air entering the lungs that makes them expand. Breathing requires physical effort and cellular energy. 8. During normal expiration the diaphragm and external intercostal muscles relax, leading to a decrease in thoracic size. 9. This decrease, combined with the natural elastic recoil of the alveoli, results in increased intraalveolar pres- sure (greater than atmospheric pressure). 10. Therefore air flows out of the alveoli into the atmo- sphere. Quiet expiration is a passive process and does not require cellular energy. Forced inspiration or expiration requires additional energy and muscular activity. In forced inspiration the sternocleidomastoid, scalene, pectoralis minor, and ser- ratus muscles contract to increase the elevation of the ribs and sternum. During forceful expiration the abdomi- nal muscles contract to increase upward pressure on the diaphragm, and the intercostal muscles contract, pulling the ribs and sternum down and inward. Compliance is the term used to refer to the ability of the lungs to expand. Compliance depends largely on the elasticity of the tissues, but can also be affected by other factors, such as alveolar surface tension and the shape, size, and flexibility of the thorax. a detergent action that reduces surface tension of the alveolar fluid (the tendency for fluid to reduce its surface area by forming droplets), facilitating inspiration and preventing total collapse of the alveoli during expiration. When inspiration is complete, the process of expiration reverses airflow in the passageways, forcing air out of the alveoli and up the bronchi, trachea, and nose. The lungs are cone-shaped structures positioned on either side of the heart. The mediastinum is the region in the center of the chest, which contains the heart, the major blood vessels, the esophagus, and the trachea. The dome-shaped muscular diaphragm forms the inferior boundary. The right lung is divided into three lobes and the left lung into two lobes because of the position of the heart, and each lobe is then divided into segments. The lung tissue (lungs, bronchi, and pleurae) is nourished by the bronchial arteries, which branch from the thoracic aorta. Each lung is covered by its own double-walled sac, the pleural membrane. The visceral pleura is attached to the outer surface of the lung and then doubles back to form the parietal pleura, which lines the inside of the thoracic cavity, adhering to the chest wall and the diaphragm. The visceral pleura lies closely against the parietal pleura, separated only by small amounts of fluid in the pleural cavity or space, which is considered only a potential space. The slightly negative pressure (less than atmospheric pressure) in the pleural cavity also assists in holding the pleura in close approximation and promoting lung expansion. The pleural fluid provides lubrication during respiratory movements and a force that provides cohesion, or “sticking together” (high surface tension), between the two pleural layers during inspiration. The thorax, consisting of ribs, vertebrae, and sternum (breastbone), provides a rigid protective wall for the lungs. The upper seven pairs of ribs (true ribs) articulate with the vertebrae and are attached to the sternum by costal (hyaline) cartilage. The next three pairs of ribs are “false” ribs, which are connected to the costal cartilage of the seventh rib, not directly to the sternum. The last two ribs (also false), the eleventh and twelfth pairs, are attached only to vertebrae and are therefore called floating ribs. Between the ribs are located the external and internal intercostal muscles, which move the thoracic structures during ventilation. APPLY YOUR KNOWLEDGE 13.1 Predict three ways by which ventilation or gas exchange could be impaired. Ventilation The Process of Inspiration and Expiration Airflow during inspiration and expiration depends on a pressure gradient, with air always moving from a 276 SECTION III Pathophysiology of Body Systems Atmospheric Pressure — 760 mm Hg Chest wall 1. Muscles contract Chest wall moves out 1. Muscles relax Chest wall moves inward Intrapleural space 4. Intrapleural pressure becomes more negative (754 mm Hg) 3. Intrapleural pressure remains negative Intrapleural pressure 756 mm Hg 3. Intrapulmonic pressure becomes negative (usually less than atmosphere–758 mm Hg) 4. Intrapulmonic pressure becomes positive (greater than atmosphere– 763 mm Hg) Intrapulmonic space–760 mm Hg (pressure of atmosphere) DiaphragmA B 2. Diaphragm descends 5. Air out 2. Diaphragm ascendsC Resting Inspiration Expiration Air Air 5. Air — 760 mm Hg flows in FIG. 13.2 Ventilation: Changes in pressure with inspiration and expiration. THINK ABOUT 13.2 a. Describe the purpose of (1) surfactant, (2) the ribs, (3) the respiratory membrane, (4) the diaphragm, (5) alveolar macrophages, and (6) the bronchial artery. b. Describe the sequence of events that takes place during inspiration. c. Explain the oxygen demands of quiet respiration versus forced respirations. d. Explain why frequent forced expirations are fatiguing. TABLE 13.1 Pulmonary Volumes Name Volume Meaning Tidal volume (TV) 500 mL Amount of air entering lungs with each normal breath Residual volume (RV) 1200 mL Amount of air remaining in the lungs after forced expiration Inspiratory reserve (IRV) 3000 mL Maximal amount of air that can be inhaled in excess of normal quiet inspiration Expiratory reserve (ERV) 1100 mL Maximal volume of air expired following a passive expiration Vital capacity (VC) 4600 mL Maximal amount of air expired following a maximal inspiration Total lung capacity (TLC) 5800 mL Total volume of air in the lungs after maximal inspiration Changes in ventilation occur during pregnancy (see Chapter 22) and with aging (see Chapter 24). Pulmonary Volumes Pulmonary volumes are a measure of ventilatory capacity, which is the measure of the air moving in and out of the lungs with normal or forced inspiration and expiration (Fig. 13.3). Pulmonary volumes can change with disease processes and are helpful in monitoring a patient’s progress or response to treatment. For example, impaired expiration can cause an increase in residual volume and therefore increased carbon dioxide levels in body fluids. Some of the basic volumes are summarized in Table 13.1. • Residual volume is the volume of air remaining in the lungs after maximum expiration. This air continues to provide gas exchange and maintains partial inflation of the lungs. • Vital capacity is another important measure that represents the maximal amount of air that can be moved in and out of the lungs. It can be altered by lung disease, size of the thorax, amount of blood in the lungs, or body position. CHAPTER 13 Respiratory System Disorders 277 • The central chemoreceptors in the medulla respond quickly to slight elevations in Pco2 (from a normal 40 to 43 mm Hg) or to a decrease in pH (increased H+) of the cerebrospinal fluid. • The peripheral chemoreceptors, located in the carotid bodies at the bifurcation of the common carotid arteries and in the aortic body in the aortic arch, are sensitive to decreased oxygen levels in arterial blood as well as to low pH. Normal oxygen levels provide a substantial reserve of oxygen in the venous blood. A marked decrease in oxygen (from approximately 105 to 60 mm Hg) is necessary before the chemoreceptors respond to hypoxemia. This control mechanism can be important when individuals with chronic lung disease adapt to a sustained elevation in Pco2 and move to a hypoxic drive. Such individuals are dependent on low oxygen levels rather than the normal slight elevation in carbon dioxide to stimulate inspiration. Therefore it is important for these patients always to remain slightly hypoxic and not be given excessive amounts of oxygen at any time. Dead space refers to the passageways or areas where gas exchange cannot take place. This is the space first filled by newly inspired air. More effort is required to open and fill the alveoli for gas exchange. Anatomic dead space includes areas such as the bronchi and bronchioles. Dead space can be increased by obstruction in the pas- sageways or collapse of alveoli. Control of Ventilation The primary control centers for breathing are located in the medulla and the pons. The inspiratory center in the medulla controls the basic rhythm by stimulating the phrenic nerves to the diaphragm and the intercostal nerves to the external intercostal muscles. These stimuli occur spontaneously in a rhythmic fashion, each lasting about 2 seconds. The expiratory center in the medulla appears to function primarily when forced expiration is required because normal quiet expiration is a cessation of activity following each inspiration. Additional centers in the pons play a role in coordinating inspiration, expiration, and the intervals for each. The rate and depth of breathing set by the medullary center can be modified by a number of factors. Any depression of central nervous system activity, for example, by drugs (such as morphine), can lead to slow, shallow breathing. Other factors include activity of the hypo- thalamus, perhaps in response to emotions; or the stretch receptors in the lungs or the Hering-Breuer reflex, which prevents excessive lung expansion; or voluntary control, as required when singing. However, voluntary control is limited by the levels of carbon dioxide in the blood. When the concentration or partial pressure of carbon dioxide (Paco2) in the blood rises, breathing resumes automatically. For this reason, a child who intentionally holds his or her breath will eventually have to breathe spontaneously. Chemical factors are most important in respiratory control. Chemoreceptors sense changes in the levels of carbon dioxide, hydrogen ions, and oxygen in blood or cerebrospinal fluid (Fig. 13.4). Inspiratory reserve volume 3000 mL Tidal volume 500 mL Vital capacity 4800 mL Inspiratory capacity 3500 mL Functional residual capacity 2400 mL Total lung capacity 6000 mL Expiratory reserve volume 1200 mL Residual volume 1200 mL 3000 mL 6000 mL 5000 mL 4000 mL 0 1000 mL 2000 mL Maximal expiration Time Maximal inspiration FIG. 13.3 Pulmonary volumes. THINK ABOUT 13.3 a. Name the major stimulus for inspiration. b. How do elevated carbon dioxide levels alter serum pH and respiratory pattern? c. State the normal serum pH and describe how compensation for decreased serum pH due to a respiratory impairment is achieved. d. Describe how acidosis affects the central nervous system and give two physiologic signs of this condition. e. Predict the effects on ventilation and carbon dioxide levels if a patient with chronic hypercapnia is given a large amount of 100% oxygen. When carbon dioxide levels in the blood increase (hypercapnia), the gas easily diffuses into the cerebro- spinal fluid, lowering pH and stimulating the respiratory center, resulting in an increased rate and depth of 278 SECTION III Pathophysiology of Body Systems respirations (hyperventilation). Hypercapnia causes respiratory acidosis, and acidosis depresses the nervous system. Hypocapnia, or low Pco2, may be caused by hyperventilation after excessive amounts of carbon dioxide have been expired. Hypocapnia causes respiratory alkalosis. To review the conditions of respiratory acidosis and alkalosis and the role of arterial blood gases, refer to Chapter 2. Gas Exchange Gas exchange, or external respiration, is the flow of gases between the alveolar air and the blood in the pulmonary circulation. Diffusion of oxygen and carbon dioxide in A. NORMAL CYCLE B. HYPOXIC DRIVE WITH CHRONIC ELEVATED Pco2 LEVELS (e.g., emphysema) CHRONIC ELEVATION OF CO2 LEVELS Slow respirations Decreased chemoreceptor stimulation Decreased PCO2 Increases respiratory rate Stimulates inspiratory muscles Stimulates central chemoreceptors in medulla Increased PCO2 in blood and CSF Removes more CO2 from body Retain more CO2 MEDULLARY CHEMORECEPTORS BECOME INSENSITIVE TO HIGH PCO2 No increase in respiration Marked decrease in O2 levels VERY LOW PO2 STIMULATES PERIPHERAL CHEMORECEPTORS Inspiratory muscles stimulated Remove CO2 and take in more O2 PCO2 decreases, PO2 increases Respirations slow Pco2 increases, PO2 decreases slightly Increased respirations FIG. 13.4 Respiratory control and hypoxic drive. the lungs depends on the relative concentrations or partial pressures of the gases, and movement of each gas always occurs from a high-pressure area to a low-pressure area. It is customary to refer to the concentration of a gas such as oxygen in a mixture as the partial pressure of that gas, for example, Po2. When the measurement refers specifically to the partial pressure of oxygen in arterial blood, it is expressed as Pao2. Each gas in a mixture moves or diffuses according to its own partial pressure gradient and independent of other gases (Dalton’s law). For example, oxygen diffuses from alveolar air, an area with a high concentration of oxygen, to the blood in the pulmonary capillary, which has a low concentration of oxygen, until the concentrations become equal (Fig. 13.5). Meanwhile, carbon dioxide diffuses out of the pulmonary capillary into the alveolar air depending on its relative concentrations. Atmospheric air contains oxygen, carbon dioxide, nitrogen, and water. Because the air is not totally expired from the alveoli during expiration and has been humidified during its passage into the lungs, alveolar air has different concentra- tions of gases than either atmospheric air or blood. The residual air in the alveoli allows continuing gas exchange between expiration and inspiration because blood continu- ally flows through the pulmonary circulation. The pulmonary circulation is composed of the pul- monary arteries, which bring venous blood (dark blue-red in color) from the right ventricle of the heart to be oxygen- ated; the pulmonary capillaries, in which diffusion or gas exchange occurs; and the pulmonary veins, which return the oxygenated blood (bright red) to the left atrium of the heart. The oxygenated blood moves from the left ventricle of the heart, which pumps the blood into the aorta, and the systemic circulation starts. APPLY YOUR KNOWLEDGE 13.2 1. Predict specific changes in structure or function that would likely decrease oxygen levels in the body. 2. Predict specific changes in structure or function that would likely increase carbon dioxide levels in the body. Factors Affecting Diffusion of Gases In addition to the partial pressure gradient, diffusion can be altered by other factors such as the thickness of the respiratory membrane. When fluid accumulates in the alveoli or interstitial tissue, diffusion, particularly of oxygen, is greatly impaired. Normally the pressure in the pulmonary circulation is very low, reducing the risk of excessive fluid in the interstitial space and alveoli. The presence of extra fluid may also impede blood flow through the pulmonary capillaries and increase surface tension in the alveoli, restricting expansion of the lung. Other major factors in gas exchange are the total surface area available for diffusion and the thickness of CHAPTER 13 Respiratory System Disorders 279 Pu lmon ary artery Pulmonary vein Inspired air Expired air Alveolus PCO2 PO2 PO2 = 160 PCO2 = 0.3 PCO2 2 2 PO2 = 40 = 45 PO PCO 2 2 = 105 = 40 PO2 = 120 mm Hg PCO2 = 27 mm Hg Lungs Diffusion of CO into alveolus Diffusion of O into blood RBC 40 105 Air Surfactant- producing cell Layer of surfactant Alveolar macrophage Squamous endothelial cell (capillary) Squamous epithelial cell (alveolar) Alveolo- capillary interspace Capillary Connective tissue cell RBC Elastic Pulmonary venule Pulmonary arteriole Alveoli A. Pulmonary capillaries around alveolus B. Cross-section of an alveolus C. Diffusion of gases fiber Blood from the right ventricle Blood returns to the left ventricle FIG. 13.5 The alveolus and diffusion of gases. Transport of Oxygen and Carbon Dioxide Only about 1% of total oxygen is dissolved in plasma because oxygen is relatively insoluble in water. This factor also limits the ease with which oxygen can diffuse. The dissolved form of the gas is that which diffuses from the alveolar air into the blood in the pulmonary capillaries and also diffuses into the interstitial fluid and the cells during the process of internal respiration. Most oxygen is transported reversibly bound to hemoglobin by the iron molecules and is called oxyhemoglobin (see Fig. 10.16A for a diagram of hemoglobin and attachments). When all four heme molecules in hemoglobin have taken up oxygen, the hemoglobin is termed fully saturated (measurement expressed as Sao2). As oxygen diffuses out of the blood into the interstitial fluid and the cells, hemoglobin releases oxygen to replace it, so dissolved oxygen is always available in the plasma, ready to diffuse into the cells. The rate at which hemo- globin binds or releases oxygen depends on factors such as Po2 (the partial pressure of dissolved oxygen), Pco2 temperature, and plasma pH (Fig. 13.6). Normally approximately 25% of the bound oxygen is released to the cells for metabolism during an erythrocyte’s trip through the systemic circulation, leaving 75% of the hemoglobin in the venous blood still saturated with oxygen. This provides a good safety margin of oxygen that is available to meet increased cell demands. Carbon dioxide, a waste product from cell metabolism, is transported in several forms. Approximately 7% is dissolved in the plasma and can easily diffuse across membranes. Roughly 20% is loosely and reversibly bound to hemoglobin, attached to an amino group on the globin portion (not the heme). This is termed carbaminoglo- bin. The majority of carbon dioxide resulting from cell metabolism diffuses into the red blood cells (RBCs), where, the alveolar membranes. The alveoli are the only structures that provide such a surface area, and both ventilation and perfusion must be adequate for diffusion to occur (see Fig. 13.20, presented later in the chapter). If part of the alveolar wall is destroyed, as in emphysema, or fibrosis occurs in the lungs, the surface area is greatly reduced. If airflow into the alveoli is obstructed or the capillaries are damaged, the involved surface area becomes nonfunctional. This imbalance is measured by the ventilation-perfusion ratio (V̇a/Q̇). An autoregulatory mechanism in the lungs can adjust ventilation and blood flow in an attempt to produce a good match. For example, if Po2 is low because of poor ventilation in an area, vasoconstriction occurs in the pulmonary arterioles, shunting the blood to other areas of the lungs where ventilation may be better. If airflow is good, the pulmonary arterioles dilate to maxi- mize gas exchange. THINK ABOUT 13.4 a. Explain why oxygen diffuses from alveolar air into the blood. b. Name the blood vessels bringing blood into the pulmonary circulation, and describe the blood in these vessels. c. Describe the effect of a thickened respiratory membrane on blood levels of oxygen and carbon dioxide. Which gas is affected more? d. Death by drowning can occur in either of two ways: by the airways filling with water (more common) or via a reflex laryngospasm (strong muscle contraction of the larynx, closing it). Explain how each mechanism causes death. 280 SECTION III Pathophysiology of Body Systems P er ce nt s at ur at io n he m og lo bi n (S O 2) Normal DECREASED AFFINITY Acute acidosis (↓ pH) High PCO2 Increased temperature High levels of 2,3-DPG Abnormal hemoglobin (right shift) INCREASED AFFINITY Acute alkalosis (↑ pH) Decreased PCO2 Decreased temperature Low levels of 2,3-DPG Carboxyhemoglobin Methemoglobin Abnormal hemoglobin (left shift) PO2 (mm Hg) 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 FIG. 13.6 Oxyhemoglobin dissociation curve. This graph illustrates the factors affecting the bond between oxygen and hemoglobin. The steep slope of the curve on the left represents the rapid dissociation of oxygen from hemoglobin as blood circulates through the tissues. This oxygen diffuses into the cells. The flat portion of the curve at the top of the graph illustrates the binding of oxygen with hemoglobin in the lungs. The lighter colored section above the line marked “normal” shows the effect of increased affinity, when more oxygen is bound to hemoglobin, termed a shift to the left. The darker area below the normal line shows a shift to the right, the condition in which more oxygen that is dissociated from hemoglobin moves into the cells. (From Lane EE, Walker JF: Clinical Arterial Blood Gas Analysis, St. Louis, 1987, Mosby.) under the influence of the enzyme carbonic anhydrase, it transitions briefly as carbonic acid, then is immediately converted into bicarbonate ions (see the following equa- tion). These bicarbonate ions can then diffuse back into the plasma to function in the buffer pair (see Chapter 2). CO H O H CO H HCO carbon dioxide water carbonic aci 2 2 2 3 3+ ←→ ←→ ++ − + ←→ dd hydrogen ions bicarbonate ions in presence of enzyme c ←→ + ( , aarbonic anhydrase) A ratio of 20 parts bicarbonate ion to 1 part carbonic acid maintains blood pH at 7.35. Thus carbon dioxide plays a major role in control of blood pH through this buffer system. Diagnostic Tests Common tests include the following: • Spirometry-pulmonary function testing (PFT) is used to test pulmonary volumes, measuring volume and airflow times. • Arterial blood gas determinations are used to check oxygen, carbon dioxide, and bicarbonate levels as well as serum pH. • Oximeters measure O2 saturation. • Exercise tolerance testing is useful in patients with chronic pulmonary disease for diagnosis and monitor- ing of the patient’s progress. • Radiography may be helpful in evaluating tumors or infections such as pneumonia or tuberculosis. • Bronchoscopy may be used in performing a biopsy or in checking for the site of a lesion or bleeding. • Culture and sensitivity tests on exudates from the upper respiratory tract or sputum specimens can identify pathogens and assist in determining the appropriate therapy. CHAPTER 13 Respiratory System Disorders 281 the airways. It is helpful in such cases to increase fluid intake to keep the secretions thin and easy to remove. An expectorant medication (eg, guaifenesin) or the use of a humidifier also may assist in remov- ing secretions. Thick or sticky mucus is particularly difficult to raise from the lungs, especially in elderly or debilitated patients. 3. Sputum or mucoid discharge from the respiratory tract may have significant characteristics depending on the abnormality causing it. Normal secretions are relatively thin, clear, and colorless or cream color. a. Yellowish green, cloudy, thick mucus is often an indication of a bacterial infection. b. Rusty or dark-colored sputum is usually a sign of pneumococcal pneumonia. c. Large amounts of purulent (contains pus) sputum with a foul odor may be associated with bronchiectasis. d. Thick, tenacious (sticky) mucus may occur in patients with asthma or cystic fibrosis. Blood-tinged secretions may result from a chronic cough and irritation that causes rupture of superficial capil- laries, but it may also be a sign of a tumor or tuberculosis. e. Hemoptysis is blood-tinged (bright red) frothy sputum that is usually associated with pulmonary edema. It is important not to confuse hemoptysis with hematemesis, which is vomitus containing blood and is usually granular and dark in color (coffee-grounds vomitus). 4. Breathing patterns and characteristics may be altered with respiratory disease (Fig. 13.7). The normal rate (eupnea) is 10 to 18 inspirations per minute, and the normal pattern is regular and effortless. Changes in General Manifestations of Respiratory Disease 1. Sneezing is a reflex response to irritation in the upper respiratory tract and assists in removing the irritant. It is associated with inflammation or foreign material in the nasal passages. 2. Coughing may result from irritation caused by a nasal discharge dripping into the oropharynx, from inflam- mation or foreign material in the lower respiratory tract, or from inhaled irritants such as tobacco smoke. An occasional cough is considered a normal event in a healthy person, but a persistent cough may be evidence of a respiratory disease or chronic irritation. Aspiration of food or fluid may cause a spasm of coughing. The cough reflex is controlled by a center in the medulla and consists of coordinated actions that inspire air and then close the glottis and vocal cords. This is followed by forceful expiration in which the glottis is opened and the unwanted material is blown upward and out of the mouth. In some cases, the product of a cough is swallowed. The effectiveness of the cough depends on the strength of the muscle action during both inspiration and expiration. A constant dry or unproductive cough is fatiguing because it interferes with sleep, and the respiratory muscles are used excessively. In such cases, a cough- suppressant medication (eg, codeine or dextrometh- orphan) may be used at night. A productive cough usually occurs when secretions or inflammatory exudate accumulate in the lungs, and removal of such fluids from the airways is beneficial. Excess secretions may become infected and tend to obstruct Rhythm is smooth and even with expiration longer than inspiration. Description Rapid superficial breathing; regular or irregular rhythm. Slow respiratory rate; deeper than usual depth; regular rhythm. Cessation of breathing. Increased depth of respiration with a normal to increased rate and regular rhythm. Periods of apnea alternating irregularly with a series of shallow breaths of equal depth. Deep regular sighing respirations with an increase in respiratory rate. Long, gasping inspiratory phase followed by a short, inadequate expiratory phase. Long, ineffective expiratory phase with shallow, increased respirations. Periodic breathing associated with periods of apnea, alternating regularly with a series of respiratory cycles; the respiratory cycle gradually increases, then decreases in rate and depth. Eupnea Pattern Tachypnea Bradypnea Apnea Hyperpnea Ataxic breathing Kussmaul respiration Apneusis Obstructed breathing Cheyne-Stokes respiration FIG. 13.7 Respiratory patterns. (From Phipps WJ, Monahan FD, Sands JK, et al: Medical-Surgical Nursing: Health and Illness Perspectives, ed 7, St. Louis, 2003, Mosby.) 282 SECTION III Pathophysiology of Body Systems as the inflamed membrane is stretched with inspira- tion or coughing. 9. Friction rub may be heard, a soft sound produced as the rough membranes move against each other. Pleural inflammation may be caused by lobar pneumonia or lung infarction. 10. Clubbed fingers and sometimes toes result from chronic hypoxia associated with respiratory or cardiovascular diseases. Clubbing is a painless, firm, fibrotic enlarge- ment at the end of the digit. 11. Changes in arterial blood gases (ABGs): Hypoxemia refers to inadequate oxygen in the blood (Pao2). Hypoxia, or inadequate oxygen supply to the cells, may have many causes: a. A deficit of RBCs or hemoglobin levels that are too low for adequate oxygen transport b. Circulatory impairment, which may lead to decreased cardiac output from the heart to the lungs or the systemic circulation c. Excessive release of oxygen from RBCs if circulation is sluggish through the system or is partially obstructed by vascular disease d. Impaired respiratory function, including inadequate ventilation, inhalation of oxygen-deficient air, or impaired diffusion e. Carbon monoxide poisoning, in which carbon monoxide binds tightly and preferentially to heme, displacing oxygen. Unfortunately, carbon monoxide does not cause obvious signs of hypoxia (rather a bright red coloring of the skin and mucosa with headache and drowsiness) or affect ventilation, but it can be fatal quickly and quietly. Hypoxia affects cell metabolism, reducing cell function and leading to anaerobic metabolism and the development of metabolic acidosis. The brain is most susceptible to an oxygen deficit because it has little storage capacity for oxygen and yet has a constant demand. Cerebral hypoxia initially stimulates the sympathetic nervous system. Decreased cell function is indicated by fatigue, lethargy or stupor, and muscle weakness. Extreme or prolonged hypoxia can result in cell death. Compensation mechanisms for hypoxia due to respira- tory impairment include increased cardiovascular activity such as tachycardia and increased blood pressure. In people with chronic hypoxia due to respiratory or circula- tory impairment, erythropoietin secretion is increased, stimulating the bone marrow to produce additional red blood cells (secondary polycythemia). Acid-base imbalance may develop from respiratory disorders (see Chapter 2). Respiratory acidosis due to excess carbon dioxide (increased carbonic acid) is more common and results from impaired expiration. Arterial blood gases in this situation indicate high Pco2 and low serum pH. Respiratory alkalosis occurs when the respira- tory rate is increased, usually because of acute anxiety or excessive intake of aspirin. the rate, rhythm, depth, and effort of ventilation are significant. a. Kussmaul respirations, deep rapid respirations or “air hunger,” are typical of a state of acidosis or may follow strenuous exercise. b. Labored respirations or prolonged inspiration or expiration times are often associated with obstruc- tion of the airways. c. Wheezing or whistling sounds indicate obstruction in the small airways. d. Stridor, a high-pitched crowing noise, usually indicates upper airway obstruction. 5. Breath sounds may be abnormal or absent in respiratory disorders. Rales and rhonchi are abnormal sounds resulting from air mixing with excessive secretions in the lungs. a. Rales are light bubbly or crackling sounds associated with serous secretions. b. Rhonchi are deeper and harsher sounds resulting from thicker mucus. c. Absence of breath sounds indicates nonaeration or collapse of a lung (atelectasis). 6. Dyspnea is a subjective feeling of discomfort that occurs when a person feels unable to inhale enough air. It may be manifested as breathlessness or shortness of breath, either with exertion or at rest. a. Severe dyspnea may be accompanied by flaring of the nostrils (nares), use of the accessory respiratory muscles, or retraction (pulling in) of the muscles between or above the ribs. For example, intercostal retractions between the ribs are visible to the observer. b. Orthopnea is dyspnea that occurs when a person is lying down. Pulmonary congestion develops as more blood pools in the lungs when the person lies down and also as the abdominal contents push upward against the lungs. Raising the upper part of the body with pillows often facilitates breath- ing in persons with respiratory or cardiovascular disorders. c. Paroxysmal nocturnal dyspnea is a sudden acute type of dyspnea common in patients with left-sided congestive heart failure. During sleep the body fluid is redistributed, leading to pulmonary edema, and the individual wakes up gasping for air and coughing (see Chapter 12). 7. Cyanosis is the bluish coloring of the skin and mucous membranes that results from large amounts of unoxygenated hemoglobin in the blood. It may develop in peripheral areas as a result of exertion or be more generalized. This may occur in patients with cardiovascular conditions as well as respiratory disease, and its presence must be considered in conjunction with other data. Cyanosis is not a reliable early indicator of hypoxia. 8. Pleural pain results from inflammation or infection of the parietal pleura. It is a cyclic pain that increases CHAPTER 13 Respiratory System Disorders 283 Infectious Diseases Upper Respiratory Tract Infections Common Cold (Infectious Rhinitis) The common cold is caused by a viral infection of the upper respiratory tract. The most common pathogen is a rhinovirus, but it may also be an adenovirus, parain- fluenza virus, or coronavirus. ■ Pathophysiology and Etiology There are more than 200 possible causative organisms, so it is difficult for an individual to develop sufficient immunity to avoid all colds. Children do acquire more colds than adults, usually as a brief, self-limiting infection, unless a secondary bacterial infection develops. The common cold is spread through respiratory droplets, THINK ABOUT 13.5 a. Define the terms sputum, rales, orthopnea, and hemoptysis. b. Differentiate a productive cough from an unproductive cough by general cause, signs, and possible complications. c. List the signs indicating a possible obstruction in the airways. Common Treatment Measures for Respiratory Disorders A number of treatment modalities are recommended for many respiratory diseases. A few examples are sum- marized in Table 13.2. TABLE 13.2 Basic Therapies for Respiratory Disorders Treatment Effect Example Avoid inhaling irritants and maintain good ventilation Reduce inflammation and infection Cigarette smoke Industrial pollutants Current immunizations Prevent infection Influenza and pneumonia vaccines Humidify air Moist mucosa resists damage Thins and removes secretions Cool-air humidifiers Croup tents Moderate exercise Improves lung function and circulation Walking, swimming Breathing and coughing Improve lung expansion and remove secretions Techniques appropriate for specific condition (eg, pursed-lip breathing) Chest physiotherapy Removes thick secretions and reduces Infections Clapping, postural drainage Oxygen Improves oxygen supply to all body cells Nasal cannula, face mask, or mechanical ventilation Drugs Decongestants Vasoconstriction in nasal mucosa, reduce edema Phenylpropanolamine, pseudoephedrine Expectorants Thin respiratory secretions for easier removal Guaifenesin Antitussives Reduce cough reflex Codeine, dextromethorphan (DM) Antihistamines Block H1 receptors to reduce allergic response Diphenhydramine, loratadine Analgesics Reduce pain Acetaminophen, codeine Antimicrobials Prophylaxis and treatment of infection (sputum culture and sensitivity) Antibacterial—penicillin Antiviral—amantadine, zanamivir Antitubercular—isoniazid rifampin Bronchodilators Stimulate beta-2 adrenergic receptors to open bronchioles Theophylline (oral), salbutamol (inhaler) Glucocorticoids Antiinflammatory, antiallergenic Beclomethasone (inhaler), prednisone (oral) Surgical Interventions Thoracentesis Removal of excess fluid from pleural cavity, prevents atelectasis Pleurisy, cancer Tracheotomy Incision into the trachea below the larynx to permit air intake Emergency obstructed airway (eg, aspiration, edema) Surgery Removes tumor, abscess, or damaged tissue Resection, lobectomy 284 SECTION III Pathophysiology of Body Systems PRIMARY VIRAL INFECTION (e.g., INFLUENZA or COMMON COLD VIRUS) Virus attaches firmly to respiratory mucosa, invades the tissue, causing necrosis, inflammation, and swelling Virus spreads along continuous mucosa invading CONGESTION OBSTRUCTED AIRWAYS EARS — OTITIS MEDIA SINUSES — SINUSITIS BRONCHI AND LUNGS — PNEUMONIA Good airflow Poor airflow Frontal sinus Ear Nasal cavity Oral cavity Trachea Lung Healthy Mucosa Virus Inflammation Necrosis Bacteria, sometimes resident flora, penetrate the damaged mucous membranes, causing secondary BACTERIAL INFECTION Bacteria invade necrotic area Inflamed tissue Purulent exudate FIG. 13.8 Complications of viral respiratory infection. which either are directly inhaled or are spread by secre- tions on hands or contaminated objects such as facial tissue. The infection is highly contagious because the virus is shed in large numbers from the infected nasal mucosa during the first few days of the infection and can survive for several hours outside the body. ■ Signs and Symptoms Initially the mucous membranes of the nose and pharynx are red and swollen, with increased secretions. The signs of a cold include the following: • Nasal congestion and copious watery discharge (rhinor- rhea, sneezing, and sometimes watery eyes) • Mouth breathing is common, and a change in the tone of voice is noticeable • Possibly a sore throat • Headache • Slight fever • Malaise • Cough may develop from the irritation of the secretions dripping into the pharynx; sometimes the feeling of stuffiness and irritation persists as the secretions become more viscous for a few days after the acute period has passed • Infection and inflammation may spread to cause pharyngitis, laryngitis, or acute bronchitis Treatment is symptomatic, consisting of acetaminophen for fever and headache and decongestants (vasoconstric- tors) to reduce the edema and congestion in the respiratory passages. A cold is a self-limiting infection. Antihistamines reduce secretions but may cause excessive drying of tissues and cough. Humidifiers aid in keeping the secre- tions liquid and easily drained. The role of vitamin C in prevention and therapy remains controversial. Antibiotics do not cure viral infections and are usually reserved for secondary bacterial infections such as sinusitis, otitis media (see Chapter 15), or tracheitis, or for prophylactic use in high-risk patients (such as those with chronic illnesses). Proper handwashing and disposal of tissues as well as avoidance of crowded areas reduce the risk of transmission to others. Secondary bacterial infections, for example, pharyngitis or “strep throat,” are usually caused by streptococcus invading inflamed and necrotic mucous membranes (Fig. 13.8). A purulent exudate forms and systemic signs such as fever develop. These bacteria should be identified by culture and treated quickly with antimi- crobial drugs to reduce the risk of rheumatic fever or CHAPTER 13 Respiratory System Disorders 285 croup tent often relieves the obstruction. The infection is usually self-limited, and full recovery occurs in several days. In some children with allergic tendencies, smooth muscle spasm may exacerbate the obstruction, requiring additional medical treatment. Epiglottitis Epiglottitis is an acute infection usually caused by the bacterial organism, H. influenzae type B. It is common in children in the 3- to 7-year-old group, although the incidence has been increasing in adults. The infection causes swelling of the larynx, supraglottic area, and epiglottis, which appears as a round, red ball obstructing the airway. Onset is rapid, fever and sore throat develop, and the child refuses to swallow. Drooling of saliva is apparent, and inspiratory stridor is heard. The child appears anxious and pale and assumes a sitting position (tripod position) with the mouth open, struggling to breathe. Caution is required during laryngeal examination to prevent reflex spasm and total obstruction of the airway. Treatment consists of oxygen and antimicrobial therapy, with intubation or tracheotomy if necessary. Influenza (Flu) Influenza is a viral infection that may affect both the upper and the lower respiratory tracts. As indicated in the discussion of this topic at the end of Chapter 6 (influenza is presented as an example of infection), there are three groups of the influenza virus—type A, the most prevalent pathogen, and types B and C. These viruses mutate constantly, preventing effective immune defense for prolonged time periods. Flu differs from a common cold in that it usually has a sudden, acute onset with fever, marked fatigue, and aching pains in the body. It may also cause a viral pneumonia. Similarly to the common cold, a mild case of influenza can be complicated by secondary problems such as bacterial pneumonia. Most deaths during flu epidemics result from pneumonia. Treatment is symptomatic and supportive unless bacte- rial infection occurs. Antiviral drugs, such as amantadine (Symmetrel, Endantadine), zanamivir (Relenza inhaler), acute glomerulonephritis arising from group A beta- hemolytic Streptococcus pneumoniae. Sinusitis Sinusitis is usually a bacterial infection secondary to a cold or an allergy that has obstructed the drainage of one or more of the paranasal sinuses into the nasal cavity (see Fig. 13.1). ■ Pathophysiology and Etiology Common causative organisms include pneumococci, streptococci, or Haemophilus influenzae. As the exudate accumulates, pressure builds up inside the sinus cavity, causing severe pain in the facial bone. The pain may be confused with headache (ethmoid sinus) or toothache (maxillary sinus). ■ Signs and Symptoms In addition to pain in the facial bones other manifestations may include the following: • Nasal congestion • Fever • Sore throat may already be present Diagnosis may be confirmed by radiograph or transil- lumination. Decongestants and analgesics are recom- mended until the sinuses are draining well, and a course of antibiotics is often required to eradicate the infection totally. Laryngotracheobronchitis (Croup) Laryngotracheobronchitis is a common viral infection, particularly in children between 1 and 2 years of age, although adults may also contract laryngitis, tracheitis, or bronchitis. Common causative organisms are parain- fluenza viruses and adenoviruses (Table 13.3). The infection begins as an upper respiratory condition with nasal congestion and cough. In the young child, the larynx and subglottic area become inflamed with swelling and exudate, leading to obstruction and a characteristic barking cough (croup), hoarse voice, and inspiratory stridor. The condition often becomes more severe at night. Cool, moisturized air from a humidifier or shower or TABLE 13.3 General Comparison of Respiratory Infections in Children Laryngotracheobronchitis Epiglottitis Bronchiolitis Age group 3 months to 3 years 3–7 years 2–12 months Cause Virus Haemophilus influenzae Virus—RSV Pathology Inflammation of mucosa of larynx and trachea obstructs airway Supraglottic inflammation and swelling of epiglottis obstructs airway Inflammation of mucosa of bronchioles obstructs small passages Onset Gradual Rapid Gradual Signs Hoarse, barking cough Inspiratory stridor Drooling, dysphagia High fever, appears ill Increasing dyspnea Paroxysmal cough, wheezing Restlessness Rapid respirations and pulse Tripod position Chest retractions Flared nares 286 SECTION III Pathophysiology of Body Systems Lower Respiratory Tract Infections Bronchiolitis (Respiratory Syncytial Virus Infection) Bronchiolitis is a common infection in young children 2 to 12 months of age and is caused by the respiratory syncytial virus (RSV), a myxovirus. It is transmitted directly by oral droplet and occurs more frequently in the winter months. Predisposing factors include a familial history of asthma and the presence of cigarette smoke. Bronchiolitis varies in severity. The virus causes necrosis and inflammation in the small bronchi and bronchioles, with edema, increased secretions, and reflex bronchospasm leading to obstruction of the small airways. Signs include wheezing and dyspnea; rapid, shallow respirations; cough; rales; chest retractions; fever; and malaise. There may be areas of hyperinflation with air trapping due to partial obstruction (see Fig. 13.19C, presented later in the chapter) or areas of atelectasis or nonaeration resulting from total obstruction (see Fig. 13.24, presented later in the chapter). Treatment is supportive and symptomatic, with monitor- ing of blood gases in severe cases to ensure that oxygen levels are adequate. Respiratory syncytial virus– immunoglobulin serum or palivizumab, an RSV mono- clonal antibody, may be administered to reduce the severity of infection, particularly in premature infants. Pneumonia Pneumonia may develop as a primary acute infection in the lungs or it may be secondary to another respiratory or systemic condition in which tissue resistance is reduced. Pneumonia is a risk following any aspiration or inflam- mation in the lung, when fluids pool or defense mecha- nisms such as cilia are reduced. In most cases the organisms enter the lungs directly, by inhalation (virus), resident bacteria spreading along the mucosa, or aspiration in secretions. Occasionally the infection is blood borne. Classification of the Pneumonias Numerous methods are available for classifying pneu- monias. Categories may be based on the causative agent, anatomic location of the infection, pathophysiologic changes, or epidemiologic data. For example, the causative agent may be a virus, bacterium, or fungus. Pneumonia may involve multiple microbes following aspiration. Usually lobar pneumonia is bacterial, the most common agent being a pneumococ- cus, but other causative organisms include Staphylococcus aureus and Legionella (legionnaires disease). Severe pneumococcal pneumonia is less common now because antibacterial medications are quickly administered, but it remains a major threat to those with chronic disease. A vaccine that provides protection against the seven most common agents of pneumonia is available for those with chronic respiratory or cardiovascular disease as well as clients older than 65 years of age. Reimmunization does not appear to be necessary, but it may be done without risk. In immune-suppressed individuals, other organisms or oseltamivir (Tamiflu) taken by adults in the first 2 days, may reduce the symptoms and duration as well as reduce the risk of infecting others. These drugs are useful in the control of flu outbreaks in hospitals or nursing homes. The incubation period for the virus is 1 to 4 days, with an average of 2, but the individual can pass the virus on a day before symptoms develop and for up to 5 days after. Prevention of influenza by vaccination is highly recom- mended for all individuals. If flu does develop following immunization, it is a mild infection. A period of 2 to 3 weeks after vaccination is required before immunity develops. Scarlet Fever An upper respiratory infection caused by group A β-hemolytic streptococcus (Streptococcus pyogenes). The incubation period is generally 1 to 2 days. Symptoms usually begin with a fever and sore throat; chills, vomiting, abdominal pain, and malaise may occur as well. The typical “strawberry” tongue (Fig. 13.9) is caused by the exotoxin produced by the bacteria. A fine rash on the chest, neck, groin, and thighs are characteristic also. Once a serious childhood disease, upper respiratory infection is now generally treatable with antibiotics. FIG. 13.9 Scarlet fever. “Strawberry” tongue with its prominent papillae. (From Zitelli BJ, Davis HW: Atlas of Pediatric Physical Diagnosis, ed 4, St. Louis, 2002, Mosby.) THINK ABOUT 13.6 a. Compare the signs of the common cold, sinusitis, influenza, and epiglottitis. b. Explain why secondary bacterial infections may commonly follow viral infections in the respiratory tract of elderly clients. c. Explain why frequent handwashing may reduce the transmission of influenza. d. Explain why antibacterial drugs are not effective against virus infections (see Chapter 6). e. Describe how antiviral agents act against infection. CHAPTER 13 Respiratory System Disorders 287 with oxygen diffusion. Next, neutrophils, RBCs, and fibrin accumulate in the alveolar exudate, forming a solid mass in the lobe, called consolidation. The presence of these RBCs in the exudate produces the typical rusty sputum associated with lobar pneumonia. Eventually the RBCs break down, and as the infection resolves, macrophages break down the exudate to allow it to be expectorated or resorbed. Because a complete lobe is usually involved in the inflammatory process, the adjacent pleurae are frequently involved, producing pleuritic pain at the affected site (pleurisy or pleuritis). As well, infection may spread into the pleural cavity, causing empyema. If not resolved quickly, empyema can cause adhesions between the pleural membranes, restricting ventilation. Chest x-rays confirm the typical distribution of the infection, and a sputum culture identifies the organism. The filling of the alveoli with exudate reduces the diffusion of gases, particularly oxygen, and decreases blood flow through the affected lobe. Hypoxia results and is more marked because the demand for oxygen increases with the higher metabolic rate associated with the infection. The oxygen deficit also leads to metabolic acidosis. Dehydration may result from the high fever, hyperventilation, and inadequate fluid intake. Typical manifestations of pneumococcal pneumonia include the following: • Sudden onset • Systemic signs of high fever with chills, marked fatigue, and leukocytosis • Dyspnea, tachypnea, tachycardia • Pleuritic pain with splinting or restriction of respiratory expansion on the affected side • Rales, heard initially over the affected lobe and then disappearing as consolidation occurs • Productive cough, with the typical rust-colored sputum • Confusion and disorientation if infection is severe or several lobes are involved such as Candida (fungus) or Pneumocystis carinii may cause pneumonia. Anatomic distribution of lesions may be diffuse and patchy throughout both lungs or lobar, meaning consoli- dated in one lobe (Fig. 13.10). In some pneumonias, such as viral, pathophysiologic changes occur primarily in the interstitial tissue or alveolar septae. In other types, such as pneumococcal, the alveoli are inflamed and filled with exudate, resulting in a solid mass in a lobe. Epidemiologic categories refer to nosocomial (hospital- acquired) pneumonia, which affects those with less resistance, the elderly, the debilitated, the malnourished, or the immune suppressed. In these cases, infection often results from gram-negative organisms such as Klebsiella pneumoniae or Pseudomonas aeruginosa. Community- acquired pneumonia may be viral or bacterial. It can affect healthy persons, such as following influenza, as well as persons with underlying cardiovascular or respira- tory disease. Aspiration pneumonia may be nosocomial or community acquired. It frequently involves aspiration of vomitus, which is irritating to tissues, or nasopharyn- geal secretions. Mixed bacteria are usually isolated from the resultant infection. When periodontal disease is marked, aspiration pneumonia results from infection by gram-negative microbes. A brief comparison of common types of pneumonia is found in Table 13.4. Lobar Pneumonia Lobar pneumonia (pneumococcal pneumonia) is usually caused by Streptococcus pneumoniae (pneumococcus), and the infection is localized in one or more lobes (Fig. 13.11). This microbe sometimes colonizes the nasopharynx without producing symptoms. The first stage in its development is congestion, in which inflammation and vascular congestion develop in the alveolar wall, and exudate forms in the alveoli. This change interferes greatly TABLE 13.4 Types of Pneumonia Lobar Pneumonia Bronchopneumonia Interstitial Pneumonia (Primary Atypical Pneumonia [PAP]) Distribution All of one or two lobes Scattered small patches Scattered small patches Cause Streptococcus pneumoniae Multiple bacteria Influenza virus Mycoplasma Pathophysiology Inflammation of alveolar wall and leakage of cells, fibrin, and fluid into alveoli causing consolidation Pleura may be inflamed Inflammation and purulent exudate in alveoli often arising from prior pooled secretions or irritation Interstitial inflammation around alveoli Necrosis of bronchial epithelium Onset Sudden and acute Insidious Variable Signs High fever and chills Mild fever Variable fever, headache Productive cough with rusty sputum Rales progressing to absence of breath sounds in affected lobes Productive cough with yellow-green sputum Dyspnea Aching muscles Nonproductive hacking cough 288 SECTION III Pathophysiology of Body Systems several species of microorganisms may cause the infection, beginning in the bronchial mucosa and spreading into the local alveoli. In many cases, pooled secretions in the lungs become infected by organisms draining from the upper passages, a hazard particularly in immobilized patients (hypostatic pneumonia). The inflammatory exudate forms in the alveoli, interfering with oxygen diffusion. Onset tends to be insidious, with moderate fever, cough, and rales. Congestion causes a productive cough with purulent sputum, usually yellow or green in color. Sputum culture and sensitivity tests indicate Treatment involves the administration of antibacte- rial medications such as penicillin in combination with supportive measures such as fluids, drugs to reduce fever, and oxygen. Pneumococcal vaccine (considered a once-in-a-lifetime immunization) is recommended par- ticularly for the elderly and those at risk because of other disease. Bronchopneumonia Bronchopneumonia occurs as a diffuse pattern of infection in both lungs, more often in the lower lobes. One or Right superior lobe Apex of lung Trachea Right primary bronchus 1. Bronchopneumonia (diffuse — bacterial) Right middle lobe 2. Lobar pneumonia (consolidation — bacterial) with pleurisy 3. Primary atypical pneumonia (interstitial — viral/ mycoplasmal) Left superior lobe Right inferior lobe Base of lung Left inferior lobe A B C FIG. 13.10 A, Types of pneumonia. B, Bron- chopneumonia. Gross section of lung showing patchy areas of consolidation and pus-filled bronchi (arrows). Also present is upper lobe emphysema. C, Lobar pneumonia. An entire lobe is uniformly consolidated (lighter color) due to an accumulation of inflammatory exudate within the alveoli. (B and C From Cross D: Underwood’s Pathology: A Clinical Approach, ed 6, Baltimore, Churchill Livingstone, Elsevier, 2013.) CHAPTER 13 Respiratory System Disorders 289 defined patches of congestion. The infection varies greatly in severity, from mild cases that may not even be diag- nosed to severe cases that may be complicated by second- ary bacterial infection. The onset of primary atypical pneumonia is often vague, with nonproductive cough, hoarseness and sore throat, headache, mild fever, and malaise. The infection is usually self-limiting. Chlamydial pneumonia, caused by the organism Chlamydia pneumoniae, is also considered a cause of PAP and pharyngitis. Infection is often mild, so sometimes it is not diagnosed. Pneumocystis carinii Pneumonia Pneumocystis carinii pneumonia (PCP), a type of atypical pneumonia, occurs as an opportunistic and often fatal infection in patients with acquired immunodeficiency syndrome (AIDS) (see Chapter 7). It also causes pneu- monia in premature infants. This microbe was formerly classified as a protozoan, now it is considered a fungus (see Fig. 7.16A). It appears to be inhaled and attaches to alveolar cells, causing necrosis and diffuse interstitial inflammation. Then the alveoli fill with exudate and fungi, including the cystic form. Its onset is marked by difficulty breathing and a nonproductive cough. For AIDS patients with low CD4 T-cell counts, prophylactic drugs such as a sulfamethoxazole-trimethoprim combination or pent- amidine aerosol are recommended. Severe Acute Respiratory Syndrome Severe acute respiratory syndrome (SARS) is of importance because its advent triggered extensive global efforts to quickly identify this previously unknown microorganism and its mode of transmission, then to develop a system to contain and control the spread of such emerging infections. These guidelines could be implemented for other emerging infectious diseases. In October 2004, the World Health Organization (WHO) revised the guidelines the appropriate choice of antibacterial treatment. Recovery usually occurs without residual lung damage. Legionnaires Disease Legionnaires disease is a pneumonia caused by a gram- negative bacterium, Legionella pneumophila. The microbe thrives in warm, moist environments, such as air con- ditioning systems and spas. It arises as a nosocomial infection in hospitals or other institutions, especially among those with other lung disease. It was unknown until a number of deaths occurred at a convention in 1976. The microbe has been difficult to identify because the organism is found inside pulmonary macrophages and requires a special culture medium. If untreated, the infection causes severe congestion and consolidation, with necrosis in the lung and possibly fatal consequences. Primary Atypical Pneumonia Primary atypical pneumonia (PAP) differs in both the causative organisms, often viral or mycoplasmal, and the pathophysiology, which involves interstitial inflammation. Mycoplasma pneumoniae is a small bacterium that lacks a cell wall and can appear in varying shapes. It is found normally in the upper respiratory tract. Mycoplasmal pneumonia is common in older children and young adults. It is transmitted by aerosol but is not considered highly contagious. Frequent cough is a prominent sign. Mycoplasma responds to erythromycin or tetracycline therapy. Viral pneumonia is often caused by influenza A or B, as well as adenoviruses and RSV. The infection frequently begins insidiously, with inflammation in the mucosa of the upper respiratory tract, and then it descends to involve the lungs. These organisms produce inflammation that is diffuse and interstitial, with little exudate forming in the alveoli. Therefore cough is unproductive, and rales are not pronounced. A radiograph may show some poorly A B FIG. 13.11 Lobar or streptococcal pneumonia. A, Respiratory secretions contain gram-positive diplococci suggesting Streptococcus pneumoniae. B, Histology of bronchopneumonia. The bronchus and surrounding alveoli contain neutrophils. (A From de la Maza LM, Pezzlo MT, Baron EJ: Color Atlas of Diagnostic Microbiology, St. Louis, 1999, Mosby. B From Damjanov I: Pathology for the Health Professions, ed 5, St. Louis, 2017, Elsevier.) 290 SECTION III Pathophysiology of Body Systems second wave of infection, among health care workers and visitors who were in direct contact with the first hospitalized SARS cases, occurred 4 weeks later. This confirmed the need for additional protective clothing for those in close contact with cases and tighter infec- tion control measures within institutions. Patients were treated in specific institutions and those in contact with active cases were quarantined at home until shown to be clear of infection. Tuberculosis Once thought to be declining and well under control, tuberculosis (TB) is increasing globally, with many new cases each year in some areas of the world, particularly among AIDS patients in Africa. From 1% to 2% of new cases are multiple-drug-resistant forms of the disease, which has complicated control of the infection and its spread within the community. Tuberculosis is a disease of poverty and crowding. Predicted new cases annually in the United States are dropping in many areas; but areas in which HIV infection and homelessness are high show rates closer to those of developing countries. Prevalence is difficult to estimate because of the large number of latent cases (many are undiagnosed). Ten percent of diagnosed infections will progress to active pulmonary TB. Two billion people worldwide are infected, and the death rate is 2000 deaths per year globally, with the highest mortality rates among those who are HIV positive. ■ Pathophysiology Tuberculosis Is An infection that is usually caused by Mycobacterium tuberculosis and primarily affects the lungs, but the pathogen may invade other organs as well. Mycobacterium is an acid-fast, aerobic, slow-growing bacillus that is somewhat resistant to drying and many disinfectants. The microbes can survive in dried sputum for weeks. They are destroyed by ultraviolet light, heat, alcohol, glutaraldehyde, and formaldehyde. The cell wall also appears to protect the organism from destruction by normal body defenses, so that the normal response by neutrophils (PMNs) to infection and production of purulent exudate does not occur. There are two stages in the pathogenesis of tuberculosis: primary infection (TB infection) and secondary infection or reinfection (TB disease) (Fig. 13.12). Primary infection occurs when the microorganisms first enter the lungs, are engulfed by macrophages, and cause a local inflam- matory reaction, usually on the periphery of the upper lobe. Some bacilli migrate to the lymph nodes, activating a type IV or cell-mediated hypersensitivity response (see Chapter 7). Lymphocytes and macrophages cluster together to form a granuloma at the site of inflammation. The granuloma contains the bacilli, some of which remain alive, forming a tubercle. In the center of the tubercle, caseation necrosis develops, forming a core of cheese-like material consisting of dead macrophages and necrotic tissue. A healthy person can resist this invasion, so these for global surveillance and reporting of SARS and labora- tory precautions. At that time, the last case of SARS had occurred in a laboratory worker in China in April 2004. The Centers for Disease Control and Prevention (CDC) will continue to focus on early detection of cases and to monitor and update information about this and other emerging diseases. Severe acute respiratory syndrome, an acute respiratory infection, was first diagnosed in China in 2002. It did not attract attention until February 2003, when China informed WHO about a new form of atypical pneumonia clustered in one province. Work began to identify the infectious agent and the genetic sequence of the virus was announced on April 14, 2003, confirming it as a previously unknown agent. (By contrast, researchers did not identify the agent for legionnaires disease until 2 years after its first appearance.) By July 2003, in excess of 8000 cases and almost 800 deaths were reported in 29 countries. The rapid spread and high morbidity and mortality rates prompted immediate cooperative action by epidemiologists and public health officials globally. The causative microbe is a coronavirus, named SARS- CoV (SARS-associated coronavirus), an RNA virus that is transmitted by respiratory droplets during close contact. To date, a close exposure to existing cases has always been identified; casual contact has not been documented. The incubation period is 2 to 7 days, with an average 4 to 6 days. The first stage presents as a flulike syndrome, with fever, headache, myalgia, chills, anorexia, and frequently diarrhea, lasting 3 to 7 days. Effects on the lungs are evident several days later, with a dry cough and marked dyspnea. Chest radiographs by day 7 indicate spreading patchy areas of interstitial congestion and hypoxia increases rapidly, with mechanical ventilation often required. Lymphopenia and thrombocytopenia are often present, as are increased C-reactive protein levels. Elevated liver enzymes were found in many cases and appeared to result from liver damage by the virus. A number of patients continue into a third stage with severe, sometimes fatal, respiratory distress. Treatment included the antiviral ribavirin and the glucocorticoid methylprednisolone. The case fatality rate is high, about 10%, increasing to greater than 50% in patients more than 60 years of age. The lack of a rapid diagnostic test (antibodies are not present until 3 weeks after onset) and the nonspecific early manifestations of SARS combine to make immediate identification of the infection difficult. Currently risk factors that may be monitored to prevent future outbreaks include the following: • Travel to China, Hong Kong, and Taiwan or close contact with such a traveler. • The presence of a cluster of undiagnosed atypical pneumonia cases. • Employment involving close contact with the virus (nursing a patient or a laboratory worker handling the virus). During the epidemic in 2003 in Canada, a CHAPTER 13 Respiratory System Disorders 291 immunosuppressed adults. If the patient with extrapul- monary TB has no cough, she or he is not considered to have a contagious disease. Secondary or reinfection tuberculosis is the stage of active infection. It often arises years after primary infection, when the bacilli, hidden in the tubercles, are reactivated, usually because of decreased host resistance. Occasionally there is a new invasion of microbes. As the organisms multiply, tissue destruction occurs, forming a large area of necrosis. Cavitation occurs, with formation of a large open area in the lung and erosion into the bronchi and blood vessels (Fig. 13.13). Hemoptysis is common as blood vessels are eroded. With cavitation, spread of the organisms into other parts of the lung is promoted, and bacilli are present in the sputum, where they may be passed to others. Bacteria may be swallowed to infect the digestive tract. Infection may also spread into the pleural cavity, causing pleuritis and adhesions. Patients with cough and positive sputum tests or x-ray showing cavitation are infectious, and proper respiratory hygiene measures must be followed. These include covering the mouth when coughing, wearing a mask when in contact with others, and avoidance of sustained close contact with others. ■ Etiology Mycobacterium tuberculosis is transmitted by oral droplets released from a person with active infection that are inhaled into the lungs. In some countries in which milk is not pasteurized, tuberculosis may be caused by the related Mycobacterium bovis, which infects cows. lesions remain very small and become walled off by fibrous tissue, eventually calcifying. These lesions in the lung and lymph nodes are referred to as Ghon complexes. When calcified, the tubercle may be visible on a chest radiograph. However, the bacilli may remain viable, in a dormant state inside the tubercle for years, and are therefore a potential danger. As long as the individual’s resistance and immune responses remain high, the bacilli remain walled off within the tubercle. The individual has been exposed to the bacillus and infected but does not have active disease and is asymptomatic. By about 6 to 8 weeks the immune response is complete. This is considered primary or latent infection. The hypersensitivity reaction first initiated by M. tuberculosis is the basis for the Mantoux tuberculin test which is used to detect exposure to the bacillus. Several weeks after exposure, the person has become hypersensi- tive and will produce a positive skin reaction, a large area of induration (a hard, raised, red area), in response to administration of tuberculoprotein. A chest x-ray and sputum culture will determine whether active infection is present. In people with low resistance for any reason, the primary infection may not be controlled but instead progress to active infection, spreading through the lungs and to other organs. Miliary or extrapulmonary tuberculosis is a rapidly progressive form in which multiple granulomas affect large areas of the lungs and rapidly disseminate into the circulation and to other tissues, such as bone or kidney. This form of infection is more common in children and Inhalation Inflammatory response Delayed hypersensitivity reaction Positive tuberculin test Bacilli to lymph nodes Type IV immune response Individual with LOW resistance Individual with HIGH resistance PRIMARY INFECTION SECONDARY OR REINFECTION Tubercle formation Cavitation Active infection Dissemination through lungs and other organs If resistance decreases later (e.g., immune suppression) –Organisms reactivated –Caseation necrosis and granuloma –Organisms walled off (Ghon complex) of Mycobacterium tuberculosis Lung FIG. 13.12 Development of tuberculosis. 292 SECTION III Pathophysiology of Body Systems • Afternoon low-grade fever and night sweats • Prolonged cough that becomes increasingly severe and, as cavitation develops, more productive • Purulent sputum often contains blood ■ Diagnostic Tests First exposure or primary infection is indicated by a positive tuberculin test result. This test is of no value (that is, it produces a false-positive result) if the person has previously received the bacillus Calmette-Guérin (BCG) vaccine for tuberculosis or has had a previous positive tuberculin test. Active infection can be confirmed by chest x-ray, acid-fast staining of sputum specimens, and sputum culture (a lengthy time required). A CT scan is more sensitive than the traditional x-ray in identifying TB lesions. Newer testing techniques involving nucleic acid amplification (NAA) from microbial genetic material provide faster confirmation. Routine testing of health care providers is common practice and prophylactic medication may be required if the person shows a new positive tuberculin test in the absence of any other signs or symptoms of infection. Detailed protocols vary with the licensing bodies responsible for professional practice and the public health statutes. ■ Treatment Although a person with latent TB may be asymptomatic, there are higher risk groups where a preventive regimen is recommended to prevent the disease from becoming the fully active form of TB. The primary regimens include use of the following drugs: • Isoniazid (INH) • Rifapentine • Rifampin A person with active tuberculosis is now usually treated at home or in a general hospital. Long-term treatment with a combination of drugs is recommended, so as to totally eradicate the infecting microbes and reduce the risk of resistant bacteria. The length of treatment varies from 6 months to a year or longer depending on the situation. Drugs of choice include the following: • Isoniazid • Rifampin • Ethambutol • Pyrazinamide • Streptomycin Sputum culture usually is negative for tuberculosis organisms after 1 to 2 months of treatment, and the risk of transmission becomes much less. Patient compliance with the drug regimen for the entire time is essential to totally eradicate the infection and prevent the develop- ment of drug-resistant microbes. The WHO recommends a directly observed therapy (DOT) regimen in all cases. The DOT program requires a health care worker to observe the administration of each drug dose in the treatment protocol. This approach requires government commitment to reduce the incidence of TB, adequate Tuberculosis occurs more frequently in persons living in crowded conditions or those whose resistance is lowered because of immunodeficiency, malnutrition, alcoholism, conditions of war, or chronic disease. There is probably a genetic susceptibility, and children are more easily infected than adults. Some factors leading to an increasing incidence are more frequent travel, an increased homeless population who are malnourished and fre- quently have other diseases, prevalence of the infection in patients with AIDS, and development of drug-resistant strains of the organism. ■ Signs and Symptoms Primary tuberculosis is asymptomatic. The onset of secondary or active pulmonary tuberculosis is insidious. Systemic signs often appear first, with vague manifesta- tions such as the following: • Anorexia • Malaise • Fatigue • Weight loss FIG. 13.13 Secondary pulmonary tuberculosis showing cavitation and scarring at the apex of the right upper lobe. (From Cross D: Underwood’s Pathology: A Clinical Approach, ed 6, Baltimore, Churchill Livingstone, Elsevier, 2013.) CHAPTER 13 Respiratory System Disorders 293 • Fever • Night sweats A skin test can differentiate histoplasmosis from TB, and the organisms can be cultured to confirm the diagnosis. Current treatment consists of the antifungal agent amphotericin B (Fungizone). Anthrax Anthrax is a bacterial infection of the skin, respiratory tract, or gastrointestinal tract of humans and cattle. Although rare in developed countries, it has gained attention as a biologic weapon. ■ Pathophysiology and Etiology The causative organism is a gram-positive bacillus that forms grayish white spores that can remain viable for long periods of time. Inhalation anthrax causes flulike symptoms following a usual incubation period of 1 to 7 days. Within 3 to 5 days severe acute respiratory distress occurs, with mediastinal widening on x-ray and fever. Shock follows quickly due to the release of toxins, and case fatality rates were 45% in the 2001 illnesses as a result of exposure to anthrax spores in Washington, DC. ■ Signs and Symptoms The different manifestations will depend primarily on the form of anthrax. Cutaneous form: • Group of blisters/bumps that may itch • Swelling around the sore • Painless open skin sore with a black center that develops from blisters/bumps • Sores often on face, neck, arms, or hands Inhalation form: • Fever and chills • Chest discomfort • Shortness of breath • Confusion or dizziness • Cough • Nausea, vomiting, or stomach pains • Headache • Sweats (often drenching) • Extreme tiredness • Body aches Gastrointestinal form: • Fever and chills • Swelling of neck or neck glands • Sore throat • Painful swallowing • Hoarseness • Nausea and vomiting, especially bloody vomiting • Diarrhea or bloody diarrhea • Headache • Flushing (red face) and red eyes • Stomach pain • Fainting • Swelling of abdomen (stomach) drugs, and adequate funding to administer them. Case finding of early active cases is also part of the protocol. Directly observed therapy is expensive in terms of human resources, but when used in highly endemic areas it has reduced TB infection rates significantly. Unfortunately, not all TB-infected individuals accept the need for supervision, drug shortages are common, and funding for DOT may not be available; as a result cure rates remain low. It is recommended that contacts of the patient be given prophylactic isoniazid for 1 year and receive tuberculin testing as well. The BCG vaccine is not widely used in North America because it is not considered sufficiently effective, particularly in adults, and its use prevents diagnosis by skin test. Because BCG immunization continues to be used in some countries, a health history should include this immunization. In North America all babies should be tested for TB on or before their first birthday unless symptoms and history suggest earlier testing. THINK ABOUT 13.7 a. Compare the causative organism and two significant signs of lobar pneumonia with those of bronchopneumonia. b. What factors predispose to bronchopneumonia in immobilized persons? c. Describe and explain the significance of a tubercle and cavitation in the progress of TB infection. d. Describe several specific precautions that could be taken by affected individuals or health professionals that would limit the spread of M. tuberculosis. Histoplasmosis Histoplasmosis is a fungal infection that is common in the midwestern United States. ■ Pathophysiology and Etiology The fungus Histoplasma capsulatum and its spores can be inhaled on dust particles. Histoplasmosis can occur as an opportunistic infection that is common in persons with AIDS, in whom the fungus tends to disseminate or spread easily throughout the body. The fungus is found as a parasite inside macrophages. The effects of histoplasmosis are similar to those of tuberculosis in that the first stage often involves asymp- tomatic, limited infection that may be followed by a second stage of active infection. This second stage involves granuloma formation and necrosis and consolidation in the lungs as well as possible spread to other organs. ■ Signs and Symptoms Manifestations include the following: • Cough • Marked fatigue 294 SECTION III Pathophysiology of Body Systems intestine of the neonate is blocked by mucus at birth, preventing the excretion of meconium shortly after birth (Fig. 13.15). In the pancreas, the ducts of the exocrine glands become blocked, leading to a deficit of pancreatic digestive enzymes in the intestine. Malabsorption and malnutrition result. Also, the obstruction and backup of secretions eventually cause damage to the pancreatic tissue, including the islets of Langerhans, resulting in diabetes mellitus in some individuals. The bile ducts of the liver may be blocked by viscid mucus, preventing bile from reaching the duodenum and interfering with digestion and absorption of fats and fat-soluble vitamins. Ultimately this abnormality also contributes to the general state of malabsorption, malnutrition, and dehydration. If obstruction is severe, the backup of bile behind the obstruction may cause inflammation and permanent damage to the liver in the form of biliary cirrhosis. The salivary glands are often mildly affected, with secretions that are abnormally high in sodium chloride and mucus plugs that cause patchy fibrosis of the sub- maxillary and sublingual glands. The sweat glands are also affected, producing sweat that is high in sodium chloride content. This is usually not a serious problem unless hot weather or strenuous exercise lead to excessive loss of electrolytes in the sweat. The reproductive system may be affected, with thick mucus obstructing the vas Anthrax is treated with the antimicrobial ciprofloxacin (Cipro) sometimes along with administration of anthrax antitoxin. There are only a few antitoxins, and they are typically administered along with the antibiotics. If anthrax infection is suspected, the local medical officer of health and federal law enforcement agencies must be contacted. Strict respiratory barrier measures are required until the source of the infection is identified and removed. Animal vaccines for protection against anthrax are in common use in North America and are effective in reduc- ing infection. Vaccination of individuals is available and recommended for those who work with the organism in the laboratory, persons who work with animal hides imported from areas with a high incidence of animal anthrax, and military personnel. Pregnant women should not be immunized with anthrax vaccine. Obstructive Lung Diseases Cystic Fibrosis Cystic fibrosis (CF) is a common inherited disorder in children. The incidence of CF differs with the ethnic community of the parents and is 1 in 3419 live births to parents who are of white, European ancestry and 1 in 12,163 to parents who are of African ancestry in the United States. In Canada the incidence rate is 1 in 3600 live births. The mean survival age in 2006 was 37 years. Many states include CF in newborn screening programs for early identification and prevention of infections. ■ Pathophysiology Cystic fibrosis, sometimes called mucoviscidosis, is a genetic disorder. Several mutations to the CFTR (cystic fibrosis transmembrane conductance regulator) gene have been identified and relate to a protein involved in chloride ion transport in the cell membrane. This defect in the exocrine glands causes abnormally thick secretions, such as tenacious mucus. The primary effects of cystic fibrosis are seen in the lungs and the pancreas, where the sticky mucus obstructs the passages; other tissues are affected less frequently. Usually several areas in the body are affected in an individual. The severity of the effects varies among individuals. In the lungs, the mucus obstructs airflow in the bron- chioles and small bronchi, causing air trapping or atel- ectasis with permanent damage to the bronchial walls (Fig. 13.14). Because stagnant mucus is an excellent medium for bacterial growth, infections are common and add to the progressive destruction of lung tissue. Organ- isms commonly causing infection in patients with cystic fibrosis include P. aeruginosa and S. aureus. Bronchiectasis and emphysematous changes are seen frequently as fibrosis and obstructions advance. Eventually respiratory failure or cor pulmonale (right-sided congestive heart failure) develops. In the digestive tract, the first indication of abnormality may be meconium ileus in newborns, in which the small FIG. 13.14 Pathology of the lung in end stage cystic fibrosis. (From Kleinerman J, Vauthy P: Pathology of the Lung in Cystic Fibrosis, Atlanta, 1976, Cystic Fibrosis Foundation.) CHAPTER 13 Respiratory System Disorders 295 • Steatorrhea (bulky, fatty, foul stools) occurs. • The abdomen distends. • Failure to gain weight indicates a lack of the pancreatic enzymes and bile needed to digest food and absorb nutrients. Fats and the fat-soluble vitamins (vitamins A, D, E, and K) are affected initially, but in turn protein and carbohydrate deficits develop. • Chronic cough and frequent respiratory infections indicate pulmonary involvement in the child. These tend to increase over time. As lung damage proceeds, hypoxia, fatigue, and exercise intolerance develop. The chest may be overinflated owing to air trapping, and rhonchi are audible. • Failure to meet the normal growth milestones is common, usually because of chronic respiratory problems. ■ Diagnostic Tests Genetic testing can identify the CFTR mutations at birth or any time after birth. Sweat is analyzed for abnormal deferens in males or the cervix in females, leading to sterility or infertility. In some males the testes and ducts do not develop normally. ■ Etiology The mutated CFTR gene for cystic fibrosis is located on the seventh chromosome, and the disease is transmitted as an autosomal recessive disorder (see Chapter 21). It is much more common in whites from northern Europe. Asymptomatic carriers form a high proportion of the population. When a family history of cystic fibrosis warrants testing, the defect can be diagnosed prenatally and in carriers with reliable results. ■ Signs and Symptoms Manifestations of cystic fibrosis include the following: • Meconium ileus may appear at birth. • Salty skin may lead to a sweat test and the diagnosis of cystic fibrosis. In some cases, the diagnosis may be delayed a few months or several years. CYSTIC FIBROSIS—AN AUTOSOMAL RECESSIVE DISORDER Excessive amounts of thick, sticky mucus obstruct ducts of exocrine glands Obstruction of airways and frequent infections Meconium ileus (intestinal obstruction in newborn) Obstruction of vas deferens blocks sperm flow Infertility Cervical mucus blocks sperm entry Excess Na+ and Cl– content Electrolyte imbalance and dehydration Obstruction of pancreatic ducts Obstruction of bile ducts in liver Biliary cirrhosis Fibrosis Diabetes mellitus Fibrosis Cor pulmonale EXOCRINE GLAND DYSFUNCTION Malabsorption Malnutrition LUNGS DIGESTIVE TRACT REPRODUCTIVE TRACT SWEAT GLANDS FIG. 13.15 Cystic fibrosis. 296 SECTION III Pathophysiology of Body Systems electrolyte content. This test may not be accurate until the infant is at least 2 to 3 weeks old. Stools may be checked for fat content and trypsin (pancreatic enzyme) content. Lung involvement can be assessed with x-rays, pulmonary function tests, and blood gas analysis. ■ Treatment Treatment of a child with cystic fibrosis requires a team or interdisciplinary approach because there is multisys- temic involvement with numerous complications and implications for the child’s growth and development. • Replacement therapy for pancreatic enzymes, for example, pancrelipase (Cotazym), and if necessary, bile salt replacement can be administered with meals and snacks to improve digestion and absorp- tion and promote general health and resistance to infection. • A well-balanced diet, with high protein, low fat, and vitamin supplements, is recommended, but the sug- gested total dietary intake is much greater than is usually recommended for a specific child or adult to allow for some malabsorption. It is important to avoid dehydration resulting from excessive losses in the sweat or stool because a fluid deficit may result in thicker and more tenacious respiratory mucus. • Intensive chest physiotherapy, including postural drainage, percussion, and coughing techniques, is a time-consuming but necessary daily exercise to ensure removal of the tenacious mucus. • The use of bronchodilators and humidifiers also promotes drainage. • Regular moderate aerobic exercise is helpful for remov- ing secretions and promoting general health. Immediate aggressive treatment is required for infections and has extended the life span of patients. In patients with advanced lung disease, oxygen therapy as well as medication for congestive heart failure may be required (see Chapter 12). With improved treatment, the life span of children with cystic fibrosis has been extended into adult- hood. Respiratory failure is the usual cause of death. Heart-lung transplants have been performed in some individuals with cystic fibrosis (see Chapter 7). Research continues to repair the genetic mutation or alter its expression. THINK ABOUT 13.8 a. Describe how cystic fibrosis affects the lungs and sweat glands. b. Describe the potential complications of cystic fibrosis in the lungs and pancreas. c. Explain the probability of cystic fibrosis occurring in a child when one parent is a carrier. Lung Cancer The lungs are common sites of both primary and second- ary lung cancer. Benign lung tumors are rare. Lung cancer ranks as the third most common cancer in the United States. The incidence has declined slightly, but the mortal- ity rate remains high. Estimates for 2017 indicate 222,500 individuals will be diagnosed in the United States with lung cancer and more than 155,870 patients with lung cancer in the United States will die. Incidence and mortal- ity rates are similar in Canada. Black men are more likely to develop lung cancer than white men. Both black and white women still have a lower rate of developing lung cancer, but the gap is definitely closing. Despite the serious prognosis of lung cancer, some patients with early stages of cancers are cured (American Cancer Society). Secondary metastatic cancer develops frequently in the lungs because the venous return and lymphatics bring tumor cells from many distant sites in the body to the heart and then into the pulmonary circulation. The hospitable environment within the small blood vessels in the lungs provides a lodging point for tumor cells (see Fig. 20.5). ■ Pathophysiology Bronchogenic carcinoma, arising from the bronchial epithelium, is the most common type of malignant lung tumor (Fig. 13.16). A number of subgroups occur. Squa- mous cell carcinoma usually develops from the epithelial lining of a bronchus near the hilum and projects into the airway (see Fig. 20.3A). Adenocarcinomas (from glands) and bronchoalveolar cell carcinomas are usually found on the periphery of the lung, making them less symp- tomatic and more difficult to detect in the early stages. The cells of adenocarcinomas may secrete mucin. Small cell or “oat cell” carcinomas are a rapidly growing type of lung cancer often located near a major bronchus in the central part of the lung. They tend to be invasive and metastasize early in their development. Large cell carci- nomas are usually found on the periphery and consist of undifferentiated large cells that have a rapid growth rate and metastasize early. An aggressive and deadly cancer called mesothelioma has recently received increased attention from the media and legal firms. Although it is not yet clear what genetic mutations cause mesothelioma, asbestos exposure has been implicated as a possible environmental cause, which has led to numerous law suits being filed on behalf of people who worked with asbestos but were never warned of the potential dangers. Pleural mesothelioma most often affects the pleura sur- rounding the lungs. Unless diagnosed in the early stages this cancer is usually fatal. Early treatments are the same as for those of any cancer. The first change in the lungs is usually metaplasia, a change in the epithelial tissue, associated with smoking or chronic irritation, which is reversible if the irritation ceases. The loss of normal protective, ciliated, pseudostratified epithelium leaves the lung tissue more CHAPTER 13 Respiratory System Disorders 297 is higher in persons who begin smoking early, persist for many years, and are considered heavy smokers (ie, they smoke more than a pack per day). Not all smokers develop lung cancer, and therefore there is probably a genetic factor involved that also influences the cellular changes (see Chapter 20). Tumors may develop in persons with chronic obstructive pulmonary disease (COPD), also associated with smoking (see Fig. 13.21C, presented later in the chapter). Occupational or industrial exposure to carcinogens such as silica, vinyl chloride, or asbestos is the other major cause of lung cancer, and the risk is greatly increased if a second factor such as cigarette smoking is also present in an occupationally exposed individual. In addition to the direct carcinogenic effect, any irritant such as smoke leads to chronic inflammation and frequent infections in the respiratory tract, which in turn cause cellular changes. For example, in the mucosa, cigarette smoking causes a change from ciliated columnar epi- thelium to squamous cell epithelium. The alterations in the respiratory mucosa as it changes through metaplasia to dysplasia demonstrate the cell mutations caused by carcinogens and could perhaps lead to earlier diagnosis. ■ Signs and Symptoms The onset of lung cancer is insidious because the early signs of cancer are often masked by signs of the predispos- ing factor, such as a “smoker’s cough.” In many cases, the cancer has already metastasized before diagnosis, and the signs of a metastatic tumor lead to diagnosis. There are four possible categories of signs of lung cancer: (1) those related to the direct effects of the tumor on the respiratory structures, (2) those representing the systemic effects of cancer, (3) those caused by associated paraneo- plastic syndromes, and (4) those resulting from metastatic tumors at other sites. 1. Early signs related to respiratory involvement include the following: vulnerable to irritants and inflammation from smoking. Various chemicals in cigarette smoke are carcinogenic and act as initiators and promoters. Dysplasia or carcinoma in situ then develops. These changes are difficult to detect. Lung cancer is staged at the time of diagnosis based on the tumor size-node involvement-metastases (TNM) classification (see Chapter 20). Stage I tumors are localized, whereas stage III lesions are disseminated. Common sites of metastases from the lungs include the brain, bone, and liver. Tumors in the lungs have many effects: • Obstruction of airflow by tumor growth into a bronchus causes abnormal breath sounds and dyspnea. • Inflammation surrounding the tumor stimulates a cough and predisposes to secondary infection. Frequent infections may occur because secretions pool distal to the tumor. • Pleural effusion, hemothorax, pneumothorax, or a combination of these is common with tumors located on the lung periphery owing to inflammation or erosion of the pleural membrane. • Paraneoplastic syndrome may accompany bronchogenic carcinoma when the tumor cell secretes hormones or hormone-like substances such as antidiuretic hormone (ADH) or adrenocorticotropic hormone (ACTH). The endocrine effects may complicate both diagnosis and treatment. This syndrome may include neuromuscular disturbances or hematologic disorders such as dissemi- nated intravascular coagulation (DIC) (see Chapter 10). • Tumors in the lungs also cause the usual systemic effects of cancer. ■ Etiology The incidence of lung cancer continues to rise and is now very high in women as well as men. Cigarette smoking is the major factor in its development. “Second-hand smoke” in the environment has been implicated in a significant number of cases. The risk of developing cancer A B FIG. 13.16 A, Bronchogenic carcinoma. B, Cytologic examination of a sputum specimen shows a squamous carcinoma cell with large nucleus (arrow). (A From Damjanov I: Pathology for the Health Professions, ed 5, St. Louis, 2017, Elsevier. B From Kumar V, Abbas AK, Fausto M: Robbins and Cotran Pathologic Basis of Disease, ed 7, Philadelphia, 2005, Saunders.) 298 SECTION III Pathophysiology of Body Systems The right lower lung is often the destination of aspirated material because anatomically the right branching bronchus tends to continue almost straight down, whereas the bronchus in the left lung branches at a sharper angle. Normally a cough removes such material from the upper tract, and the vocal cords and epiglottis prevent entry into the lower tract. ■ Pathophysiology The characteristics of the aspirate determine the specific effects on respiratory function. For example, vomitus may contain solid objects as well as highly acidic gastric secre- tions, lipids, or alcohol. The common result is obstruction, whether the aspirate is a solid object causing obstruction directly or an irritating liquid causing inflammation and swelling. In addition, inflammation may interfere with gas exchange and predispose to pneumonia. Some examples of the effects of aspirated solid objects follow: • Solid objects lodge in a passageway and totally obstruct airflow at that point. The physical size of the object is one factor, which may be augmented by inflammation and swelling in the area. A small obstruction may be asymptomatic. • A large object may occlude the trachea and block all airflow, a life-threatening situation. In such cases, no sound can be made to alert others to the problem, and consciousness is lost quickly as oxygen supplies are depleted. • Solid objects lodging in a bronchus lead to nonaeration and collapse of the area distal to the obstacle (see Fig. 13.24C, presented later in the chapter). • Sometimes solid objects create a ball-valve effect, in which air is able to pass down the tract on inspiration, but the passageway totally closes on expiration, leading to a buildup of air distal to the obstruction. • Foods such as dried beans may swell after aspiration and become more firmly lodged. • Sharp pointed objects, such as bone fragments, also lodge in a passageway. Although it does not totally occlude the airway by itself, such an object traumatizes the mucosa, causing an acute inflammatory response that adds to the barrier. The inflammatory response may stimulate bronchoconstriction. Also, an object that straddles the airway will collect any other material entering the area, increasing the obstruction. • Fatty or irritating solids such as peanuts also cause inflammation around the area, creating edema and further impeding airflow. If not removed, a granuloma or fibrous tissue develops around such material (Fig. 13.17). When liquids are aspirated, the effects are somewhat different. Irritating liquids, particularly acids (vomitus), alcohol, or oils (milk), tend to disperse into several bronchi. These materials cause severe inflammation, leading to narrow airways and increased secretions, which make the lungs more difficult to expand. In some cases, a. Persistent productive cough, dyspnea, and wheezing b. Detection on a chest x-ray taken when an individual develops pneumonia or other complications c. Hemoptysis, when tumors erode tissue d. Pleural involvement, which may lead to pleural effusion, pneumothorax, or hemothorax e. Chest pain, occurring with advanced tumors that involve the pleura or mediastinum f. Hoarseness (laryngeal nerve compression), facial or arm edema and headache (compression of the superior vena cava), dysphagia (compression of the esophagus), or atelectasis, caused by large tumors or involved lymph nodes 2. Systemic signs of lung cancer include weight loss, anemia, and fatigue. 3. Paraneoplastic syndrome is indicated by the signs of an endocrine disorder related to the specific hormone secreted. 4. Signs of metastases depend on the site. For example, metastatic bone cancer would be indicated on a bone scan and be manifested by bone pain or pathologic fracture. ■ Diagnostic Tests There is no readily available screening test for lung cancer, although research continues to identify means to diagnose tumors before metastasis and spread. Specialized helical CT scans and MRI are more effective in early diagnosis than chest x-rays, which demonstrate later lesions and complications such as atelectasis or pleural effusion. Bronchoscopy provides secretions containing malignant cells from central lesions for definitive diagnosis, and biopsy may be required for less accessible lesions. Mediastinoscopy is useful to check lymph nodes, whereas bone scans are used to detect metastasis. These are useful in the staging process. Pulmonary function tests can clarify the effects of the tumor on airflow. ■ Treatment Methods of treatment may include the following: • Radiofrequency ablation (RFA) can be used to destroy single small tumors (see Chapter 20). • Surgical resection or lobectomy may be performed on localized lesions. • Chemotherapy and radiation may be used in conjunc- tion with surgery or as palliative treatment, although many tumors are not responsive to such therapy. • Photodynamic therapy (a chemical is injected and migrates to tumor cells, where it is activated by laser light and destroys the cancer cells) is sometimes effec- tive. The prognosis is poor unless the tumor is in a very early stage of development. Aspiration Aspiration involves the passage of food or fluid, vomitus, drugs, or other foreign material into the trachea and lungs. CHAPTER 13 Respiratory System Disorders 299 reason, for example, following anesthesia or stroke, or in patients with coma or neurologic damage. Vomitus may be aspirated postoperatively from the effects of anesthet- ics or drugs. Usually a patient is not allowed to eat or drink preoperatively to reduce the risk of aspiration, but emergency situations do not allow for this precaution. Individuals who eat or drink or perhaps take medica- tions when lying down also risk aspiration because the gravitational force is of no value in moving food quickly and completely down the esophagus. Residual liquid often remains in the mouth and oropharynx, to drip at a later time into the trachea. Adults frequently aspirate food or fluid, especially when combining eating with talking at social events (sometimes called a café coronary). A chunk of meat is the common culprit, particularly if the food is not well chewed and alcohol intake has depressed protective reflexes. Because such food causes total obstruction, the person cannot speak but may have time to gesture to the chest or neck before falling unconscious, and this could be interpreted as a heart attack or coronary. It is important to sweep the mouth for any object and carry out the Heimlich maneuver before commencing cardio- pulmonary resuscitation. ■ Signs and Symptoms Common manifestations include the following: • Coughing and choking with marked dyspnea • Stridor and hoarseness are characteristic of upper airway obstruction • Wheezing • Tachycardia and tachypnea • Nasal flaring, chest retractions, and marked hypoxia • Total obstruction at the larynx or trachea prevents any sounds or cough from being produced; a person may reach for the chest or neck area • Cardiac or respiratory arrest quickly ensues ■ Prevention and Treatment Aspiration is easier to prevent than treat. Caregivers are advised to keep toys with small pieces away from toddlers and to not provide food that can choke the child. Adults should avoid talking or moving about when chewing and swallowing to reduce the risk. Avoid swallowing large chunks of food. the alveoli are involved in the inflammation, and gas diffusion is impaired. This type of inflammation may be called chemical or aspiration pneumonia; it predisposes to the development of infection later. Other potential complications include the following: • Respiratory distress syndrome may develop if inflam- mation is widespread. • Pulmonary abscess may develop if microbes are in the aspirate. • Certain materials such as solvents, if aspirated in large amounts, may be absorbed into the blood and cause systemic effects. ■ Etiology Aspiration is a common problem in young children. When children are very young, they put most objects in their mouths. Children also tend to move about with objects in their mouths, thus increasing the risk of aspiration. Smooth, round objects are most dangerous. Common examples are chunks of hot dogs, candy, nuts, grapes, and raw carrots. Buttons or coins and balloons are frequent nonfood examples. Children may accidentally aspirate toxic fluids such as cleaning materials or lighter fluid. Some fluids, such as those containing hydrocarbons, for example, turpentine, have a low viscosity and a low surface tension and therefore tend to spread in a thin film over a large area of the lung, causing extensive irritation and damage. Inhalation of substances such as baby powder can also cause inflammation in the delicate lung tissue. Children with congenital anomalies such as a cleft palate or tracheoesophageal fistula are especially at risk for aspiration until surgical repair takes place (see Chapter 17). Aspiration can occur under many different circum- stances. It is often a complication in individuals of any age when the swallowing or gag reflex is depressed for any Meat FIG. 13.17 Photomicrograph of granuloma in the lung resulting from aspiration of meat in a patient with multiple sclerosis. (Courtesy of R.W. Shaw, MD, North York General Hospital, Toronto, Ontario, Canada.) THINK ABOUT 13.9 a. Describe the incidence of lung cancer. b. Explain why (1) wheezing, (2) hemoptysis, and (3) pleural effusion may occur in patients with lung cancer. c. Explain the result of aspirating food and explain why the problem may be difficult to identify. d. Explain why an infant should never be put to bed with a bottle. 300 SECTION III Pathophysiology of Body Systems effective treatment, his or her driver’s license will be revoked. Asthma Asthma is a disease that involves periodic episodes of severe but reversible bronchial obstruction in persons with hypersensitive or hyperresponsive airways. Frequent repeated attacks of acute asthma may lead to irreversible damage in the lungs and the development of chronic asthma (chronic obstructive lung disease). Acute attacks may continue to be superimposed on the chronic condition. A significant rise in episodes of acute asthma requiring hospitalization in children has occurred since the 1990s. In the 5- to 17-year-old age group, about 15 million persons have been diagnosed with asthma in the United States. It was reported that 4 million children under age 18 had an asthma attack during one 12-month period. The number of attacks peaks in school children in September, often associated with an increase in incidence of the common cold. As well, the incidence of asthma in the general population has greatly increased, and it appears that many additional cases have not been diagnosed; thus incidence rates are probably lower than the actual occurrence of the disease. ■ Pathophysiology Asthma may be classified in different ways. It may be acute or chronic, acute referring to a single episode, and chronic referring to the long-term condition. One system rates a case of asthma on a clinical scale ranging from mild and intermittent to severe and persistent. In the traditional method based on etiology and the presence of a hypersensitivity reaction, there are two basic types of asthma. The first is often called extrinsic asthma and involves acute episodes triggered by a type I hypersen- sitivity reaction to an inhaled antigen (see Chapter 7). Frequently there is a familial history of other allergic conditions such as allergic rhinitis (hay fever) or eczema, and onset commonly occurs in children. Some patients are no longer subject to attacks after adolescence. The second type of asthma is intrinsic asthma, with onset during adulthood. In this disease other types of stimuli target hyperresponsive tissues in the airway, initiating the acute attack. These stimuli include respiratory infec- tions, exposure to cold, exercise, drugs such as aspirin, stress, and inhalation of irritants such as cigarette smoke. Many patients have a combination of the two types. All types of asthma exhibit the same pathophysiologic changes related to inflammation during an acute attack. The bronchi and bronchioles respond to the stimuli with three changes: • Inflammation of the mucosa with edema • Contraction of smooth muscle (bronchoconstriction) • Increased secretion of thick mucus in the passages (Fig. 13.18) EMERGENCY TREATMENT FOR ASPIRATION 1. The Heimlich maneuver to dislodge the solid object is recommended (stand behind the victim with encircling arms, position a fist, thumb side against the abdomen, below the sternum, place the other hand over the fist, and thrust forcefully inward and upward). 2. A foreign object may be ejected from an infant by back blows administered between the infant’s shoulder blades, while the infant’s body is supported over an arm or leg, head lower than the trunk. Sometimes an individual can use a finger probe successfully to access an object at the back of the tongue. Instrumentation may be necessary in some cases to remove the offending object. In case of total obstruction, an emergency tracheotomy is necessary. Patients with widespread inflammation should be monitored for adult respiratory distress syndrome or pneumonia. Oxygen and supportive therapy may be required as well as prophylactic antibiotics. Obstructive Sleep Apnea Sleep apnea results when than pharyngeal tissues collapse during sleep leading to repeated and momentary cessation of breathing. ■ Pathophysiology and Etiology Men are more often affected than women, and the incidence increases with age and obesity (body mass index [BMI] >30). Current estimates suggest that 3% to
5% of the adult population is affected.
■ Signs, Symptoms, and Complications
Sleep apnea is usually diagnosed when the sleeping
partner notes loud snoring with intermittent gasps for
air. Many cases go undiagnosed and untreated. Complica-
tions are directly related to chronic hypoxia and fatigue
and include type 2 diabetes, pulmonary hypertension,
right-sided congestive heart failure, cerebrovascular
accident, erectile dysfunction, depression, and daytime
sleepiness. Operating a motor vehicle or other machinery
is dangerous because the person tends to become sleepy
and unaware of changes in the environment. It is recom-
mended that patients avoid ingestion of sleeping pills
or alcohol.
■ Treatment
Treatment involves the use of a continuous positive airway
pump (CPAP) machine, which delivers humidified room
air at a pressure that maintains an open airway. Patients
using a CPAP machine during sleep prevent the progres-
sion of complications and accidents owing to sleepiness.
Oral appliances may reduce the collapse of the pharyngeal
tissues in some cases. Devices are also available to prevent
the patient sleeping in a supine position, which predis-
poses to apnea. In many jurisdictions, if the client refuses

CHAPTER 13 Respiratory System Disorders 301
bronchial wall, creating a further barrier to expiratory
airflow. Residual volume increases. As a result, it becomes
more difficult to inspire fresh air or to cough effectively
to remove the mucus. To understand hyperinflation of
the lungs, take several breaths but exhale only partially
after each inspiration. Consider how your lungs feel and
the position of your ribs. Can you take a deep breath?
Can you cough?
Total obstruction of the airway results when mucus
plugs completely block the flow of air in the already
narrowed passage. This leads to atelectasis or nonaeration
of the tissue distal to the obstruction (see Fig. 13.24C).
The air in the distal section diffuses out and is not
replaced, resulting in collapse of that section of the lung.
Both partial and total airway obstruction lead to marked
hypoxia. Oxygen levels are further depleted by the
increased demand for oxygen to supply increased muscle
activity and the stress response as the individual fights
for air. Both respiratory and metabolic acidosis result
from severe respiratory impairment. Hypoxemia causes
vasoconstriction in the pulmonary blood vessels, reducing
blood flow through the lungs and increasing the workload
of the right side of the heart.
Status asthmaticus is a persistent severe attack of asthma
that does not respond to therapy. It is often related to
inadequate medical treatment. It may be fatal owing to
severe hypoxia and acidosis leading to cardiac arrhythmias
or central nervous system depression.
Chronic asthma and chronic obstructive lung disease
may develop from irreversible damage in the lungs when
frequent and severe acute asthmatic attacks form a pattern.
The bronchial walls become thickened, and fibrous tissue
resulting from the frequent infections that follow attacks
develops in atelectatic areas. Because it is impossible to
remove all the tiny mucus plugs in the small passages,
complications are common following frequent episodes
of asthma.
■ Etiology
A family history of hay fever, asthma, and eczema is
common. Viral upper respiratory infections frequently
precipitate attacks. Contributing factors include an
increase in sedentary lifestyles, with children remaining
indoors, resulting in increased exposure to allergens amid
poor ventilation. Increased air pollution has also been a
factor.
■ Signs and Symptoms
Typical manifestations of an acute asthma attack include
the following:
• Cough, marked dyspnea, a tight feeling in the chest,
and agitation develop as airway obstruction increases.
The patient is unable to talk.
• Wheezing is characteristic as air passes through the
narrowed bronchioles.
• Breathing is rapid and labored, with use of accessory
muscles and possible chest retractions.
These changes create obstructed airways, partially or
totally, and interfere with airflow and oxygen supply.
In patients with extrinsic asthma, the antigen reacts
with immunoglobulin E (IgE) on the previously sen-
sitized mast cells in the respiratory mucosa, releasing
histamine, kinins, prostaglandins, and other chemical
mediators, which then cause inflammation, bronchospasm,
edema, and increased mucus secretion. The reaction also
stimulates branches of the vagus nerve, causing reflex
bronchoconstriction.
In the second stage of the allergic response, which
occurs a few hours later, the increased leukocytes, particu-
larly eosinophils, release additional chemical mediators
such as leukotrienes, resulting in prolonged inflammation,
bronchoconstriction, and epithelial damage. Chemotactic
factors and cytokines are released by mast cells and draw
more white blood cells. The outcome is obstruction in the
airways, partial and total, and marked hypoxia.
The precise mechanism whereby a similar response
occurs in patients with intrinsic asthma has not been
determined, but research suggests that chronic T lym-
phocyte activation possibly due to an internal antigen
is the cause. The tissues are hyperresponsive, and an
underlying chronic inflammation or imbalance in auto-
nomic innervation to the tissues is also suspected.
Partial obstruction of the small bronchi and bronchioles
results in air trapping and hyperinflation of the lungs (see
Fig. 13.18). Air passes into the areas distal to the obstruc-
tion and alveoli, but it is only partially expired. Because
expiration is a passive process, less force is available to
move air out, and forced expiration often collapses the
Smooth muscle
Excessive mucus
Inflammation
4. OBSTRUCTED
BRONCHIOLE
2. MUCUS
PLUG
1. EDEMA OF
MUCOUS MEMBRANE
3. BRONCHOSPASM
(MUSCLE CONTRACTION)
FIG. 13.18 Asthma—acute episode.

302 SECTION III Pathophysiology of Body Systems
replaced isoproterenol and epinephrine, act on
receptors to relax bronchial smooth muscle but have
minimal effects on the heart. These inhalers, properly
used, provide a measured dose of the medication
and are most effective when used at the first indica-
tion of an attack. They may also be administered
before exercise or exposure to a known stimulus.
c. Glucocorticoids such as beclomethasone (Beclovent)
may be administered by inhalation also but are more
effective in reducing the second stage of inflamma-
tion in the airways. This type of drug may be useful
when chronic inflammation develops.
3. Measures for status asthmaticus include the following:
a. Hospital care is essential when a patient does not
respond to the bronchodilator.
4. Prophylaxis and treatment of chronic asthma includes
the following:
a. Leukotriene receptor antagonists such as zafirlukast
(Accolate) and montelukast (Singulair) block inflam-
matory responses in the presence of stimuli. Medica-
tion is taken orally on a regular basis to prevent
attacks due to allergens, exercise, and aspirin.
Leukotriene receptor antagonists are not effective
in the treatment of acute attacks.
b. Cromolyn sodium is a prophylactic medication that
is administered by inhalation on a regular daily
basis. The drug inhibits release of chemical media-
tors from sensitized mast cells in the respiratory
passages and decreases the number of eosinophils,
thus reducing the hyperresponsiveness of the tissues.
It is particularly useful for athletes and sports
enthusiasts. It is of no value during an acute attack.
• Thick and tenacious or sticky mucus is coughed up.
• Tachycardia occurs and perhaps pulsus paradoxus
when the pulse differs on inspiration and expiration.
Paradoxic pulse is observed when a blood pressure
measurement is taken during an asthma attack. The
sounds registering systolic pressure are heard first
during expiration, and there is a gap of 10 mm Hg or
more before the sounds of both inspiration and expira-
tion are heard.
• Hypoxia develops.
Respiratory alkalosis develops initially because of
hyperventilation.
• Respiratory acidosis develops in time due to air trap-
ping, and marked fatigue causes decreased respiratory
effort with weaker cough. This is aggravated by
developing metabolic acidosis due to hypoxia (increased
lactic acid) and from metabolic acid accumulating from
increased metabolic activity and dehydration.
• Severe respiratory distress is evident. Hypoventilation
leads to increasing hypoxemia and respiratory
acidosis.
• Respiratory failure is indicated by decreasing respon-
siveness, cyanosis, and arterial blood gas measurements
indicating a Pao2 of less than 50 mm Hg or a Paco2
of greater than 50 mm Hg.
■ Treatment
Minimizing the number and severity of acute attacks is
necessary to prevent permanent lung damage, reduce
the risk of infection, and prevent the development of
emphysematous changes or chronic obstructive lung
disease.
1. General measures include the following:
a. Skin tests for allergic reactions are helpful in deter-
mining specific stimuli to be avoided.
b. Avoidance of common triggering factors, including
airborne irritants or drugs such as aspirin, is
recommended.
c. Good ventilation in the home, school, and workplace
is helpful.
d. Regular swimming sessions are of great benefit,
particularly to affected children, to strengthen chest
muscles and improve cardiovascular fitness as well
as reduce stress. Walking and swimming are recom-
mended for adults.
e. It has been suggested that prophylactic medication
be given as children return to school or at the first
sign of a cold.
2. Measures for acute attacks include the following:
a. Controlled breathing techniques and a reduction
in anxiety often lessen the severity and extent of
the attack because a feeling of panic frequently
aggravates the condition.
b. Many individuals carry inhalers so that they can
self-administer a bronchodilator, usually a beta2-
adrenergic agent such as salbutamol (Ventolin).
These more specific drugs, which have largely
THINK ABOUT 13.10
a. Which structures in the lungs contain a higher percentage
of smooth muscle?
b. Explain how obstruction develops in an asthmatic patient
following exposure to an inhaled allergen.
c. Compare the effects of partial and total obstruction of the
airways on ventilation and on oxygen levels in the blood.
d. Explain the timing and development of respiratory
alkalosis, respiratory acidosis, and metabolic acidosis
during an asthma attack.
Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD), some-
times also called chronic obstructive lung disease (COLD),
is a group of common chronic respiratory disorders that
are characterized by progressive tissue degeneration and
obstruction in the airways of the lungs. They are debilitat-
ing conditions that affect the individual’s ability to work
and function independently. Examples of these disorders
are emphysema, chronic bronchitis, and chronic asthma.
Their characteristics are compared in Table 13.5. In some

CHAPTER 13 Respiratory System Disorders 303
Several factors contribute to the destruction of tissue
in the alveoli. In some individuals there is a genetic
deficiency of alpha1-antitrypsin, a protein normally present
in tissues and body fluids that inhibits the activity of
proteases, which are destructive enzymes released by
neutrophils during an inflammatory response. An example
of a protease is elastase, which breaks down elastic fibers.
This destructive process seems to be accelerated in persons
with low alpha1-antitrypsin levels. This genetic tendency
is often found in individuals who develop emphysema
relatively early in life. Cigarette smoking increases both
the number of neutrophils in the alveoli and the release
and activity of elastase, but it decreases the effect of alpha1-
antitrypsin, thus greatly contributing to the breakdown
of alveolar structures. Certain pathogenic bacteria present
with infection also release proteases.
The changes in the lung tissue have many effects on
lung function:
1. The breakdown of the alveolar wall results in the
following:
• Loss of surface area for gas exchange
• Loss of pulmonary capillaries, affecting perfusion
and the diffusion of gases
• Loss of elastic fibers, affecting the ability of the lung
to recoil on expiration
• Altered ventilation-perfusion ratio as various
changes occur in the alveoli (Fig. 13.20)
• Decreased support for other structures such as the
small bronchi, which often leads to collapse of the
walls and additional obstruction of airflow during
expiration
2. Fibrosis and thickening of the bronchial walls have
resulted from chronic irritation and the frequent infec-
tions associated with smoking and increased mucus
production. These conditions lead to the following:
• Narrowed airways
• Weakened walls
• Interference with passive expiratory airflow
patients, several primary diseases overlap—for example,
asthma and bronchitis. Other conditions such as cystic
fibrosis and bronchiectasis may lead to similar obstructive
effects. In contrast, many occupational lung diseases,
such as silicosis, asbestosis, and farmer’s lung, are clas-
sified as restrictive lung diseases because the irritant causes
interstitial inflammation and fibrosis, resulting in loss of
compliance, or “stiff lung.”
Chronic obstructive pulmonary disease causes irrevers-
ible and progressive damage to the lungs. Eventually,
respiratory failure may result because of severe hypoxia
or hypercapnia. In many patients, COPD leads to the
development of cor pulmonale, right-sided congestive heart
failure due to lung disease (see Chapter 12).
The prevalence of COPD is probably underestimated
because many people are unaware they have it, particu-
larly in the early stages when symptoms are minimal or
masked by the primary problem. The percentage of
females has greatly increased, as has the number of deaths.
In 2002 there were 124,816 deaths in the United States.
In 2005 the breakdown by disease showed approximately
4.1 million persons had emphysema, 9.5 million had
chronic bronchitis, and 16 million had asthma in the
United States. The CDC states that COPD is the fourth
most common cause of mortality in the United States,
and WHO estimates that COPD will become the fourth
cause of deaths globally by 2020; the current global
mortality is 2.74 million.
Emphysema
■ Pathophysiology
The significant change in emphysema is the destruction
of the alveolar walls and septae, which leads to large,
permanently inflated alveolar air spaces (Fig. 13.19).
Emphysema may be further classified by the specific
location of the changes—for example, in the distal alveoli
(panacinar) or bronchiolar (centrilobular) area.
TABLE 13.5 Chronic Obstructive Lung Disease
Disease Characteristic Emphysema Chronic Bronchitis Asthma—Acute
Etiology Smoking, genetic Smoking, air pollution Hypersensitivity type I, hyperresponsive
tissue
Location Alveoli Bronchi Small bronchi, bronchioles
Pathophysiology Destruction of alveolar walls,
loss of elasticity, impaired
expiration, barrel chest,
hyperinflation
Increased mucous glands
and secretion,
inflammation, and
infection, obstruction
Inflammation, bronchoconstriction,
increased mucus produced, obstruction,
repeat attacks lead to damage
Cough, dyspnea Some coughing, marked
dyspnea
Early, constant cough,
some dyspnea
Cough and dyspnea, wheezing
Sputum Little Large amount, purulent Thick, tenacious mucus
Cyanosis No Yes Yes if status asthmaticus
Infections Some Frequent Some
Cor pulmonale Perhaps late Common Rare

304 SECTION III Pathophysiology of Body Systems
D
A. Normal Alveolus
B. Emphysema
C. Air Trapping
Loss of septae and capillaries
Decreased surface area
Loss of elastic fibers
Decreased recoil
Recoil
Alveolar
duct
Respiratory
bronchiole
Respiratory
bronchiole
Overinflated alveolus
Normal
expiration
Impaired
expiration
Damaged wall
collapses or airway
becomes obstructed
Loss of elasticity
Increased residual
volume and
overinflated lungs
Alveolus
FIG. 13.19 Emphysema. A, Normal alveolus. B, Emphysema. C, Air trapping. D, Upper micrograph,
Normal adult lung. Lower micrograph, Pulmonary emphysema with characteristic dilated airspaces.
(Courtesy of R.W. Shaw, MD, North York General Hospital, Toronto, Ontario, Canada. D From Klatt
E: Robbins and Cotran Atlas of Pathology, ed 3, Philadelphia, 2015, Elsevier.)
3. Progressive difficulty with expiration leads to the
following:
• Air trapping (see Fig. 13.19C), and increased residual
volume
• Overinflation of the lungs
• Fixation of the ribs in an inspiratory position and
an increased anterior-posterior diameter of the
thorax (barrel chest)
• Diaphragm appears flattened on x-rays
4. With advanced emphysema, and significant loss of
tissue, the following events occur:
• Adjacent damaged alveoli coalesce, forming very
large air spaces. Normally the uninflated lung
appears to be a solid mass. With emphysema, the
lung appears to have many large holes in it. Some-
times one can see through the scraps of remaining
tissue from one side to the other. These air-filled
spaces are called blebs or bullae (Fig. 13.21B).

CHAPTER 13 Respiratory System Disorders 305
• Infections develop frequently because secretions
are more difficult to remove past obstructions, and
airway defenses are impaired.
• Pulmonary hypertension and cor pulmonale may
develop in a late stage as the pulmonary blood
vessels are destroyed and hypoxia causes pulmonary
vasoconstriction. The increased pressure in the
pulmonary circulation increases resistance to the
• The tissue and pleural membrane surrounding large
blebs near the surface of the lung may rupture,
resulting in pneumothorax.
• Hypercapnia becomes marked.
• Hypoxic drive for inspiration develops as the
patient’s respiratory control adapts to a chronic
elevation of carbon dioxide levels, and hypoxia
becomes the driving force for respiration.
B. Decreased ventilation C. Good ventilation –
Obstruction in pulmonary
circulation
Decreased perfusion
E. Inflammation impairs ventilation, perfusion,
and diffusion of O2
D. Destruction of alveolar wall
and capillaries Decreased
ventilation and perfusion
Obstruction
Inflammation
Fluid reduces
ventilation and
diffusion
AIRFLOW
Alveolus
A. Normal ventilation
and perfusion
Capillary
Atelectasis
Thickened membrane
FIG. 13.20 Changes in ventilation and perfusion.

306 SECTION III Pathophysiology of Body Systems
forward (tripod position), to facilitate breathing. The
chest is hyperresonant on percussion. Hyperventilation
maintains adequate oxygen levels until later stages.
• Anorexia occurs.
• Fatigue that contributes to weight loss.
• Clubbed fingers develop.
• Secondary polycythemia may develop as a
compensation.
■ Diagnostic Tests
Chest x-rays and pulmonary function tests indicate the
presence of increased residual volume and total lung
capacity as well as decreased forced expiratory volume
and vital capacity.
■ Treatment
Avoidance of respiratory irritants and sources of respira-
tory infections and cessation of smoking may slow the
progress of emphysema. Treatment may include the
following:
• Immunization can guard against influenza and
pneumonia.
right ventricle, and eventually the ventricle fails.
Many patients with respiratory disease manifest
signs of heart failure (see Chapter 12).
■ Etiology
Cigarette smoking is implicated in most cases of emphy-
sema. However, a genetic factor contributes to early
development of the disease in nonsmokers. Exposure to
other air pollutants also predisposes to emphysematous
changes, which may develop in conjunction with other
chronic lung disorders, such as cystic fibrosis and chronic
bronchitis.
■ Signs and Symptoms
The onset of emphysema is insidious. As it develops the
manifestations include the following:
• Dyspnea occurs first on exertion and then progresses
until it is marked even at rest.
• Hyperventilation with a prolonged expiratory phase,
use of the accessory muscles, and hyperinflation leading
to development of a “barrel chest” mark the ventilation
difficulty. Typical posture is a sitting position, leaning
B
C
A
FIG. 13.21 Emphysema. A, Emphysema. B, Bullous emphysema. Bullae are most prominent on
the lower lobe (arrow). C, Emphysematous lung with tumor. (A From Damjanov I, Linder J: Anderson’s
Pathology, ed 10, St. Louis, 1996, Mosby. B From Klatt E: Robbins and Cotran Atlas of Pathology,
ed 3, Philadelphia, 2015, Elsevier. C Courtesy of Paul Emmerson and Seneca College of Applied Arts
and Technology, Toronto, Ontario, Canada.)

CHAPTER 13 Respiratory System Disorders 307
and overinflation that maintain oxygen levels in
emphysema, compared with the typical clinical pre-
sentation of lower oxygen levels, cyanosis, and edema,
the “blue bloater” of bronchitis.
• Severe dyspnea and fatigue interfere with nutrition,
communication, and daily activities, leading to general
debilitation.
• Pulmonary hypertension and cor pulmonale are
common.
■ Etiology
Individuals with chronic bronchitis usually have a
history of cigarette smoking or living in an urban or
industrial area, particularly in geographic locations where
smog is common. Heavy exposure to inhaled irritants
leads to inflammation and frequent infections, initiat-
ing the cycle. In some cases, asthma is an associated
condition.
■ Signs and Symptoms
Manifestations include the following:
• Constant productive cough
• Tachypnea and shortness of breath
• Frequently secretions are thick and purulent
• Cough and rhonchi are usually more severe in the
morning because the secretions have pooled during
sleep
• Airway obstruction leads to hypoxia and eventually
to cyanosis as well as to hypercapnia
• Secondary polycythemia
• Severe weight loss
• Signs of cor pulmonale (systemic edema) often develop
as the vascular damage and pulmonary hypertension
progress
■ Treatment
Reducing exposure to irritants and prompt treatment of
infection slow the progress of the disease. Influenza and
pneumonia vaccines provide useful prophylaxis, as will
antimicrobials when appropriate. Use of expectorants,
bronchodilators, and appropriate chest therapy, including
postural drainage and percussion, assist in removing
excessive mucus. Low-flow oxygen and nutritional
supplements are helpful.
Bronchiectasis
Bronchiectasis is usually a secondary problem, rather
than a primary one, that develops in patients with
conditions such as cystic fibrosis or COPD. Some cases
result from childhood infection, aspiration of foreign
bodies, or a congenital weakness in the bronchial wall.
Depending on the cause, the condition may be localized
in one lobe, or more often it is diffuse in both lungs.
The incidence in North America has decreased owing to
effective use of antibiotics in treatment of the predisposing
disorders.
• Pulmonary rehabilitation programs provide appropriate
exercise and facilitate breathing. Patients can increase
their endurance for walking and learn methods to
optimize oxygen levels.
• Learning appropriate breathing techniques such as
pursed-lip breathing can maximize expiration and
ventilation with less expenditure of energy.
• Maintenance of adequate nutrition and hydration
contributes to improved energy levels, resistance to
infection, and general well-being.
• Bronchodilators, antibiotics, and oxygen therapy may
be necessary as the condition advances.
• Lung reduction surgery has proved helpful, although
recovery time is prolonged, and there is increased risk
of complications. By removing part of the lung, air
trapping can be reduced and expiration improved.
THINK ABOUT 13.11
a. Explain the factors that interfere with oxygenation of the
blood in patients with emphysema.
b. Explain why expiration is significantly impaired in patients
with emphysema.
c. Explain why heart failure may develop in patients with
emphysema.
d. Describe and explain the preferred position for a patient
with COPD (eg, one who is having dental treatment).
Should the patient be relatively supine, upright, or
otherwise positioned?
Chronic Bronchitis
■ Pathophysiology
Although there may be some overlap in the basic condi-
tions constituting COPD, chronic bronchitis is differenti-
ated by significant changes in the bronchi resulting from
constant irritation from smoking or exposure to industrial
pollution. The effects are irreversible and progressive.
Inflammation and obstruction, repeated infections,
and chronic coughing characterize bronchitis as the
following occur:
• The mucosa is inflamed and swollen.
• There is hypertrophy and hyperplasia of the mucous
glands, and increased secretions are produced. The
number of goblet cells is increased, and there is
decreased ciliated epithelium.
• Chronic irritation and inflammation lead to fibrosis
and thickening of the bronchial wall and further
obstruction. Secretions pool distal to obstructions and
are difficult to remove.
• Oxygen levels are low. During episodes of coughing
cyanosis may be seen. Historically the characteristic
manifestations of emphysema have been differentiated
from those of chronic bronchitis by using the term “pink
puffer” to summarize the dyspnea, hyperventilation,

308 SECTION III Pathophysiology of Body Systems
lung capacity is reduced. Some pulmonary diseases may
be classified in several categories—that is, they have both
obstructive and restrictive components.
Restrictive disorders include two groups, those in which
an abnormality of the chest wall limits lung expansion and
those in which lung disease impairs expansion. The first
group includes conditions such as kyphosis or scoliosis
(affecting the thorax), poliomyelitis or amyotrophic lateral
sclerosis or botulism (respiratory muscle paralysis), or
muscular dystrophy (weak muscles).
The second group includes diseases affecting the tissues
providing the supportive framework of the lungs, rather
than airway obstruction or alveolar destruction. Idiopathic
pulmonary fibrosis is an example of such a disease that
appears to have an immune basis. This group also includes
occupational diseases in which inhaled irritants cause
chronic low-grade but damaging inflammation over a
long period of time. Loss of elastic fibers and fibrosis in
chronic conditions results in loss of compliance. Acute
forms occur as pulmonary edema and adult respiratory
distress syndrome (ARDS). A “stiff lung” and reduced
compliance reduce total lung capacity.
Pneumoconioses
Pneumoconioses are chronic restrictive diseases resulting
from long-term inhalation of irritating particles such as
asbestos (see Fig. 28.2). Table 13.6 lists some examples.
Large particles are usually captured by nasal hairs and
mucus or by cilia and mucus in the lower passages, and
then removed. The normal defenses in the upper respira-
tory system cannot handle the overload of foreign
material, especially small particles, with long-term
occupational exposure such as in mining. Although there
are minor variations in the effects, this discussion includes
the general changes. More damage occurs when larger
numbers of particles enter the lungs, the particles are
very small, the material is more reactive with tissue, and
exposure continues over a long time period. Very small
particles can penetrate into alveolar ducts and sacs.
Smoking cigarettes aggravates the condition.
■ Pathophysiology
Inflammation and fibrous tissue develops, with gradual
destruction of connective tissue. Immune responses may
■ Pathophysiology
Bronchiectasis is an irreversible abnormal dilation or
widening, primarily of the medium-sized bronchi. These
dilations may be saccular or elongated (fusiform). They
arise from recurrent inflammation and infection in the
airways. This leads to obstruction in the airways or a
weakening of the muscle and elastic fibers in the bronchial
wall, or a combination of these. Fibrous adhesions may
pull the wall of a bronchus outward, dilating it.
In dilated or ballooning areas, large amounts of fluid
constantly collect and become infected. Infecting organ-
isms are usually mixed and include streptococci, staphy-
lococci, pneumococci, and H. influenzae. These infections
then cause loss of cilia and metaplasia in the epithelium,
additional fibrosis, and progressive obstruction. The
obstructions and loss of cilia interfere with the removal
of the fluids, continuing the cycle of events.
■ Signs and Symptoms
The significant signs of bronchiectasis are chronic cough
and production of copious amounts of purulent sputum
(1 to 2 cups per day). Cough may be paroxysmal in the
morning as the purulent sputum shifts in the lungs with
changes in body position, stimulating the cough reflex.
Other signs include the following:
• Rales and rhonchi in the lungs
• Foul breath
• Dyspnea
• Hemoptysis
• Weight loss
• Anemia
• Fatigue
■ Treatment
Antibiotics, bronchodilators, and chest physiotherapy as
well as treatment of the primary condition reduce the
severity of the infections and progressive damage to the
lungs.
THINK ABOUT 13.12
a. Describe the conditions predisposing to chronic
bronchitis, and relate them to the pathologic changes
occurring in the lungs.
b. Describe the factors contributing to recurrent infections
in the lungs, and relate them to your professional practice.
c. Explain why bronchiectasis tends to be progressive.
d. Prepare a chart comparing emphysema, cystic fibrosis, and
bronchiectasis with regard to pathologic changes in the
lungs, the significant signs that can be observed in a
patient, and potential complications.
TABLE 13.6 Pneumoconioses
Disease Agent Occurrence
Coal workers’ disease
or anthracosis
Coal dust Coal mines
Silicosis Silica Stone-cutting,
sand-blasting, mines
Asbestosis Asbestos Insulation,
shipbuilding
Farmer’s lung Fungal spores Hay
Restrictive Lung Disorders
The term restrictive lung disorders applies to a group of
diseases in which lung expansion is impaired and total

CHAPTER 13 Respiratory System Disorders 309
blood from the failing left ventricle causes high pressure
in the pulmonary circulation. This may be a chronic or
acute condition. Pulmonary edema also results from
hypoproteinemia due to kidney or liver disease, in which
serum albumin levels are low. Inflammation in the lungs
with increased capillary permeability develops due to
inhalation of toxic gases, or in association with tumors.
Blocked lymphatic drainage due to tumors or fibrosis in
the lungs may cause edema. Pulmonary hypertension
may occur idiopathically or secondary to obstructive
sleep apnea that is not treated.
■ Signs and Symptoms
Signs of mild pulmonary edema include the following:
• Cough
• Orthopnea
• Rales
As congestion increases, the following conditions arise:
• Hemoptysis often occurs.
• Sputum is frothy owing to air mixed with the secretions
and blood-tinged owing to ruptured capillaries in the
lungs.
• Breathing becomes labored as it becomes more difficult
to expand the lungs. The individual feels as if he or
she is drowning.
• Hypoxemia increases.
• Cyanosis develops in the advanced stage.
Acute congestive heart failure may cause such an episode,
called paroxysmal nocturnal dyspnea, during a sleep
period (see Chapter 12).
■ Treatment
The causative factors must be treated, and supportive care
such as oxygen is offered. In severe cases positive-pressure
mechanical ventilation may be necessary. There is an
increased risk of pneumonia developing after an episode
of pulmonary edema because of the residual secretions.
Individuals with a tendency to pulmonary edema should
be positioned with the upper body elevated.
Pulmonary Embolus
A pulmonary embolus is a blood clot or a mass of
other material that obstructs the pulmonary artery or
a branch of it, blocking the flow of blood through the
lung tissue. Most pulmonary emboli are thrombi or
blood clots originating from the deep leg veins (see
Chapter 12). An embolus to the lungs travels from its
source through larger and larger veins until it reaches
the heart and pulmonary artery. It then lodges as soon as
it reaches a smaller artery in the lungs through which it
cannot pass.
Pulmonary embolus due to deep vein thrombosis (DVT)
is a leading cause of death in hospitals. More than 600,000
people in the United States have a pulmonary embolism
each year, resulting in more than 60,000 deaths, usually
within the first hour after symptoms develop.
add to the damage in the case of more reactive particles,
such as silica. As fibrosis extends, the functional areas
of the lungs, including alveoli, are lost. Inspiration
becomes difficult as compliance is lost. The tissue changes
are irreversible. Infections are common.
Asbestos fibers have two additional effects, frequently
causing pleural fibrosis and greatly increasing the risk
of lung cancer, particularly in cigarette smokers. The risk
of cancer has raised public concern regarding the presence
of asbestos insulation in schools and homes.
■ Signs and Symptoms
Onset is insidious, with dyspnea developing first. As the
disease progresses, increasing effort is required for
inspiration. Cough is common and may or may not be
productive.
■ Treatment
Identifying and ending exposure to the damaging agent
will slow the progression of the disease, as will prompt
treatment of infection.
Vascular Disorders
Pulmonary Edema
■ Pathophysiology
Pulmonary edema refers to fluid collecting in the alveoli
and interstitial area. Many conditions can lead to this
development. This accumulation of fluid reduces the
amount of oxygen diffusing into the blood and interferes
with lung expansion, also reducing oxygenation of the
blood.
Excess fluid in the alveolar tissue may develop when
the following occurs:
• Inflammation is present in the lungs, increasing capil-
lary permeability.
• Plasma protein levels are low, decreasing plasma
osmotic pressure.
• Pulmonary hypertension develops.
Normally pressure in the pulmonary capillaries is
very low, and there is minimal fluid in the air pas-
sages and alveoli. When hydrostatic pressure in the
pulmonary capillaries becomes high, for example with
congestive heart failure (see Chapter 12), this leads to a
shift of fluid out of the capillaries into the alveoli (see
Chapter 2).
Excessive amounts of fluid in the interstitial areas and
alveoli interfere with the diffusion of oxygen, causing
severe hypoxemia, as well as with the action of surfactant,
leading to difficulty in expanding the lungs, which
ultimately collapse (Fig. 13.22). Capillaries may rupture,
causing blood-streaked sputum.
■ Etiology
Pulmonary edema can result from many primary condi-
tions. With left-sided congestive heart failure, backup of

310 SECTION III Pathophysiology of Body Systems
alveoli of the involved area. Reflex vasoconstriction often
occurs in the area, further increasing the pressure in the
blood vessels.
Large emboli (usually those involving more than
60% of the lung tissue) affect the cardiovascular system,
causing right-sided heart failure and decreased cardiac
output (shock). Sudden death often results in these
cases, which involve greatly increased resistance in the
pulmonary arteries because of the embolus plus reflex
vasoconstriction due to released chemical mediators such
as serotonin and histamine. This resistance to the output
from the right ventricle causes acute cor pulmonale.
There is also much less blood returning from the lungs
to the left ventricle and then to the systemic circulation
(decreased cardiac output). This can be appreciated by
visualizing a large embolus lying across the bifurcation
■ Pathophysiology
The effects of a pulmonary embolus depend somewhat on
the material, but largely on the size and therefore the loca-
tion of the obstruction in the pulmonary circulation (Fig.
13.23). Because lung tissue is supplied with oxygen and
nutrients by the separate bronchial circulation, infarction
does not follow obstruction of the pulmonary circulation
unless the general circulation is compromised or there is
prior lung disease. Infarction usually involves a segment
of the lung and the pleural membrane in the area.
Small pulmonary emboli are frequently “silent” or
asymptomatic. However, multiple small emboli (a
“shower”) often have an effect equal to that of a larger
embolus.
Emboli that block moderate-sized arteries usually cause
respiratory impairment because fluid and blood fill the
A
O2
3. Fluid in alveolus reduces
O2 diffusion
Pulmonary capillary
Airflow
5. Hypoxemia
1. High hydrostatic
pressure
2. Interstitial
edema
4. Fluid dilutes surfactant
alveoli collapse
Blood
To
left
side
of
heart
B
FIG. 13.22 A, Pulmonary edema associated with congestive heart failure. B, Micrograph showing
pulmonary edema. Alveoli are filled with smooth slightly flocular material. (A Courtesy of R.W.
Shaw, MD, North York General Hospital, Toronto, Ontario, Canada. B From Klatt E: Robbins and
Cotran Atlas of Pathology, ed 3, Philadelphia, 2015, Elsevier.)

CHAPTER 13 Respiratory System Disorders 311
occurring during labor and delivery, tumor cell emboli
that break away from a malignant mass, or air embolus
injected into a vein.
■ Signs and Symptoms
With small emboli, manifestations may include the
following:
• A transient chest pain
• Cough
• Dyspnea (this is often unnoticed but can be significant
because it may be a warning of more emboli
developing)
For larger emboli, manifestations may include the
following:
• Chest pain occurs, which increases with coughing or
deep breathing
• Tachypnea
• Dyspnea develops suddenly
• Later, hemoptysis and fever
• Hypoxia stimulates a sympathetic response, with
anxiety and restlessness, pallor, and tachycardia
Massive emboli cause the following:
• Severe crushing chest pain
• Low blood pressure
Lung
Left
ventricle
Right
ventricle
Inferior vena cava
1. Embolus from
leg vein
5. Very large embolus
blocks all pulmonary
circulation leading to
shock and cardiac
arrest
Aorta
6. Large embolus
causes decreased
blood returning
in pulmonary vein
and decreased
cardiac output
2. Single small
embolus may
be “silent”
3. Multiple small
emboli equiva-
lent to a large
embolus blocking
circulation
Pulmonary artery
Pulmonary
vein
4. Moderate-size
embolus likely
to cause respi-
ratory distress
and pulmonary
infarction
FIG. 13.23 Pulmonary embolus.
of the pulmonary artery (a “saddle embolus”) and totally
blocking the flow of blood from the right ventricle into the
lungs.
■ Etiology
Ninety percent of pulmonary emboli have originated from
deep veins, primarily in the legs. Many travel from the
deep veins of the legs as a result of phlebothrombosis
or thrombophlebitis (see Chapter 12). Risk factors for
these emboli include immobility, trauma or surgery to
the legs, childbirth, congestive heart failure, dehydration,
increased coagulability of the blood, and cancer. Sitting
in a plane or car for a long time period can predispose
to thromboembolus. Thrombi tend to break off with
sudden muscle action or massage, trauma, or changes
in blood flow. Postoperative risk can be reduced by
early ambulation, constant mechanical movement of the
affected leg, or use of thromboembolic deterrent stockings
(TEDS).
Other types of pulmonary emboli include fat emboli
from the bone marrow resulting from fracture of a large
bone (eg, the femur, particularly if poorly immobilized),
vegetations resulting from endocarditis in the right side
of the heart, amniotic fluid emboli from placental tears

312 SECTION III Pathophysiology of Body Systems
rate can control carbon dioxide levels, because this gas
diffuses easily.
If the lungs are not reinflated quickly, the lung tissue
can become necrotic and infected, and permanent lung
damage results.
■ Etiology
A variety of mechanisms can result in atelectasis (Fig.
13.24):
• Obstructive or resorption atelectasis develops when total
obstruction of the airway due to mucus or tumor leads
to diffusion into the tissue of air distal to the obstruc-
tion; this air is not replaced.
• Compression atelectasis results when a mass such as a
tumor exerts pressure on a part of the lung and pre-
vents air from entering that section of lung. Alterna-
tively, when the pressure in the pleural cavity is
increased, as with increased fluid or air, and the
adhesion between the pleural membranes is destroyed,
the lung cannot expand.
• Increased surface tension in the alveoli occurs with
pulmonary edema or respiratory distress syndrome,
preventing expansion of the lung.
• Fibrotic tissue in the lungs or pleura (sometimes called
contraction atelectasis) may restrict expansion and lead
to collapse.
• Postoperative atelectasis commonly occurs 24 to 72 hours
after surgery, particularly abdominal surgery. A number
of factors are implicated in this situation, including
restricted ventilation due to pain or abdominal disten-
tion; slow, shallow respirations due to anesthetics and
analgesics; increased secretions due to the supine
position; and decreased cough effort.
■ Signs and Symptoms
Small areas of atelectasis are asymptomatic. Large areas
cause dyspnea, increased heart and respiratory rates, and
chest pain. Chest expansion may appear abnormal or
asymmetric, depending on the cause of the atelectasis.
For example, obstructive atelectasis leads to a potential
low pressure “gap” or space on the affected side; therefore
the mediastinum shifts toward it, and the other lung
compensates by overinflating. The affected side often
“lags” behind the unaffected side during ventilation. With
compression atelectasis, the mediastinum may shift
toward the other unaffected side.
■ Treatment
The main goal of the treatment of atelectasis is to treat
the cause and reexpand the collapsed lung.
For atelectasis as a result of surgery:
• Deep breathing exercises
• Changing body positions
• Forced coughing
For atelectasis caused by external pressure:
• Removal of fluid, tissue or tumor causing the pressure
on the lungs
• Rapid weak pulse
• Loss of consciousness
Fat emboli are distinguished by the development of acute
respiratory distress, a petechial rash on the trunk, and
neurologic signs such as confusion and disorientation.
■ Diagnosis
Diagnosis can be confirmed with the following:
• X-ray
• Lung scan
• MRI
• Pulmonary angiography
The source of the embolus can be determined using
Doppler ultrasound or venography.
■ Treatment
Assessment of risk factors in an individual situation and
preventive measures are recommended. With prolonged
bed rest, compression stockings are helpful. In some cases,
a filter can be surgically inserted in the inferior vena
cava to remove blood clots. The underlying cause of the
embolus must be considered. In patients with pulmonary
embolus due to thrombus, oxygen is administered and
usually heparin or streptokinase (fibrinolytic agents) as
well to prevent additional clots. Mechanical ventilation
may be necessary, and in some cases an embolectomy is
performed.
THINK ABOUT 13.13
a. Explain three possible causes of pulmonary edema.
b. Explain which is more likely to occur with acute
pulmonary edema—hypoxemia, hypercapnia, or both
equally.
c. Explain how a pulmonary embolus can cause immediate
death.
Expansion Disorders
Atelectasis
Atelectasis is the nonaeration or collapse of a lung or
part of a lung leading to decreased gas exchange and
hypoxia. It occurs as a complication of many primary
conditions. Treatment depends on removing the underly-
ing cause, whether obstruction or compression, before
reinflating the lung.
■ Pathophysiology
When the alveoli become airless, they shrivel up as the
natural elasticity of the tissues dominates. This process
also interferes with blood flow through the lung. Both
ventilation and perfusion are altered, and this in turn
primarily affects oxygen diffusion. Unless a large propor-
tion of the lungs is affected, the increased respiratory

CHAPTER 13 Respiratory System Disorders 313
Collapsed lung
Pleural space filled
with fluid
Parietal pleura
Visceral pleura
Separated
A. Pleural Effusion
Mediastinal
shift
Atelectasis
Obstruction in
bronchus
Airflow
obstructed
Remaining
air diffuses
into tissues
and is not replaced
Nonaeration
and collapse
C. Obstructive Atelectasis – Absorption Atelectasis
External
mass
B. Compression Atelectasis
FIG. 13.24 Atelectasis.
For atelectasis caused by blockage:
• Chest clapping or percussion
• Postural drainage
• Medications to open airways and loosen mucus
Other medical disorders or conditions that may be causing
the collapse of a lung, which prevents proper aeration,
can be treated for the underlying causes with medications,
or other procedures and therapies.
Pleural Effusion
A pleural effusion is the presence of excessive fluid in
the pleural cavity. Normally a very small amount of fluid
is present to provide lubrication for the membranes.
Effusions vary in type and mechanism according to the
primary problem. Both lungs may be involved, but more
often only one lung is affected because each lung is
enclosed in a separate pleural membrane. The effects of
effusion depend on the amount, type, and rate of accu-
mulation of the fluid.
Pleurisy or pleuritis may precede or follow pleural
effusion or occur independently. Pleurisy is a condition
in which the pleural membranes are inflamed, swollen,
and rough, often in association with lobar pneumonia.
■ Pathophysiology
Small amounts of fluid are drained from the pleural cavity
by the lymphatics and have little effect on respiratory
function. Large amounts of fluid first increase the pressure
in the pleural cavity and then cause separation of the
pleural membranes, preventing their cohesion during
inspiration. These effects prevent expansion of the lung,
leading to atelectasis, particularly when fluid accumulates

314 SECTION III Pathophysiology of Body Systems
rapidly (see Fig. 13.24A). A large amount of fluid causes
atelectasis on the affected side and a shift of the medi-
astinal contents toward the unaffected lung, limiting its
expansion also. A tracheal deviation indicates this shift.
Venous return in the inferior vena cava and cardiac filling
may be impaired because large effusions increase pressure
in the mediastinum.
■ Etiology
Different types of fluid may collect in the pleural cavity.
Exudative effusions are a response to inflammation,
perhaps from a tumor, in which increased capillary
permeability allows fluid containing protein and white
blood cells to leak into the pleural cavity. Transudates are
watery effusions, sometimes called hydrothorax, that result
from increased hydrostatic pressure or decreased osmotic
pressure in the blood vessels, leading to a shift of fluid
out of the blood vessels into the potential space in the
pleural cavity. These effusions may occur secondary to
liver or kidney disease. Hemothorax is the term used when
the fluid is blood resulting from trauma, cancer, or surgery.
Empyema occurs when the fluid is purulent as a result
of infection, often related to pneumonia.
■ Signs and Symptoms
The general signs of pleural effusion include the following:
• Dyspnea
• Chest pain
• Increased respiratory and heart rates
• Usually dullness to percussion and absence of breath
sounds over the affected area are found because air
no longer flows through the passages
• Tracheal deviation and hypotension indicate a massive
effusion that interferes with both respiratory and
circulatory function
Pleurisy is manifested by cyclic pleuritic pain and a
friction rub heard on auscultation as the rough, swollen
membranes move against each other during respiratory
movements.
■ Treatment
Measures are required to remove the underlying cause
and treat the respiratory impairment. The fluid may have
to be analyzed to confirm the cause. Chest drainage tubes
may be used to assist inflation. If a large quantity of fluid
forms, thoracocentesis (needle aspiration) is required to
remove the fluid and relieve the pressure.
THINK ABOUT 13.14
a. Compare the mechanisms involved in the development of
atelectasis in a patient with cystic fibrosis and one with
pleural effusion.
b. Explain why a large pleural effusion may have more
serious consequences than an obstruction in a major
bronchus.
c. Explain the signs of atelectasis.
Pneumothorax
Pneumothorax refers to air in the pleural cavity. The pres-
ence of air at atmospheric pressure in the pleural cavity
and the separation of the pleural membranes by air
prevent expansion of the lung, leading to atelectasis.
When pneumothorax is caused by a malignant tumor or
trauma, fluid or blood may also be present in the cavity.
For example, with fluid in the more dependent area and
air above it, the condition could be called hydropneumo-
thorax. Chest x-rays can determine the type and extent
of pneumothorax.
There are several different types of pneumothorax
(Table 13.7):
• Closed pneumothorax occurs when air can enter the
pleural cavity through an opening directly from the
internal airways. There is no opening in the chest wall.
This can be a simple or spontaneous pneumothorax
or can be secondary to another disease.
• Simple or spontaneous pneumothorax occurs when a tear
on the surface of the lung allows air to escape from
inside the lung through a bronchus and the visceral
pleura into the pleural cavity (Fig. 13.25A). As the
lung tissue collapses, it seals off the leak. Simple
pneumothorax often occurs in young men who have
no prior lung disease but perhaps an idiopathic bleb
or defect on the lung surface. Following collapse, the
mediastinum can shift toward the affected lung, allow-
ing the other lung to expand more.
• Secondary pneumothorax is associated with underlying
respiratory disease resulting from rupture of an
emphysematous bleb on the surface of the lung (see
Fig. 13.21B) or erosion by a tumor or tubercular cavita-
tion through the visceral pleura. Again, this condition
lets inspired air pass into the pleural cavity.
• Open pneumothorax refers to atmospheric air entering
the pleural cavity through an opening in the chest
wall. This could result from trauma or surgery.
• Sucking wound is used to describe a large opening in
the chest wall, in which the sound of air moving in
and out makes a typical sucking sound (see Fig. 13.25B).
Because larger quantities of air are moving in and out,
there is a greater effect on respiratory and cardiovas-
cular function.
In open pneumothorax, air enters the pleural cavity
through the opening in the chest wall and parietal pleura,
causing immediate atelectasis on the affected side. Because
more air enters the pleural cavity during inspiration, the
mediastinum pushes against the unaffected lung, limiting
its expansion. Subsequently, on expiration, as air is pushed
out of the pleural cavity through the opening, the medi-
astinal contents shift back toward the affected side.
These abnormal movements occur as the pressure
changes with rib movements on inspiration and expira-
tion. This mediastinal flutter or “to-and-fro” motion impairs
both ventilation in the unaffected lung and venous return
through the inferior vena cava. (Recall that normal

CHAPTER 13 Respiratory System Disorders 315
• Hypoxia develops and leads to a sympathetic response,
including anxiety, tachycardia, and pallor
• Interference with venous return leads to hypotension
respiratory movements and pressure changes promote
movement of venous blood upward to the heart.)
• Tension pneumothorax is the most serious form of
pneumothorax (see Fig. 13.25C). This situation may
result from an opening through the chest wall and
parietal pleura (open pneumothorax) or from a tear
in the lung tissue and visceral pleura (closed pneumo-
thorax) that causes atelectasis. The particular pattern
of damage creates a flap of tissue or a one-way valve
effect, whereby the opening enlarges on inspiration,
promoting airflow into the pleural cavity. However,
on expiration, the opening is sealed off, preventing
removal of air from the pleural cavity. Thus with each
inspiration this lesion leads to continual increases in the
amount of air in the pleural cavity. Pressure increases
on the affected side eventually push the mediastinal
contents against the other lung, compressing the other
lung and the inferior vena cava. Severe hypoxia and
respiratory distress develop quickly and can become
life threatening if the source of the valve effect and
increasing intrapleural pressure is not treated.
■ Signs and Symptoms
The general signs of pneumothorax include the
following:
• Atelectasis
• Dyspnea
• Cough
• Chest pain
• Breath sounds are reduced over the atelectatic area
• Unequal chest expansion and mediastinal shift vary
with the type of pneumothorax
TABLE 13.7 Types of Pneumothorax
Closed Open Tension
Cause Spontaneous, idiopathic
Ruptured emphysematous bleb
Puncture wound through chest wall Open—puncture through thorax
Closed—tear in lung surface
Both with flap or one-way valve
Air entry From inside lung through tear
in visceral pleura
From outside body through opening
in thorax and parietal pleura
Through the thorax or tear in lung surface
Effects Atelectasis Atelectasis Atelectasis
Leak seals as lung collapses Air enters pleural cavity with each
inspiration and leaves with each
expiration
Air enters pleural cavity with each inspiration
Flap closes with expiration, and air pressure
increases in pleural cavity pressure
One lung impaired Unaffected lung compressed by
mediastinal shift on inspiration
Unaffected lung increasingly compressed by
mediastinal shift
No additional cardiovascular
effects
Mediastinal flutter impairs venous
return to heart
Mediastinal shift reduces venous return to
heart
Signs All three types: Increased, labored respirations with dyspnea, tachycardia, pleural pain, and asymmetric chest
movements
Breath sounds absent “Sucking” noise if large
Tracheal swing
Decreased blood pressure
Breath sounds absent on affected side
Tracheal deviation to unaffected side
Increasing respiratory distress
Shock, distended neck veins, cyanosis
Hypoxemia Moderate hypoxemia Severe hypoxemia
EMERGENCY TREATMENT FOR
PNEUMOTHORAX
1. Transport to a hospital as soon as possible.
2. An open pneumothorax or sucking wound is covered with
an occlusive dressing or covering to prevent the air
moving in and out of the pleural cavity. The dressing
should be checked to ensure that a tension pneumothorax
has not developed.
3. Penetrating objects should not be removed from the chest
wall until medical assistance is available.
4. If possible, tension pneumothorax should be converted to
an open pneumothorax by removing loose tissue or
enlarging the opening.
Flail Chest
Falls and car accidents cause most chest injuries. Flail
chest results from fractures of the thorax, usually fractures
of three to six ribs in two places or fracture of the sternum
and a number of consecutive ribs. There is often contusion
with edema and some bleeding in the lung tissue adjacent
to the flail section. Atelectasis does not occur as a direct
result of the trauma but may follow as a complication if
a broken rib punctures the pleura.
■ Pathophysiology
Chest wall rigidity is lost, resulting in paradoxical
(opposite) movement during inspiration and expiration

316 SECTION III Pathophysiology of Body Systems
A. Spontaneous Pneumothorax
Tear in visceral pleura leads to
air entering pleural space from lung
Normal lung with
intrapleural pressure lower
than intraalveolar pressure or
atmospheric pressure
B. Open Pneumothorax
Air in
Air out
Trachea and mediastinum
shift to compress unaffected lung
INSPIRATION EXPIRATION
Diaphragm
Chest wall
Inferior vena cava
Air enters pleural
space through opening
in thorax and parietal
pleura
C. Tension Pneumothorax
Air in
INSPIRATION EXPIRATION
Air enters pleural
space through opening
in thorax
Trachea and mediastinum
shift from side to side (flutter)
Air cannot leave
pleural space as
valve action
seals opening
Atelectatic lung
Compression of
inferior vena cava
Atelectasis
Atelectasis
Ribs
down
Ribs
lift
FIG. 13.25 Types of pneumothorax.

CHAPTER 13 Respiratory System Disorders 317
(Fig. 13.26). A sequence of pressure changes follows,
affecting ventilation and oxygen levels.
During inspiration there is the usual decrease in pressure
inside the lungs, then the following occurs:
• The flail or broken section of ribs moves inward rather
than outward as intrathoracic pressure is decreased.
• This inward movement of the ribs prevents expansion
of the affected lung.
• A large flail section can compress the adjacent lung
tissue, pushing the air out of that section and up the
bronchus. Because air is flowing down the trachea
and into the other lung, the “stale” air from the
damaged lung crosses into the other lung, along with
newly inspired air.
On expiration:
• The unstable flail section is pushed outward by the
increasing intrathoracic pressure.
• If the flail section is large, the paradoxical movement
of the ribs alters airflow during expiration.
• Air from the unaffected lung moves across into the
affected lung as the outward movement of the ribs
decreases pressure in the affected lung.
Mediastinal flutter occurs when the flail section is large.
As the lungs shift back and forth, the mediastinum is
pushed to and fro. The pressure changes and possible
kinking of the inferior vena cava interferes with venous
return to the heart and thus reduces cardiac output and
oxygen supplies to the cells.
Hypoxia results from the limited expansion and
decreased inspiratory volume of the flail lung; the
Multiple fractured
ribs cause loss
of chest wall
rigidity
Large flail section causes
air from affected lung to
flow across to unaffected lung
Large flail section causes
air from unaffected lung to
flow into affected lung
Paradoxical
movement of
ribs
Contused lung
tissue
Mediastinal
shift
Mediastinal
shift
Low pressure inside lungs
pulls flail section inward,
compressing lung on
affected side
High pressure inside lungs
pushes flail section outward
C. ExpirationB. InspirationA. Injury to thorax
Air inspired Air expired
FIG. 13.26 Flail chest injury.
shunting of stale air between lungs, which lowers the
oxygen content of the air; and the decreased venous
return.
EMERGENCY TREATMENT FOR FLAIL
CHEST
The abnormal movement is obvious, and therefore first aid
measures include stabilizing the flail section with a flat, heavy
object, thus limiting the outward paradoxicical movement of
the thorax until surgical repair can be performed.
THINK ABOUT 13.15
a. Describe two ways in which atmospheric air can enter the
pleural cavity.
b. List in the proper sequence the changes in the structures
and the pressures that occur during normal inspiration
and inspiration with flail chest.
c. Prepare a chart comparing the cause and effects of closed
pneumothorax, tension pneumothorax, and flail chest on
ventilation and cardiovascular activity.
Infant Respiratory Distress Syndrome
Infant respiratory distress syndrome (IRDS) or neona-
tal respiratory distress syndrome (NRDS, or hyaline

318 SECTION III Pathophysiology of Body Systems
delivery. Infants born to diabetic mothers are predisposed
to this syndrome.
■ Signs and Symptoms
Respiratory difficulty may be evident at birth or shortly
after birth. Manifestations include the following:
• A persistent respiratory rate of more than 60 breaths
per minute
• Nasal flaring
• Subcostal and intercostal retractions
• Rales
• Low body temperature
• Marked chest retractions in the neonate because of
the soft chest wall (Fig. 13.28)
As infant respiratory distress syndrome continues, the
following takes place:
• Respirations become more rapid and shallow
• Frothy sputum occurs
• Expiratory grunt develops
• Blood pressure falls
• Cyanosis and peripheral edema become evident
• Signs of severe hypoxemia are decreased responsive-
ness, irregular respirations with periods of apnea, and
decreased breath sounds
■ Diagnostic Tests
Arterial blood gas analysis is helpful in monitoring both
oxygen and acid-base balance. Initially, hypoxemia (low
Pao2) and metabolic acidosis (low serum HCO3–) are
present. Respiratory acidosis (high Pco2) develops as
ventilation becomes more difficult. Chest x-rays indicate
areas of congestion and atelectasis.
■ Treatment
Glucocorticoids given to women in premature labor
appear to benefit the premature infant by speeding up
membrane disease) is a common cause of neonatal deaths,
particularly in premature infants. With improved methods
of testing for lung maturity, and more effective prenatal
and postnatal therapy as well as supportive treatment,
the mortality rate has decreased since the early 2000s.
Some children have suffered developmental impairment,
particularly those born late in the second trimester of
pregnancy.
■ Pathophysiology
During the third trimester of fetal development, the
alveolar surface area and lung vascularity greatly increase
in preparation for independent lung function immediately
after birth. Surfactant, which reduces surface tension in
the alveoli and promotes expansion, is first produced
between 28 and 36 weeks of gestation, depending on the
maturity of the individual lung. It has been shown that
in utero stress hastens the maturation of lung tissue.
Infant lung maturity can be assessed by measuring the
surfactant level of the fetus with a test such as the lecithin-
sphingomyelin (L/S) ratio in amniotic fluid, which is
obtained by amniocentesis. Initially sphingomyelin is
high, then it decreases and lecithin increases until the
ratio represents adequate surfactant function at around
35 weeks of gestation.
Normally the first few inspirations after birth are
difficult as the lungs are first inflated; then breathing
becomes easier as residual air volume increases. Without
adequate surfactant, each inspiration is difficult because
the lungs totally collapse during each expiration, thereby
requiring use of the accessory muscles and much energy to
totally reinflate the lungs. The poorly developed alveoli are
difficult to inflate, and an inadequate blood and oxygen
supply further deters the production of surfactant by
alveolar cells (see Fig. 13.5). Diffuse atelectasis results,
which decreases pulmonary blood flow and leads to reflex
pulmonary vasoconstriction and severe hypoxia.
Poor lung perfusion and lack of surfactant lead to
increased alveolar capillary permeability, with fluid and
protein (fibrin) leaking into the interstitial area and alveoli,
forming the hyaline membrane (Fig. 13.27). This further
impairs lung expansion and decreases oxygen diffusion.
Some of the surviving neonates experience brain damage
due to severe hypoxia.
A vicious cycle develops as acidosis develops from
respiratory impairment and metabolic factors. The
strenuous muscle activity needed to breathe requires
more oxygen than is available, and this leads to anaerobic
metabolism and increased lactic acid. In turn, acidosis
causes pulmonary vasoconstriction and impairs cell
metabolism, reducing the synthesis and secretion of
surfactant.
■ Etiology
Infant respiratory distress syndrome is usually related to
premature birth, but other factors are involved. It occurs
more commonly in male children and following cesarean
FIG. 13.27 Infant respiratory distress syndrome. Lung tissue
showing decreased size of alveoli. Arrow points to membrane that
interferes with gas exchange. (From Carlson B: Human Embryol-
ogy and Developmental Biology, ed 5, Philadelphia, 2014, Elsevier,
Saunders.)

CHAPTER 13 Respiratory System Disorders 319
surfactant-producing cells (Fig. 13.29). These events result
in decreased diffusion of oxygen, reduced blood flow to
the lungs, difficulty in expanding the lungs, and diffuse
atelectasis. Reductions in tidal volume and vital capacity
occur. Damage to lung tissue progresses as increased
numbers of neutrophils migrate to the lungs, releasing
proteases and other mediators. Hyaline membranes
form from protein-rich fluid in the alveoli, and platelet
aggregation and microthrombi develop in the pulmonary
circulation, causing stiffness and decreased compliance.
If the patient survives, diffuse necrosis and fibrosis are
apparent throughout the lungs.
Excess fluid in the lungs predisposes to pneumonia
as a complication. Congestive heart failure may develop.
■ Etiology
Severe or prolonged shock may cause ARDS because of
ischemic damage to the lung tissue. Inflammation in the
lungs arises directly from such events as inhalation of
toxic chemicals or smoke; excessive oxygen concentration
in inspired air; severe viral infections in the lungs; toxins
from systemic infection, particularly by gram-negative
organisms; fat emboli; explosions; aspiration of highly
acidic gastric contents; or lung trauma. Other causes
the maturation process. Synthetic surfactant, colfosceril
(Exosurf Neonatal), administered to the high-risk neonate
both as prophylaxis immediately following birth and as
necessary therapy, has greatly improved the prognosis.
Ventilation using CPAP, oxygen therapy, and nitrous oxide
drugs have improved outcomes but are not without risk.
High concentrations of oxygen may cause pulmonary
damage (bronchodysplasia) and retrolental fibroplasia
causing permanent damage to the retina of the eye and
loss of vision. Other systemic problems are often present
in the premature infant and require specialized care.
Adult or Acute Respiratory Distress Syndrome
Adult or acute respiratory distress syndrome (ARDS) is
also known as shock lung, wet lung, stiff lung, postperfu-
sion lung, and a variety of other names related to specific
causes. It is considered to be a restrictive lung disorder.
A multitude of predisposing conditions such as systemic
sepsis, prolonged shock, burns, aspiration, and smoke
inhalation may cause ARDS. The onset of respiratory
distress usually occurs 1 to 2 days after an injury or other
precipitating event. In many cases, it is associated with
multiple organ dysfunction or failure secondary to a
severe insult to the body.
■ Pathophysiology
The basic changes in the lungs result from injury to
the alveolar wall and capillary membrane, leading to
release of chemical mediators, increased permeability of
alveolar capillary membranes, increased fluid and protein
in the interstitial area and alveoli, and damage to the
Suprasternal
Supraclavicular
Substernal
Subcostal
Intercostal
FIG. 13.28 Retractions of the infant chest in IRDS. (From McCance
KL, et al: Pathophysiology: the Biologic Basis for Disease in Adults
and Children, ed 6, St. Louis, 2010, Mosby.)
ADULT RESPIRATORY
DISTRESS SYNDROME (ARDS)
CONFUSION AND DECREASED RESPONSIVENESS
SEVERE HYPOXEMIA
PROGRESSIVE METABOLIC AND RESPIRATORY ACIDOSIS
CARDIAC ARRHYTHMIAS
SHOCK
ALVEOLAR OR PULMONARY CAPILLARY WALL INJURY
Increased capillary permeability
Fluid and protein leaks into alveoli
and interstitial tissue
Cell damage
PULMONARY
EDEMA
DECREASED SURFACTANT
PRODUCTION
Decreased compliance,
labored inspiration
RESPIRATORY
INSUFFICIENCY
Decreased lung
volumes
Atelectasis
Decreased oxygen
exchange
Hypoxemia
RESPIRATORY
FAILURE
FIG. 13.29 Adult respiratory distress syndrome.

320 SECTION III Pathophysiology of Body Systems
perfusion and increases cardiac workload. The heart may
be limited in its ability to compensate for reduced oxygen
levels.
Acidosis of respiratory origin (elevated CO2) may
become decompensated because of failure in other
systems, resulting in respiratory failure. Respiratory arrest
refers to cessation of respiratory activity and is quickly
followed by cardiac arrest.
■ Etiology
Acute respiratory failure may result from acute or chronic
disorders:
• Chronic conditions such as emphysema may lead to
respiratory failure if the degenerative tissue changes
progress to the point at which ventilation and gas
exchange are minimal.
• A combination of a chronic with an acute disorder
may lead to ARF. For example, ARF may develop in
an earlier stage of emphysema or other chronic lung
disease if it is complicated by pneumonia, or pneu-
mothorax, or central nervous system depression caused
by narcotics or other depressant drugs.
• Acute respiratory disorders such as chest trauma (flail
chest or tension pneumothorax), pulmonary embolus,
or acute asthma may lead to failure.
• Many neuromuscular diseases such as myasthenia
gravis, amyotrophic lateral sclerosis (see Chapter 14),
or muscular dystrophy (see Chapter 9) ultimately cause
ARF.
■ Signs and Symptoms
The signs may be masked or altered by the primary
problem. Manifestations include the following:
• Rapid, shallow, often labored respirations
• Hypoxia and hypercapnia
• Headache
• Tachycardia
• Lethargy
• Confusion
■ Treatment
As in many other situations, the primary problem must
be resolved and supportive treatment given to maintain
respiratory function.
include disseminated intravascular coagulation (see
Chapter 10), cancer, acute pancreatitis, and uremia.
■ Signs and Symptoms
Early signs may be masked by the effects of the primary
problem. Onset is usually marked by the following:
• Dyspnea
• Restlessness
• Rapid, shallow respirations
• Increased heart rate
• Arterial blood gas measurements indicate a significant
decrease in Po2
• As lung congestion increases, rales can be heard
• Productive cough with frothy sputum may be evident
• Cyanosis and lethargy with confusion develop
A combination of respiratory and metabolic acidosis
evolves as diffusion is impaired and anaerobic metabolism
is required.
■ Treatment
The underlying cause must be successfully treated, and
supportive respiratory therapy such as oxygen therapy
and mechanical ventilation must be maintained until the
causative factors are removed and healing occurs.
Administration of fluid may be limited to minimize
alveolar edema, although this may be difficult in patients
with multisystem failure. The prognosis is generally poor,
with a case fatality rate of 30% to 40%, but depends on
the underlying problem (with infection, the case fatality
rate is 80% to 90%).
Acute Respiratory Failure
■ Pathophysiology
Acute respiratory failure (ARF) can be the result of many
pulmonary disorders. Respiratory failure is indicated
when Pao2 is less than 50 mm Hg (severe hypoxemia)
or Paco2 is greater than 50 mm Hg (hypercapnia) and
serum pH is decreasing (<7.3). Normal values are approximately 80 to 100 mm Hg for oxygen and 35 to 45 mm Hg for carbon dioxide. The abnormal values mentioned are considered inadequate for the body’s metabolic needs at rest. Oxygen is always a major concern because the lungs are the only source of oxygen for the body. The central nervous system, including the respira- tory control center, is affected. The precise figures used for these criteria may vary somewhat with the cause of the problem, but the sig- nificant factor is the trend or progressive changes in the values that occur over time. Respiratory insufficiency is the term applied to an interim state in which blood gases are abnormal but cell function can continue. Very low oxygen levels can be related to ventilation and perfusion abnormalities that arise for many reasons, sometimes from a combination of problems. A primary problem may be complicated by reflex pulmonary vasoconstriction due to hypoxia or acidosis, which further impairs lung THINK ABOUT 13.16 a. Compare the factors contributing to infant respiratory distress syndrome and ARDS. b. Describe the basic pathophysiology of respiratory distress syndrome and its initial effect on arterial blood gases. c. Using an example, explain how respiratory failure may develop and explain why this is life threatening. d. Explain how severe hypoxia and hypercapnia affect the central nervous system. CHAPTER 13 Respiratory System Disorders 321 CASE STUDY A Influenza and Pneumonia Mrs. A.H. has had an acute episode of influenza A, complicated by pneumococcal pneumonia. She lives in a seniors’ apartment building, where a number of residents have had influenza in the past month. 1. State the cause of influenza, and describe briefly how it affects the lungs. 2. Describe the normal mechanisms that defend against infection in the respiratory tract. 3. Explain why it can be expected that a number of residents in such a building would be affected by influenza. 4. What precautions could the residents take to avoid the infection? 5. What precautions could you take in your particular profession to reduce the risk of respiratory infection for yourself, your colleagues, and your patients? 6. Explain why antibacterial drugs are not directly effective in cases of influenza. Why may they be prescribed? 7. Explain why Mrs. A.H. is predisposed to develop pneumonia. Mrs. A.H. was admitted to the hospital after she developed severe chest pain and appeared confused to friends. Pneumococ- cal pneumonia was suspected. 8. Describe the appropriate diagnostic tests that would be used for Mrs. A.H., and give the rationale for each. 9. Mrs. A.H. indicates that the chest pain increases on inspiration or coughing. Explain the probable cause of this chest pain and her confusion. 10. Describe how other signs and symptoms would probably change as pneumonia develops, and give the reason for each (include the relevant respiratory and systemic signs). 11. Predict the values of arterial blood gases in Mrs. A.H. in the early stage of pneumococcal pneumonia and in the advanced stage if two lobes are involved. (Use general descriptions such as increased slightly or greatly, not specific figures.) 12. Explain how Mrs. A.H. can compensate to maintain a normal serum pH. 13. List several reasons why Mrs. A.H. may become dehydrated. 14. Explain several ways in which dehydration could complicate Mrs. A.H.’s status. 15. Describe several treatment measures that would be helpful in this case. CASE STUDY B Acute Asthma Eight-year-old B.J. has had asthma for 2 years since he had acute bronchitis. He was tested for allergies and demonstrated marked responses to a number of animals, pollens, and molds. B.J. also has a history of asthma related to exposure to very cold weather. 1. Describe the pathophysiology of an acute asthma attack in B.J. following exposure to cats. 2. Describe the early signs of an acute asthma attack and relate each of these to the changes taking place in the lungs. 3. If you were updating a medical and drug history for B.J., list several significant questions that you should ask. 4. Describe what precautions you would take if you were treating or dealing with B.J., and include your reasons. Describe your actions if B.J. had an attack while he was with you. 5. State and explain the effects of a prolonged asthma attack. 6. Explain the factors contributing to severe hypoxia and acidosis in a prolonged attack. 7. Define status asthmaticus. 8. Explain why B.J. is likely to have frequent respiratory infections. 9. Suggest several measures that B.J. can take to reduce anxiety and perhaps the risk of an asthma attack. 10. Explain how a beta2-adrenergic agent is helpful in treating asthma and how it is usually administered. CASE STUDY C Emphysema Mr. C.Y., age 71, has had significant emphysema for 6 years. He has reduced his cigarette smoking since mild congestive heart failure was diagnosed (right-sided heart failure; refer to Chapter 12). He has been admitted to the hospital with a suspected closed pneumothorax and respiratory failure. 1. Describe the pathophysiologic changes in the lungs with emphysema, and explain how these affect oxygen and carbon dioxide levels in the blood. 2. Explain the possible role of smoking in Mr. C.Y.’s case and its general effects on respiratory function (consider effects on cardiovascular function also). 3. What significant characteristics related to emphysema and heart failure would you expect to observe in Mr. C.Y.? 4. Explain how a pneumothorax has probably occurred in the presence of emphysema. 5. Explain how a pneumothorax has precipitated respiratory failure, using the effects on lung function and gas exchange in your answer. Include the criteria for respiratory failure. 6. Explain why caution must be exercised in administering oxygen to Mr. C.Y. 7. Mr. C.Y. is resting quietly. Suggest three complications of immobility that could develop in Mr. C.Y. and one preventive measure that could be taken for each. 8. Explain how congestive heart failure develops from emphysema. 9. Describe respiratory therapy that might be helpful to Mr. C.Y. With aggressive treatment, Mr. C.Y. recovered and returned home. 10. Suggest some reasons why Mr. C.Y. may not receive adequate nutrition and hydration at home. 11. Suggest other support measures that would be useful in this case. 322 SECTION III Pathophysiology of Body Systems Pneumonia may be classified in several ways, including primary or secondary, by etiology or type of causative microbe, or by the anatomic distribution of the infection in the lung. • Severe acute respiratory syndrome is an acute respira- tory infection caused by a previously unknown virus. The recent epidemic stimulated a global effort to identify the causative microbe and contain the infection. • The incidence of tuberculosis is increasing in individu- als with low host resistance. The number of drug- resistant bacteria has risen as well. The hypersensitivity reaction developing with primary infection and tubercle formation is the basis of the tuberculin (Mantoux) test. Infection can be spread when active infection or cavita- tion occurs in the lungs. • Cystic fibrosis is an inherited disorder (recessive gene) affecting the exocrine glands, particularly the mucous glands of the lungs. The pancreas, liver, and sweat glands are also involved. Airway obstructions and frequent lung infections cause permanent damage to the lungs. • Exposure to cigarette smoke and industrial carcinogens are predisposing factors to lung cancer. Prognosis is poor because early diagnosis is rare, and many types of tumors resist chemotherapy or radiation. The lungs are also common sites for secondary tumors. • Aspiration of solids or liquids may cause inflammation, laceration, or direct obstruction of airways. • Obstructive sleep apnea occurs when pharyngeal tissues collapse on expiration during sleep, leading to intermittent periods of apnea. • The pathophysiology of acute asthma is based on airway obstruction related to bronchoconstriction, inflammation and edema, and production of excessive thick mucus. Obstruction leads to severe respiratory distress and hypoxia. Status asthmaticus is a potential complication. • Emphysema (COPD) is characterized by loss of elastic- ity and destruction of alveolar walls, septae, and capillaries, leading to overinflation of the lungs and hypercapnia as well as hypoxia. • Chronic bronchitis is associated with constant irritation in the airways and frequent infections, leading to fibrosis. Cor pulmonale is a common complication. • Restrictive disorders include those with chest wall dysfunction, such as kyphosis or respiratory muscle paralysis, and those disorders causing pulmonary fibrosis and loss of compliance, such as occupational pneumoconioses (silicosis). • Pulmonary edema refers to increased fluid in the alveoli reducing oxygen diffusion and lung expansion. • Most pulmonary emboli arise from thrombi in leg veins. Moderate-sized emboli cause respiratory impair- ment; large emboli interfere with cardiovascular function. Fat emboli cause ARDS. • Atelectasis may affect part or all of a lung. Causes include airway obstruction, decreased ventilation, C H A P T E R S U M M A R Y Because the respiratory system is the sole source of oxygen for cell metabolism, respiratory impairment has wide- spread effects in the body. Respiratory or metabolic acidosis will often accompany hypoxia. Respiratory disorders may result from airway obstructions, alveolar damage, reduced lung expansion, or interference with pulmonary blood flow. • Characteristic breathing patterns, type of cough, and sputum, as well as other manifestations, are helpful in diagnosing the cause of the disorder. For example, a cough producing purulent sputum is typical of bacterial infection, and wheezing indicates airway obstruction. • Viruses cause both upper and lower respiratory tract infections, including the common cold, laryngotra- cheobronchitis (croup), influenza, bronchiolitis, and primary atypical pneumonia. • Pneumonia impairs oxygen diffusion when exudate fills the alveoli or interstitial tissue in the lungs. CASE STUDY D Cystic Fibrosis M.T., age 5 years, has cystic fibrosis, which was diagnosed fol- lowing an intestinal obstruction after birth (meconium ileus). M.T. has frequent lung infections despite daily respiratory therapy. She is given pancrelipase with her meals and snacks to facilitate digestion and absorption. At a recent checkup, M.T. was found to be shorter and under the weight range for her age. 1. M.T.’s parents would like to have another child. What is the probability that a future child would have cystic fibrosis? (Hint: What is the genetic status of each parent?) 2. Describe the basic pathophysiology of cystic fibrosis, and briefly describe the various effects in the body. 3. Explain the possible effects on airflow of mucus obstructions in the lungs. 4. Explain why M.T. has frequent infections. 5. M.T.’s parents are arranging a dental appointment for her. Describe any possible limitations in arranging the appointment, and list what precautions should be taken when she arrives for the appointment. 6. State several criteria that would be helpful in maintaining adequate nutrition for M.T. 7. If M.T. does not take pancrelipase regularly, she has steatorrhea (frequent loose, fatty stools). Explain why this occurs and how it might affect her respiratory function if prolonged. 8. Using your basic knowledge of physiology, describe the possible effects on M.T. if she fails to digest and absorb adequate amounts of protein, calcium, vitamin D, vitamin K, and iron. 9. Explain why M.T. is likely to develop bronchiectasis at a later time, and describe the significant signs of its development. 10. Explain why M.T. may have a fluid-electrolyte imbalance if she has a high fever with a lung infection. CHAPTER 13 Respiratory System Disorders 323 in adults whose lungs are damaged by ischemia or inhalation of toxic materials. Lung expansion is reduced and oxygen diffusion impaired by fluid in the lungs. • Acute respiratory failure applies to a marked deficit of oxygen, a great increase in carbon dioxide, or a combination of these factors. It may occur with acute conditions (tension pneumothorax), chronic disorders (emphysema), or chronic diseases complicated by a sec- ondary acute problem (cystic fibrosis plus pneumonia). S T U D Y Q U E S T I O N S 1. Explain the purpose of the specialized cells in the respiratory mucosa. 2. a. Describe the function of the external intercostal muscles. b. Describe the mechanism of and the energy required for quiet expiration and for forced expiration. 3. a. Describe the location of the chemoreceptors that respond to elevated carbon dioxide levels and those that respond to low oxygen levels. b. Which gas creates the primary respiratory drive under normal circumstances? 4. State and explain the effect of increased carbon dioxide levels on serum pH. 5. a. Describe how carbon dioxide is transported in the blood. b. Name a gas that can displace oxygen from hemoglobin. 6. What physiologic compensations are available for chronic hypoxia due to respiratory impairment and for chronic hypercapnia? 7. Explain how respiratory infection can cause serious respiratory obstruction in a young child and include examples. 8. a. Name the organisms that commonly cause primary atypical pneumonia. b. Compare the pathophysiologic changes in viral and pneumococcal pneumonia. 9. a. Explain the significance and limitations of a positive tuberculin test. b. Explain the conditions under which tuberculosis may be contagious. c. What measures can be taken by health care professionals to minimize the spread of infection? 10. a. Why has anthrax become an infectious disease of concern? b. How can illness from inhalation anthrax be prevented? 11. What is the primary cause of obstructive sleep apnea, and how does it affect oxygen levels in the body? 12. a. Explain how obstruction develops with chronic bronchitis. b. Explain how acute asthma causes air trapping or atelectasis. c. How does hypoxia and respiratory alkalosis develop in the early stages of an asthma attack? d. Explain why serum pH is lowered when an asthma attack persists. 13. a. Explain why the anteroposterior diameter of the chest is increased in a patient with emphysema. b. Explain why hypercapnia may be a major problem in patients with emphysema. c. Explain how each of the following develops in patients with emphysema: (1) cor pulmonale, (2) secondary polycythemia. 14. a. Define meconium ileus. b. Describe the effects of cystic fibrosis on the lungs and the liver. c. Explain several ways whereby permanent damage can occur in the lungs and in the pancreas. 15. a. Explain why the lung is a common site for secondary cancer. b. State two systemic signs or symptoms of cancer, two local respiratory signs, and two signs related to paraneoplastic syndrome. c. Explain why the prognosis for lung cancer is poor (include three factors). 16. a. List three factors predisposing to aspiration. b. Describe the potential effects of aspirating vomitus. 17. a. Describe the factors predisposing to atelectasis following abdominal surgery. b. Describe the signs of atelectasis. 18. a. Explain why pulmonary edema causes severe hypoxia. b. Trace the path of a pulmonary embolus resulting from thrombophlebitis. c. Compare the effects on respiration of a very small embolus and a very large one. 19. a. Describe the effects of a large open pneumothorax on respiratory function and on cardiovascular function. compression of the lung, or increased surface tension in the alveoli. • A large open pneumothorax impairs ventilation and circulation (venous return) due to mediastinal flutter. Flail chest injury causes paradoxic motion and decreases oxygen concentration in the alveolar air as well as impeding venous return. • Respiratory distress syndrome occurs in newborn infants, IRDS associated with prematurity, and also 324 SECTION III Pathophysiology of Body Systems b. Explain how covering an open pneumothorax improves oxygen levels. c. Explain a possible cause of increased respiratory distress following the covering of an open pneumothorax. 20. a. Explain how paradoxical motion develops with a flail chest injury and how it causes hypoxemia. b. Explain why atelectasis does not occur directly with a flail chest injury. 21. a. Compare the causes of infant and adult respiratory distress syndromes. b. Describe the signs of infant respiratory distress. c. Describe the criteria for a diagnosis of respiratory failure. 22. Respiratory problems frequently occur in patients with burns, particularly those with facial burns or who were injured in enclosed spaces such as a car or small room (see Chapter 2). Apply your knowledge to explain how each of the following affects respiratory function in a burn patient and the result: a. Inhaling carbon monoxide b. Inhaling hot air with irritant particles and gases c. A deep burn covering the chest and back 23. The “bends” or decompression sickness is a form of air embolism. When scuba or deep sea divers are under higher pressure, more nitrogen gas dissolves in the blood and tissue fluids. Usually a slow ascent to the surface (lower pressure) allows the gas to be gradually dissipated and exhaled. If a diver rises to the surface too rapidly, the gas comes out of solution, forming bubbles or gas emboli in the circulation. Explain why ischemia and pain may occur in various tissues such as muscle, joints, or the heart. 325 Review of Nervous System Anatomy and Physiology Brain Protection for the Brain Functional Areas Blood Supply to the Brain Cranial Nerves Spinal Cord Spinal Cord Spinal Nerves Reflexes Neurons and Conduction of Impulses Neurons Conduction of Impulses Synapses and Chemical Neurotransmitters Autonomic Nervous System Sympathetic Nervous System Parasympathetic Nervous System General Effects of Neurologic Dysfunction Local (Focal) Effects Supratentorial and Infratentorial Lesions Left and Right Hemispheres Level of Consciousness Motor Dysfunction Sensory Deficits Visual Loss: Hemianopia Language Disorders Seizures Increased Intracranial Pressure Early Signs Vital Signs Visual Signs Changes in Cerebrospinal Fluid Herniation Diagnostic Tests Acute Neurologic Problems Brain Tumors Vascular Disorders Transient Ischemic Attacks Cerebrovascular Accidents (Stroke) Cerebral Aneurysms Infections Meningitis Brain Abscess Encephalitis Other Infections Infection-Related Syndromes Brain Injuries Types of Head Injuries Spinal Cord Injury Congenital Neurologic Disorders Hydrocephalus Spina Bifida Cerebral Palsy Seizure Disorders Chronic Degenerative Disorders Multiple Sclerosis Parkinson’s Disease (Paralysis Agitans) Amyotrophic Lateral Sclerosis Myasthenia Gravis Huntington’s Disease Dementia Alzheimer’s Disease Other Forms of Dementia Vascular Dementia Creutzfeldt-Jakob Disease AIDS Dementia Mental Disorders Schizophrenia Depression Panic Disorders Spinal Cord Disorder Herniated Intervertebral Disc Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E C H A P T E R 14 Nervous System Disorders After studying this chapter, the student is expected to: 1. Relate the focal effect of a lesion to the specific area of damage in the brain. 2. Describe the possible effects of increased intracranial pressure on level of consciousness, motor and sensory functions, vital signs, vision, and language. 3. Explain the effects of herniation. 4. Compare the effects of brain tumors in different areas of the brain. 5. Compare transient ischemic attacks to cerebrovascular accidents. 6. Explain how cerebral aneurysms develop, their effects, and possible complications. 7. Describe the cause, pathophysiology, and manifestations of bacterial meningitis. 8. Explain how a brain abscess may cause focal and general effects. L E A R N I N G O B J E C T I V E S 326 SECTION III Pathophysiology of Body Systems afferent amnesia anencephaly anomalies aphasia athetoid atresia aura bifurcation Broca’s area catechol-O-methyltransferase (COMT) inhibitors choreiform choroid plexuses clonic cognitive coma contralateral diplopia efferent fissure flaccid foramina fulminant ganglion gyri hyperreflexia infratentorial ipsilateral labile nuchal rigidity paralysis paresis paresthesia photophobia postictal precursor pressoreceptors prodromal ptosis retina scotoma spastic stupor sulcus, sulci supratentorial sutures tetraplegia tonic transillumination Wernicke’s area K E Y T E R M S 9. Differentiate the types of hematomas, and describe the effect of a hematoma on the brain. 10. Explain how seizures may be related to infection or injury. 11. Describe how various types of spinal cord injury may occur. 12. Explain how the effects of spinal cord injury depend on the location of the damage. 13. Compare the signs of spinal shock with the permanent effects of spinal cord injury. 14. Describe the pathophysiology of hydrocephalus, differentiating the communicating from the noncommunicating types. 15. Describe the signs of increasing intracranial pressure in the neonate. 16. Describe the major types of spina bifida and the effect on a child who has the defect. 17. Describe the types of cerebral palsy and signs of each. 18. Differentiate the types of seizures. 19. Describe the pathophysiology, course, and effects of multiple sclerosis. 20. Relate the pathophysiology to the signs of Parkinson’s disease. 21. Explain how amyotrophic lateral sclerosis affects motor function and how this relates to the signs of progression. 22. Describe the pathophysiology of myasthenia gravis and its effects on the body. 23. Describe the inheritance of Huntington’s disease and the onset and early signs. 24. Describe the changes in the brain as Alzheimer’s disease develops and the effects on function. 25. Compare the disorders of schizophrenia, depression, and panic disorder with regard to the pathophysiology and effects on behavior. L E A R N I N G O B J E C T I V E S — continued Review of Nervous System Anatomy and Physiology The nervous system consists of the central and peripheral nervous systems: • Central nervous system—brain and spinal cord • Peripheral nervous system—cranial and spinal nerves; ganglia; sensory neurons, neuromuscular junctions Brain The brain is the communication and control center of the body. It receives, processes, and evaluates many kinds of input; decides on the response or action to be taken; and then initiates the response. Responses include both involuntary activity that is required to maintain homeostasis in the body (regulated by the autonomic nervous system) and voluntary actions (controlled by the somatic nervous system). With both reflex and voluntary activities, the individual is often not aware of the amount and diversity of input received or the integration or assessment of that input, but knows only of the response (Fig. 14.1). Protection for the Brain The brain is protected by the rigid bone of the skull, the three membranes or meninges, and the cerebrospinal fluid (CSF). The cranial and facial bones are connected by sutures, which are relatively immovable joints consist- ing of fibrous tissue. If pressure inside the skull increases in infants before the sutures fuse or ossify, the cranial bones may separate, causing the head to enlarge. The skull contains a number of cavities, or fossae, as well as foramina (openings) and canals through which nerves and blood vessels pass. The largest opening, the foramen magnum, is located in the occipital bone at the base of the skull, where the spinal cord emerges. Meninges The meninges consist of three continuous connective tissue membranes covering the brain and spinal cord. The meninges and the contents of the spaces between the layers are as follows: • The dura mater, the outer layer, is a tough, fibrous, double-layered membrane that separates at specific points to form the dural sinuses, which collect venous blood and CSF for return to the general circulation CHAPTER 14 Nervous System Disorders 327 Cranial nerves PNS: Spinal nerves Ganglia Peripheral nerves CNS: Brain Spinal cord PNS: Sensory receptors in skin Enteric plexuses in small intestine FIG. 14.1 Overview of the Nervous System The nervous system is divided into two components: the central nervous system composed of the brain and the spinal cord, and the peripheral nervous system containing the cranial and spinal nerves, ganglia, and sensory receptors. (From VanMeter K, Hubert R: Microbiology for the Healthcare Professional, St. Louis, 2010, Elsevier.) • The subdural space, lying beneath the dura, is a potential space (ie, normally empty, this space could fill with blood after an injury). • The arachnoid (arachnoid mater), a loose, weblike cover- ing, is the middle layer. • The subarachnoid space, which contains the CSF and the cerebral arteries and veins, lies beneath the arachnoid. • Arachnoid villi are projections of arachnoid into the dural sinuses at several places around the brain, through which CSF can be absorbed into the venous blood. • The pia mater, a delicate connective tissue that adheres closely to all convolutions on the surface of the brain, is the inner layer. Many small blood vessels are found in the pia mater (Fig. 14.2). Cerebrospinal Fluid The CSF provides a cushion for the brain and spinal cord. Similar to plasma in appearance, it is a clear, almost colorless liquid, but it differs from plasma in the concentra- tions of electrolytes, glucose, and protein (Table 14.1), which remain relatively constant. A change in the char- acteristics of the CSF is a useful diagnostic tool (see Fig. 14.11, presented later). For example, the presence of significant numbers of erythrocytes in CSF indicates bleeding in the central nervous system. Cerebrospinal fluid is formed constantly in the choroid plexuses (areas of highly vascularized tissue located in each of the four ventricles of the brain) and then flows into the subarachnoid space, where it circulates around the brain and spinal cord and eventually passes through the arachnoid villi, returning into the venous blood. To 328 SECTION III Pathophysiology of Body Systems (ie, certain antibiotics and anticancer drugs). Lipid-soluble substances, including alcohol, pass freely into the brain. maintain a relatively constant pressure within the skull (intracranial pressure), it is important for equal amounts of CSF to be produced and reabsorbed at the same rate. Blood-Brain Barrier and Blood-Cerebrospinal Fluid Barrier The blood-brain barrier is a protective mechanism pro- vided primarily by relatively impermeable capillaries in the brain. The endothelial cells of the capillaries are tightly joined together by tight junctions rather than possessing pores. This barrier limits the passage of potentially damaging materials into the brain and controls the delicate but essential balance of electrolytes, glucose, and proteins in the brain. There is a similar blood-CSF barrier at the choroid plexus to control the constituents of CSF. The blood-brain barrier is poorly developed in neonates, and therefore substances such as bilirubin (see Chapter 22) or other toxic materials can pass easily into the infant’s brain, causing damage. When fully developed, the blood- brain barrier can be a disadvantage, because it does not allow the passage of many essential drugs into the brain Dural sinus Skin Bone of skull Subdural space Dura mater Arachnoid mater M en in ge s Subarachnoid space Pia mater Brain tissue (cerebrum) Arachnoid villus FIG. 14.2 Meninges of the central nervous system (inset: note that aráchni is the Greek word for spider). (From Herlihy B: The Human Body in Health and Illness, ed 4, St. Louis, 2011, Elsevier, Saunders.) THINK ABOUT 14.1 a. List, in order, the brain coverings and spaces with their contents, from the brain tissue outward. b. Explain the effect of the production of more CSF than can be reabsorbed. Functional Areas Cerebral Hemispheres The cerebral hemispheres make up the largest and most obvious portions of the brain. The outer surface is covered by elevations, or gyri (sing., gyrus), that are separated by grooves, or sulci (sing., sulcus). The longitudinal fissure separates the left and right hemispheres. The corpus callosum consists of nerve fibers connecting the left and right hemispheres for the purpose of communica- tion between the two hemispheres. CHAPTER 14 Nervous System Disorders 329 MOTOR CORTEX Central sulcus SENSORY CORTEX Foot Leg Trunk Arm Hand Face PREMOTOR CORTEX (SKILLED MOVEMENT) Frontal lobe Lateral sulcus (fissure of Sylvius) Temporal lobe Pons Medulla Cerebellum Occipital lobe VITAL CENTERS BALANCE EQUILIBRIUM COORDINATION MEMORY INTELLECT PERSONALITY RAS Parietal lobe VISUAL AREA Visual area Visual association AUDITORY AREA WERNICKE’S AREA BROCA’S SPEECH AREA FIG. 14.3 Functional areas of the brain showing the left side of the cerebral hemispheres. Each hemisphere is divided into four major lobes, each of which has specific functions (Fig. 14.3). Complex functions, such as language and memory, involve many areas of the brain. Each hemisphere is concerned with voluntary movement and sensory function in the opposite (contralateral) side of the body, and these areas of the cortex have been well mapped. In Fig. 14.3, note the large number of nerve cells required to innervate the face compared with the amount of cortex allocated to the trunk. The cells of the motor cortex of the frontal lobe initiate specific voluntary movements, and these cells are often referred to as upper motor neurons (UMNs). Their axons form the corticospinal tracts in the spinal cord. Because the crossover of most of these tracts occurs in the medulla, damage to the motor cortex in the left frontal lobe adjacent to the longitudinal fissure (on top of the head) results in paralysis or paresis of the muscles of the right leg. Each special sensory area of the cortex has an association area surrounding the primary cortex, in which the sensory input is recognized and interpreted. For example, the occipital lobe contains the primary visual cortex, which receives the stimuli from the eye, and the surrounding association cortex identifies the object seen. If the primary cortex is damaged, the person is blind, but if the associa- tion area is damaged, the person can see an object but cannot comprehend its significance. The right and left hemispheres are generally similar in structure but not necessarily in function (Table 14.2). The term dominant hemisphere refers to the side of the brain that controls language, which in most people is the left hemisphere. There are two special areas involved in language skills. The Broca’s area is considered the motor or expressive speech area, in which the output of words, TABLE 14.1 Characteristics of Normal Cerebrospinal Fluid Appearance Clear and Colorless Pressure 9–14 mm Hg or 150 mm H2O Red blood cells None White blood cells Occasional Protein 15–45 mg/dL Glucose 45–75 mg/dL Sodium 140 mEq/L Potassium 3 mEq/L Specific gravity 1.007 pH 7.32–7.35 Volume in the system at one time 125–150 mL Volume formed in 24 hours 500–800 mL both verbal and written, is coordinated in an appropriate and understandable way. This area is located at the base of the premotor area of the left frontal lobe. The Wernicke’s area is the integration center that comprehends language received, both spoken and written. This area is located in the posterior temporal lobe and has con- necting fibers to the prefrontal, visual, and auditory areas. The left hemisphere also appears to be responsible for mathematical, problem-solving, and logical reasoning abilities. The right hemisphere has greater influence on artistic abilities, creativity, spatial relationships, and emotional and behavioral characteristics. The prefrontal cortex lies anterior to the motor and premotor cortex, and recent research indicates that it functions in coordinating complex cognitive behavior as 330 SECTION III Pathophysiology of Body Systems this purpose it has many connections to all areas of the brain. Part of the hypothalamus is involved with the limbic system. The hypothalamus provides the link for the autonomic responses, such as altered blood pressure or nausea, which occur when one experiences fear, excite- ment, or an unpleasant sight or odor. Any cognitive (intellectual) decision arising from the higher cortical centers may be accompanied by an emotional aspect mediated through the limbic system. Diencephalon The diencephalon is the central portion of the brain. It is surrounded by the hemispheres and contains the thalamus, the hypothalamus, and the epithalamus. • The thalamus consists of many nerve cell bodies, the major function of which is to serve as a sorting and relay station for incoming sensory impulses. From the thalamus, connecting fibers transmit impulses to the cerebral cortex and other appropriate areas of the brain. • The hypothalamus has a key role in maintaining homeo- stasis in the body, controlling the autonomic nervous system and much of the endocrine system through the hypophysis, or pituitary gland. It is responsible for the regulation of body temperature, intake of food and fluid, and the regulation of sleep cycles. The hypothalamus is also the key to the stress response and plays major roles in emotional responses through the limbic system and in biologic behaviors, such as the sex drive (libido). • The epithalamus acts as the connection between the limbic system and other areas of the brain. Brain Stem The inferior portion of the brain, called the brain stem, is the connecting link to the spinal cord. The brain stem consists of the pons, medulla oblongata (myelencephalon) midbrain (mesencephalon): • The midbrain is associated with vision, hearing, motor control, sleep/wake, arousal (alertness), and tempera- ture regulation. One structure in the midbrain, the reticular formation, is a network of nuclei and neurons scattered throughout the brain stem that has connec- tions to many parts of the brain. The reticular-activating system (RAS) is part of this formation and determines the degree of arousal or awareness of the cerebral cortex. In other words, these neurons decide which of the incoming sensory impulses the brain ignores and which it notices. Many drugs can affect the activity of the RAS, thus increasing or decreasing the input to the brain. • The pons is composed of bundles of afferent (incoming) and efferent (outgoing) fibers. The pons serves as a bridge between the cerebellum and cerebrum, and several nuclei of cranial nerves are also located in the pons. • The medulla oblongata contains the vital control centers that regulate respiratory and cardiovascular function well as providing components for expression of personal- ity. It plays a significant role in social relationships and impulse control. The basal nuclei (previously called the basal ganglia) are clusters of cell bodies or gray matter located deep among the tracts of the cerebral hemispheres. These are part of the extrapyramidal system (EPS) of motor control, which controls and coordinates skeletal muscle activity, preventing excessive movements and initiating accessory and often involuntary actions, such as arm swinging when walking. Two additional nuclei located in the midbrain, the substantia nigra and the red nucleus, are also connected to the basal nuclei and the EPS. The limbic system consists of many nuclei and connect- ing fibers in the cerebral hemispheres that encircle the superior part of the brain stem. The limbic system is responsible for emotional reactions or feelings, and for TABLE 14.2 Major Functional Areas of the Brain Area Function Frontal lobe Prefrontal area (left cortex) Intellectual function and personality Premotor cortex Skilled movements Motor cortex Voluntary movements Broca area (left cortex) Speech (expression) Parietal lobe Somatosensory area Sensation (eg, touch, pain) Occipital lobe Visual cortex Vision Temporal lobe Auditory cortex Hearing Olfactory cortex Smell Wernicke area (left cortex) Comprehension of speech Memory Cerebellum Body balance and position, coordinated movement Medulla oblongata Control and coordination centers for respiration and cardiovascular activity Swallow reflex center, vomiting reflex, cough reflex Nuclei of five cranial nerves Hypothalamus Autonomic nervous system Link with endocrine system Control of body temperature, fluid balance Centers for thirst, hunger Thalamus Sensory sorting and relay center Basal nuclei Coordination and control of body movement Reticular activating system Arousal or awareness Limbic system Emotional responses CHAPTER 14 Nervous System Disorders 331 Anastomoses between these major arteries at the base of the brain have several sources: • Anterior communicating artery between the anterior cerebral arteries • Posterior communicating arteries between the middle cerebral and posterior cerebral arteries • This arrangement forms the circle of Willis and provides an alternative source of blood when the internal carotid or vertebral artery is obstructed; this circle of arteries surrounds the pituitary gland and optic chiasm Blood flow in the cerebral arteries is relatively constant because the brain cells constantly use oxygen and glucose (essential nutrients for neurons) and have little storage capacity. Autoregulation is a mechanism by which increased carbon dioxide levels or decreased pH in the blood, or decreased blood pressure, in an area of the brain results in immediate local vasodilation. The pressoreceptors (baroreceptors) and chemoreceptors protect the brain from damage related to abnormal blood pressure or pH levels in the systemic flow. As mentioned, venous blood from the brain collects in the dural sinuses and then drains into the right and left internal jugular veins, to be returned to the heart. Cranial Nerves There are 12 pairs of cranial nerves. They originate from the brain stem and pass through the foramina in the skull to serve structures in the head and neck, including the eyes and ears. The vagus nerve (cranial nerve X) serves a more extensive area, branching to innervate many of the viscera. A cranial nerve may consist of motor fibers only (with associated sensory fibers from proprioceptors in the skeletal muscles) or of sensory fibers only, or it may be a mixed nerve, containing both motor and sensory fibers (Table 14.3). Four cranial nerves (III, VII, IX, and X) include parasympathetic fibers (see Parasympathetic Nervous System, presented later in the chapter). and the coordinating centers that govern the cough reflex, swallowing, and vomiting. The medulla is the location of the nuclei of several cranial nerves. It is distinguished by two longitudinal ridges on the ventral surface, termed the pyramids, marking the site of crossover (decussation) of the majority of fibers of the corticospinal (pyramidal) tracts, which results in the contralateral control of muscle function. Cerebellum The cerebellum is located dorsal to the pons and medulla, below the occipital lobe. It coordinates movement and maintains posture and equilibrium by continuously assess- ing and adjusting to input from the pyramidal system, the proprioceptors in joints and muscles, the visual pathways, and the vestibular pathways from the inner ear. THINK ABOUT 14.2 a. Describe the specific location and function of each of the following: the prefrontal cortex, somatosensory area, the RAS, the Wernicke area, the basal nuclei, and the visual association area. b. Describe white matter—what it is and what its function is—and give an example. c. Predict the effects of brain damage in the prefrontal cortex, the left frontal lobe, the cerebellum, and the hypothalamus. Blood Supply to the Brain Blood is supplied to the brain by the internal carotid arteries and the vertebral arteries. Each internal carotid artery is a branch of a common carotid artery (right or left) and includes the carotid sinus, which is the location of the pressoreceptors, or baroreceptors, which signal changes in blood pressure, and the chemoreceptors, which monitor variations in blood pH and oxygen levels. At the base of the brain, each internal carotid artery divides into an anterior and middle cerebral artery (see Fig. 14.14, presented later): • The anterior cerebral artery supplies the frontal lobe. • The middle cerebral artery supplies the lateral part of the cerebral hemispheres, primarily the temporal and parietal lobes, which constitute a high proportion of the brain tissue. Posteriorly, the vertebral arteries join to form the following: • The basilar artery, which supplies branches to the brain stem and cerebellum as it ascends. At the base of the brain, the basilar artery divides into the following: • The right and left posterior cerebral arteries, which supply blood to the occipital lobes. • The anterior, middle, and posterior cerebral arteries follow a course over the surface of each hemisphere, with many branches penetrating into the brain sub- stance (see Fig. 14.13A, presented later). THINK ABOUT 14.3 a. Explain the function of the circle of Willis. b. Describe the effect of an obstruction in the right anterior cerebral artery. c. Explain how a lack of glucose or oxygen will affect brain function. d. What are the different types of fibers and the functions of cranial nerves II, III, and IX? Describe the effects of damage to each. Spinal Cord Spinal Cord The spinal cord is protected by the bony vertebral column, the meninges, and the CSF. The cord is continuous with the medulla oblongata and ends at the level of the first lumbar vertebra. Beyond this extends a bundle of nerve roots known as the cauda equina. This arrangement is 332 SECTION III Pathophysiology of Body Systems significant because there is little risk of damaging the cord when a needle is inserted into the subarachnoid space below the first lumbar level (usually in the space between L3 and L4) to obtain a sample of CSF (see Fig. 14.11, presented later). The spinal cord consists of the white matter (outer region) containing the spinal cord tracts, composed of myelinated fibers, and the gray matter (inner region) containing the nerve cell bodies, dendrites, and nonmy- elinated axons. Within the gray matter, three distinct areas can be identified: • Ventral horn • Contain motor neurons and their axons leave via the ventral root • Dorsal horn • Contain interneurons receiving information from sensory neurons of the dorsal root ganglia • Lateral horns • Contain visceral motor neurons The white matter is composed of afferent (incoming/ sensory) and efferent (outgoing/motor) fibers that are organized into tracts and communicating fibers that run between the two sides of the spinal cord. Each tract is assigned a unique position in the white matter; a cross section of the cord would illustrate the “map” of tracts (Fig. 14.4B). The name of the tract is based on its source and destination, and the fibers in it transmit one type of impulse. For example, the lateral spinothalamic tract is made up of ascending fibers that conduct pain or tempera- ture sensations, which are relayed from spinal nerves and receptors, on the opposite side of the body, to the thalamus. The descending tracts are of two types: • The pyramidal, or corticospinal, tracts conduct impulses concerned with voluntary movement from the motor cortex (upper motor neurons) to the lower motor neurons in the anterior horn at the appropriate level of the spinal cord. Most of these tracts cross in the medulla. • The extrapyramidal tracts carry impulses that modify and coordinate voluntary movement and maintain posture. Lower motor neurons may receive both stimulatory and inhibitory input from upper motor neurons and from interneurons in the spinal cord. The sum of the input determines what activity occurs in the spinal nerves and skeletal muscles. TABLE 14.3 Major Components of Cranial Nerves Number Name Type of Fibers Function I Olfactory Sensory Special sensory—smell II Optic Sensory Special sensory—vision III Oculomotor Motor Eye movements Four extrinsic eye muscles Upper eyelid—levator palpebrae muscle PNS Iris—pupillary constrictor muscle Ciliary muscle—accommodation IV Trochlear Motor Eye movements—superior oblique eye muscle V Trigeminal Sensory General sensory—eye, nose, face and oral cavity, teeth Motor Muscles of mastication with sensory proprioceptive fibers; speech VI Abducens Motor Eye movements—lateral rectus eye muscle VII Facial Sensory Special sensory—taste, anterior two-thirds of tongue Motor Muscles of facial expression Scalp muscles PNS Lacrimal gland, nasal mucosa, salivary glands (sublingual and submandibular) VIII Vestibulocochlear Sensory Special sensory—hearing and balance (inner ear) IX Glossopharyngeal Sensory Special sensory—taste, posterior one-third of tongue General sensory—pharynx and soft palate (gag reflex) Sensory—carotid sinus for baroreceptors and chemoreceptors Motor Pharyngeal muscles—swallowing PNS Salivary gland (parotid) X Vagus Sensory Special sensory—taste, pharynx, posterior tongue General sensory—external ear and diaphragm Visceral sensory—viscera in thoracic and abdominal cavities Motor Pharynx and soft palate—swallowing and speech PNS Heart and lungs; smooth muscle and glands of digestive system XI Spinal accessory Motor Voluntary muscles of palate, pharynx, and larynx Head movements—sternocleidomastoid and trapezius muscles XII Hypoglossal Motor Muscles of tongue PNS, parasympathetic nervous system. CHAPTER 14 Nervous System Disorders 333 THE SPINAL CORD CROSS SECTION OF THE SPINAL CORD SHOWING TRACTS C-1 S-1 2 3 4 5 6 7 8 3 4 5 Parasympathetic fibers – CRANIAL NERVES III, VII, IX, X Brain stem Phrenic nerve to diaphragm – RESPIRATION Sympathetic nervous system – • HEART • BLOOD VESSELS • TEMPERATURE Intercostal muscles – RESPIRATION Parasympathetic nerves • BOWEL • BLADDER • EXTERNAL GENITALIA LEGS A B ARMS 2 3 4 5 L-1 2 3 4 5 6 7 8 9 10 11 12 T-1 2 Fasciculus gracilis or dorsal white column ascending from touch and pressure receptors in skin Posterior fissure Anterior median fissure Fasciculus cuneatus Dorsal horn Posterior spinocerebellar tract Anterior spinocerebellar tract ascending from proprioceptors in muscle and tendons for position sense Anterior corticospinal tractReticulospinal tract (fibers scattered) Lateral spinothalamic tract ascending for pain and temperature Lateral corticospinal tract descending to skeletal muscle for voluntary movement Rubrospinal tract descending for posture and muscle coordination Vestibulospinal tract Tectospinal tract FIG. 14.4 Functional areas of the spinal cord. Spinal Nerves Thirty-one pairs of spinal nerves emerge from the spinal cord, carrying motor and sensory fibers to and from the organs and tissues of the body. They are named by the location in the vertebral column where they emerge (see Fig. 14.4) and are numbered within each section. For example, there are eight pairs of cervical nerves, numbered C1 to C8. Each spinal nerve is connected to the spinal cord by two short roots. The ventral, or anterior, root is made up of efferent or motor fibers from the lower motor neurons in the anterior horn. The dorsal, or posterior, root consists of afferent or sensory fibers from the dorsal root ganglion (a collection of nerve cell bodies in the peripheral nervous system), where sensory fibers from peripheral receptors have already synapsed. The area of sensory innervation of the skin by a specific spinal nerve is called a dermatome, and these can be drawn on a “map” of the body surface (see Fig. 14.22, presented later). Assessment of sensory awareness using the dermatome map can be a useful tool in determining the level of damage to the spinal cord. Four plexuses are located where fibers from several spinal nerves branch and then re-form in different combinations to become specific peripheral nerves: the cervical, brachial, lumbar, and sacral. This networking means that the phrenic nerve, for example, consists of fibers from spinal nerves C3 to C5, and the sciatic nerve contains fibers from spinal nerves L4 to L5 and S1 to S3. Also, the fibers in each spinal nerve can be distributed in several peripheral nerves. This dispersal pattern can minimize the effects on a muscle’s contraction of damage to one spinal cord segment. Reflexes Reflexes are automatic, rapid, involuntary responses to a stimulus. A simple reflex involves a sensory stimulus from a receptor that is conducted along an afferent nerve fiber, a synapse in the spinal cord, and an efferent impulse 334 SECTION III Pathophysiology of Body Systems provide a link between neurons and capillaries for physical and probably metabolic support, as well as contributing to the blood-brain barrier. Oligodendrocytes provide myelin for axons in the CNS. Microglia have phagocytic activity. Ependymal cells line the ventricles and neural tube cavity and form part of the choroid plexus. Researchers are investigating specific roles that glial cells may play in areas such as synapses and intercel- lular communication, as well as neuronal metabolism. Regeneration of Neurons Neurons cannot undergo cell division. If the cell body is damaged, the neuron dies. In the peripheral nervous system, axons may be able to regenerate if the cell body is viable. After damage to the axon occurs, the section distal to the injury degenerates because it lacks nutrients and is removed by macrophages and Schwann cells. The Schwann cells then attempt to form a new tube at the end of the remaining axon. The cell body becomes larger and synthesizes additional proteins for the growth of the replacement axon. The new growth does not always occur appropriately or make its original connections, because the surrounding tissue may interfere. Much of spinal cord research is focused on reducing damage to neurons immediately after injury and facilitating func- tional reconnections. Conduction of Impulses A stimulus increases the permeability of the neuronal membrane, allowing sodium ions to flow inside the cell, thus depolarizing it and generating an action potential when threshold is reached. The change to a positive electrical charge inside the membrane results in increased permeability of the adjacent area, and the impulse moves along the membrane. Recovery, or repolarization, occurs as potassium ions move outward; the normal permeability of the membrane is restored, and the sodium-potassium pump returns the sodium and potassium ions to their normal locations (see Fig. 2.5). In myelinated fibers, this action potential is generated only at the nodes of Ranvier, and therefore the impulse can “skip” along rapidly (saltatory conduction). Generally the larger axons conduct impulses more rapidly than smaller ones. The synapse provides the connection between two or more neurons or a neuron and an effector site. Complex “electrical circuits” exist in the nervous system, with multiple synapses on each neuron. The electrical activity of the brain can be monitored by attaching electrodes to the scalp and measuring the brain waves by means of an electroencephalogram (EEG). that is conducted along a peripheral nerve to elicit the response. Touching a hot object with the hand thus results in an immediate movement of the hand away from the object. At the same time, connecting neurons or inter- neurons transmit the sensory information up to the brain to initiate an assessment and further action if required. Many reflexes that control visceral activities or posture take place continuously, without the individual’s aware- ness. In addition, each individual has acquired, or learned, reflexes, such as those developed when learning to ride a bicycle. Certain basic reflexes, such as the patellar (or knee-jerk reflex) or oculocephalic (doll’s head eye response) reflex are useful in diagnosis. Absent, weak, or abnormal responses may indicate the presence of a neurologic problem and sometimes can show the location of spinal cord damage. THINK ABOUT 14.4 a. At which level of the spine would a lumbar puncture occur, and why? b. Describe the general location of the cervical spinal nerves. c. Describe a dermatome and its purpose. d. Describe the path of nerve impulses involved in the withdrawal reflex that occurs when one pricks a finger on a sharp pin. Name each element in the reflex arc and state its function. APPLY YOUR KNOWLEDGE 14.1 Predict five possible points of dysfunction and explain how each might occur and the effects to be expected. Neurons and Conduction of Impulses Neurons Neurons, or nerve cells, are highly specialized, nonmitotic cells that conduct impulses throughout the central nervous system (CNS) and the peripheral nervous system. They require glucose and oxygen for metabolism. There are many variations in the specific structural characteristics of each neuron, depending on its function. The cell body has a variable number of processes, or extensions, depend- ing on the type of neuron involved. These processes make up nerves and tracts. The dendrite is the receptor site, which conducts impulses toward the cell body. The cell body contains the nucleus. The axon conducts impulses away from the cell body toward an effector site or con- necting neuron, where it can release neurotransmitter chemicals at its terminal point. Many nerve fibers are covered by a myelin sheath, which insulates the fiber and speeds up the rate of con- duction. The myelin sheath, which wraps many layers of its plasma membrane around the axon, is formed by Schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system. The interruptions in the myelin sheath are called the nodes of Ranvier. The neurons are supported and protected by large numbers of glial (neuroglial) cells. Astroglia or astrocytes CHAPTER 14 Nervous System Disorders 335 inhibiting the enzymes that normally inactivate transmit- ters or by interfering with the uptake of neurotransmitters into the axons for recycling. Synapses and Chemical Neurotransmitters A chemical synapse involves the release of neurotrans- mitters from vesicles in the synaptic buds of the axons (Fig. 14.5). These transmitters may stimulate or inhibit the postsynaptic neuron. A typical synapse consists of the terminal axon of the presynaptic neuron, containing the vesicles with neurotransmitter (synaptic vesicles), and the receptor site on the membrane of the postsynaptic neuron. The axon and the receptor site are separated by the synaptic cleft. When the action potential reaches the axon terminal, the neurotransmitter is released from the vesicles and diffuses across the cleft to act on the receptor in the postsynaptic membrane, creating a postsynaptic potential. Receptors are specific for each neurotransmitter. Neurotransmitters are then either inactivated by specific enzymes or taken up by the presynaptic axon to prevent continued stimulation. Because there are usually many impulses from a variety of neurons arriving at one postsynaptic neuron, that neuron can process the input and then transmit the net result of the information to the next receptor site. There are many neurotransmitters in the body; a few examples follow: • Acetylcholine (ACh) is present at neuromuscular junctions and in the autonomic nervous system, the peripheral nervous system, and, less commonly, the CNS. • Catecholamines, including norepinephrine, epineph- rine, and dopamine, are present in the brain. • Norepinephrine is a neurotransmitter in the sympa- thetic nervous system (SNS). • Both norepinephrine and epinephrine, when released from the adrenal medulla in response to SNS stimula- tion, circulate in the blood and interstitial fluid, ulti- mately diffusing into the synaptic cleft and stimulating the appropriate receptors in the SNS. • Serotonin is involved in mood, emotions, and sleep. • Histamine is involved in emotions, regulation of body temperature, and water balance. • Gamma-aminobutyric acid (GABA) is the most common inhibitory neurotransmitter in the brain. • Glycine is the most common inhibitory neurotransmitter in the spinal cord. The roles of many neurotransmitters in mental illness and other pathologies are being studied intensively. For example, norepinephrine and dopamine are excitatory, and thus low levels may be linked to depression. The enkephalins and beta-endorphins are of interest because they can block the conduction of pain impulses in the spinal cord and brain (see Chapter 4). Many drugs have been developed that can mimic the effects of natural chemical neurotransmitters by stimulating specific recep- tors and promoting similar effects (see Chapter 3). Other drugs are designed to bind to certain receptors but not stimulate them. These drugs block the action of normal neurotransmitters, inhibiting the activity initiated by them. Drugs can also affect neurotransmission, either by THINK ABOUT 14.5 a. If postsynaptic membrane permeability is increased, is the neuron more easily stimulated or less excitable? b. Explain the effect of the myelin sheath and the nodes of Ranvier on the conduction of impulses. c. Briefly describe, in the correct sequence, the events that occur in synaptic transmission. d. Explain how and why surface receptors on neurons are specific for certain neurotransmitters? Autonomic Nervous System The autonomic nervous system (ANS) incorporates the sympathetic and parasympathetic nervous systems. These systems generally have antagonistic effects, thereby providing a fine balance that aids in maintaining homeo- stasis in the body (Table 14.4). The autonomic system provides motor and sensory innervation to smooth muscle, cardiac muscle, and glands. Although the individual is largely unaware of this involuntary activity, it is integrated with somatic activity by the higher brain centers. The neural pathways in the motor fibers of the autonomic system differ from somatic nerves because each involves two neurons and a ganglion. The preganglionic fiber is located in the brain or spinal cord (see Fig. 14.5). This axon then synapses with the second neuron in the ganglion outside the CNS, and the postganglionic fiber continues to the effector organ or tissue. Sympathetic Nervous System The SNS, or thoracolumbar nervous system, increases the general level of activity in the body, thereby increasing cardiovascular, respiratory, and neurologic functions. The SNS is necessary for the fight-or-flight, or stress, response and is augmented by the increased secretions of the adrenal medulla in response to SNS stimuli. The preganglionic fibers of the sympathetic nerves arise from the thoracic and the first two lumbar segments of the spinal cord. The ganglia are located in two chains or trunks, one on either side of the spinal cord. In the ganglia, preganglionic fibers synapse with postganglionic fibers or connecting fibers to other ganglia in the chain. The neurotransmitters and receptors are important in the autonomic nervous system because they are closely linked to drug actions. The neurotransmitter released by preganglionic fibers at the ganglion is acetylcholine; hence these fibers are termed cholinergic fibers. Most SNS postganglionic fibers release norepinephrine, also called adrenaline (adrenergic fibers). The postganglionic fibers to 336 SECTION III Pathophysiology of Body Systems D. Blocking neurotransmitters Blocking drugNeurotransmitter E. Increased stimulation Neurotransmitter Receptor blocked by drug No stimulus by neurotransmitter Drug stimulates receptor B. Parasympathetic nervous system Acetylcholine Acetylcholine Acetylcholine Brain or spinal cord Receptor stimulated Postganglionic nervePreganglionic nerve Impulse C. Sympathetic nervous system Spinal cord Receptor stimulated Postganglionic nerve Ganglion Norepinephrine Neurotransmitters Impulse Synaptic cleft Receptor in skeletal muscle 3. Excess neurotransmitter taken up by neuron or destroyed by enzyme Nerve Impulse Impulse Impulse Impulse Impulse Impulse Impulse ImpulseImpulse A. Neuromuscular junction Spinal cord 1. Vesicle releases neurotransmitter 2. Neurotransmitter stimulates receptor Acetylcholine FIG. 14.5 Neurotransmitters at the synapse. CHAPTER 14 Nervous System Disorders 337 sweat glands and blood vessels in skeletal muscle are cholinergic. Several types of adrenergic receptors in the tissues respond to norepinephrine and epinephrine. Norepineph- rine acts primarily on alpha (α) receptors, and epinephrine acts on both alpha and beta (β) receptors. (See Table 14.4 for a summary of the major sites of the receptors and the effects of stimulation.) An organ or tissue may have more than one type of receptor, but one type is usually present in greater numbers and exerts the dominant effect. It is possible that other specific types of receptors will be discovered in the future. Drugs may be used to stimulate these receptors or to prevent stimulation (see Fig. 14.5D–E). For example, beta1-adrenergic receptors (sympathetic receptors) are located in the cardiac muscle. With SNS stimulation, epinephrine stimulates these receptors, resulting in an increased heart rate and force of contraction. In a patient with a damaged heart, drugs such as beta-adrenergic blocking agents (commonly called beta-blockers) may be used to block these receptors, thus preventing stimula- tion and the resulting excessive heart activity. A patient may, in contrast, require a drug that can stimulate the beta receptors to improve heart function (a beta-adrenergic drug). The best drugs are specific for one type of receptor in one organ or tissue and do not alter function in other areas of the body; that is, the more specific the drug action is, the milder the adverse effects of the drug. Parasympathetic Nervous System The parasympathetic nervous system (PNS), or cranio- sacral nervous system, dominates the digestive system and aids in the recovery of the body after sympathetic activity. There are two locations of PNS preganglionic TABLE 14.4 Effect of Stimulation of the Autonomic Nervous System Area SNS Receptor Sympathetic Parasympathetic Cardiovascular System Heart, blood vessels β-1 (beta-1) Increases rate and force of contractions Decreases rate and contractility Skin, mucosa, viscera α-1 (alpha-1) Vasoconstriction No innervation Skeletal muscle β-2 Vasodilation No innervation Adrenal medulla Secretion of epinephrine and norepinephrine No innervation Respiratory system β-2 Bronchodilation (smooth muscle) Bronchoconstriction Eye α-1 Pupil dilation (radial muscle) Pupil constriction (sphincter or circular muscle) Sweat glands α-1 Increased secretion Digestive system α-2 Secretions Decreased Increased Peristalsis Decreased Increased Sphincters α-1 Constricts Relaxes Urinary system Sphincters of bladder α-1 Constricts Relaxes Renin β-1 Increased secretion Male genitalia α-1 Ejaculation Erection SNS, sympathetic nervous system. fibers: cranial nerves III, VII, IX, and X at the brain stem level and the sacral spinal nerves. The vagus nerve (cranial nerve X) provides extensive innervation to the heart and digestive tract. In the PNS, the ganglia are scattered and located close to the target organ, and the neurotransmitter at both preganglionic and postganglionic synapses is ACh. There are two types of cholinergic receptors: nicotinic and muscarinic. Nicotinic receptors are always stimulated by ACh and are located in all postganglionic cholinergic neurons in the PNS and SNS. Muscarinic receptors are located in all effector cells and may be stimulated or inhibited by ACh, depending on the organ. Similar to the pharmacologic effects of drugs in the SNS, cholinergic blocking agents reduce PNS activity, whereas cholinergic or anticholinesterase agents (which prevent the enzyme cholinesterase from breaking down ACh) increase PNS activity. THINK ABOUT 14.6 a. Compare the location of the ganglia and the junction of PNS and SNS peripheral nerve fibers with those in the CNS. b. Explain how the PNS and SNS affect cardiovascular activity and blood pressure. c. List the synapses in which ACh is the neurotransmitter. d. Which part of the autonomic nervous system promotes digestion and absorption? How does this occur? e. Briefly describe the action and effect of a drug classified as an alpha-1 adrenergic blocking agent. f. Briefly describe where a cholinergic drug acts and how it affects the postsynaptic receptors. Give two examples of its possible effects on function. 338 SECTION III Pathophysiology of Body Systems Level of Consciousness Normally a person is totally aware of surrounding activi- ties and incoming stimuli and oriented to time, place, and people; the person can respond quickly and appropriately to questions, commands, or events. An individual may exert various levels of attention on different aspects of the immediate environment. The cerebral cortex and the RAS in the brain stem determine the level of conscious- ness. Information must be processed in the associa- tion areas of the cortex before one is conscious of the information. One of the early changes noted in those with acute brain disorders is a decreasing level of consciousness or responsiveness. Usually extensive supratentorial lesions must be present in the cerebral hemispheres to cause loss of consciousness, whereas relatively small lesions in the brain stem (infratentorial lesions) can affect the reticular activating system (RAS). Space-occupying masses in the cerebellum can also compress the brain stem and RAS. In addition to CNS lesions, many systemic disorders, such as acidosis or hypoglycemia, can depress the CNS, reducing the level of consciousness. Various levels of reduced consciousness may present as lethargy, confusion, disorientation, memory loss, unresponsiveness to verbal stimuli, or difficulty in arousal. Standard categories used in diagnostic tools, such as the Glasgow Coma Scale, provide consistency in the medical assessment (Table 14.5). The most serious level is loss of consciousness or coma, in which the affected person does not respond to painful or verbal stimuli and the body is motionless, although some reflexes are present. The terminal stage, deep coma, is marked by a loss of all reflexes, fixed and dilated pupils, and slow and irregular pulse and respirations. A vegetative state is a loss of awareness and mental capabilities, resulting from diffuse brain damage, although brain stem function continues, supporting respiratory, cardiovascular, and autonomic functions. There appears to be a sleep-wake cycle (eyes are open or closed), but the person is unresponsive to external stimuli. Some individuals may in time recover consciousness but often survive with significant neurologic impairment. Locked-in syndrome refers to a condition in which an individual with brain damage is aware and capable of thinking but is paralyzed and cannot communicate. Some individuals can move their eyes in a “yes” or “no” response. A diagnosis of brain death is often required to terminate medical intervention, because individuals can be main- tained artificially on cardiopulmonary support systems. The criteria for brain death include the following: • Cessation of brain function, including function of the cortex and the brain stem (eg, a flat or inactive EEG) • Absence of brain stem reflexes or responses • Absence of spontaneous respirations when ventilator assistance is withdrawn General Effects of Neurologic Dysfunction The effects of neurologic damage from different causes have many similarities, because specific areas of the brain and spinal cord have established/defined functions. Therefore damage to a certain area from a tumor or head injury, for example, can result in the same neurologic loss and signs. Also, the effects of increased pressure within the CNS are basically similar, regardless of the cause. To facilitate study and prevent repetition, these common effects are discussed in this section and are then referred to in the subsequent sections on specific disorders. Some unique variations in the effects of damage to the nervous system do occur, given the diversity of pathologic conditions and the possible combinations of effects. Local (Focal) Effects Local effects are signs related to the specific area of the brain or spinal cord in which the lesion or trauma is located (see Fig. 14.3). Examples include paresis or paralysis of the right arm that results from damage to a section of the left frontal lobe and loss of vision that results from damage to the occipital lobe. With an expand- ing lesion, such as a growing tumor or hemorrhage, additional impairment is noted as the adjacent areas become involved. Supratentorial and Infratentorial Lesions Supratentorial lesions occur in the cerebral hemispheres above the tentorium cerebelli. A lesion in this location leads to a specific dysfunction in a discrete area, perhaps numbness in a hand. The lesion must become very large before it affects consciousness. An infratentorial lesion is located in the brain stem, or below the tentorium. A relatively small lesion in this location may affect many motor and sensory fibers, resulting in widespread impair- ment, because the nerves are bundled together when passing through the brain stem. Also, respiratory and circulatory function and the level of consciousness may be impaired by a small lesion in this area. Left and Right Hemispheres Certain effects of brain damage are unique to the left or right hemisphere. These occur in addition to focal effects. In most individuals, damage to the left hemisphere leads to loss of logical thinking ability, analytic skills, other intellectual abilities, and communication skills. Right- sided brain damage impairs appreciation of music and art and causes behavioral problems. Spatial orientation and recognition of relationships may be deficient, resulting in interference with mobility and “neglect” of the contra- lateral side of the body (which is not recognized as “self”). For a further explanation of the role of the right and left hemisphere, please consult your physiology text. CHAPTER 14 Nervous System Disorders 339 Two involuntary motor responses that occur in persons with severe brain trauma include decorticate and decerebrate posturing (Fig. 14.6). Decorticate responses include rigid flexion in the upper limbs, with adducted arms and inter- nal rotation of the hands; the lower limbs are extended. This response may occur in persons with severe damage in the cerebral hemispheres. Decerebrate responses occur in persons with brain stem lesions and CNS depression caused by systemic effects. Both the upper and lower limbs are extended, as is the head, and the body is arched. Sensory Deficits Sensory loss may involve touch, pain, temperature, and position and the special senses of vision, hearing, taste, and smell. The somatosensory cortex in the parietal lobe (see Fig. 14.3), which receives and localizes basic sensory input from the body, is mapped to correspond to receptors in the skin and skeletal muscles of various body regions. The specific site of damage determines the deficit. Mapping of the dermatomes (see Fig. 14.22, presented later) assists in the evaluation of spinal cord lesions. Damage to the cranial nerves or their nuclei or to the assigned area of the brain may interfere with vision or other special senses. Visual Loss: Hemianopia Because of the unique anatomy of the visual pathway, loss of the visual field depends on the site of damage in the visual pathway (Fig. 14.7). (See Chapter 15 for review of the structure of the eye.) At the optic chiasm, the fibers in each optic nerve come together and then divide. If the optic chiasm is totally destroyed, vision is lost in • Establishment of the certainty of irreversible brain damage by confirmation of the cause of the dysfunction Drug overdose or hypothermia can cause loss of brain activity temporarily; thus a longer time period and additional testing are required before brain death can be confirmed in these cases. Motor Dysfunction Damage to the upper motor neurons in the posterior zone of the frontal lobe of cerebral cortex or to the cor- ticospinal tracts in the brain interferes with voluntary movements, causing weakness or paralysis on the opposite (contralateral) side of the body. This contralateral effect is determined by the crossover of the corticospinal tracts in the medulla. The area affected, such as a leg or arm, depends on the specific site of damage. Muscle tone and reflexes may be increased (hyperreflexia) because the intact spinal cord continues to conduct impulses with no moderating or inhibiting influences sent from the brain (spastic paralysis). This frequently leads to immobility resulting in contractures in the affected limbs. Damage to the lower motor neurons in the anterior horns of the spinal cord causes weakness or paralysis on the same side of the body, at and below the level of damage. In the area of damage, the muscles are usually flaccid (absence of tone), and reflexes are absent (flaccid paralysis). If the cord distal to the damage is intact, some reflexes in that area may be present and hyperactive (hyperreflexia). Lower motor neurons are also located in the nuclei of cranial nerves in the brain stem, and similarly, ipsilateral weakness or flaccid paralysis may result from damage to any cranial nerves containing motor fibers (see Table 14.3). TABLE 14.5 Glasgow Coma Scale and Use in Assessment Criteria Maximum Example—0700 Hours Example—0900 Hours Example—1100 Hours Eye opening Spontaneous 4 Response to speech 3 × × Response to pain 2 None 1 × Motor response Obeys commands 6 × Localizes pain 5 × Normal flexion (to pain) 4 Abnormal flexion (decorticate) 3 Abnormal extension (decerebrate) 2 None (flaccid) 2 × Verbal response Oriented to time and place 5 Confused 4 × Inappropriate words 3 × Incomprehensible 2 None 1 × Score 15 (good, normal) 13 11 4 340 SECTION III Pathophysiology of Body Systems A B C D FIG. 14.6 Decorticate and Decerebrate Posturing. A, Decorticate response. Flexion of arms, wrists, and fingers with adduction in upper extremities. Extension, internal rotation, and plantar flexion in lower extremities. B, Decerebrate response. All four extremities in rigid extension, with hyperpronation of forearms and plantar flexion of feet. C, Decorticate response on right side of body and decerebrate response on left side of body. D, Opisthotonic posturing. (From Lewis SM, Heitkemper MM, Dirksen SR: Medical-Surgical Nursing, ed 6, St. Louis, 2004, Mosby.) both eyes. Partial loss can result in a variety of effects, depending on the particular fibers damaged. Fibers from the medial (inner) half of each retina (cells receive visual stimuli) cross over to the other hemisphere, whereas fibers from the lateral or outer half of the retina remain on the same side. Thus the optic tract coursing from the optic chiasm to the occipital lobe on one side includes fibers from half of each eye. If the optic tract or occipital lobe is damaged, vision is lost from the medial half of one eye and the lateral half of the other eye; this is called homonymous hemianopia. The overall effect is loss of the visual field on the side opposite to that of the damage. In other words, damage to the left occipital lobe means loss of the right visual field because the left half of both retinas receives light waves from the right side of the visual field. If you were caring for this patient, it would be best to stand on the patient’s left side. Other types of visual loss may occur depending on the point of damage in the visual pathway. Partial loss of vision may lead to inability to coordinate input from right and left visual fields. This may lead to diplopia or double vision as well as loss of depth perception and hand-to-eye coordination. Language Disorders Aphasia refers to an inability to comprehend or to express language. There are many types of aphasia; the main types are expressive, receptive, and global (Table 14.6). Variations and combinations may occur in individual VISUAL PATHWAY Brain Occipital lobe Optic tract Optic nerve Optic chiasm (crossover) Left eye Temporal Nasal Right eye Left Visual Field Right Visual Field 1 2 3 Temporal 3 LOSS OF VISUAL FIELD 1. Damage to right eye or optic nerve Blind eye Left Right 2. Damage to optic chiasm Blind 3. Damage to right occipital lobe or right optic tract—loss of left visual field FIG. 14.7 The visual pathway. CHAPTER 14 Nervous System Disorders 341 TABLE 14.6 Aphasia Type Site of Damage Effect Expressive (motor) Broca area Left frontal lobe Cannot speak or write fluently or appropriately Receptive (sensory) Wernicke area Left temporal lobe, prefrontal Unable to understand written or spoken language Global Broca and Wernicke areas and connecting fibers Cannot express self or comprehend others’ language THINK ABOUT 14.7 a. Compare normal function and coma, using two characteristics of these levels of consciousness. b. Describe two possible areas of CNS damage that might cause flaccid paralysis. c. Describe the effects on motor function of damage to the lateral surface of the frontal lobe. d. Describe the characteristics of expressive aphasia, and state the usual location of the damage. cases. Dysphasia refers to partial impairment, which is more common, but the term aphasia is frequently used to refer to both partial and total loss of communicating ability. • Expressive, or motor, aphasia results in an impaired ability to speak or write fluently or appropriately. Such a person may be unable to find any intelligible words or construct a meaningful sentence. This type of aphasia occurs when the Broca area in the dominant (usually the left lobe) frontal lobe, inferior motor cortex, is damaged (see Fig. 14.3). • Receptive, or sensory, aphasia is an inability to read or understand the spoken word. This category does not include hearing or visual impairment. The source of the problem is the inability to process information in the brain. The individual may be capable of fluent speech, but frequently it is meaningless. Damage to the Wernicke area in the left temporal lobe results in receptive aphasia. • Global aphasia commonly describes a combination of expressive and receptive aphasia that results from major damage to the brain, including the Broca area, the Wernicke area, and many communicating fibers throughout the brain. Aphasia may also be described as fluent or nonfluent; in fluent aphasia the pace of speech is relatively normal but contains made-up words and sentences that do not make sense. Fluent aphasia is associated with damage to the Wernicke area. Nonfluent aphasia is slow and labored speech with short phrases; often small words are omitted. It is associated with damage to the Broca area. Other types of language disorders include the following: • Dysarthria, in which words cannot be articulated clearly, is a motor dysfunction that usually results from cranial nerve damage or muscle impairment. • Agraphia is impaired writing ability. • Alexia is impaired reading ability. • Agnosia is loss of recognition or association. For example, visual agnosia indicates an inability to rec- ognize objects. Thorough testing is required before a specific diagnosis can be made of any of these disorders. Seizures Seizures or convulsions are caused by spontaneous exces- sive discharge of neurons in the brain. This state may be precipitated by inflammation, hypoxia, or bleeding in the brain. Often the seizure is focal or is related to the particular site of the irritation, but it may become generalized. Frequently the seizure is manifested by involuntary repetitive movements or abnormal sensations. Increased Intracranial Pressure The skull contains brain tissue, blood, and CSF. The volume of each of these normally remains relatively constant, thus maintaining a normal pressure inside the cranial cavity. Temporary fluctuations in blood flow and blood pressure may occur with activities such as coughing or bending over. The fluids, blood and CSF, are not compressible. Because the brain is encased in the rigid, nonexpandable skull, any increase in fluid, such as blood or inflammatory exudate, or any additional mass, such as a tumor, causes an increase in pressure in the brain. The result is that less arterial blood can enter the “high pressure” area in the brain, and eventually the brain tissue itself is compressed. Both of these effects decrease the function of the neurons, both locally and generally. Eventually brain tissue dies. The pressure increases at the site of the problem initially but gradually is dispersed throughout the CNS by means of the continuous flow of CSF and blood, leading to widespread loss of function. Changes in intracranial pressure (ICP) can be monitored directly by instruments placed in the ventricles (an invasive procedure) or indirectly by methods such as radiologic examinations or assessment of the level of consciousness and vital signs. Increased ICP is common in many neurologic problems, including brain hemorrhage, trauma, cerebral edema, infection, tumors, or accumulation of excessive amounts of CSF (Fig. 14.8). All of these problems create the same general set of manifestations, which are summarized in Table 14.7. Early Signs When ICP increases, the body initially attempts to compensate for it by shifting more CSF to the spinal 342 SECTION III Pathophysiology of Body Systems to the brain. However, this adds to the fluid volume inside the skull and is also effective for only a short time. Because of these compensatory mechanisms, ICP is often significantly elevated before signs become apparent. If the cause of the increased pressure has not been removed, the first indication of increased ICP is usually a decreasing level of consciousness or decreased responsive- ness (lethargy). Additional early indications of increased ICP include the following: • Severe headache occurs from stretching of the dura and walls of large blood vessels. • Vomiting—often projectile vomiting that is not associ- ated with food intake—is the result of pressure stimu- lating the emetic center in the medulla. • Papilledema may be present, caused by increased ICP and swelling of the optic disc (Fig. 14.9). Papilledema can be observed by looking through the pupil of the eye at the retina, where the optic disc provides a “window” into the brain (see Fig. 15.1). The optic nerve (cranial nerve II) is essentially a projection of brain tissue that is surrounded by CSF and meninges and enters the eye at the optic disc, where it reflects the effects of increased ICP in the brain. These early manifestations continue to increase in severity as long as ICP continues to rise. Vital Signs If ICP continues to build, a sequence of events occurs in an effort to supply critical oxygen to the brain, as follows: 1. Cerebral ischemia develops, which stimulates a power- ful response (Cushing reflex) from the vasomotor centers in an attempt to increase the arterial blood supply to the brain. 2. Systemic vasoconstriction occurs to increase systemic blood pressure and force more blood into the brain to relieve the ischemia. 3. Baroreceptors in the carotid arteries respond to the increased blood pressure by slowing the heart rate. 4. Chemoreceptors respond to the low carbon dioxide levels that accompany the accelerated systemic circula- tion by reducing the respiratory rate. 5. As improved cerebral circulation relieves ischemia, the reflex vasoconstriction momentarily ceases. However, the increasing ICP causes ischemia to recur in a very short time, and the cycle is repeated. In other words, the brain responds to ischemia by one mechanism, whereas feedback control for blood pressure uses other mechanisms to protect the rest of the body, resulting in a conflict of interests. As ICP continues to rise, so does systemic blood pres- sure (Fig. 14.10). An increasing pulse pressure (the difference between systolic and diastolic pressures) is significant in people with ICP. The widening gap in pulse pressure results from the slow heart rate and the intermittent but rapid on-off cycle of Cushing reflex controlling systemic vasoconstriction. Cerebellar herniation Uncal herniation of temporal lobe into tentorial notch Tumor Herniation of cingulate gyrus under falx cerebri Downward displacement of brain stem through tentorial notch FIG. 14.8 Increased intracranial pressure and possible herniations. TABLE 14.7 Effects of Increased Intracranial Pressure General Signs Rationale Decreasing level of consciousness Pressure on RAS (brain stem) or cerebral cortex Headache Stretching or distortion of meninges or walls of large blood vessels Vomiting Pressure on emetic center in medulla Vital Signs Increasing blood pressure with increasing pulse pressure Cushing reflex; response to cerebral ischemia causes systemic vasoconstriction Slow heart rate Response to increasing blood pressure Signs Affecting Vision Papilledema Increased pressure of CSF causes swelling around the optic disc Pupil, fixed and dilated Pressure on cranial nerve III (oculomotor) CSF, cerebrospinal fluid; RAS, reticular activating system. cavity, for example, and increasing venous return from the brain. These compensation mechanisms are effective for only a short time. The resulting hypoxia triggers arterial vasodilation in the brain through local autoregula- tory reflexes, in an attempt to improve the blood supply CHAPTER 14 Nervous System Disorders 343 Usually one pupil ipsilateral to the lesion becomes fixed (unresponsive to light) and dilated as the PNS fibers in the affected oculomotor nerve become nonfunctional. With an additional pressure increase, both pupils become fixed and dilated (“blown”). Other signs of increased ICP may include ptosis, or “droopy eyelid,” which is another effect of pressure on cranial nerve III because innervation to the muscle of the upper eyelid is impaired, and abnormal or excessive eye movements, such as nystagmus. Changes in Cerebrospinal Fluid A specimen may be procured with a lumbar puncture by inserting a fine needle between the vertebrae at L3–4, into the subarachnoid space, and withdrawing a small sample of CSF (Fig. 14.11). A manometer may be attached to the syringe to measure pressure. The pressure of CSF is elevated (above 20 mm Hg) in patients with increased ICP. The composition of the fluid may vary with the cause of the problem (see Table 14.1). The CSF may be pinkish in color and contain erythrocytes, suggesting hemorrhage. A cloudy, yellowish fluid that contains numerous white blood cells may indicate infection, whereas abnormal protein levels in the CSF may indicate a neoplasm. Herniation When a mass, such as a blood clot or tumor, becomes large enough, it may displace brain tissue, leading to herniation. There are several different types of herniation (see Fig. 14.8). In transtentorial (central) herniation, the cerebral hemispheres, diencephalon, and midbrain are displaced downward. The resulting pressure affects the flow of blood and CSF, the RAS, and respiration. Uncal (uncinate) herniation occurs when the uncus of the Eventually severe ischemia and neuronal death prevent any circulatory control, and the blood pressure drops. Pressure and ischemia also destroy respiratory controls. Various abnormal respiratory patterns develop, such as Cheyne-Stokes respirations, with alternating apnea and periods of increasing and decreasing respirations, depend- ing on the site of the lesion (see Fig. 13.7). Visual Signs In addition to papilledema and specific reflex changes, several other significant indicators of increasing ICP are seen in the eyes. Pressure on the oculomotor nerve (cranial nerve III) affects the size and response of the pupils. A B FIG. 14.9 A, Papilledema. B, Papilledema showing displacement and folding of the retina (arrows) as well as edema and congestion of the optic nerve head. (A Courtesy John W. Payne, MD, The Wilmer Ophthalmological Institute, The Johns Hopkins University and Hospital, Baltimore, MD, from Seidel HM, Ball JW, Dains JE, et al: Mosby’s Guide to Physical Examination, ed 5, St. Louis, 2003, Mosby; B From Cotran RS, Kumar V, Collins T: Robbins Pathologic Basis of Disease, ed 6, Philadelphia, 1999, Saunders.) TIME RESPIRATION Systolic INCREASING INTRACRANIAL PRESSURE PULSE BLOOD PRESSURE ISCHEMIA IRREVERSIBLE DAMAGE Diastolic INCREASING PULSE PRESSURE COMPENSATION FIG. 14.10 Vital signs with increased intracranial pressure. 344 SECTION III Pathophysiology of Body Systems radionuclide such as technetium may be added to track perfusion in CNS. Lumbar puncture is used to check pressure and analyze the CSF for altered components. Clinical assessment routinely includes tools such as the assessment of normal reflexes and the Glasgow coma scale to assess the level of consciousness. Acute Neurologic Problems Neurologic disorders have been divided into acute problems and chronic problems. Although some overlap occurs, there are major differences in onset, course, and management of the two groups. Brain Tumors Tumors serve as a good example of space-occupying lesions that cause increased ICP because of space con- straints within the rigid skull and localized dysfunction related to their location. Therefore benign tumors as well as malignant tumors can be life threatening, unless they are in an accessible superficial location where they can be removed. Gliomas form the largest category of primary malignant tumors. They arise from one of the glial cells, the parenchymal cells in the CNS (see Fig. 20.13 for CT scan of a brain tumor). This group of tumors is further classified according to the cell of derivation (eg, astro- cytomas are the most common) and the location of the tumor. In addition, tumors may develop in the meninges (meningioma) or pituitary gland (adenoma, see Chapter 16), causing similar neurologic effects that result from pressure on the brain. Primary malignant tumors rarely metastasize outside the CNS, but multiple tumors may be present within the CNS. Secondary brain tumors are common, usually metastasizing from breast or lung tumors, and they cause effects similar to those of primary brain tumors. The combined incidence rate for brain cancer in children and adults is 22,000 in 2008 with 13,000 deaths. Case fatality rates with this cancer are relatively high. Brain cancer is responsible for greater than 2% of cancer deaths. Diagnosis is made by MRI, with a stereotactic biopsy providing confirmation. ■ Pathophysiology Primary malignant brain tumors, particularly astrocy- tomas, do not usually have well-defined margins but are invasive and have irregular projections into adjacent tissue that are difficult to totally remove (Fig. 14.12). There is usually an area of inflammation around the tumor, adding to the pressure. In some cases, obstruction of the flow of CSF or of the venous sinuses increases ICP. As the mass expands, it compresses and distorts the tissue around it, eventually resulting in herniation. A relatively small tumor in the brain stem or cerebellum can compress the medulla within a short time. However, tumors in the cerebral hemispheres, particularly in “silent” areas temporal lobe is displaced downward past the tentorium cerebelli, creating pressure on the third cranial nerve, the posterior cerebral artery, and the RAS. Cerebellar, or tonsillar (infratentorial), herniation develops when the cerebellar tonsils are pushed downward through the foramen magnum, which compresses the brain stem and vital centers and causes death. Terminus of spinal cord Lumbar subarachnoid space Filum terminale FIG. 14.11 Lumbar Puncture. Cerebrospinal fluid is obtained by inserting a needle into the subarachnoid space in the lumbar region. (From Mahon CR, Manuselis G: Textbook of Diagnostic Microbiology, ed 2, Philadelphia, 2000, Saunders.) THINK ABOUT 14.8 a. List the early signs of increased ICP. b. Explain why headache occurs with an increase in ICP. c. Describe the usual changes in vital signs that result from increased ICP in early and later stages. d. Explain why a lesion in the brain stem is more critical than one in the cerebral hemisphere. Diagnostic Tests Computed tomography (CT) scans, magnetic resonance imaging (MRI), cerebral angiography, Doppler ultrasound (for assessing patency of the carotid and intracerebral vessels), and EEG provide useful information. A CHAPTER 14 Nervous System Disorders 345 ■ Treatment Surgery is the treatment of choice, if the tumor is reason- ably accessible. Chemotherapy is often accompanied by radiation, and the prognosis for many types of tumors is improving as new drugs are developed. Some targeted drugs are being used to reduce blood flow to the tumor. It continues to be difficult to deliver drugs to CNS tumors because of the blood-brain barrier. In some cases, surgery and radiation may cause substantial damage to normal tissue in the CNS. (without obvious function), may grow quite large before their effects are noticeable. ■ Etiology Brain stem and cerebellar tumors are common in young children, and research into the cause of these tumors continues, particularly with regard to prenatal parental exposure to carcinogens and embryonic development. Tumors occur in adults most often in midlife. Adults are affected more frequently by tumors in the cerebral hemi- spheres; predisposing factors have not been established. ■ Signs and Symptoms The specific site of the tumor determines the focal signs. If the tumor grows rapidly, signs of increased ICP develop quickly, often beginning with morning headaches. Over time, these headaches increase in severity and frequency. Vomiting occurs. Lethargy and irritability may develop, along with personality and behavioral changes. In some cases, focal or generalized seizures are the first sign, as the tumor irritates the surrounding tissue. Brain stem or cerebellar tumors may affect several cranial nerves, pos- sibly causing unilateral facial paralysis or visual problems. Unlike other forms of cancer, brain tumors do not cause the usual systemic signs of malignancy because they do not metastasize outside the CNS, and they will cause death before they are large enough to cause general effects. Pituitary adenomas in the brain usually cause endo- crinologic signs, depending on the type of excess secretion (see Chapter 16). Headaches and visual signs may result from increased ICP, and compression of the adjacent optic chiasm, nerves, or tracts, resulting in visual disturbances, is common. FIG. 14.12 Brain Tumor. A, Astrocytoma in right frontal lobe has expanded the gyri (arrows indicate flattening). B, Glioblastoma. The massive mass has extensive necrosis and infiltrates across the cerebral midline (◊). (A, From Kumar V, Abbas AK, Fausto M: Robbins and Cotran Pathologic Basis of Disease, ed 7, Philadelphia, 2005, Saunders. B, From Klatt E: Robbins and Cotran Atlas of Pathology, ed 3, Philadelphia, 2015, Elsevier, Saunders.) A B THINK ABOUT 14.9 a. Explain the specific signs of dysfunction that would be expected in a young child with a cerebellar tumor. b. Choose a possible tumor site in one cerebral hemisphere and list the signs (focal and general) that would be expected as the tumor grows. c. Explain why a tumor in the cerebral hemisphere may grow quite large before any signs appear, but a brain stem tumor causes signs in the early stages. d. Explain why the general signs of cancer, such as weight loss and anemia, do not develop with brain tumors. e. Explain why the brain is a common site of metastatic cancer from the lung. Vascular Disorders Vascular disorders may be hemorrhagic or ischemic in origin. Interference with blood supply to a specific area of the brain results in local damage and manifestations 346 SECTION III Pathophysiology of Body Systems Such attacks should be investigated immediately and treatment instituted, depending on the cause, to prevent permanent brain damage. Cerebrovascular Accidents (Stroke) It is estimated that in the United States, someone has a stroke every 45 seconds. Of the approximate 700,000 strokes experienced annually, about 500,000 are first strokes and 200,000 are recurrent attacks. Cerebrovas- cular accidents (CVAs) account for more than 1 out of 15 deaths (about 160,000 per year). Incidence increases with age, most occurring in people who are over 65 years old. Strokes are considered a major cause of disability. ■ Pathophysiology A CVA (stroke) is an infarction of brain tissue that results from lack of blood. Tissue necrosis may be an outcome of total occlusion of a cerebral blood vessel by atheroma or embolus, which causes ischemia, or may be the consequence of a ruptured cerebral vessel, which causes hemorrhage and increased intracranial pressure (Fig. 14.13). Five minutes (or less) of ischemia causes irrevers- ible nerve cell damage. A central area of necrosis develops, surrounded by an area of inflammation, and function in this area is lost immediately. The tissue liquefies, leaving a cavity in the brain. The development and effects of a stroke vary with the cause. There are three common categories (Table 14.8), described as follows: • Occlusion of an artery by an atheroma is the most common cause of CVA. (Atherosclerosis is discussed in Chapter 12.) Atheromas often develop in the large arteries, such as the carotid arteries. This condition causes gradual narrowing of the arterial lumen by plaque and thrombus, leading to possible TIAs and eventually infarction. • A sudden obstruction caused by an embolus lodging in a cerebral artery: (cerebral embolus) is the second type of stroke. Thrombi may break off an atheroma, or mural thrombi may form inside the heart after a depending on the particular cerebral artery involved. If the deficit results from hemorrhage, the additional effects of increased intracranial pressure will cause local ischemia and generalized symptoms. Global cerebral ischemia, which may develop secondary to severe shock or cardiac arrest, occurs when impaired perfusion of the entire brain results in loss of function and generalized cerebral edema. In mild cases, confusion and neurologic dysfunction develop tem- porarily, followed by recovery with no permanent damage. If severe or prolonged ischemia occurs, significant diffuse necrosis or infarction results in deep coma. If death does not result, a vegetative state may ensue. Transient Ischemic Attacks A transient ischemic attack (TIA) results from a temporary localized reduction of blood flow in the brain. Recovery usually occurs within 24 hours. Transient ischemic attacks may occur singly or in a series. ■ Pathophysiology A TIA may be caused by partial occlusion of an artery, caused by atherosclerosis, or from a small embolus, a vascular spasm, or local loss of autoregulation. Transient ischemic attacks are advantageous if they serve as a warning and lead to early diagnosis and treatment of a problem before the occurrence of a cerebrovascular accident (CVA, or stroke). The brain must have a constant source of glucose and oxygen or suffer permanent damage. Not all strokes are preceded by TIAs. ■ Signs and Symptoms The manifestations of TIA are directly related to the location of the ischemia. The patient remains conscious. Intermittent short episodes of impaired function, such as muscle weakness in an arm or leg, visual disturbances, or numbness and paresthesia in the face, may occur. Transient aphasia or confusion may develop. The attack may last a few minutes or longer but rarely lasts more than 1 to 2 hours, and then the signs disappear. Repeated attacks are frequently a warning of the development of obstruction related to atherosclerosis. TABLE 14.8 Types of Cerebrovascular Accidents Thrombus Embolus Hemorrhage Predisposing condition Atherosclerosis in cerebral artery Atherosclerosis (carotid artery) or systemic source (eg, heart) Hypertension—arteriosclerosis Onset Gradual—may be preceded by transient ischemic attacks Sudden Sudden—often occurs with activity Often occurs at rest Increased ICP Minimal Minimal Present; often high Effects Localized—may be less permanent damage if collateral circulation has been established Localized unless multiple emboli are present Widespread and severe—often fatal CHAPTER 14 Nervous System Disorders 347 myocardial infarction and then break away. Emboli can also result from other materials, such as tumors, air, or infection (eg, endocarditis). • Intracerebral hemorrhage, usually caused by rupture of a cerebral artery in a patient with severe hyper- tension (see Chapter 12), is the third class of stroke. Hemorrhagic strokes are frequently more severe and destructive than other CVAs, because they affect large portions of the brain (see Fig. 14.13B). Because of the greater increase in ICP with hemorrhage, the effects are evident in both hemispheres and are complicated by the secondary effects of bleeding, in addition to the disrupted blood supply. The presence of free blood in interstitial areas affects the cell membranes and can lead to significant secondary damage as vasospasm, electrolyte imbalances, acidosis, and cellular edema develop. An MRI can determine the cause of the stroke or illustrate other possible causes of the dysfunction. Cerebral edema and an increasing area of infarction in the first 48 to 72 hours tend to increase the neurologic deficits. As the inflammation subsides, neurologic function increases. The inflammation and pressure in the brain must be minimized as quickly as possible and therapy instituted to dissolve thrombi and maintain adequate perfusion to limit the area of permanent damage. Col- lateral circulation may have already developed in areas gradually affected by atherosclerosis (see Chapter 12). Because neurons do not regenerate, an area of residual scar tissue and often cysts remains, with a permanent loss of neurons in that area (see Fig. 14.13C). In many cases, because specific functions result from integrated output from many areas, it is possible with intensive therapy for a person who has experienced a stroke to develop new neural pathways in the brain or to relearn a task, thus recovering some lost function. Complications are common. These include recurrent CVA; secondary problems related to immobility such as pneumonia, aspiration, and constipation; or contractures related to paralysis. ■ Etiology Risk factors for stroke include diabetes, hypertension, systemic lupus erythematosus, elevated cholesterol levels, hyperlipidemia, atherosclerosis, a history of TIAs, increas- ing age, obstructive sleep apnea, and heart disease. The risk factors for atherosclerosis (see Chapter 12) apply similarly to CVA. The combination of oral contraceptives and cigarette smoking has been well documented as an etiologic factor. Emboli may arise from atheromas in the large arteries, such as the carotids, or from cardiac dis- orders of the left ventricle, such as acute myocardial infarction, atrial fibrillation, or endocarditis or from an implant such as a prosthetic valve. Severe or long-term hypertension and arteriosclerosis in the elderly increase the risk of intracerebral hemorrhage. C A ANTERIOR CEREBRAL ARTERY SUPPLIES THIS AREA MIDDLE CEREBRAL ARTERY SUPPLIES THIS AREA POSTERIOR CEREBRAL ARTERY SUPPLIES THIS AREA Area of infarction and loss of function Occlusion Frontal lobe Temporal lobe Cerebellum Occipital lobe Parietal lobe B A, Effects of cerebrovascular accident (CVA). B, Exter- nal superior surface of the brain showing acute hemorrhagic infarction. Note blood vessels on surface of brain. (Courtesy of R.W. Shaw, MD, North York General Hospital, Toronto, Ontario, Canada.) FIG. 14.13 C, Cerebral subacute infarction. Liquefactive necrosis with the beginning of cystic space formation (arrowheads). (From Klatt E: Robbins and Cotran Atlas of Pathology, ed 3, Philadelphia, 2015, Elsevier, Saunders.) 348 SECTION III Pathophysiology of Body Systems whereas spatial relationships may be more severely impaired if the right side is damaged. ■ Signs and Symptoms The National Institutes of Health has developed a diagnostic stroke scale that is designed to assist with rapid diagnosis of a cerebral vascular accident in an emergency situation. The stroke scale includes commands to determine capacity for speech, level of consciousness, motor abilities, and assessment of eye movements. The scale also identifies areas of damage based on result- ing dysfunction. Signs and symptoms depend on the location of the obstruction, the size of the artery involved, and the functional area affected (see Figs. 14.3 and 14.13A). The presence of collateral circulation may diminish the size of the affected area. There are “silent” areas of the brain, in which dysfunction resulting from small infarctions is not obvious. Obstruction of small arteries may not lead to obvious signs until several small infarctions have occurred. In some cases, the effects of a stroke develop slowly over a period of hours (termed evolving stroke). Initially flaccid paralysis is present; spastic paralysis develops several weeks later, as the nervous system recovers from the initial insult. Generally the functional deficits increase during the first 48 hours as inflammation develops at the site and then subside as some neurons around the infarcted area recover. Occlusion of large arteries, such as the internal carotid artery or the middle cerebral artery, or a hemorrhage may cause severe, widespread effects, including coma, loss of consciousness, or death, almost immediately. Hemorrhagic strokes usually begin suddenly with a blinding headache and increasingly severe neurologic deficits. Specific local signs depend on the area affected. For example, occlusion of an anterior cerebral artery affects the frontal lobe. Common signs include contralateral muscle weakness or paralysis, sensory loss in the leg, confusion, loss of problem-solving skills, and personality changes. The middle cerebral artery supplies a large portion of the cerebral hemisphere; therefore lack of blood supply to this artery leads to contralateral paralysis and sensory loss, primarily of the upper body and arm. Aphasia occurs when the dominant hemisphere of the brain is affected, EMERGENCY FIRST AID FOR STROKE (CEREBROVASCULAR ACCIDENT OR BRAIN ATTACK) 1. Call 9-1-1 immediately and state the person has the symptoms of a stroke. 2. The patient should be transported to the hospital as quickly as possible with a record of common drugs used and medical conditions being treated. 3. Time between onset of the stroke and treatment is directly related to the severity of the damage to the brain. Minutes count! Because the posterior cerebral artery supplies the occipital lobe, visual loss is likely if it is occluded. ■ Treatment Rapid treatment with “clot-busting agents,” such as tissue plasminogen activator (tPA) (see Chapter 12), has reduced the effects of CVA in some individuals, but initial screening to rule out hemorrhage or other contraindications for anticoagulant drugs is essential. Surgical intervention may be possible to relieve carotid artery obstruction. Glucocorticoids may reduce cerebral edema. Supportive treatment to maximize cerebral circulation and oxygen supply is usually initiated. Assisting the patient’s return to a sitting or standing position as soon as the vital signs are stable helps to maintain muscle tone and minimize perceptual deficits. A team approach to care, including occupational and physical therapists and speech-language pathologists, encourages recovery and minimizes complications in patients in whom many basic functions are impaired. Speech, mobility, swallowing, and other functions may be affected in one individual. Correct positioning, frequent changes of position, and passive exercises to prevent muscle atrophy, contractures, and skin breakdown are required (see Chapter 25). Rehabilitation programs should be instituted as soon as possible. The underlying problem (hypertension, atherosclerosis, or thrombus) requires treatment to prevent recurrences. The prognosis varies considerably, depending on the underlying causative factors, the artery affected, and the general health status of the individual. Approximately 20% of stroke patients die within the first few days. Complete recovery is rare. However, the sooner improvement and rehabilitation therapy begin, the more optimistic the prognosis can be. Newer therapies such as constraint-induced therapy, which stimulates the use of the weaker side of the body, can be effective many years after the occurrence of a CVA. Ongoing assessment and rehabilitation are of value to any client who has experienced a CVA. WARNING SIGNS OF STROKE (CEREBROVASCULAR ACCIDENT, OR BRAIN ATTACK) 1. Sudden transient weakness, numbness, or tingling in the face, an arm or leg, or on one side of the body 2. Temporary loss of speech, failure to comprehend, or confusion 3. Sudden loss of vision 4. Sudden severe headache 5. Unusual dizziness or unsteadiness Immediate medical treatment may prevent permanent brain damage. CHAPTER 14 Nervous System Disorders 349 A small leak is likely to cause headache, photophobia (increased sensitivity of the eyes to light), and intermittent periods of dysfunction, such as confusion, slurred speech, or weakness. Nuchal rigidity, or a stiff, extended neck, often develops because the escaped blood irritates the spinal nerve roots and causes muscle contractions in the neck. A massive rupture or subarachnoid hemorrhage is manifested by an immediate, severe, “blinding” headache, vomiting, photophobia, and, perhaps, seizures or loss of consciousness. Death may occur shortly after rupture. ■ Treatment An aneurysm that is diagnosed before rupture can be treated surgically as soon as possible by clipping or tying it off. In the interim, while the patient is waiting for surgery, sudden increases in blood pressure must be prevented. Surgical clipping of the aneurysm may also Cerebral Aneurysms ■ Pathophysiology An aneurysm is a localized dilation in an artery. Cerebral aneurysms are frequently multiple and usually occur at the points of bifurcation on the circle of Willis (Fig. 14.14). These “berry” aneurysms develop where there is a weak- ness in the arterial wall where branching occurs. The force of blood at this point leads to bulging in the wall, which is often aggravated by hypertension. Initially the aneurysms are small and asymptomatic, but they tend to enlarge over years, until compression of the nearby structures (eg, a cranial nerve) causes clinical signs or rupture occurs. Rupture often results from a sudden increase in blood pressure during exertion, and bleeding occurs into the subarachnoid space (the location of the circle of Willis) and the CSF. This rupture may be a small leak or a massive tear. Blood is irritating to the meninges and causes an inflammatory response and irritation of the nerve roots passing through the meninges. This free blood also causes vasospasm in the cerebral arteries, further reducing perfu- sion and leading to additional ischemia. Hemorrhage from the ruptured vessel causes increased ICP and its associated signs. No focal signs are present because the additional blood is dispersed through the system. Sub- arachnoid hemorrhages may be classified according to their clinical effects. ■ Signs and Symptoms The enlarging aneurysm may cause pressure on the surrounding structures, such as the optic chiasm or the cranial nerves, leading to loss of the visual fields (see Figs. 14.7 and 14.14) or other visual disturbances. The mass may also result in headache as tension increases on the blood vessel wall and meninges. FIG. 14.14 Angiogram of berry aneurysm (arrowhead). (From Klatt E: Robbins and Cotran Atlas of Pathology, ed 3, Philadelphia, 2015, Elsevier, Saunders.) THINK ABOUT 14.10 a. Differentiate a TIA from a CVA with regard to the cause of each and the effects of each on function. b. Describe the three causes of CVAs and the characteristic onset of signs with each. c. Describe several factors that influence the degree of functional recovery that is attained after a CVA. d. List common signs of an expanding aneurysm and of a bleeding aneurysm. e. Why does a headache occur with a subarachnoid hemorrhage? f. Explain why skin breakdown or ulcers may occur in a person who has had a stroke and list the common sites of these problems. 350 SECTION III Pathophysiology of Body Systems • In elderly persons and young children, Streptococcus pneumoniae is a major cause of meningitis. In any age group, meningitis may be secondary to other infections, such as sinusitis or otitis, or it may result from an abscess located where the infection can spread through the bone to the meninges (eg, an abscessed tooth). Any form of head trauma or surgery can result in meningitis from a variety of microorganisms. Aseptic or viral meningitis results from an infection, such as mumps or measles. ■ Signs and Symptoms Sudden onset of meningitis is common, with severe headache, back pain, photophobia, and nuchal rigidity (a hyperextended, stiff neck). These signs result from meningeal irritation. Two other clinical signs of men- ingeal irritation include the Kernig sign (resistance to leg extension when lying with the hip flexed) and the Brudzinski sign (neck flexion causes flexion of hip and knee). Vomiting, irritability, and lethargy progressing to stupor or seizures are common early indicators of increased ICP. Fever and chills with leukocytosis indicate infection. Meningococcal infections result in a rosecolored petechial rash or extensive ecchymoses over the body (see Fig. 14.15B). Different signs, including feeding problems, irritability, lethargy, a typical high-pitched cry, and bulging fontanelles, occur in the newborn. Potential complications include hydrocephalus, if CSF flow is blocked by pus or adhesions, and cranial nerve damage. In some cases, damage to the cerebral cortex may occur, resulting in mental retardation, seizures, or motor impairment. In fulminant (rapidly progressive, severe) cases caused by highly virulent organisms, frequently meningococcal, disseminated intravascular coagulation (see Chapter 10) develops, with associated hemorrhage of the adrenal glands, or meningococcal septicemia may directly cause adrenal hemorrhage (Waterhouse-Friderichsen syndrome) (see Fig. 14.15C). These cases usually result in vascular collapse or shock and death. ■ Diagnostic Tests Examination of CSF, obtained by lumbar puncture, confirms the diagnosis. If meningitis is present, the CSF pressure is elevated; it will appear cloudy and usually contains an increased number of leukocytes. The causative organism in the CSF or blood must be identified to ensure adequate and effective treatment. ■ Treatment Aggressive antimicrobial therapy (eg, ampicillin) is required, along with specific treatment measures for ICP and seizures as needed. Glucocorticoids reduce cerebral inflammation and edema. With prompt diagnosis and treatment, the majority of patients survive. The mortality rate in neonatal meningitis is high, and there is some risk be done after rupture. Unfortunately, there is a substantial risk of rebleeding at the site of repair or from other aneurysms. Additional therapeutic measures focus on reducing the effects of increased ICP and cerebral vaso- spasm. Approximately 35% of patients die with the initial rupture, and an additional 15% die of a second rupture within several weeks. Infections Meningitis Meningitis is an infection, usually of bacterial origin, in the meninges of the CNS. Many microbes can infect the CNS, and all age groups are susceptible. Early diagnosis and treatment is essential to prevent deficits or death. ■ Pathophysiology Microorganisms reach the brain via the blood, by extension from nearby tissue, or by direct access through wounds. Microbes such as meningococcus can bind to nasopha- ryngeal cells in an individual, cross the mucosal barrier, attach to the choroid plexus, and enter CSF. Because the membranes are continuous around the CNS and CSF flows in the subarachnoid space, infection spreads rapidly through the coverings of the brain. Focal signs are absent because there is no localized mass of infection. The inflammatory response to the infection leads to increased ICP, and the pia and arachnoid layers become edematous. The common bacterial infections lead to a purulent exudate that covers the surface of the brain and fills the sulci, causing the surface to appear flat. The exudate is present in the CSF, and the blood vessels on the surface of the brain appear dilated (Fig. 14.15D). ■ Etiology Different age groups are susceptible to different organisms that cause meningitis. In some categories, vaccines have reduced the risk of meningitis: • In children and young adults, Neisseria meningitidis, or meningococcus, which is the classic meningitis pathogen, is frequently carried in the nasopharynx of asymptomatic carriers. It is spread by respiratory droplets. Epidemics are common in schools or institu- tions where close contact between the children is likely to spread the organism. Any close contacts of affected persons should be given prophylactic treatment. This type of meningitis occurs more frequently in late winter and early spring. • In neonates, Escherichia coli is the most common caus- ative organism; this form of meningitis is usually seen in conjunction with a neural tube defect, premature rupture of the amniotic membranes, or a difficult delivery. • In young children, meningitis results most often from bacterial infections caused by Haemophilus influenzae and occurs more often in the autumn or winter. CHAPTER 14 Nervous System Disorders 351 Brain Abscess An abscess is a localized infection, frequently occurring in the frontal or temporal lobes (Fig. 14.16). There is usually necrosis of brain tissue and a surrounding area of edema. A medical history may be helpful in making the diagnosis. Abscesses usually result from the spread of organisms from ear, throat, lung, or sinus infections; multiple septic emboli from acute bacterial endocarditis; or directly from a site of injury or surgery. Common organ- isms are staphylococci, streptococci, and pneumococci. of permanent brain damage in young children. Between 10% and 20% of patients with meningitis are estimated to have some neurologic deficits as sequelae. Vaccines are available as a preventive measure for some types of meningococcal, S. pneumoniae, and H. influenzae meningitis, especially when outbreaks occur. Carriers should be identified in institutional epidemics, and contacts should be notified and treated. Vaccination may be undertaken as a preventive measure when cases occur in institutions such as schools. A C B D FIG. 14.15 A, Meningitis—slide preparation of CSF showing many neutrophils with bacterial meningitis. B, Petechial rash associated with meningococcemia. C, Hemorrhage (dark areas) in the adrenal glands with Waterhouse-Friderichsen syndrome. D, Meningitis due to coliform microorganisms. The meninges are reddened from vascular congestion. Thick, greenish pus fills the subarachnoid space over both hemispheres. (A from Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, 1997, Saunders; B and C from Mahon CR, Manuselis G: Textbook of Diagnostic Microbiology, ed 2, Philadelphia, 2000, Saunders; D from Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology, ed 3, Sydney, 2004, Churchill Livingstone.) 352 SECTION III Pathophysiology of Body Systems summertime. The site of the tick bite is red with a pale center, gradually increasing in size to form the unique marker lesion, a “bull’s eye” that may become quite large and persist for some time. The microbes then dissemi- nate through the circulation, causing first, sore throat, dry cough, fever, and headache, followed by cardiac arrhythmias and neurologic abnormalities (eg, facial nerve paralysis) related to meningoencephalitis. Last, pain and swelling may develop in large joints, sometimes progressing to chronic arthritis. The effects may persist for months. Prolonged therapy with antimicrobials such as doxycycline is prescribed. Herpes simplex encephalitis occurs occasionally and is dangerous, arising from the spread of herpes simplex virus type 1 (HSV-1) from the trigeminal nerve ganglion. This virus causes extensive necrosis and hemorrhage in the brain, often involving the frontal and temporal lobes. Early treatment with an antiviral drug, such as acyclo- vir, may control the infection. Otherwise, treatment is supportive. Amoebic meningoencephalitis can be caused by the amoeba Naegleria fowleri, which thrives in warm water and is typically found in the summer months in the southern United States. This is a rare infection that results in inflammation and swelling of the brain or spinal cord. Unless diagnosed and treated early, this infection is almost always fatal. The onset of a brain abscess tends to be insidious. Focal signs indicating neurologic deficits and increasing ICP develop. Both surgical drainage and antimicrobial therapy are required. The mortality rate is around 10%. Encephalitis Encephalitis is considered an infection of the parenchymal or connective tissue in the brain and cord, particularly the basal ganglia, although various viruses demonstrate an affinity for particular types of cells. The infection may include the meninges. Necrosis and inflammation develop in the brain tissue, often resulting in some permanent damage. Early signs of infection include severe headache, stiff neck, lethargy, vomiting, seizures, and fever. Encephalitis is usually of viral origin but may be related to other organisms. In some cases, there may be consider- able delay before signs appear. A few examples of specific diseases follow. Western equine encephalitis is an arboviral infection spread by mosquitoes, which occurs more frequently in the summer months and is common in young children. St. Louis encephalitis is found throughout the United States and affects older persons more seriously than younger ones. West Nile fever is a form of encephalitis that originated in the northeastern United States but has now spread to a number of states across the country and into Canada. It is caused by a flavivirus, spread by mosquitoes, with certain birds as an intermediate host. The focus for control has been to track the spread and reduce the risk of mosquito bites in affected areas. The infection initially causes flulike symptoms with low-grade fever and headache, sometimes followed by confusion and tremors. Neuroborreliosis (Lyme disease) is caused by a spiro- chete, Borrelia burgdorferi, transmitted by tick bites in FIG. 14.16 Early brain abscess. (From Damjanov I, Linder J: Anderson’s Pathology, ed 10, St. Louis, 1996, Mosby.) THINK ABOUT 14.11 a. List the signs of developing meningitis. b. Describe the changes that occur in the CSF with meningitis. c. What are the causes of death in meningococcal infection? d. Why does an abscess cause focal signs, whereas meningitis does not? Other Infections Many other microorganisms specifically target the central or peripheral nervous systems. Brief descriptions of several of the diseases they cause are given here. Rabies (hydrophobia) is caused by a virus that is transmitted by the bite of a rabid animal. The virus travels along peripheral nerves to the CNS, where it causes severe inflammation and necrosis, particularly in the brain stem and basal ganglia. The incubation period (often 1 to 3 months) depends on the distance between the bite and access to the CNS. Onset is marked by headache and fever; nervous hyperirritability, including sensitivity to touch; and seizures. The virus also travels to the salivary glands. Difficulty swallowing, caused by muscle spasm, and foaming at the mouth are typical. Respiratory failure causes death. Immediate cleansing of CHAPTER 14 Nervous System Disorders 353 vidarabine have provided some relief from symptoms. The vaccine Zostavax has been available since 2006 and is the only shingles vaccine approved for use in the United States. It has proved to reduce the risk of developing shingles by 51% and is recommended for persons aged 60 and older. Postpolio Syndrome Postpolio syndrome (PPS) has been occurring 10 to 40 years after recovery from the original infection, with progressive and debilitating fatigue, weakness, pain, and muscle atrophy. It is estimated that 25% to 50% of individuals infected with polio will develop PPS. Symptoms have developed in individuals who, as young children in the 1950s and earlier, were diagnosed with mild forms as well as paralytic forms of polio, and in those who were misdiagnosed at the time but are now considered to have been infected. The more severe the original infection was, the more severe the effects of PPS. The syndrome does not appear to be a recurrence of latent infection, but the precise basis for the neuronal damage has not been determined. It appears that surviving motor neurons have now degenerated and died, possibly because they developed new additional axon branches to serve muscle cells as compensation for damage but could not maintain them. Reye’s Syndrome ■ Pathophysiology The cause of Reye’s syndrome has not yet been fully determined, but it is linked to a viral infection, such as influenza, in young children that have been treated with aspirin (ASA). Depending on the particular virus, signs appear 3 to 5 days after the onset of the viral infection. The number of cases has decreased with awareness of this potential danger, and acetaminophen is now used to treat fever in children. The major pathologic changes occur in the brain and the liver. A noninflammatory cerebral edema develops, leading to increased ICP. Brain function is severely impaired by cerebral edema and the effects of high ammonia levels in serum related to liver dysfunction. The liver enlarges, develops fatty changes in the tissue, and progresses to acute failure. Jaundice is not present, but serum levels of liver enzymes are elevated. The resul- tant metabolic abnormalities include hypoglycemia and increased lactic acid in the blood and body fluids, which also contribute to acute encephalopathy. In some cases, the kidneys are also affected by fatty degenerative changes, leading to increases in serum urea and creatinine levels. ■ Signs and Symptoms Manifestations vary in severity. Encephalopathy initially causes lethargy, headache, and vomiting, which are quickly followed by disorientation, hyperreflexia, hyper- ventilation, seizures, stupor, or coma. the bite area and prophylactic immunization are necessary treatments. Tetanus (lockjaw) is caused by Clostridium tetani, a spore-forming bacillus. The spores can survive for years in soil. The vegetative form is an anaerobe, thriving deep in tissues, for example, in a puncture wound. The exotoxin enters the nervous system, causing tonic muscle spasms. Symptoms of infection include jaw stiffness, difficulty swallowing, stiff neck, headache, skeletal muscle spasm, and eventually respiratory failure. The mortality rate is 50%. An antitoxin is available to counter the effects of the tetanus toxin and mechanical respiration (such as a ventilator) is often required. Immunizations are advised, with boosters as needed or after injury. Poliomyelitis (infantile paralysis) is now rare in North America because of immunization but still occurs in other parts of the world. An immunization program is under way to combat an epidemic occurring in West and Central Africa, where large numbers of young children have been infected and threatened with paralysis. The goal of the World Health Organization (WHO) is worldwide eradication through immunization. The poliovirus is highly contagious through direct contact or oral droplet. It reproduces in lymphoid tissue in the oropharynx and digestive tract; it then enters the blood and, eventually, the CNS. The virus attacks the motor neurons of the spinal cord and medulla, causing minor flulike effects in many cases, but paralysis and respiratory failure in other cases, depending on the level of the destruction. Symptoms include fever, headache, and vomiting, followed by the typical stiff neck, pain, and flaccid paralysis. Other microorganisms, such as Candida albicans or Toxoplasma gondii, may cause infection in the brain, most often in immune-suppressed individuals. Infection-Related Syndromes Herpes Zoster (Shingles) Herpes zoster or shingles is caused by varicella-zoster virus (VZV) in adults. It is seen years after the primary infection of varicella or chickenpox, which usually occurs in childhood. Shingles usually affects one cranial nerve or one derma- tome, a cutaneous area innervated by a spinal nerve (see Fig. 14.22 for dermatomes, presented later) on one side of the body. Pain, paresthesia, and a vesicular rash develop in a line, unilaterally. This may occur on the face (eg, following the trigeminal nerve) or along the path of a lumbar nerve from the spine extending around one side in the hip area. The lesions persist for several weeks and then clear in the majority of cases. In some cases, particularly in older individuals, neuralgia or pain continues after the lesions disappear. In patients with immune deficiencies, the lesions tend to spread locally. Visual impairment has resulted from involvement of the ophthalmic division of the trigemi- nal nerve. Antiviral medications such as acyclovir or 354 SECTION III Pathophysiology of Body Systems period are essential to maximize restoration of function. About 30% of patients experience some degree of residual weakness. Brain Injuries Brain injuries may involve skull fractures, hemorrhage and edema, or direct injury to brain tissue. An injury may be mild, causing only bruising of the tissue, or it can be severe and life threatening, causing destruc- tion of brain tissue and massive swelling of the brain. The skull protects the brain but can also destroy it by means of bone fragments that penetrate or compress the brain tissue and by its inability to expand to relieve pressure. Types of Head Injuries Various terms are used to classify and describe brain trauma, in some cases with overlap, as follows: • Concussion, also termed mild traumatic brain injury (MTBI), is a reversible interference with brain function, usually resulting from a mild blow to the head, which causes sudden excessive movement of the brain, disrupting neurologic function and leading to loss of conscious- ness. Amnesia, or memory loss, and headaches may follow a concussion, but recovery with no permanent damage usually occurs within 24 hours. Recurrent concussions have been shown to cause progressive and permanent brain damage; thus at-risk individu- als may need to change activities to prevent further damage. • Contusion is a bruising of brain tissue with rupture of small blood vessels and edema that usually results from a blunt blow to the head. The possibility of residual damage depends on the force of the blow and the degree of tissue injury. • Closed head injury occurs when the skull is not fractured in the injury, but the brain tissue is injured and blood vessels may be ruptured by the force exerted against the skull (Fig. 14.17). Extensive damage may occur when the head is rotated with considerable force. • Open head injuries are those involving fractures or penetration of the brain by missiles or sharp objects. • Linear fractures are simple cracks in the bone. • Comminuted fractures consist of several fracture lines but may not be complicated. • Compound fractures involve trauma in which the brain tissue is exposed to the environment and is likely to be severely damaged because bone fragments may penetrate the tissue and the risk of infection is high. • Depressed skull fractures involve displacement of a piece of bone below the level of the skull, thereby compressing the brain tissue. With this type of fracture, the blood supply to the area is often impaired, and considerable pressure is exerted on the brain. • Basilar fractures occur at the base of the skull and are often accompanied by leaking of CSF through the ears ■ Treatment. There is no immediate cure. Treatment is supportive and symptomatic, managing the metabolic imbalances and cerebral edema. The mortality rate is high if diagnosis and treatment are not initiated quickly. Average mortality is 30%, and neurologic damage is possible. Guillain-Barré Syndrome Guillain-Barré syndrome is also known as postinfectious polyneuritis, acute idiopathic polyneuropathy, and acute infectious polyradiculoneuritis. The syndrome is an inflammatory condition of the peripheral nervous system. ■ Pathophysiology The precise cause of Guillain-Barré is unknown, but evidence indicates that an abnormal immune response, perhaps an autoimmune response, precipitated by a preceding viral infection or immunization, may be responsible. Local inflammation, accompanied by accu- mulated lymphocytes, demyelination, and axon destruc- tion, occurs. These changes cause impaired nerve conduction, particularly in the efferent (motor) fibers, although afferent (sensory) and autonomic fibers may also be involved. If the cell body remains alive through the acute period, the axon can regenerate. Initially the inflammatory and degenerative processes affect the peripheral nerves in the legs; then the inflammation ascends to involve the spinal nerves to the trunk and neck and frequently includes the cranial nerves as well. The critical period develops when the ascending paralysis involves the diaphragm and respiratory muscles. Recovery is usually spontaneous with the manifestations diminish- ing in reverse order; that is, motor function is regained first in the upper body and then gradually improves in the trunk and the lower extremities. ■ Signs and Symptoms Progressive muscle weakness and areflexia, beginning in the legs, lead to an ascending flaccid paralysis, which may be accompanied by paresthesia, or pain and general muscle aching. As paralysis advances upward, vision and speech may be impaired. This process may occur rapidly over a few hours or several days. If swallowing and respiration are affected, a life-threatening situation develops. Many patients sustain autonomic nervous system impairment, manifested as cardiac arrhythmias, labile (fluctuating) blood pressure, or loss of sweating capability. ■ Treatment Treatment is primarily supportive, and a ventilator is required in many cases. The use of immunoglobulin therapy or plasmapheresis, in which IgG is separated and removed from the patient’s blood, in the early stage may shorten the acute period of the disease in some patients and hasten recovery. Physiotherapy, occupational therapy, and respiratory therapy throughout the recovery CHAPTER 14 Nervous System Disorders 355 which the skull and brain hit a solid object, which causes the brain to rebound against the opposite side of the skull, usually causing minor damage. ■ Pathophysiology Primary brain injuries are direct injuries, such as lacera- tions or crushing of the neurons, glial cells, and blood vessels of the brain. or nose. These fractures may occur when the forehead hits a car windshield with considerable force. Cranial nerve damage and dark discoloration around the eyes are common. • Contrecoup injury occurs when an area of the brain contralateral to the site of direct damage is injured as the brain bounces off the skull. This injury may be secondary to acceleration or deceleration injuries, in Depressed fracture Bone fragments penetrate brain Open Injury Closed Injury — Direct and Contrecoup Injuries Impact Rebound of skull Contrecoup injury — brain hits skull Direct injury A B Bleeding and edema FIG. 14.17 Types of head injury—closed and open. 356 SECTION III Pathophysiology of Body Systems vessels, either immediately after the injury or after some delay (Fig. 14.19). Hematoma may also develop after surgery. Hematomas and hemorrhages are classified by their location in relation to the meninges, as follows: • Epidural (extradural) hematoma results from bleeding between the dura and the skull, usually caused by tearing of the middle meningeal artery in the temporal region. Signs of trouble usually arise within a few hours of injury, when the person loses consciousness after a brief period of responsiveness. • Subdural hematoma develops between the dura and the arachnoid (Fig. 14.20). Frequently there is a small tear in a vein, which causes blood to accumulate slowly. A hematoma may be acute (signs present in about 24 hours) or subacute (increasing ICP develops over a week or so). A chronic subdural hematoma may occur in an elderly person, in whom brain atrophy allows more space for a hematoma to develop. Also, a tear in the arachnoid can allow CSF to leak into the subdural space (hygroma), creating additional pressure. • Subarachnoid hemorrhage occurs in the space between the arachnoid and pia and is associated with traumatic Primary injuries may involve a laceration or com- pression of brain tissue by a piece of bone or foreign object or rupture or compression of the cerebral blood vessels. Because the brain is not held tightly in place, the application of unusual force may rotate or shift it inside the skull. The brain tissue may be damaged by the rough and irregular inner surface of the skull or by the movement of the lobes of the brain against each other (shearing injury). Any trauma to the brain tissue causes loss of function in the part of the body controlled by that specific area of the brain. Cell damage and bleeding lead to inflammation and vasospasm around the site of the injury, increased ICP and further general ischemia and dysfunction (Fig. 14.18). After the bleeding and inflammation subside, some recovery of the neurons in the area surrounding the direct damage may occur. The central area of damage undergoes necrosis and is replaced by scar tissue or a cyst. Secondary injuries result from the additional effects of cerebral edema, hemorrhage, hematoma, cerebral vaso- spasm, infection, and ischemia related to systemic factors. Secondary brain damage is caused by the development of additional injurious factors. A hematoma is a collection of blood in the tissue that develops from ruptured blood POSSIBLE EFFECTS OF HEAD INJURY TRAUMA PRIMARY DAMAGE (direct) Tissue damage and bleeding Edema and minor bleeding Tissue damage and bleeding SECONDARY DAMAGE BLEEDING INFLAMMATION AND EDEMA HEMATOMA POSSIBLE INFECTION INCREASED INTRACRANIAL PRESSURE Compress blood vessels ISCHEMIA AND NECROSIS Tissue compressed by bone Tissue lacerated by bone fragment Rotation of brain and shearing of tissue Additional contrecoup injury PLUS Compress brain stem LOSS OF VITAL FUNCTIONS Respiratory and cardiovascular controls SKULL FRACTURE CONTUSION BRAINMOTION FIG. 14.18 Possible effects of head injury. CHAPTER 14 Nervous System Disorders 357 may precipitate cerebral vasoconstriction (vasospasm), leading to further ischemia and more damage to the neurons. Other factors that may cause secondary brain damage include infection, which is usually a significant risk in persons with open head injuries, and hypoxia, which is related to systemic injury or shock. Respiratory or car- diovascular impairment may cause additional ischemia in the brain. ■ Etiology A majority of head injuries occur in young adults as a result of sports injuries and accidents involving cars or motorcycles. In many of these accidents, excessive alcohol intake is a contributing factor. Unfortunately, a high blood alcohol level can impede neurologic assessment by masking the signs of injury. Alcohol, because of its dehydrating effects, tends to delay the onset of cerebral edema and elevation of ICP, but there may be a greater increase in ICP at a later time. Other systemic injuries, such as a chest injury or shock, can have the same effect. Falls are a common cause of head injury in any age group, but they occur more often in elderly persons. Boxers and other athletes engaged in contact sports are at risk for repeated head injury. There has been increased attention placed on head injuries that occur in American football players. Clinical studies have been identifying an assortment of neurologic problems being experienced by retired players who received concussions during their playing years. Infants, when violently shaken, can experi- ence severe damage to the brain and brain stem as the head swings. Other injuries may involve objects that fall on the head or a blow to the head. bleeding from the blood vessels at the base of the brain. Because the blood mixes with circulating CSF, a localized hematoma cannot form. • Intracerebral hematoma results from contusions or shearing injuries and may develop several days after injury. In all types of hematomas, the bleeding leads to local pressure on adjacent tissue and a general increase in ICP. Blood may be partially coagulated, forming a solid mass. When the blood accumulates slowly, the blood cells undergo hemolysis. The fluid in this area of cell breakdown exerts osmotic pressure, drawing more and more water into the area, increasing the size and pres- sure of the mass, and raising the ICP. Herniation may result from an untreated mass. Any bleeding in the brain Dura Dura EXTRADURAL OR EPIDURAL HEMATOMA Blood fills space between dura and bone A B C SUBDURAL HEMATOMA Blood fills space between dura and arachnoid TYPES OF HEMATOMAS AND THE MENINGES INTRACEREBRAL HEMATOMA Skull bone Dura Subdural space Arachnoid Subarachnoid space Pia Brain FIG. 14.19 Types of hematomas. FIG. 14.20 Chronic subdural hematoma. Compression of underlying brain and lateral ventricle. (From Perkins GD, Atlas of Colorful Neurology, ed 3, Philadelphia, 2011, Saunders.) 358 SECTION III Pathophysiology of Body Systems THINK ABOUT 14.12 a. Differentiate an open head injury from a closed head injury in terms of appearance and effects. b. Describe the location, common source, and time of development of a subdural hematoma. c. Describe three significant signs of an injury to the right occipital lobe, including one specific focal sign and two general signs. ■ Signs and Symptoms The person with a head injury manifests the charac- teristic focal signs and the general signs of increased ICP. In addition, one or more of the following may develop: • Seizures, which are often focal but may be generalized, occur because of the irritating quality of blood. • Cranial nerve impairment may occur, particularly in persons who have sustained basilar fractures. • Otorrhea or rhinorrhea (leaking of CSF from the ear or nose, respectively) occurs with fractures and tearing of the meninges, which allows fluid to pass out of the subarachnoid space. This type of trauma provides microbes with an entry point into the brain. • Otorrhagia is blood leaking from the ear through a fracture site with torn vessels and meninges. • Fever may be a sign of hypothalamic impairment or of cranial or systemic infection. • Stress ulcers may develop from increased gastric secretions. If the individual is unconscious for a prolonged period of time, other problems may develop. Immobility may cause complications such as pneumonia or decubitus ulcers (see Chapter 25). ■ Treatment CT and MRI scans are useful in determining the extent of brain injury. Glucocorticoid agents, which decrease edema, and antibiotic agents, which reduce the risk of infection, are helpful. Surgery may be necessary to reduce ICP. Blood products and oxygen may be administered to protect the remaining brain tissue. Any other injuries must be treated promptly, particularly if they interfere with respiration or circulation. Individuals with brain injuries may be examined and discharged from the hospital if no brain damage is appar- ent. The person’s family or friends are usually asked to continue to perform a simplified head injury assessment for the next day or so to detect delayed hematoma forma- tion. This routine involves awakening the person periodi- cally to check the level of consciousness (ie, response to questions and orientation to time, place, and people), checking for reactive pupils, and watching for vomiting or any change in movement, sensation, or behavior. Headache, irritability, and fatigue are often present for a few days in persons with minor injuries. The prognosis for recovery from a brain injury is better now because of improved surgical techniques, monitoring devices, supportive rehabilitation, and drug therapies. Physiotherapy is used to increase mobility. Occupational therapy addresses motor, visual, and cognitive activity, whereas speech and language therapy address com- munication. There may be permanent residual damage in specific areas of the brain, resulting in motor or sensory deficits that may cause disability. Seizures, focal or generalized, are common sequelae because of the increased irritability of tissue around the scar. Often, general fatigue, frequent headaches, and memory loss are present for some time after recovery. Spinal Cord Injury Approximately 11,000 Americans experience spinal cord injuries each year, and 200,000 Americans live with ongoing disability due to spinal cord injury. Injury to the spinal cord usually results from fracture or dislocation of the vertebrae which compresses, stretches, or tears the spinal cord (Fig. 14.21). The supporting ligaments and the intervertebral disc may be damaged also. Most injuries occur in areas of the spine that provide more mobility but less support (ie, C1 to C7 and T12 to L2) (see Fig. 14.4). A few common types of injuries are described as follows: • Cervical spine injuries may result from hyperex- tension or hyperflexion of the neck, with possible fracture. Usually damage to the disc and ligaments occurs, leading to dislocation, loss of alignment of the vertebrae, and compression or stretching of the spinal cord. • Dislocation of any vertebra may crush or compress the spinal cord and compromise the blood supply. • Compression fractures cause injury to the spinal cord when great force is applied to the top of the skull or to the feet and is transmitted up or down the spine. Diving into an empty pool, jumping from a height and landing on the feet, or an object falling on a standing person’s head may cause this injury. The shattered bone is compressed and protrudes, exerting pressure horizontally against the cord. The sharp edges of bone fragments may lacerate or tear nerve fibers and blood vessels. • Spinal cord damage also may result directly from penetration injuries, such as stab or bullet wounds. Vertebral fractures may be classified as simple (single line break), compression (crushed or shattered bone in multiple fragments), wedge (a displaced angular section of bone), or dislocation (a vertebra forced out of its normal position). Because spinal cord injuries are often unstable, immedi- ate appropriate immobilization is essential to prevent secondary damage. CHAPTER 14 Nervous System Disorders 359 with any trauma, bleeding and inflammation develop locally, creating additional pressure and further interfering with blood flow. Edema and hemorrhage extend for several segments above and below the level of injury. In addition, damaged tissue releases mediators such as norepinephrine, serotonin, and histamine in the area. These mediators cause vasoconstriction, leading to additional local ischemia and possible necrosis. Destruc- tive enzymes are released as well, causing more inflam- mation and necrosis. Initially the loss of function may appear to be extensive because of this additional compression, but as the edema subsides, there may be partial recovery of function. Regular assessment of movement and sensory response using the dermatome map (Fig. 14.22) can determine the ■ Pathophysiology Damage to the spinal cord may be temporary or perma- nent. Nerves in the spinal cord do not undergo mitosis but axonal regrowth may occur. Laceration of nerve tissue by bone fragments usually results in permanent loss of conduction in the affected nerve tracts. Complete transec- tion (severing) or crushing of the cord causes irreversible loss of all sensory and motor functions at and below the level of injury. Partial transection or crushing injuries may allow recovery of some function. Bruising is reversible damage when mild edema and minor bleeding temporarily impair conduction of nerve impulses. Any compression of the cord must be relieved quickly to maintain adequate blood supply. Prolonged ischemia and necrosis lead to permanent damage. As A B HYPERFLEXION Torn posterior longitudinal ligament Distortion of cord HYPEREXTENSION Compression of cord by ligamentum flavum and disc Torn anterior longitudinal ligament C5Anterior dislocation COMPRESSION Compression fracture of L1 C5 C FIG. 14.21 Types of spinal cord injuries. (From Copstead LC: Perspectives on Pathophysiology, Philadelphia, 1995, Saunders.) 360 SECTION III Pathophysiology of Body Systems continue to conduct impulses through the level of damage (Fig. 14.23). ■ Etiology Most spinal cord injuries occur in young men, and around 50% result from motorcycle or automobile accidents. The second most common cause is sports (eg, diving, football). The other major cause of injury is falls, which elderly persons often experience. The average age for persons with SCI has increased over the past few years and now is 38 years. ■ Signs and Symptoms There are two stages in the posttraumatic period, the early stage of spinal shock and increasing impairment, followed by recovery and recognition of the extent of degree of damage or recovery in the spinal cord. When injury occurs in the cervical region, the inflammation may extend upward to the level of C3 to C5, interfering with phrenic nerve innervation to the diaphragm and therefore affecting respiration. Ventilatory assistance may be required. In the initial period after the injury, conduction of impulses ceases in the nerve tracts and in the gray matter, a period known as spinal shock (which is a form of neurogenic shock). The extent of the injury, the amount of resultant bleeding, and the need for surgical interven- tion determine the rate and degree of recovery. The inflammation gradually subsides, phagocytes remove damaged tissue, and scar tissue begins to form. During this period, reflex activity resumes in the spinal cord below the level of injury, and any undamaged tracts C-2 C-2 C-3 C-3 T-1 L-1 L-1 S-4 L-1 L-2 L-2 L-2 L-2 L-3 L-3 L-3 L-4 L-4 L-5 L-5 S-1 Beck C-4 C-4 T-2 T-3 T-4 T-5 T-6 T-8 T-9 T-10 T-11 T-12 S-3 S-3 C-5 C-5 C-7 C-6 C-7 C-6 C-6 L-5 S-1 S-1 S-2 C-8 C-8 T-7 T-2 T-3 T-6 T-12 T-1 Trigeminal nerve (V) FIG. 14.22 Dermatomes. (From Thibodeau GA: Anatomy and Physiology, St. Louis, 1987, Mosby.) CHAPTER 14 Nervous System Disorders 361 functional loss. During the initial period of spinal shock, all neurologic activity ceases at, below, and slightly above the level of injury (see Fig. 14.23). No reflexes are present, including the skeletal muscle, sensory, and autonomic systems (bladder and bowel function). This condition may persist for days or weeks. During the period of spinal shock, signs include flaccid paralysis and sensory loss at and below the injured area, an absence of all reflex responses, and loss of central control of autonomic func- tion. In patients with cervical injury, this includes loss of control of vasomotor tone, blood pressure, diaphoresis and body temperature, and bowel and bladder emptying. Blood pressure is low and labile. Urinary retention and paralytic ileus are present. Recovery from spinal shock is indicated by the gradual return of reflex activity below the level of injury. No impulses, including reflexes, can pass through the specific area of damaged neurons. In most cases, hyperreflexia develops, because the normal inhibitory, or “dampening,” impulses cannot reach the cord levels below the injury. Following recovery from spinal shock and the return of reflexes, spastic paralysis, sensory deficits, and reflex or neurogenic bladder and bowel function (urinary incon- tinence and reflex defecation) are present below the level of damage. Gradually the extent of permanent damage is revealed. For example, a check of the dermatome response can assess sensory function. Voluntary motor activity and sensory impulses are blocked at the level of damage. The specific effects of permanent damage depend on the level at which the spinal cord trauma occurred (see Figs. 14.4 and 14.23). For example, cervical injuries affect motor and sensory function in the arms, trunk, and legs; respira- tory function; SNS function (T1 to L2); and sacral parasympathetic fibers. In patients with cervical injuries, respiratory function may continue to be a matter of concern owing to phrenic nerve impairment and the loss of intercostal muscle innervation. Blood pressure and body temperature may be labile, because central control of vasomotor tone and diaphoresis is lacking. Paralysis of all four extremities is termed tetraplegia (quadriplegia), whereas paraplegia refers to paralysis of the lower part of the trunk and legs. Trauma in the lumbar region interferes with function in the lower extremities and the sacral parasympathetic nerves. Many injuries are incomplete, and the permanent effects vary considerably among individuals. Partial cord injuries can lead to different patterns of impairment, for example, ipsilateral paralysis and contralateral loss of pain and temperature sensation, depending on the point of decus- sation and the location of the specific injured tracts. With injury of the cervical spine, stimulation of the sympathetic system may result in autonomic dysreflexia (Fig. 14.24). This is a potentially serious complication caused by a sensory stimulus that triggers a massive BRAIN ALL FUNCTION NORMAL ABOVE LEVEL OF INFLAMMATION PHRENIC NERVE MAY BE IMPAIRED DURING SPINAL SHOCK (PERIOD IMMEDIATELY FOLLOWING INJURY) NO FUNCTION A B CERVICAL INJURY Inflammation Sensory stimulus blocked at spinal cord entry point NO SENSORY OR MOTOR IMPULSES NO REFLEXES • Flaccid paralysis • No sensation • Urinary retention • Paralytic ileus • Low labile blood pressure BRAIN ALL FUNCTION NORMAL ABOVE LEVEL OF INJURY OVERVIEW OF PERMANENT EFFECTS – POSTSPINAL SHOCK CERVICAL INJURY – TOTAL BLOCK NO SENSATION NO CENTRAL CONTROL OF SNS REFLEXES PRESENT NO VOLUNTARY CONTROL • Bladder and bowel incontinence NO VOLUNTARY MOVEMENT • Spastic paralysis of arms, trunk, legs BRAIN LUMBAR INJURY • No sensation or voluntary movement NORMAL FUNCTION IN UPPER BODY NO FUNCTION AT LEVEL OF INJURY REFLEXES PRESENT • Legs – spastic paralysis • Bowel and bladder incontinence FIG. 14.23 Effects of spinal cord damage. 362 SECTION III Pathophysiology of Body Systems prevent a stroke or heart failure. This means finding and removing the cause of the stimulus and administering medication to lower blood pressure. Complications are common after spinal cord injury because of immobility and loss of function (see Chapter 25). Contractures may develop from muscle spasms and decubitus ulcers are common; respiratory and urinary infections are frequent. Sexual function and reproductive capacity are likely to be affected. The sensory and psychological components of the sexual response are usually blocked by the injury. Men may have neurogenic reflex erections. Penetration depends on sustaining this reflex, which can be difficult. Brain Pons SPINAL CORD DAMAGE Sympathetic chain ganglia 7. VAGUS NERVE TO HEART BRADYCARDIA Medulla 1. STIMULUS – PAIN OR BLADDER DISTENTION 3. BLOCKED STIMULUS ACTIVATES SNS BELOW LESION 6. VASOMOTOR CENTER STIMULATES VAGUS NERVE (CRANIAL N X) TO SLOW HEART RATE 4. SNS OUTFLOW CAUSES SYSTEMIC VASOCONSTRICTION • High blood pressure • Headache • Visual problems 5. BARORECEPTORS SENSE HIGH BLOOD PRESSURE 8. INHIBITION OF SNS BLOCKED BY DAMAGE 9. MUST REMOVE CAUSE OF ORIGINAL STIMULUS TO LOWER BLOOD PRESSURE 2. STIMULUS ENTERS SPINAL CORD AND ASCENDS TO LEVEL OF DAMAGE FIG. 14.24 Autonomic dysreflexia following spinal cord damage. sympathetic reflex response that cannot be controlled from the brain. The trigger may be any noxious stimulus in the body but most frequently is a distended bladder or decubitus ulcer. A sensory stimulus to the SNS below the level of injury can stimulate the entire chain of SNS ganglia, leading to excessive vasoconstriction, with a sudden increase in blood pressure, severe headache, and visual impairment. Bradycardia accompanies this syn- drome as the baroreceptors sense the high blood pressure and respond through the vagus nerve by slowing the heart rate. Note that the excessive vasoconstriction cannot be reduced through the cardiovascular control center. Immediate resolution of this problem is necessary to CHAPTER 14 Nervous System Disorders 363 Many men, particularly those with high-level cord injuries, are infertile, because sperm production in the testes is impaired. Women usually resume menstrual cycles once they have recovered from the acute trauma period, and they can bear children. Close monitoring of the pregnancy is necessary, and vaginal delivery may be difficult. With counseling and supportive mates, many individuals with spinal cord injury can develop or maintain sexual relationships. ■ Treatment Assessment of damage is usually carried out using the American Spinal Injury Association (ASIA)* criteria: A = Complete: No motor or sensory function is pre- served in the sacral segments S4–S5 B = Incomplete: Sensory but not motor function is preserved below the neurologic level and includes the sacral segments S4–S5 C = Incomplete: Motor function is preserved below the neurologic level, and more than half of key muscles below the neurologic level have a muscle grade less than 3 D = Incomplete: Motor function is preserved below the neurologic level, and at least half of key muscles below the neurologic level have a muscle grade of 3 or more E = Normal: Motor and sensory function are normal. Treatment and rehabilitation begin at the time of the injury. Care must be taken to immobilize the spine, maintain breathing, and prevent shock. In the hospital, traction or surgery may be required to relieve pressure and repair tissues. Glucocorticoids such as methyl- prednisolone may be administered to reduce edema and stabilize the vascular system. Other injuries require prompt treatment to minimize secondary damage caused by decreased oxygen or circulation. Ongoing care is necessary to prevent the complications related to immobility. The leading cause of death now is pneumonia, rather than renal failure. Early, extensive rehabilitation is required to learn the best ways to use the remaining function, prevent complications, and maximize independence. A team of rehabilitation profes- sionals including occupational therapists, physiotherapists, respiratory therapists (for lesions at C4 and above), and psychotherapists can assist the patient with performance of the activities of daily living, ventilation, and other body needs. Advances in technology have provided myriad assistive devices, which can be tailored to the patient’s individual needs. With improved treatment and rehabilitation, persons with SCI are living much longer, adding the complications of aging to those of SCI. These include skin breakdown, respiratory problems, digestive and urinary tract THINK ABOUT 14.13 a. Compare the immediate and permanent effects on motor function of a lumbar spinal cord injury. b. Explain why micturition may not occur immediately after an injury (urinary retention), but urinary incontinence may develop later. c. Explain several reasons why a cervical injury is much more serious than a lumbar injury. d. Explain the cause of spinal shock and its effects. *From American Spinal Injury Association: International Standards for Neurological Classification of Spinal Cord Injury, reprint Chicago, Illinois. complications, and musculoskeletal problems such as carpal tunnel syndrome and torn rotator cuff. Congenital Neurologic Disorders Down syndrome is discussed in Chapter 21. Hydrocephalus ■ Pathophysiology Hydrocephalus is a condition in which excess cerebro- spinal fluid (CSF) accumulates within the skull, compress- ing the brain tissue and blood vessels. The condition is sometimes called “water on the brain.” Because the cranial sutures have not yet closed, the infant’s head enlarges beyond the normal size as the amount of fluid increases. Excess CSF accumulates because more is produced than is absorbed, often because of obstruction to the flow at some point. In the majority of cases, production of CSF is normal, but there is a reduction in the amount reab- sorbed. Most cases are apparent shortly after birth, but some may not be diagnosed until later in childhood. There are two types of hydrocephalus. Noncommunicat- ing or obstructive hydrocephalus occurs in babies when the flow of CSF through the ventricular system is blocked, usually at the aqueduct of Sylvius or the foramen magnum (Fig. 14.25). This condition usually results from a fetal developmental abnormality, such as stenosis or a neural tube defect. In many neonates, an associated myelome- ningocele or Arnold-Chiari malformation is present. The obstruction leads to increased back pressure of fluid in the ventricles of the brain, which gradually dilates or enlarges the ventricles and compresses the blood vessels and brain tissue. In the second type, communicating hydrocephalus, the absorption of CSF through the subarachnoid villi is impaired, resulting in increased pressure of CSF in the system. In neonates, the skull can expand to some degree in the early stages of hydrocephalus to relieve the pressure, but if the condition is not treated quickly, the brain tissue is permanently damaged. In older children and adults, intracranial pressure (ICP) increases more rapidly than in neonates, because the fused sutures of the skull prevent expansion to accom- modate the increased volume of CSF. The amount of 364 SECTION III Pathophysiology of Body Systems fontanelles bulge in the early stages of hydrocephalus. Recording head size is a standard procedure after birth and often is done during routine examinations. With the currently brief periods of hospitalization after childbirth, this measurement may not be taken, but it can provide a basic reference point if a problem is suspected. In the patient with hydrocephalus, scalp veins appear dilated and the eyes show the “sunset sign,” in which the white sclera is visible above the colored pupil. Pupil response to light is sluggish. The infant is lethargic but irritable and difficult to feed. A high-pitched or shrill cry often occurs when the infant is moved or picked up. The condition must be diagnosed and treated as soon as possible to minimize brain damage. In older children and adults, the head cannot enlarge and the classical signs of increased ICP develop as the volume of CSF expands. These may include decreased memory, difficulty in coordination, and impaired balance. Often urinary incontinence is present. Depending on the underlying cause, other manifestations may be present. ■ Diagnostic Tests A CT or MRI scan can locate the obstruction or abnormal flow and determine the size of the ventricles. ■ Treatment Surgery is usually performed to remove an obstruction or provide a shunt for CSF from the ventricle into the peritoneal cavity or other extracranial site, such as the right atrium of the heart. A shunt must be replaced as the child grows. Shunts are vulnerable to blockage or infection and thus require continued close monitoring to prevent further brain damage. brain damage that results depends on the rate at which pressure increases and the time that elapses before relief occurs. Brain damage may result in major physical dis- ability and intellectual impairment because all areas of the brain are affected. ■ Etiology Developmental abnormalities are the most frequent cause of hydrocephalus, particularly stenosis or atresia (the absence of a canal or opening) at the connecting channels between the ventricles or a thickened arachnoid membrane. Obstruction may also develop at any age from tumors, infection, or scar tissue. Meningitis can cause obstructive hydrocephalus during the acute infection or lead to fibrosis in the meninges, impairing absorption. ■ Signs and Symptoms The signs of increasing CSF depend on the age of the patient. In the neonate or young infant, in whom the sutures have not yet closed, the head can enlarge and the Compressed brain Enlarged ventricles Aqueduct of Sylvius blocked Dilated lateral ventricles Third ventricle Flow of CSF blocked here Ischemia and necrosis of brain tissue FIG. 14.25 Hydrocephalus. THINK ABOUT 14.14 a. Differentiate between communicating and noncommunicating hydrocephalus. b. Explain the effects of ventricular dilation. c. Explain why there are no focal signs of hydrocephalus in neonates. Spina Bifida Spina bifida refers to a group of neural tube defects that are congenital anomalies of varying severity. They are a common developmental defect, myelomeningocele occur- ring in an estimated 1500 to 2000 of the 4 million live births per year in the United States. The incidence rate varies in different countries, with the incidence in Canada being slightly higher than that in the United States. ■ Pathophysiology The neural tube develops during the fourth week of gestation, beginning in the cervical area and progressing toward the lumbar area. The basic problem in spina bifida is failure of the posterior spinous processes on the CHAPTER 14 Nervous System Disorders 365 anencephaly (absence of the cerebral hemispheres and superior cranial vault). Environmental factors include exposure to radiation, gestational diabetes, and deficits of vitamin A or folic acid. Folic acid supplements are recommended before conception and for the first 6 weeks of pregnancy as a preventive measure. Research has shown that such supplementation reduces the incidence rate of the disorder. ■ Signs and Symptoms Meningocele and myelomeningocele are visible as a protruding sac over the spine. In myelomeningocele, the extent of the neurologic deficit depends on the level of the defect (see Fig. 14.4) and the status of the nerve tissue; sensory and motor function at and below the level of the herniation is impaired. Some degree of muscle weak- ness or paralysis is present. Bladder and bowel control is usually impaired. Depending on the level of damage and the availability of reflex and sphincter control, there may be fecal and urinary incontinence. ■ Treatment Some surgical repair of spina bifida has been done suc- cessfully in utero before birth. Controversy continues about the timing of the surgical repair of the sac if done postnatally—whether it should take place immediately or be delayed. Rupture and infection are potential complications when repair is delayed. The decision regarding surgery also depends on the presence of other anomalies (abnormal structures) that may be present in the infant. After repair, ongoing assistance and occupa- tional and physical therapy are required to manage the neurologic deficits. Local community services and the Spina Bifida Association, which has many local chapters, provide continuing support for the parents and the child. Cerebral Palsy Cerebral palsy (CP) is a group of disorders marked by some degree of motor impairment, caused by genetic vertebrae to fuse, which may permit the meninges and spinal cord to herniate, resulting in neurologic impair- ment. Any number of vertebrae can be involved, and the lumbar area is the most common location. Three types of spina bifida are common (Fig. 14.26): • Spina bifida occulta develops when the spinous processes do not fuse, but herniation of the spinal cord and meninges does not occur. The defect may not be visible, although often a dimple or a tuft of hair is present on the skin over the site. The defect may be diagnosed by means of routine x-ray examination or when mild neurologic signs manifest owing to tension on the cord during a growth period. • Meningocele is the same bony defect, but herniation of the meninges occurs through the defect, and the meninges and CSF form a sac on the surface. Transil- lumination confirms the absence of nerve tissue in the sac. Neurologic impairment is usually not present, although infection or rupture of the sac may lead to neurologic damage. • Myelomeningocele is the most serious form of spina bifida. Herniation of the spinal cord and nerves along with the meninges and CSF occurs, resulting in con- siderable neurologic impairment (see Fig. 14.26C). The location and extent of the herniation determine how much function is lost. This defect is often seen in conjunction with hydrocephalus. ■ Diagnostic Tests Alpha-fetoprotein (AFP) that has leaked from the defect into the amniotic fluid surrounding the fetus results in an elevated level in maternal blood in a specimen obtained at 16 to 18 weeks’ gestation. Amniocentesis detects the presence of the elevated AFP, and the presence of spina bifida can also be diagnosed prenatally by ultrasound. ■ Etiology Spina bifida appears to have a multifactorial basis, with a combination of genetic and environmental factors contributing to its development. There is a high familial incidence of spina bifida and associated defects, such as Vertebra Spinal cord CSF Damaged nerves Meninges MyelomeningoceleMeningoceleSpina bifida occulta CSF Meninges Meninges A B C FIG. 14.26 Spina bifida. 366 SECTION III Pathophysiology of Body Systems or a child with some mobility walks with a typical scissors gait (ie, on the toes and with crossed legs). • The second group is dyskinetic disease, which results from damage to the extrapyramidal tract, basal nuclei, or cranial nerves. This form of cerebral palsy is mani- fested by athetoid or choreiform involuntary move- ments and loss of coordination with fine movements. • The third group, ataxic cerebral palsy, commonly develops from damage to the cerebellum and manifests as loss of balance and coordination. Spasticity is manifested by increased muscle tone or resistance to passive movement, with excessive reflex responses. Unilateral use of the hands or feet and asym- metric body movements are indications of abnormality. Writhing movements or facial grimaces may indicate athetoid cerebral palsy. Feeding difficulties and constant tongue thrusting are signs of motor dysfunction and may interfere with nutrition and growth. The position of the child’s limbs when resting or when held up is often unusual (eg, scissors position of the legs). In addition to the motor deficit, cerebral palsy may be accompanied by many other problems, which depend on the other areas of brain damage. A few common areas of dysfunction are as follows: • Intellectual function • Communication and speech • Seizures • Visual problems With regard to cognitive function, one-third of persons with cerebral palsy are considered to have normal intel- ligence, one-third are mildly impaired, and one-third are severely cognitively disabled. Communication and speech development are difficult because of motor disability, possible impaired mentation, mutations, abnormal fetal formation of functional brain areas, infection, or brain damage in the perinatal period. In addition, damage usually occurs in other areas of the brain, resulting in a clinical presentation that is highly variable, depending on the specific areas affected and the severity of the trauma. The damage may occur before, during, or shortly after birth and is nonprogressive. It is estimated that there are about 500,000 individuals with CP in the United States, with approximately 10,000 children developing CP each year. With improved treat- ment, rehabilitation, and education, many individuals with CP live into adulthood. ■ Pathophysiology Pathologically, the brain tissue is altered by malformation, mechanical trauma, hypoxia, hemorrhage, hypoglycemia, hyperbilirubinemia, infection, or some other factor, resulting in necrosis. In some cases, generalized necrosis and atrophy of brain tissue have occurred, whereas in other cases only one or two localized areas of the brain are affected. Although all children have some degree of altered mobility, which provides the basis for classifying cerebral palsy, an assortment of other problems is present in individual cases. ■ Etiology Single or multiple factors may be implicated in the development of cerebral palsy. Hypoxia or ischemia is the major cause of brain damage; it may occur prenatally, perinatally, or postnatally. Hypoxia may be caused by placental complications or a difficult delivery or by vascular occlusion, hemorrhage, aspiration, or respiratory impairment in the premature infant. High bilirubin levels, resulting from problems such as prematurity or Rh blood incompatibility, may cause kernicterus, in which accumu- lated bilirubin crosses the blood-brain barrier and damages the neurons. Other causes of cerebral palsy include infection or metabolic abnormalities, such as hypoglycemia, in either the mother or the child. ■ Signs and Symptoms In some cases the effects are evident at birth, whereas in others the delay in motor development or abnormal muscle tone does not become apparent for several months. Persistence of early reflexes, such as the Moro reflex, may indicate cerebral palsy. Cerebral palsy is classified either on the basis of area affected (eg, quadriplegia or diplegia) or on the basis of the motor disability that results (Table 14.9). Three major groups of motor disability have been identified: • The first and largest group includes those with spastic paralysis, which results from damage to the pyramidal tracts (diplegia) or the motor cortex (hemiparesis), or from general cortical damage (quadriparesis). As the name indicates, this form is characterized by hyper- reflexia (excessive reflex response). For example, crossed legs are apparent when the child is held up TABLE 14.9 Cerebral Palsy Type Percentage of Cases Area of Damage Effects Spastic 65%–75% Motor cortex or pyramidal tracts Paralysis Hyperreflexia and increased muscle tone Dyskinetic 20%–25% Basal nuclei or extrapyramidal tracts Loss of motor control and coordination Athetoid or choreiform movements Ataxic 5% Cerebellum Gait disturbance Loss of balance Mixed 13% All of above Some of each of above CHAPTER 14 Nervous System Disorders 367 and visual or hearing deficits. A number of children have learning disabilities and behavioral problems, such as attention deficit disorder, spatial disorientation, and hyperactivity. Seizures, primarily of the generalized tonic-clonic (grand mal) type, are common. Visual problems, such as astig- matism and strabismus, occur frequently. ■ Treatment Because each infant has a unique set of problems, indi- vidualized and immediate therapy is necessary. Early stimulation programs with a team of health professionals are helpful in encouraging motor skills, coordination, and intellectual development. Assessment and therapy by speech and language pathologists can assist parents in dealing with feeding and swallowing problems, positioning the child correctly, reducing the effects of tongue thrusting, and encouraging communication. Physical therapy is essential to maximize physical development. Regular exercise therapy and use of devices such as braces can improve mobility and reduce deformi- ties. A program called Medek (Cuevas MEDEK Exercises [CME]) is a therapeutic exercise program offered by trained professionals to some infants and young children with developmental problems involving skeletal muscle, particularly hypotonia. This is a strenuous program of repetitive exercises designed to promote strength, mobility, and independence. No devices or machines are used. The program may be offered in private clinics or combined with traditional therapies, which are required for older children. Family members can be trained to provide regular exercise and thus reduce the incidence of complications. Occupational therapy works with the child to maximize hand function, teach the use of adaptive devices, and facilitate the development of skills associated with normal development and academic work, as well as providing adaptive devices to maximize mobility and independence. Specialists in early education for developmentally handicapped children can work with the child and the family to develop and maximize motor skills, eye-hand coordination, and reflex responses. As the child develops, simple exercises can be instituted to help him or her learn to recognize familiar objects or sounds, associating cause with effect, and identifying likes and dislikes. Appropriate medication to control seizures prevents complications. Hearing and vision require monitoring in the early stages, and some form of communication must be developed as soon as possible. Many new devices and techniques are now available to promote communication. Technologic advances, including computers, provide aids for a variety of problems and enable many individuals to live more independently and develop individual interests and skills. In a lot of areas, children with cerebral palsy are being integrated into mainstream classes in schools and other activities. THINK ABOUT 14.15 a. Compare Down syndrome (see Chapter 21) and cerebral palsy with regard to cause and effects on motor and cognitive abilities. b. Describe the factors that could interfere with communication in a child with cerebral palsy. c. Discuss how technology may provide accommodation for communication deficits. Seizure Disorders Seizures result from uncontrolled, excessive discharge of neurons in the brain. The activity may be localized or generalized. They have many possible causes. Seizure disorders are characterized by recurrent seizures, some- times called convulsions. It is estimated that 3 million to 6 million affected individuals exist in the United States. The onset occurs before age 20 in 75% of cases. Epilepsy is the old term for recurrent seizures, rarely used today because of the stigma once attached to the term. Seizure disorders are classified by their location in the brain and their clinical features, including characteristic EEG patterns during and between seizures. The inter- national classification of seizures is summarized in Box 14.1, a commonly accepted classification that incorporates current terminology and divides seizures into two basic categories, generalized and partial. Generalized seizures have multiple foci or origins in the deep structures of both cerebral hemispheres and the brain stem and cause loss of consciousness, whereas partial seizures have a single or focal origin, often in the cerebral cortex, and may or may not involve altered consciousness. However, partial seizures may progress to generalized seizures. Seizures may be primary (idiopathic) or secondary (acquired) with an identified cause, such as posttraumatic stress syndrome. Seizures can be categorized on other grounds because they may result from an abnormality in the brain or from systemic causes, such as hypoglycemia or withdrawal from certain drugs. They may be a tem- porary problem, such as febrile seizures in an infant, or they may be chronic and frequent. An individual can have more than one type of seizure. For example, absence seizures, which are common in children, may decrease or be replaced by tonic-clonic or psychomotor seizures. Common types of seizures are described in the section on signs and symptoms. ■ Pathophysiology A seizure results from a sudden, spontaneous, uncon- trolled depolarization of neurons, which causes abnormal motor or sensory activity and possibly loss of conscious- ness. The neurons in the epileptogenic focus are hyper- excitable and have a lowered threshold for stimulation. Any physiologic change, such as alkalosis or other sensory 368 SECTION III Pathophysiology of Body Systems are more common now because improved treatment of these primary conditions has led to a higher survival rate. A seizure may be initiated by a tumor, infection, or hemorrhage in the brain, or by a high fever in an infant or young child (febrile seizure). Some systemic disorders, such as renal failure or hypoglycemia, may precipitate a seizure in an individual who has no previous history of seizures. Sudden withdrawal from sedatives or alcohol can precipitate seizures as well as drugs such as cocaine. Precipitating factors, or triggers, of an individual seizure may include physical stimuli, such as loud noises or bright lights, or biochemical stimuli, such as stress, excessive premenstrual fluid retention, hypoglycemia, change in medication, or hyperventilation (alkalosis). Awareness and avoidance of the potential precipitating factors in an individual can reduce the frequency of seizures. The medical history should be updated fre- quently to note changes in precipitating factors and the type of seizure. ■ Signs and Symptoms ■ Generalized Seizures. Absence (petit mal) seizures are generalized seizures that are more common in children than adults, beginning about age 5. The seizure lasts for 5 to 10 seconds and may occur many times during the day. There is a brief loss of awareness and sometimes transient facial movements, such as twitches of the eyelids or lip smacking. Usually the child simply stares into space for a moment and then resumes the activity previously pursued. No memory of the episode is retained. Tonic-clonic (grand mal) seizures are generalized seizures that may occur spontaneously or after simple seizures. There is a pattern for this type of seizure, which usually ends spontaneously: • Prodromal signs occur in some individuals, such as nausea, irritability, depression, or muscle twitching some hours before the seizure. • An aura, such as a peculiar visual or auditory sensation, immediately precedes the loss of consciousness in many persons. • Loss of consciousness occurs, and the individual falls to the floor. • Strong tonic muscle contraction, resulting briefly in flexion, is followed by extension of the limbs and rigidity in the trunk (ictal phase). • A cry escapes as the abdominal and thoracic muscles contract, forcing air out of the lungs. The jaws are clenched tightly, and respiration ceases. • The clonic stage follows, in which the muscles alter- nately contract and relax, resulting in a series of forceful jerky movements that involve the entire body. Increased salivation (foaming at the mouth) and bowel and bladder incontinence may occur. • Contractions gradually subside spontaneously in several minutes; the body is limp and consciousness slowly returns. stimulus—for example, flashing lights—can easily activate the “irritable” neurons. These focal cells stimulate the surrounding normal cells, spreading the activity. There are various theories about the specific mechanism for seizure activity, including altered permeability of the neuronal membrane, reduced inhibitory control of neurons, or a transmitter imbalance. Each seizure lasts for a few seconds or minutes, and the excessive activity of the neurons then ceases spontane- ously. The altered pattern of electrical activity, or brain waves, during a seizure can be demonstrated on an EEG, indicating the type of seizure and its focus. Also, observa- tion and description of the seizure by bystanders, par- ticularly its initial effects, is useful in identifying the origin or focus of the seizure. Complications may arise from generalized tonic-clonic (grand mal) seizures that are severe and frequent. Injuries of varying type and severity may occur during a seizure. Recurrent or continuous seizures without recovery of consciousness are termed status epilepticus. This condition may lead to serious consequences if it is not treated promptly. Respiration is impaired during a generalized tonic-clonic seizure and skeletal muscle activity is intense; the combination of these events in status epilepticus can lead to severe hypoxia, hypoglycemia, acidosis, and decreased blood pressure, potentially resulting in brain damage. ■ Etiology Many seizure disorders are idiopathic. To date, four genes have been identified as having a role in seizure disorders. Familial incidence is more evident in young children. Children with congenital disorders, such as cerebral palsy, may have seizures resulting from the brain damage. Acquired seizures that occur after head injury or infection I. Partial seizures (focal) a. Simple 1. Motor (includes jacksonian) 2. Sensory (eg, visual, auditory) 3. Autonomic 4. Psychic b. Complex (impaired consciousness) 1. Temporal lobe or psychomotor c. Partial leading to generalized seizures II. Generalized (both hemispheres affected with loss of consciousness) a. Tonic-clonic (grand mal) b. Absence (petit mal) c. Myoclonic d. Infantile spasms e. Atonic (akinetic) f. Lennox-Gastaut syndrome (febrile seizures) III. Unclassified BOX 14.1 Classification of Seizures CHAPTER 14 Nervous System Disorders 369 (perceiving strange surroundings as familiar) occur. The person is unresponsive to people or activities during the seizure, and afterward he or she is amnesic and drowsy. ■ Diagnostic Tests A detailed medical history and description of the seizure is required. An EEG will determine the type and location of the seizure. An MRI can detect any structural abnormal- ity in the brain. ■ Treatment Any primary cause should be treated, and the specific factors that precipitate seizures should be identified and avoided. Anticonvulsant drugs, such as phenytoin (Dilantin), are prescribed to raise the threshold for neuronal stimula- tion and prevent seizures. A choice of anticonvulsant drugs is available to treat different types of seizures and for optimum control in an individual patient. In many cases, anticonvulsant drugs are combined with sedatives, such as phenobarbital, to allow a reduction in the dosage and side effects of the drugs, while simultaneously decreasing the occurrence of seizures. Phenobarbital increases liver enzyme activity and therefore may affect the dosage of other medications. Phenytoin may cause gingival hyperplasia (Fig. 14.27), which can cause dif- ficulty in maintaining good oral hygiene and create a cosmetic problem for the patient. Many anticonvulsant drugs reduce leukocyte counts, thus predisposing the patient to infection. Several drugs reduce blood-clotting capability. It is essential to continue medication as pre- scribed at set intervals and without omissions, because sudden withdrawal can cause more severe seizures or status epilepticus (prolonged or recurrent seizures), with its risk of brain damage. Once a seizure begins it cannot be stopped. Single episodes require no additional medical treatment unless • The person is confused and fatigued, with aching muscles, and falls into a deep sleep in this postictal period. EMERGENCY TREATMENT FOR SEIZURES 1. If possible, clear a space and gently place the person on the floor, positioning him or her on the side, cushioning the head, and loosening neckwear. 2. Move potentially harmful objects away from the patient. 3. Do not force a specific position or unduly restrain the person, which can cause injury. 4. Do not put anything in the person’s mouth. 5. When the seizure ends, offer reassurance and check breathing and patient orientation to surroundings. 6. If the seizure continues or immediately repeats, seek medical assistance. The person may remember the prodromal indications and occasionally the aura, but not the entire seizure (amnesia). Hypoxia is common at this time because of interference with respiration during the seizure and because some airway obstruction may be present, owing to excess saliva or tongue position. Also, the contracting muscles present an increased demand for oxygen during the seizure. Increased levels of lactic acid and carbon dioxide in the body fluids contribute to acidosis. Recurrent tonic-clonic seizures without full return to consciousness are termed status epilepticus and carry an increased risk of complications. ■ Partial Seizures. Simple partial or focal seizures arise from an epileptogenic focus, often related to a single area of damage in the cortex. They are manifested by repeated motor activity, such as jerking or turning the head or eye aside, jerky movements of a leg, or by a sensation such as tingling that begins in one area and may spread. Auditory or visual experiences, such as ringing in the ears or a sensation of light, may occur if the focus is in the related area. Memory and consciousness remain, although awareness is reduced. A Jacksonian seizure is a focal motor seizure in which the clonic contractions begin in a specific area and spread progressively; for example, the contractions “march” up the arm and then to the face. Children and adults may have temporal lobe or psycho- motor seizures, which are complex partial (unprovoked, focal) seizures that originate in the temporal lobes. They usually arise from the temporal lobe but may involve the limbic system or frontal lobe. Sometimes an aura is present, such as the perception of an odd odor. The seizure itself consists of bizarre behavior that is perhaps repetitive and purposeful but inappropriate—for example, waving or clapping the hands. Frequently visual or auditory hallucinations or feelings of déjà vu FIG. 14.27 An example of gingival hyperplasia associated with the medication phenytoin (Dilantin) used to treat seizures. (Courtesy of Evie Jesin, RRDH, BSe, George Brown College of Applied Arts and Technology, Toronto, Ontario, Canada.) 370 SECTION III Pathophysiology of Body Systems plaque varies in size, and several may coalesce into a single patch. The initial inflammation may subside, and neural function may return to normal for a short time, until another exacerbation occurs. In time neural degenera- tion becomes irreversible, and function is lost permanently. With each recurrence, additional areas of the CNS are involved. Multiple sclerosis varies in severity, occurring in mild and slowly progressive patterns in some individu- als and in rapidly progressive forms in others. ■ Etiology The onset of symptoms usually occurs in individuals between ages 20 and 40, with a peak at 30 years. The disease is more common in women by a 2 : 1 ratio. The cause is unknown, although many researchers believe it is an autoimmune disorder. However, it may be even more complex in its origins. Multiple sclerosis appears to have genetic, immunologic, and environmental com- ponents. Multiple sclerosis occurs more frequently in people of European descent, and there is an increased risk for close relatives of affected individuals. The envi- ronmental factors have not yet been determined, although it is thought that climate may play a role because the disease is more common in temperate zones (northern United States and Canada) and in individuals who grow up in temperate climates. However, there are exceptions to this factor, where MS occurs in warm climates. Viral infection and an abnormal immune response have also been suspected. ■ Signs and Symptoms The manifestations of MS are determined by the areas that are demyelinated in each individual (Fig. 14.29). Blurred vision is a common early sign. Initially weakness in the legs often occurs, resulting from plaques on the corticospinal tract. If the cranial nerves are affected, diplopia (double vision), scotoma (a spot in the visual the individual continues to be disoriented. Prolonged or recurrent seizures are life threatening and require hospital treatment with medications such as intravenous diazepam, oxygen, and fluids. During pregnancy, some women have an increased number of seizures. There is an increase in the incidence of congenital abnormalities in children born to mothers with seizure disorders; this is probably related to drug therapy. THINK ABOUT 14.16 a. Describe how a seizure develops in the brain tissue. b. Differentiate a partial seizure from a general seizure, and give an example of each. c. Describe factors that should be avoided if a patient has a history of seizures. d. List the sequence of events in a generalized tonic-clonic seizure. A B FIG. 14.28 A, Typical white matter changes around the ventricles shown on MRI in multiple sclerosis. B, Change in the spinal cord in multiple sclerosis. (From Perkin GD: Mosby’s Color Atlas and Text of Neurology, ed 2, London, 2002, Mosby.) Chronic Degenerative Disorders Multiple Sclerosis Multiple sclerosis (MS) involves a progressive demyelin- ation of the neurons of the brain, spinal cord, and cranial nerves. There are a number of types of MS, with consider- able variation in the effects, severity, and progression in any one individual. Multiple sclerosis is characterized by remissions and exacerbations, but nevertheless it is marked by progressive degeneration. Estimated incidence runs from 30 to 100 per 100,000 persons. It is the second most common cause of disability in the United States; motor vehicle accidents are the first. ■ Pathophysiology Loss of myelin interferes with the conduction of impulses in the affected fibers. It affects all types of nerve fibers— motor, sensory, and autonomic—and occurs in diffuse patches throughout the nervous system (Fig. 14.28). Research has shown that cognitive function can be impaired in the individual with MS, particularly with respect to attention to tasks and memory. The earliest lesion occurs as an inflammatory response as cells that normally do not enter the brain or spinal cord do so and attack neurons, with loss of myelin in the white matter of the brain or spinal cord. Research has identified a protein in the body’s blood clotting mechanism as a potential trigger of the immune response. Later larger areas of inflammation and demyelination, termed plaques, become visible, frequently beside the lateral ventricles in the brain, in the brain stem, and in the optic nerves. Initially the area of plaque appears pinkish and edematous, but then it becomes gray and firm. Each CHAPTER 14 Nervous System Disorders 371 activity of the brain in response to the stimulation of specific sensory pathways and can detect a slowing of conduction due to demyelination. Optical coherence tomography (OCT) is a relatively new imaging tool that can clearly show the retinal structures including the optic and retinal nerves. Because these nerves are often early targets of MS, their condition can indicate the damage caused by MS. ■ Treatment No specific treatment is available at this time, although new measures are always being investigated. Interferon beta-1b (Betaseron) appears to reduce the frequency and severity of exacerbations through its effects on the immune system. Glucocorticoid agents may help to control acute signs during exacerbations. Drugs to target the abnormal clotting proteins in the brain are being developed. Additional drugs may be prescribed as muscle relaxants or for other complications. The number of exacerbations can be reduced by avoiding excessive fatigue, stress, injury, or infection. Therapy includes physical therapy and exercise to maintain mobility. Occupational therapy is essential in assessing the need for and provision of adaptive devices to simplify work and reduce fatigue. Special problems, such as constipation or incontinence, require individual field), or dysarthria (poor articulation) may occur. Par- esthesias (areas of numbness, burning, or tingling) may develop if the sensory nerve fibers are damaged. As the number of plaques increases with each exacerbation, progressive weakness and paralysis extending to the upper limbs, loss of coordination, and bladder, bowel, and sexual dysfunction occur. Chronic fatigue is common. Sensory deficits include paresthesias and loss of position sense in the upper body, face, and legs. The clinical picture and mode of progression vary greatly among individuals. Later in the course of the disease, depression or euphoria may develop. Complications related to immobility, such as respiratory infection, decubitus ulcers, and contractures, are common as the disease progresses. ■ Diagnostic Tests There is no definitive test for multiple sclerosis, and a long delay may precede the diagnosis. A history of exacerbations and remissions, involvement of multiple focal areas, progression, and absence of other neurologic diagnostic criteria are often the basis for an initial diag- nosis of MS. Magnetic resonance imaging is used for diagnosis and monitoring and can detect multiple CNS lesions. CSF analysis can be used, as patients often have elevated protein, gamma globulin, and lymphocyte levels in the CSF. Visual evoked potential tests measure the CEREBELLUM Loss of balance Ataxia and tremor CRANIAL NERVE Diplopia Loss of vision MOTOR NERVE TRACTS Weakness Paralysis DAMAGE TO SENSORY NERVE TRACTS Paresthesia—prickling, burning sensation Demyelination Impaired function Functional FIG. 14.29 Multiple sclerosis—distribution of lesions. 372 SECTION III Pathophysiology of Body Systems Lewy bodies. Furthermore, these bodies contain an important natural and widespread protein called alpha- synuclein (A-synuclein), which researchers believe may be an important clue in finding the cause of the disease. Secondary Parkinsonism may follow encephalitis, trauma, or vascular disease. Drug-induced Parkinson’s disease is linked particularly to the use of phenothiazines (eg, chlorpromazine). The effects may be reversible or diminished when the drug is discontinued. ■ Signs and Symptoms Early signs include fatigue, muscle weakness, muscle aching, decreased flexibility, and less spontaneous change in facial expression. More obvious signs are tremors in the hands at rest and a repetitive “pill-rolling” motion of the hands. Tremors cease with voluntary movement and during sleep. As the disease advances, tremors affect the hands and feet, the face, tongue, and lips. Further motor impairment, increased muscle rigidity, difficulty in initiating movement, slow movements (bradykinesia), and a lack of associated involuntary movement occurs— for example, loss of arm-swinging when walking or spontaneous postural adjustments when sitting. The characteristic standing posture is stooped, leaning forward with the head and neck flexed (Fig. 14.30). Festination, or a propulsive gait (short, shuffling steps with increasing acceleration), occurs as postural reflexes are impaired, attention. Communication and interest must be main- tained by addressing issues such as visual impairment or speech disorders early in the course of the disease. Early intervention by a speech and language pathologist can maximize communication and assist with some feeding problems. As with any disabling condition, rehabilitation and psychosocial support are essential in maximizing function. THINK ABOUT 14.17 a. Relate the following early signs of multiple sclerosis to the location of plaques: diplopia, tremors in the legs, facial weakness. b. Relate the frequency of exacerbations to the progress of the disease. Parkinson’s Disease (Paralysis Agitans) Parkinson’s disease is a progressive degenerative disorder that affects motor function through loss of extrapyramidal activity. It is estimated that in the United States, 60,000 individuals are diagnosed with Parkinson’s disease each year and that as many as 1 million Americans have Parkinson’s disease. ■ Pathophysiology In Parkinson’s disease, dysfunction of the extrapyramidal motor system occurs because of progressive degenerative changes in the basal nuclei, principally in the substantia nigra. In this condition, a decreased number of neurons in the substantia nigra secrete dopamine, an inhibitory neurotransmitter, leading to an imbalance between excita- tion and inhibition in the basal nuclei. The excess stimula- tion affects movement and posture by increasing muscle tone and activity, leading to resting tremors, muscular rigidity, difficulty in initiating movement, and postural instability. Many patients with Parkinson’s disease have a reduced number of cortical neurons, which is charac- teristic of dementia. Diagnosis depends on the physical manifestations and clinical history. ■ Etiology Primary or idiopathic Parkinson’s disease usually devel- ops after age 60 and occurs in both men and women. Several genes have been identified in cases of familial Parkinson’s disease, but a common focus of research is the possible damaging effects of viruses or toxins on cells. Toxins that may be linked to Parkinson’s disease include manganese, carbon monoxide, carbon disulfide, and some pesticides. Recent research has focused on the mitochondrial changes in cells from patients with Par- kinson’s disease; these changes suggest periods of sig- nificant oxidative stress leading to the accumulation of free radicals within the cells. A new focus in Parkinson research also involves the presence of clumps of specific substances in the affected brain cells, which are called Stooped posture Rigidity Hips and knees slightly flexed Short, shuffling steps Tremor Masklike facies Arms flexed at elbows and wrists Tremor FIG. 14.30 Parkinson’s disease. (From Monahan FD, Drake T, Neighbors M: Nursing Care of Adults, Philadelphia, 1994, Saunders.) CHAPTER 14 Nervous System Disorders 373 Amyotrophic Lateral Sclerosis The name of this disease, amyotrophic lateral sclerosis (ALS), is indicative of the pathology: amyotrophic means “muscle wasting,” and sclerosis refers to the degenerative “hardening” of the lateral corticospinal tracts. The cause has not been identified, although a number of genes on various chromosomes have been linked to the disease. Ten percent of cases are considered familial. Most cases are random and do not reflect any ethnic trends in incidence. The disease is invariably fatal over time. The disease, also called Lou Gehrig disease, primarily affects individuals between the ages of 40 and 60, par- ticularly men. The overall prevalence rate is 3.9 per 100,000. Although the disease is not common, it has attracted public attention because there is no means of preventing the continuous and rapid decline of motor and respiratory function, whereas cognitive function remains intact. Amyotrophic lateral sclerosis has been the focus of debate by the public and legislative and medical groups regarding ethical issues surrounding euthanasia for patients with such diseases. ■ Pathophysiology Amyotrophic lateral sclerosis is a progressive degenerative disease affecting both upper motor neurons in the cerebral cortex and lower motor neurons in the brain stem and spinal cord. There is no indication of inflammation around the nerves. Studies have shown that supportive glial cells called astrocytes secrete a neurotoxin leading to the death of motor neurons. The loss of upper motor neurons leads to spastic paralysis and hyperreflexia; damage to lower motor neurons results in flaccid paralysis, with decreased muscle tone and reflexes. Sensory neurons, cognitive function, and cranial nerves III, IV, and VI to the eye muscles are not affected. The loss of neurons occurs in a diffuse and asymmetric pattern but proceeds without remission. Progressive muscle weakness eventually affects respiratory function. Although a specific diagnostic test has not been available to confirm the presence of the disease, many tests are required to eliminate other possible diagnoses. At present, a new test for specific biomarkers in CSF is under evaluation. Nerve conduction velocity tests and tests of muscle response to electrical stimulation are also used to evaluate the patient’s myoneural function. ■ Signs and Symptoms Initially in most cases, the upper extremities, particularly the hands, manifest weakness and muscle atrophy, with loss of fine motor coordination commencing with the distal fibers. Stumbling and falls are common. Muscle cramps or twitching may result from an imbalance of antagonistic muscles. The weakness and paralysis progress throughout the body. Dysarthria develops as the cranial nerves controlling speech are lost. Eventually swallowing and respiration are impaired, and a ventilator is required. leading to falls. Complex activities, such as getting up out of a chair, become slow and difficult. Other functions are affected as the voice becomes low and devoid of inflection (the person speaks in a quiet monotone) and dysarthria develops. Chewing and swal- lowing become difficult, prolonging eating time and causing recurrent drooling. The face of the patient resembles a mask, and blinking of the eyelids is reduced, resulting in a blank, staring face. Autonomic dysfunction is manifested in the later stages by urinary retention, constipation, and orthostatic hypotension. As orthostatic hypotension develops, the threat of falls increases. Urinary tract and respiratory infections are common complications. Dementia develops late in the course of the disease in 20% of affected persons. ■ Treatment Dopamine replacement therapy has been used to reduce motor impairment. Levodopa (L-dopa), a precursor of dopamine, is administered because dopamine itself does not cross the blood-brain barrier. Monoamine oxidase B (MOA-B) inhibitors, including selegiline (Eldepryl, Zelapar) and rasagiline (Azilect), are drugs that block the breakdown of L-dopa in the brain and have resulted in improvement for some individuals. Anticholinergic drugs, including benztropine (Cogentin) or trihexyphe- nidyl, are also helpful. Catechol-O-methyltransferase (COMT) inhibitors such as Entacapone (Comtan) mildly prolong the effect of levodopa therapy by blocking an enzyme that breaks down dopamine. Doctors may also prescribe amantadine to provide short-term relief of symptoms of mild, early-stage Parkinson’s disease. Several drugs are under investigation, as are new surgical pro- cedures and transplants of fetal dopamine-producing cells or adult stem cells. Drug treatment may also include the use of antidepressant drugs to deal with the depression that often develops as the disease progresses. Swallowing and speech impairments require early attention from a speech and language pathologist to maintain function as long as possible. Physical therapy is helpful in maintaining general mobility. Exercise that promotes the use of the arms and forceful movements is helpful. Occupational therapists work to improve balance, coordination, and safe use of adaptive devices. Constant monitoring and immediate treatment of respiratory and urinary tract infections can reduce the risk of damage to the organs involved. THINK ABOUT 14.18 a. Describe the pathophysiology of Parkinson’s disease. b. Describe three common manifestations that can be observed in a person with Parkinson’s disease. c. Explain why adequate nutrition and hydration may be difficult to maintain in a person with Parkinson’s disease. d. If adequate nutrition and hydration are not maintained, what potential complications may ensue? 374 SECTION III Pathophysiology of Body Systems • The head droops as the neck muscles become involved. • As the arms become weaker, it is difficult for the person to comb hair, brush teeth, or prepare and eat food. Muscle fatigue becomes more marked as the day progresses. • Upper respiratory infections occur frequently and tend to be prolonged, because it becomes more difficult to remove secretions. • Myasthenic crisis, which may occur when there is added stress—such as infection, trauma, or alcohol intake— involves an increase in weakness and fatigue, and respiratory impairment may develop. ■ Treatment • Anticholinesterase agents, pyridostigmine (Mestinon) or neostigmine (Prostigmin), may be used to tempo- rarily improve neuromuscular transmission. These agents prolong the action of ACh at the neuromuscular junction and facilitate eating and swallowing. • Glucocorticoids such as prednisone are effective in suppressing the immune system. • Immunosuppressants such as azathioprine (Imuran), mycophenolate mofetil (CellCept), cyclosporine (Sand- immune, Neoral), methotrexate (Trexall), or tacrolimus (Prograf) can also be used. • Plasmapheresis, a process that removes antibodies from the blood, may help temporarily. • Thymectomy may be helpful in reducing symptoms if hyperplasia or an adenoma is present. The long-term prognosis is increasing generalized weakness with eventual weakness of respiratory muscles. ■ Treatment At this time, no specific treatment is available to reverse the course of the degenerative process. Stem cell therapy is under investigation. The drug Rilutek (riluzole) has been developed to slow further damage to neurons; this can assist with maintaining swallowing and ventilation reflexes and is the only drug approved by the Food and Drug Administration (FDA) for treating ALS. A well- balanced program of moderate exercise and rest is helpful. Electronic communication devices are recommended for use relatively early in the course of the disease. A team approach to care can minimize the complications of immo- bility, sustain function as long as possible, and support the family. The team includes a respiratory therapist, nutritionist, speech pathologist, occupational therapist, physical therapist, psychologist, and social worker. In most cases respiratory failure occurs in 2 to 5 years, although some individuals survive for a longer period. Myasthenia Gravis Myasthenia gravis is an autoimmune disorder that impairs the receptors for acetylcholine (ACh) at the neuromuscular junction. The specific cause is not known, although many patients have thymus disorders, such as hyperplasia or benign tumors. Women are more frequently affected than men, and the age of onset is between ages 20 and 30 for women and greater than age 50 for men. ■ Pathophysiology In myasthenia gravis, IgG autoantibodies to ACh receptors form, blocking and ultimately destroying the receptor site, thus preventing any further stimulation of the muscle. This change leads to skeletal muscle weakness and rapid fatigue of the affected muscles. The facial and ocular muscles are usually affected initially, followed by the arm and trunk muscles. ■ Diagnostic Tests Several tests are available, including electromyogra- phy, to test for muscle fatigue, and an assay of serum antibodies. One test uses edrophonium chloride (Ten- silon), a short-acting anticholinesterase inhibitor, to prolong the action of ACh at the myoneural junction, resulting in a short period of increased skeletal muscle function. ■ Signs and Symptoms • Muscle weakness is noticeable in the face and eyes, and fatigue develops quickly when the muscles are being used. • Diplopia and ptosis impair vision • Speech becomes a nasal monotone. • Spontaneous facial expressions are lost, and the face appears to droop with sadness. Attempts to smile may result in what appears to be a snarl. • Chewing and swallowing become difficult as the weak- ness progresses and the risk of aspiration increases. THINK ABOUT 14.19 a. Explain why a person with myasthenia gravis might prefer a soft diet. List several potential complications of a continued soft diet. b. Describe how oral hygiene might be affected by myasthenia gravis. c. Compare the pathophysiology, significant early signs or symptoms, and course of amyotrophic lateral sclerosis, myasthenia gravis, multiple sclerosis, and Guillain-Barré syndrome Huntington’s Disease Huntington’s disease (HD), or Huntington chorea, is an inherited disorder that does not manifest until midlife. Maternal inheritance delays onset longer than inheritance from fathers. It has a prevalence of 5 per 100,000 people and affects all ethnic groups. It is estimated that 15,000 people have HD in the United States, and more than 150,000 individuals face a 50% chance of inheriting the disorder. ■ Pathophysiology Progressive atrophy of the brain occurs, with degenera- tion of neurons, particularly in the basal ganglia and the frontal cortex. The ventricles are dilated (Fig. 14.31). CHAPTER 14 Nervous System Disorders 375 With progressive degeneration, the following will occur: • Rigidity and akinesia, making any movement difficult • Personality changes • Moodiness • Behavioral disturbances that become more marked as dementia progresses ■ Diagnostic Tests The presence of the defective gene can be detected by DNA analysis. ■ Treatment No therapy is available to slow the progress of the disease. Symptomatic therapy, such as physiotherapy or tetra- benazine, a new drug approved in 2008, may reduce the choreiform movements and maintain mobility for a longer time. Other drugs may be used to treat behavior changes. In later stages the patient with HD requires significant supportive care for physical needs. Dementia There are many formal definitions of dementia, based on the following characteristics: • It is a progressive chronic disease, in which cortical function is decreased, impairing cognitive skills such as language and innumeracy, logical thinking and judgment, ability to learn new information, as well as motor coordination. • Loss of memory affects primarily short-term or recent memory but includes confusion about the events in long-term memory. Memory loss is often progressive, leading to long-term as well as short-term memory loss. • Behavioral and personality changes are usually present. These changes lead to inability to work and perform activities of daily living. Tests are available for a behavioral assessment and to distinguish between “normal forgetfulness” and memory loss related to dementia. For example, forgetful people can remember when clues are available, handle finances, and function independently. In a person with dementia, recall does not occur after being given clues, the day cannot be identified, calculations are difficult, and remind- ers are needed for meals and hygiene. There are many causes of dementia, including vascular disease (eg, arteriosclerosis), infections, toxins, and genetic disorders. Alzheimer’s disease accounts for more than 50% of those affected with dementia, with vascular causes of dementia in second place. Alzheimer’s Disease Approximately 10% of the population greater than 65 years of age has Alzheimer’s disease (AD), and this increases to over 25% in the age group greater than 85 years. Females are affected more than males. It is estimated that AD affects between 4.5 and 5.4 million Americans. There is depletion of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter in the basal nuclei and substantia nigra. Levels of ACh in the brain also appear to be reduced. ■ Etiology This condition is inherited as an autosomal-dominant trait (about a 50% probability of having an affected child) and is carried on chromosome 4. Until recently there were no diagnostic tests available to identify affected individuals before the onset of symptoms; therefore children with a high risk of inheritance were once born to affected parents before the disease was diagnosed in the parents. This combination of factors increased the incidence of the disorder. That trend is changing because testing and genetic counseling are available. However, in one in three newly diagnosed cases there is no record of family members with the disorder. ■ Signs and Symptoms The following observations are noted at the onset: • Mood swings and personality changes • Restlessness and choreiform (rapid, jerky) movements in the arms and face • Possibly early indications of intellectual impairment, such as difficulty learning new information, loss of problem-solving skills, poor judgment, inability to concentrate, and memory lapses B1 B2 A1 A2 FIG. 14.31 Huntington’s Disease. A, Coronal section of the brain shows a dilated lateral ventricle with caudate and lentiform atrophy on the left compared with a normal brain on the right. B, Reduced caudate blood flow shown on the left, compared to normal blood flow on the right, shown in single photon emission CT scan. (From Perkin GD: Mosby’s Color Atlas and Text of Neurology, ed 2, St. Louis, 2002, Mosby.) 376 SECTION III Pathophysiology of Body Systems In Alzheimer’s disease there is a progressive loss of intellectual function that eventually interferes with work, relationships, and personal hygiene. Personality changes, lack of initiative, and repetitive behavior and impairments in judgment, abstract thinking, and problem-solving abilities are characteristic of the disease. ■ Pathophysiology Typical changes in Alzheimer’s disease include progres- sive cortical atrophy, which leads to dilated ventricles, and widening of the sulci (Fig. 14.32). Neurofibrillary tangles in the neurons and senile plaques are found in large numbers in the affected parts of the brain. The plaques, which disrupt neural conduction, contain fragments NFT Amyloid A C B FIG. 14.32 Pathologic Changes in Alzheimer’s Disease. A, Amyloid plaques and neurofibrillary tangles. B, Comparison of normal and AD brains. Top, Normal brain. Bottom, Brain of a patient with Alzheimer’s disease. The AD brain shows gyral atrophy and sulcal widening greater than that seen in a person with no cognitive impairment. (From Naidich TP et al: Imaging of the Brain, ed 1, Philadelphia, 2013, Elsevier, Saunders.) from beta-amyloid precursor protein (βAPP); the role of this protein is a focus of research. Some neurofibrils and plaques have been found in the brains of elderly people whose cognitive function is not impaired, and therefore it appears that the numbers and distribution of the plaques are the significant factors. A deficit of the neurotransmitter ACh also occurs in the affected brain. No definitive diagnostic tests are available; the diag- nosis is based on observations and ruling out other possible causes. Progressive tests of memory are very helpful in making a probable diagnosis of AD. Some cases of dementia have been labeled Alzheimer’s disease and then later classified as another form of dementia. ■ Etiology The specific cause is unknown. At least four defective genes located on different chromosomes have been associated with AD. Three gene mutations on chromo- somes 1, 14, and 21 are inherited as autosomal dominant traits resulting in early onset AD. The genetic factor is also supported by the high incidence in older persons with Down syndrome (trisomy 21). One form of late onset AD has been linked to a mutation on chromosome 19. Other forms of Alzheimer’s disease appear to be multifactorial in origin. The National Institute on Aging has launched major research investigations into genetic and other suspected factors, including exposure to metals, viruses, and metabolic syndrome. ■ Signs and Symptoms There is less emphasis on differentiating the pathophysiol- ogy and signs of early versus late-onset disease. Several research projects are, however, focused on defining the signs at the time of onset and through the stages to determine the pattern of neurologic damage. Onset tends to be insidious. The course may extend over 10 to 20 years: • In the early stage, gradual loss of memory and lack of concentration become apparent. Ability to learn new information and to reason is impaired and behavioral changes, such as irritability, hostility, and mood swings, are common. • Cognitive function, memory, and language skills continue to decline. Problem solving, mathematical ability, and judgment are poor. • Apathy, indifference, and confusion become more marked. • Managing the activities of daily living becomes difficult, affecting meal preparation, dressing, and personal hygiene. Wandering is common and the person may become confused and lost, even in familiar territory. • In the late stage, the person does not recognize his or her family, lacks awareness or interest in the environ- ment, is incontinent, and is unable to function in any way. • Degenerative changes may gradually interfere with motor function. CHAPTER 14 Nervous System Disorders 377 Creutzfeldt-Jakob disease has a long incubation period after its introduction into the brain, where more abnormal prions are produced. This is followed by a rapid destruction of neurons and the formation of plaques and vacuoles (empty spaces) in the neurons (spongiform encephalopathy). Signs/Symptoms Early indicators are as follows: • Memory loss • Behavioral changes • Motor dysfunction • Progressive dementia An EEG and MRI study aids the diagnosis. The course is 6 to 12 months. No treatment is available at this time, though research is continuing on drugs, including amantadine, steroids, interferon, acyclovir, antiviral agents, and antibi- otics. Current treatment is designed to alleviate symptoms and make the patient as comfortable as possible. The prions resist common methods of sterilization and disinfection. A link has been established between bovine spongiform encephalopathy (BSE, or mad cow disease) and a variant form of CJD (vCJD), with transmission by infected beef. AIDS Dementia Dementia is common in the later stages of AIDS (for more information on AIDS, see Chapter 7). The virus itself invades brain tissue and may be exacerbated by other infections, including those of Candida or Toxoplasma species, and by tumors, such as lymphomas. Gradual loss of memory and cognitive ability and impaired motor function (eg, ataxia, weakness, and abnormal reflexes) are typical. In children with congenital HIV infection, the brain is frequently affected, causing mental retardation and delayed motor development. Mental Disorders Mental illness is classified using the Diagnostic and Statisti- cal Manual of Mental Disorders (DSM), published by the American Psychiatric Association. Mental health problems involve significant dysfunction in the areas of behavior or personality that interferes with the person’s ability to func- tion. Biochemical and structural abnormalities in the brain appear to contribute to these pathologies. Many disorders have a genetic component. Stressors may play a role in the development of the illness. Psychotic illness includes the more serious disorders, such as schizophrenia, delusional disorders, and some affective or mood disorders. Many patients with psychotic disorders receive large doses of drugs with obvious side effects. Other common mental disorders include anxiety and panic disorders, which are less severe but nevertheless disruptive. This section provides a brief introduction to the pathophysiology of several common mental disorders. Further information can be obtained from texts focusing on mental health. THINK ABOUT 14.20 a. List the early signs of Alzheimer’s disease. b. Describe three ways that AD can interfere with activities of daily living. c. Compare the effects of AD, HD, ALS, and Parkinson’s disease. ■ Treatment Although no specific treatment is available to reverse the effects of AD, occupational therapy is important in assess- ment and provision of adaptive devices to provide for a safe environment as long as is possible. Specific problems, such as depression or anxiety, are treated symptomati- cally. Many drugs are contraindicated because they add to mental confusion. Anticholinesterase drugs, such as donepezil (Aricept), have led to some temporary improve- ment resulting from improved cholinergic transmission. Moderate stimulation, perhaps in a daycare setting, is helpful, while maintaining a daily routine and exercise program is also advisable. A team approach to care is helpful in prolonging independence and supporting the family. Social workers, occupational therapists, psycholo- gists, and speech therapists can provide direction and assistance. A daily routine and secure surroundings facilitate compliance with care. Often the primary care- giver is included in such therapy programs. Survival ranges up to 20 years, with an average of 7 years. Other Forms of Dementia Vascular Dementia Vascular dementia is caused by cerebrovascular disease and frequently is a result of multiple small brain infarc- tions. It is common in persons older than age 70, par- ticularly those with hypertension. Onset is insidious, with memory loss, apathy, and inability to manage daily routines. Progression may be in stages that are connected to the infarctions and loss of brain tissue. Other neurologic impairment is common. Creutzfeldt-Jakob Disease Creutzfeldt-Jakob disease (CJD) is a rare, but rapidly progressive, form of dementia caused by infection by a prion, an altered infectious protein particle (PrP) with a preference for nervous tissue. Pathophysiology/Etiology The infecting protein appears to alter normal host PrPs or the coding gene for protein shape. Often the origin of the infection is not identified. Some cases show a familial incidence (defect in human prion protein gene) and some have been iatrogenic, including sources such as surgery, corneal transplants, or other invasive procedures. Most are sporadic. Creutzfeldt-Jakob disease is more common in older individuals. 378 SECTION III Pathophysiology of Body Systems The antipsychotic drugs (major tranquilizers or neu- roleptics) available include the following: First-Generation (Typical) Antipsychotics: • Chlorpromazine (Thorazine) • Fluphenazine (Prolixin, Moditen) • Haloperidol (Haldol) • Loxapine (Loxitane) • Perphenazine (Trilafon) • Thiothixene (Navane) • Trifluoperazine (Stelazine) This group of drugs can cause serious movement prob- lems, muscle stiffness and other side effects. These drugs frequently cause side effects related to excessive extra- pyramidal activity (or parkinsonian signs). Dystonia and tardive dyskinesia cause involuntary muscle spasms in the face, neck, arms, or legs. Tardive dyskinesia may present as chewing or grimacing, repetitive jerky or writhing movements of the limbs, tremors, or a shuffling gait. With prolonged use and high doses of these drugs, tardive dyskinesia may be irreversible. Antiparkinson agents (anticholinergics) may reduce some of these side effects, but these drugs also have adverse effects, such as blurred vision and dry mouth. Second-Generation (Atypical) Antipsychotics: • Clozapine (Clozaril) • Aripiprazole (Abilify) • Asenapine (Saphris) • Clozapine (Clozaril) • Iloperidone (Fanapt) • Lurasidone (Latuda) • Olanzapine (Zyprexa) • Paliperidone (Invega) • Risperidone (Risperdal) • Quetiapine (Seroquel) • Ziprasidone (Geodon) These drugs are atypical because they are less likely to block dopamine and cause movement disorders; however, they do increase the risk of weight gain and diabetes. Depression Depression is classified as a mood disorder, of which there are several subgroups: • Major depression, or unipolar disorder, is endogenous, and a precise diagnosis is based on biologic factors or personal characteristics. Etiologic factors include genetic, developmental, and psychosocial stressors. • Bipolar disorder involves alternating periods of depres- sion and mania. • Depression may also occur as an exogenous or reactive episode, a response to a life event, or secondarily to many systemic disorders, including cancer, diabetes, heart failure, and systemic lupus erythematosus. Depression is a common problem, and many patients with milder forms may be misdiagnosed and not receive treatment. Schizophrenia ■ Pathophysiology Schizophrenia affects approximately 1% of the population and includes a variety of syndromes, which manifest differently in each individual. Although the etiology and pathogenesis have not been fully determined, some common changes do occur in the brains of schizophrenic patients, including reduced gray matter in the temporal lobes, enlarged third and lateral ventricles, abnormal cells in the hippocampus (part of the limbic system), excessive dopamine secretion, and decreased blood flow to the frontal lobes. Some of these changes appear to be linked to the neurologic manifestations seen in schizophrenic patients, such as abnormal eye movements (staring or periodic jerky eye movements). ■ Etiology Theories about the cause of schizophrenia focus on a genetic predisposition, along with brain damage in the fetus caused by perinatal complications or viral infection in the mother during pregnancy. Twin studies show a high concordance in both monozygotic and dizygotic twins pointing to a genetic component. Onset of schizo- phrenia usually occurs between ages 15 and 25 in men and 25 and 35 in women. Stressful events appear to initiate the onset and recurrences. ■ Signs and Symptoms Symptoms may be grouped as positive (eg, delusions, bizarre behavior) or negative (eg, flat emotions, decreased speech). Both the excesses and the deficits may appear in one patient. Subtypes are based on the predominant characteristics: • Generally disorganized thought processes are the basic problem. • Communication is often impaired by inadequate language skills, including lack of appropriate associa- tion of thoughts, meaningless repetition of words or thoughts, or development of new words without accepted meanings (neologisms). • Delusions or false beliefs and ideas are persistent. Delusions may include a belief in persecution by others or ideas of grandeur or power over others. • Problem-solving ability is impaired, and the attention span is brief. • Hallucinations or abnormal sensory perceptions are common. • The patient may withdraw socially from people and show little emotion but also may experience mood swings and become anxious. Often self-care is neglected. ■ Treatment Drugs are the major therapeutic modality, often in conjunc- tion with psychotherapy and psychosocial rehabilitation and complementary health approaches. CHAPTER 14 Nervous System Disorders 379 include tyramine-containing substances, such as chocolate, aged cheese, beer, and red wine. Monoamine oxidase inhibitors are not taken with SNRIs or SSRIs due to dangerous synergistic effects. Another treatment of severe depression involves elec- troconvulsive therapy (ECT, shock treatments), which increases norepinephrine activity but may result in some memory loss. Panic Disorders Panic attacks are common but do not necessarily lead to panic disorder. Panic attack refers to a sudden brief episode of discomfort and anxiety. Panic disorder, an anxiety disorder, develops when panic attacks are frequent or prolonged. These attacks occur in situations that most individuals would not find threatening. ■ Pathophysiology A genetic factor has been implicated. An increased dis- charge of neurons may occur in the temporal lobes. Biochemical abnormalities involving the neurotransmitters norepinephrine, serotonin, and GABA may also be involved. Patients are fearful of having another panic attack, leading to increased irritability of the limbic system. ■ Signs and Symptoms Repeated episodes of intense fear without provocation, which may last for minutes or hours, characterize this disorder. Palpitations or tachycardia, hyperventilation, sweating, sensations of choking or smothering, and nausea accompany the feeling of terror. Patients who anticipate attacks may develop a fear of open spaces (agoraphobia) or a fear of being in a place where no help is available and may refuse to leave their homes. ■ Treatment Treatment consists of psychotherapy combined with drug therapy, usually antianxiety agents, such as alprazolam (Xanax) or diazepam (Valium). Antianxiety agents or minor tranquilizers, such as the benzodiazepines, potenti- ate the activity of GABA, an inhibitory neurotransmitter. Large doses may be necessary, which can cause drowsiness and ataxia. These drugs have a wide safety margin when used appropriately. In some patients, antidepressants may be prescribed. ■ Pathophysiology Depression is classified as an affective or mood disorder on the basis of characteristic disorganized emotions. It results from decreased activity by the excitatory neurotransmit- ters, norepinephrine and serotonin, in the brain. The exact mechanism has not yet been established, but twin studies do suggest a genetic component. The depressed client often has a history of major psychosocial trauma, which may contribute to the development of the disorder. ■ Signs and Symptoms Depression is indicated by the following: • A prolonged period of profound sadness marked by hopelessness and an inability to find pleasure in any activity. • Lack of energy and loss of self-esteem and motivation interfere with daily activity. • Some individuals may be irritable and agitated. The individual has difficulty in concentrating and solving problems. • Sleep disorders, such as insomnia or, occasionally, excessive sleep, usually accompany depression. • Loss of appetite and libido (sex drive) is common. The degree to which the individual is affected varies over time and among individuals. In some cases disability results as the individual is unable to meet the demands of daily life. ■ Treatment Antidepressant drugs that increase norepinephrine activity are effective in treating many cases of depression. There is concern about the increased risk of suicide in children and adolescents taking antidepressant medications without concurrent psychiatric counseling. Some common groups of drugs in use include the following: • The selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac), have fewer cardiovas- cular side effects than drugs that block norepinephrine uptake. They prolong the activity at serotonin receptors, with antidepressant and anxiolytic effects. • A new class, called serotonin-norepinephrine reuptake inhibitors (SNRIs) (eg, venlafaxine [Effexor]), may be more selective in receptor action and have fewer side effects. • The tricyclic antidepressants (TCAs), such as amitrip- tyline (Elavil), block the reuptake of the neurotransmit- ters, particularly norepinephrine, into the presynaptic neuron. These mechanisms allow the stimulation by excitatory neurotransmitters to continue in the brain. • Monoamine oxidase (MAO) inhibitors, such as tran- ylcypromine (Parnate), block the destruction of nor- epinephrine and serotonin by the enzyme MAO at the synapse. Monoamine oxidase inhibitors cause many interactions involving certain foods and other drugs that may result in a hypertensive crisis (marked increase in high blood pressure). Foods to be avoided THINK ABOUT 14.21 a. Compare three signs of schizophrenia with three signs of depression. b. Explain how antipsychotic drugs act to reduce signs of mental illness. c. Describe common signs of extrapyramidal side effects of antipsychotic drugs. d. Describe a panic attack. 380 SECTION III Pathophysiology of Body Systems of one or both legs (sciatic nerve pain). Actions such as coughing or straight leg raising usually aggravate the pain. Paresthesia or numbness and tingling may occur. If the nerve compression is extensive, muscle weakness develops. Interference with micturition (bladder empty- ing) may develop. Similarly a herniated disc in the cervical region causes pain in the neck and shoulder that radiates down the arm. Sensory impairment, reduced neck movement, and weakness may accompany the pain. The pressure may lead to skeletal muscle spasm in the neck or back, further increasing the pain. ■ Diagnostic Tests Myelography with contrast dye, CT scans, and MRI confirms the herniation. ■ Treatment Conservative treatment includes the following: • Bed rest • Application of heat or ice • Traction • Drugs, such as analgesics, antiinflammatory agents, and skeletal muscle relaxants Back education programs are helpful in establishing appropriate positions for rest and activity. It is important to note that the pressure on the disks is highest in the sitting position. Physiotherapy and an appropriate program of exercise are usually undertaken. An occupa- tional therapist can recommend appropriate modifications to daily life and workplace activities. Surgery may be considered in selected cases of unremit- ting chronic back pain and includes laminectomy or discectomy. Spinal fusion is required if several vertebrae are involved, creating added instability. Spinal Cord Disorder Herniated Intervertebral Disc ■ Pathophysiology The vertebrae are separated by cartilaginous discs, which act as cushions and provide some flexibility to the spinal column. Herniation involves protrusion of the nucleus pulposus, the inner gelatinous component of the inter- vertebral disc, through a tear in the annulus fibrosus, the tough outer covering of the disc (Fig. 14.33). Such protrusions into the extradural space, usually laterally, exert pressure on the spinal nerve root or spinal cord at the site, interfering with nerve conduction. The tear in the capsule may occur suddenly or develop gradually. Depending on which site is involved, sensory, motor, or autonomic function can be impaired. The most common location is the lumbosacral discs, at L4 to L5 or L5 to S1. Some herniations involve cervical discs between C5 and C7. If pressure on the nerve tissue or blood supply is prolonged and severe, permanent damage to the nerve may result. ■ Etiology A person may be predisposed to herniation because of degenerative changes in the intervertebral disc, resulting from age or metabolic changes. The herniation usually is caused by trauma or poor body mechanics, leading to excessive stress on the muscles, for example, by improper lifting or transfer of patients. Trauma accounts for about 50% of herniations. ■ Signs and Symptoms Signs depend on the location and extent of the protrusion (see Figs. 14.4 and 14.23). In most cases, the effects are unilateral; however, large protrusions may cause bilateral effects. Because of pressure on the sensory nerve fibers in the dorsal root, lumbosacral herniations cause pain in the lower back, radiating down the posterior aspect Nucleus pulposus Nerve root Invertebral disc Annulus fibrosus Body of vertebra Spinal cord Lamina Bone Spinous process (posterior) Herniation FIG. 14.33 Herniated intervertebral disc. THINK ABOUT 14.22 Explain how a herniated intervertebral disc causes pain in the leg. CASE STUDY A Brain Tumor Mr. A.H., age 44, had a generalized tonic-clonic seizure unexpect- edly at work. He had no history of seizures, trauma, infection, or other illness. Investigation revealed a tumor in the right parietal lobe. This was removed surgically, although the diffuse nature of the malignant mass prevented its complete elimination. Follow-up radiation treatment was recommended. 1. Describe briefly several diagnostic tests that would be of value in this case. 2. Explain the basis of this seizure activity, and describe how it might be controlled. 3. Describe each stage, in sequence, of a generalized tonic-clonic seizure. CHAPTER 14 Nervous System Disorders 381 After surgery, Mr. A.H. demonstrated considerable weakness and sensory loss on his left side. 4. Match each of these effects with the functional areas of the brain that control them. A few days after surgery, Mr. A.H. developed a bacterial infection at the operative site. 5. Explain why this infection is likely to increase motor and sensory deficits. The infection was eradicated quickly with treatment, but the tumor did not respond to radiation and chemotherapy. As a result, several tumors in the brain grew relatively large during the next 2 months. 6. The cancer treatments caused severe anemia, nausea, and vomiting. Explain how these side effects could cause other complications for Mr. A.H.; describe these complications clearly. 7. Suggest several types of therapy or assistance that would be helpful to Mr. A.H. during this period. (Extend this question to focus on your specialty area, when possible.) Mr. A.H. developed severe headaches and diplopia and became increasingly lethargic, and his seizures increased in frequency despite anticonvulsant medication. He was given medication to reduce the frequency of vomiting. 8. Explain the specific rationale for each of his manifestations. As the tumors increased in size, Mr. A.H.’s vital signs indicated increased pulse pressure. 9. Explain the cause of each of these signs. 10. Describe the changes that are likely to occur as coma develops in Mr. A.H. CASE STUDY B Spinal Cord Injury B.L., age 17, has a compression fracture at C5 to C6, a result of diving from a bridge into a river and hitting a submerged rock. Fortunately a companion who had first aid training as a lifeguard rescued her and tried to minimize any secondary damage. In the emergency department, B.L. could not move her limbs or sense touch and lacked reflexes in her limbs. 1. Explain why caution is needed when handling a person with possible spinal cord injury. 2. Describe a compression fracture and how it can affect neurologic function. 3. Explain why reflexes are absent in B.L. at this early stage. What type of paralysis is present? 4. Explain why and how B.L.’s respiratory function may be impaired at any time. 5. Explain why the full extent of permanent damage cannot be estimated in this initial period. Surgery was performed to relieve pressure and stabilize the fracture site. 6. Describe several additional factors that may result in secondary damage to the spinal cord. 7. Explain the anticipated effect in the immediate period of this injury on B.L.’s blood pressure and bladder function. Several weeks later, routine examination indicated that some spinal cord reflexes were returning in the lower extremities. 8. Explain the significance of the returning reflexes. 9. Explain why each of the following complications could develop in B.L., and state the early signs for each: a. Pneumonia b. Decubitus ulcer c. Muscle atrophy d. Contracture 10. Briefly describe how the risk for each of the above complications could be minimized. Gradually more reflexes returned. Some muscle tone and movement of the shoulder and upper arm became apparent, but no other function returned. 11. Explain how the dermatomes can assist in detecting functional areas. 12. Describe the change to be expected in bowel and bladder function as reflexes return. One day, B.L. suddenly developed a severe headache and blurred vision. Her blood pressure was 210/120 mm Hg, and her pulse was 62 beats per minute. 13. What has probably caused this effect, and what action needs to be taken? 14. Suggest the specific components for a rehabilitation program for B.L. Expand your comments in areas of particular concern to you. CASE STUDY C Increased Intracranial Pressure R.T. is a 16-year-old girl who has just received her driver’s license. She has taken several friends to a “bush party” at a classmate’s farm where beer and liquor were available. She leaves the party at 2 am after having several drinks. Her friends tease her as she attempts to put on her seat belt, and one calls her a sissy. She begins driving home without a seat belt. Her car drifts across the median and is involved in a head-on collision. Her most serious problem appears to be severe brain injury following ejection from the car. She is transported to the area trauma center, where treatment begins immediately. 1. Examination indicates papilledema in the right eye, a subdural hematoma in the temporal region, loss of consciousness and decreased responsiveness to painful stimuli. Explain how each symptom or sign is related to increased intracranial pressure. 2. Describe a subdural hematoma, its location, and how it developed and caused ICP. 3. R.T. develops bilaterally dilated pupils, and a CT scan shows ventricular shift. What are the implications of these findings? 4. Surgery is performed to reduce the pressure in her cranium, and R.T. recovers but requires rehabilitation for several deficits, including problems with hearing and memory as well as comprehension of speech. How will these deficits affect her academic work? Which regions of the cortex have been damaged? One year after the accident, R.T. returns to high school, and with the aid of a special education program for persons with head injuries, she graduates. 382 SECTION III Pathophysiology of Body Systems communicate, may be expressive, receptive, or a combina- tion, and it is often related to damage in the Broca area or the Wernicke area in the dominant hemisphere (left). Regeneration or replacement of neurons does not occur in the CNS. Increased Intracranial Pressure • The manifestations of ICP are common to all types of lesions in the brain and include a decreasing level of consciousness; headache; vomiting; increasing pulse pressure; papilledema; fixed, dilated pupils; and increasing CSF pressure. • Brain tumors, both benign and malignant, cause focal effects, increased ICP, and are often life threatening. Vascular Problems • Transient ischemic attacks are caused by temporary reductions in blood supply, causing brief impairment of speech or motor function. They may serve as a warning of impending obstruction of blood flow. • Cerebrovascular accident may result from atheroma, embolus, or hemorrhage causing total loss of blood supply to an area of the brain and subsequent infarc- tion. Cerebral edema adds to the neurologic deficit during the first 48 hours. The presence of collateral circulation or immediate clot dissolution may minimize permanent damage. • Cerebral aneurysm is frequently asymptomatic and undiagnosed until it is very large or rupture occurs. Infections • Meningitis is frequently caused by meningococcus, often carried in the upper respiratory tract, but a variety of other microbes may cause infection depending on the individual circumstances. Inflammation and swelling of the meninges leads to increased ICP, but no focal signs are present. Typical signs are severe headache, nuchal rigidity, photophobia, lethargy, and vomiting. • Encephalitis is considered an infection of the parenchy- mal or connective tissue in the brain and cord. Necrosis and inflammation develop in the brain tissue, often resulting in some permanent damage. Encephalitis is usually of viral origin but may be related to other organisms. Early signs of infection include severe headache, stiff neck, lethargy, vomiting, seizures, and fever. Injuries • Brain injury may be mild with only transient dysfunc- tion (eg, concussion) or very serious with extensive damage to brain tissue (eg, compound skull fracture). Inflammation and bleeding will increase ICP, and focal signs will reflect both the primary site and contrecoup injury. Secondary brain damage may be caused by hematoma formation, infection, or ischemia due to shock or other systemic factors. CASE STUDY D Multiple Sclerosis W.H., a 36-year-old woman, has received a diagnosis of multiple sclerosis. She has lost part of her left visual field and has weakness in her left leg. W.H.’s mother had multiple sclerosis. 1. State the factors in the history and the diagnostic tests that would indicate multiple sclerosis as a diagnosis. 2. Describe the pathophysiology of multiple sclerosis. 3. State the possible locations of the lesions that have caused visual and motor deficits. 4. Describe the typical course of multiple sclerosis that W.H. can expect in future. 5. Suggest several measures that can be used to minimize exacerbations. 6. Explain why adequate nutrition and hydration are important in patients with chronic neurologic conditions, including specific potential complications that may be avoided. 7. Explain why a program of moderate activity is important for W.H. CASE STUDY E Alzheimer’s Disease D.N. developed Alzheimer’s disease at age 50. Early signs were vague and included occasional errors in judgment and increased criticism of others, noted only in retrospect. Several years later, following several episodes of extreme anger, a diagnosis of Alzheimer’s disease was made. At this time, it was suspected that his father had also had AD but had died from an unrelated cause before a diagnosis could be made. 1. Why is a diagnosis difficult in the early stage of AD? 2. Could there be a familial factor? 3. Describe the pathologic changes that occur in the brain with AD. The neurologist prescribed galantamine (Reminyl), an anticholinesterase inhibitor, and regular attendance at a group center offering appropriate activities. 4. How would this drug be useful in treating AD? The degeneration progressed rapidly over the next 2 years. The maximum dose of galantamine is no longer effective. He is confused about any change and not capable of performing simple activities. Communication is impaired, including that with family members. 5. Describe what might be expected in the final stage of AD. C H A P T E R S U M M A R Y The brain and spinal cord are mapped in specific areas related to functions. Damage to a certain area results in a precise dysfunction and manifestations (focal signs) regardless of the exact cause. Damage to the right side of the brain (motor or sensory cortex) affects the contralateral side of the body. Loss of consciousness occurs when the RAS is depressed or large areas of the cerebral cortex are damaged. Aphasia, the inability to CHAPTER 14 Nervous System Disorders 383 • Spinal cord injury may result from a dislocation or fracture of a vertebra related to flexion, hyperextension, compression, or penetration injury. Additional neu- rologic damage is caused by hemorrhage, inflammation, or vasospasm. Immediately after the injury, a period of spinal shock develops in which reflexes and all functions cease at and below the level of injury. Fol- lowing this period, reflexes return below the level of injury, and other functions may return, depending on the extent of spinal cord damage and the level of the injury. Cervical injury is particularly dangerous because of the risk of respiratory failure related to phrenic nerve dysfunction. Congenital Neurologic Disorders • Hydrocephalus occurs in the neonate when excessive amounts of cerebrospinal fluid force separation of the cranial bones, enlargement of the head, and compres- sion of brain tissue. A shunt may be used to reroute CSF to prevent continued damage. • Spina bifida involves a number of developmental neural tube defects. In myelomeningocele, the most serious form, the spinal cord and nerves as well as meninges and CSF herniate through the vertebral defect, resulting in neurologic dysfunction at and below that level of the spinal cord. • Cerebral palsy refers to a group of disorders resulting from brain damage during fetal development or in the neonate, all of which involve a motor disability. Various other abnormalities (eg, seizures or cognitive impairment) are present in each child depending on the areas of the brain that are damaged. • Seizure disorders consist of a diversity of conditions caused by intermittent episodes of excessive uncon- trolled neuronal discharge in the brain. Generalized seizures of the tonic-clonic type (grand mal) follow a typical pattern of initial aura, loss of consciousness, tonic muscle contraction, a cry, clonic muscle contrac- tion, cessation, and postictal recovery. Chronic Degenerative Diseases • Multiple sclerosis is marked by progressive loss of myelin from nerves in the CNS, resulting in a loss of motor, sensory, and autonomic functions. The clinical effects vary with the individual, depending on the specific areas affected and the number of exacerbations. • Parkinson’s disease involves a deficit of dopamine caused by degenerative changes in the basal nuclei. Extrapy- ramidal dysfunction leads to tremors, muscular rigidity, and loss of the commonly associated involuntary movements such as arm swinging. • Amyotrophic lateral sclerosis is a disorder marked by degeneration of upper and lower motor neurons, hence by progressive wasting of skeletal muscle, whereas other functions such as intellect persist. • Huntington’s disease is unusual because the effect of the autosomal dominant trait is not evident until midlife. Atrophy of the brain and decreased neurotransmitters cause choreiform movements and progressive cognitive impairment. • Alzheimer’s disease is a form of dementia or progressive loss of intellectual function and personality changes. Cortical atrophy and other pathologic changes in the neurons disrupt conduction, and in time all functions deteriorate. Mental Disorders • Schizophrenia is linked to specific chemical and physical abnormalities in the brain, resulting in dis- organized thought processes, delusions, or decreased responsiveness. • Depression encompasses a number of mood disorders linked to deficits of excitatory neurotransmitters. It may also develop secondary to a number of systemic disorders. • Panic disorder is diagnosed when panic attacks, periods of intense fear and anxiety, occur at frequent intervals and persist. Chemical imbalance is considered to be the underlying cause. Spinal Cord • Herniated intervertebral disc is a common problem in older individuals or in cases of spinal trauma or undue stress. A tear occurs in the annulus fibrosus, allowing the inner nucleus pulposus to protrude and exert pressure on the spinal nerve or root, causing pain and weakness. S T U D Y Q U E S T I O N S 1. a. List the contents of the subdural space, subarachnoid space, and dura mater. b. Describe the specific location, and list the functions of each of the following: auditory association area, prefrontal area, Broca area, cerebellum, RAS. c. Using Table 14.2, Table 14.3, or Fig. 14.3, describe the effects of damage to each area of the brain. 2. Draw a simple line diagram of the circle of Willis at the base of the brain by doing the following: a. Draw a line to show the division between the two hemispheres and label the top “frontal” and the bottom “occipital.” b. In the lower half of the drawing, show the basilar artery dividing into two posterior cerebral arteries, and extend each down and to the side to the occipital lobes. 384 SECTION III Pathophysiology of Body Systems 10. a. List several causative organisms of meningitis and the age groups primarily affected by each. b. Describe the significant signs of brain infection, including signs of meningitis and brain abscess and general signs of infection. 11. a. Compare open and closed head injuries, including a description of each, their effects, and their potential complications. b. Describe the location, usual cause, and basic effect of an epidural hematoma. 12. a. Describe two ways in which the spinal cord can be damaged in a fall. b. Explain why it is difficult to predict the degree of permanent damage to the spinal cord during the first few days. c. Describe the usual effects of transection of the spinal cord at C4–C5 immediately after injury and after recovery from spinal shock. Explain why there is a difference in the effects over time. d. Describe the cause and effect of autonomic dysreflexia. How are the signs different from those of a stress response? 13. a. Compare the pathophysiology of communicating and noncommunicating hydrocephalus. b. Explain why hydrocephalus occurs in adults. 14. Compare myelomeningocele with cerebral palsy in terms of etiology and effects on motor function and communication. 15. a. Describe the sequence of events in a generalized tonic-clonic seizure. b. Define status epilepticus. c. Explain why a focal seizure may occur in a person with a head injury. 16. Compare the pathophysiology and early signs of multiple sclerosis and Parkinson’s disease. 17. Describe the changes occurring in the brain with Alzheimer’s disease, and compare its early effects on function with the later effects. 18. Compare depression and panic disorder in regard to the following: a. Classification b. Two significant signs or symptoms c. Recommended drug therapy 19. Describe the factors leading to herniation of the intervertebral disc. 20. Explain why pain is a common indicator of a herniated intervertebral disc. c. Midway on the line and on either side of it, draw a circle showing each carotid artery. d. Draw two branches from each carotid: one extending upward toward the frontal lobe and one outward and away from your central line. e. Label the arteries you have drawn. f. Add the communicating arteries to complete the circle, and label them. 3. a. Explain why the circle of Willis is important in the cerebral circulation. b. Predict the effects of obstruction of the left middle cerebral artery. c. Explain why a constant supply of oxygen and glucose to the brain is necessary. 4. a. Describe the characteristics of a spinal cord tract, using an example. b. Differentiate an upper motor neuron from a lower motor neuron by location and function. c. Describe a nerve plexus and how it affects nerve distribution. d. Describe an acquired reflex, and include an example. 5. Compare the location and three basic effects of the SNS and the PNS. 6. a. Describe how the effects of deep coma differ from normal consciousness. b. Describe the sites of damage that would cause left-sided hemiplegia, receptive aphasia, and loss of hearing. 7. a. Describe the visual signs of increased ICP. b. State the rationale for headache with increased ICP. c. Describe what changes occur in vital signs (ie, blood pressure, pulse, respiration) with rising ICP. 8. a. State the common signs and symptoms of a frontal lobe tumor. b. Predict the initial and progressive signs of a tumor growing in the left parietal lobe. c. Compare the effects of similar-sized tumors in the occipital lobe and the brain stem. d. Explain why there are general signs of increasing pressure in a person with a brain tumor. 9. a. Compare the pathophysiology and effects of TIAs and CVAs. b. Compare the origins and extent of damage in the three categories of CVAs. c. Describe several important factors in minimizing permanent damage from a CVA. 385 Sensory Receptors The Eye Review of Structure and Function Protection for the Eye The Eyeball Fluids in the Eye The Visual Pathway Diagnostic Tests Structural Defects Infections and Trauma Conjunctivitis Trachoma Keratitis Glaucoma Cataracts Detached Retina Macular Degeneration The Ear Review of Structure and Function Parts of the Ear Pathway for Sound The Semicircular Canals Hearing Loss Ear Infections Otitis Media Otitis Externa Chronic Disorders of the Ear Otosclerosis Ménière’s Syndrome Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Define sensory receptors, and classify them by location and stimuli. 2. Describe the common structural defects impairing vision: hyperopia, presbyopia, myopia, astigmatism, amblyopia, and nystagmus. 3. Describe common infections in the eye and their possible effects on vision. 4. Explain how intraocular pressure may become elevated and how it may affect vision. 5. Compare the signs of chronic glaucoma, acute glaucoma, cataract, macular degeneration, and detached retina. Include the rationale for each. 6. Describe how the retina may become detached and the possible effects on vision. 7. Describe the types of hearing loss with an example of each. 8. Describe otitis media and its cause, pathophysiology, and signs. 9. Describe the pathophysiology and signs of otosclerosis and of Ménière’s syndrome. 10. Explain how permanent hearing loss is caused by acute otitis media, chronic otitis media, Ménière’s syndrome, and damage to the auditory area of the brain. L E A R N I N G O B J E C T I V E S diplopia exteroceptors ototoxic photophobia proprioceptors ptosis refraction tinnitus trachoma visceroceptors visual acuity K E Y T E R M S C H A P T E R 15 Disorders of the Eyes, Ears, and Other Sensory Organs Sensory Receptors Sensory receptors/sense organs are classified into two categories: general senses and special senses. Special senses include the eye and the ear. Sensory receptors can be classified by their location: • Exteroceptors: Located close to the body surface and sometimes referred to as cutaneous receptors. Examples include receptors for touch, pressure, temperature, and pain. • Visceroceptors (interoceptors): Located internally and provide information about the environment around the viscera. • Proprioceptors: Provide information about body movement, orientation, and muscle stretch. Propriocep- tors are of the referred to as muscle sense. 386 SECTION III Pathophysiology of Body Systems • The anterior portion of the three layers differs from the posterior section because these tissues must permit the passage of light rays. • The outer layer is a tough fibrous coat, the posterior portion of which is the sclera and the anterior portion the cornea. The sclera is visible as the “white” of the eye, and the cornea is a transparent bulging portion through which light rays pass and are refracted. (If you look at another person’s eye from the side, you can observe the curve of the cornea.) The cornea does not contain blood vessels but is nourished by the fluids around it and by oxygen diffusing from the atmosphere. This source of oxygen is a concern for individuals wearing contact lenses for long periods of time. • The middle layer of the eye, or uvea, is made up of the choroid, a dark, vascular layer adjacent to the sclera in the posterior portion of the eye. The dark color absorbs the light, preventing reflection of light within the orbit. The numerous blood vessels in the choroid supply nutrients to the outer layers of the retina. In the anterior part of the eye, the choroid develops into the ciliary body and iris. The ciliary body consists of the ciliary muscle, which controls the shape of the lens to focus the image of near and distant objects accurately and clearly on the retina, and the ciliary processes, which secrete aqueous humor, the fluid in the anterior cavity of the eye. The iris is a circular structure surrounding the pupil, an opening through which light rays pass into the interior of the eye. The iris is pigmented and gives the eye its distinctive brown or blue tone. The iris contains two muscles that control the size of the pupil. The circular, or sphincter, muscle contracts in response to parasympathetic stimuli or excessive light on the retina, resulting in a constricted or small pupil. Parasympathetic nervous system fibers reach the iris from cranial nerve III. Under sympathetic nervous system control, the radial muscles of the iris, when contracted, cause the pupil to dilate or open. This function is easier to remember if it is associated with the stress (see Chapter 26) or fight-or- flight response, in which sympathetic stimulation leads to pupil dilation and improved vision, especially in dim light. The lens is a transparent biconvex structure made up of an elastic capsule surrounding an orderly alignment of fibers. There are no blood vessels or nerves to interfere with the transparency, nor are there organelles in the cells, which subsequently limits repair in these cells. Nutrients are provided from the aqueous humor. Together with the cornea, the lens provides refractive power for the light entering the eye. Current interest relates to the mechanism by which these cells have lost the organelles and become transparent. The suspensory ligament connects the lens to the ciliary body. The shape of the lens is altered as the contraction of the ciliary muscle alters tension on the suspensory Sensory receptors are classified by their stimuli: • Mechanoreceptors: Stimulated by a mechanical force: touch, pressure, equilibrium, hearing • Chemoreceptors: Activated by a change in chemical concentration—taste, smell • Thermoreceptors: Stimulated by a change in tempera- ture—warm and cold receptors • Photoreceptors: Respond to light stimuli • Nociceptors: Respond to any tissue damage, the sensa- tion produced is pain • Osmoreceptors: Specialized receptors concentrated in the hypothalamus that recognize changes in the osmotic pressure of body fluids The Eye Review of Structure and Function Visual information is received from light rays that pass through the transparent cornea and then through the lens, which focuses the image on the receptor cells of the retina, the rods and cones. These visual stimuli are conducted by the optic nerves to the occipital lobe of the brain for interpretation and processing before they are sent to other appropriate areas of the brain. Protection for the Eye The eye is well protected in the bony orbit of the skull. The eyelids (palpebrae) and eyelashes deflect foreign material in the air away from the eyes and protect the eye from excessive sunlight and drying. The levator palpebrae superior, the muscle of the upper eyelid, is controlled by the oculomotor nerve (cranial nerve III). The eyelids are lined with a thin mucous membrane, the conjunctiva, which continues over the sclera of the eye. The continual secretion of tears washes away particles, microbes, and irritating substances. This watery secretion contains lysozyme, an antibacterial enzyme. The tears form in the lacrimal gland located on the superior lateral area of the orbit. They flow across the eye and drain into the lacrimal canals in the medial corner of the eye and then into the nasal cavity through the nasolacrimal duct. The tears keep the external tissues of the eye moist and healthy. The Eyeball Six skeletal muscles (extrinsic muscles) control the move- ment of the eyeball in the bony orbit. They originate on the orbit and insert onto the sclerae on the outside of the eyeball. There are four straight (rectus) muscles and two angled (oblique) muscles, which are coordinated to move and rotate the eye and are under the control of cranial nerves III, IV, and VI. The eyeball consists of a spherical three-layered wall filled with fluid (Fig. 15.1): CHAPTER 15 Disorders of the Eyes, Ears, and Other Sensory Organs 387 • The posterior cavity is the space between the lens and the retina, and it contains the transparent, jellylike vitreous humor. This material is formed during embry- onic development and holds the retina approximated against the choroid to ensure diffusion of nutrients as well as to maintain the shape and size of the eyeball. Sometimes “floaters” may pass through a person’s visual field, small specks or shadows that move about and eventually settle to the inferior portion of the eye. These are strands that form in the vitreous humor, more often with aging. • The anterior cavity between the cornea and the lens is further divided into the anterior chamber, extending from the cornea to the iris, and the posterior chamber, between the iris and the lens. The chambers are con- nected through the pupil. The anterior cavity is filled with aqueous humor, which is continuously secreted by the ciliary processes into the posterior chamber. It flows through the pupil into the anterior chamber and drains into the reticular network and canal of Schlemm (see Fig. 15.4, presented later). This canal encircles the eye at the junction of the cornea and iris and returns the fluid to the blood. To maintain normal intraocular pressure inside the eye (normal range 12 to 20, average 15 mm Hg), the amount of aqueous humor formed should equal the amount reabsorbed. Normal pressure maintains the shape of the eye. The ligament. This adjustment in lens curvature, or accom- modation, bends the light rays (refraction) entering the eye sufficiently to focus a sharp image on the retina. The inner layer of the wall of the eye is the retina. This multilayered coat is present only in the posterior two- thirds of the eye because light rays passing through the lens cannot bend enough to reach the retina if it is present in the anterior part of the eye. The retina consists of a pigmented layer and several layers of neurons. In the center of the posterior retina is the macula lutea, a yel- lowish area containing a depression called the fovea centralis, which is an area containing many cones that provides the most acute vision. The innermost layers of the retina consist of the rods and cones, which are light-sensitive photoreceptor nerve cells. Rods are specialized for dim light (for night vision), and cones are color sensitive. The light energy is absorbed by the rods and cones and converted into electrical energy in the neurons. Three types of cones, red, green, and blue, determine color perception. Color blindness is common in males and results from a deficit of one type of cone owing to an abnormal gene on the X chromosome (sex-linked recessive gene) (see Chapter 21). Fluids in the Eye The eye is divided into two cavities by the lens and ciliary body: Retina Choroid Sclera Fovea centralis Optic disc (“blind spot”) Retinal vein Optic nerve Central retinal artery and vein Retinal artery Medial rectus muscle Lateral rectus muscle Cornea (SITE OF KERATITIS) Pupil Iris Canal of Schlemm Ciliary muscle Suspensory ligament Lens (SITE OF CATARACT) Anterior chamber Posterior chamber Conjunctiva (SITE OF CONJUNCTIVITIS) SITE OF DETACHED RETINA Anterior cavity (aqueous humor) Meninges Posterior cavity (vitreous humor) FIG. 15.1 Structure of the eye. 388 SECTION III Pathophysiology of Body Systems Diagnostic Tests Basic tests include the following: • The Snellen chart or similar eye charts, consisting of lines of progressively smaller letters and numbers, measure visual acuity. • Visual field tests are used to check central and periph- eral vision. • Tonometry assesses intraocular pressure by checking the resistance of the cornea. • An ophthalmoscope can be used to examine the interior structures. • Gonioscopy measures the angle of the anterior chamber. • Muscle function and coordination can also be tested. Many other sophisticated tests are available for specific disorders. Neurologic damage to the visual pathway is covered in Chapter 14. Retinopathies are discussed in Chapter 12 under Hypertension, and in Chapter 16 under Diabetes Mellitus. Structural Defects Structural defects interfere with the focusing of a clear image on the retina: • Myopia, nearsightedness, occurs when the image is focused in front of the lens, perhaps because the eyeball is too long (Fig. 15.2). • Hyperopia, or farsightedness, develops if the eyeball is too short and the image is focused behind the retina. In cases of myopia and hyperopia, the blurred image can be corrected with a lens, such as a concave lens for myopia, which refocuses the image on the retina. • Presbyopia refers to farsightedness associated with aging, when the loss of elasticity reduces accommodation. • Astigmatism develops from an irregular curvature in the cornea or lens. • Strabismus (squint or cross-eye) results from a deviation of one eye, resulting in double vision (diplopia). Strabismus may be caused by a weak or hypertonic muscle, a short muscle, or a neurologic defect. In young children, strabismus must be treated immediately to prevent the development of amblyopia, the suppression by the brain of the visual image from the affected eye. • Nystagmus is an involuntary abnormal movement of one or both eyes. It may be a back-and-forth rhythmic motion, jerky movement, or circular motion. This abnormality may result from neurologic causes, from inner ear or cerebellar disturbances, or from drug toxicity. aqueous humor supplies nutrients to the lens and cornea, which lack blood vessels. The Visual Pathway To review the physiology of vision: light rays from an object pass through the cornea, where they are refracted, and then through the aqueous humor and pupil. The curvature of the lens is adjusted to refract the light rays so that they converge on the retina, providing a sharp image of the object. The light continues through the transparent aqueous humor to the retina, where the photoreceptor neurons, the rods and cones, are stimulated. The light energy is converted into an electrical stimulus, which is transmitted by the optic nerve to the occipital lobe of the brain, where the image is identified and integrated with other information. The double image projected from different angles by the two eyes provides a wider visual field, and the central overlap of visual fields provides depth perception. The nerve impulses from the ganglion cells of the retina converge in the fibers of the optic nerve (cranial nerve II), which leaves the eye at the optic disc in the posterior portion of the eye. The central retinal artery and vein, which supply the retina and other structures, also pass through the optic disc. There are no rods or cones at the optic disc, forming the “blind spot.” Because the optic nerve is essentially a projection of brain tissue surrounded by cerebrospinal fluid and meninges, it reflects pressure in the brain (see Chapter 14). Assessment of the eye can often provide useful information about other problems in the body, such as hypertension or vascular changes as a result of diabetes. The optic nerves carry visual stimuli to the occipital lobes of the brain (see Fig. 14.3). At the optic chiasm, half of the fibers from each optic nerve cross to pass to the occipital lobe in the opposite hemisphere (see Fig. 14.7). Therefore the left occipital lobe receives images from the right visual field. Damage to the left occipital lobe results in loss of the right visual field. THINK ABOUT 15.1 a. Explain why one may have a “runny nose” when crying. b. Describe the outer layer of the eye, naming and locating the parts and describing the function of each. c. List the parts of the eye that do not contain blood vessels, and explain how they are nourished. d. Explain the effect of sudden fear or anger on the size of the pupil. e. List the functions of the oculomotor nerve. f. Describe the location and function of the photoreceptor cells. g. Describe the type of impulses carried by the optic nerve. APPLY YOUR KNOWLEDGE 15.1 Explain why a hit to the back of the head might result in a person “seeing stars.” CHAPTER 15 Disorders of the Eyes, Ears, and Other Sensory Organs 389 the fingers or contaminated towels. Antibiotic treatment is required to reduce contagion and prevent damage to the cornea. Contact lenses are a frequent source of infection in the eye, both conjunctivitis and keratitis (Fig. 15.3B–C). Other sources are contaminated medication or makeup. Medications or eye makeup should not be used past the expiry date or instructions. The infectious agent could be one of a variety of microorganisms. Chlamydia trachomatis and gonorrhea cause infection in the reproductive tract (sexually transmitted disease, or STD) and may infect the eyes of newborns, who are routinely given medication after birth to prevent this infection. Neisseria gonorrhoeae is frequently transferred to the eyes by self-inoculation, causing conjunctivitis (Fig. 15.3A). Redness and very heavy discharge running out of the eyes are typical. Trachoma Trachoma is an eye infection caused by Chlamydia tra- chomatis that causes follicles to develop on the inner surface of the eyelids. It occurs in situations in which • Diplopia (double vision) or paralysis of the upper eyelid (ptosis) may be caused by trauma to the cranial nerves, resulting in paralysis of the extraocular muscles. Infections and Trauma A stye (hordeolum) is an infection involving a hair follicle on the eyelid, usually by staphylococci. A swollen, red mass forms on the eyelid, which is uncomfortable when blinking. Conjunctivitis Conjunctivitis is a superficial inflammation or infection involving the conjunctiva lining the eyelids and covering the sclera. Allergens, bacteria, viruses, or irritating chemicals in the air are a frequent cause of inflammation, resulting in redness, itching, and excessive tearing with a watery discharge. Organisms such as Staphylococcus aureus cause the highly contagious “pinkeye,” which occurs frequently in children. The sclera of the eye and eyelid appears red, and there is a purulent discharge. Pinkeye is spread by Correction by biconcave lens Correction by biconvex lens Cornea Lens Retina Focus on retina after correction Location of focused image if uncorrected Blurred image at retina Focus on retina after correction Location of image if uncorrected Myopia (nearsightedness) with correction Hyperopia (farsightedness) with correction B A Uncorrected Corrected refraction FIG. 15.2 Refraction defects in the eye. 390 SECTION III Pathophysiology of Body Systems Trauma to the cornea also increases risk of visual loss. The cornea is finely structured to provide a transparent pathway for light. Abrasions may develop from foreign bodies caught under the eyelid, a damaged contact lens, or objects directly scratching the cornea. Abrasions can be seen using a fluorescein stain in the eye. Penetration injuries may cause damage to the internal structures or loss of the vitreous humor. The eye is susceptible to damage from chemicals, splashes, or fumes. Prompt and prolonged flooding of the eye with cool running water is important. It may be necessary to hold the eye open to accomplish the flushing. Preventive measures such as wearing protective glasses, avoiding touching the eyes, and cleaning contact lenses appropriately can greatly reduce the risks of trauma to the eye. Glaucoma ■ Pathophysiology Glaucoma results from increased intraocular pressure caused by an excessive accumulation of aqueous humor. Narrow-angle glaucoma occurs when the angle between the cornea and the iris in the anterior chamber is decreased there is not adequate water to wash the face and eyes or flies carry the organism to the eyes. Although common in children, it can occur in any age group. If not effectively treated with antibiotic ointments, the eyelids become scarred and the lashes turn inward to abrade the cornea. Globally, trachoma is the most common cause of vision loss, but it is also easily treated and prevented. The patient reports a “scratchy” eye and no exudate is normally present. Everting the upper eyelid shows the characteristic pearl-like follicles. Keratitis Keratitis is an inflammation of the cornea, usually accompanied by severe pain. Severe pain and photopho- bia (sensitivity to light) develop because it has numerous pain receptors (trigeminal nerve-cranial nerve V); it is typically caused by infection or injury. The herpes simplex virus is an example of a cause of corneal inflammation and ulceration. The virus may be transferred from a herpes lesion around the mouth by the fingers or in a dental office by spray of contaminated saliva. With keratitis there is increased risk of ulceration eroding the cornea and scar tissue interfering with vision. Corneal involve- ment is best treated by an ophthalmologist. 6% 7% 9% 3% 18% 4% 18%35% Pseudomonas aeruginosa Klebsiella pneumoniae Serratia marcescens Enterobacter species Staphylococcus aureus Stenotrophomonas maltophilia gpos, other gneg, otherC A B FIG. 15.3 Infections in the eye. A, Gonococcal conjunctivitis showing redness and copious discharge in the eye caused by Neisseria gonorrhoeae. B, Growth of Pseudomonas aeruginosa surrounds the soft contact lens of a patient with ulcerative keratitis. C, Trends in bacteria recovered from contact lenses and solutions. gneg, gram-negative; gpos, gram-positive. (From Mahon CR, Manuselis G: Textbook of Diagnostic Microbiology, ed 2, Philadelphia, 2000, Saunders.) CHAPTER 15 Disorders of the Eyes, Ears, and Other Sensory Organs 391 retinal cells, causing ischemia and damage to the retinal cells. The anterior portion of the retina is affected first, including the receptor cells for peripheral vision. If pres- sure inside the eyeball continues to increase, more of the retina and the optic nerve will be damaged. When observed through the pupil, the optic disc appears eroded or “cupped” as the optic nerve fibers are compressed (Fig. 15.5). Damage to the retina and optic nerve is irreversible, and eventually blindness results. ■ Etiology Chronic glaucoma develops frequently in older individu- als, usually beginning after age 50. Narrow-angle glaucoma may be caused by a developmental abnormality, aging, or scar tissue in the eye from trauma or infection. Congenital glaucoma occurs as an inherited disorder of several types, both recessive and dominant. by factors such as an abnormal anterior insertion of the iris. With aging, the lens enlarges, pushing the iris more forward and to the side. This anatomic position may block the outflow of aqueous humor when the pupil is dilated and the thickened iris fills the narrow angle (Fig. 15.4). Pressure inside the eyeball can increase significantly within an hour of pupil dilation, blocking drainage of fluid. This leads to acute glaucoma, in which there is a sudden marked increase in intraocular pressure. Chronic glaucoma, sometimes referred to as wide-angle or open-angle glaucoma, is a common degenerative dis- order in older persons, affecting 1% to 2% of the popula- tion in the United States. The trabecular network and canal of Schlemm become obstructed, and the outflow of aqueous humor gradually diminishes. Intraocular pressure increases slowly and usually asymptomatically. The increased pressure compresses the blood flow to the Lens Anterior chamberCornea Iris Canal of Schlemm Trabecular meshwork Ciliary body (formation of aqueous humor) Posterior chamber Normal intraocular pressure (10–20 mm Hg) A. NORMAL FLOW OF AQUEOUS HUMOR Lens Degeneration and obstruction of trabecular meshwork and canal of Schlemm decreases absorption of aqueous humor High intraocular pressure B. CHRONIC (OPEN-ANGLE) GLAUCOMA Lens Narrow iridocorneal angle blocks drainage into canal of Schlemm High intraocular pressure C. ACUTE (NARROW- OR CLOSED-ANGLE) GLAUCOMA Canal of Schlemm Trabecular mesh Enlarged detail Iris in anterior position Absorption of aqueous humor FIG. 15.4 Glaucoma. 392 SECTION III Pathophysiology of Body Systems a regular basis, to control intraocular pressure and minimize the risk of retinal damage. If the condition is unresponsive to drugs, laser trabeculoplasty or trabecu- lectomy may be required to deepen the anterior chamber and thus increase the drainage of aqueous humor. Acute glaucoma (narrow-angle), if severe, may require surgery, such as removal of part of the iris, to open a passageway for drainage into the canal of Schlemm (iridectomy). Laser iridotomy is a popular noninvasive procedure. Cataracts A cataract occurs when the normally clear lens becomes cloudy and interferes with light transmission (Fig. 15.6). The size, site, and density of the opacity/cloudiness vary among individuals and may differ in one individual’s two eyes. The changes may be caused by degeneration related to aging or metabolic abnormalities such as diabetes. Excessive exposure to sunlight may be a factor. Congenital cataracts are usually a result of maternal infection due to rubella or toxoplasmosis. Traumatic cataracts are the result of blows to the eye, which imprint iris pigment on the lens. These injuries are often associated with sports activities in which eye protection is not used. Blurred vision that progresses over the visual field and becomes darker with time is the only indicator. The rate at which impairment develops varies considerably, and a cataract in one eye may advance more quickly than one in the other eye. When severe enough to interfere with the person’s ability to function or work, the damaged lens can be removed and replaced by an artificial intra- ocular lens. Tests are essential to assess retinal function, intraocular pressure, and the possible presence of other lesions such as tumors before surgery. ■ Signs and Symptoms Chronic glaucoma has an insidious onset. Increased intraocular pressure is the initial indicator of chronic glaucoma. Routine screening tests are recommended as individuals age because increased intraocular pressure is often the only sign. Loss of peripheral vision may not be noticed initially except by a screening test because individuals automatically adjust the direction of the eyes to focus on an object. As pressure increases over time, corneal edema and altered light refraction lead to blurred vision and the appearance of “halos” around lights. Mild eye discomfort develops as the corneal pain receptors are stimulated by the increased pressure. In individuals with narrow-angle glaucoma, acute episodes of glaucoma may be triggered by pupil dilation resulting from adrenergic drugs such as those used for colds or hay fever (vasoconstrictors or decongestants, which may cause pupil dilation), by stress, or by pro- longed periods in darkened rooms. As intraocular pressure rises rapidly, eye pain, nausea, and headache develop, vision is blurred, and the cornea appears bulging and cloudy. The pupil is dilated and unresponsive to light. This situation requires prompt treatment to prevent permanent damage. ■ Treatment Chronic glaucoma is treated by regular administration of eyedrops to reduce secretion of aqueous humor (eg, timolol or betaxolol, beta-adrenergic blocking agents) or to constrict the pupil (eg, pilocarpine, a miotic or cho- linergic agent). Some drugs also reduce the intraocular pressure through inhibition of carbonic anhydrase. Drug interactions and side effects should be carefully checked with any new medication that is prescribed. It is essential to maintain treatment, administering the medication on FIG. 15.5 Glaucomatous cup: loss of nerve fibers leads to excavation of the optic disc. (From Cotran RS, Kumar V, Collins T: Robbins Pathologic Basis of Disease, ed 6, Philadelphia, 1999, Saunders.) FIG. 15.6 Appearance of eye with cataract. (Courtesy of Ophthalmic Photography at the University of Michigan W.K. Kellogg Eye Center, Ann Arbor, from Black JM, Hawks JH: Medical-Surgical Nursing: Manage- ment for Positive Outcomes, ed 7, Philadelphia, 2005, Saunders.) CHAPTER 15 Disorders of the Eyes, Ears, and Other Sensory Organs 393 Central vision with high acuity first becomes blurred and then is lost. There is no treatment to reverse the effects. Depth perception is also affected. There is no pain. Peripheral vision is not affected (Fig. 15.7). Visual field tests and angiography assist diagnosis. ■ Treatment For the dry type of AMD, nutrition is assessed to ensure that vitamin, mineral, and antioxidant intake are sufficient. A high-dose formulation of antioxidants and zinc has been shown to reduce the risk of advanced AMD and its associated vision loss. In the wet type of AMD, photodynamic therapy (photo- sensitive drug plus laser) may help seal off neovasculature. The older method, laser photocoagulation, may also be used to seal vessels without the photo-activated drug Visudyne, which is used in photodynamic therapy. The new drug, pegaptanib (Macugen) may slow vascular growth in cases of the wet type, and therapy using the drug antivascular endothelial growth factor (anti-VEGF) has shown promise. An intraocular shot of an anti-VEGF drug inhibits the formation of new blood vessels behind the retina and may keep the retina free of leakage. Cataract surgery is usually day surgery, and the patient is quickly ambulatory. The degenerated material inside the lens is broken up by phacoemulsification and removed by suction, and the intraocular lens is placed in position to replace the natural lens that was removed. Peripheral iridectomy (an excision of a portion of the periphery or root of the iris) may be included to prevent postoperative glaucoma. Detached Retina A detached retina is an acute problem that occurs when the retina tears away from the underlying choroid because of marked myopia, degeneration with aging, or scar tissue that creates tension on the retina. The tear allows vitreous humor to flow behind the loose retinal portion (see Fig. 15.1). As increased vitreous humor continues to seep behind the retina, an increasing portion of the retina is lifted away from the choroid. The retinal cells cease to function as they are deprived of nutrients diffusing from the blood vessels of the choroid. This loss of function results in an area of blackness in the visual field. If separa- tion continues, the retina is deprived of its source of nutrients in the choroid and dies. There is no pain related to the tear, but initially the patient may see light or dark floating spots in the visual field, resulting from blood or exudate leaking from the tear. A darkened or blind area develops, which increases in size with time. Typically, this event has been described as a “dark curtain” drawn across the visual field. Surgical intervention such as scleral buckling or laser therapy is required as soon as possible to close any holes and reattach the retina in its proper position against the choroid to restore the source of nutrients to the retinal cells before irreversible damage occurs. Retinal detach- ment may recur and requires immediate attention to prevent vision loss. Macular Degeneration Age-related macular degeneration (AMD) is a common cause of visual loss in older persons. It appears to arise from a combination of genetic factors and environmental exposure (eg, ultraviolet rays and drugs). A similar condition found in younger persons has a stronger genetic basis. Degeneration occurs at the fovea centralis in the macula lutea, with its high density of cones, at the central point of the retina. There are two types of degeneration: • The more common type is the dry or atrophic AMD, in which deposits form in retinal cells, gradually destroying them. • In the wet or exudative form, neovascularization occurs, with the formation of abnormal, leaky blood vessels, rapidly destroying the retina. In both types, nutrients can no longer pass from the choroids to the retina. A Normal Vision Age-related Macular DegenerationB FIG. 15.7 A, Normal vision. B, Age-related macular degeneration. (From National Eye Institute, National Institutes of Health.) 394 SECTION III Pathophysiology of Body Systems This tube equalizes pressure in the middle ear with pressure in the external ear canal. This equaliza- tion is important if atmospheric pressure changes suddenly, as when an airplane takes off. Chewing or swallowing helps to equalize the pressure on either side of the tympanic membrane. The middle ear cavity is also continuous with the mastoid air cells in the mastoid process of the temporal bone around the ear. A continuous mucous membrane lines the middle ear cavity, the mastoid cells, the auditory tube, and the respiratory tract. This is significant because it provides a path for direct spread of infection through these structures. • The inner ear is called the labyrinth. It is composed of two parts, the cochlea and the semicircular canals, joined by a vestibule. These structures consist of a bony labyrinth filled with a fluid, perilymph, inside of which is a membranous labyrinth filled with endolymph. The cochlea contains a complex arrange- ment of membranes surrounding the organ of Corti, where specialized hair cells (nerve receptors) provide stimuli to the sensory neurons for hearing. These neurons form the cochlear branch of the auditory nerve (cranial nerve VIII), which conducts impulses to the temporal lobe for reception and interpretation of sound. Some fibers from each ear cross to the auditory cortex in the opposite hemisphere, and some fibers remain on the same side, meaning that each auditory area receives some sound from each ear. Pathway for Sound Hearing begins with sound waves in the air. The height of a wave determines the loudness of the sound, and the The Ear Review of Structure and Function Parts of the Ear The ear is divided into three anatomic sections, the external ear, the middle ear, and the inner ear (Fig. 15.8): • The external ear consists of the pinna, or visible flap on the side of the head, and the external auditory meatus or canal. This canal passes through the temporal bone to the tympanic membrane or eardrum, which marks the separation between the external and middle ear. • The middle ear consists of the tympanic cavity, a hollow area in the bone, which contains three tiny bones, the malleus, incus, and stapes, which compose the ossicles. The malleus is adjacent to the tympanic membrane, and the stapes fits against the oval window, a mem- brane connecting the middle ear and the inner ear. The middle ear cavity opens into the auditory or eustachian tube, which connects to the nasopharynx. Pinna External auditory canal External Ear Middle Ear Inner Ear Nasopharynx Auditory (eustachian) tube Vestibule Cochlea containing organ of Corti Cochlear nerve Auditory nerve (VIII) Vestibular nerve Oval window Semicircular canals Stapes Incus Malleus Auditory ossicles Temporal bone Tympanic membrane FIG. 15.8 Structure of the ear. THINK ABOUT 15.2 a. Explain why infection or trauma involving the cornea is more serious than that involving the conjunctiva. b. Describe the characteristic signs of cataract development. c. Compare wide-angle and narrow-angle glaucoma, including the pathophysiology and signs of each. d. Explain the cause of blindness with cataract, acute glaucoma, detached retina, and damage to the optic chiasm. e. Describe the two types of macular degeneration and current treatments. CHAPTER 15 Disorders of the Eyes, Ears, and Other Sensory Organs 395 ibuprofen, the diuretic furosemide, and some antineo- plastic agents have caused temporary or permanent hearing loss. The early sign of toxicity is often tinnitus, a ringing or buzzing in the ears. This condition can be addressed with noise suppression therapy, medica- tions that help reduce the severity of the condition, and even forms of alternative medicines, such as lipo-flavonoids, which have been tried with no exten- sive testing to confirm the claims of success. There appears to be no cure for this condition, just therapies to reduce the symptoms. • Sudden, very loud sounds or prolonged exposure to loud noise can damage the delicate hair cells because of the force exerted by excessive movement in response to the sound. This type of damage is often associated with occupational hazards or loud music. • Presbycusis is the sensorineural loss that occurs in elderly people owing to a reduced number of hair cells or receptor cells or other degeneration in the cochlea. • Congenital deafness may be inherited or may result from infection or trauma during pregnancy or delivery. Most deaf infants are born to hearing parents. Early diagnosis and treatment are essential for development of the child. Hearing impairment in young children often interferes with speech and social development, as well as other interactions with persons and with learning ability. In many areas, newborns are screened for hearing deficits. Additional tests can determine the source of the deficit. Audiologists and otolaryngologists may be consulted to determine the optimum therapy. Regular therapy with a speech-language pathologist is helpful. Lip reading and sign language (American Sign Language, ASL) may be learned. Many assistive devices are now available to improve communication skills. Hearing aids may be used if appropriate for the indi- vidual hearing deficit. Various types of hearing aids to amplify sound are available to improve hearing capacity. Cochlear implants have been in existence for some years. They are used successfully in some cases of sensorineural loss in very young congenitally deaf children or in adults, following appropriate screening by the medical team. With an implant, any sound is picked up by an external microphone and bypasses many structures in the ear to stimulate the auditory nerve (Fig. 15.9). The auditory area of the brain then interprets this input. The mechanism can be used when the receptor cells in the cochlea are not functioning, but the auditory nerve is intact. In very young children with profound hearing loss, the develop- ing brain usually quickly adapts to the stimuli from the cochlear implant. Working with speech and language pathologists, they are able to develop normal speech and language skills in a short time. Adults who formerly could hear and speak also are able to match the “old” sounds to the new stimuli. However, deaf children older than age 7 have had little success with this prosthesis. Controversy exists as to the need for cochlear implant therapy. Some parents who are deaf, deafened, or hard number of sound waves per time period, or frequency, determines the pitch (high or low): 1. Sound waves enter the external ear canal and strike the tympanic membrane, causing it to vibrate. 2. Vibration of the tympanic membrane causes the malleus to vibrate, and then the incus and the stapes. 3. The motion of the stapes against the oval window initiates movement of the perilymph and endolymph in the cochlea. 4. These “water waves” stimulate movement of the membranes and hair cells in the organ of Corti, which converts the stimulus into a nerve impulse. 5. The nerve impulses are conducted to the auditory area in the temporal lobe of the brain, where the sound is received and interpreted. The Semicircular Canals The semicircular canals in the inner ear include three structures, each at right angles to the other two; the sense of balance and equilibrium is focused in the crista ampul- laris, located in the ampulla of each semicircular canal and in the macula in the vestibule. These contain the receptor hair cells, which can be stimulated by motion of the endolymph fluid in response to head movements or position changes. Because of the arrangement of the canals, movement in any direction can be detected. Any stimulus is conducted by the vestibular branch of the auditory nerve to the medulla oblongata and other parts of the brain. Many additional connections to the cerebellum, to incoming proprioceptive impulses (joints, muscles, and tendons), and to visual stimuli are required for the coordination of righting reflexes to maintain body position. Vestibular damage causes vertigo, a sense of rotation of self or the environment. Hearing Loss Hearing loss is of two basic types, conduction deafness and sensorineural deafness (sometimes sensorineural is broken down into sensory and neural deafness). Tests comparing conduction by air through the external canal and conduction through the mastoid bone can assist in differentiating the type of deafness. Conduction deafness occurs when sound is blocked in the external ear or middle ear. Consider the following examples: • An accumulation of wax or a foreign object in the external ear canal can block sound waves. • Scar tissue or adhesions may impair the function of the tympanic membrane or ossicles. • Sensorineural impairment develops with damage to the organ of Corti or the auditory nerve. This damage can result from infection, particularly viral infections including rubella, influenza, and herpes or damage from head trauma or other neurologic disorders affecting the auditory nerve or temporal lobe. • Ototoxic drugs such as the antibiotics streptomycin, neomycin, and vancomycin, the analgesics aspirin and 396 SECTION III Pathophysiology of Body Systems Ear Infections Otitis Media Otitis media is an inflammation or infection of the middle ear cavity. ■ Pathophysiology Exudate builds up in the cavity, causing pressure on the tympanic membrane and interfering with the movement of the membrane and the ossicles. Usually the auditory tube is obstructed by inflammation, preventing drainage of the fluid into the nasopharynx. Enlarged adenoids may compress the tube. The middle ear cavity is encased in rigid bone, and therefore increasing pressure eventually causes rupture of the tympanic membrane. Prolonged infection is likely to produce scar tissue and adhesions, leading to permanent conductive hearing loss. Chronic infection may lead to mastoiditis, infection involving the mastoid cells of the temporal bone. ■ Etiology The mucosa of the middle ear cavity may become inflamed because of allergies or infection that spreads along the of hearing and have children who are hearing impaired do not consider deafness to be a disability; therefore they do not consider cochlear implants a necessary or valuable treatment option for their children. If a cochlear implant is chosen for treatment, it is preferable to use an implant at an early age if it is to be successful. 1 Sound enters the system through a tiny microphone behind the ear. 7 The brain receives the signals and interprets them as sound. 5 The transmitting coil, a plastic- covered ring about 1 inch in diameter, sends the codes across the skin to the receiver/stimulator. 2 The sound is sent from the microphone to the speech processor through the thin cord that connects them. 3 The speech processor selects and codes the elements of sound that are most useful for understanding speech. 4 These electronic codes are sent back up through the thin cable to the transmitter. 6 The receiver/stimulator contains an integrated circuit that converts the codes into special electrical signals and sends them along the electrode array. The electrode array is a set of 22 tiny electrode bands arranged in a row around a piece of tapered flexible tubing. Each electrode has a wire connecting it to the receiver/ stimulator. The coded electrical signals are sent to specific electrodes. Each electrode is programmed separately to deliver signals that can vary in loudness and pitch. These electrodes then stimulate different hearing nerve fibers, which send the messages on to the brain. Receiver Electrode Cochlea MicrophoneTransmitter Processor FIG. 15.9 Cochlear implant to restore hearing. (From Black J, Hawks J: Medical Surgical Nursing: Clinical Management for Positive Outcome, ed 8, St. Louis 2009, Saunders, Elsevier.) THINK ABOUT 15.3 a. Describe the location of the middle ear, including its boundaries, and the openings from it. Describe the structures in the middle ear and their function. b. Compare the advantages and disadvantages of the auditory tube and its relationship to the middle ear. c. Describe the location of the auditory nerve receptors, and trace the connection to the brain. d. Predict the effect on hearing capacity of damage to (1) the cochlea in the right ear, (2) the left auditory nerve, and (3) the left temporal lobe. e. Which parts of the hearing pathway can a cochlear implant replace? f. Explain why a cochlear implant may not be successful in older children who are deaf. CHAPTER 15 Disorders of the Eyes, Ears, and Other Sensory Organs 397 media. Although antibacterials are needed in recurrent otitis media, some physicians treat initial infections for at least 48 hours with ibuprofen (Advil) or acetaminophen (Tylenol) to reduce discomfort. The child is then reassessed, and if the condition has not resolved, antibacterials are administered. Decongestants may be useful in reducing the edema and obstruction in the auditory tube. Young children with recurrent otitis media may require inser- tion of drainage tubes through the tympanic membrane temporarily to relieve congestion. A person with an ear infection should use caution if planning to use air transportation because the pressures inside and outside the ear must be equalized to prevent additional damage (barotrauma). Chewing gum or swallowing during rapid ascent or descent may help. Scar tissue on the tympanic membrane or an open tear may follow infection and impair hearing. Recurrent infection may cause adhesions or damage to the ossicles. In these cases, surgery may be necessary to restore a functional tympanic membrane and ossicles (eg, tympanoplasty) or treat chronic mastoiditis (eg, mastoidectomy). Mastoiditis is less common now with antimicrobial treatment of ear infections. Cholesteatoma, a cystlike mass, may develop with chronic otitis media and the accompanying ruptured tympanic membrane. Epithelial cells collect and become infected, forming a mass in the middle ear cavity that eventually erodes the ossicles and surrounding bone, impairing hearing. Surgical intervention is required. Treatment of otitis media in the toddler or infant is essential if proper speech patterns are to develop. Children with a history of otitis media and delayed or impaired speech should be assessed by a speech therapist or speech pathologist as well as an audiologist. continuous mucosa from the nasopharynx and respiratory structures. This happens more easily in infants and young children because the auditory canal is shorter and wider and forms more of a right angle to the nasopharynx, thereby facilitating drainage of respiratory secretions into the auditory tube. Also, infants tend to spend more time in a recumbent position, and feeding in a supine position encourages reflux of fluid into the ear. Otitis media occurs more frequently in the winter months when there is an increase in upper respiratory infections. Common bacterial causes include Haemophilus influenzae, particularly in young children, and pneumo- cocci, beta-hemolytic streptococci, and staphylococci. Viral infection may also lead to otitis media, which is frequently complicated by a secondary bacterial infection. Bacterial infections result in a purulent discharge. ■ Signs and Symptoms Occasionally otitis media is asymptomatic. More often there is severe pain or earache (otalgia) related to the pres- sure on the tympanic membrane and the nerve receptors in the cavity. The tympanic membrane appears red and bulging (Fig. 15.10). An infant or young child tends to rub or pull at the ear to express distress. Mild hearing loss or a feeling of fullness/congestion is common. Signs of infection, such as fever and nausea, may be present. Rupture of the tympanic membrane results in a purulent discharge from the external ear canal, accompanied by relief of pain. ■ Treatment American and Canadian medical associations have ques- tioned the use of antibacterials to routinely treat otitis A B FIG. 15.10 A, Normal tympanic membrane. B, Tympanic membrane with otitis media. (A Courtesy Richard A. Buckingham, Clinical Professor, Otolaryngology, Abraham Lincoln School of Medicine, University of Illinois, Chicago, from Seidel HM, Ball JW, Dains JE, et al: Mosby’s Guide to Physical Examination, ed 5, St. Louis, 2003, Mosby. B Courtesy Michael Hawke, MD, from Zitelli BJ, Davis HD: Atlas of Pediatric Physical Diagnosis, ed 4, St. Louis, 2002, Mosby.) 398 SECTION III Pathophysiology of Body Systems • Electronystagmography (ENG), which evaluates balance by assessing eye movement • The fluid test, which checks for an abnormal buildup in inner ear • Electrocochleography (ECOG) test, which looks at response to sounds • Magnetic resonance imaging (MRI) to rule out a tumor or other abnormal structures Treatment of attacks consists of drugs such as dimenhy- drinate, diazepam, or antihistamines. Home exercise programs have assisted in reducing the individual’s sensitivity to motion. In severe cases surgery may be helpful to provide a shunt, remove excess endolymph, or resect the vestibular nerve. Otitis Externa Otitis externa, sometimes called swimmer’s ear, is an infection of the external auditory canal and pinna. It is usually of bacterial origin but occasionally is fungal. It may be associated with swimming, irritation or the introduction of organisms when cleaning the ear, or frequent use of earphones or earplugs. Pain, purulent discharge, and a hearing deficit are common signs of otitis externa. Otitis externa can be differentiated from otitis media because pain is usually increased with movement of the pinna. Chronic Disorders of the Ear Otosclerosis Otosclerosis involves an imbalance in bone formation and resorption. With development of excess bone in the middle ear cavity, the stapes becomes fixed to the oval window, blocking conduction of sound into the cochlea. Otosclerosis appears to develop from a genetic factor, primarily in young adult females. Surgical removal of the stapes (stapedectomy) and replacement by a prosthesis restores hearing. If laser surgery is used in an early stage, the stapes may be freed and no prosthesis is required. Ménière’s Syndrome Ménière’s syndrome is an inner ear or labyrinth disorder occuring in adults 30 to 50 years of age. It usually affects only one ear. Excessive endolymph develops intermit- tently, stretching the membranes and interfering with the function of the hair cells in the cochlea and vestibule. Rupture of the labyrinth membrane may allow perilymph to mix with endolymph, increasing volume and causing an attack. The increased fluid may also be of vascular origin. Each attack may last minutes or hours and causes the following conditions: • Severe vertigo: a sensation of whirling and weakness, is often accompanied by loss of balance and falls • Tinnitus (excess noise like a roaring motor or ringing) • Unilateral hearing loss • Nausea and sweating • Inability to focus • Nystagmus: an involuntary, rapid movement of the eyeball • A feeling of pressure in the ear. Repeated occurrences lead to permanent damage to the hair cells, with permanent loss of hearing and vertigo. The acute episodes occur over several months, followed by a brief period of relief, and then the cycle repeats. Stress is a predisposing factor, as are other conditions that affect blood flow. Changes in barometric pressure may precipitate an attack. Improvement occurs with stress reduction; avoidance of smoking, alcohol, and caffeine; observance of a low-sodium diet; and use of a mild diuretic. Diagnostic tests include the following: • Balance tests, such as rotary-chair and video head impulse tests THINK ABOUT 15.4 a. Explain why infants and young children are predisposed to otitis media. b. Explain why earache is often severe in persons with acute otitis media. c. Explain two ways in which permanent hearing loss may develop with ear infections. d. Differentiate conductive hearing loss from sensorineural loss, and give an example of each. e. Explain why Ménière’s syndrome causes both hearing loss and vertigo. CASE STUDY A Glaucoma Mr. A., age 72, has been treated for chronic glaucoma for 6 years. He has lost some peripheral vision but does not feel seriously impaired. There is one incident in his history 2 years ago when he decided to discontinue his eyedrops for a month because he was comfortable and there was no change in his vision. He developed some eye discomfort and blurred vision. Examination confirmed elevated intraocular pressure (IOP) but little additional permanent damage. Since then an increased strength of eyedrops was ordered to control IOP. 1. Describe the pathophysiologic change in chronic glaucoma. 2. Why is there decreased peripheral vision? 3. Explain the reason for eye discomfort and blurred vision with increased IOP. Mr. A. consulted his doctor about a dark area in his field of vision. It developed suddenly, although he had noticed a few dark floaters recently. He has no pain or discomfort, but the dark area is increasing in size. A detached retina in the right eye is diagnosed. 4. Explain the cause of the (1) floaters and (2) dark area in the visual field. 5. Why is it essential to reattach the retina immediately? CASE STUDY B Ménière’s Syndrome Mrs K., age 42, had several episodes of vertigo with nausea and temporary loss of hearing. She also has essential hypertension, CHAPTER 15 Disorders of the Eyes, Ears, and Other Sensory Organs 399 C H A P T E R S U M M A R Y Sensory organs can be classified into general senses and special senses. The eye and ear are special senses, complex structures that provide a major proportion of the body’s sensory functions. These organs are vulnerable to damage from trauma, infection, and degenerative processes. Loss of vision or hearing can cause significant changes in lifestyle, employment opportunities, and relationships. The Eye • Inflammation may be caused by allergens, irritants, trauma, or microorganisms. Keratitis is more serious than conjunctivitis, because it involves the transparent cornea and therefore raises the potential for permanent visual loss. Keratitis is indicated by severe pain and photophobia. • Glaucoma is characterized by increased intraocular pressure resulting from an excessive amount of aqueous humor in the anterior cavity. The common type, chronic wide-angle glaucoma, is a degenerative condition that causes retinal damage and loss of peripheral vision. If pressure is not controlled, the optic nerve is damaged. • A cataract is a degenerative process with increasing opacity of the lens of the eye, resulting in blurred vision. • A detached retina requires immediate treatment to prevent permanent visual loss, because the retinal cells are deprived of nutrients. • Macular degeneration is manifested by loss of visual acuity and central vision in older persons. The Ear • Hearing loss may be categorized as conduction deafness when the cause is located in the external or middle ear, or as sensorineural deafness when the inner ear (organ of Corti) or the auditory nerve is damaged. • Otitis media is inflammation or infection of the middle car, frequently secondary to allergies or upper respira- tory infections. Permanent hearing loss may result if the tympanic membrane or ossicles are damaged. • Otosclerosis involves excessive bone formation fixing the stapes to the oval window, blocking sound conduction. • Ménière’s syndrome is characterized by episodes of increasing endolymph in the inner ear, impairing both hearing and equilibrium. Ultimately permanent damage to the nerve receptor cells occurs. CASE STUDY C Congenital Deafness in a Young Child O.R. was diagnosed when 2 weeks old with severe-to-profound sensorineural hearing loss. Pregnancy and delivery were normal, and O.R. was healthy at birth with no evidence of other congenital problems. There was no family history of deafness. 1. Explain the meaning of sensorineural hearing loss. 2. Explain several ways in which profound deafness could affect a child’s growth and development. His parents began classes in American Sign Language (ASL). English and Hindi were spoken in the home. Over a period of time, three types of behind-the-ear hearing aids were tried on O.R., all without success. Other options to assist O.R. were explored. Following assessment, O.R. was deemed a good candidate (good health and cognitive ability) and received a cochlear implant at age 18 months. 3. How does a cochlear implant differ from the normal hearing process? 4. How is the child’s brain promoting the development of verbal skills? He received speech and language therapy and was soon responding to sounds and voices. In several months he was using some words in English and Hindi as well as continuing with ASL. By age 3 he was able to put several words together, although his words were not always clear. His verbal skills continue to develop, and he is now able to attend a preschool program. 5. Why is family interest and support necessary for the successful development of communication skills? 6. What impact might O.R.’s exposure to three languages have on the development of his communication skills? S T U D Y Q U E S T I O N S 1. Describe the classification of senses by their sensory input. 2. Describe the function of each of the following structures in the eye: sclera, cornea, lens, choroid, and ciliary process. 3. Compare the signs of chronic glaucoma, acute glaucoma, cataract, detached retina, and macular degeneration. 4. Describe the progress of a sound wave until it is identified in the brain. 5. Describe two ways in which otitis media can impair hearing permanently. 6. Explain why Ménière’s syndrome affects balance and hearing. controlled by medication. Following tests to rule out other possible causes, Ménière’s syndrome was diagnosed. 1. Explain how the attacks of vertigo are caused. 2. How might hypertension aggravate the attacks? 3. List three therapeutic measures that may reduce the severity of attacks. The attacks continue, although less frequently. She now has lost considerable hearing in the right ear and has difficulty maintaining balance on stairs and on heights. 4. Explain why there is permanent loss of hearing and loss of balance. Mrs. K. had surgery on the right ear, which has reduced the attacks of vertigo, but deafness in the right ear continues. 400 Review of the Endocrine System Endocrine Disorders Diagnostic Tests Treatment Insulin and Diabetes Mellitus Type 1 and Type 2 Diabetes Parathyroid Hormone and Calcium Pituitary Hormones Growth Hormone Antidiuretic Hormone (Vasopressin) Diabetes Insipidus Inappropriate Antidiuretic Hormone Syndrome Thyroid Disorders Goiter Hyperthyroidism (Graves Disease) Hypothyroidism Diagnostic Tests Adrenal Glands Adrenal Medulla Adrenal Cortex Cushing Syndrome Addison Disease Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Explain the homeostasis of hormones. 2. Name the endocrine glands and the hormones they secrete. 3. Describe the function of each hormone discussed. 4. Differentiate the action of steroid and nonsteroid hormones on the target cell. 5. Explain the relationship between metabolic syndrome and diabetes mellitus. 6. Differentiate type 1 and type 2 diabetes mellitus. 7. Compare the causes and development of hypoglycemia and hyperglycemia. 8. Describe the common degenerative effects of diabetes mellitus. 9. Explain the relationship between parathyroid hormone and calcium and their changes with various disorders. 10. Describe the possible effects of a pituitary tumor. 11. Compare the effects of an excess and a deficit of growth hormone in a child and an adult. 12. List the causes and effects of diabetes insipidus and inappropriate antidiuretic hormone syndrome. 13. Describe the causes of goiter. 14. Explain the effects of an excess and a deficit of thyroid hormones. 15. List the possible causes of Cushing syndrome. 16. Compare the effects of Cushing and Addison diseases. L E A R N I N G O B J E C T I V E S anabolic catabolism ectopic exocrine gluconeogenesis glucosuria hyperglycemia hypoglycemia ketoacidosis ketones ketonuria macroangiopathy microangiopathy negative feedback neuropathy polydipsia polyphagia polyuria tropic hormones K E Y T E R M S C H A P T E R 16 Endocrine System Disorders Review of the Endocrine System The major endocrine glands are scattered throughout the body and include the hypothalamus, pituitary gland (hypophysis), the pineal gland, the two adrenal glands, the thyroid gland, the four parathyroid glands, the endocrine portion of the pancreas, the gonads, and the thymus (Fig. 16.1). Also, local hormones are secreted in the digestive tract, which regulate its secretions and motility. These hormones are discussed in Chapter 17. Endocrine glands secrete hormones directly into the blood, in contrast to exocrine glands, which secrete into a duct, such as mucus, serous glands, or pancreatic duct. CHAPTER 16 Endocrine System Disorders 401 • Thyroid hormone • Calcitonin • Parathyroid glands • Parathyroid hormone • Adrenal cortex • Mineralocorticoids • Glucocorticoids • Gonadocorticoids • Adrenal medulla • Epinephrine and norepinephrine • Pancreas • Insulin • Glucagon • Somatostatin • Pineal gland • Melatonin • Ovaries • Estrogen • Progesterone • Testis • Testosterone • Classification by chemical structure: • Steroids—steroids are lipids; they enter the cell and nucleus and act directly in the nucleus to engage in transcription (messenger RNA) • Nonsteroids—need a second messenger system to finally activate the formation of mRNA Following release from an endocrine gland, the hor- mones circulate to target cells in other glands or tissues. After acting on specific receptors on or in the target cells, the hormones are metabolized or inactivated by the target tissues or the liver and excreted by the kidneys to prevent excessive amounts from accumulating in the body over a period of time. Table 16.1 provides a brief review of major hormones, their sources, and primary effects. The release of hormones from glands is most frequently controlled by a negative feedback mechanism (Fig. 16.2). For example, as levels of blood glucose increase, the secretion of insulin increases, thus increasing movement of glucose into the cells and lowering the level in the blood. When glucose levels decrease, insulin secretion decreases. The endocrine and nervous systems work together to regulate metabolic activities. The hypothalamus and pituitary gland constitute a complex control system for some hormones. The hypothalamus initially secretes releasing or inhibiting hormones; for example, thyrotropin- releasing factor acts on the pituitary gland to secrete thyroid-stimulating hormone. When determining the cause of a hormonal deficit or excess, it is necessary to check pituitary hormone levels as well as those of the target gland. For example, a deficit of thyroxine could result from a pituitary problem (decreased secretion of TSH) or a problem in the thyroid gland. In the latter case, blood levels of TSH would be high, whereas thyroxine levels would be low (see Fig. 16.13, presented later in the chapter, for the thyroid hormone feedback system). Pineal gland Pituitary gland Parathyroid gland (on posterior surface of the thyroid gland) Thyroid gland Adrenal gland Ovary Pancreas Testis Thymus FIG. 16.1 Locations of major endocrine glands. (From: Applegate E: The Anatomy and Physiology Learning System, ed 4, St. Louis, 2011, Saunders, Elsevier.) Hormones are chemical messengers that may be clas- sified by action, source, or chemical structure. For example, several hormones affect blood glucose levels, including insulin, glucagon, epinephrine, cortisol, and growth hormone. • Classification by source: • Hypothalamus • Releasing and inhibiting hormones • Antidiuretic hormone (ADH—vasopressin) • Oxytocin • Both ADH and oxytocin are produced in the hypo- thalamus and transported to the neurohypophysis (posterior pituitary) where they are stored and released upon the appropriate stimulus • Pituitary • Growth hormone (GH) • Prolactin • Follicle stimulating hormone (FSH) • Luteinizing hormone (LH) • Thyroid-stimulating hormone (TSH) • Adrenocorticotropic hormone (ACTH) • Thymus • Thymosin and thymopoietin • Thyroid 402 SECTION III Pathophysiology of Body Systems Another variable affecting hormone levels in the body is the rate or timing of secretion. Some hormones, such as thyroid hormone, are maintained at fairly constant levels, whereas others are released in large amounts intermittently as the demand occurs. Some hormones, such as estrogen, follow a cyclic pattern in women. Adrenocorticotropic hormone and cortisol are secreted in a diurnal pattern, the highest levels occurring in the morning and the lowest levels at night. If an individual’s sleep pattern changes, the hormonal secretion changes with it. However, any acute stress leads to the sympathetic In some cases, secretion is controlled by more than one mechanism (eg, aldosterone is regulated by renin secretion and serum levels of Na+ and K+). To assist in maintaining a well-controlled blood level of a substance such as calcium, a balance of several hormones, such as parathyroid hormone and calcitonin, is required. These are antagonistic hormones and have opposing actions on serum calcium. The blood level of glucose is critical to nervous system function and fluid balance; therefore, as mentioned, it is controlled by a number of hormones. TABLE 16.1 Sources of Major Hormones and Primary Effects Hormone Source Primary Effects Hypothalamic-releasing hormones Hypothalamus Stimuli to anterior pituitary to release specific hormone Hypothalamic-inhibiting hormones Hypothalamus Decrease release of specific hormone by anterior pituitary Growth hormone (GH, somatotropin) Pituitary—anterior lobe (adenohypophysis) Stimulates protein synthesis Adrenocorticotropic hormone (ACTH) Adenohypophysis Stimulates adrenal cortex to secrete primarily cortisol Thyroid-stimulating hormone (TSH) Adenohypophysis Stimulates thyroid gland Follicle-stimulating hormone (FSH) Adenohypophysis Women: stimulates growth of ovarian follicles and estrogen secretion; men: stimulates sperm production Luteinizing hormone (LH) Ade nohypophysis Women: stimulates maturation of ovum and ovulation; men: stimulates secretion of testosterone Prolactin (PRL) Adenohypophysis Stimulates breast milk production during lactation Antidiuretic hormone (ADH, or vasopressin) Pituitary—posterior lobe (neurohypophysis) Increases reabsorption of water in kidney Oxytocin (OT) Neurohypophysis Stimulates contraction of uterus after delivery Stimulates ejection of breast milk during lactation Insulin Pancreas—beta cells of islets of Langerhans Transport of glucose and other substances into cells Lowers blood glucose level Glucagon Pancreas—alpha cells Glycogenolysis in liver Increases blood glucose level Parathyroid hormone (PTH) Parathyroid gland Increases blood calcium level by stimulating bone demineralization and increasing absorption of Ca++ in the digestive tract and kidneys Calcitonin Thyroid gland Decreases release of calcium from the bone to lower blood calcium level Thyroxine (T4) and triiodothyronine (T3) Thyroid gland Increases metabolic rate in all cells Aldosterone Adrenal cortex Increases sodium and water reabsorption in the kidney Cortisol Adrenal cortex Antiinflammatory and decreases immune response Catabolic effect on tissues; stress response Norepinephrine Adrenal medulla General vasoconstriction Epinephrine Adrenal medulla Stress response Visceral and cutaneous vasoconstriction Vasodilation in skeletal muscle Increases rate and force of heart contraction Bronchodilation CHAPTER 16 Endocrine System Disorders 403 endocrine disorders cause distinctive changes in the individual’s physical appearance, which may be helpful in diagnosis. The most common cause of endocrine disorders is the development of a benign tumor, or adenoma. Adenomas may be secretory, causing excess hormone, or they may have a destructive effect on the gland, causing a hormonal deficit. Due to the location in the bony sella turcica on the inferior surface of the brain, an adenoma of the pituitary gland will cause increased intracranial pressure and neurologic effects. In some cases, the target cells are resistant or insen- sitive to the hormone, thus creating the effect of a hormone deficit. This lack of response may result from a genetic defect, an autoimmune response, or excessive demand on the target cells. An example of this receptor insensitivity to insulin may be seen in type 2 diabetes mellitus. Other causes of hormonal imbalances include congenital defects in the glands, hyperplasia or infection in the glands, abnormal immune reactions, and vascular problems. Not all hormones are covered in this chapter. However, if the normal effects of a hormone are known, it is possible nervous system overriding this pattern, resulting in a great outflow of ACTH and cortisol. = GLUCOSE = INSULIN = GLUCAGON Capillary Pancreas Liver 6. Gluconeogenesis in liver 1. High blood glucose 4. Low blood glucose 2. Beta cells of pancreas increase secretion of insulin 5. Alpha cells secrete glucagon 3. Insulin promotes transport of glucose into cells FIG. 16.2 Negative feedback mechanism with glucose and insulin and glucagon. THINK ABOUT 16.1 a. State and explain the effect of a high-carbohydrate meal on insulin secretion. b. Explain why it is beneficial for more than one hormone to control certain activities (eg, blood pressure). c. Construct a feedback chart for the glucocorticoids (hydrocortisone). d. Describe the effect on the natural secretion of hormone from the pituitary gland and the adrenal gland when large amounts of glucocorticoids are administered. Endocrine Disorders There are essentially two categories of endocrine problems: an excessive amount of hormone and a deficit of hormone. The manifestations of hormonal disorders reflect the actions of the hormone. Frequently 404 SECTION III Pathophysiology of Body Systems affect lipid metabolism. Many tissues and organs in the body are adversely affected by diabetes. Some types of cells are not affected directly by the deficit of insulin. Insulin is not required for the transport of glucose into brain cells. This is fortunate, because neurons require glucose constantly as an energy source. In the digestive tract, insulin is not required for glucose absorption. Exercising skeletal muscle can utilize glucose without proportionate amounts of insulin. This can be significant because excessive exercise can deplete blood glucose and result in hypoglycemia. Conversely, exercise is helpful in controlling blood glucose levels in the pres- ence of an insulin deficit. Type 1 and Type 2 Diabetes There are two basic types of diabetes: types 1 and 2 (Table 16.2). The classification system has been revised to better reflect the pathology. Type 1, formerly insulin- dependent diabetes mellitus, type I, or juvenile diabetes, is the more severe form. It occurs more frequently in children and adolescents but can develop at any age. Although there is a genetic factor in the development of the disease, the insulin deficit results from destruction of the pancreatic beta cells in an autoimmune reaction, resulting in an absolute deficit of insulin in the body and therefore requiring replacement therapy. The amount of insulin required is equivalent to the metabolic needs of the body based on dietary intake and metabolic activity. Acute complications such as hypoglycemia or ketoacidosis are more likely to occur in this group. About 1 in every 400 to 500 children has type 1 diabetes; type 1 diabetes to predict the effects of an excess or a deficit. Diagnostic tests and treatment follow similar patterns. Diagnostic Tests Levels of tropic hormones (hormones that have a stimulat- ing effect on other endocrine glands) secreted by the pituitary gland, as well as the levels of hormones secreted by the target gland, must be evaluated to determine the source of an endocrine disorder. In some patients, an excessive amount of hormone may arise from an ectopic (outside) source, such as a bronchogenic cancer, rather than from a gland. In such cases, the levels of tropic hormones are low. Blood tests are commonly used to check serum hormone levels, frequently making use of radioimmunoassay methods or, more recently, immunochemical methods (enzyme-multiplied immunoassay technique or chemo- luminescence). The effectiveness of a hormone can be measured; for example, blood glucose or blood calcium levels may reflect the activity of the respective hormones. Twenty-four-hour urine tests are helpful for ascertaining daily levels of hormones or their metabolites rather than using a random level taken at a specific moment. Stimula- tion or suppression tests can be performed to confirm the hyperfunction or hypofunction of a gland. Scans, ultrasound, and magnetic resonance imaging are also helpful for checking the location and type of lesion that may be present. Biopsy is essential to eliminate the possibility of malignancy. Treatment Treatment depends on the cause of the problem. Hormone deficits may be treated with replacement therapy; for example, insulin is used to treat diabetes mellitus. Adenomas causing excessive secretions may be removed surgically or by radiation therapy. Removal may be essential when pressure from the mass causes additional problems. For example, pituitary tumors cause pressure inside the skull, compressing brain tissue. Insulin and Diabetes Mellitus Diabetes mellitus is caused by a relative deficit of insulin secretion from the beta cells in the islets of Langerhans or by the lack of response by cells to insulin (insulin resistance). To simplify the text, insulin deficit is used to cover both decreased secretion of the hormone and insulin resistance. Insulin is an anabolic hormone (building up or synthesis of complex substances from simple molecules). Deficient insulin results in abnormal carbohydrate, protein, and fat metabolism because the transport of glucose and amino acids into cells is impaired, as well as the synthesis of protein and glycogen. In turn, these metabolic abnormalities TABLE 16.2 General Comparison of Type 1 and Type 2 Diabetes Type 1 Type 2 Age at onset Children and adults Older but also younger adults Onset Acute Insidious Etiology Autoimmune destruction Familial, lifestyle, and environmental factors, obesity Family history Body weight Thin Obese Plasma insulin level Very low Decreased or normal Treatment Insulin replacement Diet and exercise or oral hypoglycemic agents or insulin replacement Occurrence of hypoglycemia or ketoacidosis Frequent Less common CHAPTER 16 Endocrine System Disorders 405 • Diabetes insipidus—diabetes not related to blood sugar levels, but an insensitivity of the kidneys to ADH ■ Pathophysiology An insulin deficit leads to the following sequence of events. Initial Stage 1. Insulin deficit results in decreased transportation and use of glucose in many cells of the body. 2. Blood glucose levels rise (hyperglycemia). 3. Excess glucose spills into the urine (glucosuria) as the level of glucose in the filtrate exceeds the capacity of the renal tubular transport limits to reabsorb it. 4. Glucose in the urine exerts osmotic pressure in the filtrate, resulting in a large volume of urine to be excreted (polyuria), with the loss of fluid and electro- lytes (eg, sodium and potassium) from the body tissues. 5. Fluid loss through the urine and high blood glucose levels draw water from the cells, resulting in dehydra- tion (see Chapter 2). 6. Dehydration causes thirst (polydipsia). 7. Lack of nutrients entering the cells stimulates appetite (polyphagia). occurs in approximately 10% of all individuals diagnosed with diabetes. It is a major factor predisposing to strokes (cerebrovascular accident), heart attacks (myocardial infarction), peripheral vascular disease and amputation, kidney failure, and blindness. Type 2 diabetes, formerly referred to as non-insulin- dependent diabetes mellitus, type II, or mature-onset diabetes, is based on decreased effectiveness of insulin or a relative deficit of insulin. This abnormality may involve decreased pancreatic beta cell production of insulin, increased resistance by body cells to insulin, increased production of glucose by the liver, or a combina- tion of these factors. This form of diabetes may be controlled by adjusting the need for insulin by taking the following steps: • Regulating dietary intake • Increasing the use of glucose, such as with exercise • Reducing insulin resistance • Stimulating the beta cells of the pancreas to produce more insulin Type 2 is a milder form of diabetes, often developing gradually in older adults, the majority of whom are overweight. However, there has been an increased incidence in adolescents and younger adults who are identified with metabolic syndrome, a complex of several pathophysiologic conditions marked by obesity, cardio- vascular changes, and significant insulin resistance due to increased adipose tissue (see Chapter 23). Individu- als with metabolic syndrome often have developed vascular or other chronic complications before diagnosis. A major concern at this time is the rapid climb in incidence of type 2 diabetes, with prevalence now estimated at about 9% (18 million) of the population younger than 20 years of age. With increasing obesity in the population, it is anticipated that future incidence will increase sig- nificantly. Also, it is thought that there may be one undiagnosed case for every two to three diagnosed cases. The prevalence of type 2 diabetes increases with age, with approximately half the cases found in persons older than 55 years of age. There is a higher prevalence among African Americans, Hispanic Americans, and Native Americans. Gestational diabetes may develop during pregnancy and disappear after delivery of the child (see Chapter 22). Approximately 5% to 10% of women who have gestational diabetes develop type 2 diabetes some years later. A number of other types of diabetes and glucose intolerance vary in cause and severity. The following discussion focuses on types 1 and 2. A number of other types of diabetes are recognized and include the following: • Prediabetes—an early manifestation of type 2 diabetes • Latent autoimmune diabetes in adults—a slow-onset type 1 autoimmune diabetes • Maturity-onset diabetes of the young—a rare form caused by a mutation in an autosomal dominant gene THINK ABOUT 16.2 List the signs, including the rationale for each, of developing diabetes. Progressive Effects If the insulin deficit is severe or prolonged, the process continues to develop, resulting in additional consequences, ultimately diabetic ketoacidosis. This occurs more fre- quently in persons with type 1 diabetes. 8. Lack of glucose in cells results in catabolism of fats and proteins, leading to excessive amounts of fatty acids and their metabolites, known as ketones or ketoacids, in the blood. Ketones consist of acetone and two organic acids: beta-hydroxybutyric acid and acetoacetic acid. Because the liver and other cells are limited in the amount of lipids, fatty acids, or ketones they can process com- pletely within a given time, excessive amounts of ketones in the blood cause ketoacidosis. The ketoacids bind with bicarbonate buffer in the blood, leading to decreased serum bicarbonate and eventually to a decrease in the pH of body fluids. (Note that ketones can also accumulate in people on starvation diets.) 9. Ketoacids are excreted in the urine (ketonuria). Some diabetic patients test their urine for ketones. 10. However, as dehydration develops, the glomerular filtration rate in the kidney decreases, and excretion of acids becomes more limited, resulting in decom- pensated metabolic acidosis, which has life-threatening 406 SECTION III Pathophysiology of Body Systems acute and chronic. Glucose intake must be balanced with use. Treatment measures depend on the severity of the insulin deficit and may change over time. There are essentially three levels of control: 1. Diet and exercise 2. Oral medication to increase insulin secretion or reduce insulin resistance 3. Insulin replacement Diet Therapy is based on maintaining optimum body weight (weight reduction may be necessary) as well as control of blood glucose levels. This is important for persons with both types of diabetes. Recommended diets include more complex carbohydrates with a low glycemic index in contrast to simple sugars, which have a high glycemic index and elevate blood glucose rapidly; adequate protein; as well as maintaining low cholesterol and low lipid levels. Increased fiber with meals appears to reduce surges in blood sugar associated with food intake. The total amount of food intake, as well as the distribu- tion of the constituents, is important. Food intake must match available insulin and metabolic needs, including activity level. Various methods of meal planning are available from the diabetic associations and local diabetic clinics to ensure that the patient ingests a good balance of the various nutrients and provide information on the exchange of food components without disruption of goals. Nutritionists can be consulted on an individual basis in many diabetic clinics. ■ Signs and Symptoms Some common signs of all types of diabetes include the following: • Hunger and fatigue • Thirst • Polyuria, indicated by urinary frequency, which is often noticed by the patient at night (nocturia) with the excretion of large volumes of urine • Dry mouth • Itchy skin • Blurred vision As type 2 diabetes develops, weight gain or increased abdominal girth is common, whereas in type 1 weight loss is common. As blood glucose rises in the early stage, fluid loss is significant, and appetite increases. Typically, the three Ps—polyuria, polydipsia, and polyphagia—herald the onset of diabetes. If the insulin deficit continues, the patient progresses to the stage of diabetic ketoacidosis. ■ Diagnostic Tests Fasting blood glucose level, the glucose tolerance test, and the glycosylated hemoglobin (HbA1c) test are used to screen people with clinical and subclinical diabetes. There is less emphasis now on the “prediabetic stage,” because tissue and organ damage appear to commence at an early stage. At present, a fasting blood sugar equal to or greater than 126 mg/dL, taken on more than one occasion, confirms a diagnosis of diabetes. The test for HbA1c is used to monitor long-term control (8 to 12 weeks) of blood glucose levels. The test should be repeated every 3 months. The acceptable level for HbA1c has been lowered to 7% and is likely to be lowered again to 6% (normal), so as to reduce the serious long-term effects of hyperglycemia. Patients with diabetes can monitor themselves at home by taking a sample of capillary blood from a finger and checking it with a portable monitoring machine (Glu- cometer). When performed regularly, this self-monitoring test helps reduce the fluctuations in blood glucose levels and therefore the risk of complications. Urine tests for ketones are helpful for those who are predisposed to ketoacidosis. Arterial blood gas analysis is required if ketoacidosis develops. Serum electrolytes may be checked as well. ■ Treatment Maintenance of normal blood glucose levels is important to minimize the complications of diabetes mellitus, both THINK ABOUT 16.3 In people with diabetes mellitus type 1, explain the reason for (a) ketoacidosis and (b) ketonuria. potential (diabetic ketoacidosis [DKA] or diabetic coma). THINK ABOUT 16.4 How would omission of a meal affect blood glucose levels and insulin balance? Exercise A regular moderate exercise program is very beneficial to the diabetic. Exercise can increase the uptake of glucose by muscles substantially without an increase in insulin use. It also assists in weight control, reduces stress, and improves cardiovascular fitness. There is a risk that hypoglycemia may develop with exercise, particularly strenuous or prolonged exercise. The increased use of glucose by skeletal muscle, plus the increased absorption of insulin from the injection site, may lower blood glucose levels precipitously. Increasing carbohydrate intake by eating a snack to compensate for exercise can decrease this risk. Oral Medications • Metformin (Glucophage) is usually the first medication prescribed in the treatment of type 2 diabetes when diet and exercise alone are not effective; it reduces insulin resistance and glucose production. CHAPTER 16 Endocrine System Disorders 407 Complications Many factors can lead to fluctuations in serum glucose levels and subsequent changes in cell metabolism throughout the body. These changes may result from variations in diet or physical activity, the presence of infections, or alcohol use. Complications may be acute (eg, hypoglycemia) or chronic. Long-term complications such as vascular disease result from degenerative changes in the tissues. Stable blood glucose levels reduce the risk of complications. Acute Complications Hypoglycemia (Insulin Shock) ■ Pathophysiology Hypoglycemia is precipitated by an excess of insulin, which causes a deficit of glucose in the blood (Fig. 16.3). It usually occurs in patients with type 1 diabetes, often quite suddenly, following strenuous exercise, an error in dosage, vomiting, or skipping a meal after taking insulin. Many individuals are able to recognize their own response. The lack of glucose quickly affects the nervous system, because neurons cannot use fats or protein as an energy source. ■ Signs and Symptoms The manifestations of hypoglycemia are related directly to the low blood glucose levels, not to the high insulin levels. One group of signs is related to impaired neurologic function resulting from the lack of glucose. These signs include the following: • Poor concentration • Slurred speech • Lack of coordination and staggering gait; persons with hypoglycemia are sometimes assumed to be intoxicated with alcohol The second group of signs is related to the hypoglycemic state stimulating the sympathetic nervous system, resulting in the following: • Increased pulse • Pale, moist skin • Anxiety • Tremors If hypoglycemia remains untreated, loss of consciousness, seizures, and death will follow. ■ Treatment Treatment consists of immediate administration of a concentrated carbohydrate, such as sweetened fruit juice or candy. If the person is unconscious, glucose or glucagon may be given parenterally (usually intravenously). Hypoglycemia can be life threatening or can cause brain damage if it is not treated promptly. It is wise to verify that patients who have come for other treatments have eaten and taken the appropriate medications before the appointment to minimize the risk of a hypoglycemic episode during the appointment. Appointments should be scheduled so that meals are not unduly delayed or missed. • Sulfonylureas such as glyburide (DiaBeta, Glynase), glipizide (Glucotrol), and glimepiride (Amaryl) help the body to create more insulin. • Meglitinides, which include repaglinide (Prandin) and nateglinide (Starlix), also stimulate insulin production • Thiazolidinediones such as rosiglitazone (Avandia) and pioglitazone (Actos), act like metformin in reducing insulin resistance. • DPP-4 inhibitors such as sitagliptin (Januvia), saxagliptin (Onglyza), and linagliptin (Tradjenta) help reduce blood sugar levels. • GLP-1 receptor agonists such as Exenatide (Byetta) and liraglutide (Victoza) slow digestion and help lower blood sugar levels. • SGLT2 inhibitors, which include canagliflozin (Invokana) and dapagliflozin (Farxiga), prevent the kidneys from reabsorbing the sugar into the blood. Frequently a combination of diet, exercise, and oral hypoglycemic drugs is effective in treating mild forms of diabetes. Insulin Replacement Insulin can be used for replacement therapy. It must be injected subcutaneously because it is a protein that is destroyed in the digestive tract if taken orally. Continuous infusions via a small pump are favored by some diabetics and may provide better control. The primary form of insulin used now is a biosynthetic form of insulin, identical to human insulin (Humulin), synthesized by bacteria using recombinant DNA tech- niques. Insulin is standardized in units for subcutaneous administration and is produced in three forms: rapid- onset, short-acting (regular) insulin; intermediate-acting (Lente) insulin; and slow-onset, long-acting (protamine zinc or Ultralente) insulin. Newer insulins on the market have a very rapid onset, 15 minutes, or last for 24 hours, in an attempt to provide better control of serum levels. A physician must carefully monitor any transition from one type of insulin to another. Blood glucose levels should be checked at more frequent intervals during any changes. The type of insulin used and its effective period can be important factors in predicting periods of potential hypoglycemia in individual patients, and food intake can be timed to coincide with peak insulin levels, thus avoiding hypoglycemia. Each patient has an individual- ized schedule of insulin administration. Injection sites must be rotated to minimize skin damage. Insulin types may be mixed for administration, and several injections may be required in 1 day. Insulin dosage may also require adjustment under special circumstances such as infection with high fever or vomiting, or at the time of surgery. Continuous control of blood glucose levels minimizes the risk of potential complications for the patient. Improved self-monitoring devices are helpful. Small, computerized recording and data bank devices have improved the compliance of young adults. 408 SECTION III Pathophysiology of Body Systems ■ Pathophysiology Ketoacidosis usually develops over a few days and may be initiated by an infection or stress, which increases the demand for insulin in the body. It may also result from an error in dosage or overindulgence in food or alcohol (Fig. 16.4). ■ Signs and Symptoms The signs and symptoms of diabetic ketoacidosis are related to dehydration, metabolic acidosis, and electrolyte imbalances (Table 16.3). Signs of dehydration include the following: • Thirst • Dry, rough oral mucosa • Warm, dry skin • Pulse is rapid but weak and thready • Low blood pressure as the vascular volume decreases Diabetic Ketoacidosis (DKA). As indicated earlier, DKA results from insufficient insulin, which leads to high blood glucose levels and mobilization of lipids. It is more common in type 1 patients. 6. Excess insulin transports glucose into cells 5. Increased gluconeogenesis SNS = Insulin G = Glucose • weakness, confusion • pallor • diaphoresis • tremors • tachycardia Clinical signs3. Hypoglycemia Decreased CNS function 4. Stimulates SNS 2. Increased transport of glucose into cells 1. Excess insulin in blood 8. Blood glucose levels decrease further 7. No glucose intake 9. Neurons cannot function 10. Coma and death Glucose intake Return to normal state G G G G GBlood Cell –G –G FIG. 16.3 Hypoglycemic shock (insulin shock). EMERGENCY TREATMENT FOR HYPOGLYCEMIC SHOCK 1. If conscious, immediately give sweet fruit juice (liquids are absorbed more quickly), honey, candy, or sugar. 2. If unconscious, give nothing by mouth. Intravenous glucose 50% is required. 3. Note: Diabetic ketoacidosis (diabetic coma or hyperglycemia) also causes loss of consciousness. The emergency treatment is insulin, fluid, and sodium bicarbonate. Assessment should be done to differentiate the cause. CHAPTER 16 Endocrine System Disorders 409 electrolytes. Serum potassium levels may decrease when insulin is administered because insulin promotes transport of potassium into cells. Bicarbonate administration is essential to reverse the acidosis, as well as specific treat- ment to resolve the causative factor of the diabetic ketoacidosis episode. • Oliguria (decreased urine output) indicates that compensation mechanisms to conserve fluid in the body are taking place Ketoacidosis leads to the following: • Rapid, deep respirations (Kussmaul respirations) • Acetone breath (a sweet, fruity smell) • Lethargy and decreased responsiveness, indicating depression of the central nervous system owing to acidosis and decreased blood flow Metabolic acidosis develops as ketoacids bind with bicarbonate ions in the buffer, leading to these reactions: • Decreased serum bicarbonate levels and decreased serum pH (see Chapter 2) • As dehydration progresses, renal compensation is reduced, acidosis becomes decompensated • A fall in serum pH • Loss of consciousness Electrolyte imbalances include imbalances of sodium, potassium, and chloride and have the following signs: • Primarily abdominal cramps • Nausea and vomiting • Lethargy and weakness Actual serum values of electrolytes may be misleading because the proportion of water lost can affect the serum level even though the electrolytes were lost in the urine. Serum sodium is often low, but the potassium concentra- tion may be elevated because of acidosis (see Chapter 2). If the condition remains untreated, central nervous system depression develops owing to the acidosis and dehydration, leading to coma. ■ Treatment Treatment of diabetic ketoacidosis involves the administra- tion of insulin as well as replacement of fluid and Decreased insulin secretion or increased insulin-resistant cells Decreased glucose transport into cells Polyphagia Hyperglycemia (high blood glucose)(hunger) (thirst) Polyuria Ketoacidosis Ketonuria Dehydration Acidosis Electrolyte imbalance Glucosuria (excess glucose spills into urine) (osmotic diuresis— large volume) (acidic waste—formed in large amounts) Lipolysis Ketone bodiesGluconeogenesis Glycogenolysis and (catabolism) Polydipsia (loss in urine) FIG. 16.4 Development of diabetic ketoacidosis. THINK ABOUT 16.5 a. Describe three signs that would help differentiate someone with hypoglycemia from someone with diabetic ketoacidosis. b. Describe and explain the loss of consciousness that occurs with (1) hypoglycemia and (2) diabetic ketoacidosis. THINK ABOUT 16.6 Compare the characteristics of the urine and the effects on pulse and respiration of hypoglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic nonketotic coma. Hyperosmolar Hyperglycemic Nonketotic Coma. Hyper- osmolar hyperglycemic nonketotic coma develops more frequently in patients with type 2 diabetes. Often the patient is elderly with an infection or one who has overindulged in carbohydrates, thereby using more insulin than anticipated. In these cases, hyperglycemia and dehydration develop because of the relative insulin deficit, but sufficient insulin is available to prevent ketoacidosis. Therefore the condition may be difficult to diagnose initially. Severe cellular dehydration results in neurologic deficits, muscle weakness, difficulties with speech, and abnormal reflexes. 410 SECTION III Pathophysiology of Body Systems Chronic Complications Degenerative changes occur in many tissues with both types of diabetes, particularly when blood glucose levels are poorly controlled. The insulin deficit and glucose excess cause a number of alterations in metabolic path- ways involving carbohydrates, lipids, and proteins. Vascular Problems. Changes occur in both the small and large arteries because of degeneration related to the metabolic abnormalities associated with diabetes (Table 16.4). Microangiopathy, in which the capillary basement membrane becomes thick and hard, causes obstruction or rupture of capillaries and small arteries, and it results in tissue necrosis and loss of function. Retinopathy is a leading cause of blindness (Fig. 16.5). Retinal changes can be observed through the pupil of the eye. Diabetic nephropathy, or vascular degeneration in the kidney glomeruli, eventually leads to chronic renal failure (Fig. 16.6). It is responsible for 40% of patients in end-stage renal failure. Macroangiopathy, like atherosclerosis, affects the large arteries (see Chapter 12), thus leading to a high incidence of heart attacks, strokes, and peripheral vascular disease in diabetics. Obstruction of the arteries in the legs fre- quently results in ulcers on the feet and legs that are slow to heal (Fig. 16.7). Ulcers are aggravated when TABLE 16.3 Progressive Effects of an Insulin Deficit (Diabetic Ketoacidosis) Signs Rationale Early Signs Hyperglycemia Lack of Insulin Hunger (polyphagia) Compensation for cell starvation Glucosuria Glucose in filtrate exceeds tubule transport Polyuria Osmotic diuresis due to glucosuria Thirst (polydipsia) Response to water loss Weakness and weight loss Loss of fluid and lack of glucose to cells Progressive Signs Increasing hyperglycemia Gluconeogenesis owing to response by epinephrine, cortisol, and glucagon Dehydration Polyuria Skin warm and dry; decreased turgor Decreased interstitial fluid Oral mucosa rough and dry Decreased interstitial fluid Eyeballs sunken and soft Decreased interstitial fluid Decreased blood pressure Decreased blood volume Pulse—rapid, thready Compensation—sympathetic nervous system Lethargy, weakness, confusion Decreased oxygen and glucose to the brain resulting from hypovolemia; also acidosis and electrolyte imbalance Ketoacidosis Catabolism of Fats and Protein Serum bicarbonate and serum pH low Compensation for acidosis Rapid, deep respirations (air hunger or Kussmaul respirations) Compensation for acidosis Acetone breath—sweet, fruity odor Acetone expired Ketonuria Ketoacids excreted in urine Nausea, vomiting, weakness Loss of Na+, K+, Cl− in urine and ketonemia Late Signs Coma Central nervous system depression owing to acidosis and dehydration TABLE 16.4 Vascular Problems With Diabetes Macroangiopathy • Myocardial infarction (heart attack) • Cerebrovascular accident (stroke) • Peripheral vascular disease (ischemia, gangrene, and amputation affecting the legs) Atherosclerosis in large arteries related to hyperlipidemia, hypertension, and degenerative changes in the intimal layer of the arterial wall Microangiopathy • Kidneys Diabetic nephropathy Chronic renal failure Thickening of the capillary basement membrane, leading to occlusion or rupture • Eyes Retinopathy Microaneurysms, neovascularization, and fibrosis Leads to blindness • Nervous system Neuropathy in the central nervous system and peripheral nerves Decreased function of sensory, motor, and autonomic nervous system fibers Note—In addition to ischemia, there is also a metabolic abnormality that causes degeneration of myelin and deficit of myo-inositol, essential in the conduction of nerve impulses. CHAPTER 16 Endocrine System Disorders 411 traumatic surgery to remove vascular obstructions, using angioscopic bypass surgery. This is very helpful to diabet- ics, who tend to have delayed healing. Neuropathy. Peripheral neuropathy is a common problem for diabetics. This leads to impaired sensation, numbness, tingling, weakness, and muscle wasting. It results from peripheral neuropathy is present, reducing pain sensation. Peripheral vascular disease also causes intermittent claudication (pain with walking), which greatly impairs mobility. Decreased blood flow predisposes to frequent infection and gangrenous ulcers. In some cases, vascular problems necessitate amputation if gangrene develops. New surgical techniques allow for less invasive, less Microaneurysm Blood flow Ruptured aneurysm, hemorrhage, and exudate Retinal cells die Neovascularization with rupture and fibrosis Retina with aneurysms and exudate A FIG. 16.5 A, Diabetic retinopathy in the eye. B, Retina from a case of advanced diabetic micro- angiopathy showing several aneurysms. (From Cotran RS, Kumar V, Collins T: Robbins Pathologic Basis of Disease, ed 6, Philadelphia, 1999, Saunders.) 412 SECTION III Pathophysiology of Body Systems and legs tend to persist because of vascular impairment, and healing is slow, contributing to a high incidence of gangrene and resultant amputation. Fungal infections such as Candida occur frequently and persist on the skin in body folds (Fig. 16.8), in the oral cavity (see Fig. 17.5B), and vagina. The urinary tract is a common site of infection, particularly if bladder function is compromised, and predisposes the patient to cystitis and pyelonephritis. Periodontal disease (infection in the tissues around the teeth) (see Fig. 16.8) and dental caries (infection and decay in teeth) are much more common in diabetics. ischemia and altered metabolic processes. Degenerative changes occur in both unmyelinated and myelinated nerve fibers. The risks of tissue trauma and infection are greatly increased when vascular impairment and sensory impairment coexist. Autonomic nerve degeneration develops as well, leading to bladder incontinence, impotence, and diarrhea. Impaired vasomotor reflexes may cause dizziness when a person stands up. Infections. Infections are more common and tend to be more severe in diabetics, probably because of the vascular impairment, which decreases tissue resistance, the delay in healing because of insulin deficit, and the increased glucose levels in body fluids that support infection. Wound healing is slow, predisposing to infection in case of trauma or surgery. Diabetics are also susceptible to tuberculosis, which is increasing in incidence. Infections in the feet FIG. 16.6 Diabetes mellitus with nodular glomerulosclerosis. (From: Klatt E: Robbins and Cotran Atlas of Pathology, ed 3, Philadelphia, 2010, Saunders, Elsevier.) FIG. 16.7 Classic neuropathic diabetic foot ulcer. Note ulceration in the callus is well circumscribed. The lesion is painless. (From the Michigan Diabetes Research and Training Center, University of Michigan, Ann Arbor.) A FIG. 16.8 A, Periodontal disease in a diabetic. Note the inflam- mation and infection. (Courtesy of Evie Jesin, RRDH, BSc, George Brown College of Applied Arts and Technology, Toronto, Ontario, Canada.) B, Candidiasis in the right axilla with satellite pustules. (From Stone DR, Gorbach SL: Atlas of Infectious Diseases, Philadelphia, 2000, Saunders.) B CHAPTER 16 Endocrine System Disorders 413 The newborn infant is usually larger than average in size and predisposed to complications. Good prenatal care decreases these risks. Cataracts. Clouding of the lens of the eye is another degenerative process related to the abnormal metabolism of glucose, and it results in accumulated sorbitol and water in the lens, destroying the transparency. Cataracts may eventually lead to blindness and should be removed when they impair visual function (see Chapter 15). A summary of complications of diabetes may be found in Fig. 16.9. Pregnancy. Complications for both the mother and the fetus may occur during pregnancy. Maternal diabetes may become more severe, control is more difficult with the continual hormonal and metabolic changes, and there is an increased incidence of spontaneous abortions and abnormalities in infants born to diabetic mothers. Eyes Cataract Retinal microaneurysms Heart Myocardial infarction Arrhythmias Kidneys Nephropathy and infection Neuropathy Impotence and infertility Urinary incontinence Numbness, weakness Peripheral vascular disease Ulcers Delayed healing Gangrene Brain Cerebrovascular accident (Atherosclerosis) Diabetes mellitus Decreased insulin available Increased blood glucose Altered lipid and protein metabolism Hypoglycemic shock Diabetic ketoacidosis Acute complications FIG. 16.9 Potential complications of diabetes mellitus. APPLY YOUR KNOWLEDGE 16.1 Explain why research efforts into pancreatic beta cell transplants are being strongly supported. THINK ABOUT 16.7 a. Describe all the factors that may lead to a persistent infected foot ulcer in patients with diabetes. b. Suggest several precautions for foot care that should be taken to prevent foot ulceration. Parathyroid Hormone and Calcium Hypoparathyroidism may be caused by a congenital lack of the four parathyroid glands, following surgery or radiation in the neck region, or as a result of autoimmune disease. Hypoparathyroidism leads to hypocalcemia, or low serum calcium levels. Hypocalcemia affects nerve and muscle function in different ways. Low serum calcium levels result in weak cardiac muscle contractions but also increase the excitability of nerves, leading to spontaneous contraction of skeletal muscle. This causes muscle twitching and spasms, com- monly known as tetany, which is usually observed first 414 SECTION III Pathophysiology of Body Systems in the face and hands. Hypocalcemia does not weaken skeletal muscle contractions because sufficient calcium is stored in skeletal muscle cells. Cardiac muscle cells, on the other hand, do not have large stores of calcium but rely instead on calcium from the blood for contraction. Hyperparathyroidism may be caused by an adenoma, hyperplasia, or secondary to renal failure. It causes hypercalcemia, or high serum calcium levels. Hypercalcemia leads to forceful cardiac contractions (see Table 2.7 for signs of calcium imbalance). The most serious effects of hyperparathyroidism occur in the bone tissue. Increased parathyroid hormone (PTH) causes calcium to leave the bone, leading to osteoporosis, weakening the bone so that it fractures easily (see Chapter 9). Hypercalcemia also increases one’s predisposition to kidney stones (see Chapter 18). Calcium metabolism may be modified by other factors, such as the presence of vitamin D and serum phosphate levels. Therefore calcium imbalance may not be caused by hormone disorders. Serum levels of PTH and calcium may vary depending on the specific cause of the problem. For instance, in patients who are immobile or have bone cancer, hypercalcemia may be present along with a low level of PTH (Fig. 16.10). In patients with severe renal disease, there is decreased activation of vitamin D in the kidneys (see Chapter 18). Vitamin D is essential for calcium absorption and metabolism. Renal failure also leads to retention of phosphate ion and hyperphospha- temia. Because calcium and phosphate have a reciprocal relationship, hypocalcemia results. In this case, hypocal- cemia leads to high levels of PTH. Therefore any changes in the bone, kidneys, or digestive tract are significant in determining the cause of calcium imbalance, as are serum levels of calcium, phosphate, and PTH. A comparison of the common effects of parathyroid imbalances is found in Fig. 16.11. Treatment of parathyroid disorders depends on the cause. Any underlying disorder should be treated. Chronic hypoparathyroidism may be treated with calcium and vitamin D. Parathyroidectomy may be required for hyperparathyroidism. whether it is in the pituitary gland, the hypothalamus, or the target gland (see Fig. 16.2). Benign adenomas are the most common cause of pituitary disorders. They lead to two groups of manifesta- tions in the patient: • The effect of the mass as it enlarges and causes pressure in the skull (increased intracranial pressure, see Chapter 14). Signs of pressure on brain tissues include increasing headaches, seizures, and drowsiness. Visual defects such as hemianopsia are common because of pressure on the adjacent optic chiasm. • The effect of the tumor on hormone secretion. The hormonal effects of the adenoma depend on which specific cells in the pituitary are involved and their location. For example, growth hormone is produced in cells in the anterior wings of the gland, whereas prolactin- producing cells are scattered throughout the gland. The tumor cells may secrete an excessive amount of a particular hormone (eg, somatotropic cells secrete GH). Or the excess hormone could be ACTH or prolactin. Sometimes more than one hormone is secreted. In some cases, the adenoma may destroy an area of pituitary cells, causing a deficit of a particular hormone (eg, decreased ACTH and therefore decreased adrenal cortex activity). With some tumors, hemorrhage or infarction can occur, causing a sudden increase in intracranial pressure and destroying part of the pituitary (pituitary apoplexy). Untreated adenomas eventually destroy all types of cells, resulting in panhypopituitarism (diminution or cessation of pituitary function resulting in loss of gonadal function and the degrading of thyroidal and adrenal function). Pituitary adenomas make up more than 10% of intra- cranial tumors. They occur primarily in persons 30 to 50 years of age. Tumors are usually removed by surgery or radiation therapy. Replacement of one or more hormones is necessary after this therapy or any time that deficits develop. Vascular thrombosis and infarction associated with obstetric delivery or other cardiovascular disorders damage the pituitary, causing hypopituitarism. Hypo- thalamic disorders include tumors or infection. Growth Hormone Dwarfism, or short stature, may be caused by a number of factors, one of which is a deficit of growth hormone (GH, somatotropin) or somatotropin-releasing hormone (Fig. 16.12). In some cases of pituitary adenomas, other types of pituitary cells are also affected, resulting in multiple deficits. Usually the pituitary dwarf has normal intelligence, normal body proportions, and some delay in skeletal maturation and puberty. Replacement therapy for GH deficiency in a child before closure of the epiphyses is available. Gigantism, or tall stature, results from excess GH before puberty and fusion of the epiphyses. THINK ABOUT 16.8 a. Describe three ways in which increased secretion of PTH can increase blood levels of calcium. b. Describe the effect of increased calcitonin secretion on blood calcium levels. c. Explain how malabsorption of calcium from the intestine would affect serum calcium and serum PTH. d. Compare the effects of hypocalcemia on cardiac and skeletal muscle, and explain the rationale for each. Pituitary Hormones As mentioned, it is important to determine the source of the imbalance in hormones controlled by the pituitary, CHAPTER 16 Endocrine System Disorders 415 weakness at the wrist and hand) or arthritis. A protruding mandible or jaw (prognathia, see Fig. 16.12C) and a large tongue (macroglossia) are common. Initially the patient notices a need for a larger shoe or glove size. In addition, GH affects glucose metabolism and the effectiveness of insulin, resulting eventually in diabetes. Hypertension and cardiovascular disease also develop with untreated acromegaly. Acromegaly refers to the effects of excess GH secretion in the adult, usually by an adenoma. The bones become broader and heavier, and the soft tissues grow, resulting in enlarged hands and feet, a thicker skull, and changes in the facial features (see Fig. 16.12B). Thickening of the skull bones may compress nerves and blood vessels passing through the foramina. Overgrowth of bones and cartilage may lead to carpal tunnel syndrome (pain and 1. Low blood Ca++ Ca++ Ca++ Ca++ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + NORMAL CONTROL AND FEEDBACK OF CALCIUM EFFECT OF IMMOBILITY ON SERUM Ca++ AND PTH EFFECT OF RENAL DISEASE ON SERUM Ca++ AND PTH Immobility High blood Ca++ Bone releases Ca++ Low serum PTH Inhibits parathyroid secretion Pathology blocks normal feedback Renal disease Low serum Ca++ Stimulates parathyroid gland B C A High serum PTH Pathology blocks normal feedback 2. Stimulate secretion of PTH 6. Ca++ used 4. High blood Ca++ 3. Release of Ca++ from bone Increased reabsorption of Ca++ from kidney Increased absorption of Ca++ from intestines 5. Inhibit secretion of PTH FIG. 16.10  Calcium and parathyroid hormone (PTH) relationships. •, PTH; +, Ca++. 416 SECTION III Pathophysiology of Body Systems • Thirst, eventually causing severe dehydration (note that glucose is not present in the urine with diabetes insipidus as it is in cases of diabetes mellitus) ■ Treatment Replacement therapy for ADH is available. Inappropriate Antidiuretic Hormone Syndrome ■ Pathophysiology Inappropriate ADH syndrome, also called syndrome of inap- propriate ADH, is due to excess ADH, which causes retention of fluid. In some cases, the additional ADH is temporary, triggered by stress, or may be secreted by an ectopic source (eg, a bronchogenic carcinoma). ■ Signs and Symptoms The signs are related to severe hyponatremia, which causes mental confusion and irritability. ■ Treatment Diuretics and sodium supplements are used to correct the problem, as well as to investigate any underlying cause. Antidiuretic Hormone (Vasopressin) Diabetes Insipidus ■ Pathophysiology Diabetes insipidus results from a deficit of ADH. This deficit may originate in the neurohypophysis. Head injury or surgery may cause a temporary condition. In some cases, the condition is considered to be nephrogenic, when the renal tubules do not respond to the hormone. The latter may be genetic or linked to electrolyte imbalance or drugs. ■ Signs and Symptoms The following clinical manifestations arise: • Polyuria with large volumes of dilute urine Skeletal muscle Muscle spasm Tetany Heart Weak cardiac muscle contraction Arrhythmias Hypotension Gastrointestinal Increased peristalsis Diarrhea, nausea Cramps Decreased peristalsis Constipation, nausea Bone Osteoporosis, fractures Kidneys Polyuria, thirst Renal insufficiency Renal calculi Nervous system Increased neuroexcitability Tingling in fingers and around mouth Hyperactive reflexes Muscle weakness Decreased tone Forceful cardiac contraction Arrhythmias, bradycardia Hypertension Decreased neuroexcitability Apathy, fatigue Personality change HYPOPARATHYROIDISM HYPOCALCEMIA HYPOPARATHYROIDISM HYPERCALCEMIA FIG. 16.11 Common effects of parathyroid hormone imbalances. THINK ABOUT 16.9 a. Explain why longitudinal bone growth cannot occur in patients with acromegaly. b. Compare dwarfism, gigantism, and acromegaly, including abnormal hormone secretion, age affected, and the effect of hormonal change. CHAPTER 16 Endocrine System Disorders 417 ■ Pathophysiology Endemic goiter may affect large groups of people in a specific geographic area. It is a hypothyroid condition that occurs in regions where there are low iodine levels in the soil and food (eg, mountainous areas or around the Great Lakes). Normally iodine is “trapped” by the thyroid gland and used to synthesize triiodothyronine (T3) and thyroxine (T4) (see Fig. 16.14B). This dietary deficiency leads to low T3 and T4 (thyroid hormone) production and a compensatory increase in TSH from the pituitary, producing hyperplasia and hypertrophy in the thyroid gland (see Fig. 16.14C). The use of iodized salt has solved this problem to a large extent. Goitrogens are foods that contain elements that block synthesis of T3 and T4 but increase TSH secretion. Thyroid- stimulating hormone causes hyperplasia of the gland Thyroid Disorders The two thyroid hormones, thyroxine and triiodothyro- nine, are secreted by the thyroid gland in response to hypothalamic-pituitary secretion of thyroid-stimulating hormone (Fig. 16.13). Disorders may result from pituitary or thyroid gland dysfunction. Goiter Goiter refers to an enlargement of the thyroid gland, which is often visible on the anterior neck. Goiters are caused by various hypothyroid and hyperthyroid conditions. A goiter can become very large, compressing the esophagus and interfering with swallowing, or it can cause pressure on the trachea. It can also be of cosmetic concern (Fig. 16.14A). FIG. 16.12 Effects of growth hormone. A, Primary gigantism. A 22-year-old man with gigantism due to excess growth hormone (left) with his identical twin. (From Black J, Hawks J: Medical Surgical Nursing: Clinical Management for Positive Outcome, ed 8, St. Louis, 2009, Saunders, Elsevier.) B, The patient’s hands and face show clinical signs of acromegaly. (From Jarvis C: Physical Examination and Health Assessment, Philadelphia, 1992, Saunders.) C, Progressive facial changes associated with acromegaly. (From Lewis S, et al: Medical-Surgical Nursing: Assessment and Management of Clinical Problems, ed 10, St. Louis, 2017, Elsevier.) B C 418 SECTION III Pathophysiology of Body Systems and can promote goiter formation when such substances are ingested in large quantities. These foods include cabbage, turnips, and other related vegetables. Lithium and fluoride may also be goitrogenic. Toxic goiter is a hyperthyroid condition resulting from hyperactivity of the thyroid gland, perhaps due to excessive stimulation by TSH, which produces a large nodular gland. ■ Treatment Goiter treatment depends on the size of the goiter, the signs and symptoms, and the underlying cause. Various treatments are available: • Hyperthyroidism and hypothyroidism medications such as levothyroxine (Levothroid, Synthroid) • Surgery—total or partial thyroidectomy • Radioactive iodine—hormone replacement may become necessary as this method may result in an underactive thyroid Hyperthyroidism (Graves Disease) There are various forms of hyperthyroidism, with increased T3 and T4 secretion. Graves disease provides an example. Hypothalamus TRH TSH 6. NEGATIVE FEEDBACK High levels of T3 and T4 inhibit secretion of TSH and TRH 5. TARGET CELLS increase metabolism T3 and T4 TSH 2. HYPOTHALAMUS increases secretion of TRH into blood 3. PITUITARY glandular cells increase secretion of TSH into circulation 4. THYROID GLAND increases secretion of T3 and T4 into blood 1. STIMULUS (cold or stress) FIG. 16.13 Hypothalamus-pituitary-thyroid gland feedback mechanism with thyroid hormone. ■ Pathophysiology Graves disease occurs more frequently in women older than 30 years of age and is related to an autoimmune factor. It is manifested by the signs of hypermetabolism, toxic goiter, and exophthalmos (Table 16.5). Increased stimulation of the sympathetic nervous system magnifies the metabolic effects. ■ Signs and Symptoms Exophthalmos is evident by the presence of protruding, staring eyes and decreased blink and eye movements (Fig. 16.15). It results from increased tissue mass in the orbit pushing the eyeball forward and from increased sympathetic stimulation affecting the eyelids. If untreated, visual impairment may result from optic nerve damage or corneal ulceration. Thyrotoxic crisis, or thyroid storm, is an acute situation in a patient with uncontrolled hyperthyroidism, usually precipitated by infection or surgery. It is life threatening because of the resulting hyperthermia, tachycardia, and heart failure and delirium. ■ Treatment Graves disease is treated by a course of radioactive iodine, surgical removal of the thyroid gland, or the use of CHAPTER 16 Endocrine System Disorders 419 O CH2 NH2CHCOOH THYROXINE (T4) OH O CH2 NH2CHCOOH OH TRIIODOTHYRONINE (T3) B. STRUCTURE OF THYROID HORMONES C. GOITER DEVELOPMENT Four iodine atoms Three iodine atoms TRH TSH 1. Low blood levels of T3 and T4 stimulate hypothalamus 2. Hypothalamus increases TRH secretion 3. Pituitary increases TSH secretion 4. TSH stimulates the thyroid gland 5. Increased TSH leads to enlarged gland 6. Goiter 7. Iodine deficit 9. Hypothyroidism 8. Decreased synthesis of T3 and T4 A FIG. 16.14 Endemic goiter and hypothyroidism. (A, from Wilson JD, Foster DW: Williams Textbook of Endocrinology, ed 8, Philadelphia, 1992, Saunders.) 420 SECTION III Pathophysiology of Body Systems Severe hypothyroidism occurs in several forms: • Hashimoto thyroiditis is a destructive autoimmune disorder • Myxedema, severe hypothyroidism in adults (myxedema refers to the nonpitting edema manifested as facial puffiness and a thick tongue); myxedema coma refers to acute hypothyroidism resulting in hypotension, hypoglycemia, hypothermia, and loss of consciousness, a life-threatening complication occurring in undiag- nosed or untreated elderly patients. • Cretinism, untreated congenital hypothyroidism, may be related to iodine deficiency during pregnancy or may be a developmental defect. The thyroid gland may be nonfunctional or absent. Neonatal screening is standard in many areas of the country; it leads to early treatment and prevents the mental retardation that accompanies early hypothyroidism. Lack of treatment results in severe impairment of all aspects of growth and development because thyroid hormone affects the metabolism of all cells. For example, the child may have difficulty feeding, delayed tooth eruption, maloc- clusion, and a large protruding tongue, demonstrating stunted skeletal growth and extreme lethargy. Diagnostic Tests Current tests for thyroid disorders include checks of blood levels of T4 and T3, as well as serum TSH levels, and the uptake of radioactive iodine (a T3 uptake test). Scans may be used to search for the presence of tumor nodules. Antibody assays may also be required to confirm a specific diagnosis. FIG. 16.15 Hyperthyroidism showing exophthalmos. (From Wilson JD, Foster DW: Williams Textbook of Endocrinology, ed 8, Philadelphia, 1992, Saunders.) THINK ABOUT 16.10 a. Why do weight loss and insomnia occur with hyperthyroidism? b. Why are cold intolerance and bradycardia common with hypothyroidism? c. What is a goiter, and how may it develop? antithyroid drugs. Following treatment, there is a risk that patients may develop hypothyroidism or hypoparathyroidism. Hypothyroidism Mild hypothyroidism is common and is easily treated by replacement doses of thyroid hormone. Signs of hypothyroidism are listed in Table 16.5. Adrenal Glands Adrenal Medulla Pheochromocytoma is a benign tumor of the adrenal medulla that secretes epinephrine, norepinephrine, and sometimes other substances. Occasionally there are multiple tumors, or the tumor originates in the sympathetic ganglia. It may be bilateral or unilateral. It is a relatively rare tumor, but it is one of the “curable” causes of hypertension if it is diagnosed. The signs it produces—headache, heart palpitations, sweating, and intermittent or constant anxiety—are related to elevated blood pressure. Frequently catecholamines are released intermittently, causing sudden hypertension and severe headache. TABLE 16.5 General Comparison of Hypothyroidism and Hyperthyroidism Hypothyroidism Hyperthyroidism Serum levels of T3 and T4 Low High Metabolic rate Low High Goiter Present with endemic goiter Present with Graves disease Skin Pale, cool, with edema Flushed and warm Temperature tolerance Cold intolerance Heat intolerance Eyes No changes Exophthalmos with Graves disease Cardiovascular Bradycardia, enlarged heart Tachycardia, increased blood pressure Nervous system Lethargic, slow intellectual functions Restless, nervous, tremors Body weight Some weight increase with decreased appetite Thin, but increased appetite CHAPTER 16 Endocrine System Disorders 421 • Suppression of the immune response and the inflam- matory response with atrophy of the lymphoid tissue, predisposing the client to infection • Stimulation of erythrocyte production • Emotional lability and euphoria Health care professionals will have two concerns: 1. The risk of infection in the patient with Cushing syndrome and the need for precautions; infection may be local or systemic (eg, tuberculosis) 2. A decreased stress response in a patient with iatrogenic Cushing syndrome because of the atrophy of the adrenal cortex; therefore the doses of medication may have to be increased before and during a stressful event; similarly dosage must be gradually reduced over a period of time to permit resumption of normal secretory function by the gland Treatment depends on the underlying cause. Adrenal Cortex Cushing Syndrome Cushing syndrome is caused by an excess of glucocor- ticoids (eg, hydrocortisone or cortisol). The mechanism for the excess amount of hormone and the effect on related hormones depends on the cause. Excess glucocorticoids may result from various conditions: • Adrenal adenoma (Fig. 16.16) • Pituitary adenoma (Fig. 16.17) or Cushing disease • An ectopic carcinoma that causes paraneoplastic syndrome (see Fig. 16.17C and Chapter 20) • Iatrogenic conditions, such as the administration of large amounts of glucocorticoids for many chronic inflammatory conditions (see Fig. 16.17D and Chapter 5) Glucocorticoids are essential for the stress response and essential for life. They perform many important functions in the body. But in excess amounts, they produce many unfortunate effects. This is why prolonged treatment with these drugs is not recommended. Typical changes associated with Cushing syndrome include the following: • Characteristic change in the person’s appearance; a moon face (round and puffy) and a heavy trunk with fat at the back of the neck (buffalo hump) and wasting of muscle in the limbs (Fig. 16.18) • Fragile skin that may have red streaks as well as increased hair growth (hirsutism) • Catabolic effects such as osteoporosis and decreased protein synthesis, which will delay healing • Metabolic changes include increased gluconeogenesis and insulin resistance, which may lead to glucose intolerance; this may result in diabetes mellitus or exacerbate an existing diabetic state • Retention of sodium and water (mineralocorticoid effect), leading to hypertension, edema, and possible hyperkalemia A B FIG. 16.16 Cushing syndrome. A, Girl before onset of disease. B, The same girl 4 months after diagnosis. Note the characteristic moon face. (From: Zitelli B, Davis H: Atlas of Pediatric Physical Diagnosis, ed 5, St. Louis, 2007, Mosby.) THINK ABOUT 16.11 a. Explain how diagnostic tests could distinguish a pituitary Cushing syndrome from an adrenal Cushing syndrome. b. List the catabolic effects of excess glucocorticoids. Addison Disease Addison disease refers to a deficiency of adrenocortical secretions, the glucocorticoids, mineralocorticoids, and androgens. ■ Pathophysiology An autoimmune reaction is the common cause. The gland may be destroyed by hemorrhage with meningococcal infection or by viral, tubercular, or histoplasmosis infec- tions. Destructive tumors may also cause hypoactivity. 422 SECTION III Pathophysiology of Body Systems Pituitary tumor Increased ACTH secretion Increased cortisol secretion Enlarged adrenal cortex Enlarged adrenal cortex gland Adrenal cortex atrophy Increased ACTH secretion Inhibit hypothalamic pituitary ACTH secretion Feedback ineffective Increased secretion cortisol Increased secretion cortisol No secretion cortisol A. PITUITARY TUMOR (increased serum ACTH and cortisol) B. ADRENAL CORTEX TUMOR (increased serum cortisol, decreased ACTH) C. PARANEOPLASTIC SYNDROME (increased serum ACTH and cortisol) D. IATROGENIC (increased serum cortisol, decreased ACTH) Feedback Inhibit ACTH secretion Lung cancer Ingested cortisol medication Blood FIG. 16.17 Cushing syndrome—causes and feedback effects. CHAPTER 16 Endocrine System Disorders 423 ■ Signs and Symptoms The major effects of these hormonal deficits include the following: • Decreased blood glucose levels • Poor stress response • Fatigue • Weight loss • Frequent infections Low serum sodium concentration, decreased blood volume, and hypotension, accompanied by high potas- sium levels, result from the mineralocorticoid (aldosterone) deficit and lead to cardiac arrhythmias and failure. Other manifestations include decreased body hair due to a lack of androgens and hyperpigmentation in the extremities, skin creases, buccal mucosa, and tongue, because of increased ACTH resulting from low cortisol secretion. A comparison of Cushing syndrome and Addison disease is found in Table 16.6. ■ Treatment Replacement therapy with the necessary hormones controls the diseases. Increased doses may be required in times of stress. Mood swings, insomnia, and loss of libido Supraclavicular fat pad Buffalo hump Thinning hair Moon face and ruddy complexion Hirsutism Truncal obesity with pendulous breasts and abdomen Broad purple striae Thinning pubic and axillary hair in women Ecchymoses Impaired wound healing and immune response Thin, fragile skin Thinning extremities with muscle wasting and fat mobilization FIG. 16.18 Cushing syndrome—typical appearance. (From Monahan FD, Drake T, Neighbors M: Nursing Care of Adults, Philadelphia, 1994, Saunders.) TABLE 16.6 Comparison of Addison Disease and Cushing Syndrome Addison Disease (Adrenal Insufficiency) Cushing Syndrome Deficit of corticosteroids (glucocorticoids, mineralocorticoids) Excess glucocorticoids (cortisol) High risk of infection High risk of infection Poor stress response Poor stress response Weight loss, fatigue Moon face, buffalo hump, obese trunk, muscle wasting in limbs, osteoporosis Anorexia, nausea, diarrhea Striae, bruising of skin, high risk of infection Hypotension, syncope Hypertension, glucose intolerance Hyperpigmentation Fatigue, weakness, delayed healing CASE STUDY A Diabetes Mellitus Type 1 Mr. M. has had type 1 diabetes for 15 years. He has just been admitted to the hospital with severe pyelonephritis, a kidney infection. 1. Describe the pathophysiology of type 1 diabetes. 2. Explain why urinary tract infections are common in people with diabetes. Explain how acute renal failure could develop. Mr. M. has had the infection for a week and has developed mild ketoacidosis because of the infection. Analysis of arterial blood gases indicates that his serum bicarbonate level is low, and his serum pH is just below normal range. 3. Explain why infection may lead to ketoacidosis. 4. Describe the characteristics of Mr. M.’s respirations that you would expect to observe while ketoacidosis is present. Include the rationale for your answer. 5. If Mr. M.’s serum pH continues to decrease below normal, how would that pH affect cell and organ function? 6. Mr. M. is voiding large volumes of urine (polyuria). Explain the reason for this reaction. 7. Describe three signs of excessive fluid loss. 8. Mr. M.’s vision has deteriorated in the past 3 years because of retinopathy. Explain how retinopathy impairs vision. 9. Describe two problems related to diabetes that Mr. M. might encounter because of his reduced vision. CASE STUDY B Diabetes Mellitus Type 2 Mr. F. was diagnosed with type 2 diabetes mellitus at age 46. At that time, he was overweight, enjoyed foods with high car- bohydrate and fat content, and led a sedentary life. His family history indicated that his mother and his brother had diabetes. 424 SECTION III Pathophysiology of Body Systems Weight loss, appropriate diet, and exercise were recommended to reduce blood glucose levels. 1. List the factors contributing to diabetes mellitus in this case. At age 50, Mr. F. noticed that his vision was cloudy, particularly in one eye. Cataracts were removed from both eyes. 2. Describe a cataract, and explain how diabetes promotes cataract formation. 3. Glyburide (DiaBeta) was prescribed at this time. Describe the action of this drug. At age 56, a blister developed on the heel of one foot, which did not heal. An ulcer formed and persisted. Finally the foot was placed in a cast for 13 weeks to promote healing. 4. Explain several factors contributing to the delayed healing in Mr. F. 5. Why was it necessary in this case to remove the cast and replace it each week? Peripheral neuropathy with total loss of sensory function had developed in both feet. Motor function was not directly affected. Orthopedic shoes were ordered and arrangements made for a podiatrist to provide regular foot care. 6. Why is it essential that Mr. F. examine his feet carefully each day? At this time body weight had again increased substantially and blood pressure was elevated. Fosinopril (Monopril) was prescribed, along with recommendations for weight loss and regular exercise. 7. Describe the usual manifestations of hypertension. At age 60, routine monitoring during a workout at the health club indicated atrial fibrillation. During consultation, the cardiolo- gist also noted his blood pressure was very high. 8. State the purpose of the following medications prescribed at this time (see Chapter 18): fosinopril (Monopril), atorvastatin (Lipitor), amlodipine (Norvasc), warfarin (Coumadin), and sotalol (Sotacor). Since that time, continued regular exercise and dietary modification have maintained weight at recommended levels. Blood pressure is within normal range, HbA1c is below 7, and atrial fibrillation is controlled. 9. What does this HbA1c value mean? 10. Why does Mr. F. bruise easily? What precautions would be advisable at this time? 11. Briefly review the effects of diabetes over time in this case. 4. Why is persistent elevated blood pressure a serious concern in a patient (see Chapter 12)? Several years later, C.S. experienced an episode of severe pain leading to a diagnosis of renal calculi and hypercalcemia related to an additional metabolic abnormality. 5. How does hypercalcemia cause renal calculi, and how do renal calculi cause severe pain (see Chapter 18)? Dietary restrictions on calcium intake and increased fluid intake were recommended to reduce the risk of additional calculi. 6. How might reduced calcium intake affect C.S.? 7. Following a routine checkup and laboratory tests 2 years later, simvastatin (Zocor) was prescribed. Why is a cholesterol-lowering agent useful in the treatment of diabetes? 8. A daily low dose of enteric-coated acetylsalicylic acid (ASA) was recommended. Why is this helpful in diabetics? Recently blood glucose levels have been elevated. Medication was changed to glyburide, but side effects in C.S. were marked. A combination of metformin and rosiglitazone has been pre- scribed as well as regular exercise and careful dietary control. 9. Explain why it is important to maintain low blood glucose levels. 10. Suggest several reasons why blood glucose levels may increase periodically. CASE STUDY C Gestational Diabetes Mellitus Following delivery of the second child, C.S.’s blood pressure and blood glucose remained elevated, leading to a diagnosis of type 2 diabetes. In addition to regular exercise, metformin was prescribed and a nutritionist developed an appropriate diet. 1. Describe the pathophysiology of type 2 diabetes. 2. Briefly describe how diet, exercise, and this drug each contribute to reduction of blood glucose. 3. Explain how stressors might affect blood glucose levels and blood pressure. Hydrochlorothiazide (Hydro DIURIL) and irbesartan (Avapro) were prescribed to reduce blood pressure. CASE STUDY D Pituitary Adenoma and Acromegaly C.M., age 20 years, was admitted to the emergency department with severe headache, photophobia, drowsiness, and slight neck rigidity, suggestive of meningitis. Her medical history indicated good general health. She had been treated for carpal tunnel syndrome 3 years before, and she had noted an increase in hand and foot sizes over the past several years. In the past week, she had experienced severe headaches associated with nausea and vomiting. Tests on CSF did not confirm meningitis. Blood tests indicated low levels of thyroxine, cortisol, and gonadotropins, but high levels of growth hormone. Radiographic tests showed a space- occupying lesion in the sella turcica. A diagnosis of pituitary adenoma with acromegaly was established. The acute episode had resulted from infarction of the pituitary gland (pituitary apoplexy). C.M. recovered from the infarction and was discharged from the hospital. The infarction had reduced the GH secretion to some extent. Thyroxine and cortisol levels were low normal; no replacement therapy was recommended at this time. 1. Define adenoma, and describe the location of the pituitary gland. 2. Explain the rationale for the neurologic signs and symptoms leading to admission (see Chapter 14). 3. Explain the effects of acromegaly in C.M. How long was the adenoma likely present? 4. Explain the low blood levels of thyroxine, gonadotropins, and cortisol. Two years later C.M. was experiencing temporary paresthesias in both hands in the morning. Also headaches had become more frequent and were accompanied by visual signs such as spatial distortion. Cold sensitivity and fatigue persisted. She felt her CHAPTER 16 Endocrine System Disorders 425 complications such as vascular and nerve degeneration are common. Early signs include polyuria, polydipsia, polyphagia, hyperglycemia, and glucosuria. Parathyroid Hormone • Calcium levels in the blood may be altered by many factors, such as renal disease, immobility, bone disease, and malabsorption syndromes, as well as by parathy- roid hormone. • Hypoparathyroidism leads to hypocalcemia with tetany and possible cardiac arrhythmias. • Hyperparathyroidism is a cause of osteoporosis and renal calculi. Pituitary Hormones • Pituitary tumors may affect the level of one or more hormones and may stimulate secretion or impair secretion. • A pituitary disorder may alter tropic hormone levels, affecting the activity of glands such as the thyroid. • A deficit of GH is one cause of dwarfism. • Excess GH causes gigantism in children, acromegaly in adults. • Diabetes insipidus results from a deficit of ADH, causing dehydration. Thyroxine and Triiodothyronine (T3 and T4) • Goiter refers to an enlargement of the thyroid gland that can develop with both hypothyroid and hyper- thyroid conditions. • Graves disease is an example of hyperthyroidism, an autoimmune disorder manifested by signs of hyper- metabolism, goiter, and exophthalmos. • Severe hypothyroidism is present in Hashimoto thyroiditis, an inflammatory autoimmune disorder, and cretinism, an untreated congenital condition impairing mental and physical development, or in myxedema with hypometabolism in adults. Adrenal Glands • Pheochromocytoma is a benign tumor of the adrenal medulla, important as a treatable cause of hypertension. • Cushing syndrome is caused by excess glucocorticoids resulting from a pituitary or adrenal cortical tumor, an ectopic tumor, or ingestion of glucocorticoids. The major effects include catabolic action on bone, muscle, and skin and depressed inflammatory and immune responses. • Addison disease results from a deficit of glucocorticoids, mineralocorticoids, and androgens, affecting blood glucose levels, fluid and electrolyte balance, and the stress response. foot size had increased, but not her hand size. No other abnormali- ties were apparent. 5. Suggest a reason for these manifestations. A 6-month course of bromocriptine (Parlodel—a dopamine agonist that reduces GH secretion and shrinks the tumor) was ordered, which did reduce GH levels to some extent. However, after medication was discontinued, headaches, nausea, hot flashes, and paresthesias recurred. Several months later, a course of radiotherapy to the pituitary commenced and resulted in lower GH levels and symptomatic improvement. 6. How would radiotherapy reduce the symptoms? Tests a few months later indicated T4, cortisol, and LH levels were below normal. T4 replacement therapy was commenced. C.M. was given a supply of prednisone to take in the event of illness or increased stress. 7. Why is it necessary to maintain T4 levels? Why is increased cortisol required during stress? Because of continued amenorrhea (lack of menstruation) since the pituitary infarction, a course of Pergonal (gonadotro- pins) was given to induce ovulation when pregnancy was desired. A healthy male infant was delivered. Hydrocortisone replacement was taken throughout the pregnancy. 8. Explain how the pituitary infarction caused amenorrhea. A few years later, type 2 diabetes mellitus developed, con- trolled by diet. 9. How does acromegaly predispose to type 2 diabetes? No further signs of acromegaly have occurred. Thyroxine replacement continues, and hydrocortisone is available in the event of illness. Complete evaluation of endocrine function, including hydrocortisone day curve, continues on an annual basis to monitor replacement hormone requirements. 10. Explain why hormone levels require frequent monitoring. C H A P T E R S U M M A R Y Together with the nervous system, the endocrine system is responsible for maintaining homeostasis in the body and controlling any necessary changes. Endocrine glands secrete hormones into the circulating blood for transport to the target cells. Endocrine disorders usually result from an excess or a deficit of a specific hormone, often caused by a benign adenoma. Insulin • Diabetes mellitus is caused by a deficit of insulin secretion or increased tissue resistance to insulin action, leading to abnormal carbohydrate, fat, and protein metabolism. Type 1, or insulin-dependent diabetes, requires insulin replacement and is subject to acute complications such as hypoglycemic shock. Type 2, or non-insulin- dependent diabetes, a milder form, may be controlled by diet, exercise, or oral hypoglycemics, but long-term 426 SECTION III Pathophysiology of Body Systems S T U D Y Q U E S T I O N S 1. Why may a spontaneous fracture occur in persons with hyperparathyroidism? 2. Compare the effects of hypocalcemia on skeletal muscle and cardiac muscle. 3. Explain why a teenager with diabetes mellitus would be more likely than an older adult to have acute complications. 4. Compare the signs of diabetic ketoacidosis and hyperosmolar hyperglycemic nonketotic coma. 5. How would the characteristics of the urine differ in untreated diabetes mellitus and diabetes insipidus? 6. Compare three manifestations that differ in hyperthyroidism and hypothyroidism. 7. Explain why glucocorticoids are considered catabolic hormones, and list two specific catabolic effects. 8. Explain why untreated Addison disease could be life threatening. 9. Describe the effects of hyperaldosteronism. 10. State the hormone imbalance involved in each of the following, and list two significant effects of each condition: a. Gigantism b. Cretinism c. Pheochromocytoma d. Myxedema e. Acromegaly f. Diabetes insipidus 427 Review of the Digestive System Structures and Their Functions Upper Gastrointestinal Tract Liver Pancreas Lower Gastrointestinal Tract Neural and Hormonal Controls Digestion and Absorption Common Manifestations of Digestive System Disorders Anorexia, Vomiting, and Bulimia Diarrhea Constipation Fluid and Electrolyte Imbalances Pain Malnutrition Basic Diagnostic Tests Common Therapies and Prevention Upper Gastrointestinal Tract Disorders Disorders of the Oral Cavity Congenital Defects Inflammatory Lesions Infections Dental Problems Hyperkeratosis Cancer of the Oral Cavity Salivary Gland Disorders Dysphagia Esophageal Cancer Hiatal Hernia Gastroesophageal Reflux Disease Gastritis Acute Gastritis Gastroenteritis Chronic Gastritis Peptic Ulcer Gastric and Duodenal Ulcers Stress Ulcers Gastric Cancer Dumping Syndrome Pyloric Stenosis Disorders of the Liver and Pancreas Gallbladder Disorders Jaundice Hepatitis Viral Hepatitis Toxic or Nonviral Hepatitis Cirrhosis Liver Cancer Acute Pancreatitis Pancreatic Cancer Lower Gastrointestinal Tract Disorders Celiac Disease Chronic Inflammatory Bowel Disease Crohn Disease (Regional Ileitis or Regional Enteritis) Ulcerative Colitis Irritable Bowel Syndrome Appendicitis Diverticular Disease Colorectal Cancer Intestinal Obstruction Peritonitis Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Describe the various causes of vomiting and the vomiting process. 2. Differentiate diarrhea from constipation. 3. Differentiate cleft lip from cleft palate. 4. Describe the common oral infections and periodontal disease. 5. Explain the common causes of dysphagia. 6. Differentiate the types of hiatal hernias and explain their effects. 7. List the causes of acute gastritis, and describe the common signs. 8. Compare the effects of acute gastritis, chronic gastritis, and gastroenteritis. 9. Describe the etiology, signs, and possible complications of peptic ulcers. 10. Describe the pathophysiology, etiology, and early signs of gastric cancer. 11. Explain how dumping syndrome develops, and list the signs associated with the syndrome. 12. Explain how pyloric stenosis interferes with normal function, and list the common manifestations. 13. Describe how gallstones develop and the signs of obstruction. 14. Differentiate the types of jaundice. 15. Compare the types of infectious hepatitis. 16. Describe the common manifestations of hepatitis. 17. Explain why the cause of toxic hepatitis should be identified quickly. 18. Differentiate the types of cirrhosis. 19. Describe the pathophysiology and manifestations of cirrhosis. 20. Describe the pathophysiology, signs, and possible complications of acute pancreatitis. 21. Explain how gluten toxicity may affect individuals with celiac disease. 22. Describe the signs of malabsorption. 23. Compare Crohn disease with ulcerative colitis. L E A R N I N G O B J E C T I V E S C H A P T E R 17 Digestive System Disorders 428 SECTION III Pathophysiology of Body Systems the tissues and facilitates the passage of the contents along the tube. The epithelial cells of the mucosa have a rapid turnover rate because of the “wear and tear” associated with the food and secretions passing along the tract. 2. The submucosal layer, which is composed of connective tissue, including blood vessels, nerves, lymphatics, and secretory glands. 3. Circular smooth muscle fibers. 4. Longitudinal smooth muscle fibers. These two smooth muscle layers are responsible for transport or motility in the tract. 5. The outer layer of the wall, which comprises the visceral peritoneum, or serosa. The peritoneum is a large serous membrane in the abdomi- nal cavity (see Ready Reference 1). The parietal peritoneum covers the abdominal wall and the superior surface of the urinary bladder and uterus, and then it continues, reflecting back to form the visceral peritoneum, which encases the organs, such as the stomach and intestine. This arrangement creates a double-walled membrane in the abdominal cavity, which is similar to the pleural and pericardial membranes. Pain receptors connected to spinal nerves are located in the parietal peritoneum. The peritoneal cavity refers to the potential space between the parietal and visceral peritoneum. A small amount of serous fluid is present in the cavity to facilitate the neces- sary movement of structures such as the stomach. Numerous lymphatic channels drain excessive fluid from the cavity. Because serous membranes are normally thin, some- what permeable, and highly vascular, the peritoneal Review of the Digestive System The general purpose of the digestive system is to effi- ciently process ingested food and fluids and the various secretions from glands. First, they are broken down into their separate constituents; then, the desired nutrients, water, and electrolytes are absorbed into the blood for use by the cells, and waste elements are eliminated from the body. Within this system, the liver can reassemble the component nutrients into new materials as the body needs them. For example, the proteins in milk are digested by enzymes in the digestive tract, producing the component amino acids, which are then absorbed into the blood. The individual amino acids are used by the liver cells to produce new proteins, such as albumin or prothrombin, or they may circulate unchanged in the blood to be taken up by individual cells as necessary. Structures and Their Functions The digestive system, sometimes called the gastrointestinal tract, alimentary tract, or gut, consists of a long hollow tube, which extends through the trunk of the body, and its accessory structures: the salivary glands, liver, gallblad- der, and pancreas (Fig. 17.1). The digestive tract is divided into two sections, the upper tract, consisting of the mouth, esophagus, and stomach, and the lower tract, consisting of the intestines. Although variations occur along the tube, the wall of the gut basically has five continuous layers: 1. The inner layer is the mucosa, which includes the important mucus-producing cells. Mucus protects autodigestion bolus calculi cholestasis chyme colostomy fecalith gastrectomy gluconeogenesis glycogen hematemesis hepatocytes hepatotoxins hyperbilirubinemia icterus ileostomy impaction mastication melena mesentery multiparity occult periodontitis retroperitoneal rugae sinusoids steatorrhea stricture tenesmus ulcerogenic K E Y T E R M S 24. Describe the symptoms and the various causes of irritable bowel syndrome. 25. Describe the stages in the development of acute appendicitis and the signs associated with each stage. 26. Explain how diverticulosis and diverticulitis develop. 27. Describe the causes and possible characteristics of colorectal cancer. 28. Relate the location of colorectal cancer to the possible signs. 29. Describe the common causes of intestinal obstruction. 30. Differentiate the causes and significant signs of mechanical obstruction from those of paralytic ileus. 31. Explain the progressive effects of intestinal obstruction and the related signs. 32. Differentiate chemical peritonitis from bacterial peritonitis, including causes for each. 33. Describe the pathophysiology of peritonitis and possible complications. L E A R N I N G O B J E C T I V E S — continued CHAPTER 17 Digestive System Disorders 429 The greater omentum is a layer of fatty peritoneum that hangs from the stomach like an apron over the anterior surface of the transverse colon and the small intestine. The lesser omentum is part of the peritoneum that suspends the stomach and duodenum from the liver. When inflammation develops in the intestinal wall, the greater omentum, with its many lymph nodes, tends to adhere to the site, walling off the inflammation and temporarily localizing the source of the problem. Inflammation of the omentum and peritoneum may lead to scar tissue and the formation of adhesions between structures in the abdominal cavity, such as loops of intestine, restricting motility and perhaps leading to obstruction. membranes are useful as an exchange site for blood during peritoneal dialysis in patients with kidney failure (see Chapter 18). However, such an extensive membrane may also facilitate the spread of infection or malignant tumor cells throughout the abdominal cavity or into the general circulation. The mesentery is a double layer of peritoneum that supports the intestines and conveys blood vessels and nerves to supply the wall of the intestine. The mesentery attaches the jejunum and ileum to the posterior (dorsal) abdominal wall. This arrangement provides a balance between the need for support of the intestines and the need for considerable flexibility to accommodate peri- stalsis and varying amounts of content. Hard palate Mouth Tongue Tooth Sublingual salivary gland Trachea Esophagus Parotid salivary gland Oropharynx Submandibular salivary gland Liver Gallbladder Common bile duct Duodenal papilla Duodenum Large intestine Ascending colon Ileocecal valve Ileum Cecum Appendix Anus Rectum Sigmoid colon Jejunum Descending colon Transverse colon Pancreas Pyloric sphincter Stomach Cardiac sphincter Diaphragm Events • Chew food • Saliva–add water and digest carbohydrate Mouth Esophagus • Swallow Stomach • Mix and dilute chyme • Gastric secretions - Digest protein - Add intrinsic factor - Acidic Small intestine • Bile emulsifies fat • Pancreatic secretions • Intestinal secretions - Digest fat, protein, and carbohydrate • Absorption of nutrients Colon • Absorbs water and electrolytes Rectum • Storage until defecation FIG. 17.1 Anatomy of the digestive system with associated events. 430 SECTION III Pathophysiology of Body Systems swallowing (or deglutition) becomes an involuntary activity. The swallowing center coordinates the actions required to move food or fluid into the stomach, without aspiration into the lungs, by means of cranial nerves V, IX, X, and XII in the following steps: • The soft palate is pulled upward. • The vocal cords are approximated. • The epiglottis covers the larynx. • Respiration ceases. • The bolus is seized by the constricted pharynx. • As the bolus of food moves into the esophagus, distend- ing the wall, peristalsis is initiated, pushing the food down the esophagus. • The distal part of the esophagus passes through the hiatus (opening) in the diaphragm to join the stomach in the abdominal cavity. • The lower esophageal (gastroesophageal, or cardiac) sphincter relaxes in advance of the bolus, allowing it to drop into the stomach. The pressure in this sphincter normally prevents reflux of gastric contents back up the esophagus. The esophagus is composed of skeletal muscle at the superior end that is gradually replaced by smooth muscle fibers. The entire The kidneys and pancreas are located posterior to the stomach against the abdominal wall and behind the parietal peritoneum. They are covered with peritoneum only on the anterior surface and are therefore referred to as retroperitoneal organs. Upper Gastrointestinal Tract Oral Cavity Food and fluid are taken into the body through the mouth, where the initial phase of mechanical breakdown and digestion takes place, and are then stored in the stomach, where processing continues. The mouth is separated from the nasal cavity by the hard and soft palates. A large variety of microorganisms make up the resident flora of the mouth. In the mouth, or oral cavity (Fig. 17.2), mastica- tion takes place as the teeth break down solid food and mix it with saliva. Salivary secretions from the parotid, sublingual, and submandibular glands enter the mouth through the salivary ducts, moisturizing and lubricating (with mucins) the food particles and facilitating the passage of solid material down the esophagus to the stomach. Saliva also contains the enzyme amylase, which begins the digestion of carbohydrate in the mouth (Table 17.1). Perhaps you have noted how chewing crackers can bring a sweet taste in the mouth as the starch is broken down. The tongue and cheeks facilitate the move- ment and mixing of the food in the mouth. Chewing is usually considered a voluntary action, but reflex chewing can occur if voluntary control is lost. Esophagus When food is ready to be swallowed, the tongue pushes the bolus or ball of food back to the pharyngeal wall, where receptors of the trigeminal and glossopharyngeal nerves relay the information to the swallowing center in the medulla. Because the reflex is activated at this point, Upper central incisor Hard palate Soft palate Uvula Opening of sublingual ducts Upper lip Gingivae (gums) Canine (cuspid) Premolar (bicuspid) Palatoglossal arch Molar Fauces Palatine tonsil Tongue Lingual frenulum Sublingual fold Opening of submandibular gland FIG. 17.2 The oral cavity. TABLE 17.1 Major Digestive Enzymes and Their Actions Enzyme Source Action Salivary amylase Parotid gland Splits starch and glycogen into disaccharides Pepsin Gastric chief cells Initiates splitting of proteins Pancreatic amylase Pancreas Splits starch and glycogen into disaccharides Pancreatic lipase Pancreas Splits triglycerides into fatty acids and monoglycerides Trypsin, chymotrypsin, carboxypeptidase Pancreas Splits proteins into peptides Pancreatic nucleases Pancreas Splits nucleic acids into nucleotides Intestinal peptidase Intestinal mucosa Converts peptides into amino acids Intestinal lipase Intestinal mucosa Converts fats into fatty acids and glycerol Intestinal sucrase, maltase, lactase Intestinal mucosa Converts disaccharides into monosaccharides CHAPTER 17 Digestive System Disorders 431 The hepatocytes, or liver cells, are arranged in lobules, and each lobule has plates of cells radiating from central veins, which eventually drain blood back into the general circulation through the hepatic veins and inferior vena cava (see Fig. 17.20, presented later in the chapter). Channels or sinusoids filled with blood from two sources pass between the plates of hepatocytes. Entering the sinusoid is blood from branches of the hepatic artery, carrying oxygen to the liver cells, and venous blood from the portal vein, which transports nutrients absorbed from the stomach and intestines (hepatic portal circulation), as well as from the pancreas and spleen. The arterial and venous blood mix and flow slowly through the sinusoids, permitting the hepatocytes to do their jobs. The sinusoids are lined with endothelial cells and Kupffer cells, which remove and phagocytose any foreign material and bacteria from the digestive tract before the blood enters the general circulation. As blood flows through the sinusoids, many substances are exchanged to facilitate liver functions. Absorbed nutrients are taken up by the hepatocytes to be stored (eg, the minerals iron and copper, or vitamins A, B6, B12, D, and K, and folic acid). Many blood components such as iron or amino acids are monitored, and those that have been depleted as the blood circulates through the body are replaced. Blood glucose levels are maintained; glucose is essential for brain function. In conjunction with the hormone insulin, the liver responds to high levels of blood glucose by glycogenesis, converting glucose to glycogen (a large polysaccharide similar to amylopectin that is a stored form of glucose), which is stored in the liver. Alternatively, the hepatocytes break down liver glycogen to glucose (glycogenolysis) when blood glucose levels drop and glucagon secretion increases. Gluconeogenesis, the formation of glucose from molecules that are not themselves carbohydrates, may take place when blood glucose levels drop, under the influence of hormones such as cortisol or epinephrine. Conversion of one amino acid into another takes place as needed to maintain the amino acid pool in the blood and meet the body’s needs. Both synthesis and control of blood levels of other materials, such as plasma proteins, clotting factors, or lipoproteins, are accomplished. Syn- thesis of cholesterol occurs in the liver for use in the production of steroid hormones, such as cortisol or the sex hormones, and bile salts. Hormones, such as aldosterone and estrogen, are inactivated and prepared for excretion. Ammonia, a nitrogen waste resulting from protein metabolism in the intestine or liver, is removed from the blood and converted to urea, enabling it to be excreted by the kidneys. Drugs and alcohol are detoxified before excretion. The detoxifica- tion process makes such substances less harmful and increases the solubility of many substances, facilitating their excretion. tube is lined with mucous membrane and is closed, except when swallowing is in progress. Stomach The stomach is an expansible muscular sac that acts as a reservoir for food and fluid. The stomach can hold 1 to 1.5 liters of food and fluid. When empty, the stomach wall falls into folds, or rugae. The outer surface is covered by visceral peritoneum. The wall of the stomach consists of three smooth muscle layers—longitudinal and circular layers and an additional oblique muscle layer—plus the mucosa and submucosa. The epithelial cells of the mucosa are tightly packed to prevent penetration of acid or pepsin into the wall. Numerous glands are located in the mucosa, and there is a layer of thick protective mucus covering the inner surface. Constant mixing and churning of food occurs as secretions are added from the gastric glands. These secretions dilute the gastric contents, which at this point consist of a semifluid, homogeneous, creamy material called chyme, and initiate the digestion of protein. The gastric glands located in the fundus of the stomach contain parietal cells that secrete hydrochloric acid and chief cells that secrete pepsinogen, which is converted to the active form, pepsin, by the action of hydrochloric acid. Intrinsic factor, required for the absorption of vitamin B12 in the ileum, is also produced by the parietal cells (see Chapter 10 for a discussion of pernicious anemia). The gastric secretions act as a defensive mechanism because of the highly acidic pH (around 2), which destroys many microorganisms that enter the stomach from the resident flora in the mouth or from food or utensils. Glands in the cardiac and pyloric areas secrete protective mucus. Also, enteroendocrine cells in the glands secrete a variety of chemicals, the most important of which is the hormone gastrin, which is released when food enters the stomach and then stimulates the parietal and chief cells. Depending to some extent on the type of food ingested, gastric emptying proceeds slowly, with small amounts of chyme (1 to 3 mL) passing intermittently through the pyloric sphincter into the duodenum. Secretions from the liver and the exocrine pancreas are added to the chyme in the duodenum through the ampulla of Vater and duodenal papilla (see Fig. 17.18, presented later in the chapter). Liver The liver is located in the upper right quadrant (URQ) of the abdomen under the diaphragm and serves as the “metabolic factory” of the body. It is a large organ covered by a fibrous capsule, distention of which causes a dull, aching pain. The liver cells can regenerate, but if the organizational structure of the lobule, with its unique arrangement of blood vessels and bile ducts, is altered by necrosis and scar tissue, the regenerated areas may not be functional. 432 SECTION III Pathophysiology of Body Systems distal direction. The contents move slowly along the tube, influenced by both mixing and propulsive movements of the wall. Digestion continues in the duodenum while many enzymes are added to the chyme and an alkaline pH is attained. The ileum is the major site of absorption of nutrients. The significant feature of the small intestine is the presence of plicae circulares, transverse folds of the mucosa covered with villi and microvilli (see Fig. 17.32A, presented later in the chapter). These numerous tiny projections greatly increase the absorptive surface area of the small intestine. Each villus is supplied with a capillary network, nerves, and a lacteal, which is a ter- minal lymphatic vessel that is essential for the absorption of lipids. At the base of the villi are the intestinal crypts, deep pockets from which new epithelial cells (simple columnar absorptive cells) arise. Cells in the crypts produce fluid with a pH of around 7, as well as enzymes such as enterokinase, which activate pancreatic proen- zymes, and hormones such as cholecystokinin. Other enzymes produced by the cells of the intestinal mucosa include peptidases, nucleosidases, lipase, sucrase, maltase, and lactase. Many goblet cells in the mucosa secrete large quantities of mucus into the intestine to protect the intestinal wall and buffer the acid chyme. Large Intestine The ileocecal valve marks the entry point from the ileum into the large intestine or colon. Hanging down at this point is a pouch, the cecum, from which the blind-ending appendix (vermiform appendix) extends. Moving supe- riorly from the cecum is the ascending colon, which becomes the transverse colon and then passes down the left side as the descending colon. This structure terminates as the sigmoid colon, rectum, and anal canal. The anus is the opening to the exterior. Absorption of large amounts of water and electrolytes takes place in the colon. This “recycling” process is of critical importance in maintaining the fluid and acid-base balances in the body, because large volumes of fluids and ions, such as bicarbonate and sodium, are recovered from the added secretions and ingested fluids. General digestion and absorption of nutrients cease in the colon. Resident bacteria assist in further breakdown of certain food materials (one cause of intestinal gas) and convert bilirubin to urobilinogen, which gives the feces the typical brown color. In the ileum, large masses of lymphoid tissue, called Peyer patches, limit the spread of these bacteria into the small intestine. Some of these bacteria are beneficial to the human host, synthesizing vitamin K, for example, which is required for the production of clotting factors, such as prothrombin and fibrinogen, in the liver. Colonic movements are slow to allow absorption of fluid and formation of the solid feces. The transverse and descending colon are marked by mass movements, strong peristaltic contractions that occur several times Damaged or old erythrocytes are removed from the blood to facilitate the recycling of iron and protein from hemoglobin (see Figs. 10.7 and 17.21 [presented later]). The liver, as well as the spleen (see Chapter 11), serves as a blood reservoir because it is capable of releasing a large quantity of blood into the general circulation when blood volume is depleted. The hepatocytes of the liver constantly produce bile, a mixture of water, bile salts, bile pigment (conjugated bilirubin), cholesterol, and electrolytes, including bicarbon- ate ions. Bile is vital for digestion and serves as a vehicle for the removal of bilirubin and excess cholesterol from the body. The bile salts, formed from cholesterol, are essential for the emulsification of fats and fat-soluble vitamins (vitamins A, D, E, and K) before they can be absorbed from the intestine. Most bile salts are reabsorbed from the distal ileum and recycled to the liver through the enterohepatic circulation. Bicarbonate ions in bile assist in neutralizing gastric acid, increasing the pH of the small intestine so that intestinal and pancreatic enzymes can function. Bile is an exocrine secretion, flowing through small canaliculi in the liver and draining into larger ducts until it reaches the right or left hepatic duct and then the common bile duct. A sphincter in this duct usually directs the flow of bile into the gallbladder for storage but may allow it to flow onward into the duodenum. After surgical removal of the gallbladder, the storage facility is lost, but the liver constantly secretes bile and small amounts continuously enter the duodenum. Pancreas The pancreas lies posterior to the stomach, with its larger end or “head” adjacent to the duodenum. The cells of the exocrine pancreas are arranged in lobules throughout the organ; they secrete digestive enzymes, electrolytes, and water into tiny ducts, which eventually drain into the main pancreatic duct that traverses the length of the pancreas. The pancreatic duct, carrying secretions from the exocrine pancreas, joins the common bile duct and then enters the duodenum. The major proteolytic enzymes in pancreatic secretions are trypsin and chymotrypsin, carboxypeptidase, and ribonuclease (see Table 17.1). Also, pancreatic amylase aids in the digestion of carbohydrates and lipase helps to digest fats. The enzymes are secreted in inactive form and are activated after they enter the duodenum. The pancreatic cells produce a trypsin inhibitor to reduce the risk of enzyme activation within the pancreas. Pan- creatic secretions also contain bicarbonate ion, which assists in the neutralization of hydrochloric acid in the duodenum. Lower Gastrointestinal Tract Small Intestine The small intestine has three sections, the duodenum, the jejunum, and the ileum, moving in a proximal to CHAPTER 17 Digestive System Disorders 433 leading to reduced secretions and regeneration of epi- thelial cells. The PNS, through the facial (cranial nerve VII) and glossopharyngeal (cranial nerve IX) nerves, maintains a continuous flow of saliva in the mouth, which is essential to keep the tissues moist, effect a continuous cleansing action, and facilitate speech. A dry mouth for any reason leads to a sensation of thirst, a protection against dehydra- tion. The sight, thought, or presence of food in the mouth stimulates increased salivary secretions, and these secre- tions usually continue for a time after swallowing, which is helpful in cleansing the mouth and teeth. When food reaches the stomach, distention or stretching of the stomach and the increased pH caused by food intake activate the PNS, increasing peristalsis and gastric secretions. Peripheral nervous system stimulation also increases bile and pancreatic secretions. As digestion in the stomach progresses, peristaltic movements force small amounts of chyme, 2 to 3 mL at a time, into the duodenum. Depending on the amount and type of food involved, the stomach empties within 2 to 6 hours after a meal. Fluids pass through rapidly, whereas fats progress slowly. The presence of food in the intestine stimulates intestinal activity but inhibits gastric activity, through the entero- gastric reflex, to prevent overloading of the duodenum and to allow sufficient time for intestinal digestion and absorption. Food passes through the small intestine at a fairly constant rate. After eating, a reflex increase in peristalsis around the ileocecal valve occurs, which moves the ileal contents into the cecum and colon. These anticipa- tory actions make the digestive tract into an efficient production line. Peristaltic movements in the colon are usually slow. The gastrocolic reflex stimulates a mass movement of the contents from the colon into the rectum when food enters the stomach. Hormones play a major role in the process of digestion and absorption (see Table 17.2). Gastrin is secreted by mucosal cells in the pyloric antrum of the stomach in response to distention of the stomach or the presence of substances such as partially digested protein, alcohol, or caffeine in the stomach. Gastrin enters the blood and circulates, then returns to stimulate the gastric cells to increase secretions, increase gastric motility, and relax the pyloric and ileocecal sphincters, thus promoting stomach emptying. In the presence of the chemical histamine that is released from local mast cells, stimulation of the parietal cells by the PNS or gastrin leads to increased secretion of hydrochloric acid. The histamine receptors on parietal cells are histamine2 (H2) receptors, not the histamine1 (H1) receptors on cells involved in allergic responses. When chyme enters the duodenum, mucosal cells release hormones. Secretin and cholecystokinin (CCK) are two important ones. Secretin decreases gastric secre- tions and increases the bicarbonate ion content of pan- creatic secretions and bile when the chyme is highly acidic. Cholecystokinin inhibits gastric emptying, stimulates daily. Large pouches, or haustra, in the colon wall allow for expansion as more solid material collects. Feces consist primarily of fiber and other indigestible material, sloughed mucosal cells, and bacteria. Increased bulk or fiber in the intestine increases intestinal motility and the rate of passage, leading to a larger fecal mass and thus more frequent defecation, or bowel movements. The rectum stores the solid feces until sufficient disten- tion of the rectal wall stimulates the defecation reflex as follows: 1. Sensory nerve impulses from the stretch receptors in the rectal wall are transmitted to the sacral spinal cord. 2. The sacral parasympathetic nerves transmit motor impulses, which stimulate peristalsis and relax the internal anal sphincter. 3. Pelvic muscles contract and voluntary relaxation of the external anal sphincter allows defecation to occur. 4. Elimination of feces can be assisted by increasing intraabdominal pressure through voluntary contraction of the abdominal muscles and the diaphragm. 5. If, under voluntary control, the external anal sphincter remains closed, the defecation reflex subsides temporar- ily. As the fecal mass increases, the reflex is stimulated again. THINK ABOUT 17.1 a. Describe the purpose of mastication and its effectiveness. b. Where are carbohydrates digested? Name the enzymes responsible. c. Explain why the liver is referred to as the “metabolic factory” of the body. d. State the likely times of glycogenolysis or glycogenesis relative to food intake or lack of intake. e. Explain why the contents of the small intestine are relatively liquid and the contents of the descending colon are solid. f. Describe one unique structural feature and the purpose of each of the following: mouth, stomach, small intestine, pancreas, and rectum. g. Explain the functions of mucus in the digestive tract. Neural and Hormonal Controls Stimulation of the parasympathetic nervous system (PNS), primarily through the vagus nerve (cranial nerve X), results in increased motility, or peristalsis, and increased secretions in the digestive system (Table 17.2; see also Chapter 14). During the initial cephalic phase before eating, pleasant smells, thoughts, or the sight of food can effect PNS stimulation. Conversely, emotions such as fear or anger stimulate the sympathetic nervous system (SNS), which inhibits gastrointestinal activity. Sympathetic nervous system activity also causes vasoconstriction, 434 SECTION III Pathophysiology of Body Systems Proteins are first split into peptides, or short chains of amino acids, in the stomach and intestine and then further broken down by peptidases into amino acids, many of which are absorbed by a sodium co-transport system in the small intestine. Lipids, or fats, primarily triglycerides, must first be emulsified (dispersed into tiny droplets) by bile (the bile salt component) in the small intestine; enzymes then act on the fats, forming monoglycerides and free fatty acids. These lipid-soluble molecules can diffuse across the cell membrane. Many recombine to form triglycerides again. Then, bound to protein, the lipids form chylomicrons, most of which diffuse into the lacteals or lymph capillaries in the microvilli. The lacteals join the lymphatic circulation, which empties into the general circulation. Eventually the lipids reach the liver or adipose cells. Short-chain fatty acids may diffuse directly into the blood. Fat-soluble vitamins (eg, vitamins A, D, E, and K) or other lipid-soluble materials do not require digestion but are absorbed with the fats. If for any reason lipids are not absorbed, large molecules, such as fat-soluble vitamins, cannot be absorbed. For example, this problem may occur when individuals consume mineral oil as a laxative on a regular basis. Mineral oil remains in the intestine, and the fat- soluble vitamins are excreted with the oil. Very small lipid-soluble molecules, such as alcohol, may be absorbed from the empty stomach into the blood by simple diffusion through the cell membranes. This promotes a high blood alcohol level within a short time after ingestion. The presence of food in the stomach delays such absorption. Water-soluble vitamins (eg, vitamins B and C) and minerals (eg, iron, copper, and zinc) diffuse into the blood. Vitamin B12 must be bound to intrinsic factor before absorption. Electrolytes (Na+, K+, Cl−, HCO3−, and so on) may be absorbed by active transport or diffusion into the blood. Water is absorbed by osmosis. About 7000 mL pancreatic secretions with increased digestive enzymes, and stimulates contraction of the gallbladder to increase bile flow into the duodenum. Variations in the digestive secretions and the rate of flow of chyme through the tract depend on the amount and type of food entering the digestive tract. For example, gastric emptying is delayed when the duodenum is full or when a meal high in fat content is ingested. TABLE 17.2 Major Controls in the Digestive Tract and Their Effects Hormone Source Stimulus Effects Gastrin Gastric cells Food in the stomach Protein, caffeine, or high pH of chyme Increases gastric secretions and motility, and promotes gastric emptying Cholecystokinin Intestinal mucosal cells Protein and fat in the duodenum Inhibits gastric secretions and motility; stimulates pancreatic enzyme secretion; stimulates gallbladder contractions and release of bile Secretin Intestinal mucosal cells Acidic chyme in the duodenum Stimulates bile and pancreatic secretions with high bicarbonate content Neural Controls Source Stimulus Effects Parasympathetic nervous system Vagus nerve Taste food Increases secretions and peristalsis Sympathetic nervous system Sympathetic nervous system Stress Decreases secretions and peristalsis; stimulates vasoconstriction in the mucosa APPLY YOUR KNOWLEDGE 17.1 How might a severe neck injury have adverse effects on the digestive system? Digestion and Absorption Nutrients are broken down chemically into simple molecules that are absorbed along with electrolytes and water into the blood and transported to the liver through the hepatic portal system. Complex carbohydrates, such as starches, are digested first in the mouth and then in the intestine. They are broken down by enzymes into simple sugars (monosaccharides) that are absorbed in the intestine, primarily in the jejunum and ileum. Glucose and galactose are absorbed by a co- transport mechanism with sodium that is already bound to a transport protein. Fructose is absorbed by facilitated diffusion. The process of active transport for sodium requires cellular energy (stored by adenosine triphosphate [ATP]), and therefore healthy cells with a good blood supply. On occasion, when a highly concentrated solution of glucose enters an empty stomach, glucose may diffuse quickly from the stomach into the blood. This rapid action can be effective in reversing hypoglycemia in a person with diabetes mellitus. CHAPTER 17 Digestive System Disorders 435 activities involved in vomiting (Fig. 17.3). The vomiting center is activated by many conditions, among which are the following: • Distention or irritation in the digestive tract • Stimuli from various parts of the brain in response to unpleasant sights or smells, or ischemia • Pain or stress • The vestibular apparatus of the inner ear (motion sickness) • Increased intracranial pressure (see Chapter 14), causing sudden projectile vomiting without previous nausea or food intake • Stimulation of the chemoreceptor trigger zone in the medulla by drugs, toxins, and chemicals Drugs may also cause vomiting by direct irritation of the digestive mucosa. Toxins may result from infecting microorganisms anywhere in the body. Toxic chemicals may be endogenous, as in kidney failure, or exogenous (ie, from external sources). The vomiting reflex includes the following involuntary activities: 1. Taking a deep breath 2. Closing the glottis and raising the soft palate 3. Ceasing respiration, which minimizes the risk of aspira- tion of vomitus into the lungs, where it may cause significant inflammation and obstruction of the airways 4. Relaxing the gastroesophageal sphincter 5. Contracting the abdominal muscles, which squeezes the stomach against the diaphragm and forces the gastric contents upward and out of the mouth 6. Promoting expulsion of the contents of the stomach by reverse peristaltic waves in the proximal duodenum and antrum Retching may precede vomiting and involves the same reflex, but the chyme ascends in the esophagus and then falls back into the stomach. This process may take place several times before complete vomiting occurs. Recurrent vomiting can be exhausting and painful because the strong muscle contractions continue with each episode and the source of renewed energy—food—is not available. There is an increased risk of aspiration when the person is supine or unconscious or when drugs depress the vomiting reflex, because the barriers to the respiratory tract may not be completely closed off or the vomitus may not be completely expelled. The cough reflex may also be suppressed. This is a common problem with postoperative vomiting or vomiting after heavy alcohol intake. The characteristics of vomitus can be significant: • The presence of blood leads to vomitus resembling coffee grounds, or hematemesis, a brown, granular material resulting from the partial digestion in the stomach of protein in the blood. If hemorrhage is extensive, then red blood may be obvious in the vomitus. Blood, as a “foreign material,” is irritating to the gastric mucosa. • Yellow- or greenish-stained vomitus usually contains bile from the duodenum. of water is secreted into the digestive tract each day, and approximately 2300 mL is ingested in food and fluids. Of this amount, only 50 to 200 mL leave the body in the feces. It is obvious that severe vomiting or diarrhea can quickly interrupt the recycling mechanism and affect fluid and electrolyte balance in the body. Drugs are primarily absorbed in the intestine, although some small acidic molecules, such as aspirin, may be absorbed in the stomach. Other small molecules may be absorbed through the oral mucosa. Some drugs are broken down by digestive enzymes. The presence of certain foods or drugs, such as antacids, can interfere with absorption of other drugs. Large amounts of food in the stomach and intestine can also delay absorption of drugs. THINK ABOUT 17.2 a. Describe how the PNS affects the digestive tract, and name the major nerve responsible. b. Give two reasons why it is important to control the rate of flow of chyme through the digestive tract. c. State the source and purpose of gastrin. d. State the final form in which carbohydrate and protein are absorbed into the blood. e. Describe three general ways in which absorption of nutrients could be impaired. Common Manifestations of Digestive System Disorders Anorexia, Vomiting, and Bulimia The manifestations of anorexia, nausea and vomiting, may be signs of digestive system disorders or other conditions elsewhere in the body. For example, systemic infection, uremia (kidney failure), emotional responses such as fear, motion sickness, pressure in the brain, overindulgence in food, drugs, or pain may initiate these signs. However, nausea and vomiting are common indicators of gastrointestinal disorders, and the charac- teristics of the vomitus and the vomiting pattern can be helpful in diagnosis. Vomiting is also considered a body defense because it removes noxious substances from the body. In addition, anorexia and vomiting can contribute to serious complications, such as dehydration, acidosis, and malnutrition: • Anorexia (loss of appetite) often precedes nausea and vomiting. Nausea is a generally unpleasant subjective feeling, which may be stimulated by distention, irrita- tion, or inflammation in the digestive tract. Often, increased salivation, pallor, sweating, and tachycardia may occur with nausea and vomiting. • Vomiting, or emesis, is the forceful expulsion of chyme from the stomach and sometimes from the intestine. The vomiting center in the medulla coordinates the 436 SECTION III Pathophysiology of Body Systems complications can include tears of the esophagus, constipation, diarrhea, and electrolyte/nutritional imbalances and deficiencies. Treatment methods include counseling and support groups as well as psychotherapy, nutritional therapy, and antidepressive drugs. Diarrhea Diarrhea is an excessive frequency of stools, usually of loose or watery consistency, and may be acute or chronic. The presence of blood, mucus, or pus in the stool may be helpful in diagnosing or monitoring a disease. Diarrhea is frequently accompanied by nausea and vomiting when infection or inflammation of the digestive tract develops, but in other cases it occurs alone. Often, diarrhea is accompanied by cramping pain. Severe or prolonged diarrhea may lead to dehydration, electrolyte imbalance, acidosis, and malnutrition. • A deeper brown color may indicate content from the lower intestine, typical of recurrent vomiting in persons with intestinal obstruction. • Recurrent vomiting of undigested food from previ- ous meals indicates a problem with gastric emptying, such as pyloric obstruction. • Bulimia is an eating disorder in which an individual binges and overeats followed by inducing vomiting, taking laxatives, or starving themselves to avoid weight gain. Although clinically considered a behavioral disorder, the results have a significant adverse effect on the digestion process and some of its structures. Damage to structures of the oral cavity such as the oral mucosa and the teeth are often evident as regular vomiting exposes the structures to stomach acid. Many who suffer from bulimia also experience anorexia. The exact cause is not known, but studies have revealed multiple factors that could be involved. In addition to visible damage to structures of the oral cavity, other 3. Hypersalivation, pallor, sweat, tachycardia 4. Glottis closes; soft palate rises to close off airway Distention or irritation of digestive tract Unpleasant sights or smells Medulla Vomitus Pain Fear Chemicals, drugs stimulate chemoreceptor trigger zone Increased intracranial pressure Motion stimulates vestibule in inner ear 1. Stimulus to vomiting center 5. Deep inspiration, diaphragm contracts 8. Antiperistaltic waves 6. Gastroesophageal sphincter and fundus of stomach relax 2. Vomiting (emetic) center coordinates reflex through cranial nerves V, VII, IX, X, and XII 9. Increased pressure forces chyme upward from stomach out of mouth 7. Abdominal muscles contract forcefully FIG. 17.3 The vomiting or emetic reflex. CHAPTER 17 Digestive System Disorders 437 abnormalities are relative to the individual’s normal pattern. Constipation is the condition in which there are less frequent bowel movements than normal and small hard stools result. It may be an acute or chronic problem. In some individuals, periods of constipation may alternate with periods of diarrhea. In these cases, emptying of the bowel with diarrhea may lead to decreased peristalsis, which results in increased time available for reabsorption of fluid, leading to dry, hard feces. This dry mass then irritates the intestinal mucosa, leading to inflammation and increased secretions. Once the hard feces have been expelled, a period of diarrhea may follow. Causes of constipation include the following: • Increased age and weakness of the smooth muscle in the intestines • Inadequate dietary fiber, leading to less bulk in the intestine and decreased peristalsis • Inadequate fluid intake • Failure to respond to the defecation reflex because of pain or inconvenient timing • Muscle weakness and inactivity, which impede defecation • Neurologic disorders, such as multiple sclerosis or spinal cord trauma, which predispose the individual to constipation • Drugs, such as opiates (eg, codeine) and other central nervous system depressants or anticholinergics (drugs that block the PNS), which slow peristalsis • Some antacids, iron medications, and bulk laxatives (with insufficient fluid intake), which can predispose patients to constipation • Obstruction caused by tumors or strictures, which may delay passage and cause excessive reabsorption of fluid Chronic constipation may lead to the development of hemorrhoids or diverticulitis. Severe constipation can lead to fecal impaction (retention of feces in the rectum and colon) and intestinal obstruction, usually indicated by pain and abdominal distention. In some cases, watery diarrhea masks a fecal impaction because fluid pushes past a well-lodged fecal plug. Fluid and Electrolyte Imbalances Dehydration and hypovolemia are common complications of digestive tract disorders. When vomiting and diarrhea occur, perhaps combined with insufficient fluid intake, fluid shifts from the blood into the digestive tract. If the loss persists, eventually intracellular fluid is decreased (see Chapter 2). Hypovolemia with impaired circulation and cellular dehydration may decrease function in all tissues and organs. Infants and elderly persons are particularly vulnerable to losses incurred with vomiting and diarrhea because of the unique proportions and distribution of fluid in the body in these individuals and the decreased ability of their kidneys to compensate quickly for losses. Diarrheal diseases, often referred to collectively as enterocolitis, can be classified in different ways. Some common types are the following: • Large-volume diarrhea (secretory or osmotic) leads to a watery stool, resulting from increased secretions into the intestine. This type of diarrhea is often related to infections or a short transit time, which limits reabsorp- tion, or to increased osmotic pressure of the intestinal contents, causing them to retain water. A common cause of osmotic diarrhea is lactose intolerance, in which lactose remains undigested and unabsorbed inside the intestine, thereby increasing the osmotic pressure of the contents. • Small-volume diarrhea often occurs in people with inflammatory bowel disease, and the stool may contain blood, mucus, or pus. The diarrhea may be accompa- nied by abdominal cramps and urgency. The differentia- tion between the two types of diarrhea is not always marked. • Steatorrhea is “fatty diarrhea,” marked by frequent bulky, greasy, loose stools, often with a foul odor. These stools are characteristic of malabsorption syndromes, such as celiac disease or cystic fibrosis, in which the food intake is not digested or absorbed. Fat is usually the first dietary component affected, and the presence of fat interferes with the digestion of other nutrients. The abdomen is often distended because of the bulk remaining in the intestines. Malnutrition is apparent in other tissues, unless disguised by edema caused by hypoproteinemia. • Blood may occur in a normal stool or with diarrhea or constipation or with inflammatory conditions: • Frank blood refers to red blood, often on the surface of the stool. This blood usually results from lesions in the rectum or anal canal; it has not been “digested.” • Occult blood refers to small, hidden amounts of blood that are not visible to the eye but are detectable on tests of a stool specimen (eg, the guaiac test). This may be caused by small bleeding ulcers in the stomach or small intestine. • Melena is a dark-colored (tarry) stool that results from significant bleeding that has occurred higher in the digestive tract; intestinal bacteria have acted on the hemoglobin, causing the dark color. Gas develops normally in the digestive tract from swallowed air and digestive and bacterial action on food. Certain foods or alterations in motility also promote gas production. Excessive gas may manifest as belching (expulsion through the mouth), abdominal distention and discomfort, or flatus (expulsion through the anus). Constipation Bowel patterns differ among individuals, depend- ing on factors such as diet and activity, and therefore 438 SECTION III Pathophysiology of Body Systems • Colicky, often severe pain results from recurrent smooth muscle spasm or contraction and occurs in response to severe inflammation or obstruction; for example, it may occur when the system attempts to propel an obstructing gallstone through the bile duct. Somatic pain is characterized by a steady, intense, often well-localized abdominal pain, which indicates involve- ment or inflammation of the parietal peritoneum, which contains numerous pain receptors. This forms the basis for the “rebound tenderness” that is identified over an area of inflammation, such as that which develops with acute appendicitis. To elicit the response, pressure is applied slowly to the abdomen by the fingers, and then suddenly released, resulting in a sharp pain at the site. Somatic pain receptors are directly linked to spinal nerves and may cause a reflex spasm of the overlying abdominal muscles, which leads to a rigid abdomen or “guarding.” The patient tends to hold the body immobile with the hip joint flexed and the thigh drawn up. Referred pain is a common phenomenon and may delay diagnosis because the source of the pain is perceived as a site distant from its origin. Referred pain results when visceral and somatic nerves converge at one spinal cord level, and the source of the visceral pain is then perceived as the same as that of the somatic nerve. Common sites of referred pain may be seen in Fig. 4.3. Malnutrition Nutritional deficits may be limited or general and have many causes related to gastrointestinal function. There may be a specific problem, such as a vitamin B12 deficiency linked to a lack of intrinsic factor from the gastric mucosa. Malabsorption, liver damage, or a bleeding ulcer may cause iron deficiency. General malnutrition may result from chronic anorexia, vomiting, or diarrhea related to gastrointestinal malfunc- tion or other systemic causes. For example, chronic inflammatory bowel disorders may cause anorexia, diarrhea, and malabsorption, or vomiting and diarrhea may be related to external factors such as cancer treat- ments (radiation and chemotherapy). “Wasting syndrome,” or chronic diarrhea accompanying acquired immunode- ficiency syndrome (AIDS), leads to malnutrition and dehydration. Interference with bile and pancreatic secretions by mucus plugs in persons with cystic fibrosis is another example of a systemic disease that may lead to malabsorption and malnutrition. Special diets or “fad” diets for weight loss may result in a lack of certain required elements if a proper balance of nutrients has not been assured. For example, eight essential amino acids are required simultaneously in the diet and are present in animal products. A vegetarian diet must be carefully developed to include foods that provide these amino acids. Some weight-loss diets do not contain all necessary elements. It is recommended Electrolytes such as sodium are lost in both vomiting and diarrhea because both mucus and enzyme secretions contain large amounts of electrolytes. Gastric secretions are high in chloride ion. Diarrhea leads to significant losses of potassium ion. (The effects of these imbalances may be reviewed in Chapter 2.) Acid-base imbalances are common with vomiting and diarrhea. Initially, vomiting leads to loss of hydrochloric acid, resulting in metabolic alkalosis from loss of hydrogen ion and hypochloremia with increased serum bicarbonate levels (see Chapter 2). If vomiting is severe, there is a change to metabolic acidosis. Duodenal secretions containing large quanti- ties of bicarbonate ion are lost, ketoacidosis develops owing to a glucose deficit, and lactic acid accumulates as a result of hypovolemia and impaired tissue perfu- sion as well as increased muscle activity, which all lead to acidosis. Metabolic acidosis may also accompany diarrhea in the presence of heavy losses of bicarbon- ate ion in the stool and lack of absorption of fluid and glucose. The accompanying dehydration may limit the ability of the kidneys to respond to acidosis, leading to decompensation. THINK ABOUT 17.3 a. Explain three specific causes of vomiting; include a variety of factors. b. Describe the specific actions of the vomiting reflex that prevent aspiration. c. Explain the similarities and differences between anorexia and bulimia. d. Explain the changes in arterial blood gases to be expected in the early stage of vomiting and with diarrhea. Pain Pain in the digestive system is often difficult to describe in specific terms. A variety of descriptors may be applied. Visceral pain fibers are connected to the autonomic nervous system; therefore autonomic responses, such as pallor and sweating or nausea and vomiting, frequently accompany this type of pain. Following are types of visceral pain that arise from the organs in the digestive system and are often difficult to localize: • A burning sensation frequently accompanies inflam- mation and ulceration in the upper digestive tract; it is related to oral ulcerations when located in the mouth and to heartburn when substernal in location. • A dull, aching pain (in the right upper quadrant of the abdomen) is typical of stretching of the liver capsule caused by swelling. • Cramping or diffuse pain is characteristic of inflam- mation, distention, or stretching of the intestines. CHAPTER 17 Digestive System Disorders 439 Common Therapies and Prevention Many digestive tract disorders require a team approach to assist with the many facets of the disease: 1. Dietary modifications are helpful in the treatment of many gastrointestinal disorders. For example, a gluten- free diet is recommended for people with celiac disease, thus removing the source of the problem. Reduced intake of alcohol and coffee (containing caffeine) may promote the healing of ulcers, and increased fiber and fluid intake may reduce constipation. Limited fat content along with increased caloric intake and vitamin supplements are recommended for patients with many malabsorption syndromes. A diet that is restricted in calories is important in dealing with obesity and is usually paired with an exercise program. Other factors in the diet, such as the type of fat, the inclusion of antioxidants, and the vitamin and mineral content, are of concern to many with respect to prevention of disease. 2. Stress reduction techniques are useful in many patients with peptic ulcer or chronic inflammatory bowel disorders, in which exacerbations have been shown to be stress related. These techniques are also important in the treatment of adolescents or teenagers with digestive tract disorders because the disease may affect their social activities and body image. Severe or prolonged stress, whether resulting from a physical stressor such as infection or trauma or an emotional stressor such as fear or anger, does affect the digestive tract. These effects result from stimulation of the SNS, leading to vasoconstriction and ischemia of the mucosa, with subsequent inflammation and ulceration. Also, SNS stimulation decreases peristalsis, resulting in prolonged contact of secretions and irritants with the mucosa. The stress response also promotes glucocor- ticoid secretion, which has catabolic effects if it is continued over a long term. High cortisol levels lead to reduced regeneration of the mucosa and delayed healing of lesions. A stressful environment predisposes the individual to poor nutritional habits, such as increased caffeine intake and indulgence in snack foods. 3. Drugs are used to treat many gastrointestinal disorders, and a great variety of medications are available to treat the diverse types of gastrointestinal problems. Examples of common medications are summarized in Table 17.3. Many individuals treat themselves for minor digestive discomfort. It is always important to check specifically on self-prescribed medications when taking a patient history, because many individuals do not think that over-the-counter drugs are of any importance. Such medications may mask signs of disease or may themselves be the cause of a problem. If possible, it is better to identify and treat the cause of a problem rather than the symptom. • Antacids are a common medication used for many purposes. The primary component of antacids is that a nutritionist be consulted before embarking on any new diet. In a child, growth and development may be delayed or impaired by malabsorption or malnutrition. At any stage, the outcomes probably include chronic fatigue, reduced resistance to infection, and impaired healing. Obesity occurs when the energy value of food con- sumed is greater than that required by the body. The standard assessment for obesity is determination of body mass index (BMI). In an adult a BMI greater than 30 is indicative of obesity; BMI charts are inside the back cover of the text. (See Chapter 23 for a discussion of adolescent obesity.) Obesity may be related to ingestion of foods high in fats and simple sugars and low in fiber. Such a condition is often seen in individuals who do not include fresh fruits or vegetables in their diet. It is currently estimated that one in four Americans is obese. Major complications of obesity include hyperten- sion, atherosclerosis, type 2 diabetes, obstructive sleep apnea, arthritis, and congestive heart failure. The current epidemic of obesity among adolescents and adults is expected to increase the need for health care services significantly. Basic Diagnostic Tests Radiographs are useful diagnostic tools in digestive system disorders. X-ray films, often using a contrast medium such as barium (in oral solution or enema), are useful in outlining many gastrointestinal system structures and abnormalities, and ultrasound may demonstrate unusual masses. Computed tomography (CT) scans and magnetic resonance imaging (MRI) can be used to check liver and pancreatic abnormalities. Radioactive elements may be used in tracer studies when the uptake of a particular molecule is being analyzed. Techniques such as fiberoptic endoscopy allow improved visualization or biopsy of various segments of the digestive tract, such as the esophagus. Sigmoidoscopy and colonoscopy have become routine preventive and monitoring tools for cancer. Laboratory analysis of stool specimens or gastric washings can provide evidence of infection, bleeding, tumors, or malabsorption problems. Specimens may need to be repeated over a prescribed time period, particularly if a parasitic infection is suspected. Blood tests can be used to check liver function by evaluating serum protein levels, clotting times, serum liver enzymes, and bilirubin levels. Pancreatic problems may be detected by serum enzyme levels or stool analysis for enzymes and fat content. Blood tests can also be used to monitor tumor markers—for example, carcinoembry- onic antigen (CEA) in patients with colon cancer—although these tests cannot stand alone as diagnostic tools or monitoring devices. It is usual for the patient to experience a variety of tests before a diagnosis can be made. 440 SECTION III Pathophysiology of Body Systems • Sulfasalazine (Salazopyrin or Azulfidine), an antiinflam- matory and antibacterial agent, may be used to treat acute episodes of inflammatory bowel disease. • Antibacterials, such as clarithromycin (Biaxin) or azithromycin (Zithromax), are effective against Heli- cobacter pylori infection and are usually combined with a proton pump inhibitor such as omeprazole (Prilosec). Metronidazole is used to treat protozoal, helminthic as well as bacterial infections. • Sucralfate (Carafate or Sucrate) is a coating agent, used to enhance the gastric mucosal barrier against irritants, allowing ulcers to heal. • Anticholinergic/antispasmodic drugs reduce PNS activity and may be used to reduce secretions and motility as well as reduce painful spasms. Examples include pirenzepine, which inhibits gastric acid, and propantheline bromide, which decreases gastrointestinal motility and spasm as well as reducing gastric acid. Alosetron (Lotronex) is designed to relax the colon and slow the movement of waste through the lower bowel. • Histamine2 blockers (H2 receptor antagonist drugs), such as cimetidine (Tagamet) or ranitidine (Zantac), may be useful in some cases of ulcers. • Proton (acid) pump inhibitors, such as lansoprazole (Prevacid) or omeprazole (Prilosec or Losec), are a newer group of drugs that reduce gastric secretions by interfering with the exchange of H+ and K+ in the usually calcium carbonate, aluminum hydroxide, magnesium hydroxide, or a combination of these. Examples are Maalox or Gelusil. • Antiemetics, taken to relieve vomiting, include drugs such as dimenhydrinate (Dramamine, Gravol) or phenothiazines such as prochlorperazine (Compazine). Cannabinoids such as nabilone (Cesamet) may be a successful antiemetic for chemotherapy-induced vomiting. • Laxatives or enemas, of which there are many types, are used to treat acute constipation. Fluid intake should be increased while taking these medications. Bulk supple- ments (eg, psyllium hydrophilic mucilloid [Metamucil]) or stool softeners (eg, docusate sodium [Colace]) are helpful, particularly for recurrent constipation and are less likely to cause adverse effects than other laxatives. Chronic constipation is best treated by the addition of fiber and fluid to the diet, rather than persistent use of laxatives, which may aggravate the problem. Lubipro- stone (Amitiza) works by increasing fluid secretion in the small intestine to help with the passage of stool. • Antidiarrheals, such as loperamide (Imodium), or narcotics such as codeine or paregoric, may reduce peristalsis and relieve cramps when diarrhea is not relieved by dietary changes. • Infections causing diarrhea are frequently self-limiting, but specific antimicrobial drugs may be required in some cases. TABLE 17.3 Examples of Drugs Used in Digestive System Disorders Classification Example Action Antiemetic Dimenhydrinate (Dramamine) Prochlorperazine (Stemetil) Reduces vomiting resulting from drugs, motion sickness, and radiation treatment Antidiarrheal Loperamide (Imodium) Codeine, paregoric Reduces intestinal motility Antiinflammatory Prednisone (Deltasone—a glucocorticoid) Sulfasalazine (Azulfidine) Reduces inflammation Prednisone blocks immune response Sulfasalazine has antibacterial action Acid-reduction Ranitidine (Zantac): blocks H2 receptors Lansoprazole (Prevacid): proton (H+) pump inhibitor Reduces secretion of hydrochloric acid in the stomach Antimicrobial Clarithromycin (Biaxin) Metronidazole (Flagyl) Tetracycline Cefoperazone Amoxicillin Combination therapy for Helicobacter pylori infection Drugs as indicated by culture and sensitivity Coating agent Sucralfate (Carafate) Covers ulcer to allow healing Antacid Aluminum-magnesium combinations (Maalox) Reduces hyperacidity Laxative Psyllium (Metamucil) (bulk) or docusate sodium (Colace) (stool softener) With water, increases fecal bulk and intestinal motility Anticholinergics Pirenzepine, propantheline bromide Reduce parasympathetic nervous system activities— reduced secretions and mobility Histamine2 blockers Tagamet, Zantac Inhibit acid production in stomach Proton pump inhibitors Prevacid, Prilosec Reduce gastric secretions CHAPTER 17 Digestive System Disorders 441 stomach. They are used in combination with antibacteri- als to treat H. pylori infection. THINK ABOUT 17.4 a. Describe and state the mechanism of referred pain and colicky pain. b. Describe the vomiting reflex, noting possible causes of aspiration during vomiting. c. Explain why altered blood clotting times and serum protein levels may indicate the presence of liver disease. d. Explain how the use of over-the-counter medications may exaggerate or mask symptoms and sometimes exacerbate the disorder. e. Explain how regular use of bulk laxatives can promote peristalsis and relieve constipation. APPLY YOUR KNOWLEDGE 17.2 Explain why using an antiprotozoal drug like metronidazole may be more stressful on the body than most antibacterial drugs. Upper Gastrointestinal Tract Disorders Disorders of the Oral Cavity Congenital Defects Cleft lip and cleft palate are common developmental abnormalities of the mouth and face and arise in the second or third month of gestation (Fig. 17.4). Cleft lip and cleft palate appear to be multifactorial in origin and are related to a number of inherited and environmental factors. One or both defects may be present in various degrees of severity. B D A Unilateral cleft lip C Unilateral cleft palate and lip (complete) (complete) FIG. 17.4 Cleft lip and palate. A, Unilateral cleft lip. B, Unilateral cleft lip. C, Unilateral cleft palate and lip. D, Following surgical repair of cleft palate and lip. Note suture line on palate and missing anterior teeth that interfere with speech and eating. (B From Behrman RE, Kliegman RM, Arvin AM: Slide Set for Nelson Textbook of Pediatrics, ed. 15, Philadelphia, 1996, Saunders. D Courtesy Evie Jesin, George Brown College of Applied Arts and Technology, Toronto, Ontario, Canada.) 442 SECTION III Pathophysiology of Body Systems accompanied by a tingling sensation. Central ulceration develops, with a punched-out whitish appearance sur- rounded by a red border. The ulcers heal spontaneously in a week or so. Infections The oral cavity has a large and varied resident flora (microflora), including many types of bacteria in addition to fungi, viruses, and protozoa. These microorganisms thrive in the crevices of the mouth, where it is moist and warm and food particles provide plentiful nutrients. They generally are harmless; however, they may cause oppor- tunistic infections, such as candidiasis, or cause secondary infection when there are open lesions in the oral cavity. The oral cavity and pharynx may also harbor pathogens in certain individuals (carriers). Some of the resident bacteria, such as strains of viridans streptococci, (a hemolytic streptococci) and Staphylococcus aureus, are of concern when they enter the bloodstream at the points where the body’s defenses may be compro- mised. An example of a dangerous infection arising in the oral cavity is when the mucosal barrier is broken during dental procedures, and the circulation and replica- tion of the organisms can subsequently cause a transient bacteremia. These bacteria may travel to the valves of the heart where an infection can damage the valves, resulting in bacterial endocarditis (see Chapter 12). Therefore prophylactic medication with amoxicillin or an alternative is sometimes recommended when there is a risk of bacteremia. (Current recommendations are available from the American Dental Association and the American Heart Association.) Candidiasis Candida albicans, often part of the normal resident flora of the mouth, is an opportunistic pathogen under certain conditions. Oral candidiasis (thrush) is a common fungal infection that occurs in individuals who have received broad-spectrum antibiotics, cancer chemotherapy, or glucocorticoids and in those who have diabetes or are immunosuppressed. It is often an initial indication of infection in AIDS patients and may extend into the esophagus in such cases. The infection may also be seen in young infants as they develop resident flora, or it may be transmitted by the mother. Chronic infection on the palate is seen in persons with dentures that are poorly fitted or worn at night (Fig. 17.5A). Candidal infection may appear as a red, swollen area as in Fig. 17.5A or as irregular patches of a white curdlike material (see Fig. 17.5B) on the mucosa or tongue that can be wiped off (a diagnostic clue) to reveal erythema at the base. Nystatin (Mycostatin), a topical antifungal agent, is the usual treatment. Herpes Simplex Type 1 Infection Herpetic stomatitis may be associated with herpes labialis (cold sores or fever blisters). Herpes infection is usually Cleft lip, which may be unilateral or bilateral (on either side of the midline), results from failure of the maxillary processes to fuse with the nasal elevations or failure of the upper lip to fuse at some time between 4 and 8 weeks of fetal development. Cleft palate involves failure of the hard and soft palates to fuse between 7 and 12 weeks of gestation, creating an opening between the oral cavity and the nasal cavity. The infant has feeding problems because there is insuf- ficient force developed in the mouth to suck and a high risk of aspirating fluid into the respiratory passages. Speech development is also impaired. Temporary mea- sures include the use of special nipples or dental appli- ances that close off the nasal cavity. Surgical repair of the defect is necessary, and additional plastic surgery to correct growth defects or improve appearance is usually indicated (see Fig. 17.4D). Therapy with a speech-language pathologist and orthodontist promotes normal develop- ment. A multidisciplinary team is frequently required over a prolonged period when major clefts are present. Inflammatory Lesions Aphthous ulcers (aphthous stomatitis or canker sores) are a common problem. Although the precise cause of canker sores is not clear, it is suspected that a number of factors or conditions contribute to an outbreak of these sores. Some of the possible factors include these: • A minor injury to the mouth from dental work, overzealous brushing, sports mishaps, or an accidental cheek bite • Toothpastes and mouth rinses containing sodium lauryl sulfate • Food sensitivities, particularly to chocolate, coffee, strawberries, eggs, nuts, cheese, and spicy or acidic foods • A diet lacking in vitamin B12, zinc, folate (folic acid), or iron • An allergic response to certain bacteria in your mouth • Helicobacter pylori, the same bacteria that cause peptic ulcers • Hormonal shifts during menstruation • Emotional stress • Celiac disease, a serious intestinal disorder caused by a sensitivity to gluten, a protein found in most grains • Inflammatory bowel diseases, such as Crohn disease and ulcerative colitis • Behçet disease, a rare disorder that causes inflammation throughout the body, including the mouth • A faulty immune system that attacks healthy cells in your mouth instead of pathogens, such as viruses and bacteria • HIV/AIDS, which suppresses the immune system Aphthous ulcers are small, shallow, painful lesions occurring on the movable mucosa, the buccal mucosa, the floor of the mouth, the soft palate, and the lateral borders of the tongue. Initially a red macule appears, CHAPTER 17 Digestive System Disorders 443 present, the acute stage may be alleviated somewhat by prompt use of antiviral medications (such as topical acyclovir [Zovirax], Valtrex, and Famvir), thus decreasing the shedding of the virus, the risk of transmission, and the discomfort. Herpes simplex virus may spread to the eyes, causing conjunctivitis and keratitis (see Chapter 15), either by contaminated fingers or through droplets sprayed from the mouth, for example, during dental treatment. Dental personnel are also vulnerable to herpetic whitlow, an acute and painful infection of the finger (Fig. 17.6). Syphilis Syphilis is an infection caused by the spirochete Treponema pallidum, whose most common route of transmission is through direct contact during sexual activity. Syphilis may cause oral lesions that contain microorganisms and are highly contagious during the first and second stages (see Chapter 19). The primary stage is characterized by a chancre, a painless ulcer usually found on the tongue, lips, or palate. The lesion heals spontaneously (without treatment) in 1 or 2 weeks. The second stage may be manifested by red macules or papules on the palate, similar to the typical skin rash occurring at this stage, or by mucous patches—multiple, irregular, loose, white necrotic material on the mucosa, which is highly infec- tious. Again, this lesion heals spontaneously. Because these lesions may be missed, immediate treatment of the infection and control of transmission may be hampered. Both stages of syphilis are treated with long-acting penicillin, usually by injection. Dental Problems Caries Dental caries (tooth decay or cavities) is an infection involving any number of bacteria normally found in the oral cavity, but the primary microorganisms involved are Streptococcus mutans (as the initiator), followed by increased numbers of Lactobacillus and other acid-producing resident A FIG. 17.5 Thrush. A, Micrograph of the fungus Candida albicans in the yeast form (this fungus can also form filamentous mycelia), which is responsible for an oral infection called thrush. C. albicans can also cause vaginal infections in women. B, Oral candidiasis illustrating the white plaques. (A From VanMeter K, Hubert R: Microbiology for the Healthcare Professional, St. Louis, 2010, Elsevier. B From Zitelli BJ, Davis HW: Atlas of Pediatric Physical Diagnosis, ed 4, St. Louis, 2002, Mosby.) FIG. 17.6 Herpetic whitlow. (Courtesy of Mark Drapkin, Newton- Wellesley Hospital, Newton, Massachusetts. From Stone DR, Gorbach SL: Atlas of Infectious Diseases, Philadelphia, 2000, Saunders.) caused by herpes simplex virus type 1 (HSV-1) and is transmitted by kissing or close contact, often in childhood. The initial infection is frequently asymptomatic, but the virus remains dormant in the body in a sensory ganglion, often the trigeminal nerve ganglion. When activated by stress, trauma, or another infection (such as a common cold), the virus migrates along the nerve to the skin or mucosa around the mouth, causing a burning or stinging sensation at the site, which is fol- lowed by development of vesicles (blisters) as the virus reproduces and causes necrosis of the host cells (see Fig. 8.9). These vesicles rupture, leaving a shallow, painful ulcer, which releases a clear fluid containing many organ- isms and then crusts over. The lesions heal spontaneously in 7 to 10 days, when the virus again migrates along the trigeminal nerve to the sensory ganglion, where it enters a latent stage. Recurrences are common. In immunosup- pressed patients, multiple lesions may develop in the oral cavity and pharynx (herpetic gingivostomatitis). HSV-1 is often present in the saliva for some time after the vesicle has healed. Although no cure is available at 444 SECTION III Pathophysiology of Body Systems called pregnancy tumor) may occur from hormonal changes associated with pregnancy or the use of oral contraceptives. Gingival hyperplasia occurs with long- term use of drugs, such as phenytoin (Dilantin) or cyclosporine (see Fig. 14.27). Necrotizing periodontal disease, also called trench mouth (formerly acute necrotizing ulcerative gingivitis [ANUG]) is a common infection caused by anaerobic opportunistic bacteria in individuals in whom tissue resistance is decreased by stress, smoking, disease, or nutritional deficits. The gingivae around the mandibular anterior teeth (lower jaw) are affected, showing white pseudomembranous necrotic areas surrounded by red and swollen areas. The gingivae are painful and bleed easily. Débridement and antibiotics may be needed. Periodontitis More serious forms of periodontal disease develop when there is an increase in activity of gram-negative anaerobic bacteria as they enter the plaque. Major destructive microbes in periodontal disease include Porphyromonas gingivalis (formerly Bacteroides oralis), Actinobacillus actinomycetemcomitans, and Bacteroides forsythus. These microbes secrete toxins and enzymes destructive to the tissues and white blood cells (WBCs). Such infection is not contagious. In addition to poor oral hygiene, periodontitis is aggravated by smoking, which promotes calculus forma- tion (see Fig. 17.7D); cancer and chemotherapy; diabetes mellitus with decreased tissue resistance and poor healing (see Fig. 16.8A); and HIV infection (AIDS), in which periodontitis is rapidly progressive and often resistant to treatment (see Fig. 17.17D, presented later in the chapter). When periodontal disease develops, plaque and calculus have progressed on the tooth beneath the gingival margin, causing inflammation in the tissues around the root of the tooth. The subgingival areas are colonized by these gram-negative anaerobic bacteria, which ultimately destroy the periodontal attachment of the tooth and the surrounding alveolar bone. An enlarging periodontal pocket forms around the tooth, promoting more anaerobic bacterial activity and active infection. The mucosa is red and swollen and bleeds easily, and the teeth feel loose (see Fig. 17.7E, presented later in the chapter). Major treatment, including drugs and surgical procedures, is required to eradicate the infection and prevent loss of teeth. Hyperkeratosis An example of hyperkeratosis is leukoplakia, a whitish plaque or epidermal thickening of the mucosa that occurs on the buccal mucosa, palate, lower lip, or tongue (Fig. 17.8). The cause cannot always be identified but may be related to smoking or chronic irritation. These lesions require monitoring because, in some cases, epithelial dysplasia beneath the plaque develops into squamous cell carcinoma. flora in the oral cavity. These bacteria act on sugars in ingested food to create large quantities of lactic acid that dissolve the minerals (calcium and phosphate) in tooth enamel, leading to erosion of the tooth surface and cavity formation. If untreated, bacterial action and decay may continue to penetrate the tooth surface until the internal structures of the tooth are infected (pulpitis) or periapical abscesses form at the root of the tooth. Caries is promoted by frequent intake of sugar and acids such as carbonic acid in soft drinks and by the presence of multiple pits or fissures in the tooth surface. Xerostomia (dry mouth), plaque formation, and peri- odontal disease also increase the incidence of caries. Fluoride, as an anticaries treatment, decreases the solubil- ity of the minerals in enamel (fluorapatite replaces hydroxyapatite) and enhances the remineralization process. Excessive fluoride ingestion during tooth matura- tion can cause hypocalcification, a condition resulting in deficient calcification of tooth enamel. Periodontal Disease The periodontium consists of the gingivae (gums) and the anchoring structures for the teeth, which include the alveolar bone around the teeth, the cementum (or outer covering of the root of the tooth), and the periodontal ligament joining the cementum to the bone. Periodontitis is the infection and damage to the periodontal ligament and bone by microorganisms and the subsequent loosen- ing and possible loss of the teeth. There are currently eight categories of periodontal disease, ranging from mild gingival disease to severe periodontitis. Periodontal disease is often caused by poor oral hygiene but can also be aggravated by systemic diseases and medications. Gingivitis Normally the gingivae, or gums surrounding the teeth, are firm, light pink with a stippled appearance, well shaped, and anchor the teeth firmly (Fig. 17.7A). Changes in the gingivae may reflect local or systemic problems. Gingivitis, or inflammation of the gingiva, causes the gingival tissue to become red, soft, and swollen and to bleed easily. This may result from accumulated plaque, which is a mass of bacteria and debris adhering to the tooth, particularly near the gingivae. The involved microbes secrete substances that enable them to adhere to the tooth surface and to plaque. Calculus, or tartar, refers to calcified plaque, which is more irritating to tissue because of its hard, rough surface (see Fig. 17.7C). Poor oral hygiene also predisposes to gingivitis. However, toothbrush trauma (see Fig. 17.7B), resulting from improper or excessive brushing or use of abrasives, can create extensive grooving on the tooth surface, increase plaque retention and damage to the gingivae, and amplify tooth sensitivity. Systemic factors can alter the gingivae. Development of a dark line on the gingival margin is an indicator of lead poisoning (see Chapter 28). Overgrowth (sometimes CHAPTER 17 Digestive System Disorders 445 Routine dental care is important in identifying these lesions in an early stage. Common sites are the floor of the mouth and the lateral borders of the tongue (Fig. 17.9). There may be multiple lesions. The carcinoma appears initially as a whitish thickening and then develops into either a nodular mass or an ulcerative lesion, which persists. Intraoral cancer spreads first to the regional lymph nodes and nodes in the neck. Cancer of the Oral Cavity The common cancer of the oral cavity is squamous cell carcinoma. These cancers are more common in persons older than age 40, particularly smokers, those with preexisting leukoplakia, or those with a history of alcohol abuse. Malignant tumors inside the oral cavity have a poor prognosis because they tend to be hidden and painless. BA D E C FIG. 17.7 Dental problems. A, Healthy periodontium. The gingiva (gum) is light pink, stippled, and firm around the teeth. B, Toothbrush trauma. Improper brushing has led to loss of tooth substance and grooving of the root. C, Calculus or calcified plaque on tooth surface. D, Smoking leads to extensive calculus, staining on the teeth, and increased risk of periodontal disease. E, Severe periodontal disease with bone loss and caries in the root of the tooth. (A-E Courtesy Evie Jesin, George Brown College of Applied Arts and Technology, Toronto, Ontario, Canada.) 446 SECTION III Pathophysiology of Body Systems usually bilateral, swelling of the gland (Fig. 17.10). Although a vaccine has been available since the early 2000s, mumps outbreaks have occurred in college-aged adults; in such outbreaks, revaccination is recommended to limit the spread of the disease. Noninfectious parotitis may develop in debilitated or elderly patients who lack adequate fluid intake and mouth care. Tumors such as benign adenomas tend to affect the parotid glands of older individuals. The most frequent malignant tumor of the salivary gland is mucoepidermoid carcinoma, occurring primarily in the parotid glands. FIG. 17.8 Leukoplakia. Leukoplakia of the lateral edge of the tongue. (From Black J, Hawks J: Medical-Surgical Nursing: Clinical Manage- ment for Positive Outcome, ed 8, St. Louis, 2009, Saunders, Elsevier.) FIG. 17.9 Squamous cell carcinoma on the floor of the mouth under the tongue. (From Odom RB, James WD, Berger TG: Andrews’ Diseases of the Skin, ed 9, Philadelphia, 2000, Saunders.) FIG. 17.10 Mumps with unilateral parotid swelling. (From the Centers for Disease Control and Prevention Public Health Image Library, ID #: 4491.) THINK ABOUT 17.5 Prepare a chart comparing the cause and characteristics of one inflammatory disorder, one infectious disorder, and one tumor of the oral cavity. Dysphagia Dysphagia, or difficulty in swallowing (Fig. 17.11), has many causes. It may result from a neurologic deficit, a muscular disorder, or a mechanical obstruction. Dysphagia may manifest as pain with swallowing, an inability to swallow larger pieces of solid material, or difficulty swallowing liquids, depending on the cause of the problem. Neurologic causative factors include infection, stroke, brain damage, and achalasia, which results from failure of the lower esophageal sphincter to relax owing to loss of innervation. This leads to an accumulation of food and dilation of the lower esophagus as entry of food into the stomach is delayed. Often chronic inflammation develops in the esophagus, and reflux of this food may lead to aspiration when the person assumes a supine position. There is an increased risk of esophageal carci- noma in an individual who has had long-term achalasia. Kaposi sarcoma may occur in patients with AIDS. The typical lesion is a brownish or purple macular lesion, usually on the palate, which eventually becomes a nodular mass. Lip cancer (usually on the lower lip) is obvious and accessible and has a good prognosis. It usually spreads locally. This cancer is common in smokers, particularly pipe smokers. Salivary Gland Disorders Sialadenitis refers to inflammation of the salivary glands, infectious or noninfectious. The parotid gland is most frequently affected, both by infectious agents and tumors. Bacterial infection may spread from the mouth. Mumps, infectious parotitis, is a viral infection leading to marked, CHAPTER 17 Digestive System Disorders 447 Fibrosis Compression Diverticulum Food Esophagus Scar tissue contracts Tumor Undigested food in pouch obstructs esophagus Food Food Congenital tracheoesophageal fistula Food Developmental defect – connection between esophagus and trachea Congenital atresia Food A D F G E B C Developmental defect–tube with blind ends Neurologic damage to cranial nerves V, VII, IX, X, and XII Achalasia Food Loss of peristalsis in lower esophagus Stomach Food collects here FIG. 17.11 Causes of dysphagia. Muscle impairment may result from muscular dystrophy. Mechanical obstructions include the following: • Congenital atresia is a developmental defect in which the upper and lower esophageal segments are separated; the upper section ends in a blind pouch. Reflux of feedings occurs in the infant with congenital atresia, leading to aspiration. In many cases there is a connecting fistula from one of the segments to the trachea. Surgical correction is required as soon as 448 SECTION III Pathophysiology of Body Systems Hiatal Hernia In patients with hiatal hernia, part of the stomach protrudes through the opening (hiatus) in the diaphragm into the thoracic cavity. Normally the digestive tract is loosely attached to the diaphragm. There are two types of hiatal hernia (Fig. 17.13). With a sliding hernia, the more common type, a portion of the stomach and the gastroesophageal junction move above the diaphragm, particularly when the person is in the supine position. In the standing position, the herniated portion slides back down into the abdominal cavity. In a rolling or paraesophageal hernia, part of the fundus of the stomach moves up through an enlarged or weak hiatus in the diaphragm. In this type of hernia, the blood vessels in the wall of the stomach may be compressed, leading to ulceration. Food often lodges in the pouch created by the herniated portion, resulting in inflammation of the mucosa, reflux of food up the esophagus, and dysphagia, as the mass of food enlarges and obstructs the passageway. Chronic esophagitis eventually may cause fibrosis and stricture. Often an incompetent gastroesophageal sphincter is seen possible to prevent aspiration and provide fluid and nutrients to the infant. • Stenosis, or narrowing of the esophagus, may be a developmental or acquired defect; the acquired form is usually secondary to fibrosis accompanying chronic inflammation, ulceration (esophagitis), or radiation therapy. Stenosis or stricture may also result from scar tissue that formed after accidental ingestion of corrosive chemicals, such as lye or other cleaning materials. Accidental ingestion of such damaging substances should not be treated by inducing vomiting to remove the chemical, because this would cause additional tissue damage. Stenosis may require treatment with repeated mechanical dilation by bougies or surgery if food intake is severely limited by the obstruction. • Esophageal diverticula are outpouchings of the esopha- geal wall that result either from congenital defects or inflammation. The accumulated food in the pouch obstructs the flow of food down the esophagus; causes irritation, inflammation, and scar tissue in the wall; and often is regurgitated upward at a later time, with the possibility of aspiration into the respiratory tract. Signs of diverticula include dysphagia, foul breath, chronic cough, and hoarseness. Occasionally, ulcers may form in the esophageal wall and bleed. • Tumors may be internal or external. External tumors are located outside the esophagus, perhaps in a medi- astinal lymph node, and compress the esophagus. Esophageal Cancer Esophageal cancer is primarily squamous cell carcinoma and is most commonly found in the distal esophagus. Tumors in the esophagus either form circumferential strictures or grow out into the lumen of the esophagus; both types cause significant dysphagia in later stages (Fig. 17.12). Esophageal cancer is associated with chronic irritation— for example, from chronic esophagitis, achalasia, hiatal hernia, alcohol abuse, and smoking. Unfortunately, the initial signs of dysphagia occur relatively late in the course of the disease, and the prognosis currently is poor. FIG. 17.12 Squamous cell carcinoma of the esophagus. (From Wilcox C.M.: Atlas of Clinical Gastrointestinal Endoscopy, 2007, Philadelphia, Saunders.) Esophagus Hiatus Part of fundus above diaphragm Sac and peritoneum in mediastinum Stomach A B C Diaphragm Normal stomach Sliding hiatal hernia Paraesophageal hernia FIG. 17.13 Types of hiatal hernia. CHAPTER 17 Digestive System Disorders 449 Acute gastritis may result from the following: • Infection by many types of microorganisms (eg, bacteria and viruses) • Allergies to foods such as shellfish or drugs • Ingestion of spicy or irritating foods, such as hot peppers, particularly if the person is unaccustomed to a spicy diet • Excessive alcohol intake • Ingestion of aspirin or other ulcerogenic drugs (espe- cially on an empty stomach) • Ingestion of corrosive or toxic substances • Radiation or chemotherapy ■ Signs and Symptoms The basic signs of gastrointestinal irritation are present. Anorexia, nausea, or vomiting develops, the severity of which varies with the situation. Hematemesis indicates ulceration and bleeding in the stomach. Epigastric pain, cramps, or general discomfort may be present. Depending on the cause, other signs may be present; for example, fever and headache usually accompany infection. In some cases, particularly with infections, diarrhea may develop (see the next section, Gastroenteritis). Acute gastritis is usually self-limiting, with complete regeneration of the gastric mucosa in 1 or 2 days. In persons with severe or prolonged vomiting, there is a danger of dehydration, electrolyte loss, and metabolic acidosis, all of which require supportive treatment. Certain infections may require treatment with antimicrobial drugs. Gastroenteritis Gastroenteritis is the involvement of the stomach and the intestines in an inflammatory process. It is usually caused by infection but may also result from allergic reactions to foods or drugs. Inflammation of the gastric mucosa stimulates vomiting, whereas diarrhea results when the inflammation of the intestines causes increased motility, impaired absorption, and in some cases, increased secretions. Nausea and abdominal cramps are usually present. Fever and malaise are common. Many microorganisms may be transmitted by fecally contaminated food and water. Common causes of food- borne infections are summarized in Table 17.4. Most infections are mild and self-limiting, but occasionally serious illness results when the host is immunosuppressed or the agent is more virulent. Often a food- or water-borne illness will involve a large number of cases; in some outbreaks, entire com- munities may be infected. It is imperative that in times of disaster clear instructions be given about the safety of food and water. Safe sanitation must be put in place as quickly as possible to prevent further illness requiring the use of scarce health resources. Some infections are seasonal or occur as epidemics. For example, rotaviruses cause serious infection, with vomiting and watery diarrhea, sometimes with ulceration and bleeding, in young children in temperate climates in individuals with hiatal hernia, which increases the risk of reflux. Factors contributing to hiatal hernia include shortening of the esophagus, weakness of the diaphragm, or increased abdominal pressure (eg, from pregnancy). The signs of hiatal hernia include heartburn or pyrosis, a brief substernal burning sensation, often accompanied by a sour taste in the mouth, which occurs after meals and results from reflux of the gastric contents up the esophagus. Frequent belching (gas) often accompanies this regurgitation. The discomfort is increased by lying down after eating, bending over, or coughing. Dysphagia is common, either because of inflammation of the esopha- gus or because the mass of food collected in the pouch compresses the esophagus. Persistent, mild, substernal chest pain after meals is a frequent complaint because of inflammation or distention of the pouch. The symptoms can often be reduced by eating frequent, small meals and avoiding a recumbent position after meals. Gastroesophageal Reflux Disease Gastroesophageal reflux disease (GERD) involves the periodic flow of gastric contents into the esophagus. It is often seen in conjunction with hiatal hernia as well as other conditions. The severity of GERD depends on the competence of the lower esophageal sphincter (LES) or the relative pressures on either side of the LES. For example, either a decrease in LES pressure or an increase in intraabdominal pressure allows more of the gastric contents to reflux back into the esophagus. Delayed gastric emptying may also be a factor. Episodes of reflux causing heartburn frequently occur 30 to 60 minutes after eating or at night. Frequent reflux of gastric acid leads to inflammation and ulceration of the mucosa and eventual fibrosis and stricture in the esophagus. Eliminating factors that reduce LES pressure, such as caffeine, fatty foods, alcohol intake, cigarette smoking, and certain drugs, may relieve the discomfort. Avoidance of spicy foods and use of medication may reduce reflux and inflammation. Gastritis Gastritis is an inflammation of the stomach that may occur in many forms. Gastritis may be acute or chronic; these terms represent two different diseases. Acute gastritis may be a mild, transient irritation with only vague signs, or it may be a more severe ulcerative or hemorrhagic episode. Acute Gastritis In acute gastritis, the gastric mucosa is inflamed and appears red and edematous. It may be ulcerated and bleeding if the mucosal barrier (the tightly packed epithelial cells and layer of thick mucus) is severely damaged or the circulation is poor, which reduces tissue resistance. 450 SECTION III Pathophysiology of Body Systems can adhere to the mucosa and secrete an enterotoxin, causing gastroenteritis, particularly among children in nursery schools or travelers in the form of common “traveler’s diarrhea.” Some strains are invasive and cause five forms of intestinal disease: • Enterotoxigenic E. coli (ETEC) causes diarrhea in infants and travelers in countries in which proper sanitation is lacking. The organism colonizes the small intestine and produces enterotoxins that may cause minor discomfort to severe cholera-like symptoms. • Enteroinvasive E. coli (EIEC) penetrates and reproduces in and destroys the epithelial cells of the colon. The organism does not produce enterotoxins but causes severe diarrhea and fever. • Enteropathogenic E. coli (EPEC) is very similar to EIEC; however, it is reported to produce an enterotoxin similar to shigella. • Enteroaggregative E. coli (EAggEC) produces persistent diarrhea in young children. In addition to producing an enteroaggregative heat-stable toxin, it also produces during the winter months. Epidemics of viral gastroen- teritis are common in day care centers and institutions. Careful handwashing and food handling can reduce outbreaks. The infection is usually self-limiting, although sup- portive treatment may be needed for fluid and electrolyte losses, particularly in young children and the elderly. A stool culture is helpful in identifying the causative organ- ism in persistent cases. Infection by Clostridium difficile in patients on broad- spectrum antibiotics causes severe enteritis. This gram- positive bacillus exists as a spore until it reaches the colon. The vegetative form damages the intestinal mucosa, causing diarrhea that is sometimes mild and other times severe. Outbreaks have occurred in many hospitals, resulting in some fatalities. Escherichia coli Infection Escherichia coli (E. coli) is usually a harmless microbe that is normally resident in the intestine. Some infective types TABLE 17.4 Common Infections Transmitted by Food and Water Pathogen Source Incubation Pathophysiology Manifestations Staphylococcus aureus Food handlers Inadequate cooking or refrigeration of custards, salad dressing, cold meats 1–7 hr (2–4, average) Enterotoxin (exotoxin), heat-stable Sudden severe nausea, vomiting, and cramps; sometimes diarrhea Subnormal body temperature and low blood pressure Escherichia coli (traveler’s diarrhea) Fecal contamination of food and water 10–12 hr Various strains may release enterotoxins (increase secretions) or invade the mucosa Profuse watery diarrhea, sometimes with blood or mucus Vomiting and abdominal cramps often present Salmonella species Fecal contamination of food or undercooked or raw eggs, poultry, shellfish Contaminated work surfaces 6–72 hr Organisms multiply in intestine, causing inflammation and ulceration Sudden diarrhea, abdominal pain, and fever Sometimes vomiting Rotavirus Oral-fecal (infants) 24–72 hr Inflammation and loss of villi Vomiting, severe watery diarrhea, fever Norwalk virus Oral-fecal (adults/older children), shellfish, fomites 24–48 hr Damage villi Vomiting, diarrhea, and cramps, headache, fever Entamoeba histolytica (amebic dysentery) Fecal contamination of water and vegetables 2–4 wk Protozoan parasite with cyst stage and active trophozoite stage; may invade mucosa, causing abscesses Diarrhea with blood and mucus, may alternate with constipation Fever and chills Listeria sp. Found in soil and water 30–70 days Granulomas Flulike with diarrhea. Clostridium botulinum Spores in poorly canned food or prepared meat 12–36 hr Neurotoxin (exotoxin) causes nerve paralysis Visual problems, dysphagia, then flaccid paralysis and respiratory failure Possibly early vomiting or diarrhea Campylobacter sp. Handling raw poultry, undercooked poultry, raw milk, contaminated water 2–5 days Infection causes tissue damage to the ileum, jejunum, and colon Diarrhea, nausea CHAPTER 17 Digestive System Disorders 451 Peptic Ulcer Gastric and Duodenal Ulcers It is estimated that 25 million Americans will have peptic ulcer during their lifetime, and the incidence rate in the United States is between 500,000 and 850,000 cases per year. About 1 million hospitalizations occur annually, with 6500 deaths per year due to peptic ulcer disease. Although incidence rates are dropping in some areas, the prevalence rate is 14.5 million people in the United States. This disease has caused significant disability and illness in the past and continues to require hospitalization and surgery in patients who do respond to drug treatment. ■ Pathophysiology Peptic ulcers occur most commonly in the proximal duodenum (duodenal ulcers) but are also found in the antrum of the stomach (gastric ulcers) or lower esophagus (Figs. 17.14 and 17.15). Peptic ulcers usually appear as single, small, round cavities with smooth margins that penetrate the submucosa. Once acid or pepsin penetrates the mucosal barrier, the tissues are exposed to contin- ued damage because acid diffuses into the gastric wall. Ulcers may erode more deeply into the muscularis and eventually may perforate the wall. An area of inflam- mation surrounds the crater. When the erosion invades a blood vessel wall, bleeding takes place. Bleeding may involve a persistent loss of small amounts of blood or massive hemorrhage, depending on the size of the blood vessel involved. Chronic blood loss may be detected by the presence of iron-deficiency anemia or occult blood in the stool; one of these may be the first indicator of peptic ulcer. The mucosal barrier is composed essentially of the tightly packed epithelial cells with tight junctions that can regenerate quickly and are covered by a thick layer of bicarbonate-rich mucus. The development of peptic ulcers begins with a breakdown of the mucosal barrier, which results from an imbalance between the mucosal defense system and forces that are potentially damaging to it. Given the material that is ingested by the stomach and the fact that the powerful and highly acidic gastric secretions can digest protein in food, it is remarkable that the gastric defenses can maintain the integrity of the tissues as well as they do. Many factors may contribute to the decreased resistance of the mucosa or excessive hydrochloric acid or pepsin secretion. Impaired mucosal defenses seem to be a more common condition in gastric ulcer development, whereas increased acid secretion is a predominant factor in duodenal ulcers. Currently considered to be of major significance is infection with the bacteria Helicobacter pylori, found in most persons with peptic ulcer disease, although their precise role is not totally understood. Not all persons with H. pylori infection develop ulcers, but eradication of the infection promotes rapid healing of the ulcer. Helicobacter a hemolysin produced by strains that commonly cause urinary tract infections. • Enterohemorrhagic E. coli (EHEC) is caused by a specific strain of O157:H7. These highly virulent strains are present in cows, and infection has arisen from food and water contaminated with these strains, such as water runoff from contaminated pastures into wells, partially cooked ground beef or unpasteurized milk, or from contamination by other oral-fecal routes (eg, diapers or direct contact). These strains of E. coli release verocytotoxins (shigella-like toxins) in the intestine, which cause damage to the mucosa and to the blood vessel walls, and subsequently may affect blood vessels in the kidneys and elsewhere. The onset is acute, with severe watery diarrhea and cramps, progressing to bloody diarrhea and lasting up to a week. In some individuals, the toxin is absorbed and circulates to cause hemolysis of blood cells, leading to anemia and thrombocytopenia, and also acute renal failure, requiring dialysis (see Chapter 18). A few individuals have experienced neurologic effects, such as seizures. Deaths have occurred, particularly in young children and elderly persons. The diagnosis depends on identification of these particular strains from stool samples (usually only the microbial class is identified in the routine laboratory test). Chronic Gastritis Chronic gastritis is characterized by atrophy of the mucosa of the stomach, with loss of the secretory glands. The loss of the parietal cells leads to achlorhydria and lack of secretion of intrinsic factor, which is required for the absorption of vitamin B12. Infection with Helicobacter pylori is often present. Chronic gastritis is often seen in individuals with chronic peptic ulcers, those who abuse alcohol, and the elderly. Autoimmune disorders—for example, pernicious anemia—are associated with a type of chronic gastric atrophy. Many cases are idiopathic. The signs of chronic gastritis, which are often vague, include mild epigastric discomfort, anorexia, or intolerance for certain foods, usually spicy or fatty foods. Persons with chronic gastritis have an increased risk of peptic ulcers and gastric carcinoma. Treatment involves appropri- ate antibiotics and proton pump inhibitors. THINK ABOUT 17.6 a. Explain how each of the following entities causes dysphagia: achalasia, cancer of the esophagus, atresia. b. Explain how chronic reflux of gastric contents into the esophagus may cause hiatal hernia. c. Define pyrosis. d. Explain how prolonged vomiting leads to acidosis and dehydration. e. What is indicated by occult blood in the stool of a person with gastroenteritis? 452 SECTION III Pathophysiology of Body Systems ions in the protective mucus and reducing secretion of protective prostaglandins • Excessive glucocorticoid secretion or medication (eg, prednisone with its catabolic effects) • Ulcerogenic substances that break down the mucus layer, such as aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), or alcohol • Atrophy of the gastric mucosa (chronic gastritis) Increased acid-pepsin secretions are associated with the following: • Increased gastrin secretion pylori are known to secrete cytotoxins and the enzymes protease, phospholipase, and urease (which releases ammonia), all of which cause damage to mucosal defenses. In addition, the mucosal barrier may be damaged by the following: • An inadequate blood supply (eg, vasoconstriction caused by stress, smoking, or shock; circulatory impair- ment in elderly persons; scar tissue; or severe anemia), which interferes with the rapid regeneration of the epithelium and the production of sufficient mucus, as well as reducing the secretion of alkaline bicarbonate Esophagus Esophageal ulcer Gastroesophageal sphincter Fundus Greater curvature Gastric ulcer Antrum Gastric carcinoma Pyloric sphincter Duodenal ulcers Duodenum Common locations Peptic ulcer Mucus Mucosa Muscle layers Blood vessel (potential hemorrhage) Gastric carcinoma Erosion due to carcinoma Malignant cells Perforated ulcer Stomach contents Peritoneal cavity Inflammation Chyme flows from inside stomach through wall into peritoneal cavity Perforated ulcer Serosa (visceral peritoneum) Submucosa B C A D FIG. 17.14 Peptic ulcer. A, Typical locations of peptic ulcer and gastric carcinoma. B–C, Comparison of peptic ulcer and carcinoma. D, Perforated ulcer. CHAPTER 17 Digestive System Disorders 453 A second potential complication, perforation, occurs when the ulcer erodes completely through the wall, allowing chyme to enter the peritoneal cavity (see Fig. 17.14D). This process results in chemical peritonitis, inflammation of the peritoneal membranes and other structures in the abdominal cavity. Eventually this inflam- mation causes increased permeability of the intestinal wall, passage of bacteria and their toxins into the peri- toneal cavity, and bacterial peritonitis. Hemorrhage is not necessarily present when perforation occurs. Third, obstruction of the digestive tract may result later from stricture caused by scar tissue around the pylorus or duodenum, particularly in people with protracted or recurrent ulceration. ■ Etiology Infection with H. pylori is considered an underlying cause of the majority of cases of peptic ulcers. Peptic ulcers are more common in men than women, and people in developed countries have a higher incidence, perhaps because of lifestyle factors. A genetic factor seems to be involved in the frequent familial incidence of duodenal ulcers; also, these ulcers are more common in persons with blood group O. Gastric ulcers are more common in older individuals, those with scar tissue, and those who regularly take ulcerogenic antiinflammatory medications (aspirin or NSAIDs). Multiple factors, such as those listed, are usually involved in the cause. ■ Signs and Symptoms Epigastric burning or aching pain is common with ulcers, usually 2 to 3 hours after meals and at night. This cyclic pain is often relieved by ingestion of food or antacids. Intake of spicy foods may initiate pain at mealtime. Heartburn, nausea, vomiting, and weight loss may occur. Vomiting is most likely to occur after intake of alcohol • Increased vagal stimulation or increased sensitivity to stimuli • Increased number of acid-pepsin secretory cells in the stomach (a genetic anomaly) • Increased stimulation of acid-pepsin secretion by alcohol, caffeine, or certain foods • Interference with the normal feedback mechanism that reduces acid-pepsin secretion when the stomach is empty • Rapid gastric emptying Severe or prolonged stress appears to affect both sides of the balance, reducing mucosal blood flow and motility, leading to stasis of chyme, and increasing glucocorticoid effects. Also, stress may promote behaviors that are often implicated in ulcer development, such as increased caf- feine and alcohol intake, cigarette smoking, and altered eating patterns, which often include both irregular hours for meals and ingestion of irritating foods. Healing of peptic ulcers is difficult because the lesion cannot be isolated from the irritants in the environment. During the healing process, granulation tissue forms deep in the cavity, and new epithelial tissue regenerates from the edges. This granulation tissue often breaks down because it is subject to damage by the chyme. Because a longer time is often required for healing, more fibrous scar tissue develops at the site. The ulcers tend to recur because predisposing factors remain or the scar tissue itself interferes with the blood supply to the area. Several complications may accompany peptic ulcer. The ulcer may erode a blood vessel, causing hemorrhage, a common complication (Fig. 17.14B). Rupture of a small blood vessel causes continued loss of small amounts of blood, usually apparent as occult blood in the stool, whereas erosion of a large blood vessel leads to massive hemorrhage, indicated by hematemesis and shock. Hemorrhage may be the first sign of a peptic ulcer. BA FIG. 17.15 A, Bleeding ulcer on gastric mucosa. B, Early gastric cancer (superficial adenocarcinoma of the stomach). Note the flat surface of the tumor and the absence of rugae. (A From Black J, Hawks J: Medical-Surgical Nursing: Clinical Management for Positive Outcome, ed 8, St. Louis, 2009, Saunders, Elsevier.) B From Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology, ed 3, Sydney, 2004, Churchill Livingstone.) 454 SECTION III Pathophysiology of Body Systems esophagus. Adenocarcinoma occurs most frequently. The lesion is most often an ulcerative type with an irregular crater and a raised margin. Other forms of gastric cancer may infiltrate the gastric wall, causing thickening, or may appear as a protruding mass or polyp. Early gastric carcinoma is a lesion confined to the mucosa and sub- mucosa, whereas advanced gastric carcinoma involves the muscularis layer. Eventually the tumor extends into the serosa and spreads to the lymph nodes (regional and supraclavicular) and to the liver and ovaries. Gastric cancer is asymptomatic in the early stages and usually is not diagnosed until it is well advanced, at which point the prognosis is poor. ■ Etiology Geographic differences are marked in the development of gastric carcinoma, for which there is a high incidence in Japan, Iceland, Chile, and Hungary, but a significant decline (21,000) is evident in the United States, perhaps due to dietary changes. Japan has instituted a screening program for gastric carcinoma in an effort to improve the statistics in that country. Helicobacter pylori infection is associated with a higher risk of gastric carcinoma. Diet also appears to be a key factor, and a move to a different geographic location may result in a change in risk level. Food preservatives, such as nitrates or nitrites, and smoked foods increase the risk. Genetic influences play a role; the risk is increased in family members and individuals with blood group A. The presence of chronic atrophic gastritis or polyps in an individual also increases the likelihood of cancer. ■ Signs and Symptoms Manifestations are usually vague and mild until the cancer is advanced. The initial signs include anorexia, feelings of indigestion or epigastric discomfort, weight loss, fatigue, or a feeling of fullness after eating. Incidental tests may reveal occult blood in the stool or iron-deficiency or particularly irritating food. In some patients, weight gain occurs because the person discovers that more frequent food intake relieves the discomfort between meals. Iron-deficiency anemia or the presence of occult blood in the stool may be a diagnostic indicator. ■ Diagnostic Tests Fiberoptic endoscopy or barium x-ray may be used for diagnosis. Biopsy may be done endoscopically. ■ Treatment Drug therapy usually consists of a combination of drugs, including two or three antimicrobial drugs and medication to reduce acid secretion, for example, Helidac. Antimi- crobial therapy may include clarithromycin, tetracycline, metronidazole, and bismuth subsalicylate to eradicate H. pylori. An H2 receptor-antagonist, such as cimetidine (Tagamet), or the proton (H+) pump inhibitor omeprazole (Prilosec), reduces gastric secretions (see Table 17.3). In some individuals, a coating agent such as sucralfate may be helpful, or antacids may provide symptomatic relief. Cures rates of 90% have been reported with appropriate drug treatment. Reducing exacerbating factors such as excessive coffee intake is also useful. Vagotomy may be performed to reduce acid secretions in refractory cases. Surgery (partial gastrectomy or pyloroplasty) may be required in patients with perforated or bleeding ulcers. Stress Ulcers Stress ulcers result from severe trauma, such as burns or head injury, or occur with serious systemic problems, such as hemorrhage or sepsis. Ulcers in the presence of burns are often called Curling ulcers, those seen with head injury are termed Cushing ulcers, and others may be referred to as ischemic ulcers. Multiple ulcers, usually gastric ulcers, form within hours of the precipitating event, as the blood flow to the mucosa is greatly reduced, leading to reduced secretion of mucus and epithelial regeneration (see Fig. 17.16). The mucosal barrier is lost, and acid diffuses into the mucosa. In people with Cushing ulcers, increased vagal stimula- tion of acid secretion often occurs. The first indicator of stress ulcers is usually hemorrhage because of the rapid onset and masking by the primary problem. Prophylactic medications are usually administered as soon as possible to minimize the risk of stress ulcer development in cases of trauma. Gastric Cancer ■ Pathophysiology Gastric cancer arises primarily in the mucous glands; most tumors occur in the antrum or pyloric area, and some affect the lesser curvature of the stomach or cardia (see Figs. 17.14 and 17.15). There has been an increase in tumors in the upper stomach near the entrance to the FIG. 17.16 Multiple stress ulcers of the stomach, highlighted by dark digested blood on their surfaces. (From Kumar V, Abbas AK, Fausto M: Robbins and Cotran Pathologic Basis of Disease, ed 7, Philadelphia, 2005, Saunders.) CHAPTER 17 Digestive System Disorders 455 gastrectomy) because the pyloric sphincter is removed. Large quantities of ingested food are rapidly “dumped” into the intestine. The storage stage in the stomach, which includes appropriate dilution of chyme by gastric secretions, is missed. The hyperosmolar chyme draws more fluid from the vascular compartment into the intestine (Fig. 17.17), adding to the intestinal distention and increasing intestinal motility. These changes lead to signs that occur during or shortly after meals, including abdominal cramps, nausea, and diarrhea. The concurrent hypovolemia causes diz- ziness or weakness, rapid pulse, and sweating. In addition, individuals with dumping syndrome may experience hypoglycemia 2 to 3 hours after meals. The rapid gastric emptying and absorption lead to high blood glucose levels and increased insulin secre- tion, which results in a rapid drop in blood glucose level with no reserve nutrients advancing slowly from the stomach. Rebound hypoglycemia then develops anemia and precipitate a search for the cause and earlier diagnosis. ■ Treatment Diagnosis is frequently late because of the vague symp- toms and tendency for individuals to self-treat. The prognosis varies with the stage of the cancer; those with stage 1 disease have a 78% survival rate, and those in stage 3 have an 8% survival rate. Survival rates for those with metastatic disease are less than 7%. Surgery (gastric resection), combined with chemotherapy and radiation, is the usual treatment and may relieve symptoms when used as a palliative measure. Vitamin B12 injections are usually required after gastrectomy. Dumping Syndrome Dumping syndrome, in which control of gastric emptying is lost, may occur after gastric resection (eg, partial 2. Gastric resection Decreased gastric capacity and loss of pyloric sphincter 4. Fluid shifts from blood into small intestine to dilute hypertonic chyme 5. Hypovolemia • Decreased blood pressure • Faint, weak, dizzy • Tachycardia • Pallor, diaphoresis Stomach resected Small intestine Capillary Food 6. Distended intestine • Pain, cramps • Nausea and vomiting 7. Rapid digestion and absorption of food intake 8. Hyperglycemia and increased insulin secretion 9. Hypoglycemia • Weak, confused • Tachycardia • Pallor, diaphoresis Immediate effects No stored food available from stomach 2–3 Hours later 1. Food intake 3. Large amount of undiluted chyme is “dumped” into small intestine FIG. 17.17 Dumping syndrome (postgastrectomy). 456 SECTION III Pathophysiology of Body Systems THINK ABOUT 17.7 a. Explain why infection was not thought to be the cause of peptic ulcer in the past. b. Explain three factors that predispose to peptic ulcer formation. c. Explain why the prognosis for gastric cancer is poor. d. Explain why dizziness, weakness, and tachycardia may occur (1) immediately after a meal in a postgastrectomy patient and (2) 2 to 3 hours after eating. • Cholangitis is inflammation usually related to infection of the bile ducts. • Choledocholithiasis pertains to obstruction by gallstones of the biliary tract. ■ Pathophysiology Gallstones vary in size and shape and may form initially in the bile ducts, gallbladder, or cystic duct. They may consist primarily of cholesterol or bile pigment (bilirubin) or may be of mixed content, including calcium salts (Fig. 17.19). The content of the stone depends on the primary factor predisposing to calculus formation. several hours after eating, with tremors, sweating, and weakness. These problems can usually be resolved by dietary changes, including consumption of frequent small meals that are high in protein and low in simple carbohydrates. Also, fluids should be taken between meals rather than with meals. These measures reduce the hypertonicity of the chyme and the fluctuations in blood glucose. In some cases, medication may be used to decrease intestinal motility. Pyloric Stenosis Narrowing and obstruction of the pyloric sphincter may be a developmental defect in infants, or it may be acquired later in life, usually because of the presence of fibrous scar tissue. In the congenital form, the pyloric muscle is hypertrophied and can be palpated as a hard mass in the abdomen. Signs of stenosis usually appear within several weeks after birth, first as episodes of regurgitation of some food and then as projectile vomiting occurring immediately after feeding. Vomitus may be ejected some distance from the infant and does not contain bile. Stools become small and infrequent. The infant fails to gain weight, is dehy- drated, and is irritable because of persistent hunger. Surgery is required to remove the obstruction. In persons with acquired pyloric obstruction, interfer- ence with gastric emptying leads to a persistent feeling of fullness and then to an increased incidence of vomiting with or after meals. The vomitus typically contains food from previous meals. Disorders of the Liver and Pancreas Gallbladder Disorders The gallbladder and biliary tract are frequently affected by one or more interrelated problems involving the forma- tion of gallstones (Fig. 17.18). At least 10% of the popula- tion has gallstones, and 500,000 surgical procedures are done per year in the United States to treat gallbladder disease. • Cholelithiasis refers to formation of gallstones, which are masses of solid material or calculi that form in the bile. • Cholecystitis refers to inflammation of the gallbladder and cystic duct. Liver Small bile duct Hepatic duct Cystic duct Common bile duct Tail of pancreas Pancreatic ducts Greater duodenal papilla (ampulla of Vater) Head of pancreas Duodenum Gallstone Gallbladder Major duodenal papilla (sphincter of Oddi) FIG. 17.18 The biliary ducts and pancreas with possible locations of gallstones. FIG. 17.19 Resected gallbladder containing mixed gallstones. (From Kissane JM, ed: Anderson’s Pathology, ed 9, St. Louis, 1990, Mosby.) CHAPTER 17 Digestive System Disorders 457 Chronic cholecystitis is manifested by milder signs, although the course may be punctuated by acute episodes. Signs often include intolerance to fatty foods, excessive belching, bloating, and mild epigastric discomfort. ■ Treatment The gallbladder and gallstones may be removed using laparoscopic surgery. In many cases, the stones are fragmented by such methods as extracorporeal shock wave lithotripsy (using high-energy sound waves), sometimes assisted by the administration of bile acids or drugs to break down the stone. Cholesterol stones appear white or crystalline, whereas bilirubin stones are black. Small stones may be “silent” and excreted in the bile, whereas larger stones are likely to obstruct the flow of bile in the cystic or common bile ducts, causing pain. Note the comparative size of the stones and the bile ducts (see Fig. 17.18). Gallstones tend to form when the bile contains a high concentration of a component such as cholesterol or there is a deficit of bile salts. Inflammation or infection in the biliary structures may provide a focus for stone formation or may alter the solubility of the constituents, fostering the development of a calculus. Whether inflammation or infection is primary or secondary to stone formation is not always clear. Once a focus or nucleus forms, the stone tends to grow, as additional solutes are deposited on it, particularly if bile flow is sluggish. The presence of gallstones may cause irritation and inflammation in the gallbladder wall (cholecystitis), and this susceptible tissue may then be infected. Infecting organisms are usually Escherichia coli or enterococci, which gain access to the gallbladder through the sphincter of Oddi or from the portal veins or adjacent lymph nodes. When a stone obstructs bile flow in the cystic or common bile duct, biliary colic develops, consisting of severe spasms of pain resulting from strong muscle contractions attempting to move the stone along. Obstruc- tion of the biliary system at the sphincter of Oddi may also cause pancreatitis because the pancreatic secretions are backed up or bile refluxes into the pancreatic ducts. ■ Etiology Cholesterol gallstones occur twice as often in women as men. They tend to develop in individuals with high cholesterol levels in the bile. Factors that indicate a high risk for gallstones include obesity, high cholesterol intake, multiparity (several children), and the use of oral con- traceptives or estrogen supplements. Bile pigment stones are more common in individuals with hemolytic anemia, alcoholic cirrhosis, or biliary tract infection. ■ Signs and Symptoms Gallstones are frequently asymptomatic. However, larger calculi may obstruct a duct at any time, causing sudden severe waves of pain (biliary colic) in the upper right quadrant of the abdomen or epigastric area, often radiat- ing to the back and right shoulder. Nausea and vomiting are usually present. The pain increases for some time and then may decrease if the stone moves on. If the pain continues, and jaundice develops as the bile backs up into the liver and blood, surgical intervention may be necessary. There is also a risk of a ruptured gallbladder if obstruction persists. Acute cholecystitis is usually associated with some degree of obstruction and inflam- mation. Severe pain is often precipitated by eating a fatty meal; fever, leukocytosis, and vomiting accompany the pain. THINK ABOUT 17.8 a. Differentiate cholelithiasis from choledocholithiasis. b. Explain three factors predisposing to cholesterol gallstones. c. Describe how a cholesterol stone forms. d. Describe the pain typical of an acute episode of gallstone obstruction, and give the rationale for it. Jaundice Jaundice (icterus) refers to the yellowish color of the skin and other tissues that results from high levels of bilirubin in the blood. The color is usually apparent first in the sclera, or white area of the eye. Bilirubin is a product of the hemolysis of red blood cells (RBCs) and the breakdown of hemoglobin (see Fig. 17.4). Jaundice, or hyperbilirubinemia, is not itself a disease but rather is a sign of many different types of primary disorders. These disorders are classified into three groups (see Fig. 17.21): 1. Prehepatic jaundice results from excessive destruction of red blood cells and is characteristic of hemolytic anemias or transfusion reactions. Liver function is normal, but the liver is unable to handle the additional bilirubin. Physiologic jaundice of the newborn is common 2 to 3 days after birth. Increased hemolysis of red blood cells, combined with the immature infant liver, leads to a transient mild hyperbilirubinemia. 2. Intrahepatic jaundice occurs in individuals with liver disease, such as hepatitis or cirrhosis. It is related to an impaired uptake of bilirubin from the blood and decreased conjugation of bilirubin by the hepatocytes. 3. Posthepatic jaundice is caused by obstruction of bile flow into the gallbladder or duodenum and subsequent backup of bile into the blood. Congenital atresia of the bile ducts, obstruction caused by cholelithiasis, inflammation of the liver, or tumors all result in posthepatic jaundice. The type of jaundice present in an individual may be indicated by increases in the serum bilirubin level and changes in the stools (see Fig. 17.21). For example, serum 458 SECTION III Pathophysiology of Body Systems levels of unconjugated bilirubin (indirect-reacting) are elevated in prehepatic jaundice, whereas posthepatic jaundice results from increased amounts of conjugated bilirubin (direct) in the blood. In patients with liver disease, both intrahepatic and posthepatic jaundice may be present because inflammation or infection both impairs hepatocyte function and obstructs the bile canaliculi, leading to elevations in the blood of both unconjugated and conjugated bilirubin. In persons with posthepatic jaundice, the obstruction prevents bile from entering the intestine, interfering with digestion and resulting in a light-colored stool. Also, the bile salts that enter the blood and tissues as bile backs up cause irritation and pruritus (itching) of the skin. Treatment depends on removing the cause. Phototherapy is effective in mild forms, whereby exposure to ultraviolet light promotes the conjugation of bilirubin. Hepatitis Hepatitis refers to inflammation of the liver. It may be idiopathic (such as a fatty liver) or result from a local infection (such as viral hepatitis), from an infection elsewhere in the body (eg, infectious mononucleosis or amebiasis), or from chemical or drug toxicity. Mild inflammation impairs hepatocyte function, whereas more severe inflammation and necrosis may lead to obstruction of blood and bile flow in the liver and impaired liver cell function. Given the many functions of the liver, damage to the liver cells has extensive effects in the body. Fortunately, the liver has a good functional reserve and excellent regenerative powers. Viral Hepatitis ■ Pathophysiology Although a number of viruses may affect the liver cells, hepatitis is considered to result from infection by a group of viruses that specifically target the hepatocytes. These include hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). Other viruses that cause hepatitis have not yet been fully identified; meanwhile they have been temporarily designated F and G or non-A–E hepatitis virus. The liver cells are damaged in two ways: by direct action of the virus (eg, hepatitis C) or via cell-mediated immune responses to the virus (eg, hepatitis B). Cell injury results in inflammation and necrosis in the liver. Both the hepatocytes and the liver appear swollen, and diffuse necrosis may be present. With severe inflammation, biliary stasis may develop, leading to backup of bile into the blood. The degree of inflammation and damage varies. Many cases are mild and are not identified. Some cases show a few manifestations but not jaundice; in other cases fulmi- nant hepatitis develops with massive necrosis and liver failure. Depending on the severity of the inflammation, the hepatic cells may regenerate, or fibrous scar tissue may form in the liver. Scar tissue often obstructs the channels used for blood and bile flow, interfering with the unique organization of the liver lobule and leading to further damage from ischemia (Fig. 17.20). Chronic inflammation occurs with hepatitis B, C, and D and is defined as persistent inflammation and necrosis of the liver for more than 6 months. This type of disease eventually causes permanent liver damage (fibrosis) and cirrhosis. There is also an increased incidence of hepatocel- lular cancer associated with chronic hepatitis. Hepatitis B, C, and D may exist in a carrier state, in which asymptomatic individuals carry the virus in their hepatocytes but can transmit the infection via their blood or body fluids to others. Carriers may be individuals who have never had active disease or have a chronic low-grade infection. ■ Etiology The viruses causing hepatitis vary in their characteristics, mode of transmission, incubation time, and effects. These are summarized in Table 17.5. Hepatitis A. Also called infectious hepatitis, hepatitis A is caused by a small RNA virus called the hepatitis A virus, or HAV. It is transmitted primarily by the oral-fecal route, often from contaminated water or shellfish. Outbreaks may occur in day care centers. Sexual transmission has occurred in the homosexual population. Hepatitis A has a relatively short incubation period of 2 to 6 weeks. It causes an acute but self-limiting infection and does not have a carrier or chronic state. Fecal shedding of the virus (the contagious period) begins several weeks before the onset of signs (Fig. 17.22A). At this time, the first antibodies, IgM-HAV, appear, followed shortly by the second group of antibod- ies, IgG-HAV, which remain in the serum for years, providing immunity against further infection. A vaccine is available for those who are traveling to an endemic area or anyone with any liver disease; this vaccine is administered to both children and adults. Gamma globulin provides temporary protection and may be administered to those just exposed to HAV. Hepatitis B. In 2006 the Centers for Disease Control and Prevention (CDC) received reports of 4758 new cases in the United States but estimate the occurrence rate is 10 times that number, with many cases being asymptomatic. Further, there are more than 1 million carriers in the country and 4000 to 5000 deaths annually from associated cirrhosis and cancer. More than 50% of those who test HIV-positive are also positive for hepatitis B. Global estimates are more than 2 billion cases, with 350 million of those being carriers. Unfortunately, 50% of cases are asymptomatic, facilitating transmission to others. Formerly called serum hepatitis, this form of hepatitis is caused by the hepatitis B virus (HBV), a partially CHAPTER 17 Digestive System Disorders 459 the individual is asymptomatic but is contagious for the disease. Hepatitis B has a relatively long incubation period, averaging about 2 months. Long incubation periods make it more difficult to track sources and contacts for infections. A window, or prolonged lag time, occurs before the serum markers or symptoms become present, during which time the virus cannot be detected but can be transmitted to others. Hepatitis B virus infection is transmitted primarily by infected blood but is found in many body secretions. Blood transfusions are currently processed to reduce the risk of transmission. Intravenous drug abusers have a double-stranded DNA virus. The whole virion is often called a Dane particle. This virus is more complex and consists of three antigens: two core antigens (HBcAg and HBeAg) and one surface antigen (HBsAg). Each antigen stimulates antibody production in the body (see Fig. 17.22). These serum antigens and antibodies are useful in diagnosing and monitoring the course of hepatitis, including the development of chronic hepatitis. For example, early in the course of the infection, infected liver cells produce large amounts of HBsAg. When this antigen persists in the serum, it poses a high risk of continued active infection and damage to the liver (chronic disease). A carrier state is also common for HBV, in which Sublobular vein Left lobe Falciform ligament Hepatic artery Vena cava Portal vein Portal area Hepatic lobule Right lobe Central vein Hepatic artery Bile ductPortal triad Portal vein Central vein Liver plate Sinusoids Bile canaliculus Bile duct Portal vein Hepatic artery Portal triad A A B FIG. 17.20 A, Liver lobules showing the portal areas and central vein. B, Portion of liver lobule. (From Gartner L, Hyatt J: Color Textbook of Histology, ed 3, Philadelphia, 2007, Saunders, Elsevier.) 460 SECTION III Pathophysiology of Body Systems TABLE 17.5 Types of Hepatitis Disease Agent Transmission Incubation Period Serum Markers Carrier/Chronic Hepatitis A (infectious) HAV (RNA virus) Oral-fecal 2–6 wk Anti-HAV IgM anti-HAV IgG None Hepatitis B (serum) HBV (DNA double- strand virus) Blood and body fluids 1–6 mo (average, 60-90 days) HBsAg anti-HBs HBcAb IgM HBcAb IgG HBeAg, HBeAb Carrier and chronic Hepatitis C HCV (RNA virus) Blood and body fluids 2 wk–6 mo (average, 6–9 wk) Anti-HCV Carrier and chronic Hepatitis D, chronic (delta) HDV (defective RNA virus requires presence of HBV) Blood and body fluids 2–10 wk Anti-HDV IgM Anti-HDV IgG Chronic Hepatitis E HEV (RNA virus) Oral-fecal contamination 2–9 wk HE Ag None Toxic hepatitis Hepatotoxins; chemicals or drugs Direct exposure Days to months N/A Acute or chronic Chronic noninfectious hepatitis Autoimmune, metabolic, idiopathic N/A N/A Various autoantibodies Chronic N/A, not applicable. Process Hemolysis of erythrocytes Excessive Increased in blood Normal Normal Normal Normal liver cannot process excessive amounts of bilirubin Hemoglobin Heme Liver cells Conjugated bilirubin Bile Intestine Feces Normal or darker color Light color (e.g., Gallstones) PREHEPATIC OR HEMOLYTIC JAUNDICE POSTHEPATIC OR OBSTRUCTIVE JAUNDICE (e.g., Hemolytic anemia) Obstructed flow to intestine causes backup to liver and blood Increased in blood Normal Increased in blood Hepatocellular damage prevents conjugation and excretion Inflammation obstructs flow to hepatic duct (e.g., Hepatitis) INTRAHEPATIC JAUNDICE Increased in blood Unconjugated bilirubin in blood Variable Iron Globin FIG. 17.21 Types of jaundice. CHAPTER 17 Digestive System Disorders 461 Time12 Weeks2–6 Weeks TimeYears Antigen levels rise, then fall Antibody levels rise in blood 6–25 Weeks (average 8 weeks) Fecal HAV No carrier or chronic state lgG-anti-HAV (antibody in blood) lgM-anti-HAV (antibody in blood) Acute stage Recovery stage Recovery lgM-anti-HBc lgG-anti-HBc IgG-anti-HBs Anti-HBeHBeAg Acute stage Virus in blood and feces HBsAg C on ce nt ra tio n in b lo od B. Hepatitis B — Acute A. Hepatitis A C. Hepatitis B — Chronic Infection R el at iv e se ru m c on ce nt ra tio n HBsAg HBeAg IgM-anti-HBc Months Years Antigen levels remain elevated Anti-HBe FIG. 17.22 Serologic changes seen with hepatitis. 462 SECTION III Pathophysiology of Body Systems and enlarged (hepatomegaly), causing a mild aching pain. In severe cases, blood clotting times may be prolonged, because the synthesis of blood clotting factors is impaired. This stage tends to last longer in patients with hepatitis B. 3. The posticteric or recovery stage is marked by a reduc- tion in signs, although this period may extend over some weeks. On average, the acute stage of hepatitis A lasts 8 to 10 weeks, whereas hepatitis B is prolonged over 16 weeks. ■ Treatment There is no method of destroying hepatitis viruses in the body at this time. Gamma globulin, if available, may be helpful when given early in the course. Supportive measures such as rest and a diet high in protein, carbo- hydrate, and vitamins are most useful. Chronic hepatitis B and C may be treated with inter- feron α and lamivudine (Epivir or 3TC) to decrease viral replication, although this treatment is effective in only 30% to 40% of individuals. A combination of slow-acting interferon and the antiviral drug ribavirin has reduced the rate of viral replication in 80% of HCV patients. Otherwise, gradual destruction of the liver occurs, leading to cirrhosis or hepatocellular cancer. high incidence of HBV infection. Hemodialysis increases the risk, as does exposure to blood or body fluids in health care workers if barrier precautions are not taken. Sexual transmission has been noted, and HBV can be passed to the fetus during pregnancy. Activities such as tattooing and body piercing may transmit the virus. An HBV vaccine is available for long-term protection for those in high-risk groups, including health professionals, and is now routinely administered to children. Hepatitis B virus immune globulin is available as a temporary measure. Hepatitis C. Formerly called non-A-non-B (or NANB) hepatitis, hepatitis C is the most common type of hepatitis transmitted by blood transfusions. The virus is a single- stranded RNA virus. Approximately half the cases enter a chronic disease state. The World Health Organization estimates that 130 million to 170 million people are infected globally, and the CDC estimates the prevalence rate in the United States to be 3.2 million cases. Hepatitis C virus infection increases the risk of hepatocellular carcinoma. This form of hepatitis may exist in a carrier state. Hepatitis D. The agent for hepatitis D is also called delta virus. This incomplete RNA virus requires the presence of hepatitis B virus (HBsAg) to replicate and produce active infection. The hepatitis D virus infection usually increases the severity of HBV infection. Hepatitis D virus is also transmitted by blood; there is a high incidence of infection in intravenous drug abusers. Hepatitis E. Hepatitis E is caused by HEV, a single- stranded RNA virus, and is spread by the oral-fecal route. It is similar to HAV and lacks a chronic or carrier state. It is more common in countries in Asia and Africa, where it causes a fulminant hepatitis that produces a high mortality rate in pregnant women. ■ Signs and Symptoms The manifestations of acute hepatitis vary from mild or asymptomatic to severe disease that is often rapidly fatal. The course of hepatitis has three stages: first, the preicteric or prodromal stage; next, the icteric or jaundice stage; and last, the posticteric or recovery stage (Fig. 17.23): 1. The onset of the preicteric stage may be insidious, with fatigue and malaise, anorexia and nausea, and general muscle aching. Sometimes fever, headache, a distaste for cigarettes, and mild upper right quadrant discom- fort are present. Serum levels of liver enzymes (eg, aspartate aminotransferase [AST] or alanine amino- transferase [ALT]) are elevated. 2. The icteric stage marks the onset of jaundice as serum bilirubin levels rise. As biliary obstruction increases, the stools become light in color, the urine becomes darker, and skin becomes pruritic. The liver is tender EXPOSURE TO HEPATITIS B VIRUS (HBV or serum hepatitis) Incubation period (asymptomatic) average 6–8 weeks ACUTE INFECTION 4–12 weeks CARRIER STATE (asymptomatic) PREICTERIC STAGE Malaise, fever, joint pain ICTERIC STAGE Jaundice FULMINANT INFECTION Severe necrosis and liver failure DEATH RECOVERY CHRONIC INFECTION LONG-TERM MILD INFECTION CIRRHOSIS LIVER FAILURE HEPATIC CANCER FIG. 17.23 The course of hepatitis B infection. CHAPTER 17 Digestive System Disorders 463 ■ Pathophysiology Cirrhosis is a disorder in which the liver demonstrates extensive diffuse fibrosis and loss of lobular organization (see Fig. 17.20). Nodules of regenerated hepatocytes may be present but are not necessarily functional because the vascular network and biliary ducts are distorted (Fig. 17.24). Even if the primary cause is removed, further damage is likely because fibrosis interferes with the blood supply to liver tissues or the bile may back up, leading to ongoing inflammation and damage. Initially the liver is enlarged, but it becomes small and shrunken as fibrosis proceeds. In many cases degenerative changes are asymptomatic until the disease is well advanced. Liver biopsy and serologic tests may determine the cause and extent of the damage. The progressive changes that occur in biliary and postnecrotic cirrhosis are directly linked to inflammation, necrosis, and fibrosis associated with the primary condition. In patients with alcoholic liver disease, or portal cirrhosis, there are several stages in the development of hepatocel- lular damage related to the effects of alcohol. Alcohol and its metabolites, such as acetaldehyde, are toxic to the liver cells and alter many metabolic processes in the liver. Secondary malnutrition may aggravate the damaging effects on liver cells. 1. The initial change in alcoholic liver disease is the accumulation of fat in liver cells, causing fatty liver. Other than enlargement of the liver or hepatomegaly, this stage is asymptomatic and is reversible if alcohol intake is reduced. 2. In the second stage, alcoholic hepatitis, inflammation and cell necrosis occur. Fibrous tissue forms, an irreversible change. Acute inflammation may develop when alcohol intake increases or binge drinking becomes more excessive. This second stage may also be asymptomatic, or it may manifest with mild symp- toms, such as anorexia, nausea, and liver tenderness. In some patients, after an episode of excessive alcohol intake, there may be sufficient damage to precipitate liver failure, encephalopathy, and death. Toxic or Nonviral Hepatitis A variety of hepatotoxins, such as chemicals or drugs, may cause inflammation and necrosis in the liver. These reactions may be direct effects of the toxins or an immune response (hypersensitivity) to certain materials. Toxic effects may result from sudden exposure to large amounts of a substance or from long-term exposure, perhaps in the workplace. Hepatotoxic drugs include acetaminophen, halothane, phenothiazines, and tetracycline. Toxic chemi- cals include solvents such as carbon tetrachloride, toluene, or ethanol. Reye syndrome, which occurs when aspirin is used in the presence of viral infections, also causes toxic effects on the liver. Hepatocellular damage can result from either of two processes, inflammation with necrosis, or cholestasis (obstructed flow of bile). The signs of toxicity are similar to those of infectious hepatitis. The toxic chemical must be removed from the body as quickly as possible to reduce the risk of permanent liver damage. THINK ABOUT 17.9 a. Explain how prehepatic jaundice might develop and the expected change in serum bilirubin. b. Describe the difference among hepatitis types A through E with regard to type/structure of the virus and transmission. c. Describe how serum markers may indicate the presence of chronic viral hepatitis. d. Explain why the individual who is a carrier for HBV is considered a threat to public health. FIG. 17.24 Cirrhosis of the liver due to hepatitis C infection. (From Cotran R et al: Robbins Pathologic Basis of Disease, ed 6, Philadelphia, 1999, Saunders.) Cirrhosis Cirrhosis is a disorder in which there is progressive destruction of liver tissue leading eventually to liver failure, when 80% to 90% of the liver has been destroyed. It is the result of a number of chronic liver diseases. About 28,000 persons die of cirrhosis each year in the United States, and 50% of these deaths are alcohol related. Cirrhosis may be classified by the structural changes that take place (eg, micronodular or macronodular) or the cause of the disorder. In some cases, cirrhosis may be linked to specific underlying disorders, particularly congenital problems or inherited metabolic disorders. The four general categories of cirrhosis based on cause are as follows: 1. Alcoholic liver disease (the largest group, also called portal or Laënnec cirrhosis) 2. Biliary cirrhosis, associated with immune disorders and those causing obstruction of bile flow, for example, stones or cystic fibrosis, in which mucous plugs form in the bile ducts 3. Postnecrotic cirrhosis, linked with chronic hepatitis or long-term exposure to toxic materials 4. Metabolic, usually caused by storage disorders such as hemochromatosis 464 SECTION III Pathophysiology of Body Systems into the esophageal veins, creating large distended and distorted veins (varicose veins or varices) near the mucosal surface of the esophagus. These veins are easily torn by food passing down the esophagus. Hemorrhage of these esophageal varices is a common complication of cirrhosis. The high pressure in the portal veins and lymphat- ics, in conjunction with other factors, also affects fluid shifts in the hepatic portal system, leading to 3. The third stage, or end-stage cirrhosis, is reached when fibrotic tissue replaces normal tissue, significantly altering the basic liver structure to the extent that little normal function remains. Signs of portal hypertension or impaired digestion and absorption are the usual early indicators of this stage. The pathophysiologic effects of cirrhosis evolve from two factors: the loss of liver cell functions and interference with blood and bile flow in the liver. Major functional losses in persons with cirrhosis include the following: • Decreased removal and conjugation of bilirubin • Decreased production of bile • Impaired digestion and absorption of nutrients, particularly fats and fat-soluble vitamins • Decreased production of blood clotting factors (pro- thrombin, fibrinogen) and plasma proteins (albumin) • Impaired glucose/glycogen metabolism • Inadequate storage of iron and vitamin B12 • Decreased inactivation of hormones, such as aldoste- rone and estrogen • Decreased removal of toxic substances, such as ammonia and drugs These changes are linked with clinical signs in Table 17.6. Altered blood chemistry, including abnormal levels of electrolytes or amino acids, and excessive ammonia or other toxic chemicals affect the central nervous system, leading to hepatic encephalopathy. Serum ammonia levels correlate well with the clinical signs of encephalopathy. Ammonia is an end product of protein metabolism in the liver or intestine, and then it is converted by liver cells into urea for excretion by the kidneys. The ingestion of a meal high in protein or an episode of bleeding in the digestive tract may cause a marked elevation in serum ammonia concentration and may precipitate severe encephalopathy. The second group of effects is related to the obstruction of bile ducts and blood flow by fibrous tissue as follows: • Reduction of the amount of bile entering the intestine, impairing digestion and absorption • Backup of bile in the liver, leading to obstructive jaundice with elevated conjugated and unconjugated bilirubin levels in the blood • Blockage of blood flow through the liver, leading to high pressure in the portal veins, or portal hypertension • Congestion in the spleen (splenomegaly), increasing hemolysis • Congestion in intestinal walls and stomach, impairing digestion and absorption • Development of esophageal varices (see Figs. 17.25 and 17.26) • Development of ascites, an accumulation of fluid in the peritoneal cavity that causes abdominal distention and pressure Because the esophageal veins have several points of anastomosis, or collateral channels to join with the gastric veins, the increased pressure of blood extends TABLE 17.6 Common Manifestations of Liver Disease Signs or Symptoms Pathophysiology Fatigue, anorexia, indigestion, weight loss Metabolic dysfunction in the liver, such as decreased gluconeogenesis; decreased bile for digestion and absorption; portal hypertension, leading to edema of intestinal wall and interfering with digestion and absorption Ascites Portal hypertension, elevated aldosterone and ADH levels, decreased serum albumin level, lymphatic obstruction in liver General edema Elevated aldosterone and ADH levels, decreased serum albumin level Esophageal varices, hemorrhoids Portal hypertension and collateral circulation Splenomegaly Portal hypertension Anemia Decreased absorption and storage of iron and vitamin B12, malabsorption, splenomegaly, bleeding Leukopenia, thrombocytopenia Splenomegaly, possible bone marrow depression by ammonia and other toxins Increased bleeding, purpura Decreased absorption of vitamin K, decreased production of clotting factors by liver, thrombocytopenia Hepatic encephalopathy, tremors, confusion, coma Metabolic dysfunction with inability to remove ammonia from protein metabolism and other toxic substances Gynecomastia, impotence, irregular menses Impaired inactivation of sex hormones (eg, estrogen) leads to imbalance Jaundice Impaired extraction and conjugation of bilirubin; decreased production of bile and obstruction of bile flow Pruritus Bile salts in the tissues resulting from biliary obstruction ADH, antidiuretic hormone. CHAPTER 17 Digestive System Disorders 465 a shift of fluid out of the blood and into the peritoneal cavity. ■ Signs and Symptoms Initial manifestations of cirrhosis are often mild and vague and include the following: • Fatigue • Anorexia • Weight loss • Anemia • Diarrhea • Dull aching pain in the upper right quadrant of the abdomen As cirrhosis advances, the following may occur: • Ascites and peripheral edema develop. • Increased bruising is evident. • Esophageal varices form. • Eventually jaundice and encephalopathy occur (see Table 17.6). • An imbalance in sex hormone levels secondary to impaired inactivation mechanisms leads to spider nevi on the skin, testicular atrophy, impotence, gyneco- mastia, and irregular menses. Esophagus Bulging esophageal varices Short gastric veins Anastomosis Backup of blood into spleen (splenomegaly) Stomach Splenic vein Coronary (gastric) vein High pressure in inferior mesenteric vein High pressure in superior mesenteric vein High pressure in portal vein Scar tissue obstructs blood flow through liver Very little blood returns through hepatic vein Inferior vena cava FIG. 17.25 Development of esophageal varices. FIG. 17.26 A bleeding esophageal varix. (From Black J, Hawks J: Medical-Surgical Nursing: Clinical Management for Positive Outcome, ed 8, St. Louis, 2009, Saunders, Elsevier.) ascites (Fig. 17.27). Portal hypertension increases the hydrostatic pressure in the veins and lymphatics; the increased serum aldosterone levels result in increased sodium ion and water in the extracellular compartment; and the decreased serum levels of albumin lower the plasma osmotic pressure. All these factors contribute to 466 SECTION III Pathophysiology of Body Systems intake. High carbohydrate intake and vitamin supple- ments are necessary. Serum electrolytes may have to be balanced, possibly requiring the use of diuretics (eg, furosemide) to reduce body fluids. Paracentesis to remove excess fluid may be necessary, followed by albumin transfusions to prevent third spacing of fluid. Antibiotics such as neomycin are useful to reduce intestinal flora and control serum ammonia levels. Ruptured esophageal varices need emergency treatment. Portocaval shunts may be used to reduce portal hypertension. Liver transplants provide another option (see Chapter 7). Many tests are required before transplant to determine the tissue match and general health status. Transplanting part of the liver from a suitable living donor (LDLT) has become more common because the wait time is less than that for a cadaver donor (about 18,000 persons await liver transplant, whereas only 5000 cadaver organs will likely be available). The liver tissue is able to grow in both donor and recipient providing a complete functional organ for both. This process was first used successfully in children, in whom size of the transplant is an issue, and now is being used in adults. It is riskier in adults because more donor tissue (half the liver) is required. Currently living donor liver transplant is the standard practice in pediatric transplants, and adult-to-adult transplants are being done in all major transplant centers in the United States. LIVER DAMAGE Blocked lymphatics Increased fluid in peritoneal cavity Portal hypertension Increased hydrostatic pressure in portal circulation Decreased synthesis of albumin Decreased plasma osmotic pressure Decreased blood volume plus reduced inactivation of aldosterone and ADH Increased serum aldosterone and ADH Increased Na+ and water retention ASCITES Fluid shifts out of portal circulation into peritoneal cavity Upward pressure on diaphragm impairs respiration Increased risk of peritonitis Impaired digestion and absorption FIG. 17.27 Development of ascites with cirrhosis. • Complications involve ruptured esophageal varices, leading to hemorrhage, circulatory shock, and acute hepatic encephalopathy. Acute encephalopathy manifests as follows: • Asterixis, a “hand-flapping” tremor • Confusion • Disorientation • Convulsions • Coma • Chronic encephalopathy characterized by personality changes, memory lapses, irritability, and disinterest in personal care Another complication of cirrhosis is the presence of frequent infections, often respiratory or skin infections. These infections are encouraged by excessive fluids in the tissues that interfere with the diffusion of nutrients and thus lead to delayed tissue regeneration and healing. Also, decreased protein availability in the body and anemia impair tissue maintenance. Pruritus causes scratching of the skin that may damage the skin barrier, leading to infection. A summary of the effects of cirrhosis and liver failure is illustrated in Fig. 17.28. ■ Treatment Supportive or symptomatic treatment, such as avoiding fatigue and exposure to infection, is necessary. Dietary restrictions include restrictions on protein and sodium CHAPTER 17 Digestive System Disorders 467 estrogen, or insulin (see Chapter 20). Because of the minimal early indications, the cancer is usually advanced at diagnosis. Chemotherapy is the usual treatment. If the tumor is localized, a lobectomy or radiofrequency ablation procedure may be used to remove it. Liver Cancer Although secondary tumors are common in the liver, primary malignant tumors are relatively rare, making up less than 2% of all cancers. However, the number of cases and deaths are climbing for unknown reasons. The American Cancer Society has predicted 40,710 new cases and 28,920 deaths in the United States in 2017. There has not been a significant decrease in either incidence or mortality rates for liver cancer. The most common primary tumor is hepatocellular carcinoma, developing in cirrhotic livers (Fig. 17.29). Cirrhosis may be secondary to metabolic disorders or hepatitis. Tumors may also result from prolonged exposure to carcinogenic chemicals. Secondary or metastatic cancer often arises from areas served by the hepatic portal veins or that spread along the peritoneal membranes (see Fig. 20.6 for a photograph of metastatic liver cancer). The signs of liver cancer initially are mild, general, and similar to those of other liver diseases; they include anorexia and vomiting, fatigue, weight loss, and hepatomegaly. Portal hypertension and splenomegaly are common. Paraneoplastic syndromes occur with this cancer, with tumor cells producing substances similar to erythropoietin, Jaundice Pulmonary Edema and infections Skin Spider nevi, pruritus Esophageal varices Ascites Distended abdominal veins Gastrointestinal hemorrhage Rectal varices Testicular atrophy and impotence Increased bruising Edema Encephalopathy Confusion, lethargy Gynecomastia (males) Splenomegaly Anorexia, nausea Impaired digestion and absorption Weight loss Fatigue Amenorrhea (female) Nodular liver (fibrosis) FIG. 17.28 Effects of advanced cirrhosis. FIG. 17.29 Metastatic malignant liver tumor. (From Black J, Hawks J: Medical-Surgical Nursing: Clinical Management for Positive Outcome, ed 8, St. Louis, 2009, Saunders, Elsevier.) 468 SECTION III Pathophysiology of Body Systems widespread inflammation of the peritoneal membranes, or chemical peritonitis. The inflammatory response, including vasodilation and increased capillary permeability, leads to hypovolemia and circulatory collapse. Severe pain, caused by the autodigestion of nerves and the inflammation, contributes to shock (neurogenic shock). Chemical peritonitis results in bacterial peritonitis as intestinal bacteria escape through the more permeable membranes (see Fig. 17.44, presented later in the chapter). Septicemia or general sepsis may result from the escape of bacteria and toxins from the intestines into the general circulation if the inflammatory process is not controlled quickly. Other complications, which may cause death, are adult respiratory distress syndrome and acute renal failure. The process is summarized in Fig. 17.31. ■ Etiology Although many factors may precipitate acute pancreatitis, the two major causes are gallstones and alcohol abuse. Gallstones may obstruct the flow of bile and pancreatic secretions into the duodenum or cause reflux of bile into the pancreatic duct, thus activating trypsinogen. Alcohol appears to stimulate an increased secretion of pancreatic enzymes and to contract the sphincter of Oddi, blocking FIG. 17.30 Acute pancreatitis. Note the dark areas of hemorrhage in the head of the pancreas and a pale area of fat necrosis around the upper left pancreas. (From Cotran R, et al: Robbins Pathologic Basis of Disease, ed 6, Philadelphia, 1999, Saunders, Elsevier.) PRECIPITATING FACTORS: ALCOHOL CONSUMPTION, BILIARY TRACT OBSTRUCTION, CANCER, MUMPS VIRUS ACUTE PANCREATITIS ACTIVATION OF PANCREATIC ENZYMES INSIDE THE PANCREATIC DUCTS (e.g., trypsin, peptidase, elastase, amylase, lipase) AUTODIGESTION OF PANCREATIC TISSUE Active enzymes leak into peritoneal cavity and continue to destroy tissue with massive inflammation Enzymes and cell contents leak into general circulation and may cause: TISSUE NECROSIS AND SEVERE INFLAMMATION OF PANCREAS SEVERE PAIN HEMORRHAGE AND SHOCK PERITONITIS AND HYPOVOLEMIC SHOCK SHOCK DISSEMINATED INTRAVASCULAR COAGULATION ADULT RESPIRATORY DISTRESS SYNDROME FIG. 17.31 Pathophysiology of acute pancreatitis. THINK ABOUT 17.10 a. Explain how the structure of the liver is altered by cirrhosis. b. At which stage(s) is alcoholic liver disease reversible, and why? c. State the rationale for each of the following manifestations of cirrhosis: excessive bleeding, ascites, jaundice, and weight loss. d. Explain why a transplanted liver (portion) is able to grow and function but a cirrhotic liver cannot. Acute Pancreatitis ■ Pathophysiology Pancreatitis is an inflammation of the pancreas resulting from autodigestion of the tissues. It may occur in acute or chronic form. Acute pancreatitis is considered a medical emergency. The autodigestion follows premature activation of the pancreatic proenzymes within the pancreas itself. It appears that activation of the proenzyme trypsinogen into trypsin is the trigger; in turn, trypsin converts other proenzymes and chemicals into active forms. The activated enzymes, trypsin, and the proteases amylase and lipase digest the pancreatic tissue, leading to massive inflam- mation, bleeding, and necrosis (Fig. 17.30). The pancreas is composed of delicate tissue and lacks a fibrous capsule that might contain the effects of auto- digestion. In some cases, pseudocysts or pancreatic abscesses may develop if the local inflammatory response is successful in localizing the injury. Otherwise, destruction by trypsin and other enzymes progresses into tissues surrounding the pancreas. Lipase causes fat necrosis, binding calcium ions (see pancreatic calcification in x-ray in Ready Reference 5). Blood vessels are eroded by elastase (a protease), leading to hemorrhage. Damaging products—for example, cytokines and prostaglandins—released by tissue necrosis lead to CHAPTER 17 Digestive System Disorders 469 disease. Metastases occur early, and effective treatments for metastatic disease are still in clinical research trials. Mortality is close to 95%. Liver failure, resulting from hepatobiliary obstruction, is often the cause of death. flow, but there may be other mechanisms. Alcoholics may have chronic pancreatitis, and the acute episode may be an exacerbation of the chronic form, rather than a separate entity. ■ Signs and Symptoms Sudden onset of acute pancreatitis may follow intake of a large meal or a large amount of alcohol. • Severe epigastric or abdominal pain radiating to the back is the primary symptom. Pain increases when the individual assumes a supine position. • Signs of shock—low blood pressure, pallor and sweat- ing, and a rapid but weak pulse—develop as inflam- mation and hemorrhage cause hypovolemia. • Low-grade fever is common until infection develops, when body temperature may rise significantly. • Abdominal distention and decreased bowel sounds occur as peritonitis leads to decreased peristalsis and paralytic ileus. ■ Diagnostic Tests Serum amylase levels rise within the first 12 to 24 hours and fall after 48 hours. Serum lipase levels are also elevated and remain so for approximately a week. Hypocalcemia is common after calcium ions bind to fatty acids in areas of fat necrosis. Leukocytosis is an indicator of inflammation and infection. ■ Treatment All oral intake is stopped, and bowel distention is relieved to reduce pancreatic stimulation. Shock and electrolyte imbalances are treated. Analgesics, such as meperidine, may be given for pain relief (but not morphine, which causes spasm of the sphincter of Oddi). The mortality rate is around 20%, and it is higher in individuals with concomitant diseases or elderly persons. Pancreatic Cancer Pancreatic (exocrine) cancer is increasing in incidence in North America with an estimated 53,670 cases and 43,090 deaths in the United States for (American Cancer Society) 2017. The major established risk factor appears to be cigarette smoking. Pancreatitis and dietary factors have also been implicated. The common form of the neoplasm is adenocarcinoma, which arises from the epithelial cells in the ducts. A tumor at the head of the pancreas usually causes obstruction of biliary and pancreatic flow, leading to weight loss and jaundice as early manifestations. Cancer of the body and tail of the pancreas frequently remains asymptomatic until it is well advanced and involves the nearby structures, such as the liver, stomach, lymph nodes, or posterior abdominal wall and nerves. Pain becomes severe as the cancer progresses, eroding tissues. Unless the tumor is diagnosed early and can be removed surgically, it is usually not diagnosed until later in the THINK ABOUT 17.11 a. Explain why the liver is a common site of secondary cancer. b. Explain the concept of autodigestion, and describe two specific effects of this process in the pancreas. Lower Gastrointestinal Tract Disorders Celiac Disease Celiac disease, also called celiac sprue or gluten enteropathy, is a malabsorption syndrome that is considered to be primarily a childhood disorder. However, it may also occur in adults, usually at middle age. There is a related disorder, tropical sprue, which is bacterial in origin and often occurs in epidemics in tropical areas. Celiac disease appears to be linked to genetic factors and consists of a defect in the intestinal enzyme that prevents further digestion of gliadin, a breakdown product of gluten. Gluten is a constituent of certain grains: wheat, barley, rye, and oats. The combination of a digestive block with an immunologic response in the person results in a toxic effect on the intestinal villi. The villi atrophy, resulting in decreased enzyme production and less surface area available for absorption of nutrients (Fig. 17.32). Thus the result of celiac disease is malabsorption and malnutrition, which typically manifest as follows: • Steatorrhea • Muscle wasting • Failure to gain weight • Irritability and malaise In an infant, the first signs of the disorder usually appear as cereals are added to the diet, at around 4 to 6 months of age. The condition can be diagnosed by a series of blood tests (celiac blood panel) that check for autoantibodies, a duodenal biopsy, and, lastly, adopting a gluten-free diet to assess if health improves under the new conditions. Fortunately celiac disease can usually be treated by maintaining a gluten-free diet, using corn and rice for grains. The intestinal mucosa returns to normal after a few weeks without gluten intake. Patients should be monitored because of an increased incidence of intestinal lymphoma. Chronic Inflammatory Bowel Disease Crohn disease and ulcerative colitis are chronic inflam- matory bowel diseases, the causes of which are unknown. 470 SECTION III Pathophysiology of Body Systems distribution called skip lesions, with affected segments clearly separated by areas of normal tissue (Fig. 17.33). Initially inflammation occurs in the mucosal layer with the development of shallow ulcers. The ulcers tend to coalesce to form fissures separated by thickened elevations or nodules, giving the wall a typical cobblestone appear- ance. The progressive inflammation and fibrosis may affect all layers of the wall (transmural), leading eventually to a thick, rigid “rubber hose” wall. This change leaves a narrow lumen (“string sign”), which may become totally obstructed. Granulomas indicative of chronic inflamma- tion may be found in the wall and the regional lymph Prevalence is estimated in the range of 500,000 cases in the United States, ranging from mild to severe. A genetic factor appears to be involved because there is a high familial incidence, and inflammatory bowel disease (IBD) is much more common among certain groups, namely whites, particularly Ashkenazi Jews (from Eastern Europe). Investigative studies on an immunologic abnormality continue because many individuals have high levels of various antibodies or human leukocyte antigen (HLA) and a cytokine, interleukin (IL) in the blood, and T lymphocytes that are cytotoxic to the mucosa. Two genes have been identified, which, if defec- tive, are linked to Crohn disease. In many patients, particularly those with ulcerative colitis, there are mani- festations of immune abnormalities elsewhere in the body, including iritis, ankylosing spondylitis, arthritis, and nephrolithiasis. There are many similarities between Crohn disease and ulcerative colitis, and there may be an overlap in their clinical presentation in some individuals (Table 17.7). Both diseases occur in males and females. Crohn disease often develops during adolescence, whereas ulcerative colitis more frequently appears in the second or third decade. These diseases are characterized by remissions and exacerbations as well as considerable diversity in the severity of clinical effects. Crohn Disease (Regional Ileitis or Regional Enteritis) ■ Pathophysiology Crohn disease may affect any area of the digestive tract, but it occurs most frequently in the small intestine, particularly the terminal ileum and sometimes the ascend- ing colon. Inflammation occurs in a characteristic TABLE 17.7 Inflammatory Bowel Disease Characteristic Crohn Disease Ulcerative Colitis Region affected Terminal ileum, sometimes colon Colon, rectum Distribution of lesions Transmural, all layers Skip lesions Mucosa only Continuous, diffuse Characteristic stool Loose, semiformed Frequent, watery, with blood and mucus Granuloma Common No Fistula, fissure, abscess Common No Stricture, obstruction Common Rare Malabsorption, malnutrition Yes Not common BA FIG. 17.32 A, Normal small intestinal mucosa with villi appearing as fingers and leaves. B, Celiac disease–flat intestinal mucosa with total villus atrophy. (From Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology, ed 3, Sydney, 2004, Churchill Livingstone.) CHAPTER 17 Digestive System Disorders 471 to hypoproteinemia, avitaminosis, malnutrition, and possibly steatorrhea. Other complications are common. Adhesions between two loops of intestine may develop when the subserosa is inflamed. The ulcers may penetrate the intestinal wall, nodes. The damaged wall impairs the ability of the small intestine to process and absorb food. The inflammation also stimulates intestinal motility, decreasing the time available for digestion and absorption. Interference with digestion and absorption in the small intestine may lead A. "Skip lesions" — distribution of affected segments alternating with normal segments of bowel Affected segments Colon Normal ileum B. Changes in the intestinal wall Rigid, thickened wall (fibrosis) C E Normal thin flexible wall Inflammation Narrow lumen leading to obstruction Ulcers in mucosa D. Fistula–abnormal opening between two structures Inflammation and erosion of wallThick wall FIG. 17.33 Regional ileitis (Crohn disease). A, “Skip lesions.” B, Narrowing and obstruction. C, Inflamed and edematous section of the alimentary canal due to Crohn disease. D, Diagram of fistula. E, Crohn disease with stricture and proximal ulceration (arrow: ileocecal valve). (C From Frazier M, Drzymkowski J: Essentials of Human Diseases and Conditions, ed 5, St. Louis, 2013, Elsevier, Saunders. E From Goljan E: Pathology, ed 4, Philadelphia, 2014, Elsevier, Saunders.) 472 SECTION III Pathophysiology of Body Systems ulcerative colitis is the increased risk of colorectal carci- noma, which may be predicted by detection of metaplasia and dysplasia in the mucosa. ■ Signs and Symptoms Diarrhea is present, consisting of frequent watery stools marked by the presence of blood and mucus and accom- panied by cramping pain. During severe exacerbations, blood and mucus alone may be passed frequently, day or night, accompanied by tenesmus (persistent spasms of the rectum associated with a need to defecate). Rectal bleeding may be considerable and contributes to severe iron-deficiency anemia. Fever and weight loss may be present. ■ Treatment of Irritable Bowel Diseases • Exacerbations are often precipitated by physical or emotional stressors. It is helpful to identify and remove, if possible, the specific factors that apply in each individual. It is beneficial to use a team approach to the treatment of IBD because treatment involves multiple aspects of care. • Specific measures usually include antiinflammatory medications, such as sulfasalazine (sulfapyridine with 5-aminosalicylic acid) or glucocorticoids. These drugs may be administered systemically, both orally and parenterally, or topically, as an enema or suppository. In some refractive cases, other immunosuppressive agents may be used. • Antimotility agents, such as loperamide or anticho- linergic drugs (see Table 17.3), are used for symptomatic relief in mild or moderate cases. • Nutritional supplements are frequently required, particularly during acute episodes. Total parenteral nutrition (intravenous) may be required during severe exacerbations. The recommended diet is usually high in protein, vitamins, and calories but low in fat. Low-bulk diets reduce intestinal stimulation during exacerbations. • Antimicrobials, including metronidazole or ciprofloxa- cin, are required for secondary infection. causing abscesses to form. Fistulas, a connecting passage between two structures, may form as the ulcer erodes through the intestinal wall. Fistulas may be found between two loops of intestine (see Fig. 17.33D), the intestine and the bladder, or the intestine and the skin. Perianal fissures and fistulas are common. ■ Signs and Symptoms The course of Crohn disease is variable. Exacerbations are marked by diarrhea with cramping abdominal pain. The stool is typically soft or semiformed. Melena may occur if the ulcers erode blood vessels. Pain and tenderness are often centered in the right lower quadrant. Anorexia, weight loss, anemia, and fatigue are associ- ated with malabsorption and malnutrition. Children experience delayed growth and sexual maturation result- ing from a lack of adequate protein and vitamins, par- ticularly fat-soluble vitamins A and D. Treatment with glucocorticoids also hampers growth. In addition, many psychological implications are characteristic of this type of chronic illness. Ulcerative Colitis ■ Pathophysiology The inflammation commences in the rectum and pro- gresses in a continuous fashion proximally through the colon. The small intestine is rarely involved. The mucosa and submucosa are inflamed, commencing at the base of the crypts of Lieberkühn (mucus-secreting goblet cells). The tissue becomes edematous and friable, and ulcerations develop (Fig. 17.34). In an attempt to heal, granulation tissue forms, but it is vascular and fragile and bleeds easily. When the ulcers coalesce, large areas of the mucosa become denuded, but there are residual “bridges” of intact mucosa over the ulcers. This tissue destruction interferes with the absorption of fluid and electrolytes in the colon. In severe acute episodes, a serious complication, toxic megacolon, may develop, as inflammation impairs peri- stalsis, leading to obstruction and dilation of the colon, usually the transverse colon. A concern with long-term A B FIG. 17.34 Ulcerative colitis. Normal colon (A) and colon affected by ulcerative colitis (B). (From Forbes C, Jackson W: A color atlas and text of clinical medicine.) CHAPTER 17 Digestive System Disorders 473 THINK ABOUT 17.12 a. Explain the characteristics of steatorrhea. b. Explain how the pathologic changes seen in celiac disease lead to malabsorption. c. Prepare a chart comparing Crohn disease and ulcerative colitis by location and characteristics of the lesions, manifestations, and potential complications. d. Explain several ways in which an adolescent’s growth and development could be impaired by Crohn disease. • Psychosocial factors: The IBS symptoms in this case may be caused by factors such as emotional stress, which in turn affects the autonomic nervous system, the neuroendocrine pathway, and pain responses. ■ Signs and Symptoms Manifestations of IBS may include: • Lower abdominal pain • Diarrhea • Constipation • Alternating diarrhea and constipation • Gas • Bloating • Nausea There may also be fecal urgency and incomplete evacuation of the bowels. After defecation the symptoms usually subside. ■ Diagnosis Diagnosis of IBS is based on the established signs and symptoms and the exclusion of any structural or metabolic problems that can produce similar manifestations. Test for food allergies, bacterial or parasitic infections, and problems such as lactose intolerance may also be used to confirm the disorder. A protocol referred to as Rome III criteria has been established as a guideline for diagnosing IBS. ■ Treatment There is no single cure for IBS. The treatment is individual- ized to address the specific symptoms. These treatments may include laxatives, fiber supplements, antidiarrheal medication, antidepressants, analgesics for pain, anti- spasmodic medication, and medications to balance the serotonin levels. There are currently two medications specifically approved for the treatment of IBS: alosetron (Lotronex), which is designed to relax the colon and slow the movement of waste through the lower bowel, and lubiprostone (Amitiza), which works by increasing fluid secretion in the intestine to help with the passage of stool. These medications are prescribed almost exclusively for women. Because of the variety of causes, research into new treatments and therapies is ongoing. Appendicitis A common acute problem in young adults, occurring in 10% of the population, appendicitis is an inflammation and infection in the vermiform appendix (see Fig. 17.1). ■ Pathophysiology The development of appendicitis usually follows a pattern that correlates with the clinical signs, although variations may occur because of the altered location of the appendix or underlying factors: 1. Obstruction of the appendiceal lumen by a fecalith, gallstone, or foreign material or from twisting or spasm is commonly an initiating factor. • Immunotherapeutic agents, such as azathioprine, are effective as long-term therapy. • Surgical resection—usually ileostomy or colostomy, procedures that create an artificial opening on the surface of the abdomen—is necessary for complications, such as obstruction or fistulas, or for severe exacerba- tions that do not respond to medication. In some cases, surgical intervention may provide a temporary rest for the intestine and can be reversed to restore normal anatomy later. Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a gastrointestinal dis- order with manifestations of abdominal pain/discomfort and changes in normal bowel habits. This disorder affects up to 20% of the worldwide population, and statistics show it is more common in young and middle-aged women. The types of IBS are identified based on the primary symptoms of diarrhea, constipation, or pain. ■ Pathophysiology The different types of IBS are as follows: • Abnormal gastrointestinal motility and secretion: Those with diarrhea-type IBS experience rapid transit time of feces through the bowel, whereas those with constipation/bloating IBS have delayed transit time through the bowel. The cause may be hypersensitivity or the effect of serotonin on the enteric nervous system. • Visceral hypersensitivity: This type causes increased sensitivity to visceral pain. Causes are similar to those of abnormal motility and secretion but may also include the involvement of activated mast cells and T lym- phocytes and effects on the autonomic and central nervous systems in processing information, resulting in increased pain. • Postinfectious IBS: This type may cause low-grade inflammation and abnormal immune response in the gut. It is often associated with bacterial enteritis. • Overgrowth of flora: This form of IBS may cause constipation and bloating due to methane gas pro- duction. This gas production is a result of the over- growth of the normal intestinal flora found in the gut. • Food allergy or intolerance: Certain food antigens may activate the immune response in the mucosa, causing a hypersensitivity reaction and IBS symptoms. 474 SECTION III Pathophysiology of Body Systems 8. Increasing pressure inside the appendix causes increased necrosis and gangrene in the wall (infection in necrotic tissue). The wall of the appendix appears blackish. 9. If the appendix ruptures or perforates, it releases its contents into the peritoneal cavity. This leads to general- ized peritonitis, which may be life threatening (see Fig. 17.35C). ■ Signs and Symptoms Sometimes appendicitis develops “silently” or manifests with significant variations. In classic cases, a sequence of signs occurs, as follows: • General periumbilical pain related to the inflammation and stretching of the appendiceal wall occurs initially. • Nausea and vomiting are common. • Pain becomes more severe and localized in the lower right quadrant (LRQ) of the abdomen (Fig. 17.36). 2. Fluid builds up inside the appendix and microorgan- isms proliferate. 3. The appendiceal wall becomes inflamed and purulent exudate forms. The appendix is swollen. Blood vessels in the wall are compressed (Fig. 17.35). 4. The increasing congestion and pressure within the appendix leads to ischemia and necrosis of the wall, resulting in increased permeability. 5. Bacteria and toxins escape through the wall into the surrounding area. This breakout of bacteria leads to abscess formation or localized bacterial peritonitis. 6. An abscess may develop when the adjacent omentum temporarily walls off the inflamed area by adhering to the appendiceal surface. In some cases, the inflam- mation and pain subside temporarily but then recur. 7. Localized infection or peritonitis develops around the appendix and may spread along the peritoneal membranes. BA C FIG. 17.35 A, Appendicitis. Appendix is inflamed and distended with yellowish pus. B, Smear of drainage from a ruptured appendix showing infection by fecal flora and gram-positive and gram- negative bacteria. C, Liver affected by acute peritonitis resulting from a ruptured appendix. Note: The liver is covered by a purulent exudate. (A From Black J, Hawks J: Medical-Surgical Nursing: Clinical Management for Positive Outcome, ed 8, St. Louis, 2009, Saunders, Elsevier. B From Mahon CR, Manuselis G: Textbook of Diagnostic Microbiology, ed 2, Philadelphia, 2000, Saunders. C Courtesy of RW Shaw, North York General Hospital, Toronto, Ontario, Canada.) CHAPTER 17 Digestive System Disorders 475 • A Diverticulum is a herniation or outpouching of the mucosa through the muscle layer of the colon wall, frequently in the sigmoid colon. • Diverticulosis is asymptomatic diverticular disease. Usually multiple diverticula are present (Fig. 17.37). • Diverticulitis refers to inflammation of the diverticula. It is a common problem in the Western world, primarily affecting older individuals. ■ Pathophysiology Diverticula form at gaps between bands of longitudinal muscle that coincide with openings in the circular muscle bands that permit blood vessels to pass through the wall. Longitudinal muscle also occurs in three bands, rather than as a continuous sheet. Congenital weakness of the wall may also be a contributing factor. These weaker areas of the wall bulge outward when pressure increases, frequently inside the lumen of the intestine, for example, in the presence of strong muscle contractions. Consistently low-residue diets, irregular bowel habits, and aging lead to chronic constipation and then to muscle hypertrophy in the colon, with elevated intraluminal pressures, and finally to the gradual develop- ment of diverticula. Potential complications include • Lower right quadrant tenderness develops (classically at the McBurney point, midway between the umbilicus and the iliac crest). Localized pain results from involve- ment of the parietal peritoneum over the appendix. The location of the appendix does vary among indi- viduals, and this can be diagnostically misleading. • If rupture occurs, the pain usually subsides temporarily as the pressure is relieved. • Pain recurs as a steady, severe abdominal pain as peritonitis develops. • Low-grade fever and leukocytosis occur as inflamma- tion develops. • Signs indicating the onset of peritonitis include a rigid, boardlike abdomen, tachycardia, and hypotension. ■ Treatment Surgical removal of the appendix and the administration of antimicrobial drugs are the standard treatment. Diverticular Disease Diverticular disease refers to various problems related to the development of diverticula (singular, diverticulum). Diverticula may be congenital or acquired. 2. Localized: severe LRQ pain, deep localized tenderness on palpation as parietal peritoneum over appendix becomes inflamed 1. General periumbilical pain increasing in severity as inflamed appendix is distended 3. RUPTURE; PAIN DECREASES temporarily when appendix ruptures and spills contents into peritoneal cavity 4. Peritonitis causes severe steady abdominal pain as infection spreads FIG. 17.36 Typical progression of pain in acute appendicitis. 476 SECTION III Pathophysiology of Body Systems the second leading cause of cancer-related deaths. Accord- ing to information collected in 2013, 136,119 persons in the United States were diagnosed with colorectal cancer, with 51,813 deaths. Overall 1 in 21 to 23 Americans will develop colon cancer if preventive measures do not improve. Many of the deaths could be prevented by early treatment of precancerous lesions, such as polyps, and early detection of malignancy. The American Cancer Society recommends fecal tests for occult blood (FOBT), every year for those older than 40 years old and a sig- moidoscopy every 3 to 5 years for those older than 50 years old. Following a survey, the CDC and American Cancer Society are promoting a routine screening for all persons greater than age 50—to include FOBT, sigmoid- oscopy, and colonoscopy—to ensure more early detection and treatment. For specific information on the tests that are being used and the rationale for the use of each one, see the American Cancer Society website. Video camera capsules have been tested for identification of polyps and malignancies in the gastrointestinal tract; these require the same bowel preparation as do more invasive proce- dures. The US Congress has mandated screening for colorectal cancer as part of the “Welcome to Medicare” physical to be done within 6 months of qualifying for Medicare benefits. Malignant tumors are rare in the small intestine. intestinal obstruction, perforation with peritonitis, and abscess formation. ■ Signs and Symptoms In many cases, diverticular disease remains asymptomatic. Sometimes there is mild discomfort, diarrhea, or constipa- tion and flatulence, which can be excused for other reasons. With diverticulitis, inflammation, related to stasis of feces in the pouches, develops in the diverticula. Lower left quadrant cramping or steady pain and tenderness with nausea and vomiting indicate inflammatory disease. A slight fever and elevated white blood cell count accompany the discomfort. ■ Treatment During acute episodes of diverticulitis, food intake is reduced, and antimicrobial drugs are taken as required. Diverticular disease is treated by increasing the bulk in the diet, omitting foods such as seeds and popcorn, and encouraging regular bowel movements without constipation. Colorectal Cancer In the United States, colorectal cancer ranks high as a lethal cancer in individuals older than age 50, and it is A B FIG. 17.37 A, Diverticulosis of the sigmoid colon. B, Low-power micrograph of diverticulum of the colon showing protrusion of mucosa and submucosa through the muscle wall. (A From Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology, ed 3, Sydney, 2004, Churchill Livingstone. B From Kumar V, et al: Robbins Basic Pathology, ed 8, Philadelphia, 2007, Saunders-Elsevier.) CHAPTER 17 Digestive System Disorders 477 growths, which are common in the left colon, or as project- ing polypoid masses, which are common in the right colon. Flat ulcerating lesions occur less frequently. All types of carcinomas invade the wall, the mesentery, and the lymph nodes and metastasize to the liver. Staging is based on the degree of local invasion, lymph node involvement, and the presence of distant metastases (see Chapter 20). Most adenocarcinomas release carcinoembryonic antigen (CEA) into the blood. Detection of this antigen has limited value as a screening tool because it is also elevated in other conditions, such as ulcer- ative colitis. However, the presence of the antigen is useful to monitor for recurrence after removal of a tumor. ■ Etiology This cancer occurs primarily in persons older than age 55. It is more common in the Western hemisphere. The ■ Pathophysiology Most malignant neoplasms develop from adenomatous polyps, of which there are diverse types. A polyp is a mass, often on a stem, that protrudes into the lumen, and many polyps represent genetic abnormalities (Fig. 17.38). As polyps increase in size, they carry an increased risk of dysplasia and malignant changes. These adenocarcinomas are distributed about equally in the right (or ascending) colon, the left (or descending) colon, and the distal sigmoid colon and rectum. In recent years, an increasing number of tumors have been found in the right colon using barium enema or CT scans. Lesions in this location are more difficult to diagnose at an early stage because a routine rectal digital examina- tion or proctosigmoidoscopy does not suffice. Tumors in the sigmoid colon and rectum are more easily accessible. Carcinomas may manifest differently—for example, as circumferential or annular constrictive “napkin-ring” B A Stricture due to circumferential growth Dilated colon proximal to stricture Many small polyps Large polyp with atypical cells Pedunculated polyp FIG. 17.38 Colorectal cancer. A, Circumferential malignant growth (cancer) obstructing flow of feces and causing proximal dilation of the colon. B, Polyposis and malignant changes. (Courtesy of RW Shaw, North York General Hospital, Toronto, Ontario, Canada.) 478 SECTION III Pathophysiology of Body Systems Ascending colon “Liquid stool” • Occult blood in stool or melena (ulceration) • Anemia, fatigue • Late-palpable mass Descending colon “Solid stool” • Constipation, discomfort (obstruction) • Abdominal fullness and distention • Red or dark blood in stool Rectum “Solid stool” • Abdominal discomfort and cramps • Ribbon or pellet stool • Incomplete emptying • Red blood on surface of stool Transverse colon “Semisolid stool” • Anemia, occult blood in stool • Change in bowel habits FIG. 17.39 Common signs and symptoms of colorectal cancer related to location. An unexplained change in bowel habits, such as alternating diarrhea and constipation, may be a sign of malignancy. Bleeding may be indicated by occult blood or melena if it arises from the proximal colon. Frank (red) blood and mucus on or near the surface of the stool usually signify bleeding from a lesion in the rectum. ■ Treatment Colorectal cancer is treated by surgical removal of the involved area, usually requiring a colostomy, an artificial opening into the abdominal wall where feces may be continually collected in a bag (Fig. 17.40). Both curative and palliative surgery may be accompanied by radiation and chemotherapy. Chemotherapy may be used in conjunction with radiation after surgery. Current recommendations are for the use of two drugs in a protocol that may include oral medication as well as intravenous drugs. The choice of drug protocol will depend on the stage of the cancer and the patient’s overall health history. A new drug treatment, cetux- imab, targets growth factor signals responsible for cell reproduction. Early diagnosis is essential. Localized lesions (Dukes stage A or TNM stage I cancer) confined to the mucosa carry a 5-year survival rate of greater than 90%. Once lymph nodes are involved (Dukes stage C or TNM stage III), the 5-year survival rate drops significantly. presence of familial multiple polyposis or long-term ulcerative colitis in a patient increases the risk of cancer developing, often at a younger age. Genetic factors are responsible for the increased occurrence of colorectal cancer among close relatives. Environmental factors, such as diet, also appear to play a major role in carcinogenesis. Diets high in fat, sugar, and red meat are thought to produce carcinogenic substances, particularly long term. Low-fiber diets increase risk because they prolong the contact time of the mucosa with carcinogens. ■ Signs and Symptoms Although most carcinomas remain asymptomatic until they are well advanced, the initial signs of colorectal cancer depend largely on the location of the growth and the characteristics of the feces at that location in the colon (Fig. 17.39). For example, an annular lesion in the rectosigmoid area, where the fecal mass is relatively solid, causes partial obstruction with dilation of the proximal colon (see Fig. 17.38). Vague cramping pain, small flat pellets or “ribbon” stool, and a feeling of incomplete emptying are common signs of cancer in this location. Cancer in the right colon, where the fecal material is liquid, does not cause obstruction but often manifests only as general systemic signs, such as fatigue, weight loss, or iron-deficiency anemia. CHAPTER 17 Digestive System Disorders 479 Sigmoid Colostomy—made from the sigmoid part of the colon Stoma • Not painful • Aways red and moist • May bleed easily A C B • Output: Fully formed stool • Pouch: One-piece drainable, One-piece closed, Two-piece drainable, Two-piece closed, or Stomacap (if irrigated) FIG. 17.40 Colostomy. A, Sigmoid colostomy. A surgically created opening into the colon through the abdominal wall. B, The stoma is the new opening on the abdomen. It is always red and moist, is not painful, but may bleed easily. C, A plastic pouch to collect stools is attached to the stoma. (Courtesy of Hollister Incorporated, Patient Education Series.) THINK ABOUT 17.13 a. Describe, in the order in which they develop, each stage of the pain seen with acute appendicitis, including the location and type of pain and the reason for it. b. Define diverticulitis, and explain how diverticula develop and become inflamed. c. State two factors that predispose a patient to colorectal cancer. d. Explain why the signs of colorectal cancer vary with the location of the tumor. Intestinal Obstruction Intestinal obstruction refers to a lack of movement of the intestinal contents through the intestine. Because of its smaller lumen, obstructions are more common and occur more rapidly in the small intestine, but they can occur in the large intestine as well. Depending on the cause and location, obstruction may manifest as an acute problem or a gradually developing situation. For example, twisting of the intestine could cause sudden total obstruction, whereas a tumor leads to progressive obstruction. Intestinal obstruction occurs in two forms. Mechanical obstructions result from tumor, adhesions, hernias, or other tangible obstructions (Fig. 17.41). Functional, or adynamic, obstructions result from neurologic impair- ment, such as spinal cord injury or a lack of propulsion in the intestine, and are often referred to as paralytic ileus. Although the result can be the same, these types manifest somewhat differently and require different treatments. ■ Pathophysiology When mechanical obstruction of the flow of intestinal contents occurs, a sequence of events develops (Fig. 17.42) as follows: 1. Gases and fluids accumulate in the area proximal to the blockage, distending the intestine. Gases arise primarily from swallowed air, but they also result from bacterial activity in the intestine. 2. Increasingly strong contractions of the proximal intestine occur in an effort to move the contents onward. 3. The increasing pressure in the lumen leads to more secretions entering the intestine and also compresses the veins in the wall, preventing absorption, as the intestinal wall becomes edematous. 480 SECTION III Pathophysiology of Body Systems Inguinal hernia Tumor Diverticulitis Volvulus Blood vessels compressed Intestine twisted on itself in a knot Telescoping of ileum inside adjacent section of colon Intussusception Blood vessels drawn in between layers and compressed BA C D E Appendix Ileum Colon narrowed by scar tissue Diverticulum filled with feces Inflammation FIG. 17.41 A–E, Causes of intestinal obstruction. CHAPTER 17 Digestive System Disorders 481 As the affected intestinal wall becomes necrotic and more permeable, intestinal bacteria or toxins can leak into the peritoneal cavity (peritonitis) or the blood supply (bacteremia and septicemia). 8. In time, perforation of the necrotic segment may occur, leading to generalized peritonitis. Functional obstruction or paralytic ileus usually results from neurologic impairment. Peristalsis ceases and disten- tion of the intestine occurs as fluids and electrolytes accumulate in the intestine. In this type of obstruction, reflex spasms of the intestinal muscle do not occur, but the remainder of the process is similar to that of mechani- cal obstruction. ■ Etiology Functional obstruction or paralytic ileus is common in the following situations: • After abdominal surgery, in which the effects of the anesthetic combined with inflammation or ischemia 4. The intestinal distention leads to persistent vomiting with additional loss of fluid and electrolytes. With small intestinal obstructions, there is no opportunity to reabsorb fluid and electrolytes, and hypovolemia quickly results. 5. If the obstruction is not removed, the intestinal wall becomes ischemic and necrotic as the arterial blood supply to the tissue is reduced by pressure. If twisting of the intestine (eg, volvulus) has occurred or immedi- ate compression of arteries (eg, intussusception or strangulated hernia) results from the primary cause of obstruction, the intestinal wall becomes rapidly necrotic and gangrenous. 6. Ischemia and necrosis of the intestinal wall eventually lead to decreased innervation and cessation of peri- stalsis. A decrease in bowel sounds indicates this change. 7. The obstruction promotes rapid reproduction of intestinal bacteria, some of which produce endotoxins. 5. Increased pressure on wall causes more fluid to enter intestine 7. Continued pressure on intestinal wall causes edema and ischemia of wall and decreased peristalsis 2. Increased fluid and gas lead to distention 4. Severe vomiting from distention and pain leads to dehydration and electrolyte imbalance Vomitus 1. Site of obstruction 3. Distention causes increased peristalsis to force contents past obstruction, leading to colicky pain Intestine empty (no absorption) Increased fluid and gas Vein Bacteria 8. Prolonged ischemia causes increased permeability and necrosis of wall. Intestinal bacteria and toxins leak into blood and peritoneal cavity (peritonitis) 6. Decreased blood pressure and hypovolemic shock as (third-spacing) fluid shift into intestine continues FIG. 17.42 Effects of intestinal obstruction. 482 SECTION III Pathophysiology of Body Systems • Intussusception may occur secondary to polyps or tumors that pull a section of bowel forward with them (see Fig. 17.41C) • Volvulus (twisting of a section of intestine on itself), which may be linked to adhesions; in many cases, the cause of intussusception or volvulus is unknown • Hirschsprung disease, or congenital megacolon, a condition in which parasympathetic innervation is missing from a section of the colon, impairing motility and leading to constipation and eventually obstruction; Hirschsprung disease often occurs in conjunction with other anomalies • Gradual obstruction from chronic inflammatory condi- tions, such as Crohn disease or diverticulitis ■ Signs and Symptoms • With mechanical obstruction of the small intestine, severe colicky abdominal pain develops as peristalsis increases initially. • Borborygmi (audible rumbling sounds caused by movement of gas in the intestine) and intestinal rushes can be heard as the intestinal muscle forcefully contracts in an attempt to propel the contents forward. The signs of paralytic ileus differ significantly in that bowel sounds decrease or are absent, and pain is steady. • Vomiting and abdominal distention occur quickly with obstruction of the small intestine. Vomiting is recurrent and consists first of gastric contents and then bile-stained duodenal contents. No stool or gas is passed. • Restlessness and diaphoresis with tachycardia are present initially. • As hypovolemia and electrolyte imbalances progress, signs of dehydration, weakness, confusion, and shock are apparent. Obstruction of the large intestine develops slowly and signs are mild. Constipation and mild lower abdominal pain are common, followed by abdominal distention, anorexia, and eventually vomiting and more severe pain. ■ Treatment The underlying cause is treated, and fluids and electrolytes are replaced. Surgery and antimicrobial therapy are required as soon as possible for any strangulation; para- lytic ileus may require decompression by suction. Peritonitis Peritonitis is an inflammation of the peritoneal membranes that may result from chemical irritation or directly from bacterial invasion of the sterile peritoneal cavity. Chemical irritation, unless resolved quickly, ultimately leads to bacterial peritonitis. It is usually an acute condition and requires treatment of the primary cause as well as the effects. The incidence of peritonitis and septicemia has decreased with the prophylactic use of antibiotics, but peritonitis remains a threat in many situations. in the operative area interfere with conduction of nerve impulses • In the initial stage of spinal cord injuries (spinal shock) • With inflammation related to severe ischemia • In pancreatitis, peritonitis, or infection in the abdominal cavity • With hypokalemia, mesenteric thrombosis, or toxemia Mechanical obstruction may result from the following: • Adhesions (from previous surgery, infection, or radia- tion) that twist or constrict the intestine, the most common cause of obstruction • Hernias (protrusion of a section of intestine through an opening in the muscle wall; Fig. 17.43) • Strictures caused by scar tissue • Masses, such as tumors or foreign bodies • Intussusception (the telescoping of a section of bowel inside an adjacent section) b c a A B FIG. 17.43 A, Hernia with infarcted intestine. The sac consists of the abdominal wall covered by skin (a) at a site weakened by scar tissue, forming a protrusion into which a loop of intestine is compressed (b). This protrusion obstructs the blood flow to the intestinal wall (c) (black infarcted area) as well as the flow of feces inside the intestine. B, Intussusception due to an adenocarcinoma (light-colored circular mass) causing acute intestinal obstruction. (A Courtesy of RW Shaw, North York General Hospital, Toronto, Ontario, Canada. B From Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology, ed 3, Sydney, 2004, Churchill Livingstone.) CHAPTER 17 Digestive System Disorders 483 provides a means of rapid dissemination of irritants or bacteria throughout the abdominal cavity. Abdominal distention is evident, and the typical rigid, boardlike abdomen develops as reflex abdominal muscle spasm occurs in response to involvement of the parietal peritoneum. Whatever the cause, this membrane is rapidly involved in the inflammatory response, which leads to vasodilation and increased permeability. The membrane becomes edematous and red. The many blood vessels in the membranes can leak large volumes of fluid into the peritoneal cavity. Hypovolemic shock results as this process of “third-spacing” occurs (see Chapter 12). The fluid, protein, and electrolytes sequestered in the peri- toneal cavity are not recycled into the circulating blood and therefore are of no value to the maintenance of body fluid balance. This fluid becomes purulent as infection spreads. Nausea and vomiting, resulting from the intes- tinal irritation and pain, add to the fluid loss. Two complications may develop if intervention is delayed. When inflammation persists, nerve conduction is impaired and peristalsis decreases, leading to obstruction of the intestines (paralytic ileus). The inflamed membranes ■ Pathophysiology Inflammation of the peritoneal membranes may commence with the presence of chemical irritants, such as bile, chyme, or foreign objects in the peritoneal cavity. This inflammation then increases the permeability of the intestinal wall, permitting enteric bacteria to enter the peritoneal cavity (Fig. 17.44). Necrosis or perforation of the intestinal wall also allows infection directly by enteric organisms. Initially when local inflammation develops in the abdominal cavity, the peritoneum and omentum tend to produce a thick, sticky exudate, which helps the adjacent tissues to stick together and temporarily seal the area, localizing the source of the problem. In some cases the inflammation subsides and an abscess forms that may flare up at a later time. This local inflamma- tion may also reduce peristalsis in the area, decreasing the risk of spreading toxins or bacteria at the time. However, unless the original cause of the problem is removed, it is likely that the inflammation or infection will spread. The peritoneum consists of a large sterile expanse of highly vascular tissue that covers the viscera and lines the abdominal cavity. This peritoneal structure Some causes of CHEMICAL PERITONITIS Perforated ulcer Ruptured gallbladder Pancreatitis Ruptured spleen Hemorrhage into peritoneal cavity Ruptured bladder INFLAMMATION of intestinal wall Some direct causes of BACTERIAL PERITONITIS Perforated appendix Intestinal obstruction Mesenteric thrombosis Pelvic inflammatory disease Septic abortion Increased permeability Intestinal bacteria leak out into peritoneal cavity BACTERIAL PERITONITIS Localized temporarily by omentum Abscess INFECTION AND INFLAMMATION OF PERITONEAL MEMBRANES Parietal peritoneum • Constant Reflex contraction of abdominal muscle • Rigid (board-like) abdomen Fluid shift from peritoneal and intestinal blood vessels (third-spacing) • Hypovolemic shock Fibrous scar tissue Adhesions Obstruction at a later time Impaired nerve transmission Decreased peristalsis Paralytic ileus (obstruction) • Decreased or absent bowel sounds severe pain FIG. 17.44 Development of peritonitis. 484 SECTION III Pathophysiology of Body Systems permit intestinal bacteria and toxic materials to migrate into the blood and then into the general circulation, which may lead to septicemia. ■ Etiology Peritonitis develops secondarily to many conditions, some of which are the following: • Chemical peritonitis may result from the enzymes released with pancreatitis, urine leaking from a rup- tured bladder, chyme spilled into the peritoneal cavity from a perforated ulcer, bile escaping from a perforated gallbladder, or blood or any other foreign material in the cavity. • Bacterial peritonitis may be caused by direct trauma affecting the intestines (eg, penetrating injury), a ruptured appendix, or intestinal obstruction, particu- larly when blood vessels are compressed and the wall becomes gangrenous. • Any abdominal surgery may lead to peritonitis if foreign material remains in the abdomen or infection develops at the site. • Pelvic inflammatory disease in women, in which infection ascends through the uterus and into the fallopian tubes, providing direct access to the peritoneal cavity, may result in peritonitis (see Chapter 19). ■ Signs and Symptoms Sudden, severe, generalized abdominal pain occurs with localized tenderness at the site of the underlying problem. The pain tends to increase with any movement, and the individual often restricts breathing. Other manifestations include the following: • Vomiting • Signs of dehydration and hypovolemia • Decreased skin turgor • Dry buccal mucosa • Pallor • Low blood pressure • Agitation and tachycardia • Fever and leukocytosis as the inflammation and infec- tion develop • Abdominal distention, and a rigid abdomen signaling involvement of the parietal peritoneum • Decreased bowel sounds, indicating the onset of paralytic ileus and secondary obstruction ■ Treatment Depending on the primary cause of the peritonitis, surgery is often required to correct the cause and drain sites of infection. Massive doses of antimicrobial drugs that are specific for the major causative organism, which is usually of enteric origin, are needed, as well as the replacement of fluids and electrolytes. Nasogastric suction to relieve abdominal distention is often required, as is treatment to combat paralytic ileus, when appropriate. The prognosis depends on the underlying cause and the rapidity of treatment. CASE STUDY A Gastroenteritis Baby K., age 14 months, has vomiting and diarrhea and is crying continuously because of what appears to be severe abdominal pain. The suspected cause is gastroenteritis attributable to Staphylococcus aureus from milk custard that had not been properly stored. 1. Briefly describe how S. aureus in the custard could cause vomiting and diarrhea. 2. Describe the fluid and electrolyte imbalances that can be expected in Baby K. 3. What arterial blood gas levels would you expect to find in this child with gastroenteritis? 4. Describe the signs of dehydration that can be expected in a child. 5. Explain the process and factors involved by which a young child can quickly develop vascular collapse if vomiting and diarrhea are severe. 6. Explain why water alone would not be adequate treatment for Baby K. CASE STUDY B Peptic Ulcer and Peritonitis Ms. X., age 76, has been admitted to the emergency department with severe generalized abdominal pain and vomiting. No sig- nificant findings were immediately evident to indicate a cause. Six hours later, Ms. X.’s blood pressure began to drop, and her pulse was rapid but thready. Exploratory abdominal surgery revealed a perforated gastric ulcer and peritonitis. 1. Describe the process by which an ulcer develops. 2. Suggest several possible factors contributing to ulcer formation. 3. Explain why peptic ulcer may not be diagnosed in an early stage of development. 4. Describe the process of perforation of an ulcer and the development of bacterial peritonitis. 5. Explain why Ms. X. showed signs of shock. Following surgery, Ms. X. had no bowel sounds, and her abdomen was distended. 6. Describe how paralytic ileus could have developed. Ms. X. was given antibiotics, intravenous fluids, and intra- venous alimentation (total parenteral nutrition). THINK ABOUT 17.14 a. Explain why the characteristics of the pain differ with mechanical and functional obstruction. b. Explain how each of the following conditions causes an intestinal obstruction: (1) intussusception, (2) adhesion, and (3) inguinal hernia. c. Explain (1) how an obstruction can lead to bacterial peritonitis, and (2) how peritonitis can lead to obstruction. d. Explain the cause of hypovolemic shock with peritonitis. e. What factors lead to metabolic acidosis in bacterial peritonitis? CHAPTER 17 Digestive System Disorders 485 CASE STUDY C Hepatitis B and Cirrhosis J.B., age 35, has had chronic hepatitis B for 9 years. The origin of his acute infection was never ascertained. 1. Describe the pathophysiology of acute hepatitis B infection. 2. If J.B. had known about his exposure, could any treatment measures have been undertaken at the time? 3. Describe two signs of the preicteric stage and three signs of the icteric stage of acute hepatitis B infection. 4. What serum markers remain high when chronic hepatitis B is present? 5. Explain the circumstances under which J.B. could transmit the virus (including the various stages of the disease [preicteric, icteric, and so on] as well as the mode of transmission). 6. Explain how cirrhosis develops from chronic hepatitis B. 7. Explain why the early stage of cirrhosis is relatively asymptomatic. J.B.’s cirrhosis is now well advanced. He has developed ascites, edema in the legs and feet, and esophageal varices. His appetite is poor, he is fatigued, and he has frequent respiratory and skin infections. Jaundice is noticeable. 8. What factors predispose J.B. to each of the manifestations listed in the preceding paragraph? 9. If a cure for hepatitis B were discovered at this point, how would this affect J.B.’s prognosis? J.B. has been admitted with hematemesis and shock resulting from ruptured esophageal varices. 10. Explain why each of the following events occur: (1) excessive bleeding from trauma, (2) increased serum ammonia levels, and (3) hand-flapping tremors and confusion. 7. Explain the reason for each of these treatments. 8. Explain why older individuals may have difficulty compensating for fluid and electrolyte imbalances. 9. List other potential complications of immobility for which Ms. X. is at risk during a prolonged recovery. CASE STUDY D Crohn Disease Mr. P.T., age 19, has had Crohn disease, affecting the ileum and part of the jejunum, for 5 years and has had numerous exacerba- tions. Several members of his extended family have a history of Crohn disease. 1. Describe the pathophysiology of Crohn disease. 2. Suggest several possible exacerbating factors for Crohn disease. 3. Describe the common signs of an exacerbation. 4. Explain how nutritional deficits may occur with Crohn disease. 5. Mr. P.T. has delayed growth. (He is much shorter than his classmates.) Suggest several specific contributing factors to retarded growth in a young person. 6. Mr. P.T. has developed a fistula between the ileum and the bladder. Describe the effect of a fistula. There is considerable risk of intestinal obstruction developing in Mr. P.T. at some point in the near future. 7. Explain how this obstruction could gradually form. 8. Suggest several manifestations of an acute obstruction in the ileum, and specify the reason for each one. 9. Describe the potential complications of an intestinal obstruction that is not treated promptly. CASE STUDY E Colon Cancer This case study incorporates several general aspects of malignant tumors (refer to Chapter 20 if necessary). Not all details can be included, but the events provide an opportunity to integrate information. Mrs. R.C., age 82, has a history of uterine cancer that began 12 years ago. A hysterectomy was performed at that time, fol- lowed by radiation (an implant of radioactive material). This was deemed successful. Vaginal bleeding developed 2 years later, and a tumor located between the vagina and bladder was treated with radiation and eradicated. Since that time, she has remained relatively healthy and led an active life. Now Mrs. R.C. has developed some abdominal discomfort, fatigue, and loss of energy, but blood tests and ultrasound failed to reveal any specific cause or abnormality. Continued pain and indigestion, combined with knowledge of her history, prompted a repeat of the tests 3 months later, again all negative. 1. Suggest possible reasons for negative tests. Pain continued, and occasional vomiting developed as well as inability to eat a large meal. A weight loss of 30 pounds was evident. Other illness delayed further tests for several months. A colonoscopy uncovered a malignant tumor in the upper descending colon. At this time a small opening was prepared in the intestine to allow passage of semiliquid foods. 2. List the signs indicating intestinal obstruction. Why have these signs been slow in developing? Two months later during surgery, a colostomy was created and healing seemed to be satisfactory. Only a small amount of the tumor had been removed. The oncologist determined that radiation was not an option given the history and chemotherapy was not effective with this malignant cell. 3. Describe possible reasons why additional treatment would not be recommended in this case. Following surgery, Mrs. R.C.’s food intake improved and she gained some weight. However, a pulmonary embolus developed several weeks after surgery and was treated with anticoagulants. 4. List the factors contributing to a pulmonary embolus in this case. A month later, the stoma began bleeding slightly and protrud- ing. Slight rectal bleeding also developed. The stoma became very large, painful, and unmanageable. Surgery was performed to construct another stoma. Nevertheless, loose stools were evacuated from the rectum, indicating the tumor had invaded other parts of the intestine. Following this surgery, Mrs. R.C. experienced increasing weakness and abdominal pain with a general decline in health until her death 6 weeks later. 5. List the evidence indicating the spread of malignant cells. 6. Briefly discuss your impressions of the events in this case history. 486 SECTION III Pathophysiology of Body Systems and the ability to cause chronic disease or exist in a carrier state. • Cirrhosis is the result of extensive fibrosis in the liver, thus impairing many metabolic processes, such as storage and conversion of nutrients, production of clotting factors and plasma proteins, detoxification, and bile production. • Acute pancreatitis involves autodigestion of the pancreas and surrounding tissue, resulting in severe pain, hemorrhage, shock, or peritonitis. Lower Gastrointestinal Tract • Crohn disease and ulcerative colitis are two forms of chronic inflammatory bowel disease of unknown cause, characterized by recurrent diarrhea. • Irritable bowel syndrome (IBS) is a complex gastro- intestinal disorder characterized by abdominal pain and changing bowel habits. There are a number of types based on the causes and symptoms. Treatment is individualized due to the variety of symptoms and underlying causes. • Acute appendicitis is caused by obstruction and infec- tion. The increasing pressure may cause rupture and generalized peritonitis. • Colorectal carcinoma is a common tumor, more difficult to diagnose at an early stage if located in the ascending or transverse colon. Obstruction in the rectum or sigmoid can be detected. • Intestinal obstruction, if caused mechanically by a stricture or volvulus, causes severe colicky pain, marked bowel sounds, and vomiting. With obstruction due to paralytic ileus, severe steady pain results and bowel sounds are absent. • Peritonitis resulting from a perforated ulcer or ruptured bladder may initially be termed chemical, but infection and bacterial peritonitis follow as intestinal bacteria leak out of the intestines. Severe generalized pain and abdominal rigidity are significant signs. C H A P T E R S U M M A R Y The digestive system is subject to frequent transient inflammatory or infectious conditions as well as chronic disorders that cause serious malnutrition and fluid- electrolyte imbalances. The liver and pancreas perform major metabolic functions in addition to their roles in the digestion and absorption of essential nutrients. Upper Gastrointestinal Tract • Many infections of the oral cavity, including herpes simplex virus, candidiasis, and periodontal disease, cause localized pain and interfere with food intake and nutrition. • Acute gastritis or gastroenteritis can cause serious fluid and electrolyte imbalances in infants and elderly persons. Gastroenteritis is typically caused by infections by microorganisms, many entering the tract through the consumption of contaminated water or food. • Peptic ulcer results from erosion of the mucosal barrier and is frequently associated with infection by H. pylori. Serious complications include hemorrhage and perforation. • Dumping syndrome may develop following gastric resection with removal of the pyloric sphincter, allow- ing gastric contents to enter the small intestine at a rapid rate in concentrated form. Liver and Pancreas • Cholelithiasis refers to gallstone formation, commonly due to excess cholesterol in the bile. Severe colicky pain results when gallstones obstruct a bile duct. • Jaundice or hyperbilirubinemia is a sign of a primary problem such as hemolytic anemia or liver disease. • Hepatitis includes a group of viral infections of the liver that may be differentiated by the structure of the virus, the mode of transmission and incubation period, S T U D Y Q U E S T I O N S 1. a. List the defense mechanisms that reduce the risk of infection in the oral cavity. b. State the locations of resident (normal) flora in the digestive tract. c. State the approximate pH of gastric secretions and two purposes served by this pH level. 2. a. Explain how the liver responds to high blood glucose levels. b. Describe six functions of the liver (include a variety of functions). 3. a. What is the major site of absorption of water and electrolytes? b. Which substances are absorbed primarily by active transport and which are absorbed by osmosis? c. Explain why tissue damage hinders active transport. 4. Describe the location and role of the parasympathetic nervous system in defecation. 5. a. Explain the purpose of the enterogastric reflex. b. Describe two results of an excessively rapid flow of chyme through the digestive tract. 6. a. Name the common electrolytes lost because of diarrhea. b. State the major effect on the body of sodium loss and potassium loss. c. State and explain what arterial blood gas levels may be expected in the presence of severe vomiting. CHAPTER 17 Digestive System Disorders 487 7. Define steatorrhea, and explain several possible causes of this manifestation. 8. Explain several ways in which severe stress can affect the digestive tract. 9. Explain how an H2 antagonist agent affects gastric function. 10. Explain how dysphagia may result from the following: a. stricture b. diverticulitis 11. Explain why hiatal hernia is aggravated by the following: a. intake of a large meal b. lying down after a meal 12. a. Explain several mechanisms by which intestinal infection can cause diarrhea. b. Explain how fluid balance and acid-base balance are altered by diarrhea. 13. a. Explain why peptic ulcers often do not heal quickly but tend to persist or recur. b. Describe the common differences between gastric ulcer and gastric cancer. 14. a. Define cholecystitis. b. List factors that predispose to cholelithiasis. c. Trace a gallstone on its path from a bile canaliculus to the duodenum, and note the different possible effects caused by obstruction at various locations. 15. a. State a common cause of posthepatic jaundice and the significant change in serum bilirubin that occurs with it. b. Describe the common manifestations of acute hepatitis. 16. Describe how chronic hepatitis may affect liver tissue. 17. a. Describe the three common types of cirrhosis, and give one cause of each. b. State the rationale for each of the following signs of cirrhosis: nausea, abdominal pain (upper right quadrant), esophageal varices, and hepatic encephalopathy. 18. Describe possible obstructive effects of liver cancer. 19. Explain two causes of shock resulting from acute pancreatitis. 20. a. Explain why malnutrition may develop from Crohn disease. b. Explain the process by which chronic bleeding may cause anemia. c. Explain, using an example, how a fistula develops in patients with Crohn disease. d. Compare the characteristics of diarrhea typical of Crohn disease with that of ulcerative colitis. 21. List the various symptoms and possible causes of irritable bowel syndrome. 22. Describe the pathophysiology involved in the various stages of acute appendicitis. 23. a. Explain how a long-term, low-residue diet contributes to the development of diverticula. b. Explain how chronic diverticulitis can cause intestinal obstruction. 24. List the common early signs of colorectal cancer, relating each to a particular site. 25. Explain why the prognosis for colorectal cancer is relatively poor. 26. Explain how intestinal obstruction results from volvulus, paralytic ileus, and tumor. 27. Explain how hypovolemia develops with intestinal obstruction. 28. a. Explain how the peritoneal membranes may provide a defense in the early stage of acute appendicitis. b. Explain how the structure of the peritoneal membrane may be a disadvantage after the appendix ruptures. c. Explain how shock develops with acute peritonitis. 488 Review of the Urinary System Structures and Anatomy Kidneys Renal Arteries and Veins Incontinence and Retention Diagnostic Tests Urinalysis Appearance Abnormal Constituents (Present in Significant Quantities) Blood Tests Other Tests Diuretic Drugs Dialysis Disorders of the Urinary System Urinary Tract Infections Cystitis and Urethritis Pyelonephritis Inflammatory Disorders Glomerulonephritis (Acute Poststreptococcal Glomerulonephritis) Nephrotic Syndrome (Nephrosis) Urinary Tract Obstructions Urolithiasis (Calculi, or Kidney Stones) Hydronephrosis Tumors Renal Cell Carcinoma Bladder Cancer Vascular Disorders Nephrosclerosis Congenital Disorders Adult Polycystic Kidney Wilms Tumor (Nephroblastoma) Renal Failure Acute Renal Failure Chronic Renal Failure Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Compare the etiology, pathophysiology, and manifestations of cystitis and pyelonephritis. 2. Explain the development of acute poststreptococcal glomerulonephritis, as well as its signs and symptoms, including laboratory tests and possible complications. 3. Describe the etiology and significant manifestations of nephrotic syndrome. 4. Explain the common signs and symptoms of urinary tract obstruction. 5. List common causes of urinary calculi. 6. Explain how hydronephrosis develops and its effects on the kidney. 7. Describe the incidence and early signs of adenocarcinoma of the kidney, bladder cancer, and Wilms tumor. 8. Explain how nephrosclerosis affects (a) the kidney and (b) systemic blood pressure. 9. Describe the etiology, usual age at onset, manifestations, and outcome of adult polycystic disease. 10. Compare acute and chronic renal failure with regard to common causes, pathophysiology, signs and symptoms, and possible complications. 11. Explain how peritoneal dialysis or hemodialysis substitutes for a nonfunctioning kidney, including limitations of the therapy. L E A R N I N G O B J E C T I V E S anasarca anuria azotemia calculi dialysis dialysate dysuria frequency glucosuria hematuria micturition nidus nocturia oliguria osteodystrophy polyuria proteinuria pyuria renal colic retroperitoneally trigone ultrafiltration urgency K E Y T E R M S C H A P T E R 18 Urinary System Disorders CHAPTER 18 Urinary System Disorders 489 Reabsorption is one process that takes place in the tubules. In the proximal convoluted tubule, most of the water is reabsorbed into the blood in the peritubular capil- laries, along with glucose and other nutrients and some electrolytes. Reabsorption of nutrients and electrolytes involves the use of active transport (eg, sodium ions), which requires carrier molecules and an energy source. Sodium absorption may be linked to the cotransport of other molecules (eg, glucose or amino acids with Na+). Anions such as chloride may be reabsorbed by electrochemical gradient or by cotransport with Na+. If a substance such as glucose is present in excessive amounts in the filtrate, there are insufficient carrier molecules in the tubules for complete reabsorption into the blood in the peritubular capillaries. Therefore the excess glucose is present in the urine. This limit on reabsorption is called the transport or tubular maximum (eg, approximately 310 mg/min for glucose). Thus per- sistent glucosuria (the presence of glucose in urine) is an indication of hyperglycemia associated with diabetes mellitus. Water is reabsorbed by osmosis. As the filtrate progresses through the loop of Henle and the distal convoluted tubule, electrolytes and water are adjusted to the body’s current needs. Hormones control the reabsorption of fluid and elec- trolytes (see Chapter 2): • Antidiuretic hormone from the posterior pituitary controls the reabsorption of water by altering the permeability of the distal convoluted tubule and col- lecting duct. • Aldosterone, secreted by the adrenal cortex, controls sodium reabsorption and water by exchanging sodium ions for potassium or hydrogen ions in the distal convoluted tubule. • Atrial natriuretic hormone from the heart is the third hormone controlling fluid balance by reducing sodium and fluid reabsorption in the kidneys. Concurrently the acid–base balance of the blood is maintained, with removal of excess acids and replacement of buffers such as bicarbonate (see Chapter 2). Review of the Urinary System The functions of the urinary system are: • Removal of metabolic wastes (nitrogenous and acidic) • Removal of hormones, drugs, and other foreign material from the body • Regulation of water, electrolytes, and acid–base balance in the body • Secretion of erythropoietin • Activation of vitamin D • Regulation of blood pressure through the renin– angiotensin–aldosterone system THINK ABOUT 18.1 a. Explain the function of erythropoietin and the effects of a deficit of this hormone. b. Explain the function of vitamin D and the possible effects of a deficit of this vitamin. Structures and Anatomy Kidneys The two kidneys are bean-shaped structures, each the size of a fist, located behind the peritoneum (that is, retroperitoneally) on the posterior abdominal wall. The kidneys are covered by a fibrous capsule and are embedded in fat, with the superior portion also protected by the lower ribs (Fig. 18.1). Inside each kidney is the cortex, or outer layer, in which the majority of the glomeruli are located, and the medulla, or inner section of tissue, which consists primarily of the tubules and collecting ducts. Inside the medulla lie the renal pelvis and calyces, through which urine flows into the ureter (Fig. 18.2). Each kidney consists of over a million nephrons, the functional units of the kidney (Fig. 18.3). The renal corpuscle consists of Bowman’s capsule (glomerular capsule), which is the blind end of the proximal convo- luted tubule. This capsule surrounds a network of capil- laries, called the glomerulus or glomerular capillaries. These form the filtration unit for the blood. During filtration, a large volume of fluid, including wastes, nutrients, electrolytes, and other dissolved substances, passes from the blood into the tubule. Cells and protein remain in the blood (Table 18.1). When the filtration pressure increases, more filtrate forms and more urine is produced. The filtrate flows into the tubules. The tubule consists of three parts: the proximal convoluted tubule, the loop of Henle, and the distal convoluted tubule. Here reabsorption of essential nutrients, water, and elec- trolytes takes place and secretion of certain wastes and electrolytes occurs. The collecting ducts transport the urine to the renal pelvis. TABLE 18.1 Composition of Blood, Filtrate, and Urine Substance Blood Filtrate Urine Water (L) 180 180 1.4 Cells Yes No No Glucose (mg/L) 1000 1000 0 Protein (mg/L) 40,000 0–trace 0–trace Urea (mg/L) 260 260 18,000 Na+ (mEq/L) 142 142 128 K+ (mEq/L) 5 5 60 HCO3− (mEq/L) 28 28 14 490 SECTION III Pathophysiology of Body Systems THINK ABOUT 18.2 Which of the following substances does the body normally retain? Which does it normally excrete? (1) glucose, (2) sodium ions, (3) bicarbonate ions, (4) acids A L P R S R I L S L I R Left kidney Inferior vena cava Abdominal aorta Common iliac artery and vein Renal vein Renal artery Spleen Twelfth rib Adrenal gland Liver Right kidney Ureter Urinary bladder Urethra A Eleventh rib Twelfth rib Right kidney Spinous process of fourth lumbar vertebra Spinous process of first lumbar vertebra Lower edge of pleura Left kidney Muscle Spinous process of vertebra Renal artery Abdominal aorta Peritoneal cavity Renal fat pad Peritoneum Left kidney Renal vein Inferior vena cava B FPO C Liver Stomach Spleen Left kidney Lienorenal ligament Gastrosplenic ligament Lesser sac Greater sac Hepatic artery Bile duct Portal vein Inferior vena cava Epiploic foramen Falciform ligament Lesser omentum Aorta Visceral peritoneum Parietal peritoneum Retroperitoneum FIG. 18.1 Location of Urinary System Organs. A, Anterior view of the urinary organs with the peritoneum and visceral organs removed. B, Surface markings of the kidneys, eleventh and twelfth ribs, spinous processes of L1 to L4, and lower edge of the pleura (posterior view). C, Horizontal (transverse) section of the abdomen showing the retroperitoneal position of the kidneys. (A From Barbara Cousins. B From Abrahams P, Marks S, Hutchings R: McMinn’s Color Atlas of Human Anatomy, ed 5, Philadelphia, 2003, Mosby, C From Kelley L, Petersen C: Sectional Anatomy for Imaging Professionals, ed 3, St. Louis, 2013, Elsevier, Mosby.) Active secretion of some wastes and drugs from the blood into the filtrate also occurs in the distal tubule (Fig. 18.4). The organization of the nephrons within a kidney is complex and must be maintained for effective renal function. The blood vessels and the collecting tubules and ducts for the filtrate must be functionally integrated to fulfill the purpose of the system. Scar tissue can interfere with blood or filtrate flow and thus can lead to secondary damage and progressive destruction of the kidney. Renal Arteries and Veins A large amount of blood enters and leaves the kidney at the hilum through the renal artery and vein. Twenty percent to 25% of the cardiac output enters the renal arteries from the aorta; thus the kidneys are processing a large volume of blood at any given time. Each renal artery passes through the renal pelvis, dividing several times during its passage (see Fig. 18.2). No anastomoses, or junctions, exist between the interlobar and arcuate arteries, meaning that no alternative blood supply is CHAPTER 18 Urinary System Disorders 491 determines the glomerular filtration rate (GFR). By constricting or dilating the arterioles, the amount of blood in the glomerular capillaries is adjusted, and filtration is normally maintained regardless of fluctuations in the systemic blood pressure. For instance, if the afferent arteriole is dilated and the efferent arteriole is constricted, hydrostatic pressure in the glomerular capillaries will increase and GFR will increase (Fig. 18.5). The degree of constriction in the arterioles is controlled primarily by three factors: local autoregulation, the sym- pathetic nervous system (SNS), and the renin–angiotensin mechanism. 1. Autoregulation refers to the small, local reflex adjust- ments in the diameter of the arterioles that are made in response to minor changes in blood flow in the kidneys. This adjustment maintains the normal filtra- tion rate. 2. The SNS increases vasoconstriction in both arterioles when stimulated. 3. Renin is secreted by the juxtaglomerular cells in the kidney when blood flow in the afferent arteriole is reduced for any reason (see Fig. 18.5). Through a series of enzyme reactions, renin acts on the plasma protein angiotensinogen to produce angiotensin I, and as the blood passes through the lung, angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II, which is a powerful systemic vasoconstrictor. If blood flow in the kidney is seriously impaired, as it is when blood pressure drops, both the SNS and the renin–angiotensin mechanism are activated to restore blood pressure and blood flow to vital areas. available to a lobe of the kidney that is deprived of its blood supply, perhaps by an embolus (eg, a blood clot). Any obstruction to blood flow would therefore cause that particular lobe to undergo necrosis and infarction. The interlobar arteries divide several times, eventually forming the afferent arterioles, which supply the glomerular capillaries (see Fig. 18.3). The arrangement of blood vessels in the kidney is unique because the blood from the glomerular capillaries then flows into another arteriole, the efferent arteriole, and then into a second capillary network, the peritubular capillaries or vasa recta. Therefore two arterioles and two sets of capillaries are included in each nephron. This blood supply also provides nourish- ment to the renal tissues. Note that the kidney tubules are last to receive nutrients. To summarize the renal blood flow: renal artery → interlobar artery → arcuate artery → interlobular artery → afferent arteriole → glomerular capillaries → efferent arteriole → peritubular capillaries → interlobular vein → arcuate vein → interlobar vein → renal vein. The names of the blood vessels match the structures. S L I M Capsule (fibrous) Cortex Minor calyces Major calyces Renal pelvis Fat Medulla Ureter Medullary pyramid Renal papilla of pyramid Renal column Interlobular arteries Renal sinus Hilum FIG. 18.2 Internal Structure of the Kidney. Coronal section of the right kidney in an artist’s rendering. (Adapted from Brundage DJ: Renal Disorders. Mosby’s Clinical Nursing Series, St. Louis, 1992, Mosby.) THINK ABOUT 18.3 a. Trace the movement of a glucose molecule in the renal artery through the kidney and into the renal vein, naming each structure and process in sequence. b. Trace the progress of an acid waste from the distal convoluted tubule to the point of excretion. The purpose of the dual arterioles is to control the pressure in the glomerular capillaries and consequently the glomerular filtration pressure. This pressure THINK ABOUT 18.4 a. Explain the effect on hydrostatic (blood) pressure within the glomerular capillaries and on filtration if the afferent arteriole is severely constricted. b. Explain the effect of prolonged severe vasoconstriction on the renal tissue. c. Explain the effect of renin on filtration. d. Explain the change in filtration if excess glucose is present in the blood entering the kidney. Blood pressure is closely related to kidney function, and frequently it is elevated with renal disease. When the blood flow or blood pressure in the afferent arteriole decreases for any reason, the renin–angiotensin–aldosterone triad is stimulated. Angiotensin not only causes systemic vasoconstriction; it also stimulates the secretion of aldosterone. This hormone increases the reabsorption of sodium and water to increase blood volume, thus increas- ing blood pressure. Serum renin levels can determine whether this mechanism is a factor in hypertension (high blood pressure), in which case renin-blocking drugs (beta-adrenergic blocking drugs) can be prescribed (see Chapter 12). 492 SECTION III Pathophysiology of Body Systems Bowman’s capsule Filtrate flow Glomerulus Proximal convoluted tubule Distal convoluted tubule Collecting duct Loop of Henle Urine to renal pelvis A B C Urine flow BOWMAN’S CAPSULE AND TUBULES BLOOD SUPPLY TO A NEPHRON COMPLETE NEPHRON Arcuate artery Peritubular capillary Efferent arteriole Arcuate vein Glomerular capillaries (glomerulus) Efferent arteriole Peritubular capillaries Arcuate artery Arcuate vein Distal convoluted tubules Loop of Henle Proximal convoluted tubule Glomerular capillaries Afferent arteriole Interlobular artery Juxtaglomerular cells Collecting duct Afferent arteriole FIG. 18.3 The Nephron. A, Glomerulus and tubules. B, Blood supply to the nephron. C, Complete nephron. When the filtrate has been processed in the tubules and collecting ducts, it is considered to be urine. Urine is transported through the collecting ducts to the renal calyces and pelvis and then into the ureters, where peri- staltic movements assist its flow to the urinary bladder. The renal pelvis, calyces, ureters, and bladder are lined with transitional epithelium that is not permeable to water and can resist the irritation of constant contact with urine. The bladder is composed of smooth muscle that falls in rugae, or folds, to form an expandable sac. It is located CHAPTER 18 Urinary System Disorders 493 the urethra, and this continuous mucosa facilitates the spread of infection through the urinary tract (an ascending infection). Micturition (urination, voiding) occurs when a reflex is stimulated by increased pressure as the bladder distends. The reflex is transmitted by parasympathetic nerves extending to the sacral spinal cord. If the time is appropriate, under voluntary control, the external and internal sphincters of the bladder and the pelvic diaphragm relax while the bladder muscle contracts, emptying the bladder. Incontinence and Retention Incontinence, or the loss of voluntary control of the bladder, has many causes. Young children must learn voluntary control as the nervous system matures. Enuresis defines involuntary urination by a child after age 4 to 5, when bladder control can be expected. Most children have nocturnal enuresis only. The majority of cases Filtrate Proximal convoluted tubule Distal convoluted tubule Collecting duct Urine 1. FILTRATION Afferent arteriole Efferent arteriole Glomerular capillaries Peritubular capillaries 2. REABSORPTION Vein Juxtaglomerular cells CELLS AND PROTEIN REMAIN IN BLOOD WATER Na+ WATER WATER (by osmosis) Na+ Cl- WATER (ADH effect) 3. REABSORPTION SECRETION H+ DRUGS K+ Na+ B- (Aldosterone effect) AA GLUCOSE KEY AA Amino acids B- Bicarbonate ions Cl- Chloride ions H+ Hydrogen ions K+ Potassium ions Na+ Sodium ions FIG. 18.4 Schematic illustration of formation of urine. retroperitoneally in the pelvic cavity. The bladder has openings for the two ureters to bring urine in as well as an outlet for the urethra through which urine flows out of the body. The triangular section outlined by these three openings is called the trigone (see Fig. 18.1). The female urethra is 3 to 4 cm long. It is relatively short and wide and opens onto the perineum anterior to the vagina and anus. The proximity of the urethra to these two sources promotes infection of the bladder in women. The male urethra is about 20 cm long and passes through the penis. At the base of the male bladder is the prostate gland, which plays a role in semen production and frequently is hypertrophied in older men, obstructing urine flow (see Chapter 19 for reproductive disorders). During orgasm in the male, a sphincter closes off the flow of urine and semen is ejaculated through the urethra. The mucosa lining the urinary tract is continuous through the urethra, bladder, and ureter to the pelvis of the kidney. Organisms can easily enter the system through 494 SECTION III Pathophysiology of Body Systems body. Catheters are common sources of infection in the urinary tract because they are irritating to the tissue and, when inserted, may be a means of introducing bacteria directly into the bladder if sterile technique is not used. Catheters prevent kidney damage due to backup of urine, collect urine, and prevent skin breakdown in the incon- tinent client. appear to be related to factors such as a developmental delay, sleep pattern, or psychosocial aspects rather than to a physical defect. Stress incontinence occurs when increased intraabdominal pressure forces urine through the sphincter. This can occur with coughing, lifting, or laughing, but occurs more frequently in women after the urogenital diaphragm has become weakened by multiple pregnancies or age. Overflow incontinence results from an incompetent bladder sphincter. In the elderly, a weakened detrusor muscle may prevent complete emptying of the bladder, leading to frequent emptying and incontinence. Spinal cord injuries or brain damage frequently cause a neurogenic bladder, which may be spastic or flaccid, due to interference with central nervous system (CNS) and autonomic nervous system control of the bladder emptying. Retention is an inability to empty the bladder. It may be accompanied by overflow incontinence. Note that a spinal cord injury at the sacral level blocks the micturition reflex, resulting in retention of urine or failure to void. Retention also may occur after anesthesia, either general or spinal. Inability to control urine flow may be managed by wearing pads or briefs that contain the urine. A catheter is a tube inserted in the urethra that drains urine from the bladder to a collecting bag outside the NORMAL FILTRATION Glomerular capillaries Afferent arteriole Efferent arteriole Bowman’s capsule Filtrate to proximal convoluted tubule A B C D Increased filtrate Increased glomerular hydrostatic pressure EFFERENT ARTERIOLE: CONSTRICTION Vasoconstriction– decreased blood flow Vasodilation–increased blood flow Increased filtrate AFFERENT ARTERIOLE: DILATION Vasoconstriction–decreased blood flow Decreased filtrate Low glomerular hydrostatic pressure AFFERENT ARTERIOLE: CONSTRICTION Increased glomerular hydrostatic pressure FIG. 18.5 Control of Glomerular Filtration Rate (GFR). A, Normal filtration. B, Afferent arteriole: dilation. C, Efferent arteriole: constriction. D, Afferent arteriole: constriction. THINK ABOUT 18.5 Locate the urinary bladder relative to the uterus and rectum in a woman. Briefly explain two possible implications of this location. Diagnostic Tests Urinalysis The constituents and characteristics of urine may vary with dietary intake, drugs, and the care with which a specimen is handled. Urine normally is clear and straw- colored and has a mild odor. Urine pH is in the range of 4.5 to 8.0. The following lists offer general guidelines CHAPTER 18 Urinary System Disorders 495 to common abnormalities noted in freshly voided speci- mens. An “old” specimen will not provide accurate information. See the inside front cover of this book for normal values. Appearance • Cloudy—may indicate the presence of large amounts of protein, blood cells, or bacteria and pus • Dark color—may indicate hematuria (blood), excessive bilirubin content, or highly concentrated urine • Unpleasant or unusual odor—may indicate infection or result from certain dietary components or medications Abnormal Constituents (Present in Significant Quantities) • Blood (hematuria)—small (microscopic) amounts of blood are often associated with infection, inflammation, or tumors in the urinary tract; large numbers of red blood cells (gross hematuria) indicate increased glo- merular permeability or hemorrhage in the tract • Protein (proteinuria, albuminuria)—indicates the leakage of albumin or mixed plasma proteins into the filtrate due to inflammation and increased glomerular permeability • Bacteria (bacteriuria) and pus (pyuria)—indicate infection in the urinary tract (Fig. 18.6A) • Urinary casts (microscopic-sized molds of the tubules, consisting of one or more cells, bacteria, protein, and so on)—indicate inflammation of the kidney tubules (see Fig. 18.6B) • Specific gravity indicates the ability of the tubules to concentrate the urine; a very low specific gravity (dilute urine) usually is related to renal failure (assuming normal hydration) • Glucose and ketones (ketoacids) are found in the urine when diabetes mellitus is not well controlled (see Chapter 16) C B A FIG. 18.6 A, Urinalysis—smear shows infection with heavy purulence and presence of gram-negative and gram-positive organ- isms (E. coli and Enterococcus faecalis) (density of microbes 105/mL urine). B, Urinalysis—red blood cell cast. C, Urinalysis—calcium oxalate crystals in the urine. (A From Mahon CR, Manuselis G: Textbook of Diagnostic Microbiology, ed 2, Philadelphia, 2000, Saunders. B and C From Stepp CA, Woods M: Laboratory Procedures for Medical Office Personnel, Philadelphia, 1998, Saunders.) THINK ABOUT 18.6 a. Explain the presence of the abnormal constituents of urine. b. Explain why hematuria and proteinuria reflect a glomerular problem rather than a tubular problem in the kidney. Blood Tests Like most other diseases, urinary tract disorders produce abnormalities that can be detected by various blood tests. Some of the more commonly used tests and implications are described here. • Elevated serum urea (blood urea nitrogen [BUN]) and serum creatinine—indicate failure to excrete nitrogen wastes (resulting from protein metabolism) due to decreased GFR • Metabolic acidosis (decreased serum pH and decreased serum bicarbonate)—indicates decreased GFR and failure of the tubules to control the acid–base balance (see Chapter 2) 496 SECTION III Pathophysiology of Body Systems Diuretic Drugs Diuretics, commonly referred to as “water pills,” are used to remove excess sodium ions and water from the body, therefore increasing the excretion of water through the kidneys and urinary output. In turn, this reduces fluid volume in the tissues (edema) and blood. They are prescribed for many disorders other than renal disease, including hypertension, edema, congestive heart failure, liver disease, and pulmonary edema (see Chapter 12). There are several mechanisms by which urine volume can be increased. A few examples of diuretic drugs are listed in Table 18.2. The most commonly used drug group inhibits sodium chloride reabsorption in the tubules. Examples of this group include hydrochlorothiazide (Hydro Diuril), a mild diuretic, and furosemide (Lasix), which is more potent. Hydrochlorothiazide is useful because it has an additional antihypertensive action, the mechanism for which is unknown. The major side effect of these drugs is excessive loss of electrolytes, which may cause muscle weakness or cardiac arrhythmias. Because these drugs may cause marked loss of potassium, patients may require dietary supplements such as bananas or replacement by potassium chloride tablets. Another group of diuretics, the potassium-sparing type (eg, spironolactone [Aldactone]), may be given in combination with thiazides to minimize the risk of hyperkalemia or hypokalemia (high or low serum potassium levels). Many combinations of diuretics with other drugs, such as hydrochlorothiazide/propranolol or hydrochlorothiazide/ quinapril, are available to treat hypertension or heart failure. These drugs are usually administered in the morning because they often cause urinary frequency for a period of time (the need to urinate often). Patients taking diuretics should be observed for dizziness or orthostatic hypotension when moving from a supine to an upright position. Many individuals also have xerostomia, or dry mouth, with increased risk of dental caries. • Anemia (low hemoglobin level)—indicates decreased erythropoietin secretion and/or bone marrow depres- sion due to accumulated wastes • Electrolytes—depend on the related fluid balance; that is, retention of fluid if GFR is decreased may result in a dilution effect, and laboratory values are therefore not a true reflection of renal status; however, abnormal levels may still cause clinical effects and require monitoring and treatment • Antibody level—antistreptolysin O (ASO) or antistrep- tokinase (ASK) titers are used for diagnosis of post- streptococcal glomerulonephritis • Renin levels—indicate a cause of hypertension Other Tests • Culture and sensitivity studies on urine specimens are used to identify the causative organism in a urinary infection and select drug treatment (see Chapter 6). • Clearance tests, such as creatinine or insulin clearance, or radioisotope studies are used to assess GFR. • Radiologic tests, such as radionuclide imaging, angi- ography, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and intravenous pyelography (IVP), may be used to visualize the structures and any abnormalities in the urinary system (see Ready Reference 5). • Cystoscopy visualizes the lower urinary tract and may be used in performing a biopsy or removing kidney stones. • Biopsy may be used to acquire tissue specimens to allow microscopic examination of suspicious lesions in the bladder or kidney. THINK ABOUT 18.7 What is the normal pH range for the blood and urine? What serum and urine pH would indicate that acidosis had developed? TABLE 18.2 Examples of Diuretic Drugs Name of Drug Action Use hydrochlorothiazide (Hydro DIURIL) Inhibits reabsorption of Na+ and water in distal tubule (thiazide type) Increases excretion of fluid in hypertension, congestive heart failure (CHF), edema furosemide (Lasix) Decreases reabsorption of Na+ and water in the proximal and distal tubules and the loop of Henle (a loop diuretic) Reduces body fluids in hypertension, CHF, edema, renal disease, liver disease spironolactone (Aldactone) Aldosterone antagonist, blocks reabsorption of Na+ and K+ in distal tubule (potassium-sparing diuretic) Decreases Na+ and water in body, but conserves K+ in CHF, hypertension, liver disease acetazolamide (Diamox) Carbonic anhydrase inhibitor blocks reabsorption of Na+ and secretion of H+ Reduces fluids in CHF, glaucoma mannitol (intravenous) Increases osmotic pressure and water in the filtrate, reduces Na+ absorption (osmotic diuretic) Cerebral edema, glaucoma CHAPTER 18 Urinary System Disorders 497 transplants, it may be required if rejection occurs or between transplants (see Chapter 7). Dialysis is a demand- ing procedure for both the patient and the family. Diet, particularly protein and electrolytes, and fluid intake are severely restricted. There are two forms of dialysis: hemodialysis and peritoneal dialysis (Fig. 18.7). Hemodialysis is provided in a hospital, dialysis center, or at home with special equipment and training. During the procedure, the patient’s blood moves from an implanted shunt or catheter Dialysis Dialysis provides an “artificial kidney,” which can be used to sustain life after the kidneys fail. (There is con- siderable reserve in the renal system; an individual can function normally with half of one kidney.) Dialysis is used to treat someone who has acute renal failure until the primary problem has been reversed, or it can be used for patients in end-stage renal failure, perhaps until a transplant becomes available. In people with renal A C B No movement of cells and protein Diffusion Hi Lo concentration Osmosis and hydrostatic pressure Blood Dialysate Water P P P Na+ H+ H+ B B B BB B Na+H+ N K+ K+ K+ N Na+ Na+H+ N N H+K+ N P Semipermeable membrane Blood (Blood enters) (Blood leaves) Dialysate P P Na+ H+ B B B B B B Na+ H+ K+ K+ N Na+ H + N H+ N Time H+ K+ K+ KEY Blood cells Protein Acids Nitrogen wastes (urea) Bicarbonate ion (buffer) Potassium ion Sodium ion H+ N B End of dialysis Beginning dialysis Water K+ Na+ PRINCIPLES OF DIALYSIS Clean blood to patient’s venous circulation Heparin pump Bubble detector BloodTubing pump Dialysis fluid Proportioning pump Dialysis fluid concentrate Toxins diffuse through membrane Quality control Temperature Conductivity From water source To drain Blood leak detector Toxin-laden blood from patient’s arterial circulation Membrane DIALYZER Dialysate Effluent FIG. 18.7 A, Typical hemodialysis system. B, Peritoneal dialysis through an abdominal catheter. C, Principles of dialysis. (A and B From deWitt S, Kumagi C: Medical Surgical Nursing: Concepts and Practice, ed 2, St. Louis, 2013, Elsevier, Saunders.) 498 SECTION III Pathophysiology of Body Systems Disorders of the Urinary System Urinary Tract Infections Urinary tract infections (UTIs) are extremely common. It is estimated that 6 million Americans are affected annually. Urine generally provides an excellent medium for growth of microorganisms. Cystitis and urethritis are considered infections of the lower urinary tract, whereas pyelonephritis is an upper tract infection (Fig. 18.8). Most infections are ascending, arising from organisms in the perineal area and traveling along the continuous mucosa in the urinary tract to the bladder and then along the ureters to the kidneys. Occasionally pyelonephritis results from a blood-borne infection. The common causative organism is Escherichia coli, which is one of the resident flora of the intestine (approxi- mately 85%). The virulent forms of E. coli can adhere to the mucosa of the bladder by means of fimbriae or pili and therefore are not washed out when the bladder empties. Other organisms associated with UTIs include Klebsiella, Proteus, Enterobacter, Citrobacter, Serratia, Pseu- domonas, Enterococcus, coagulase-negative Staphylococcus, Chlamydia, and Mycoplasma. In men, urethritis and prostatitis may accompany lower tract infections. ■ Etiology Women are anatomically more vulnerable to infection than men because of the shortness and width of the urethra, its proximity to the anus, and the frequent irrita- tion to the tissues. The irritation may be caused by sexual activity, baths, and the use of some feminine hygiene products. Improper hygiene practices during defecation or menstruation also increase risk. Older men with prostatic hypertrophy and retention of urine frequently develop infections. Because the male reproductive tract shares some of the structures of the urinary tract, any infection of the prostate or testes is likely to extend to the urinary structures. Congenital abnormalities are a common cause of infection in children, particularly where obstructions to flow or reflux are present. The elderly are at increased risk because of the tendency toward incomplete emptying, reduced fluid intake, impaired blood supply to the bladder, and immobility. Common predisposing factors for UTIs in both men and women include incontinence with incomplete emptying of the bladder, retention of urine in the bladder, and any obstruction to urine flow, which tends to result in growth of organisms because bacteria are not promptly THINK ABOUT 18.8 Explain why a dialysis solution would initially be low in urea but high in bicarbonate content. in an artery, often in the arm, through a tube to a machine where the exchange of wastes, fluid, and electrolytes takes place. A semipermeable membrane separates the patient’s blood from the dialysis fluid (dialysate), and the constituents move between the two compartments. For example, wastes move from blood to the dialysate and bicarbonate ion moves into the blood from the dialysate. Blood cells and protein remain in the blood, unable to pass through the semipermeable membrane. Movement occurs by ultrafiltration, diffusion (by a concentration gradient), and osmosis. After the exchange has been completed, the blood is returned to the patient’s vein. Heparin or another anticoagulant is administered to prevent clotting, requiring monitoring of blood-clotting times. Hemodialysis is usually required three times a week, each session lasting about 3 to 4 hours. The patient may feel uncomfortable during the session because fluid and electrolyte balances change quickly, but usually he or she feels much better after the treatment. The feeling of well-being then dissipates gradually as wastes accumulate before the next treatment. Dialysis has potential complications. The shunt may become infected, or blood clots may form. Eventually the blood vessels involved at the shunt become sclerosed or damaged, and a new site must be selected. Patients on dialysis have an increased risk of infection by the hepatitis B or C virus or human immunodeficiency virus. Peritoneal dialysis can be administered in a dialysis unit or at home. It may be done at night while the patient sleeps or continuously while the patient is ambulatory (this is called continuous ambulatory peritoneal dialysis). In this procedure, the peritoneal membrane, which is very large in surface area, thin, and highly vascular, serves as the semipermeable membrane. A catheter with entry and exit points is implanted in the peritoneal cavity. The dialyzing fluid (diasylate) is instilled through the catheter into the cavity and remains there, allowing the exchange of wastes and electrolytes to occur by diffusion and osmosis. Then the dialysate is drained from the cavity by gravity into a container. This process requires more time than hemodialysis. However, the more continuous exchange process prevents excessive and sudden changes in fluid and electrolyte levels in the body, and the components of a dialysis solution can be adapted to individual needs. The major complication of peritoneal dialysis is the potential for an infection resulting in peritonitis. Newer methods under investigation make use of charcoal absorbent and ultrafiltration techniques to prevent infec- tion or inflammation. Prophylactic antibiotics are given with either form of dialysis whenever there is a risk of transient bacteremia; for example, with any invasive procedure or tissue trauma. Any additional problem occurring in the patient, such as infection, may also alter dialysis requirements. Caution is required with many drugs because toxic levels can build up in the blood. CHAPTER 18 Urinary System Disorders 499 flushed out of the bladder by voiding. Pregnancy, scar tissue, and renal calculi (kidney stones) all contribute to infection because the urine and any contaminants do not flow freely through and out of the system. Infection may also result from decreased host resistance present with immunosuppression or diabetes mellitus (vascular impairment and glucosuria). Direct contamination of the urethra and bladder may result from fecal incontinence. As mentioned, instruments or catheters may directly introduce bacteria into the bladder and frequently traumatize the bladder wall, breaking the barrier to infection. PYELONEPHRITIS Ureter Purulent exudate CYSTITIS Bladder Urethra Ascending infection from intestine Inflammation or trauma of mucosa Residual urine Prostatic hypertrophy VESICOURETERAL REFLUX Bladder empties Residual urine Urine reflux Defective valve Stasis of urine IMMOBILITY BLOOD-BORNE ORGANISMS OBSTRUCTION E. coli Abscess and necrosis FIG. 18.8 Causes of infection in the urinary tract. THINK ABOUT 18.9 a. List several factors that would predispose a pregnant woman with diabetes to cystitis. b. Why does male anatomy make it likely that a reproductive system infection may extend into the urinary system? Cystitis and Urethritis ■ Pathophysiology With cystitis, the bladder wall, and with urethritis, the urethra are inflamed, red, swollen, and in some cases, 500 SECTION III Pathophysiology of Body Systems • Amoxicillin • Fosfomycin (which is prescribed for pregnant women) The patient is encouraged to substantially increase fluid intake. In some cases pockets of infection persist in the bladder. Therefore it is essential to follow up on the course of antibiotics with urinalysis 4 to 6 weeks after the course of drugs has been completed to ensure that the infection has been totally eradicated. Chronic cystitis tends to be asymptomatic and therefore can persist and spread to the kidneys, where it causes more damage. The infection tends to recur unless the predisposing factors are removed. Chronic pyelonephritis often causes insidious damage, with areas of obstructive scar tissue that promote continued infection and eventually cause chronic renal failure. Cranberry juice may be recommended as a prophylactic measure. The tannin content appears to reduce the capability of E. coli to adhere to the bladder mucosa. ulcerated. The bladder wall is irritated and hyperreactive, and bladder capacity is usually reduced. ■ Signs and Symptoms In some cases, the manifestations are very mild and may be unnoticed. • Pain is common in the lower abdomen. • Dysuria (painful urination), urgency (need to void immediately), frequency (short intervals between voiding), and nocturia (need for urination during the sleep period) occur as the inflamed bladder wall is irritated by urine. • Systemic signs of infection may be present (fever, malaise, nausea, and leukocytosis). • The urine often appears cloudy and has an unusual odor. • Urinalysis indicates bacteriuria (the presence of bacteria in the urine), pyuria, and microscopic hematuria (see Fig. 18.6A). Pyelonephritis ■ Pathophysiology One or both kidneys may be involved. The infection extends from the ureter into the kidney, involving the renal pelvis and medullary tissue (tubules and interstitial tissue). Purulent exudate fills the kidney pelvis and calyces, and the medulla is inflamed. Abscesses and necrosis can be seen in the medulla and may extend through the cortex to the surface of the capsule. If the infection is severe, the exudate can compress the renal artery and vein and obstruct urine flow to the ureter. Bilateral obstruction is likely to result in acute renal failure (see Fig. 18.16C, presented later in the chapter). Recurrent or chronic infection can lead to fibrous scar tissue forming over a calyx, leading to loss of tubule function and hydronephrosis. If severe and bilateral, it can eventually cause chronic renal failure. ■ Signs and Symptoms The signs of cystitis, such as dysuria, are also present, because infection is present in both kidneys and bladder. Pain associated with renal disease is usually a dull aching pain in the lower back or flank area, resulting from inflam- mation that stretches the renal capsule. Systemic signs are usually more marked in pyelonephritis. Urinalysis results are similar to those for cystitis except that urinary casts, consisting of leukocytes or renal epi- thelial cells, are present, reflecting the involvement of the renal tubules. ■ Treatment UTIs are treated promptly with antibacterial drugs such as: • Trimethoprim-sulfamethoxazole (Bactrim, Cotrim, Septra) • Nitrofurantoin (Furadantin) • Cephalosporins (Keflex, Duricef) • Carbapenems (Doribax) THINK ABOUT 18.10 List the signs and symptoms of pyelonephritis that indicate that infection is present and mark those indicating that kidney involve- ment (local or systemic) exists. Inflammatory Disorders Glomerulonephritis (Acute Poststreptococcal Glomerulonephritis) There are many forms of glomerulonephritis. A representa- tive form of glomerular or nephritic disease is acute poststreptococcal glomerulonephritis (APSGN), which follows streptococcal infection with certain strains of group A beta-hemolytic Streptococcus. These infections usually originate as upper respiratory infections, middle ear infections, or “strep throat.” Certain strains of Staphy- lococcus are occasionally responsible for initiating the immune disorder in the kidney. Acute glomerulonephritis develops 10 days to 2 weeks after the antecedent infection. Primarily APSGN affects children between the ages of 3 and 7 years, especially boys. ■ Pathophysiology The antistreptococcal antibodies, formed as usual from the earlier streptococcal infection, create an antigen– antibody complex (type III hypersensitivity reaction) that lodges in the glomerular capillaries and activates the complement system to cause an inflammatory response in the glomeruli of both kidneys (Fig. 18.9). (See Chapter 7 for a review of the immune response.) This leads to increased capillary permeability and cell proliferation (Fig. 18.10) and results in leakage of some protein and large numbers of erythrocytes into the filtrate. The specific mechanisms of damage are not totally clear, but immu- noglobulin G and C3 (complement) are present in glo- merular tissue and serum C3 is reduced. CHAPTER 18 Urinary System Disorders 501 ■ Diagnostic Tests • Blood tests show elevated serum urea and creatinine as GFR decreases. • Blood levels of Anti-DNase B, streptococcal antibodies, ASO, and ASK are elevated. • Complement level is decreased. It is probably a causative factor in the inflammatory damage that occurs in the kidney. • Metabolic acidosis, with decreased serum bicarbonate and low serum pH, is present. • Urinalysis confirms the presence of proteinuria, gross hematuria, and erythrocyte casts (see Fig. 18.6B). ■ Treatment Sodium restrictions may apply, and in severe cases, protein and fluid intake is decreased. Drug treatment includes glucocorticoids to reduce the inflammation and antihy- pertensives to reduce high blood pressure. In most cases, recovery takes place with minimum residual damage, although it is important to prevent future exposure to streptococcal infection and recurrent inflammation due to another hypersensitivity reaction. In children, the edema usually recedes in 5 to 10 days and hypertension decreases in 2 to 3 weeks. Proteinuria When the inflammatory response is severe, the conges- tion and cell proliferation interfere with filtration in the kidney, causing decreased GFR and retention of fluid and wastes. Acute renal failure is possible if blood flow is sufficiently impaired. The decreased blood flow in the kidney is likely to trigger increased renin secretion, which leads to elevated blood pressure and edema (see Fig. 18.14, presented later in the chapter). Severe prolonged inflammation causes scarring of the kidneys. ■ Signs and Symptoms • The urine becomes dark and cloudy (“smoky” or “coffee-colored”) because of the protein and red blood cells that have leaked into it. • Facial and periorbital edema occur initially, followed by generalized edema as the colloid osmotic pressure of the blood drops and sodium and water are retained. • Blood pressure is elevated due to increased renin secretion and decreased GFR. • Flank or back pain develops as the kidney tissue swells and stretches the capsule. • General signs of inflammation are present, including malaise, fatigue, headache, anorexia, and nausea. • Urine output decreases (oliguria) as GFR declines. STREPTOCOCCAL INFECTION ANTIBODY FORMATION Several weeks later — elevated ASO and ASK titer ANTIGEN - ANTIBODY COMPLEX Deposits in glomerulus ACUTE INFLAMMATION AND DAMAGE INCREASED PERMEABILITY OF CAPILLARY CELL PROLIFERATIONGLOMERULUS SWELLING Hematuria Albuminuria CONGESTION—DECREASED GFR Oliguria and elevated serum urea STIMULATION OF RENIN SECRETION Elevated BP and edema Majority A few Some FULL RECOVERY ACUTE RENAL FAILURE DEATH CHRONIC GLOMERULONEPHRITIS (fibrosis) CHRONIC RENAL FAILURE FIG. 18.9 Development and course of poststreptococcal glomerulonephritis. 502 SECTION III Pathophysiology of Body Systems Nephrotic Syndrome (Nephrosis) The nephrotic syndrome is secondary to a number of renal diseases as well as to a variety of systemic disorders (eg, systemic lupus erythematosus, exposure to toxins or drugs). However, lipoid nephrosis, also known as minimal change disease, is a primary disease in young children ages 2 to 6 years. ■ Pathophysiology The pathogenesis is not well established, but the following sequence develops: 1. There is an abnormality in the glomerular capillaries and increased permeability that allows large amounts of plasma protein, primarily albumin, to escape into the filtrate. 2. This results in marked hypoalbuminemia with decreased plasma osmotic pressure and subsequent generalized edema. 3. Blood pressure may remain low or normal in many cases because of hypovolemia, or it may be elevated depending on angiotensin II levels. 4. The decreased blood volume also increases aldosterone secretion, leading to more severe edema. 5. The other significant components of nephrotic syn- drome are the high levels of cholesterol in the blood and lipoprotein in the urine. The cause of the hyper- lipidemia and lipiduria is not totally clear, although it appears to be related to the response of the liver to heavy protein loss. ■ Signs and Symptoms Urinalysis indicates marked proteinuria, lipiduria, and casts (fatty, epithelial, and hyaline). Cells may be present with certain primary diseases. Urine is often frothy. The significant sign of nephrosis is the massive edema (anasarca) associated with weight gain and pallor. This excessive fluid throughout all tissues impairs appetite (ascites), breathing (pleural effusion), and activity (swollen legs and feet). Skin breakdown and infection may develop because arterial flow and capillary exchange are impaired. and hematuria improve but often persist for some time. Prophylactic antibiotics may be needed. Postrecovery testing is recommended to ensure that chronic inflam- mation is not present. Some cases, particularly in adults, are not easily resolved. Acute renal failure occurs in approximately 2% of cases. Chronic glomerulonephritis develops in about 10%, which gradually destroys the kidneys through end-stage renal disease or uremia. NORMAL GLOMERULUS Capillary open — blood flow Endothelial cell MILD GLOMERULONEPHRITIS SEVERE GLOMERULONEPHRITIS Narrow capillary lumen — GFR decreases P P P P Swollen endothelial cell and membrane Immune complex deposits — inflammation RBC and protein leaks into filtrate — hematuria and proteinuria Cell proliferation Swollen cells Immune complex deposits — severe inflammation Little blood flow — oliguria = RBC = PROTEIN FIG. 18.10 Schematic representation of changes occurring in the nephron with acute poststreptococcal glomerulonephritis. THINK ABOUT 18.11 a. Explain the development of inflammation in the kidney with APSGN. b. Describe the signs of APSGN related to (1) increased glomerular permeability and (2) decreased GFR. THINK ABOUT 18.12 Compare the characteristics of the urine in a child with pyelo- nephritis, APSGN, or nephrotic syndrome. ■ Treatment Glucocorticoids such as prednisone are prescribed to reduce the inflammation in the kidney. Angiotensin- converting enzyme inhibitor drugs, such as ramipril, may decrease protein loss in the urine. Antihypertensive and antilipemic therapy may be required in some individuals. Nephrotic syndrome tends to recur and requires frequent monitoring and continued treatment. Recurrences may be treated with cytotoxic therapies such as cyclophos- phamide. When administered long term to children, glucocorticoids have significant negative effects on growth CHAPTER 18 Urinary System Disorders 503 because of stasis of urine resulting in chemical changes in the urine (see Chapter 25). Increasing fluid intake (at least eight glasses of water per day) can assist in removing small stones quickly from the urinary tract. Stones usually cause manifestations only when they obstruct the flow of urine (eg, in the ureter). Calculi may lead to infection because they cause stasis of urine in the area and irritate the tissues. This may be an early indica- tion of calculi formation. When located in the kidney or ureter, calculi may cause the development of hydronephrosis, with dilation of calyces and atrophy of renal tissue related to the back pressure of urine behind the obstructing stone (Fig. 18.12). ■ Etiology Approximately 75% of calculi are composed of calcium salts, with the remainder consisting primarily of uric acid (a breakdown product of purine nucleotides) or urates, struvite (magnesium ammonium phosphate), or cystine (rare), depending on the predisposing factor. Calculi should be examined and urinalysis completed to determine the content of the stones and the predispos- ing factors. Calcium stones (phosphate, oxalate, or carbonate) form when calcium levels in the urine are high due to hyper- calcemia, perhaps due to a parathyroid tumor or other metabolic disorder (see Fig. 18.6C). The solubility of calcium salts and uric acid also varies with the pH of the urine. Calcium stones form readily when the urine (see Chapter 5). Sodium intake may be restricted, but protein intake is usually increased. Urinary Tract Obstructions In older men, the urinary tract is frequently obstructed by benign prostatic hypertrophy or prostatic cancer. These topics are discussed in Chapter 19. Common causes of obstruction in men and women include tumors, inflam- mation, scarring, stenosis, congenital defects, and renal calculi (Fig. 18.11) Urolithiasis (Calculi, or Kidney Stones) Kidney stones are a common problem and frequently recur if the underlying cause is not treated. ■ Pathophysiology Calculi can develop anywhere in the urinary tract. Stones may be small or very large (eg, staghorn calculus, a very large stone that forms in the renal pelvis and calyces in the shape of a deer’s antlers). Calculi tend to form when there are excessive amounts of relatively insoluble salts in the filtrate or when insuf- ficient fluid intake creates a highly concentrated filtrate. Once any solid material or debris forms, deposits continue to build up on this nidus, or focus, and eventually form a large mass. Cell debris from infection may also form a nidus. Immobility may result in calculi in the kidney Pregnancy Carcinoma of cervix Endometriosis Extrinsic compression Blood clot Transitional cell carcinoma of bladder Transitional cell carcinoma of renal pelvis Uretal stone Polycystic kidney Hydronephrosis Dysplasia-agenesis of ureter Posterior vesicoureteral valve (reflux) Urethral sphincter Urethral stenosis Prostate hypertrophy Ureteropelvic valve Ureteropelvic stricture Fibrous band Stenosis Ureteral orifice Urogenital diaphragm FIG. 18.11 Major sites of urinary tract obstruc- tion. (From McCance KL, et al: Pathophysiology: The Biologic Basis for Disease in Adults and Children, ed 6, St. Louis, 2010, Mosby.) 504 SECTION III Pathophysiology of Body Systems fragmentation of larger stones—such as extracorporeal shockwave lithotripsy, which uses sound waves to break up the stone, and laser lithotripsy, which uses a uretero- scope to locate the stone and a scope-mounted laser to destroy it—have been quite successful and have decreased the need for invasive surgery, which is a procedure called percutaneous nephrolithotomy. In some cases, drugs may be used to partially dissolve the stones. Prevention of recurrence related to specific risk factors is of primary importance. Treatment of the underlying condition, adjustment of urine pH by ingestion of addi- tional acidic or alkaline substances, and increased fluid intake all minimize the risk of recurrence. Hydronephrosis Hydronephrosis occurs as a secondary problem, a com- plication of calculi, but also of tumors, scar tissue in the kidney or ureter, and untreated prostatic enlargement. Developmental defects are common in the urinary tract and may cause obstruction by kinking or stenosis of a ureter. Obstructive uropathy can be diagnosed by ultra- sonography in the fetus, allowing for immediate or neonatal corrective surgery, thus preventing major kidney damage. Urine is continually forming. Any prolonged interfer- ence with urine outflow through the system results in back pressure and a dilated area filled with urine in the ureter or kidney (see Fig. 18.12B). In the kidney, continued buildup of urine, particularly over a prolonged period, causes necrosis of the tissue because of direct pressure and compression of the blood vessels. Hydronephrosis is frequently asymptomatic unless mild flank pain occurs CALCULI Dilated area filled with urine Renal tissue atrophy Urine flow B HYDRONEPHROSIS A FIG. 18.12 A, Renal calculi and hydronephrosis. B, Hydronephrosis with dilation of the renal pelvis and calyces and atrophy of renal tissue. (From Cotran R, et al: Robbins Pathologic Basis of Disease, ed 6, Philadelphia, 1999, Saunders, Elsevier.) THINK ABOUT 18.13 Explain how decreased fluid intake or dehydration predisposes to calculi in the urinary tract. is highly alkaline. Inadequate fluid intake is a major factor in calculus formation. Calcium oxalate stones may develop in people following vegetarian diets high in oxalate that lead to increased levels of oxalate in the urine. Uric acid stones develop with hyperuricemia (due to gout, high-purine diets, or cancer chemotherapy), espe- cially when the urine is acidic. Infection may cause stones consisting of mixed inorganic salts because in such cases the urine pH is alkaline and debris from the infection may act as a focus for the deposition of crystals. ■ Signs and Symptoms Stones in the kidney or bladder are frequently asymp- tomatic, unless frequent infections lead to investigation. Sometimes flank pain occurs because of distention of the renal capsule. Obstruction of the ureter causes an attack of “renal colic,” consisting of intense spasms of pain in the flank area radiating into the groin that last until the stone passes or is removed. This pain is caused by vigorous contrac- tions of the ureter in an effort to force the stone out. The severe pain may be accompanied by nausea and vomiting, cool moist skin, and rapid pulse. Radiologic examination confirms the location of the calculi. ■ Treatment Small stones can be passed eventually and the urine strained to catch stones for analysis. Newer methods of CHAPTER 18 Urinary System Disorders 505 The initial sign is usually painless hematuria, either gross or microscopic. Other manifestations include dull, aching flank pain; a palpable mass; unexplained weight loss; and anemia or erythrocytosis (depending on the tumor’s effects on erythropoietin secretion). Paraneoplastic syndromes such as hypercalcemia (increased parathyroid hormone) or Cushing syndrome (increased adrenocor- ticotropic hormone) are common. This tumor tends to be silent; therefore diagnosis is made in one-third of cases after metastasis to lungs, liver, or bone has occurred. Removal of the kidney (nephrec- tomy) is the treatment because the tumor is usually unresponsive to radiation or chemotherapy. The 5-year survival rate varies from 96% in stage I to 23% in stage IV; newer treatment measures and diagnostic technology may result in higher survival rates. Bladder Cancer Malignant tumors of the bladder commonly arise from the transitional epithelium lining the bladder in the trigone area. This cancer often develops as multiple tumors and tends to recur. It is diagnosed by urine cytology (malignant cells in the urine) and biopsy. The tumor is invasive through the wall to adjacent structures, and it metastasizes through the blood to pelvic lymph nodes, liver, and bone. Staging categories range from an in situ tumor through the degree of bladder wall invasion to metastasis. The early sign is hematuria, gross or microscopic. Dysuria or frequency may develop, and infection is common. Bladder cancer has a high incidence in individuals working with chemicals in laboratories or industry, particularly with dyes, rubber, and aluminum. More than 50% of patients are cigarette smokers. Other predispos- ing factors are recurrent infection and heavy intake of analgesics. Treatment includes surgical resection of the tumor in 90% of cases, chemotherapy, and radiation. Urinary diver- sion (eg, ileal loop, the creation of an alternative internal or external urine-collecting unit using part of the ileum) may be required after surgery. Photoradiation (a combina- tion of drug and laser treatment) has been successful in some early cases. Instillation of bacillus Calmette-Guérin vaccine (BCG—a biologic response modifier intended to strengthen the immune response) into the bladder after resection has reduced recurrences of superficial tumors (see Chapter 20). Continued monitoring is necessary to detect recurrences in an early stage. Five-year survival rates vary from 85% in stage I to 16% in stage IV. Vascular Disorders Nephrosclerosis ■ Pathophysiology Nephrosclerosis involves vascular changes similar to those of arteriosclerosis in the kidney. Some vascular changes occur normally with aging, but these excessive as the renal capsule is distended or unless infection develops. It can be diagnosed with ultrasonography, radionucleotide imaging, CT scan, or IVP. If the cause is not removed, bilateral hydronephrosis could lead to chronic renal failure. Tumors Benign tumors are rare in the urinary tract. Malignant tumors of the bladder occur primarily in men after age 50. Men are 3 to 5 times more likely to get bladder cancer in their lifetime than women. Other cancers can also arise in the kidneys, ureters, and urethra but are less common than bladder cancer. Renal Cell Carcinoma Renal cell carcinoma (adenocarcinoma of the kidney) is a primary tumor arising from the tubule epithelium, more often in the renal cortex (Fig. 18.13). The American Cancer Society estimated that there would be 62,700 new cases of renal cell carcinomas in 2016, resulting in 14,240 deaths. It tends to be asymptomatic in the early stage and often has metastasized to liver, lungs, bone, or CNS at the time of diagnosis. This cancer occurs more frequently in men and smokers and is uncommon in people 45 years old or younger. FIG. 18.13 Renal cell carcinoma. A well-circumscribed spherical tumor is bulging through the cortical surface. Areas of hemorrhage and cysts can be seen in the tumor. (From Cooke RA, Stewart B: Colour Atlas of Anatomical Pathology, ed 3, Sydney, 2004, Churchill Livingstone.) 506 SECTION III Pathophysiology of Body Systems all can assist in maintaining renal blood flow and reducing blood pressure. These drugs are discussed in Chapter 12 (see Table 12.1). Sodium intake should be reduced as well. changes cause thickening and hardening of the walls of the arterioles and small arteries and narrowing or occlu- sion of the lumina of the blood vessels. Such changes reduce the blood supply to the kidney, causing ischemia and atrophy, and stimulate the secretion of renin, ulti- mately increasing the blood pressure (Fig. 18.14). Con- tinued ischemia can lead to gradual destruction of renal tissue and chronic renal failure. Often such damage is asymptomatic until a late stage. It is often difficult to determine whether the primary lesion has developed in the kidney or if it is secondary to essential hypertension (see Chapter 12), diabetes mellitus (see diabetic nephropathy and Fig. 16.6 in Chapter 16), or another condition. In any case, a vicious cycle can develop with the kidneys and hypertensive changes, and this must be broken to prevent renal failure or other complications of hypertension such as congestive heart failure. ■ Treatment Drugs such as antihypertensive agents, diuretics, ACE inhibitors, and beta blockers (which block renin release) 7. Renal vascular damage Nephrosclerosis 2. Decreased blood to nephrons Stimulate 3. Renin-angiotensin-aldosterone 4. Systemic vasoconstriction 5. Sodium and water retention Ischemia Renal tissue Necrosis Fibrosis Interference with blood flow Atrophy of kidney 8. Chronic renal failure Blood volume 1. Hypertension Less space and more fluid for circulating blood Increased blood pressure Arteriole/arteries 6. Na+ H 2 O FIG. 18.14 The relationship between hypertension and the kidney. THINK ABOUT 18.14 Explain factors that may contribute to elevated blood pressure in the client with renal disease. Congenital Disorders It is estimated that 10% of infants are born with an abnormality in the urinary system. Some examples follow: • Vesicoureteral reflux is due to a defective valve in the bladder mentioned in the discussion on UTIs. • Agenesis refers to a developmental failure of one kidney to develop. This is asymptomatic and usually is an incidental finding if diagnosed at all. • Hypoplasia, or failure to develop to normal size, is often a unilateral defect. Sometimes it results from fibrosis CHAPTER 18 Urinary System Disorders 507 in the kidney rather than being a true developmental flaw. • Ectopic kidney is a kidney and its ureter displaced out of normal position. A common location is lower in the abdominal or pelvic cavity. Kidney function is normal. In this position the ureter may become kinked, causing obstruction or infection. • Fusion of the two kidneys during development is a common malformation, resulting in a single “horse- shoe” kidney. Usually kidney function is normal. Adult Polycystic Kidney The most common form of this genetic disease is transmit- ted as an autosomal-dominant gene on chromosome 16. There are no indications in the child and young adult; the first manifestations usually appear around age 40 years, when chronic renal failure becomes symptomatic and dialysis is required. This condition is responsible for about 10% of the patients with end-stage chronic renal failure. In some cases, early diagnosis is possible when high blood pressure occurs and is difficult to control or when secondary polycythemia develops due to increased erythropoietin secretion. Diagnosis can be confirmed by an abdominal CT scan or MRI. Multiple cysts develop in both kidneys and gradually expand over the years, first enlarging the kidneys and then compressing and destroying kidney tissue until chronic renal failure occurs (Fig. 18.15). In some cases, cysts are found in other organs such as the liver, or cerebral aneurysms are found. Polycystic disease in children is transmitted as a recessive gene and is manifest at birth. However, in this case, the child is either stillborn or dies during the first months. FIG. 18.15 Adult polycystic disease. (From Stevens A: Core Pathology, ed 3, London, 2010, Mosby.) Wilms Tumor (Nephroblastoma) This is a rare tumor occurring in children. It is associated with defects in tumor-suppressor genes on chromosome 11 and may occur in conjunction with some other con- genital disorders. It is usually unilateral. The tumor presents as a large encapsulated mass. Wilms tumor is usually diagnosed at ages 3 to 4 years, when the large abdominal mass becomes obvious (often a waistband on clothes does not fasten or a unilateral bulge appears). In some cases the child develops high blood pressure. Pulmonary metastases may be present at diagnosis. The prognosis for the child depends on the histologic results as well as the stage of the tumor at diagnosis. Tumors showing a favorable histology (less aggressive) have an average 5-year survival rate of 90%. Renal Failure Acute Renal Failure ■ Pathophysiology The kidneys may fail to function for many different reasons. Either directly reduced blood flow into the kidney or inflammation and necrosis of the tubules cause obstruc- tion and back pressure, leading to greatly reduced GFR and oliguria (reduced urine output) or anuria (no urine output). Both kidneys must be involved. The failure is usually reversible if the primary problem is treated successfully. Dialysis may be used to replace the kidney function during this period. In some cases, the kidneys sustain a degree of permanent damage. ■ Etiology Acute renal failure has numerous causes (Fig. 18.16): • Acute bilateral kidney disease, such as glomerulone- phritis, which reduces GFR. • Severe and prolonged circulatory shock or heart failure, which results in tubule necrosis. Shock associated with burns or crush injuries or sepsis frequently causes renal failure. With burns, the damaged erythrocytes break down in the circulation, releasing free hemo- globin that may accumulate in the tubules, causing obstruction. Hemoglobin also is toxic to tubule epi- thelium, causing inflammation and necrosis (see Chapter 5, Burns). When skeletal muscle is crushed in an accident, myoglobin is released with similar effects. • Nephrotoxins such as drugs, chemicals, or toxins, which cause tubule necrosis and obstruction of blood flow. Industrial chemicals such as the solvent carbon tetra- chloride may cause acute renal failure when exposure is intense. Long-term, low-level exposures may cause gradual damage, eventually leading to chronic renal failure. The list of frequently used drugs possibly 508 SECTION III Pathophysiology of Body Systems Casts ISCHEMIA 5. Decreased GFR NEPHROTOXINS 1. Filtrate becomes concentrated PYELONEPHRITISC B A Purulent exudate and abscesses block flow of blood and urine 3. Normal lumen Obstructed lumen OLIGURIA 2. Severe shock Vasoconstriction Decreased blood flow 1. GLOMERULUS 2. Concentrated nephrotoxin tubule wall becomes swollen and necrotic 6. OLIGURIA 4. Filtrate: high back pressure • Ischemia • Swelling • Necrosis • Obstruction 3. FILTRATE: High back pressure 4. OLIGURIA 2. TUBULE FIG. 18.16 Causes of Acute Renal Failure. A, Nephrotoxins. B, Ischemia. C, Pyelonephritis. CHAPTER 18 Urinary System Disorders 509 THINK ABOUT 18.15 Focusing on the circulation through the nephron, explain why severely decreased blood flow in the afferent arteriole could cause tubule necrosis and obstruction. causing tubule damage is growing longer and now includes sulfa drugs, phenacetin, nonsteroidal anti- inflammatory drugs (NSAIDS), acetaminophen and aspirin, and penicillin. When patients take these drugs, fluid intake should be greatly increased to reduce the risk of kidney damage. • Occasionally mechanical obstructions such as calculi, blood clots, or tumors, which block urine flow beyond the kidneys and cause acute renal failure. ■ Signs and Symptoms Acute renal failure usually develops rapidly. Blood tests show elevated serum urea nitrogen (BUN) and creatinine as well as metabolic acidosis and hyperkalemia, confirm- ing the failure of the kidneys to remove wastes. ■ Treatment It is important to reverse the primary problem as quickly as possible to minimize the risk of necrosis and permanent kidney damage with uremia (see Chronic Renal Failure). Dialysis may be used to normalize body fluids and maintain homeostasis during the oliguric stage. Recovery from acute renal failure is evidenced by increased urine output (diuretic stage). It may take a few months before the epithelium lining the renal tubules recovers totally, so fluid and electrolyte balance may not return to normal for some time. Chronic Renal Failure Chronic renal failure is the gradual irreversible destruction of the kidneys over a long period. It may result from chronic kidney disease, such as bilateral pyelonephritis or congenital polycystic kidney disease, or from systemic disorders, such as hypertension or diabetes. As mentioned, long-term exposure to nephrotoxins is a cause. The gradual loss of nephrons is asymptomatic until it is well advanced because the kidneys normally have considerable reserve function. Once advanced, the progress of chronic renal failure may be slowed but cannot be stopped because the scar tissue and loss of functional organization tend to cause further degenerative changes. ■ Pathophysiology Chronic renal failure has several stages (Fig. 18.17), progressing from decreased renal reserve, to insufficiency, to end-stage renal failure or uremia. In the early stages of decreased reserve (around 60% of nephrons lost) there is a decrease in GFR, serum creatinine levels that are consistently higher than average but within normal range, serum urea levels that are normal, and no apparent clinical signs. The remaining nephrons appear to adapt, increasing their capacity for filtration. The second stage (around 75% of nephrons lost), or that of renal insufficiency, is indicated by a change in blood chemistry and manifestations. At this point, GFR is decreased to approximately 20% of normal and there is significant retention of nitrogen wastes (urea and creati- nine) in the blood. Tubule function is decreased, resulting in failure to concentrate the urine and control the secretion and exchange of acids and electrolytes. Osmotic diuresis occurs as the remaining functional nephrons filter an increased solute load. This stage is marked by excretion of large volumes of dilute urine (low fixed specific gravity). Erythropoiesis is decreased, and the patient’s blood pressure is elevated. The cardiovascular system must compensate for these effects (see Chapter 12). Uremia, or end-stage renal failure (more than 90% of nephrons lost), occurs when GFR is negligible. Fluid, electrolytes, and wastes are retained in the body, and all body systems are affected. In this stage, marked oliguria or anuria develops. Regular dialysis or a kidney transplant is required to maintain the patient’s life. A comparison of acute and chronic renal failure may be found in Table 18.3. ■ Signs and Symptoms The early signs of chronic renal failure include: • Increased urinary output (polyuria), manifested as frequency and nocturia • General signs such as anorexia, nausea, anemia, fatigue, unintended weight loss, and exercise intolerance TABLE 18.3 Comparison of Acute Renal Failure and Chronic Renal Failure Characteristic Acute Renal Failure Chronic Renal Failure Causes Severe shock Nephrosclerosis Burns Diabetes mellitus Nephrotoxins, massive exposure Nephrotoxins, long-term exposure Acute bilateral kidney infection or inflammation Chronic bilateral kidney inflammation or infection Polycystic disease Onset Sudden, acute Slow, insidious Early signs Oliguria, increased serum urea Polyuria with dilute urine Anemia, fatigue, hypertension Progressive signs Recovery— increasing urine output End-stage failure or uremia If prolonged failure—uremia Oliguria, acidosis, azotemia 510 SECTION III Pathophysiology of Body Systems • Systemic infections such as pneumonia (common) due to poor tissue resistance related to anemia, fluid retention, and low protein levels ■ Diagnostic Tests Anemia, acidosis, and azotemia are the key indicators of chronic renal failure. 1. Metabolic acidosis becomes decompensated (serum pH below 7.35) in the late stage as GFR declines and tubule function is lost (see Chapter 2). 2. Azotemia refers to the presence of urea or other excess nitrogen wastes in the blood, as indicated by elevated serum creatinine and urea levels. 3. Anemia becomes severe. 4. Serum electrolyte levels may vary depending on the amount of water retained in the body. Usually hypo- natremia and hyperkalemia occur, as well as hypo- calcemia and hyperphosphatemia. ■ Treatment Chronic renal failure affects all body systems, as indicated earlier. It is difficult to maintain homeostasis of fluids, electrolytes, and acid–base balance. Drugs are available to stimulate erythropoiesis and reduce phosphate levels. • Bone marrow depression and impaired cell function caused by increased wastes and altered blood chemistry • High blood pressure As the kidneys fail completely (end-stage failure), uremic signs appear: • Oliguria • Dry, pruritic, and hyperpigmented skin, easy bruising • Peripheral neuropathy—abnormal sensations in the lower limbs • Impotence and decreased libido in men, menstrual irregularities in women • Encephalopathy (lethargy, memory lapses, seizures, tremors) • Congestive heart failure, arrhythmias • Failure of the kidney to activate vitamin D for calcium absorption and metabolism, combined with urinary retention of phosphate ion, leading to hypocalcemia and hyperphosphatemia with osteodystrophy (a defect in bone development related to calcium and phosphate metabolism; see Fig. 18.18), osteoporosis, and tetany (see Chapter 9) • Possibly uremic frost on the skin and a urine-like breath odor in the terminal stage or if infection is present No. of NEPHRONS TIME 0 2 million Function 100% Renal insufficiency End-stage failure (uremia) Decreasing renal reserve (asymptomatic) Normal kidneys Fibrotic area Extensive damage Nonfunctional area Fibrotic kidneys shrink FIG. 18.17 Development of chronic renal failure. CHAPTER 18 Urinary System Disorders 511 In addition, specific drugs may be required to treat hypertension, arrhythmias, heart failure, and other complications. Drug dosages need to be carefully con- sidered and adjusted if necessary in patients with uremia because of the kidney’s decreased ability to excrete drugs in a timely manner. Clients are subject to many complications, which in turn affect the uremia. For instance, a simple infection increases the wastes in the body, compromising all body systems. Intake of fluid, electrolytes, and protein must be restricted because the kidneys are limited in their ability to excrete excess wastes and fluid. Children with kidney failure have retarded growth and renal rickets. In the uremic stage, dialysis or a transplant is required. Organ transplants are discussed in Chapter 7. OSTEODYSTROPHY WITH CHRONIC RENAL FAILURE LOSS OF FUNCTIONAL KIDNEY TISSUE DECREASED SERUM CALCIUM STIMULATE PARATHYROID HORMONE SECRETION INCREASED CALCIUM RESORPTION FROM BONE DECREASED ACTIVATION OF VITAMIN D DECREASED PHOSPHATE ION EXCRETION DECREASED CALCIUM ABSORPTION From the intestines INCREASED SERUM PHOSPHATE Increased serum calcium + phosphate deposits in tissue BONE DEMINERALIZATION Decreased bone mass Spontaneous fractures Renal rickets in a child FIG. 18.18 The development of osteodystrophy in chronic renal failure. CASE STUDY A Nephrosclerosis and Chronic Renal Failure Mr. H., age 68 years, has a long history of hypertension. He has had more headaches recently, his legs and feet are swollen, and he has noticed that more frequent voiding, both during the day and at night, is necessary. He constantly feels tired and does not feel hungry. Mr. H.’s blood pressure is 170/110, his pulse is 94, and he has gained 12 pounds in the last 2 months. Diagnostic test findings related to the blood and urine include elevated serum creatinine and urea levels, low serum bicarbonate, low hemoglobin and hematocrit, and low serum sodium. The urine contains protein and has a very low specific gravity. The diagnosis is renal insufficiency, or chronic renal failure, due to nephrosclerosis. 1. Describe how nephrosclerosis leads to chronic renal failure. 2. Explain the cause of the edema and the weight gain. 3. State three factors contributing to fatigue. 4. Explain why Mr. H.: a. is voiding frequently. b. has a very dilute urine. 5. Explain why Mr. H. has: a. high blood pressure. b. anemia. c. metabolic acidosis. 6. List the signs indicating that Mr. H. has progressed into uremia, or end-stage renal failure. 7. List three reasons why development of pneumonia is a high risk in Mr. H. CASE STUDY B Acute Poststreptococcal Glomerulonephritis D.K., age 4 years, has been diagnosed with APSGN 1 month after he was ill with tonsillitis. His face, abdomen, and legs are swollen, and he is not interested in his toys. He is short of breath when he moves about. His urine is dark and cloudy and is scant in volume. 1. Explain how D.K.’s tonsillitis is probably related to the development of APSGN. 2. Explain why his urine is dark. 3. State two other significant characteristics you would expect to find in the urine. 4. State three abnormalities likely to be found on examination of D.K.’s blood, and explain the reason for each. 5. Explain why D.K. is producing very small amounts of urine. 6. Explain why acute renal failure could develop. CASE STUDY C Nephrotoxicity G.R. is a successful collage artist. He works with adhesives, paints, and solvents, which often must be heated to produce textured artworks. During the summer months he works out of THINK ABOUT 18.16 a. Compare acute and chronic renal failure with respect to cause, reversibility, and urinary output at onset. b. If uremia is untreated or if complications occur, metabolic acidosis can become decompensated. What change occurs in serum pH at this point, and what is the effect on overall cell metabolism in the body? c. Why is there an increased risk of drug toxicity in the later stages of renal failure? 512 SECTION III Pathophysiology of Body Systems C H A P T E R S U M M A R Y Kidney disease may affect one or more of the glomeruli, the tubules, or the blood vessels of the nephrons, thus altering filtration or reabsorption and secretion and the excretion of wastes. Scar tissue may interfere with the essential organization of the nephrons within the kidney. Renal disease often has numerous systemic effects, including elevated blood pressure. • Dialysis, either peritoneal or hemodialysis, may replace kidney function temporarily or long term. doors and in the colder weather works in his studio, which is equipped with an exhaust fan. On very cold days he sometimes turns off the fan. He has been working very long hours to prepare for his upcoming winter show. Several times in the past few days he has commented to his partner that he feels weak, nauseated, and unable to work. He has noticed that he is not producing as much urine and thinks that this is due to decreased fluid intake during work. His partner contacts his doctor and takes him to the emergency department as directed. When seen in the emergency clinic, his blood pressure is 170/96, he has an abnormal pulse, and blood tests reveal elevated BUN, K+, and creatinine levels. Further tests lead to a diagnosis of acute renal failure due to tubular necrosis. 1. What are possible causes of acute renal failure in this case? 2. How have the kidneys been damaged; will they recover normal function? 3. What is the cause of nausea and fatigue? 4. Explain how hypertension has developed in G.R. 5. Explain the cause of oliguria. G.R. is hospitalized and treated with steroid medication and emergency hemodialysis. Four days later he begins to void large volumes of urine. 1. What is the significance of diuresis in this case? 2. What can G.R. expect in the future; what changes need to be made in regard to his work to prevent recurrence of acute renal failure or the development of chronic renal failure in the future? Urinary Tract Infections • Cystitis, infection of the bladder, may ascend along the continuous mucosa to cause pyelonephritis. The common cause is E. coli. Urinalysis confirms the diagnosis. Follow-up testing is necessary to ensure complete eradication of the infection. • Urethritis is the infection and inflammation of the urethra Inflammatory Disorders • Acute poststreptococcal glomerulonephritis, an example of a childhood inflammatory disease, is caused by an abnormal immune reaction. Mild glomerular inflam- mation causes leakage of erythrocytes and protein into the filtrate; severe inflammation reduces GFR and excretion of wastes. • Nephrosis or nephrotic syndrome is associated with many abnormal conditions. Significant manifestations are severe generalized edema, proteinuria, and lipiduria. Obstructions • Urinary calculi, formed primarily of calcium salts, may obstruct urinary flow, causing hydronephrosis and predisposition to infection. • Renal cell carcinoma and bladder cancer are frequently manifested initially by painless hematuria. Renal Failure • Acute renal failure is reversible and may result from bilateral renal inflammation, severe shock, or neph- rotoxins. It is indicated by sudden oliguria, increased serum urea, and acidosis. • Chronic renal failure develops from the gradual destruc- tion of nephrons. The process is irreversible and ultimately results in uremia with retention of body wastes and loss of homeostasis. It is asymptomatic until the stage of renal insufficiency, indicated by production of large volumes of dilute urine, increasing serum urea, elevated blood pressure, anemia, and fatigue. S T U D Y Q U E S T I O N S 1. Trace the blood flow through the kidney, naming the blood vessels in order. 2. Trace the filtrate and the major changes in it from Bowman’s capsule to the urethra. 3. If the sympathetic nervous system causes vasoconstriction in the kidney, how does this increase blood pressure? How does it affect urine output? 4. Compare the signs/symptoms of cystitis and pyelonephritis. 5. Compare the causes and pathophysiology of acute pyelonephritis, APSGN, and nephrotic syndrome. 6. How might urinary tract infections lead to calculus formation? 7. Compare the pathophysiology of acute and chronic renal failure. 8. Describe all the factors contributing to the lethargy of someone with chronic renal failure. CHAPTER 18 Urinary System Disorders 513 9. A client with chronic renal failure on hemodialysis is having extensive dental work performed. What precautions need to be taken in this case? 10. List the substances that should pass from the blood into the dialyzing fluid. 11. Why is protein intake restricted in patients with kidney disease? 12. Explain how a respiratory infection such as pneumonia can aggravate the effects of uremia. 13. Explain how a child’s growth and development may be affected by chronic nephrosis and renal failure. 14. Differentiate the causes of frequent voiding associated with cystitis and with renal insufficiency. 15. Differentiate the causes of urinary retention and anuria. 514 Disorders of the Male Reproductive System Review of the Male Reproductive System Structure and Function Hormones Congenital Abnormalities of the Penis Epispadias and Hypospadias Disorders of the Testes and Scrotum Cryptorchidism Hydrocele, Spermatocele, and Varicocele Inflammation and Infections Prostatitis Balanitis Tumors Benign Prostatic Hypertrophy Cancer of the Prostate Cancer of the Testes Disorders of the Female Reproductive System Review of the Female Reproductive System Structure and Function Hormones and the Menstrual Cycle Structural Abnormalities Menstrual Disorders Menstrual Abnormalities Endometriosis Infections and Inflammation Candidiasis Pelvic Inflammatory Disease Benign Tumors Leiomyoma (Fibroids) Ovarian Cysts Polycystic Ovarian Syndrome Fibrocystic Breast Disease Malignant Tumors Carcinoma of the Breast Carcinoma of the Cervix Carcinoma of the Uterus (Endometrial Carcinoma and Uterine Sarcomas) Ovarian Cancer Infertility Sexually Transmitted Diseases Bacterial Infections Chlamydial Infection Gonorrhea Syphilis Viral Infections Genital Herpes Condylomata Acuminata (Genital Warts) Protozoan Infection Trichomoniasis Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Describe the causes of infertility in males and females. 2. Describe the common congenital abnormalities in males and females. 3. Compare benign prostatic hypertrophy with cancer of the prostate. 4. Describe the incidence and pathophysiology of testicular cancer. 5. Compare the common menstrual disorders. 6. Describe endometriosis and its complications. 7. Explain how pelvic inflammatory disease develops and its effects. 8. Describe breast lesions, fibrocystic breast disease, and breast cancer. 9. Compare the common benign and malignant tumors in the cervix, uterus, and ovaries. 10. Describe the common sexually transmitted diseases. L E A R N I N G O B J E C T I V E S dyspareunia exogenous gynecomastia hirsutism lactation leukorrhea meatus menarche spermatogenesis K E Y T E R M S C H A P T E R 19 Reproductive System Disorders CHAPTER 19 Reproductive System Disorders 515 gonadotropins secreted by the adenohypophysis. In addition to the testes, the male reproductive system includes an extensive duct system connected to accessory glands and structures that form and transport the semen preparatory to ejaculation from the penis during sexual intercourse (see Fig. 19.1). Spermatogenesis, the production of spermatozoa, is a continuous process. It takes approximately 60 to 70 days to complete the process of development. 1. The testes consist of many lobules containing the seminiferous tubules, the “sperm factories” of the body. 2. Efferent ducts conduct the multitudes of sperm into the epididymis, where the sperm mature. 3. Peristaltic movements in the epididymis assist the sperm to move on into the ductus deferens (vas deferens) and then to the ampulla, where the now-motile sperm may be stored for several weeks until ejaculation occurs (see Fig. 19.1). Vasectomy, which is one method of birth control, involves cutting or obstructing the vas deferens to block the passage of sperm. When semen is formed at the time of emission, fluid contain- ing many substances is gathered from the various accessory structures entering the ejaculatory duct and urethra: • The seminal vesicles, located behind the bladder, provide a secretion that includes fructose to nourish the sperm. • The prostate gland, which surrounds the urethra at the base of the bladder, adds an alkaline fluid to provide an optimum pH of around 6 for fertilization. (The vaginal secretions and the initial sperm-containing fluid are acidic.) • The bulbourethral glands (Cowper glands), situated near the base of the penis, secrete an alkaline mucus, which probably neutralizes any residual urine in the urethra. Disorders of the Male Reproductive System Review of the Male Reproductive System Structure and Function The male gonads, the testes, are suspended by the sper- matic cord in the scrotum, a sac outside the abdominal cavity (Fig. 19.1). The spermatic cord refers to a collection of vessels, nerves, and the ductus deferens (vas deferens) surrounded by a fascia. The testes constantly produce sperm and the sex hormone testosterone. The scrotal sac consists of a layer of skin that is continu- ous with the skin of the perineal area plus an inner muscle layer and fascia. The scrotal covering is loose and falls into folds, or rugae. A connective tissue septum separates the two testes within the scrotum. Each testis and attached epididymis is enclosed in the tunica vaginalis, a double-walled membrane with a small amount of fluid between the layers (see Fig. 19.1). The spermatic cord contains arteries, veins, and lymphatics for the testes (see Fig. 19.3). The testes are positioned outside the abdominal cavity to provide an optimum temperature for sperm production, 2°F to 3°F (1°C to 2°C) below normal body temperature. The scrotal muscle draws the testes closer to the body whenever the environmental temperature drops. When the temperature climbs, the muscle relaxes, letting the testes drop away from the body. The fetal testes descend from the abdominal cavity through the inguinal canal into the scrotum during the third trimester of pregnancy. Then the inguinal canal closes (see Fig. 19.2). At puberty the testes mature and begin to produce sperm and testosterone under the influence of the Urinary bladder opened Seminal vesicle Ejaculatory duct Rectum Prostate gland Bulbourethral gland Spongy urethra Membranous urethra Prostatic urethra Ampulla Ureter Surface of urinary bladder Penis Ductus deferens Epididymis Urethra Testis Glans penis Scrotum Seminiferous tubules Prepuce (foreskin) Parietal peritoneal membrane FIG. 19.1 Anatomy of the male reproductive system. 516 SECTION III Pathophysiology of Body Systems Congenital Abnormalities of the Penis Epispadias and Hypospadias Epispadias refers to a urethral opening on the dorsal (upper) surface of the penis, proximal to the glans. If the urethral defect extends proximally and affects the urinary sphincter, incontinence may result. Infections may result from stricture at the opening. In some cases, this condition is associated with exstrophy of the bladder, which is a failure of the abdominal wall to form across the midline. Hypospadias is a urethral opening on the ventral (under) surface of the penis. If the opening occurs in the proximal section of the penis, it is considered more severe and may be accompanied by chordee, ventral curvature of the penis. Other abnormalities such as cryptorchidism are often associated with hypospadias. Surgical reconstruction, which may be performed in stages, is recommended for both epispadias and hypo- spadias to provide normal urinary flow and normal sexual function. Disorders of the Testes and Scrotum Cryptorchidism Maldescent of the testis, or cryptorchidism, occurs when one or both of the testes fails to descend into the normal position in the scrotum during the latter part of pregnancy (Fig. 19.2). The testis may remain in the abdominal cavity or discontinue the descent at some point in the inguinal canal or above the scrotum. In some cases, the testis assumes an abnormal position outside the scrotum; this is called an ectopic testis. In many cases, spontaneous descent occurs during the first year after birth. The reason for maldescent is not fully understood. Possible factors include hormonal abnormalities, a short The total volume of semen ejaculated at one time is 2 to 5 mL. Semen consists primarily of fluid, but contains 100 to 200 million sperm. Hormones Gonadotropic hormones released by the adenohypophysis or anterior pituitary gland include: • Follicle-stimulating hormone (FSH), which initiates spermatogenesis • Luteinizing hormone (LH, or interstitial cell–stimulating hormone), which stimulates testosterone production by the interstitial cells (Leydig cells) in the testes Testosterone is essential for the maturation of sperm. Serum levels of testosterone provide a negative feedback system for the continuous control of gonadotropin secretions, there being no cyclic hormones in males (see Chapter 16). Other functions of testosterone include the develop- ment and maintenance of secondary sex characteristics such as male hair distribution, deeper voice, and maturing of the male external genitalia. Also, testosterone is an anabolic steroid hormone that promotes protein metabo- lism and skeletal muscle development, influencing the physical changes seen in the adolescent male (see Chapter 23). These steroid hormones are being abused more frequently by both males and females who are athletes or are interested in body building or altered body image. Unfortunately, serious adverse effects are associated with such use, such as liver damage, cardiovascular disease, and damage to the reproductive structures. Scrotum Testicle remains in upper scrotum Normal location of testicle Testicle remains in inguinal canal Testicle remains in pelvic cavity Peritoneal membrane Testicle forms in abdomen and descends through retroperitoneal space during last months of fetal development Possible abnormal locations FIG. 19.2 Cryptorchidism and possible positions of the undescended testis. THINK ABOUT 19.1 a. Describe the location and function of the (1) testis, (2) seminal vesicle, and (3) epididymis. b. Explain how testosterone levels are maintained, including an explanation of negative feedback. CHAPTER 19 Reproductive System Disorders 517 Normal epididymis Hydrocele A B C Twisting of testis or spermatic cord, compressing blood vessels Torsion of testis Normal testis Hydrocele – a collection of clear fluid in space between visceral and parietal layers of tunica vaginalis Varicocele Varicose veins (dilated) in spermatic cord FIG. 19.3 Abnormalities of the scrotum. spermatic cord, or a small inguinal ring. If the testis remains undescended, the seminiferous tubules degener- ate, and spermatogenesis is impaired. Of concern is the increased risk of testicular cancer in cryptorchid testes (see Chapter 23). Therefore surgical positioning of the testes in the scrotum before age 2 is advisable. Hydrocele, Spermatocele, and Varicocele Hydrocele occurs when excessive fluid collects in the potential space between the layers of the tunica vaginalis (Fig. 19.3A). This may occur around one or both testes and can be distinguished by transillumination. Hydrocele may occur as a congenital defect in a newborn when peritoneal fluid accumulates in the scrotum. This fluid may be reabsorbed in time. The fluid may continue to escape from the peritoneal cavity if the proximal portion of the processus vaginalis, a section of peritoneal membrane, does not close off as expected after descent of the testes. Usually the scrotum fills with more fluid during the day, becoming larger and firmer, and then the fluid subsides during the night. The other common finding in an infant in whom the processus vaginalis remains open is an inguinal hernia, which is a loop of intestine that passes through the abnormal opening (see Fig. 17.41A). Such a hernia usually leads to intestinal obstruction. Surgical repair is recom- mended if the opening remains patent or herniation persists because there is a risk that the herniated intestinal loop may become strangulated. Acquired hydrocele may result from scrotal injury, an infection, a tumor, or unknown causes. Acquired hydro- celes are more common after middle age. Large amounts of fluid may compromise the blood supply to the testis, requiring aspiration. A spermatocele is a cyst containing fluid and sperm that develops between the testis and the epididymis outside the tunica vaginalis. It may be related to an abnormality of the tubules. If the cyst is large, it may be surgically removed. A varicocele is a dilated vein in the spermatic cord, usually on the left side. It frequently develops after puberty and results from a lack of valves in the veins, permitting backflow of blood and increased pressure in the veins. Varicocele may be mild, and scrotal support minimizes the heavy feeling. If it is extensive, the vari- cocele is painful or tender and leads to infertility because of the impaired blood flow to the testes and decreased spermatogenesis. In this case, surgical treatment of the abnormal veins is necessary. Torsion of the testis occurs when the testis rotates on the spermatic cord, compressing the arteries and veins. Ischemia develops, and the scrotum swells. Immediate treatment is required manually and surgically to restore blood flow to the testis. Testicular torsion frequently occurs during puberty, both spontaneously and after trauma. 518 SECTION III Pathophysiology of Body Systems Chronic prostatitis is usually related to repeated infection by E. coli. ■ Signs and Symptoms Acute and chronic infections are manifested by: • Dysuria • Urinary frequency and urgency, similar to cystitis • Accompanying fever and chills (acute infections) • Low back pain or lower abdominal discomfort • Severe inflammation in the prostate, which may cause obstruction of the urinary flow through the urethra, resulting in a decreased urinary stream, hesitancy in initiating urination, incomplete bladder emptying, and nocturia or frequency • Systemic signs such as fever, malaise, anorexia, and muscle aching In nonbacterial prostatitis, the urinary signs are present, often intermittently, but the systemic signs are less marked. ■ Treatment Antibacterial drugs such as ciprofloxacin (Cipro) are recommended for bacterial infections. Follow-up tests should confirm complete eradication. Nonbacterial prostatitis can be treated by antiinflammatory drugs as well as by prophylactic antibacterials. Balanitis Balanitis is a fungal infection of the glans penis that can be transmitted during sexual activity. The fungus, Candida albicans, causes the infection primarily in uncircumcised males. Balanitis first appears as penile vesicles that later develop into patches that cause severe burning and itching. Diagnosis is accomplished by the identification of the presence of Candida. Treatment involves topical antifungal medications such as miconazole, tolnaftate, and clotrimazole. Inflammation and Infections Prostatitis The National Institutes of Health (NIH) recognizes four categories of prostatitis: • Category 1, acute bacterial • Category 2, chronic bacterial • Category 3, nonbacterial • Category 4, asymptomatic inflammatory It is considered an ascending infection or inflammation with multiple causes. The prostate is somewhat protected from ascending infection by the flushing action of urina- tion and ejaculation and by an intact mucous membrane. Also, the prostatic secretions contain antimicrobial factors. However, the close association of the male reproductive tract with the urinary tract, including the continuous mucosa, promotes the spread of infection through the structures, and prostatitis is therefore closely associated with urinary tract infections. The causes of the common nonbacterial form of prostatitis and prostatodynia (painful prostate) have not been established. ■ Pathophysiology Acute bacterial prostatitis causes a tender, swollen gland, typically soft and boggy on palpation. The urine contains large quantities of microorganisms, pus, and leukocytes. Expressed prostatic secretions also contain many organ- isms, confirming the source of the infection. However, this process may be painful and may actually spread the infection or cause bacteremia in acute cases. Nonbacterial prostatitis is indicated by large numbers of leukocytes in the urine and prostatic secretions, although the prostate gland is not markedly enlarged. In patients with chronic prostatitis the prostate is only slightly enlarged, irregular, and firm because fibrosis is more extensive. In most cases of prostatitis the urinary tract is infected and signs of dysuria, frequency, and urgency occur. Other parts of the reproductive tract (e.g., the epididymis or testes) may be involved as well. ■ Etiology Acute bacterial prostatitis is usually an ascending infection (it progresses up the urethra) and is caused primarily by Escherichia coli (E. coli) but sometimes by Pseudomonas, Proteus, Enterobacter, Klebsiella, Serratia, or Streptococcus faecalis. It occurs: • In young men in association with urinary tract infec- tions due to invasion by coliform bacteria from the intestines (see Chapter 18) • In older men with benign prostatic hypertrophy • In association with sexually transmitted diseases (STDs) such as gonorrhea • With instrumentation such as catheterization • Sometimes from hematogenous spread (through the blood) THINK ABOUT 19.2 a. Describe the appearance and functional changes in a baby boy with (1) epispadias and (2) hydrocele. b. Compare the typical signs of acute bacterial prostatitis, chronic bacterial prostatitis, and acute nonbacterial prostatitis. Tumors Benign Prostatic Hypertrophy ■ Pathophysiology Benign prostatic hypertrophy (BPH) is a common disorder in older men, with an estimated 50% of men over 65 years experiencing some form varying from mild to severe. Although called hypertrophy, the change is actually hyperplasia of the prostatic tissue with formation of nodules surrounding the urethra (Fig. 19.4). These changes lead to compression of the urethra and variable degrees CHAPTER 19 Reproductive System Disorders 519 FIG. 19.4 Prostatic hyperplasia. (From Cross S: Underwood’s Pathol- ogy: A Clinical Approach, ed 6, Churchill Livingstone, 2013, Elsevier.) BENIGN PROSTATIC HYPERTROPHY (BPH) NODULES (hyperplasia and hypertrophy) FORM IN THE INNER PROSTATE URETHRA IS COMPRESSED OBSTRUCTION TO FLOW OF URINE INCOMPLETE EMPTYING OF BLADDER Bladder distention HYDRONEPHROSIS Frequency INFECTION (cystitis) ASCENDS TO KIDNEYS (pyelonephritis) KIDNEY DAMAGE Difficulty initiating micturition Dribbling FIG. 19.5 Complications of benign prostatic hypertrophy. of urinary obstruction. Thus hyperplasia appears to be related to an imbalance between estrogen and testosterone that results from the hormonal changes associated with aging. No connection between BPH and prostatic carci- noma has been identified. Rectal examination reveals an enlarged gland. Incom- plete emptying of the bladder due to the obstruction leads to frequent infections (Fig. 19.5). Continued obstruc- tion causes a distended bladder, dilated ureters, hydro- nephrosis, and possible renal damage (see Chapter 18). If significant obstruction and urinary retention develop in the patient, surgical intervention, using one of several techniques, is required. ■ Signs and Symptoms The initial signs indicate obstruction of urinary flow. Hesitancy, dribbling, and decreased force of the urinary stream are direct results of the narrowed urethra. Incom- plete bladder emptying leads to frequency, nocturia, and recurrent urinary tract infection. ■ Treatment Only a small percentage of cases require intervention. Drugs to reduce the androgenic effects and slow nodular growth include dutasteride (Avodart). When surgery is not desirable, alpha-adrenergic blockers such as tam- sulosin (Flomax) relax smooth muscle in the prostate and bladder, resulting in increased flow of urine. A com- bination of finasteride (Proscar) and doxazosin (Cardura) has been shown to greatly reduce the progression of hypertrophy and possible obstruction of the urethra. Surgery may be recommended when obstruction is severe, and several procedures are available. Choice depends on the man’s overall health status and the degree of obstruction. Cancer of the Prostate Prostate cancer is common in men older than 50 years and ranks high as a cause of cancer-related death in men. The American Cancer Society estimated that in 2017 there will be 161,360 new cases of prostate cancer in the United States resulting in 26,730 deaths, which is the second- leading cause of death from cancer in American men. One in seven men is expected to develop prostatic cancer during their lifetime. ■ Pathophysiology Most tumors are adenocarcinomas arising from the tissue near the surface of the gland (rather than in the central area, as in BPH). There may be more than one focus of neoplastic cells. Tumors vary in degree of cellular differentiation; the more undifferentiated or anaplastic tumors are much more aggressive, growing and spreading at a faster rate. Many tumors are androgen dependent. Prostate cancer is both invasive to regional tissues such as lymph nodes or urethra and metastatic to bone (Fig. 19.6). With better screening of men older than 50 years for this cancer, many more individuals are being diagnosed in earlier stages than in the past. Five-year survival rates vary considerably: Localized cancers have a 100% survival rate, whereas regional spread reduces the rate to 89%, and distant metastases of bone or other organs have a 37% survival rate. 520 SECTION III Pathophysiology of Body Systems Note that BPH alone does not predispose to prostatic cancer. ■ Signs and Symptoms A hard nodule in the periphery of the gland, often in the posterior lobe, may be detected on digital rectal examination. The tumor tends not to cause early urethral obstruction because of its location. As the tumor develops, some obstruc- tion occurs, producing signs of hesitancy, a decreased stream, urinary frequency, or bladder infection (cystitis). ■ Diagnostic Tests Two serum markers are helpful—prostate specific antigen (PSA), which provides a useful screening tool for early detection as well as supportive data for the diagnosis, and prostatic acid phosphatase, which is elevated when metastatic cancer is present. PSA may be elevated with BPH or infection, so it is not diagnostic by itself, and there have been false-positive and false-negative results. These serum markers may be useful in monitoring the effectiveness of treatment. It is recommended that all men older than age 50 be tested regularly. Men who are considered high risk for prostatic cancer due to ethnicity or family history should begin testing at age 45. Ultrasonography using a small ultrasound probe and biopsy confirm the diagnosis. Bone scans and monoclonal antibody scans are useful for detecting early metastases. Diagnosis is based on three criteria: an elevated PSA, abnormality on digital rectal exam, and biopsy results, which are expressed as a numeric value based on the Gleason scale, which is based on the proportion of abnormal cells present in the biopsy specimen. ■ Treatment Surgery (radical prostatectomy) and radiation (including implants) are the treatments of choice. There is risk of impotence or incontinence. When the tumor is androgen sensitive, orchiectomy (removal of the testes) or antites- tosterone drug therapy (e.g., flutamide [Euflex]) may be suggested to reduce hormonal effects. New chemotherapy protocols are now in clinical trials. Approximately 30% of men deemed “cured” have a recurrence of the cancer after 5 years. Cancer of the Testes Benign tumors of the testes are extremely rare, and the majority of tumors that occur in the testes are malignant, arising from germ cells. Although testicular cancer is not common, with about 1 in 263 men being affected during their lifetime, there is concern because it occurs primarily in the 15- to 35-year-old age group and the incidence is increasing. The cause for the increase in cases is not known, and the rate of increase has slowed recently. Testicular cancer is the most common solid tumor in young men. Certain types of testicular cancer may occur in other groups, such as younger children or older males. ■ Etiology Five to ten percent of prostatic cancers are caused by inherited mutations, and the mutation in the HPC1 gene, which has been identified as the cause of these cancers. Other causes include high androgen levels (either intrinsic or extrinsic), increased insulin-like growth factor, and recurrent prostatitis. Prostatic cancer is common in North America and Northern Europe but not in countries farther east. The incidence is higher in the African American population than in Caucasians, indicating a possible genetic factor. Testosterone receptors are found on cancer cells. A B FIG. 19.6 Carcinoma of prostate. A, Schematic of prostate tumor. B, Carcinoma of the prostate extending into the rectum and urinary bladder. (B from Damjanov I, Linder J: Pathology: A Color Atlas, St. Louis, 2000, Mosby.) CHAPTER 19 Reproductive System Disorders 521 ■ Etiology This tumor has a heredity pattern with a change in chromosome number 12 in some families, and there is a possible relationship with infection or trauma. An established predisposing factor is cryptorchidism, or maldescent of the testes. ■ Signs and Symptoms Testicular tumors present as hard, painless, usually unilateral masses. The testis may be enlarged or may feel heavy. Eventually there may be a dull aching pain in the lower abdomen. In some cases, hydrocele or epididymitis may develop because of inflammation, or gynecomastia (enlarged breasts) may become evident if hormones are secreted by the tumor. ■ Diagnostic Tests Tests such as ultrasound, computed tomography (CT) scans, and lymphangiography and the presence of tumor markers (e.g., AFP and hCG) are useful in diagnosis. If a solid mass is seen during diagnostic imaging, surgical removal of the entire testis is done rather than a local biopsy of the mass. This is done to reduce the possibility of spread of tumor cells. ■ Treatment Treatment of testicular cancer using a combination of surgery (orchiectomy), radiation therapy, and sometimes chemotherapy has greatly improved the prognosis. Orchiectomy does not usually interfere with sexual function. However, radiation or chemotherapy may temporarily reduce fertility for a few months. Men who are scheduled for these treatments may wish to consider sperm banking before the procedure. Cancer cells are not transmitted in the semen. For this reason, regular monthly testicular self-examination is recommended to check for an unusual hard mass. Illustrated instructions are available from The American Cancer Society and medical clinics. ■ Pathophysiology Testicular cancer may originate from one type of cell, for example, a seminoma, or may be mixed, consisting of cells from a variety of sources and with varying degrees of differentiation. A teratoma consists of a mixture of different germ cells (Fig. 19.7). A common mixed tumor is a teratoma, derived from one or more of the germ cell layers, combined with an embryonal carcinoma, which has poorly differentiated cells. Some malignant tumors secrete human chorionic gonadotropin (hCG) or alpha-fetoprotein (AFP), which serve as a useful serum marker for both diagnosis and follow-up monitoring. Some testicular neoplasms may spread at an early stage, for example, choriocarcinoma, whereas others, such as seminomas, remain localized for a more prolonged period. Testicular tumors follow a typical pattern when spreading, first appearing in the common iliac and paraaortic lymph nodes and then in the mediastinal and supraclavicular lymph nodes. Metastases spreading through the blood to the lungs, liver, bone, and brain occur at a later time. Several staging systems are used, based on the extent of the primary tumor, the degree of lymph node involve- ment (retroperitoneal or otherwise), and the presence of distant metastases. Malignant tumor Spermatic cord FIG. 19.7 Cancer of the testes-spermatic cord and left testis with mixed embryonal teratoma and choriocarcinoma. (Courtesy of R.W. Shaw, MD, North York General Hospital, Toronto, Ontario, Canada.) THINK ABOUT 19.3 a. Compare BPH and prostatic cancer in terms of the characteristic location of the tumor and the early signs. b. List the factors predisposing patients to testicular cancer. c. Explain the signs of cancer of the testes and differentiate early from later signs. d. Explain why bone scans can be important in determining the prognosis of prostatic cancer. Disorders of the Female Reproductive System Review of the Female Reproductive System Structure and Function The female external genitalia, or vulva, include the mons pubis, labia, clitoris, and vaginal orifice. The mons pubis 522 SECTION III Pathophysiology of Body Systems or introitus is situated between the urethral meatus (anterior) and the anus (posterior) (Fig. 19.8). The vagina is a muscular, distensible canal extending upward from the vulva to the cervix. It is lined with a mucosal mem- brane and falls in rugae, or folds, allowing expansion during coitus (intercourse) or childbirth. The mucosa consists of stratified squamous epithelial cells, which are hormone sensitive. This mucous membrane is continuous up through the uterus and fallopian tubes, enabling the consists of the adipose tissue and hair covering the symphysis pubis. The labia majora, the outer fold, and the labia minora inside it are long, thin folds of skin extending back and down from the mons pubis, protecting the orifices. Sebaceous glands and sweat glands are located in the folds. The clitoris is a small projection of erectile tissue located anterior to the urethra. It is analogous to the male penis and is very sensitive to touch. In the vagina, the entryway to the reproductive tract, the orifice S A I P Ovarian ligament Suspensory ligament (of uterine tube) Uterine tube Body of uterus Fundus of uterus Round ligament Vesicouterine pouch Parietal peritoneum Urinary bladder Pubic symphysis Urethra Clitoris Labium minus Vagina A Anus Fornix of vagina Coccyx Cervix Rectouterine pouch (of Douglas) Uterosacral ligament Ureter Labium majus Sacral promontory UterusOvary Fallopian tube B FIG. 19.8 Female Reproductive Organs. A, Diagram (sagittal section) of pelvis showing location of female reproductive organs. B, Ovaries, fallopian tubes, uterus, and vagina of a postmenopausal woman. Note the relative sizes of the structures. (A, From Patton KT, Thibodeau GA: Anatomy & Physiology, ed 8, St Louis, 2013, Mosby. B, Courtesy of R.W. Shaw, MD, North York General Hospital, Toronto, Ontario, Canada.) CHAPTER 19 Reproductive System Disorders 523 The female gonads are the ovaries, which produce the ova (the female gamete), one each month during the reproductive years between menarche (onset) and menopause. The two ovaries are suspended by ligaments, one on either side of the uterus. These ovaries supply the ovum and the sex hormones for the female, primarily estrogen and progesterone, on a cyclic basis (Fig. 19.9). The female breast plays a significant role in the reproductive system. It responds to cyclic hormonal changes and is responsible for lactation, the provision of breast milk to the newborn. Mammary tissue develops under the influence of increased estrogen secretion, commencing at puberty. The breast consists of 15 to 20 lobes supported by ligaments. Muscle and fatty tissue are interspersed among the lobes and their subunits, the lobules and the acini. The acini are the basic functional units of the breast tissue, consisting of epithelial cells that secrete milk and contracting cells that move the milk into ducts. The breast tissue also has a system of collecting and ejecting ducts for milk that culminate in openings in the nipple. The breast is well supplied with blood vessels, lymphatics, and nerves. Sebaceous glands are found in the areola, the pigmented tissue surrounding the nipple (Fig. 19.10). During the menstrual cycle, the higher estrogen and progesterone levels increase both the vascularity of the breast and the proliferation and dilation of the ducts, leading to increased fullness and tenderness of the breasts premenstrually. It is recommended that breast self- examination be performed shortly after the conclusion of menses, when hormone levels are low and the breasts are small and less nodular. This examination should be performed at the same time each month to allow com- parison of the normal characteristics of the breast. Postmenopausally, examination should be done at regular intervals such as the day of the month the woman’s birthday falls on. Hormones and the Menstrual Cycle Hormonal secretions, release of ova, and associated endometrial changes occur in a cyclic pattern in women during the reproductive years (see Fig. 19.9). The average cycle is 28 days, but a range of 21 to 45 days is considered normal. Some women experience irregular menstrual cycles. The cycle consists of the following phases: • First, menstruation, or menses, occurs (the sloughing of the endometrial tissue that occurs when implantation of the ovum has not occurred). • The endometrial proliferation stage follows, when increasing FSH is secreted by the anterior pituitary gland, resulting in maturation of an ovarian follicle. • The maturing follicle secretes estrogen, causing pro- liferation or thickening of the functional layer of the endometrium. • At midpoint, as LH levels greatly increase, ovulation takes place with release of the mature ovum. spread of infection. After menopause and the decline in estrogen secretions, the mucosa becomes thin and fragile. Bartholin glands (the greater vestibular glands) are located on either side of the vaginal orifice and secrete mucus in response to sexual stimulation to facilitate penile penetration into the vagina during intercourse. Skene glands, located by the external urethral meatus, also secrete mucus to keep the tissues moist. Both of these sets of mucus-secreting glands are easily obstructed and infected. Leukorrhea, the normal vaginal discharge, is produced by these glands; the secretions are relatively clear or whitish and contain mucus and sloughed cells. The amount fluctuates during the menstrual cycle. Before puberty and after menopause vaginal pH is around 7, but during the reproductive years it is more acidic, between 4 and 5, due to an increased population of Lactobacillus. The acidic pH and the thickness of the epithelium provide protection against infection. The upper vagina surrounds the cervix, which is the lower part or neck of the uterus. The endocervical canal is the passageway between the internal os of the cervix at the uterine end and the external os at the vaginal end. The external os is a small opening filled with thick mucus that acts as a barrier to vaginal flora attempting to ascend into the uterus. The lining of the endocervical canal is continuous with that of the uterus and the vagina but differs in composition. The endocervical canal is lined with columnar epithelial cells, which change to squamous epithelium in the vagina. The point of change is known as the transformation zone or squamous-columnar junction, and this is the common site of cervical dysplasia and cancer. The uterus is a muscular sac within which a fertilized ovum may be implanted and develop. Note the relative sizes of the uterus and other structures in Fig. 19.8. The pear-shaped body of the uterus is called the corpus. It is loosely suspended by ligaments in the pelvic cavity to allow for expansion during pregnancy. Normally it is anteverted, or tipped forward, resting on the urinary bladder (see Fig. 19.8). The uterine wall is made up of three layers: the outer perimetrium or parietal peritoneum; the thick, middle layer of smooth muscle, or myometrium; and the inner endometrium. The endometrium consists of a functional layer that is responsive to hormones during the menstrual cycle and an underlying basal layer that is responsible for the regeneration of the endometrium after menses. The two fallopian tubes (oviducts) originate near the top of the uterus, just under the fundus, the top part of the corpus. Each tube curves up and out, ending in a flared opening over the ovary. This end portion has a fringe of fimbriae, moving fingerlike projections that draw the released ovum into the tube. Cilia and peristaltic movements in the fallopian tube continue to move the ovum toward the uterus. Usually the ovum is fertilized by a sperm in the distal fallopian tube and then it con- tinues on to the uterus, where it is implanted at a suitable site in the endometrium. 524 SECTION III Pathophysiology of Body Systems in hormone levels and basal body temperature (early morning) that occur during the cycle may be useful in determining the anticipated time of ovulation or fertile periods in women. • The ovarian follicle is now converted by LH into the corpus luteum, which increases production of progesterone. • Progesterone enhances the development of endometrial blood vessels and glycogen-secreting glands in prepara- tion for the implantation of a fertilized ovum. If fertilization does not occur, estrogen and progesterone levels drop and the corpus luteum and endometrium degenerate, resulting in menstruation and beginning another cycle. Hormonal levels fluctuate considerably in the female during the cycle, a result of complex interactions involving the hypothalamus, the anterior pituitary, and the ovary (see Chapter 16). The feedback mechanism involves estrogen and progesterone acting on the anterior pituitary gland to control the release of LH and FSH. The changes Events in ovary Follicle Corpus luteum Endometrial changes Ovulation 0 5 10 15 20 25 Menses Preovulatory Day of menstrual cycle Hormone levels FSH Estrogen LH Progesterone Postovulatory FIG. 19.9 Female Reproductive Cycles. (From Gartner L, Hiatt, J: Color Textbook of Histology, ed 3, Philadelphia, 2007, Saunders.) THINK ABOUT 19.4 a. Describe the location and structure of (1) the ovary, (2) the cervix, and (3) the labia. b. Describe the lining of the reproductive tract in sequence from the vagina through the fallopian tubes. c. At what time in the menstrual cycle is the level of the following hormones high, and what is the effect of this elevation? (1) LH, (2) progesterone, (3) estrogen, and (4) FSH CHAPTER 19 Reproductive System Disorders 525 and repeated pregnancies separated by short intervals. A genetic component also appears to be a factor. The effects often become apparent some years after the original injury has occurred, usually around menopause, when the decreasing hormonal levels contribute further to tissue atrophy. More than one structure may be affected in any one individual. Uterine displacement or prolapse is the descent of the cervix or uterus into the vagina (see Fig. 19.11B). Prolapse is classified as: • First degree if the cervix drops into the vagina • Second degree if the cervix lies at the opening to the vagina and the body of the uterus is in the vagina • Third degree (procidentia) if the uterus and cervix protrude through the vaginal orifice Although the early stage of prolapse may be asymptom- atic, the more advanced stages cause discomfort and a feeling of heaviness in the vagina. Protrusion of the cervix causes irritation and infection. Prolapse may be treated by surgery or by using a pessary (support device) to maintain the uterus in position. A cystocele is a protrusion of the urinary bladder into the anterior wall of the vagina (see Fig. 19.11C). The bladder cannot be emptied completely, and recurrent cystitis is common. A rectocele is a protrusion of the rectum S A I P S L I RSuspensory ligaments (of Cooper) Adipose tissue Nipple pores Lactiferous sinus Lactiferous duct Duct Ductule Alveolus Pectoralis major muscle Fascia of pectoral muscles Intercostal muscle Clavicle Pectoralis major muscle Alveoli Areola (with areolar glands) Nipple A B FIG. 19.10 The Female Breast. A, Sagittal section of a lactating breast. Notice how the glandular structures are anchored to the overlying skin and to the pectoral muscles by the suspensory liga- ments of Cooper. Each lobule of glandular tissue is drained by a lactiferous duct that eventually opens through the nipple. B, Anterior view of a lactating breast. Overlying skin and connective tissue have been removed from the medial side to show the internal structure of the breast and underlying skeletal muscle. In nonlactating breasts, the glandular tissue is much less prominent, with adipose tissue making up most of each breast. (From Patton KT, Thibodeau GA: Anatomy & Physiology, ed 8, St. Louis, 2013, Mosby.) Structural Abnormalities The normal position of the uterus is slightly anteverted (tipped forward) and anteflexed (bent forward over the bladder), with the cervix downward and back. The posi- tion of the uterus may vary because of a minor congenital anatomic alteration, childbirth, or a pathologic condition such as scar tissue or a tumor. Examples of uterine displacement are shown in Fig. 19.11A. A retroverted uterus is tipped backward. The uterus may be excessively curved or bent, either retroflexed (bent backward) or anteflexed (bent forward). In most cases, there are no deleterious effects from such changes in position. In some cases, infertility may result if the cervix is not positioned appropriately to facilitate the passage of sperm. Often malposition does not cause any symptoms. Marked retroversion may cause back pain, dysmenorrhea (painful menstruation), and dyspareunia (painful intercourse). With aging or excessive stretching or trauma, the supporting ligaments, fascia, and muscles for the uterus, bladder, and rectum may become weakened (pelvic relaxation), and these organs may shift out of their normal position in the pelvis. Factors predisposing patients to this condition include difficult childbirth including prolonged labor, multiple births, birth of a large baby, 526 SECTION III Pathophysiology of Body Systems such as tumors, stress, sudden weight loss, eating dis- orders, or participation in competitive sports, leading to reduced body fat. Systemic factors such as anemia or chemotherapy may also cause secondary amenorrhea. Dysmenorrhea refers to painful menstruation and may be primary or secondary. Primary dysmenorrhea has no organic foundation and develops when ovulation com- mences. The majority of women experience some dis- comfort, but for many the pain is sufficient to interrupt normal activities. In many cases, dysmenorrhea is relieved after childbirth. The severe cramping pain is related to the excessive release of prostaglandin during endometrial shedding. This prostaglandin causes strong uterine muscle contractions and ischemia. Pain develops 24 to 48 hours before or at the onset of menses and lasts for 24 to 48 hours. In addition, nausea and vomiting, headache, and dizziness may accompany the cramps as the prostaglan- dins enter the systemic circulation. Some relief may be afforded by the use of a heating pad, exercise, or medica- tions such as ibuprofen (Advil), a nonsteroidal antiinflam- matory drug, that inhibits prostaglandin synthesis. An alternative treatment is the use of oral contraceptives, into the posterior wall of the vagina (see Fig. 19.11D). The mass may be small or large enough to drop into the vaginal opening. Interference with defecation and a feeling of pressure in the pelvis are the common indicators. Rectocele and cystocele, if severe, require surgical repair. Menstrual Disorders Menstrual Abnormalities Amenorrhea, or absence of menstruation, may be primary or secondary. In the primary condition, menarche has never occurred. This may result from a genetic disorder such as Turner syndrome (a chromosome abnormality, XO, in which the ovaries do not function). Congenital defects affecting the hypothalamus, central nervous system, or pituitary or congenital absence of the uterus and congenital uterine hypoplasia (infantile uterus) may also interfere with the normal process. Secondary amenor- rhea is the cessation of menstruation in an individual who previously experienced menstrual cycles. It frequently results from an impediment in the hypothalamic–pituitary axis. The hypothalamus may be suppressed by conditions Normal position of uterus First-degree prolapse (uterus enters vagina) Rectum Anteflexion Uterus flexed anteriorly on itself Normal Retrocession Normal Retroflexion-flexion posteriorly Abnormal uterine positions Uterine prolapse B D C A Cystocele Urinary bladder bulges into vagina Rectum bulges into vagina Rectocele Normal— uterus flexed 45 degrees anteriorly Retroversion Normal BladderColon Third degree Second degree First degree Bladder Second-degree prolapse (uterus drops through vagina) Third-degree prolapse (procidentia) (cervix is outside vagina) FIG. 19.11 Structural abnormalities of the uterus. CHAPTER 19 Reproductive System Disorders 527 The primary manifestation of endometriosis is dys- menorrhea. The pain may persist throughout menses and typically becomes more severe each month. Dyspa- reunia, or painful intercourse, may occur if the vagina and supporting ligaments are affected by adhesions. The cause of endometriosis has not been established. Proposed mechanisms include migration of endometrial tissue up through the fallopian tubes into the peritoneal cavity during menstruation, development from embryonic tissue at other sites, spread of endometrium through the blood or lymph, or transplantation of tissue during surgery such as a cesarean section. Treatment measures include hormonal suppression of the endometrial tissue, with relief of the pain associated with the monthly cycle, or surgical removal of the ectopic endometrial tissue. Pregnancy and lactation also result in amenorrhea and atrophy of the ectopic tissue. These measures do not cure endometriosis, but they do delay further damage and alleviate the symptoms. which lead to anovulatory cycles that are not painful. Secondary dysmenorrhea results from pelvic disorders such as endometriosis, uterine polyps or tumors, or pelvic inflammatory disease (PID). Abnormal menstrual bleeding is a common concern. Examples of abnormal patterns include: • Menorrhagia (increased amount and duration of flow) • Metrorrhagia (bleeding between cycles) • Polymenorrhea (short cycles of less than 3 weeks) • Oligomenorrhea (long cycles of more than 6 weeks) The usual cause of an altered pattern is lack of ovulation; however, this condition may also result from hormonal disorders such as thyroid abnormalities or pathologic condi- tions such as tumors. Any change in the woman’s individual pattern is significant and should be investigated. Premenstrual syndrome (PMS) is a condition that begins a week or so before the onset of menses and ends with the onset of menses. The cause is not completely under- stood, but research on hormonal factors continues. In most women PMS causes nuisance symptoms such as breast tenderness, weight gain, abdominal distention or bloating, irritability, emotional lability, sleep disturbances, depression, headache, and fatigue. Some women have increased mental concentration and activity, whereas others are lethargic. These manifestations are severe in 3% to 8% of women reporting PMS; the more severe form of the disorder is termed premenstrual dysphoric syndrome. Treatment measures are tailored to the indi- vidual and may include hormonal therapy and the use of diuretics or antidepressants as necessary. Endometriosis Endometriosis affects about 5 million women in the United States and is defined as the presence of endometrial tissue outside the uterus on structures such as the ovaries, ligaments, or colon (Fig. 19.12). On occasion, it may affect distant sites such as the lungs. This ectopic endometrium responds to cyclic hormone variations, growing during the proliferation and secretory stages of the menstrual cycle and then degenerating, shedding, and bleeding. Because there is no exit point for this blood and blood is irritating to tissues when it does not belong there, local inflammation and pain result. The inflammation recurs with each cycle and eventually causes the develop- ment of fibrous tissue. Although it may be possible to palpate nodular tissue, the diagnosis is confirmed by laparoscopy. Fibrous tissue may cause adhesions and obstruction of the involved structures, such as the urinary bladder or colon. When the uterus is pulled out of its normal position (e.g., into retroversion) by adhesions, infertility frequently results. The fallopian tube may be blocked or the ovary covered by fibrous tissue, preventing movement of the ovum into and through the tube, ultimately causing infertility. When endometrial tissue occurs on the ovary, a “chocolate cyst” develops, a fibrous sac containing old brown blood (see Fig. 19.12B). THINK ABOUT 19.5 a. Describe each of the following: (1) second-degree uterine prolapse, (2) cystocele, and (3) retroversion of the uterus. Explain the secondary problems that may occur with second- or third-degree prolapse. b. Differentiate the following terms from one another: (1) dysmenorrhea, (2) premenstrual syndrome, and (3) menorrhagia. c. Explain the process by which endometriosis can cause infertility. Infections and Inflammation Many infections of the vagina (vaginitis) and cervix (cervicitis) are considered STDs and are included in the section on these diseases later in this chapter. Other inflammations of the female reproductive organs often caused by infections include salpingitis (inflammation of the oviduct or fallopian tube), urethritis (inflammation of the urethra), oophoritis (inflammation of the ovaries), and mastitis (inflammation of the mammary gland). In addition to infections caused by organisms passed on through sexual contact, other infections may arise through non–sexually transmitted organisms such as Staphylococcus aureus, which is the bacteria primarily responsible for toxic shock syndrome and mastitis. Candidiasis Candidiasis is one form of vaginitis that is not sexually transmitted. It is a yeast infection caused by C. albicans (Monilia) and usually occurs as an opportunistic superficial infection of mucous membranes or skin (see Fig. 6.7). Infection may follow antibiotic therapy for an unrelated bacterial infection elsewhere in the body (which creates a more alkaline pH and upsets the balance of resident 528 SECTION III Pathophysiology of Body Systems Pelvic Inflammatory Disease PID is an infection of the reproductive tract, particularly the fallopian tubes and ovaries. The condition includes cervicitis endometritis (uterus), salpingitis, and oophoritis. The infection may be acute or chronic. PID is a common problem and is a matter of concern because of the potential acute complications such as peritonitis and pelvic abscess as well as the long-term problems of infertility and the high risk of ectopic pregnancy. ■ Pathophysiology The infection usually originates as a vaginitis or cervicitis and is polymicrobial, often involving several causative bacteria. The microbes ascend through the uterus into Posterior surface of uterus and uterosacral ligaments Umbilicus Anterior cul-de-sac and bladder Perineum Cervix Appendix Ileum Ovary Uterine wall Fallopian tube Posterior cul-de-sac Colon A B Peritoneum FIG. 19.12 Endometriosis. A, Possible ectopic sites. B, Distended uterus with the development of endometriosis (dark purple patches). (B From Huether S, McCance K: Understanding Pathophysiol- ogy, ed 6, St. Louis, 2017, Elsevier.) flora) or may develop because of decreased resistance (e.g., in immune-deficiency states) or increased glycogen or glucose levels in the secretions (e.g., with pregnancy, use of oral contraceptives, or diabetes). Candidiasis causes red and swollen pruritic mucous membranes and a thick, white, curdlike discharge. White patches may adhere to the vaginal wall. Dysuria (painful urination) and dyspareunia (painful intercourse) may be present. Short-course treatment can include medications such as butoconazole (Gynazole-1), clotrimazole (Gyne- Lotrimin), miconazole (Monistat 3), and terconazole (Terazol 3). For long-course treatment, azole medications are effective. To prevent recurrence, the predisposing factors need to be addressed. CHAPTER 19 Reproductive System Disorders 529 ■ Etiology The majority of infections arise from STDs such as gonor- rhea (Neisseria gonorrhoeae) and chlamydiosis (Chlamydia trachomatis). Multiple organisms are present in many cases. Other potential agents include Bacteroides, Gard- nerella vaginalis, group B streptococci, E. coli, Pseudomonas, Haemophilus influenzae, and Enterococcus. A prior episode of vaginitis or cervicitis, often with few signs, frequently precedes the development of PID. Infec- tion is likely to become acute during or immediately after menses, when the endometrium is more vulnerable. PID may also result from insertion of an intrauterine device (IUD, a contraceptive device) or other instrument contaminated by organisms from the lower reproductive tract or other source. Any instrument or device is likely to traumatize the tissue or perforate the wall, leading to inflammation and infection (see Fig. 19.13B—note the adhesions around the IUD). Infection may also be associ- ated with abortion or childbirth. Historically PID was the fallopian tubes (Fig. 19.13). The early stage of inflam- mation promotes additional invasion of bacteria into the mucosa. The tubal walls become edematous, and the lumen is filled with purulent exudate, effectively obstruct- ing the tube and restricting drainage into the uterus. The exudate drips out of the fimbriae onto the ovary and surrounding tissue. The peritoneal membranes attempt to localize the infection initially, but peritonitis may develop (see Chapter 17). Abscesses may form as the inflammatory response struggles to contain or wall off the infection. Pelvic abscesses may be life threatening if not quickly drained surgically. Infection may spread, resulting in septicemia. The most common cause of death in women with PID is septic shock. Adhesions and strictures are common sequelae; they affect the tubes and ovaries, leading to infertility or ectopic pregnancy (implantation of the fertilized ovum in the fallopian tube). Adhesions or scar tissue may also affect the surrounding structures such as the colon. B Adhesions formed Ovary SALPINGITIS Fallopian tube opens into peritoneal cavity Peritoneum CERVICITIS VAGINITIS Uterosacral ligament ENDOMETRITIS Ascending infection OOPHORITIS PERITONITIS— Infection spreads into peritoneal cavity Uterus A FIG. 19.13 Pelvic Inflammatory Disease. A, Spread of infection. B, Uterus perforated by intrauterine device (IUD) leads to localized inflammation in peritoneal cavity and omentum forming adhesions around IUD. (B, Courtesy of R.W. Shaw, MD, North York General Hospital, Toronto, Ontario, Canada.) 530 SECTION III Pathophysiology of Body Systems hormone dependent, growing rapidly during pregnancy and decreasing in size with increasing fibrosis after menopause. Fibroids are often asymptomatic until they grow large enough to be palpated. Abnormal bleeding such as menorrhagia may be an indicator of fibroid development. Large tumors may cause pressure on adjacent structures, leading to urinary frequency or constipation and a heavy sensation in the lower abdomen. Large fibroids may interfere with implantation of the fertilized ovum or the course of pregnancy. Treatment of large tumors involves hormonal therapy or surgery. Ovarian Cysts A variety of cysts occur frequently on the ovaries. Fol- licular and corpus luteal cysts are common and develop unilaterally in both ruptured and unruptured follicles. These functional ovarian cysts last approximately 8 to 12 weeks and disappear without complications. They are usually multiple small, fluid-filled sacs located under the serosa covering the ovary. On occasion, a cyst may become large enough to cause discomfort, urinary reten- tion, or menstrual irregularities (Fig. 19.15). Bleeding resulting from rupture can cause more serious inflam- mation in the peritoneal cavity and requires surgical intervention. With a large cyst there is also risk of torsion of the ovary. Ultrasound examination or laparoscopy can be used to identify a cyst. Polycystic Ovarian Syndrome In polycystic ovarian syndrome, or Stein–Leventhal syn- drome, large ovaries containing cysts and covered with a thick capsule develop (Fig. 19.16). Associated hormonal abnormalities include elevated androgen, estrogen, and LH levels and decreased FSH levels. The usual fluctuations or peaks in FSH and LH are missing. Ovulation does not occur. The basic problem is a dysfunc- tion in the hypothalamic–pituitary control system. The cause is unknown, although in some women an inherited factor has been demonstrated. Young women manifest hirsutism (abnormal hairiness), amenorrhea, and infertility. Medications such as clomiphene, an antiestrogen agent, may stimulate ovulation, or surgical wedge resections of the ovaries may help control the hormone levels. Oral contraceptives are used to reduce androgen secretions and masculinization effects. In women who have insulin resistance, treatment with an antihyperglycemic drug such as metformin may result in ovulation. Fibrocystic Breast Disease Also called benign breast disease or fibrocystic change, this includes a broad range of breast lesions. There is some confusion between the normal physiologic changes in the breast that occur during the menstrual cycle and abnormal or pathologic changes. Fibrocystic disease refers the feared complication of illegal abortions or deliveries under primitive conditions. Occasionally infection in the reproductive tract may result from blood-borne organisms or from an infection in the peritoneal cavity related to conditions such as appendicitis. ■ Signs and Symptoms Lower abdominal pain is usually the first indication of PID. Pain may be sudden and severe or gradually increas- ing in intensity. Characteristically it is a steady pain that increases with walking. Tenderness is common during pelvic examination. Purulent discharge is evident at the cervical os. Dysuria may be noted. The presence and extent of fever and leukocytosis depend on which caus- ative organisms are involved. Peritonitis is indicated by increasing abdominal distention and rigidity. ■ Treatment Aggressive treatment with appropriate antimicrobials such as cefoxitin and doxycycline is required. Recurrent infections are common; therefore it is recommended that sexual partners be treated with antibiotics and that follow-up examinations are scheduled to ensure complete eradication of the infection. THINK ABOUT 19.6 a. Describe three factors predisposing patients to vaginal candidiasis, and identify the causative organism. b. Explain how infection in the vagina can cause PID. c. List the signs of PID and the reasons for them. d. Explain why PID is considered a serious condition. Benign Tumors Leiomyoma (Fibroids) A leiomyoma is a benign tumor of the myometrium, the cause of which is unknown. These uterine tumors are common in women during the reproductive years, occur- ring in more than 30% of women, particularly Asian and African American women. After menopause the tumors tend to shrink. As benign tumors, they are not considered precancerous. Fibroids are classified by location, developing in the uterine wall (intramural), beneath the endometrium (submucosal), or under the serosa (subserosal). The two latter forms may develop as polyps, with the submucosal type projecting inward into the uterine cavity and the subserosal type growing outward into the pelvic cavity (Fig. 19.14). Fibroids usually occur as multiple well-defined but unencapsulated masses, which vary widely in size. Large leiomyomas degenerate in the central region, undergoing necrosis and forming cysts. These benign tumors are CHAPTER 19 Reproductive System Disorders 531 Three categories of lesions have been designated, based on the risk of development of breast cancer: One category is nonproliferative lesions, which include microcysts and fibroadenomas. These are not considered precancerous. Fibroadenomas are specific benign tumors that appear as singular, movable masses. These tumors are usually excised. The second category includes proliferative lesions (with epithelial hyperplasia in the ducts) in which there are no atypical cells. The risk of developing breast cancer in to the presence of nodules or masses in the breast tissue that change during the menstrual cycle in response to fluctuating hormone levels, particularly estrogen. The connective tissue of the breast is gradually replaced by dense fibrous tissue. Increasing fluid in the breast during the secretory phase of the menstrual cycle accumulates in cysts bound by fibrous tissue, unable to escape. In addition, the epithelial cells in the ducts proliferate in response to hormones. The cysts enlarge over time, often causing more degeneration of normal tissue. ENDOMETRIAL POLYP (BENIGN)SUBSEROSAL LEIOMYOMA OVARIAN CYST (BENIGN) Ovary Corpus Isthmus Cervix Endocervical canal Vagina External os Vaginal wall Internal os Perimetrium Myometrium Endometrium Fallopian tube ENDOMETRIAL (UTERINE) CANCER OVARIAN CANCER CERVICAL CARCINOMA VULVAR CARCINOMA VAGINAL CARCINOMA SUBMUCOSAL LEIOMYOMA (BENIGN FIBROID) A Large fibroid with central degeneration Small fibroid B C FIG. 19.14 A and B, Types of benign uterine fibroids. C, Leiomyoma of the myometrium. (B, Courtesy of R.W. Shaw, MD, North York General Hospital, Toronto, Ontario, Canada. C, From Cross S: Underwood’s Pathology: A Clinical Approach, ed 6, Churchill Livingstone, 2013, Elsevier.) 532 SECTION III Pathophysiology of Body Systems Malignant Tumors Neoplasms of the breast, cervix, and uterus are covered in this section. Ovarian cancer is discussed in Chapter 20 as well as in this chapter. Carcinoma of the Breast Carcinoma of the breast is a common malignancy in women and a major cause of death. Rarely breast cancer occurs in males. The incidence of breast carcinoma continues to increase after age 20, and more women are developing the malignancy at a younger age. The National Cancer Institute of the NIH reports that in 2015 there were 231,840 new female cases in the United States resulting in 40,290 female deaths, and a 2016 report estimated 2600 new male cases and 440 male deaths. The overall incidence and mortality rate for this cancer have been increasing for a period of years, but now seem to be decreasing. The American Cancer Society estimates that there are currently 15.5 million survivors of breast cancer living in the United States. ■ Pathophysiology Malignant tumors develop in the upper outer quadrant of the breast in approximately half the cases; the central portion of the breast is the next most common location (see Fig. 20.2B). Most tumors are unilateral, although bilateral primary tumors may develop in some cases. There are different types of breast carcinomas, but the majority arises from cells of the ductal epithelium. This cancer infiltrates the surrounding tissue and fre- quently adheres to the skin, causing dimpling. The tumor becomes fixed when it adheres to the muscle or fascia of the chest wall. The malignant cells spread at an early stage, first to the nearby lymph nodes. Tumors in the upper outer quadrant and central breast area spread to the axillary lymph nodes. In most cases, several nodes are affected at the time of diagnosis. Widespread dissemination follows quickly, including metastases to the lungs, brain, bone, and liver (see Fig. 20.5 for illustration of breast cancer metastases). Tumor cells are graded on the basis of the degree of differentiation or anaplasia (see Chapter 20). The tumor is then staged based on the size of the primary tumor, the involvement of lymph nodes, and the presence of metastases. The presence of estrogen or progesterone receptors on the tumor cells is a major factor in determining how to treat the individual cancer. Such a tumor is hormone dependent because its growth is enhanced by the par- ticular hormone. ■ Etiology The majority of cases occur in women over age 50. A strong genetic predisposition has been supported by the this group increases if there is also a family history of breast cancer. The third category, a small one, requires monitoring, particularly if a family history of breast cancer is present. These lesions show proliferative changes with atypical cells. Breast biopsy can detect atypical cells and can differentiate benign from malignant cells. The cysts or nodules feel firm and movable and vary in size during the cycle. The effects are more marked before menstruation, with the breasts becoming heavy, painful, and tender. Treatment is largely symptomatic but may include dietary changes such as reduction of caffeine and fat intake and drugs such as the androgen danazol. Fluid may be aspirated from cysts. Cysts may be removed if they manifest premalignant changes. Often there is some improvement after menopause. 1 cm FIG. 19.15 Large ovarian cyst of borderline malignancy. (From Cross S: Underwood’s Pathology: A Clinical Approach, ed 6, Churchill Livingstone, 2013, Elsevier.) FIG. 19.16 Surgical view of polycystic ovaries. (From Huether S, McCance K: Understanding Pathophysiology, ed 6, St. Louis, 2017, Elsevier.) CHAPTER 19 Reproductive System Disorders 533 Chemotherapy and radiation (adjuvant therapy) are useful for eradicating any undetected micrometastases remaining in such a high-risk cancer, even with a very small localized mass, and are used as palliative measures as well. Current trials involve implants of radioactive seeds in surrounding tissue after surgery to provide localized radiation without the need for daily treatment. If the tumor proves to be responsive to estrogen, postoperative therapy includes removal of the hormonal stimulation. In a premenopausal woman, the ovaries are removed. A sequence of hormone-blocking agents such as tamoxifen (Nolvadex), raloxifene (Evista), and toremifene (Fareston) or similar agents targeting the estrogen receptors in the tumor reduces the risk of cancer recurrence in postmenopausal women. The drug fulves- trant (Faslodex) blocks estrogen receptors on cancer cells and signals the cell to destroy the receptors. There is some concern that selective estrogen receptor modulators inhibit estrogen receptors in breast cells, but may activate uterine cells, leading to endometrial proliferation. There is also a class of drugs that stop the body from making estrogen after menopause and includes the drugs anas- trozole (Arimidex), letrozole (Femara), and exemestane (Aromasin). Other targeted drug therapies include the following drugs: • Trastuzumab (Herceptin) and pertuzumab (Perjeta) help block the production of a growth factor protein, thus causing cancer cells to die. • Ado-trastuzumab (Kadcyla) combines trastuzumab with a cell-killing drug. • Lapatinib (Tykerb) also targets growth factor protein and can be used in combination with chemotherapy. • Palbociclib (Ibrance) is used in women with advanced hormone receptor–positive breast cancer. • Everolimus (Afinitor) targets a pathway that plays a role in the growth of cancer cells. It is used in combina- tion with exemestane in women with advanced breast cancer. • Women with stage III or IV breast cancer may receive bevacizumab (Avastin) to reduce the growth of blood vessels in secondary tumors. The prognosis is relatively good for tumors without nodal involvement, but as the number of lymph nodes affected by the cancer increases, the prognosis becomes more negative. Breast cancer may recur many years later, but generally the longer the time elapsed without recurrence, the lower the risk of recurrence. Current statistics with respect to prognosis can be found on the American Cancer Society website. Breast self-examination is recommended for all women older than 20 years as a measure to reduce mortality and identify cancers in an early stage. Indeed, many tumors are discovered by women during breast self-examination. Recent studies have questioned this practice, citing the risk of surgical biopsy when the lump is a benign cyst. It is important to note that the comparator group in this study was women who had a yearly breast exam by a identification of specific genes related to breast cancer, BRCA-1 and BRCA-2. Familial occurrence that is propor- tional to the numbers of affected relatives and the close- ness of the relationships has been well documented. The other major factor in the etiology of breast cancer is hormones—specifically, exposure to high estrogen levels. Circumstances such as a long period of regular menstrual cycles (for example, from an early menarche to late menopause), nulliparity (no children), and delay of the first pregnancy, all of which are associated with longer exposure to estrogen, appear to promote cancer development. The role of exogenous estrogen in oral contraceptives or postmenopausal supplements remains controversial. Current formulations for oral contraceptives containing reduced levels of estrogens have considerably reduced the risks. Other factors predisposing to breast carcinoma include fibrocystic disease with atypical hyperplasia, prior carcinoma in the uterus or in the other breast, and exposure of the chest to radiation (particularly in young women). Lack of exercise, smoking, and a high-fat diet have been identified as risk factors in some studies. Prior abortion does not increase the risk of developing breast cancer. Considerable research continues to identify nongenetic risk factors that may be modified during the woman’s life. ■ Signs and Symptoms The usual initial sign is a single small, hard, painless nodule. The mass is freely movable in the early stage but later becomes fixed. Other signs as the tumor becomes more advanced include dimpling of the skin, retraction of or discharge from the nipple, and a change in breast contour. Biopsy confirms the diagnosis of malignancy. ■ Treatment Surgery, combined with radiation and chemotherapy, provides effective treatment for many cases. Surgical removal of the tumor, involving minimal tissue loss as in a lumpec- tomy, is the preferred method in stage I and stage II, although a more radical approach involving a mastectomy may be necessary in more advanced cases. Either surgical approach may be combined with radiation after surgery. Women may opt for mastectomy and breast reconstruction if there is a strong genetic risk of recurrence of the cancer. In some cases hormone therapy may be used as well. In addition, some lymph nodes are removed according to the existing lymphatic pathway from the tumor. The number of lymph nodes removed depends on the spread of tumor cells. (The nodes are checked during surgery.) Subsequent surgical reconstruction may be desired by some patients. Removal or radiation of lymph nodes impairs lymphatic drainage from the arm, resulting in swelling and stiffness. Physiotherapy and exercise are important in maintaining mobility and reducing swelling. 534 SECTION III Pathophysiology of Body Systems skilled practitioner familiar with breast changes. Many women do not access such professionals on a regular basis. Mammography is used as a routine screening tool because it can detect lesions before they become palpable or masses deep in the breast tissue (Fig. 19.17). Ultrasound and magnetic resonance imaging (MRI) are also used to identify and characterize masses. Diagnostic testing of exudates from the breast or fine needle ductal biopsy through the nipple is also used in some settings. Each diagnostic measure has its strengths and weaknesses. It is important for the woman to discuss screening and diagnostic measures with her physician. Routine screening is shown to reduce mortality from breast cancer. A B FIG. 19.17 Mammogram showing bilateral invasive ductal carci- noma. A, Left breast. The larger mass was palpable. The smaller right mass was not palpable (arrow). B, Right breast. Multiple masses are shown. (From Powell DE, Stilling CB: Diagnosis and Detection of Breast Diseases, St. Louis, 1993, Mosby.) THINK ABOUT 19.7 a. Compare the signs of fibrocystic disease and breast cancer. b. Explain why chemotherapy and radiation may be recommended after surgery for breast cancer even when no lymph nodes appear to be involved. c. Explain the recommended treatment for estrogen- dependent breast cancer in premenopausal and postmenopausal women. d. Discuss the importance of breast cancer screening and early diagnosis. in situ. The American Cancer Society estimated 12,990 new cases of cervical cancer resulting in 4120 deaths in the United States in 2016. The average age at onset for carcinoma in situ is 35, whereas invasive carcinoma manifests at approximately age 45. Nearly one in five cancers is diagnosed after age 65; thus women need to be screened after menopause. More cases are occurring in women in their 20s and 30s. Hispanic American women have twice the risk of developing cervical cancers than women in other ethnic groups. Five-year survival rates for noninvasive cancer are 90%—with invasion the rate drops to 70%. ■ Pathophysiology The early changes in the cervical epithelial tissue consist of dysplasia, which is initially mild but becomes progres- sively more severe (Fig. 19.18). This dysplasia usually occurs at the junction of the columnar cells with the squamous epithelial cells of the external os of the cervix (the transformation zone). The majority of cervical car- cinomas arise from squamous cells. Cervical intraepithelial neoplasia is graded from I to III based on the amount of dysplasia and the degree of cell differentiation. Grade III consists of carcinoma in situ in which many disorganized, undifferentiated, abnormal cells are present (severe dysplasia). Because the time span from mild dysplasia to carcinoma in situ may be 10 years, there are many opportunities for detec- tion in this early stage. The Pap smear allows an examina- tion of scrapings of the cervical cells and those that slough from the site and are present in the local secretions. These cells indicate the presence of dysplasia long before any signs of cancer appear. Carcinoma in situ is a noninvasive stage, to be followed by the invasive stage. Fig. 19.19 illustrates the stages. Invasive carcinoma has varying characteristics, some- times appearing as a protruding nodular mass or perhaps as ulceration, and sometimes infiltrating the wall. Eventu- ally all characteristics are present in the lesion. As the carcinoma spreads in all directions into the adjacent tissues, including the uterus and vagina, it may also invade the uterine wall and extend into the ligaments, bladder, or rectum. Metastases to lymph nodes or distant sites occur rarely and at a very late stage. Staging of the carcinoma begins with stage 0, representing carcinoma in situ; stage I represents cancer restricted to the cervix; and stages II to IV indicate further spread to the surrounding tissues. ■ Etiology Cervical cancer is strongly linked to oncogenic STDs such as herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) strains 16, 18, 31, 34, or 45. The Centers for Disease Control and Prevention (CDC) defines cervical carcinoma as a sexually transmitted infection. The virus may exert direct effects on the host cell or may cause an antibody reaction; increased viral antibodies Carcinoma of the Cervix The number of cases of invasive cancer and the number of deaths from cervical cancer have declined by 74% with the increased use of the Papanicolaou (Pap) smear for screening and early diagnosis while the cancer is still CHAPTER 19 Reproductive System Disorders 535 Normal squamous epithelial cells in transformation zone of the cervix1. Dysplasia – mild2. Dysplasia – severe3. Malignant neoplasm4. Carcinoma in situ5. Invasive carcinoma6. decreased cell adhesion and invasion of local tissues, lymph nodes detected by Pap test; removal of irritant or carcinogen or DNA repair gene exposure to irritant or carcinogen changes cell DNA additional exposure to carcinogen; eg, viral infection (STD) alters DNA in dysplasic cells proliferation of undifferentiated cells superficial, small localized mass remains for some years FIG. 19.18 Development of carcinoma of the cervix. FIG. 19.19 Cancer of the Cervix. A, Positive Pap smear indicative of cervical cancer. B, Cervical intraepithelial neoplasia (stage II). C, Cervical intraepithelial neoplasia (CIN) stages. Lesions are predominantly around the external os. (A From Christiansen JL, Grzybowski JM: Biology of Aging, St Louis, 1993, Mosby. B From Huether S, McCance K: Understanding Pathophysiology, ed 6, St. Louis, 2017, Elsevier. C From Huether S, McCance K: Understanding Pathophysiology, ed 5, St. Louis, 2012, Elsevier, Mosby.) A CIN IIB Normal CIN 1 CIN 2 CIN 3 C have been associated with the increasing dysplasia. A vaccine (Gardasil) against HPV-6, HPV-11, HPV-16, and HPV-18 has been developed and shown to reduce the risk of cervical carcinoma. Gardasil immunization is recommended by the CDC for all girls before adolescence. In 2009 data from the Vaccine Adverse Event Reporting System prompted the Food and Drug Administration (FDA) to look into reports of dangerous adverse effects being reported by users of the vaccine. In 2014 it was reported by the CDC that initial research confirmed the 536 SECTION III Pathophysiology of Body Systems THINK ABOUT 19.8 a. Explain the following terms and give an example of each: (1) dysplasia, (2) carcinoma in situ, (3) carcinogenic, and (4) invasive. b. Explain how viruses can be carcinogenic. c. Explain why vaginal bleeding or abnormal discharge indicates a more advanced stage of cervical cancer. FIG. 19.20 Endometrial adenocarcinoma showing extensive myometrial invasion by the carcinoma. (From Cross S: Underwood’s Pathology: A Clinical Approach, ed 6, Churchill Livingstone, 2013, Elsevier.) malignant changes develop from endometrial hyperplasia, with the cells gradually becoming more atypical. Excessive estrogen stimulation appears to be the major factor in the development of hyperplasia. This cancer is a relatively slow-growing tumor and may infiltrate the uterine wall, leading to a thickened area, or it may mushroom out into the endometrial cavity (Fig. 19.20). Eventually the tumor mass fills the interior of the uterus and extends through the wall into the surrounding structures. Endometrial cancers are graded from 1, indicating well-differentiated cells, to grade 3, indicating poorly differentiated cells. Staging of the cancer is based on the degree of localiza- tion. In stage I, tumors are confined to the body of the uterus. In stage II, cancer is limited to the uterus and the cervix. In stage III, the cancer has spread outside the uterus but remains within the true pelvis; and in stage IV, the tumor has spread to the lymph nodes and distant organs. Five-year survival rate for stage I is 99%, stage II is 80%, stage III is 60%, and stage IV is 32%. ■ Etiology Individuals with a history of increased estrogen levels have a higher incidence of uterine cancer. Exogenous safety of the vaccine; however, the CDC and the FDA are continuing to monitor safety data. High-risk factors for cervical carcinoma include multiple sexual partners, promiscuous partners, participa- tion in sexual intercourse during the early teen years, and a patient history of STD. Other environmental factors, such as smoking, are considered to predispose women to cervical cancer. ■ Signs and Symptoms Cervical cancer is asymptomatic in the early stage but can be detected by the Pap test. The invasive stage is indicated by slight bleeding or spotting or a slight watery discharge. Anemia or weight loss may accompany the local signs. ■ Treatment Biopsy is used to confirm the diagnosis. Surgery combined with radiation (either an implant of radioactive material or external radiation—see Chapter 20) is the recommended treatment. The 5-year survival rate is 100% when the carcinoma is still in situ. The prognosis for a patient with invasive carcinoma depends on the extent of spread of the cancer cells. Carcinoma of the Uterus (Endometrial Carcinoma and Uterine Sarcomas) Carcinomas of the uterus remain a common cancer in women older than 40 years, with the majority of cases occurring in the 55- to 65-year age range. The American Cancer Society estimated that there would be 60,050 new cases diagnosed in the United States in 2016, resulting in 10,470 deaths. A simple screening test is not available for this cancer; the Pap test does not screen for it. However, the early indicator is excessive vaginal bleeding, which in a postmenopausal woman is a significant sign demand- ing investigation. ■ Pathophysiology Uterine cancers are derived from connective tissue or muscle and are termed leiomyosarcomas. These tumors have a poor prognosis and frequently have metastasized to the lungs by the time diagnosis is made. For more information on sarcomas, see Chapter 9. The majority of endometrial carcinomas are adeno- carcinomas arising from the glandular epithelium. The CHAPTER 19 Reproductive System Disorders 537 The lack of a reliable screening test and the hidden nature of the cancer hinder early diagnosis. A large mass may be detected by pelvic exam. Transvaginal ultrasound CT scans, MRI, pelvic exams, and CA125 (a protein whose high levels indicate ovarian cancer) tests are current tools for diagnosis. Treatment involves surgery and chemotherapy. Infertility Infertility, or sterility affecting a couple’s reproductive capacity, may be caused solely by male conditions, solely by female conditions, or by combined male and female factors. Each of these categories occurs in approximately equal proportions. A couple is considered infertile after a year of unprotected intercourse fails to produce a pregnancy. Infertility occurs in approximately 15% of couples in North America. Male problems include changes in sperm or semen, hormonal abnormalities, or physical obstruction of sperm passage. Semen analysis assesses specific charac- teristics such as the number, normality, and motility of sperm. Ability of the sperm to penetrate the cervical mucus and the presence of sperm antibodies are also considered. Hormonal imbalances may result from either pituitary disorders or testicular problems. Ductal obstructions may result from congenital problems or scar tissue related to prior events such as infection. Many drugs are now available for the treatment of erectile dysfunction. Decreased fertility has many possible causes: • Infertility may be associated with hormonal imbalances resulting from altered function of the hypothalamus, anterior pituitary gland, or ovaries/testes. Altered function may occur in women after the use of oral contraceptives. For example, the feedback system may not be functioning or may be suppressed by stress, extreme exercise, or training, or the ovaries may be abnormal (e.g., in the Stein–Leventhal syndrome). • Increasing age of the parents at the time of the first attempt at conception is another possible cause. • Structural abnormalities may prevent pregnancy, for example, a small or bicornuate (divided) uterus or uterine fibroids. • The fallopian tubes, epididymis, or vas deferens may be obstructed by scar tissue resulting from infection or endometriosis. • Infection of the testes may “burn out” sperm-producing cells. • Chemotherapy may reduce viability of sperm or ova. • Workplace toxins and environmental pollutants may reduce viable sperm. • Access of viable sperm may be reduced by a change in vaginal pH due to infection or the use of douches, excessively thick cervical mucus, or the development of antibodies in the woman to particular sperm. estrogen taken by postmenopausal women is associated with an increased risk of endometrial cancer, and currently the guidelines for use and the dosage of estrogen have been reduced to minimize this danger. Other causes of hyperestrinism include infertility or the earlier ingestion of sequential oral contraceptives. The current practice of combining estrogen with progestin reduces the risk of hyperplasia in the uterus, but is still associated with an increased risk of breast cancer. There is also an increased incidence of cancer in obese women and in those with diabetes or hypertension. ■ Signs and Symptoms Painless vaginal bleeding or spotting is the key sign of endometrial cancer because the cancer erodes the surface tissues. The Pap smear is not a dependable assessment tool for detecting abnormal endometrial cells. Direct aspiration of uterine cells provides a more accurate cell sample, with biopsy required to confirm the diagnosis. Late signs of malignancy include a palpable mass, dis- comfort or pressure in the lower abdomen, and bleeding after intercourse. ■ Treatment Surgery and radiation constitute the usual treatment measures, with chemotherapy in the later stages. With chemotherapy, a combination of two drugs, such as Gemcitabine and Cisplatin, is used. THINK ABOUT 19.9 a. Differentiate a uterine fibroid from uterine cancer. b. Explain why the cure rate for cervical cancer is much better than that for ovarian cancer (refer to Chapter 20). c. List the tumors whose development is influenced by hormones, and explain how these may be treated. Ovarian Cancer Ovarian cancer is of concern because only about 25% of ovarian cancer is diagnosed in the early stage, at which time the prognosis is favorable. This cancer has long been considered a silent tumor. The American Cancer Society estimated 22,280 new cases in the United States in 2016, resulting in an estimated 14,240 deaths. Two-thirds of the women diagnosed with ovarian cancer are older than age 55. Genetic factors have a role in its development. There are different types of ovarian cancer tumors, which vary in virulence. These types include serous, mucinous, and endometrioid tumors. The serous tumors account for the majority of malignant cases of ovarian cancer. Early indications of ovarian cancer include feeling of bloating and fullness, indigestion, frequent urination, backache, and pain with intercourse. 538 SECTION III Pathophysiology of Body Systems diagnosis to uncover the presence of second infections are necessary. 3. Frequently STDs are asymptomatic, particularly in women, thus promoting the spread of infection by persons who are unaware that they are carrying the microbes. 4. No cure is available for viral STDs such as herpes or HIV (see discussion of HIV-AIDS in Chapter 7), although drugs are available that may help to limit the acute stage of infection. 5. Drug-resistant microorganisms are becoming increas- ingly common, thus raising the inherent risks associated with STDs. 6. Infections may be transmitted by an infected mother to a fetus or newborn, frequently resulting in congenital defects or death or disability for the child. 7. Partners of an infected person are difficult to trace, notify, and treat. 8. Condoms are often not used or used improperly in high-risk situations. The abuse of alcohol and the use of date rape drugs have increased the incidence of unprotected sex. In this section, several of the more common STDs are discussed. A summary may be found in Table 19.1. Bacterial Infections Chlamydial Infection Chlamydial infection is considered one of the most common STDs and the leading cause of PID. The pathogen is the bacterium C. trachomatis, a gram-negative obligate intracellular parasite, which requires a host cell to reproduce (see Fig. 6.8). As in gonorrhea, chlamydiae invade the epithelial tissue of the urogenital tract, causing inflammation. In most males chlamydial infection becomes evident in several weeks after exposure as urethritis (nongonococ- cal urethritis) and epididymitis. Manifestations of ure- thritis include dysuria, itching, and a whitish discharge from the penis. Epididymitis manifests as a painful, swollen scrotum, usually unilateral, accompanied by fever. The inguinal lymph nodes are swollen. Proctitis (rectal inflammation with bleeding and discharge) may occur in anyone practicing anal intercourse. Females are often asymptomatic until PID develops. A few experience urethritis, bartholinitis, cervicitis, or salpingitis. Signs of urethritis include dysuria and urinary frequency. Infection in Bartholin glands causes a purulent discharge and cyst formation. Cervicitis may be asymp- tomatic, or a purulent discharge with inflamed tissues may be evident at the cervical os. Spread to the fallopian tubes leads to the development of PID. Newborns may be infected during passage through the cervix and vagina, resulting in infection in the eyes (conjunctivitis) or in the lungs because of aspiration of infected secretions (pneumonia). The usual treatment for chlamydial infection is tetracycline or azithromycin for • Recent evidence implicates cigarette smoking by either the male or female partner and secondhand smoke as a deterrent to pregnancy. It is estimated that 25% of fertilized ova fail to implant and develop into a viable embryo. The reasons for this are many and may include chromosomal or genetic anomalies. Because the woman is not aware of the fertilization, little, if any, research is available on such implantation failures. A broad range of tests is available to assess each group of factors in a progressively more detailed manner. It is usual to test the male partner first because the tests are not invasive. The woman’s general health status is investigated to rule out any systemic causes. The woman may record basal body temperature, times of intercourse, and men- strual cycles to determine the optimal time for fertilization. Physical abnormalities may be assessed by means of a pelvic examination and by tests such as ultrasound, CT scans, or laparoscopy. Hysteroscopy is another method of detecting uterine abnormalities. Tubal insufflation (using gas and a pressure measurement) or a hystero- salpingogram (radiograph or x-ray with contrast material) can ascertain the patency of the tubes and uterus. Evalu- ation of hormone levels throughout the menstrual cycle requires extensive testing. Other possible factors such as cervical mucus and the presence of sperm antibodies require specific tests. Frequently a combination of factors contributes to infertility; therefore it is best to conduct a range of tests. Sexually Transmitted Diseases STDs, formerly called venereal diseases, encompass a broad range of infectious diseases that are spread by sexual contact. Although the incidence of gonorrhea has decreased a little, the incidence of other STDs has increased, resulting in an overall increase. The actual figures are probably much higher than those stated because many cases of STD are not reported. The increased numbers have been attributed to societal changes in many countries, including factors such as increased participation in premarital sex, particularly among young adults; an increased divorce rate; and an increased number of sexual partners on the part of some individuals. Many people do not take protective measures against STDs, especially when hormonal contraceptives are used to prevent pregnancy. In addition to the standard STDs such as gonorrhea, syphilis, and chlamydial infection, there is evidence that infections such as hepatitis B may be spread by sexual contact. HIV is spread by both heterosexual and homosexual exchange of body fluids. Among the many concerns about STDs: 1. Immunity against recurrent infection is not achieved during the first infection with many STDs; therefore recurrent infections are common. 2. Because more than one STD may be present in any one individual at a given time, careful testing and CHAPTER 19 Reproductive System Disorders 539 the infected person and any sexual partners. Chlamydia and gonorrhea are often seen together in the same client, and thus newer protocols call for treatment of both infections simultaneously with a combination of doxy- cycline and azithromycin. Gonorrhea Gonorrhea is caused by N. gonorrhoeae, a gram-negative aerobic diplococcus (gonococcus). Many strains of N. gonorrhoeae have become resistant to penicillin and tetracycline. The bacteria use pili to attach to the epithelial cells and then damage the mucosa, causing an inflammatory reaction and formation of a purulent exudate. The most common site of inflammation in males is the urethra, which results in dysuria and a purulent urethral discharge. Epididymitis may follow (Fig. 19.21). Some men are asymptomatic. In females, the infection usually involves the endocervical canal and frequently is asymptomatic. It may also affect Skene and Bartholin glands, causing more visible manifestations such as a change in the appearance of the vaginal discharge from clear, slightly white to thick greenish, yellow, or creamy white. PID, a serious complication, frequently follows as the infection ascends along the mucosa. Females may experience infection in the anus and rectum when infected exudate spreads from the vagina. Women are prone to develop bacteremia and gonococcal arthritis, with multiple joint inflammations. TABLE 19.1 Sexually Transmitted Diseases Infection Cause Signs Complications Treatment/Cure Chlamydia Chlamydia C. trachomatis Mild dysuria and discharge or asymptomatic Arthritis Female—PID and infertility Neonates—conjunctivitis and pneumonia Antimicrobial therapy, e.g., azithromycin Retest for eradication Gonorrhea Bacterium N. gonorrhoeae Dysuria and discharge Mild or asymptomatic in women Arthritis Male—prostatitis and epididymitis Female—PID and infertility Neonates—conjunctivitis Antibacterial drugs (penicillin or ceftriaxone + doxycycline) Some drug-resistant strains Retest for eradication Syphilis Bacterium T. pallidum Primary Syphilis— Painless ulcer or chancre at site of entry Secondary Syphilis— Rash, fever, headache Tertiary Syphilis—Gumma, neurosyphilis, or cardiovascular system damage Congenital syphilis in child Penicillin G—long-acting Retest for eradication Genital Herpes Virus Herpes simplex 2 (HSV-2) Vesicles and ulcers Recurs Meningitis Fetus/neonate damage No cure Antiviral drug, e.g., oral acyclovir, reduces activity and shedding Genital Warts Virus Human papillomavirus (HPV) Soft gray mass or polyp None Can be removed, but rarely cured Trichomoniasis Protozoa T. vaginalis Asymptomatic, or women may have discharge and dysuria None Antimicrobial drugs, e.g., metronidazole Orogenital contact leads to pharyngeal infection manifested as pharyngitis, tonsillitis, or lymphade- nopathy. Gonococcal conjunctivitis may be seen in Fig. 15.3. The newborn may become infected during the birth process, resulting in the eye infection called oph- thalmia neonatorum. Considering the resistant strains of the organism, the suggested drugs are ceftriaxone and doxycycline. Culture and sensitivity tests may be required to determine effective drugs. Syphilis The prevalence of syphilis had been decreasing in the period between 1990 and 2000. The rate increased from 2001 to 2009 but again showed a decrease in 2010. Reasons for the increase vary, but it has also been noted that there has been an increase in antibiotic-resistant strains of the pathogen. The causative organism of syphilis is Treponema pallidum, an anaerobic spirochete (so called because of its corkscrew shape). Dark-field or electron microscopy is required for identification (Fig. 19.22A). Serum antibod- ies also provide a diagnostic test. Syphilis is a systemic infection that consists of four stages, and the organism can be isolated from lesions in the first two stages. 1. The primary stage is identifiable by the presence of a chancre, a painless, firm, ulcerated nodule that develops at the point of contact on the skin or mucosa about 3 weeks after exposure (see Fig. 19.22B). The organisms 540 SECTION III Pathophysiology of Body Systems FIG. 19.21 Epididymitis due to gonorrhea or nongonococcal urethritis. (From Huether S, McCance K: Understanding Pathophysiol- ogy, ed 5, St. Louis, 2012, Elsevier, Mosby.) B A FIG. 19.22 Syphilis. A, Scanning electron micrograph shows Treponema pallidum (thin spirals) adjacent to an erythrocyte. B, Penile syphilitic chancre, painless papule with central ulceration at the inoculation site on the penis. (From Mahon CR, Manuselis G: Textbook of Diagnostic Microbiology, ed 2, Philadelphia, 2000, Saunders.) destruction (e.g., in the hard palate) and pathologic fractures, whereas gummas in the liver manifest as nodules similar to those of cirrhosis. The cardiovascular system is most frequently affected by gummas, showing damage to the arterial wall and development of aortic aneurysms. Neurosyphilis damages the central nervous system, resulting in dementia, blindness, and motor disabilities (tabes dorsalis). A concern with syphilis is the development of congenital syphilis if the fetus is infected after the fourth month of gestation. The child may die in utero or survive with active infection or multiple abnormalities, particularly in the bones (e.g., saddlenose). Malformations of the teeth (e.g., Hutchinson incisors and mulberry molars) are typical. Inflammation and fibrosis damage the liver and lungs. Transmission occurs by contact with exudate from the skin and mucosal lesions or by body fluids, including semen, blood, and vaginal secretions, during sexual contact. It is likely that syphilis can be transmitted during reproduce in the chancre and initiate an immune response. This lesion heals spontaneously (without treatment) in several weeks. Such lesions are frequently missed because they may not be visible (e.g., they may be in the cervix in the female) and are asymp- tomatic. Regional lymphadenopathy may also be present in this stage. 2. By the time the chancre heals, the organisms have entered the general circulation, and if untreated, the second stage of the infection begins with a widespread symmetric rash, usually maculopapular and reddish, on the skin and mucous membranes, particularly the palate. This typical rash may be found on the palms of the hands and the soles of the feet. Mucous patches (loose, white, necrotic material) may appear on the tongue. General signs of infection—malaise, low-grade fever, sore throat, stomatitis, and anorexia—are common. Again, these lesions are self-limiting and disappear spontaneously in a few weeks. 3. The patient then enters the latent stage, which may persist for years. Sometimes the skin lesions recur, but usually the person is asymptomatic, although serologic evidence of disease remains. 4. Some untreated patients never develop tertiary syphilis, and treatment has reduced the incidence of this stage. The typical lesion of this stage is the gumma, an area of necrosis and fibrosis. Bone gummas lead to CHAPTER 19 Reproductive System Disorders 541 Viral Infections Viral STDs constitute a serious problem because antiviral agents reduce the severity of the acute stage of infection by inhibiting viral reproduction and shedding of viruses, but they usually do not eradicate the infection. HIV-AIDS may be considered an STD in some cases and has been described in Chapter 7. Genital Herpes Herpes genitalis is usually caused by HSV-2, although some cases result from HSV-1. HSC-1 is the agent that also causes herpes labialis, or cold sores (discussed in Chapter 8), and may cause genital lesions if oral sex is practiced or if it is autoinoculated by the hands. The lesions are similar, and a tingling and burning sensation at the site usually precedes the appearance of the actual lesion. The lesion characteristic of herpes is a vesicle (blister) surrounded by an erythematous area (Fig. 19.23). The vesicle ruptures after several days, leaving a painful the first few years of the latent stage as well as during the first two stages. Treatment consists of long-acting benzathine penicillin G or doxycycline and tetracycline for patients who are allergic to penicillin. For neurosyphilis infections, ceftri- axone is recommended. THINK ABOUT 19.10 a. Describe the causative organisms for (1) chlamydial infection, (2) gonorrhea, and (3) syphilis. b. Explain how salpingitis may develop in women with chlamydial infection. c. Compare syphilis and gonorrhea in terms of the early signs, distribution of organisms, and potential long-term effects if untreated. d. Give two reasons why STDs are difficult to control (i.e., why it is difficult to reduce the incidence). FIG. 19.23 Genital Herpes. A, Herpes simplex virus in a cervical specimen. Infected cervical cells stain brown. (From de la Maza LM, Pezzlo MT, Baron EJ: Color Atlas of Diagnostic Microbiology. St. Louis, 1997, Mosby.) B, Genital herpes in the female and male. Note the blisters and ulceration. (From Behrman RE, Kliegman RM, Arvin AM: Slide set, Nelson Textbook of Pediatrics, ed 15, Philadelphia, 1996, Saunders.) A B 542 SECTION III Pathophysiology of Body Systems Genital warts may be removed by a number of different methods, including surgery, laser, cryotherapy, and topical caustics, but they tend to recur. Protozoan Infection Trichomoniasis Trichomoniasis is caused by Trichomonas vaginalis, an anaerobic flagellated protozoan, which is an extracel- lular parasite (see Fig. 6.8). The infection is usually asymptomatic in men, with the organisms residing primar- ily in the urethra. In women the infection may be subclini- cal and then flare up when the microbial balance of the vagina shifts. Trichomoniasis is a localized infection, with the organism attaching to the squamous epithelium of the vaginal and urethral mucosa and to Bartholin glands. Active infection causes a copious yellowish, foul-smelling discharge as well as inflammation and itching of the mucosa. Systemic treatment of both partners is necessary with drugs such as metronidazole (Flagyl) or tinidazole. Although rare, infections of the male genital tract have also been attributed to Trypanosoma species, Leish- mania donovani, Entamoeba histolytica, Acanthamoeba species, Toxoplasma gondii, and Plasmodium falciparum. ulcerated area and watery exudate. Eventually a crust forms over the ulcer, and it heals spontaneously in 3 to 4 weeks. Sometimes the initial episode is very mild and not noticed. In women, the lesion is usually found on the cervix, vulva, or urethra. Men have lesions on the penis, scrotum, or urethra. Vesicles may also appear on the buttocks or thighs. Systemic signs may be present during the acute stage, including fever, headache, and lymphadenopathy. Following this acute stage, the herpes virus usually migrates along the dermatome to the dorsal sacral root ganglion and there enters a latent stage. Body secretions may contain viruses for a time after the visible lesion heals. When reactivated, the virus migrates back to the mucosa or skin and enters the host cells for replication, forming a new vesicle. Reactivation may be triggered by many factors, such as respiratory infections or stress. Recurrent herpes is more common with HSV-2 than with HSV-1. Prodromal signs, such as tingling or burning, signal recurrence before the lesion appears. The fluid in the vesicles contains many viruses and may spread the infection to the eyes or skin elsewhere if caution and careful handwashing are not practiced. Active lesions in the vagina or cervix may transmit herpes virus to an infant during a vaginal delivery, frequently causing death or severe central nervous system damage. Delivery by cesarean section is advocated. Cervical cancer frequently develops in women with genital herpes. Frequent Pap tests are suggested to monitor any tissue changes. An antiviral agent such as acyclovir (Zovirax) may be applied topically or taken orally to lessen the active stage of infection and reduce the shedding of viruses to some extent; drug-resistant strains of HSV have been identified. This treatment may lessen the symptoms but does not cure the infection. Condylomata Acuminata (Genital Warts) Certain types of HPV cause genital warts, an STD that is increasing in frequency. HPV is a circular, double- stranded DNA virus. There are many types of HPV, of which several affect the genital tract. Several of these types also are considered to be a cause of cervical cancer. The incubation period for this infection may be as long as 6 months, and the disease may be asymptomatic, depending on the location of the lesions. Pregnancy promotes the growth and spread of genital warts. The condylomata, or warts, vary in appearance from soft, fleshy projections or cauliflower-like masses to flat lesions, to small pointed masses. Flat condylomata require preliminary treatment with acetic acid before they can be visualized. Biopsy is useful in differentiating condylomata from other causes of dysplasia or hyper- keratoses. In women the lesions may be present in the cervix or vagina, and in men they frequently are found on the penis. THINK ABOUT 19.11 a. Describe the causative organism and its classification for (1) trichomoniasis and (2) genital herpes. b. Compare the early manifestations of chlamydial infection, syphilis, and genital herpes. c. Explain why genital herpes tends to recur. CASE STUDY A Benign Prostatic Hypertrophy Mr. Humpert, age 71, presented to his physician with dysuria, urinary frequency, and urgency. After urinalysis, cystitis was diagnosed. Benign prostatic hypertrophy was noted. 1. What is the purpose of the prostate gland? 2. Describe the changes that occur in the prostate with BPH and the reason for these changes. 3. Explain how BPH predisposes a patient to cystitis. The infection was treated with antibacterial drugs, and Mr. H. was asked to return for follow-up. 4. List the manifestations of BPH, along with the reasons for them, that Mr. H. is likely to experience as the disease continues to develop. As the disease progresses, Mr. H. is reluctant to consider surgical treatment. 5. Is there a high risk of developing a prostatic malignancy if treatment is delayed? CHAPTER 19 Reproductive System Disorders 543 C H A P T E R S U M M A R Y The reproductive systems of the male and female consist of the gonads, or testes, and ovaries, respectively, com- bined with a complex system of ducts and auxiliary structures. In the male, the reproductive system shares some parts with the urinary system. Reproductive function is dependent on close links with the endocrine, cardio- vascular, and nervous systems. Unfortunately, the reproductive systems are a major site of malignant tumors and infections. Disorders of the Male Reproductive System • Torsion of the testis must be treated quickly to prevent ischemic damage. • Prostatitis may be associated with urinary tract infec- tions and STDs. • Benign prostatic hypertrophy occurs in older men, causing urinary obstruction, but is not associated with malignancy. • Cancer of the prostate may be androgen dependent and usually metastasizes at an early stage to bone. • Testicular self-examination for early detection of testicular cancer is recommended for young men. Disorders of the Female Reproductive System • Endometriosis is a cause of dysmenorrhea and infertility. • Candidiasis is a frequent opportunistic vaginal infection in women. • Pelvic inflammatory disease is a serious bacterial infection caused by microbes such as Chlamydia ascending into the fallopian tubes and entering the peritoneal cavity to cause peritonitis and, later, strictures, adhesions, and infertility. • Some forms of fibrocystic breast disease require monitor- ing for malignant cell changes. • Routine screening to ensure early detection is recom- mended for breast cancer, particularly in women with family history. The tumor usually manifests initially as a single hard, painless nodule. • Incidence of cervical cancer is increasing because of viral STDs, although early detection with Pap tests has improved the prognosis. Infertility and Sterility • Causes may be based in the male or the female or in a combination of factors related to production of ova or sperm, structural defects, or hormone imbalances. Sexually Transmitted Diseases • These infections include chlamydia, gonorrhea, syphilis, herpes, genital warts, and trichomoniasis. They have increased in numbers, with more drug- resistant microbes and viral infections making control difficult. CASE STUDY C Gonorrhea and PID P.J., age 23 years, tested positive for gonorrhea 6 months ago. She had no signs of infection, but her partner had been diagnosed and was being treated for gonorrhea. In this case, the penicillinase- producing organisms proved to be resistant to penicillin, and treatment continued with ceftriaxone. 1. Describe the usual signs of gonorrhea in a male. 2. Explain the meaning of the term drug-resistant as it relates to microbes and how it might be determined (see Chapter 6). Six months later, P.J. was admitted to the emergency depart- ment with severe abdominal pain and vomiting. A purulent cervical discharge was obvious, and initial examination of the exudate indicated infection by N. gonorrhoeae as well as other microorganisms. A tentative diagnosis of PID was given. 3. Describe how gonorrhea leads to PID. 4. Explain why peritonitis is a potential complication of PID. 5. Give several reasons why infertility may be a sequela to PID. CASE STUDY B Breast Cancer Mrs. Ann Thompson, age 52, felt a small hard, painless lump in the upper outer quadrant of her left breast during regular breast self-examination. Her mother and a cousin had had breast cancer. Mrs. A.T. has no children and still has menstrual cycles. After seeing her physician and having a mammogram, a biopsy was scheduled, which confirmed that the nodule was malignant. 1. List the factors in the patient’s history that increase the risk of developing breast cancer. 2. Describe other possible signs of breast cancer. 3. Explain why this lump is not typical of a benign condition. A lumpectomy was performed on Mrs. A.T., and a number of axillary lymph nodes were removed. 4. Explain why the axillary lymph nodes were removed. 5. The tumor cells tested positive for estrogen receptors. Explain the significance of this information and the implications for Mrs. A.T. 6. Mrs. A.T.’s lung and bone scans were negative. Explain the purpose of these scans. Only two of the axillary lymph nodes were positive for tumor cells. The prognosis appeared good, but the oncologist recommended a course of radiation and chemotherapy (refer to Chapter 20). 7. Explain why additional treatment is recommended in this case. 8. Explain why Mrs. A.T. will have an increased risk of infection after she starts the radiation and chemotherapy treatments. 9. Explain why Mrs. A.T. will have to undergo frequent mammograms and checkups for the next few years. 544 SECTION III Pathophysiology of Body Systems S T U D Y Q U E S T I O N S 1. Describe the structure and function of the: a. Scrotum b. Spermatic cord c. Prostate gland 2. List the functions of testosterone. 3. Describe the altered function resulting from: a. Hypospadias b. Cryptorchidism 4. Explain why BPH occurs in older males. 5. List the signs of BPH. 6. Compare the typical sites of metastasis for prostatic and testicular cancer. 7. State and explain one significant effect of cystocele. 8. Explain the cause of pain resulting from: a. Endometriosis b. Primary dysmenorrhea 9. Explain the potential problem resulting from the break in continuity between the fallopian tubes and the ovaries. 10. Describe the structure and purpose of each layer in the uterine wall. 11. Describe the defenses against infection in the female reproductive tract. 12. Describe the effects of increased estrogen secretion during the menstrual cycle. 13. Describe the causative organism and the manifestations of vaginal candidiasis. 14. Explain how an abscess may develop with PID. 15. Explain why most forms of fibrocystic breast disease are not considered precancerous, but some lesions require monitoring. 16. List the disorders characterized by pain related to the menstrual cycle. 17. Define the terms invasive and metastatic and give an example of each from the reproductive disorders. 18. Compare the early signs and the reasons for them of: a. Cervical cancer b. Uterine cancer c. Ovarian cancer (refer to Chapter 5) 19. List three hormone-dependent reproductive disorders and describe the role of the hormone in each case. 20. Name and describe the characteristics of the organism causing chlamydial infection. 21. Explain, using specific examples, two reasons why STDs may go undetected. 22. Describe the manifestations of the secondary stage of syphilis. 23. Explain how antiviral agents may reduce the transmission of herpes simplex virus. 24. List the STD and the organism that causes (a): a. Chancre b. Vesicle c. Gumma d. Purulent exudate e. Pharyngitis f. Wart CHAPTER 20 Neoplasms and Cancer 545 545 Factors Contributing to Pathophysiology Review of Normal Cells Benign and Malignant Tumors Nomenclature Characteristics of Benign and Malignant Tumors Malignant Tumors: Cancer Pathophysiology Effects of Malignant Tumors Local Effects of Tumors Systemic Effects of Malignant Tumors Diagnostic Tests Spread of Malignant Tumors Staging of Cancer Etiology Carcinogenesis Risk Factors and Prevention Host Defenses Treatment Surgery Radiation Therapy Chemotherapy Other Drugs Gene Therapy Nutrition Complementary Therapies Prognosis Examples of Malignant Tumors Skin Cancer Ovarian Cancer Brain Cancer Cancer Incidences Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Distinguish between benign and malignant tumors, their characteristics, and terminology. 2. Describe the warning signs of cancer. 3. Explain the local and systemic effects of cancer. 4. Name and describe common diagnostic tests. 5. Discuss the spread of malignant tumors by invasion, metastasis, and seeding related to the staging of cancer. 6. Describe the stages involved in carcinogenesis, specific risk factors, and possible preventive measures. 7. Explain the host defenses against cancer. 8. Discuss possible treatment measures, including radiation and chemotherapy, as well as nutrition. 9. Describe and differentiate among three examples of malignant tumors: skin cancer, ovarian cancer, and brain cancer. L E A R N I N G O B J E C T I V E S anemia antineoplastic atypical biopsy chromosomes cytologic differentiation genomic tumor assessment infiltrate metastasis micrometastases nadir oncology palliative pneumonia prognosis prophylactic radiofrequency ablation radioisotopes recurrence remission seeding thrombocytopenia total parenteral nutrition K E Y T E R M S C H A P T E R 20 Neoplasms and Cancer S E C T I O N IV 546 SECTION IV Factors Contributing to Pathophysiology altered in the parent cell, this mutation is passed on to the daughter cells. Different cells experience different life spans (species specific); for example, erythrocytes live for approximately 120 days, but some leukocytes survive only a few days. Highly specialized cells such as neurons cannot undergo mitosis, but they have a long life span of many years. Epithelial cells usually replicate very rapidly because of the demand for replacement caused by constant “wear and tear” on surface tissues. There are usually several layers of tightly packed cells, with the upper layers being sloughed off or shed and replaced by regenerating cells from the lower layers. Some types of cells can increase their reproductive rate on demand; for example, bone injury increases osteoblast activity. Cell reproduction always requires an adequate blood supply to the area and sufficient quantities of essential nutrients such as amino acids, glucose, and oxygen. Normally, cell growth and reproduction are also subject to stimuli such as hormones and inhibition by contact with nearby cells. Review of Normal Cells The cell is the functional and structural unit in the human body. Cells vary in their degree of development, depend- ing on the differentiation or specialization required for a particular cell’s function; for example, neurons and cardiac muscle cells are highly developed, whereas fibroblasts are less so. Normally cells are organized in an orderly arrangement in a tissue and differentiated to fulfill that tissue’s purpose. When cells become disorga- nized or undifferentiated or their growth becomes uncontrolled, their specialized functions are lost. Every cell has an outer plasma membrane enclosing the fluid cytoplasm or intracellular fluid. The membrane is semipermeable, controlling passage of materials into and out of the cell. It also maintains the cell’s shape. The nucleus of the cell consists of DNA, the genetic material that controls the particular cell’s function and structure, enclosed in the nuclear membrane. The cytoplasm contains various nutrients, proteins, glucose, and electrolytes required for cell metabolism. Additional substances are present, depending on the cell’s function—for example, glycogen in liver cells or lipids in fat cells. Other structures are located in the cytoplasm, such as ribosomes, granules that produce proteins; mitochondria providing energy in the form of adenosine triphosphate (ATP) for cell activities; lysosomes containing digestive enzymes to break down unwanted materials; and the Golgi complex to process and r elease proteins. Organelles inside the cell have many metabolic functions, such as the synthesis of protein or transport of cell products and wastes outside the cell membrane. The plasma membrane includes special protein molecules or receptors for substances such as hormones, chemical transmitters, or drugs, which affect the cell’s function. Cells may communicate with each other by chemicals or by forming protein channels between cells. Research is focused on this communication, seeking to learn the “what and how” of the transfer between cells and whether this knowledge could lead to the prevention of some diseases or new treatments. Cell membranes also have specialized mechanisms to adhere to each other and maintain an organized arrangement in a tissue or organ. Regulator genes control mitosis for different types of cells. Growth factors such as cytokines signal proliferation, whereas inhibitors inside cells prevent excessive growth. During its lifespan, each cell follows the basic cell cycle of growth and reproduction or mitosis. (See Fig. 20.10 later in this chapter for a schematic drawing of the cell cycle.) The timing of each event varies with the specific cell type. Epithelial cells that reproduce rapidly may complete the cycle in a few hours. Other cells spend months completing one cycle. Genetic control over growth and reproduction is exerted through DNA, and the daughter cells are identical to the parent cell. If DNA is APPLY YOUR KNOWLEDGE 20.1 Discuss several ways by which the normal process of cell replica- tion can be altered and state the various outcomes. THINK ABOUT 20.1 a. Which types of cells have rapid rates of mitosis? b. Which cells never undergo mitosis? What is the result of damage in tissues such as these? Cellular aging occurs naturally over time and results in an altered structure of the cell, decreased function, and, in time, cell death. The processes of cellular aging and changes in cell control systems are not fully under- stood. Certain cells undergo apoptosis, programmed cell death (see Chapter 1). Current theories on the aging process focus on a programmed number of reproductive cycles available for a specific cell type and the effects of wear and tear causing cell damage (see Chapter 24). Changes in DNA can alter cell structure and function or cause cell death. DNA can mutate spontaneously during mitosis or as a result of exposure to chemicals, viruses, radiation, and other environmental hazards. Rapid rates of mitosis associated with tissue trauma or other stimuli may increase the risk of errors occurring in the chromo- somes, cell enzymes, or cell components. Mutant cells may change function as well as lose control of mitosis. Seriously defective cells usually die or are destroyed by the immune system. Benign and Malignant Tumors A neoplasm or tumor is a cellular growth that is no longer responding to normal body controls. The cells continue to reproduce when there is no need for them. This CHAPTER 20 Neoplasms and Cancer 547 TABLE 20.1 Tumor Nomenclature Root Suffix Example Fatty tissue: lip- Benign: -oma Lipoma: benign tumor of fatty tissue Gland tissue: adeno- Malignant epithelial tissue: -carcinoma Adenocarcinoma: malignant tumor of epithelial lining of a gland Fibrous tissue: fibro- Malignant connective tissue: -sarcoma Fibrosarcoma: malignant tumor of fibrous tissue THINK ABOUT 20.2 a. What does the term chondroma mean? Neuroma? Adenocarcinoma? b. What term is applied to a malignant bone tumor? (Hint: Bone is osteo.) TABLE 20.2 Characteristics of Benign and Malignant Tumors Benign Tumors Malignant Tumors Cells Similar to normal cells Varied in size and shape with large nuclei Differentiated Many undifferentiated Mitosis fairly normal Mitosis increased and atypical Growth Relatively slow Rapid growth Expanding mass Cells not adhesive, infiltrate tissue Frequently encapsulated No capsule Spread Remains localized Invades nearby tissues or metastasizes to distant sites through blood and lymph vessels Systemic effects Rare Often present Life-threatening Only in certain locations (e.g., brain) Yes, by tissue destruction and spread of tumors excessive growth deprives other cells of nutrients. Many neoplasms are unable to function as normal tissue cells because they consist of atypical (abnormal) or immature cells. The characteristics of each tumor depend on the specific type of cell from which the tumor arises, resulting in a unique appearance and growth pattern. The expand- ing mass creates pressure on surrounding structures. Nomenclature Tumors are named according to a system (Table 20.1). The root word, such as chondro, is the cell of origin, in this case, cartilage. Depending on the type of tissue in which a tumor is located, the suffix indicates malignant tumors (carcinoma for epithelial tissue, sarcoma for con- nective tissue). The suffix -oma alone indicates a benign tumor (e.g., lipoma). However, a number of neoplastic disorders have acquired unique names that are recognized in medical practice. Examples include Hodgkin disease, Wilms tumor, and leukemia. Oncology is the study of malignant tumors, otherwise known as cancer. Characteristics of Benign and Malignant Tumors Characteristics of specific tumors vary considerably depending on the cell of origin. The general characteristics of each type are summarized in Table 20.2. Benign tumors usually consist of differentiated cells that reproduce at a higher-than-normal rate. The benign tumor is often encapsulated and expands but does not spread (Fig. 20.1). It is usually freely moveable on palpation. Tissue damage results from compression of adjacent structures such as blood vessels. A benign tumor is not considered life threatening unless it is in an area such as the brain where the pressure effects can become critical. By comparison, malignant tumors are usually made up of undifferentiated, nonfunctional cells that do not appear organized. The cells tend to reproduce more rapidly than normal and often show abnormal mitotic figures. These cells have lost cellular connections with each other, and reproduction is not inhibited in the presence of other similar cells. Tumor cells infiltrate or spread into sur- rounding tissue and may easily metastasize or break away to spread to other organs and tissues (Fig. 20.2). Malignant Tumors: Cancer Pathophysiology A tumor manifests as an enlarging space-occupying mass composed of more primitive or dysplastic cells. Normal organization, growth inhibition, contact controls, and cell–cell communication are absent. Cell membranes, including surface antigens, are altered. The expanding mass compresses nearby blood vessels, leading to necrosis and an area of inflammation around the tumor, and increases pressure on surrounding structures. Malignant cells do not adhere to each other but often break loose from the mass, infiltrating into adjacent tissue. Tumor cells often secrete enzymes such as collagenase, which break down protein or cells, adding to the destruction and facilitating the tumor’s spread into adjacent tissue. Inflammation and the loss of normal cells lead to a progressive reduction in organ function. 548 SECTION IV Factors Contributing to Pathophysiology months or years. This condition offers an excellent opportunity for early diagnosis of cervical cancer and certain oral cancers. Grading of tumors is based on the degree of differentia- tion of the malignant cells—a grade I tumor has well- differentiated cells similar to the original cells, whereas a grade IV tumor is undifferentiated with cells varying in size and shape (anaplasia); this type of tumor is considered highly malignant and likely to progress quickly. As a tumor mass enlarges, the inner cells are frequently deprived of blood and nutrients and die. This necrosis can lead to more inflammation and infection at the site. Some cancer cells secrete growth factors, which stimulate angiogenesis, the development of new capillaries in the tumor, thus promoting tumor development. Antiangio- genesis factors have also been located, and several new drugs are based on this blocking action. These drugs are of limited effect in clients receiving chemotherapy because the reduction in blood vessel development impairs the delivery of chemotherapy agents to the tumor. Tumor cells may increase the uptake of nutrients or “trap” nutrients, depriving normal cells and preventing any tissue regeneration. Some neoplasms develop very rapidly, whereas others remain in situ for a long time. In situ refers to neoplastic cells in a preinvasive stage of cancer that may persist for Tissue invasion Abnormal cells Irregular size and shape Slowly expanding mass Irregular shapeand surface Necrosis Invasion of blood vessels Malignant TumorBenign Tumor Relatively normal cells Capsule FIG. 20.1 Characteristics of benign and malignant neoplasms. 1 cm BA FIG. 20.2 A, Fibroadenoma, benign tumor of the breast. B, Invasive carcinoma of the breast. (From Cross S: Underwood’s Pathology: A Clinical Approach, ed 6, 2013, Elsevier.) THINK ABOUT 20.3 a. Why is infection likely to occur at the tumor site? b. Explain the characteristics of undifferentiated cells. c. How are cells in a biopsy specimen from a tumor identified as malignant? CHAPTER 20 Neoplasms and Cancer 549 Effects of Malignant Tumors All health care workers should be aware of the early indicators of possible malignancies. The classic warning signs of cancer are listed in the following box. WARNING SIGNS OF CANCER 1. Unusual bleeding or discharge anywhere in the body. 2. Change in bowel or bladder habits (e.g., prolonged diarrhea or discomfort). 3. A change in a wart or mole (i.e., color, size, or shape). 4. A sore that does not heal (on the skin or in the mouth, anywhere). 5. Unexplained weight loss. 6. Anemia or low hemoglobin and persistent fatigue. 7. Persistent cough or hoarseness without reason. 8. A solid lump, often painless, in the breast or testes or anywhere on the body. Air Lung A B Feces (liquid) POLYPOID TUMOR CIRCUMFERENTIAL TUMOR EXTERNAL MASS Feces (solid) Colon Rectum TYPES OF TUMOR GROWTH OBSTRUCTING THE COLON TUMOR BLOCKING AIR FLOW IN BRONCHUS FIG. 20.3 A and B, Obstruction by tumors. if it collects in an area, can cause pressure on nerves (see Chapter 4). • Obstruction can result when a tumor compresses a duct or passageway from an external position or grows inside a passageway or around a structure (Fig. 20.3). Obstruction may occur in ducts or tubes in the body, such as those in the digestive tract. Blood supply or lymphatic flow may be restricted, leading to ulceration and edema. Air flow in the bronchi or nerve conduction may be blocked. Obstructions can cause serious complications for the patient, even in the early stage. In the late stage, prevention of obstruction may form the rationale for continuing palliative treatment. • Tissue necrosis and ulceration may lead to infection around the tumor, particularly in areas where normal flora can become opportunistic. For example, infection is likely to be associated with cancer in the oral cavity. Host resistance to microbial invasion is often reduced with cancer. Systemic Effects of Malignant Tumors Systemic or general effects of cancer include the following: • Weight loss and cachexia (severe tissue wasting) occur with many malignancies. Contributing factors include anorexia, fatigue, pain, stress, and the increased demands placed on the body by reproducing tumor cells (nutrient trapping), altered carbohydrate and protein metabolism, and cachectic factors produced by macrophages in response to the tumor. This in turn leads to added fatigue and weakness and tissue breakdown. • Anemia or decreased hemoglobin is a common problem resulting from anorexia and decreased food intake, chronic bleeding with iron loss, and bone marrow depression. Anemia decreases the oxygen available to cells, leading to fatigue and poor tissue regeneration. • Severe fatigue may be caused by inflammatory changes, cachexia, anemia, stress, and treatment schedules. Psy- chological factors involved in facing a life-threatening illness can also lead to fatigue and depression. Even if cancer is not present, any of these signs could be the indicator of some other disease process, therefore it should be assessed by a physician. A critical observation can save a life. Sometimes a client may need encourage- ment to have such warning signs investigated. Local Effects of Tumors • Pain is not usually an early symptom of cancer; rather, it occurs when the tumor is well advanced. Pain is a warning of a problem; therefore it is helpful if it occurs early, but this is rare. The severity of the pain depends on the type of tumor and its location. Pain may be caused by direct pressure of the mass on sensory nerves, particularly where space is restricted (e.g., bone cancer). Dull, aching pain results from the stretching of a visceral capsule, such as occurs in the kidney or liver. Inflammation also contributes to pain because of increased pressure on the nerves and the irritation of nerve endings by chemical mediators (see Chapter 5). Secondary causes of pain include infection, ischemia, and bleeding. Blood can be “irritating” to tissues and, 550 SECTION IV Factors Contributing to Pathophysiology erythrocytopenia, and leukopenia, and these may limit treatment if cell counts fall too low. • Tumor markers are substances, enzymes, antigens, or hormones produced by some neoplastic cells. These tumor cell markers can be used to screen high-risk individuals, confirm a diagnosis, or monitor the clinical course of a malignancy. Examples include carcinoem- bryonic antigen for colon cancer, human chorionic gonadotropin for testicular cancer, alpha-fetoprotein for hepatocellular cancer, CA125 for ovarian cancer, and prostate specific antigen for prostate cancer. Many of these substances are present with other diseases; therefore their presence does not necessarily indicate a positive diagnosis. Chromosome markers, such as Philadelphia chromosome for chronic myelocytic leukemia, are also useful. Specific genes have been linked to certain cancers, such as BRAC-1, which is associated with a higher probability of breast or ovarian cancer. Genetic testing does not indicate whether a cancer is present or whether one will develop in the future; it simply indicates increased risk. • X-ray, ultrasound, magnetic resonance imaging, and computed tomography (CT) scans are methods of examin- ing changes in tissues or organs (see Ready Reference 5 for information on these tests). In some cases radioisotopes may be used during these procedures to trace metabolic pathways and assess function. • Cytologic tests are used to screen high-risk individuals, confirm a diagnosis, or follow a clinical course and monitor change. Histologic and cytologic examinations are used to evaluate biopsies of suspicious masses and check sloughed cells in specific tissues (exfoliative cytology). This is the only dependable confirmation of malignancy. An accurate evaluation depends on good technique and preservation of the specimen. For example, a regular Pap test examining cervical cells is a screening tool for cell changes indicating the development of cervical cancer. Increased use of this test has led to early detection and a greatly improved prognosis for cervical cancer patients. Breast biopsy may be done by an interventional radiologist using ultrasound to visualize the mass and a wide bore to extract a tissue sample for histologic examination. This is done in the ultrasound laboratory often immediately after a mass is detected by mammography. It is rela- tively painless, and the woman returns to normal activity shortly after the test. • Genomic tumor assessment identifies genetic mutations that are independent of heredity but only occur with the disease itself. For more detailed information and current updates refer to http://www.cancercenter.com/ cancer-genomics/ Spread of Malignant Tumors Tumors spread by one or more methods, depending on the characteristics of the specific tumor cells. They produce secondary tumors that consist of cells identical to the • Infections such as pneumonia occur frequently as host resistance declines. Tissue breakdown develops, and the immune system is less effective. The host’s immobil- ity contributes to infection in the lungs because of stasis of secretions in the lungs and a weaker cough effort. • Bleeding may occur because the tumor cells may erode the blood vessels or cause tissue ulceration. Bone marrow depression and hypoproteinemia may con- tribute to poor clotting. Chronic bleeding is common in the digestive tract, where the mucosa fails to regenerate quickly. Chronic blood loss leads to iron- deficiency anemia (see Chapter 10). • Paraneoplastic syndromes are additional problems associ- ated with certain tumors, such as bronchogenic car- cinoma in the lungs. Tumor cells release substances that affect neurologic function or blood clotting or have hormonal effects. For example, the cells of a bronchogenic carcinoma may produce adrenocortico- tropic hormone, leading to the manifestations of Cushing syndrome in the patient. This syndrome may confuse the diagnosis of cancer, complicate the monitor- ing and treatment of the patient, and cause change in body image. THINK ABOUT 20.4 a. Differentiate local from systemic signs of malignant neoplasms and include an example of each. b. Explain the systemic effects of malignant tumors with regard to (1) pain, (2) bleeding, (3) weight loss, and (4) fatigue. Diagnostic Tests Tests are important in the early detection of cancer and in long-term monitoring of the patient subsequent to the diagnosis. Routine screening tests and self-examination programs need to be promoted, especially in high-risk clients. Frequent monitoring during and after treatment, as well as ongoing follow-up, are important in assessing the effectiveness of treatment and providing warning of recurrence. A single diagnostic test is not usually 100% reliable by itself because there may be false-negative or false- positive results. The only definitive test for malignancy requires examination of the tumor cells themselves. Other results should be assessed in conjunction with associated data. The following are some types of tests used for the diagnosis of cancer: • Blood tests are important both as an indicator of a problem and in monitoring the effects of chemotherapy and radiation. Hemoglobin and erythrocyte counts may be low—a general sign of cancer. In some types of cancer, such as leukemia, the cell characteristics are diagnostic when confirmed by a bone marrow examina- tion. Therapy frequently results in thrombocytopenia, http://www.cancercenter.com/cancer-genomics/ http://www.cancercenter.com/cancer-genomics/ CHAPTER 20 Neoplasms and Cancer 551 often several are removed. Usually the lymph nodes are removed or treated to eradicate any micrometas- tases that may be missed, particularly in cancers that are known to spread at an early stage (e.g., breast cancer). Many cancers spread by normal venous and lymphatic flow, and therefore the lungs and liver are common secondary sites for many tumors (Fig. 20.6). Note the large number of secondary tumors in the liver shown in this figure. However, some cancers are more selective and spread to unusual sites. • Seeding refers to the spread of cancer cells in body fluids or along membranes, usually in body cavities. Again, the tumor cells break away and travel easily with the movement of fluid and tissue. An example is ovarian cancer, in which the large peritoneal mem- brane encourages dispersion of the tumor cells throughout the peritoneal cavity (Fig. 20.7). Malignant cells may also be dislodged from the tumor if excessive handling occurs during diagnostic procedures or surgery, leading to further spread. primary (parent) tumor. Many cancers have spread prior to diagnosis, and this factor must be considered before treatment begins. There are three basic mechanisms for the spread of cancer: • Invasion refers to local spread, in which the tumor cells grow into adjacent tissue and destroy normal cells (Fig. 20.4). Tumor cells are loosely attached to other cells and secrete lytic enzymes that break down tissue. The origin of the word cancer is the Latin word meaning “crablike,” a good image of an invasive tumor. • Metastasis means spread to distant sites by blood or lymphatic channels. In this case the tumor cells erode into a vein or lymphatic vessel, travel through the body, and eventually lodge in a hospitable environment to reproduce and create one or more secondary tumors (Fig. 20.5). Only a few tumor cells survive this transfer, but it only takes a few to start a new tumor. Frequently the first metastasis appears in the regional lymph nodes, which localize the tumor cells for a time. These lymph nodes are checked at the time of surgery, and Cervix Uterus Vagina Basement membrane Tumor cells in situ Surface Basement membrane broken Surface Cervix Uterus VaginaUrethra Bone Urinary Bladder Uterus Colon Rectum 1. Carcinoma in situ— noninvasive 2. Cervix-invasive carcinoma 3. Vagina involved 4. Widespread invasion FIG. 20.4 Invasive carcinoma of the cervix. 552 SECTION IV Factors Contributing to Pathophysiology • Spread (invasion or metastasis) of the tumor (M) A simplified version of staging is presented in Box 20.1. Subgroups for each stage have also been established for many types of cancer. Generally stage I tumors are small and well localized, easy to treat, and have a good prog- nosis, whereas stage IV tumors are well advanced, difficult to treat at multiple sites, and have a poorer prognosis. Some tumors are staged using a system similar to that Staging of Cancer Staging of cancer is a classification process applied to a specific malignant tumor at the time of diagnosis. It may be repeated at critical points. The staging system describes the extent of the disease at the time and therefore provides a basis for treatment and prognosis. Staging systems are based on the: • Size of the primary tumor (T) • Extent of involvement of regional lymph nodes (N) 6. Multiple tumors Arterial route Lymphatic vessel 4. Tumor cells lodge in hospitable capillary bed 5. Secondary tumor grows and spreads Lungs 1. Primary tumor 3. Vein Vein Lymphatic duct 6. Brain metastasis 4. Lung metastasis– secondary 6. Liver metastasis 6. Ovary metastasis 5. Aorta carries tumor cells from lungs to all organs 2. Spread to axillary lymph node 1. Primary breast cancer 3. Follow lymphatic to vena cava 2. Lymph node FIG. 20.5 Metastatic breast cancer. CHAPTER 20 Neoplasms and Cancer 553 and tumor-suppressor genes. Changes in cell DNA are at the root of malignant transformation (see Fig. 21.2 for a diagram of DNA). Carcinogenesis is the process by which normal cells are transformed into cancer cells. Malignant tumors develop from a sequence of changes over a relatively long period. A combination of factors or repeated exposure to a single risk factor leads to changes that activate or change gene expression, leading to transformation of the normal cell into a malignant cell. Some specific cancers have well-established risk factors (e.g., bronchogenic carcinoma or lung cancer and cigarette smoking). The multiplicity of developmental steps in carcinogenesis is supported by the fact that not all cigarette smokers develop cancer. It is difficult to establish precise predispos- ing or causative (etiologic) factors for each cancer because it takes many years to gather sufficient documentation, and frequently multiple factors are involved. The role of oncogenic viruses has been confirmed with evidence that particular strains of human papillomavirus are agents of carcinogenesis in cervical cancer. Exposure to radiation continues to lead to leukemia, and ultraviolet radiation (sun) leads to skin cancer. Also, the incidence of some cancers has changed without adequate explanation. Diagnostic techniques continue to improve, and as more data become available, statistical and etiologic relation- ships change. The stages in carcinogenesis have been organized in the following manner: 1. Initiating factors or procarcinogens cause the first irreversible changes in the cell DNA. Genetic changes or exposure to an environmental risk may cause this first mutation (Fig. 20.8). This initial change does not create an active neoplasm. 2. Exposure to promoters later causes further changes in DNA, resulting in less differentiation and an increased rate of mitosis. Dysplasia or anaplasia may be evident at this time. This process may lead to development of the tumor. Promoters include hormones and envi- ronmental chemicals. The prolonged time interval shown but the terminology is different. Information on staging of a particular type of tumor is easily available on websites maintained by the American Cancer Society or the Canadian Cancer Society. Etiology Carcinogenesis Research is proceeding into the various genes responsible for cell growth and replication and the mechanisms that activate or inhibit the activities of these genes. Discoveries to date include genes that repair DNA, genes that program cell death (apoptosis), genes that cause cancer (oncogenes), FIG. 20.6 Liver with multiple metastatic tumors. (Courtesy of Paul Emmerson, Toronto, Ontario, Canada.) Uterus Intestine Liver Diaphragm Peritoneal cavity with fluid 3. Secondary liver tumor 2. Continuous peritoneal membrane 1. Primary ovarian tumor FIG. 20.7 Ovarian cancer spread by seeding throughout the peritoneal cavity. BOX 20.1 Example of Staging Breast Cancer T Size of tumor N Involvement of lymph nodes M Presence of metastasis Breast Cancer Stage I: T1—tumor 2 cm or less in diameter; N0—no lymph nodes involved; M0—no metastasis Stage II: T0 to T2—tumor less than 5 cm in diameter; N1—nodes involved; M0—no metastasis Stage III: T3—tumor larger than 5 cm in diameter; N1 or N2—nodes involved; tumor may be fixed; M0—no metastasis Stage IV: T4—tumor any size but fixed to chest wall or skin; N3—clavicular nodes involved (spread); M1—metastasis present 554 SECTION IV Factors Contributing to Pathophysiology INITIATION 1. Irreversible mutation of DNA 2. Repeated exposure to carcinogens. Additional risk factors PROMOTERS 3. Additional changes to DNA and cell structure CANCER CARCINOGENS PROCESS CELL Normal cell Nucleus Membrane Possible intervention by DNA-repair genes 1. Mutant cell Proliferation of initiated cells Possible immune surveillance and destruction of mutant cell Genetic–oncogene factor Radiation – sun Virus Cigarettes Hormones Food additives S Industrial factors 3. Malignant cell 2. Membrane changes FIG. 20.8 Multistage carcinogenesis. CHAPTER 20 Neoplasms and Cancer 555 TABLE 20.3 Risk Factors Risk Factors (Carcinogen) Example Genetic Factors: Oncogenes that regulate all growth Breast cancer: high family incidence; retinoblastoma: inherited Leukemia: chromosomal abnormalities Viruses: Oncogenic viruses alter host cell DNA Hepatic cancer: hepatitis virus Cervical cancer: papillomavirus (HPV) or herpes simplex II; Kaposi sarcoma: HIV Radiation: Ultraviolet rays (sun), x-rays, gamma rays, and radioactive chemicals cause cumulative chromosomal damage in cells Skin cancer: sun exposure Leukemia: radiation exposure Chemicals: Exposure to both natural and synthetic products in excess may be hazardous; the effects of carcinogenic agents depend on the amount and duration of exposure Lung cancer: asbestos, nickel Leukemia: solvents (e.g., benzene) Bladder cancer: aniline dyes and rubber Biologic Factors: Chronic irritation and inflammation with increased mitosis Colon cancer: ulcerative colitis; oral cancer: leukoplakia Age: Increasing Many cancers are more common in older persons Diet: Natural substances, additives, or processing methods Colon cancer: high-fat diet; gastric cancer: smoked foods Hormones Endometrial cancer: estrogen and multiple factors involved complicate efforts by researchers to establish risk factors for many cancers. 3. Continued exposure and changes in DNA result in a malignant tumor that is capable of growth and invasion of local tissue. 4. Changes in the regulation of growth result in cells that are capable of detaching from the tumor and spreading to distant sites (metastasis). The process of carcinogenesis varies greatly with respect to time. Some tumors develop relatively rapidly, whereas others require decades to develop to the point at which they can be diagnosed. Knowing the speed with which tumor cells reproduce and spread is significant in making treatment decisions. Tumors that metastasize readily and exhibit cells that reproduce quickly are described as “aggressive.” Risk Factors and Prevention Risk factors are summarized in Table 20.3. Risk factors associated with geographic areas or ethnic groups may relate to environmental influences or diet as well as genetic variables. Some risk factors such as foods can be avoided. Other factors, such as genetic predisposition, cannot be avoided but can be addressed by encouraging frequent screening and therefore early diagnosis. The list “Seven Steps to Health” (Box 1.1) includes some specific measures to reduce the common risk factors for cancer such as limiting sun exposure, ensuring regular medical and dental examinations and screening, or altering diet. For example, increasing fiber content in the diet and reducing fats decreases the risk of breast cancer. Deeply pigmented fresh fruits and vegetables provide antioxidants such as vitamins A and E, chemicals that protect cells against damaging substances called THINK ABOUT 20.5 a. Suggest possible reasons for the increased incidence of many cancers in the elderly. b. Why may it take several years for developments in tumor marker research to result in diagnostic technologies and treatments? free radicals. Free radicals form in cells from exposure to radiation or certain products from metabolic processes. Foods containing antioxidants are now promoted to offset this problem. Host Defenses Cancer suppressor genes present in the body can inhibit neoplastic growth. The immune system appears to offer protection by reacting to changes in the membranes of some tumor cells, which are seen as “foreign.” The immune response includes both cell-mediated and humoral immunity (see Chapter 7). Cytotoxic T lympho- cytes, natural killer cells, and macrophages are involved in immune surveillance and the destruction of “foreign” or abnormal cells. Temporary or long-term immunode- ficiency has been shown to increase the risk of cancer. For example, HIV infection or AIDS decreases the number of T lymphocytes. Cancers such as Kaposi sarcoma and lymphomas occur frequently in AIDS patients (see Chapter 7). Treatment Basic treatment measures are surgery, chemotherapy, immunotherapy, or radiation or a combination thereof, depending on the specific cancer. Not all cancer cells are sensitive to radiation or chemotherapy. Hematopoietic 556 SECTION IV Factors Contributing to Pathophysiology Chemotherapy and radiation therapy are administered in repeated doses at intervals that maximize tumor cell death but minimize the effects on normal tissues. Not all cancer cells are destroyed in one treatment. In solid tumors only the surface layers are affected during each treatment. Between treatments, the tumor may grow slightly (Fig. 20.9). Therefore treatment continues for a long time, whether curative or palliative. It is important that any infections, dental problems, or other potential complications be treated before com- mencing therapy. For example, any loose or extensively damaged teeth might be removed, caries and periodontal disease treated, and a good oral hygiene program instituted. During therapy it is risky to implement major procedures because of the tendency toward hemorrhage and the possibility of severe infection as a result of immunosup- pression and poor healing capabilities of the patient. Other therapeutic measures may involve nutritional counseling, physiotherapy, occupational therapy, or assistance with other specific problems such as speech therapy. Associated with physical treatment measures is the need to support the client psychologically. The thought of cancer brings great fear and anxiety to clients, fear of death, fear of the treatment and disfigurement, and anxiety cancers such as leukemia are treated by chemotherapy because the cancer cells are dispersed in the blood. Solid tumors are frequently removed by surgery, which is then followed by chemotherapy or radiation (or both) if the tumor cells are sensitive to these therapies. Immuno- therapy stimulates the patient’s immune system to target the cancer and attack it. Treatment may be: • Curative if the tumor is small and localized. • Palliative if the cancer is advanced. Palliative treatment is intended to reduce the manifestations and complica- tions related to the cancer and to prolong life. For example, decreasing the size of a tumor may lessen the pressure on a nerve, relieving pain, or reduce pressure on the esophagus or bronchus. Adjuvant therapy is additional prophylactic (preventa- tive) treatment used in cancers that are known to metastasize early in their development, producing secondary tumors that are too small to be detected (micrometastases). For example, after apparent complete removal of a localized breast tumor with no evidence of spread, chemotherapy and radiation may be administered as a precaution in case a few cancer cells have broken away to a lymph node or adjacent tissue. May recur N U M B E R O F M A LI G N A N T C E LL S TIME 4. Early surgery Possible adjuvant chemotherapy and radiation KEY Development of tumor before treatment Progress of tumor after treatment Size of malignant tumor 3. Diagnosis 2. Signs appear 5. Radiation Chemotherapy Late treatment, surgery, radiation, and/or chemotherapy Death Death Palliative treatmentResists treatment X 1. Tumor growth 6. Cure 6. Cure FIG. 20.9 The effects of treatment on a solid tumor. CHAPTER 20 Neoplasms and Cancer 557 have daily treatments for a 6-week period on an outpatient basis. No radiation remains in the body after treatment. • Internal insertion of radioactive materials at the tumor site may be used to treat specific cancers such as cervi- cal or oral tumors. This is accomplished by sealing the radioisotope (e.g., radium) in a “seed” or needle and implanting the device at the site (brachytherapy). • Brachytherapy is now being used to treat breast cancer in the early stages when radioactive material is implanted in surrounding tissue after removal of the tumor. If this method proves successful over time, it would replace the daily administration required now for this high-risk cancer. • Another method is to instill a radioisotope (e.g., 198Au or radioactive gold salt) in a solution in a body cavity, such as the pleural cavity, to control excessive inflammatory exudate or blood from the tumor. These clients must be monitored to ensure that there is no leakage or loss of radioactive materials. For certain cancers, radioisotopes may be given orally (e.g., 131I [radioactive iodine] for thyroid cancer because iodine goes directly to the thyroid gland). Precautions are required when clients have internal sources of radiation to minimize radiation exposure of other persons. Minimal risk is incurred when the half-life (period when significant radiation is emitted) of a specific radioisotope is short; the cumulative time of exposure is as short as possible; the distance between the source and the individual is great; and shielding materials (e.g., lead aprons), which block penetration by radiation, are used to protect body regions not affected by the cancer. Adverse effects of radiation depend on the dose and extent of penetration of radiation into the body. Normal cells that rapidly reproduce, such as those in the skin and mucosa (epithelial cells), bone marrow, and gonads, are also damaged by radiation. 1. Bone marrow depression is the most serious negative effect, so blood cell counts are constantly monitored. Decreased leukocytes greatly increase the risk of infection, decreased platelets may cause excessive bleeding, and decreased erythrocytes contribute to fatigue and tissue breakdown. If blood cell counts are reduced to a critical level, treatment may need to be postponed or blood transfusions may be necessary. Pneumonia and septicemia are common life-threatening complications because body defenses are reduced. 2. Epithelial cell damage includes damage to blood vessels (vasculitis) and skin. Skin becomes inflamed (as in a sunburn), and hair loss (alopecia) occurs. The mucosa of the digestive tract is damaged, resulting in some nausea, vomiting, and diarrhea and the attendant risk of malnutrition and dehydration. Also, inflammation and ulceration in the digestive tract may lead to bleed- ing, as indicated by melena or hematemesis (blood in the stool or vomitus). With head or neck radiation, the oral mucosa may become ulcerated, and xerostomia related to long-term disability. Many factors are involved. Some clients have a substantial support system, whereas others do not. Treatment can last for months or years, and monitoring continues for a lifetime. THINK ABOUT 20.6 Suggest some benefits to the patient who chooses to have palliative treatment rather than curative radiation therapy. Surgery Surgery involves the removal of the tumor and surround- ing tissue, including the nearby lymph nodes if required. The tumor cells and the boundaries are checked to confirm the diagnosis and to ensure their complete removal. The surgical approach may involve the use of a laparoscope and several small incisions. This approach minimizes tissue damage and improves recovery time for the patient. In some cases removal of adequate surrounding tissue may result in considerable impact on function, for example, in the brain or with skeletal muscle damage. Sometimes complete removal of the tumor may be impos- sible, but reducing the size of the mass may prevent complications and alleviate some symptoms. An alternative to surgery for small single tumors in the lungs or liver is radiofrequency ablation. This process is less invasive, easier for the patient to tolerate, and does not require the loss of an entire lobe of the organ as may happen with surgery. An interventional radiologist uses CT scans and ultrasound to guide a needle and electrodes into the tumor. Heat is supplied in the form of radio waves to destroy the malignant cells and tissue immediately surrounding the tumor. Radiation Therapy Radiation may be used alone (e.g., for some lymphomas) or combined with other therapies to treat radiosensitive tumors. Radiotherapy causes mutations or alterations in the targeted DNA, thus preventing mitosis or causing immediate cell death. Radiation also damages blood vessels, cutting off blood supply to the tumor cells and starving them. Radiation is most effective on cells under- going DNA synthesis or mitosis; therefore it destroys the more rapidly dividing cells in the body, both tumor cells and normal cells (radiosensitive cells). Some types of cancer are radioresistant or unresponsive to radiation. Radiation may be used before surgery to shrink a tumor or destroy loose surface cells, or may be begun after healing of the surgical site (approximately 6 weeks). Ionizing radiation consists of either electromagnetic waves such as x-rays or gamma rays (from radioactive substances such as radium or cobalt) or high-energy, penetrating particles (electrons, protons). There are several methods of administration: • External sources, such as a cobalt machine, deliver radiation for a short period to a specific site in the body. This method frequently requires the client to 558 SECTION IV Factors Contributing to Pathophysiology Chemotherapy Some types of cancer cells respond well to certain anti- neoplastic drugs, whereas other types of cells are resistant to this therapy. Chemotherapy may be used alone (as in leukemias) or may be combined with surgery or radiation. Drugs are most effective against the most rapidly repro- ducing cells and on small tumor masses. Usually therapy commences approximately 6 weeks after surgery, allowing time for some recovery. In most treatment protocols, a combination of two to four drugs, each from a different classification, is given to a patient at periodic intervals. The classifications include antimitotics, antimetabolites, alkylating agents, and antibiotics. The drugs interfere with protein synthesis and DNA replication at different points in the tumor cell cycle, thus destroying the cells. A cell cycle is essentially a mini life cycle of growth and reproduction. The choice of drugs and the timing sequence depend on the cell cycle of the particular tumor cell. So each type of cancer is matched to a specific drug treatment. When each drug acts at a different point in the cell cycle, the maximum number of malignant cells can be destroyed. Fig. 20.10 illustrates the combination of: • Adriamycin (doxorubicin), an antitumor antibiotic that binds DNA and inhibits synthesis of nucleic acids, (dry mouth) may develop, thereby making it more difficult for the client to eat many foods and increasing the risk of damage to teeth. Swelling may impair swallowing and ventilation. 3. Abdominal radiation is likely to damage the ovaries or testes, leading to sterility or the risk of teratogenesis. Sperm banking or egg retrieval and storage should be discussed with the client before starting treatment. 4. In addition, radiation often produces a nonspecific fatigue and lethargy accompanied by mental depression. Long-term effects of radiation include inflammation, necrosis, and scar tissue along the pathway of the radiation and at the tumor site. At some later time, scar tissue may cause adhesions or obstruction and other secondary problems (see Chapter 5). THINK ABOUT 20.7 a. Explain why the client with cancer may lack adequate nutrition to maintain normal tissue needs. b. Explain the adverse effects radiation therapy can have on a patient’s immune system, digestion, reproductive functions, and possible congenital issues. 4- 6 ho urs 1-2 hours 4-6 hours 10-12 hours BLEOMYCIN DACARBAZINE DOXORUBICIN (Adriamycin) ABVD therapy for Hodgkin disease 1. Doxorubicin (Adriamycin) blocks S-phase and is active in other phases 2. Bleomycin inhibits DNA synthesis in S-phase 3. Vinblastine blocks mitosis 4. Dacarbazine any phase G0 Resting state Differentiation (No further division, [e.g., neurons]) S Synthesis M Mitosis (DNA replication) (Maturation or protein + RNA synthesis) (Protein + RNA synthesis) cell growth or Gap G1 cell growth or Gap G2 DOXORUBICIN (Adriamycin) VINBLASTINE Example of Time Epithelial Cell FIG. 20.10 The cell cycle and chemotherapy. CHAPTER 20 Neoplasms and Cancer 559 inflammation and damage in the digestive tract. In some cases, nausea and vomiting develop before chemotherapy administration related to anxiety or past experience. • Antiemetic drugs such as ondansetron (Zofran) may be helpful in decreasing vomiting. Alternatives include dexamethasone (Decadron) and prochlorperazine (Stemetil). • Epithelial cells are easily damaged because of the ongoing mitosis. Hair loss (alopecia) and breakdown of skin and mucosa occur frequently. Stomatitis in the mouth and diarrhea are common problems and contribute to malnutrition. Candidal infections are common in the mouth. • In addition, some antineoplastic drugs have unique damaging effects in specific areas—for example, fibrosis in the lungs or damage to myocardial cells. acting primarily on cells in the S phase (DNA synthesis) but with some activity in other stages (e.g., altering the cell membrane) • Bleomycin, also an antitumor antibiotic that inhibits DNA synthesis • Vinblastine, a cell-cycle–specific antimitotic drug that acts on cells in the M stage (mitosis) • Dacarbazine, an alkylating agent nonspecific drug acting at several points in the cycle This combination is the “ABVD” regimen for treating Hodgkin lymphoma, still the most effective drug treatment for this cancer, although many other combinations have been tried. This combination of drugs is administered intravenously on day 1 and day 15 and then repeated every 4 weeks. Every 4 weeks, hydrocortisone may be added to the combination. There are a large number of specific protocols, and new ones are being researched constantly in an effort to improve effectiveness and minimize adverse effects. Research on adjuvant carrier molecules, which increase cellular uptake of chemotherapy drugs, is providing information on more effective delivery of such drugs. High doses of the drugs are administered to maximize damage to the tumor; then a rest period is provided to allow recovery of normal tissues. A cycle may be repeated at specific weekly or monthly intervals. Many drugs are administered intravenously on an outpatient basis. Lower dosages or milder drugs may be used as palliative therapy. Adverse effects (side effects) may be quite marked with drug therapy. As with radiation, the normal cells are also damaged, most commonly the skin and mucosa, bone marrow, and gonads. The need to minimize adverse effects is another factor in choosing the combination. For example, not all drugs in a combination can seriously depress the bone marrow, but rather, one of the drugs in the combination may cause nausea or hair loss. • Bone marrow depression is the limiting factor with chemotherapy, and dangerously low blood counts may require transfusions or cessation of therapy until the bone marrow recovers. Blood tests are taken before each treatment to check cell count. The nadir, or point of lowest cell count (neutropenia or leukopenia), may occur at different points in the cycle depending on the particular drug. If the count is too low, treatment may need to be postponed, and antibiotics or hospi- talization may be required. Hemorrhage is a major risk with thrombocytopenia. Infections are common with neutropenia, septicemia with tumors in the gastrointestinal tract, and pneumonia with lung cancers. Skin infections are common, particularly if immobility or malnutrition has led to skin breakdown. Of course, in cases in which the blood cells are already reduced in number or function, as with the leukemias, the effects of chemotherapy can be critical. • Vomiting may occur during or shortly after treatment due to direct chemical stimulation by the drug of the emetic or vomiting center in the brain. Vomiting may continue after treatment in response to the mucosal THINK ABOUT 20.8 Explain several ways by which the treatment of cancer by chemotherapy may temporarily create additional health problems for the patient. Other Drugs Hormones are frequently prescribed during cancer treat- ment in addition to the basic treatment. A glucocorticoid such as prednisone is used to decrease mitosis and increase erythrocyte counts (see Chapter 5). For the patient, these drugs improve appetite and a sense of well-being. They also decrease inflammation and swelling around the tumor. Sex hormones are beneficial when tumor growth is dependent on such hormones; for example, estrogens may slow the growth of prostate cancer. Hormone- blocking agents are often effective in reducing tumors and preventing recurrences. Tamoxifen is an example of an estrogen-blocking agent used in clients with estrogen- dependent breast cancer; it has been particularly useful in postmenopausal women. Other related agents are being assessed for long-term effects. A newer drug, exemestane (Aromasin), has been useful with fewer side effects in advanced cases of postmenopausal, hormone-dependent breast cancer in which tamoxifen is not effective. This drug blocks the conversion of androgens to estrogens by the enzyme aromatase. Biologic response modifiers are agents that augment the natural immune response in the body to improve surveil- lance and removal of abnormal cells. Included in this group are a natural product of human cells, interferon, and bacillus Calmette-Guérin (BCG) vaccine (for tuber- culosis). Interferon has not been as effective as expected, primarily due to undesirable and often dangerous side effects such as negative effects on areas of the immune system, but investigation into this area continues. The BCG vaccine may be injected near the tumor or instilled in a cavity such as the bladder when cancer is present. 560 SECTION IV Factors Contributing to Pathophysiology Research continues to study many of these, although trials have not shown significant benefit of such approaches. Gene Therapy Gene therapy is an experimental cancer treatment designed to: • Replace mutated genes with a healthy copy of the gene • Inactivate a mutated gene • Introduce a new gene For more detailed and continuing updates, please refer to: https://ghr.nlm.nih.gov/primer#therapy Nutrition Patients with advanced cancer are often malnourished. Contributing factors include change in taste sensations, anorexia and vomiting, sore mouth or loss of teeth, pain and fatigue, malabsorption due to inflammation in the digestive tract, altered metabolism, and nutrient trapping by the tumor. These factors may result from the tumor itself or from the effects of chemotherapy and radiation. The use of measures such as ice and mouth rinses is suggested to reduce the discomfort of ulcers and inflam- mation. Frequent small amounts of nonirritating and favorite foods are better tolerated. These small meals can be planned to be attractive to the patient and optimize protein and vitamin intake. Pain control and antiemetic drugs may increase appetite. If necessary, total parenteral nutrition may be used. It involves the administration of a nutrient mixture directly into a peripheral vein. Complementary Therapies Many alternative approaches are used to treat or “cure” cancer. These nonmedical therapies are referred to as complementary. They range from the use of a raw food macrobiotic diet, to the use of insulin and glucose to accompany chemotherapy. Although some complementary therapies have shown benefit when combined with medical therapy, there is no research-based evidence to show that any complementary therapy on its own will prolong life or reduce metastasis. Clients choosing to use complementary therapies should advise their oncology team that they are doing so. Cancer treatment is a complex science, and the public is demanding better therapeutic outcomes; thus complementary therapy may offer hope for a better outcome. It is important that the health care worker is aware of complementary therapies and can direct patients to the appropriate information about any such treatment. Additional information on alternative or complementary therapy in general is in Chapter 3 of this text. Prognosis A “cure” for cancer is generally defined as a 5-year survival without recurrence after diagnosis and treatment. In some cases, several periods of remission (no clinical signs) may occur before the disease becomes terminal. It stimulates the movement of macrophages and T lymphocytes to the site, where they may destroy the tumor cell. Other than BCG for treatment of bladder cancer, these are not a first-line treatment at this time. Identifying and acting on molecular targets, perhaps in the immune response, is seen as a way of developing new drugs with fewer side effects. Trastuzumab (Her- ceptin) is used to treat advanced breast cancer. It is an antibody that binds cell receptor sites, blocking growth signals and stimulating immune defenses. Another new group achieving a favorable response consists of drugs with antibody action labeled with radioisotopes. An example is tositumomab (Bexxar) used for non-Hodgkin lymphoma. It exerts antibody action against antigen on the tumor cells, destroying them. In this case, radioactive iodine has a half-life of 8 days. There have been reports of allergic reactions. Another focus for investigation is the angiogenesis inhibitor drug group (e.g., angiostatin or endostatin). Angiogenesis means new blood vessels, and as a tumor grows and spreads, so must new blood vessels. Antian- giogenesis drugs block the stimulus for endothelial cell (blood vessel walls) growth by various mechanisms and therefore reduce local blood flow and starve the tumor cells. It was hoped that these drugs would have fewer adverse effects and could be combined with traditional chemotherapy for more effective treatment. To date the results have not met expectations, possibly because blocking the growth of blood vessels also reduces the delivery of chemotherapy to the cells in the tumor. Bevacizumab (Avastin) has prolonged the life of individu- als with colorectal cancer. It has antibody activity against vascular endothelial growth factor, which is secreted by many tumor cells and required to form blood vessels. Analgesics for pain control are an important part of therapy, particularly when cancer is advanced (see Chapter 4). Determining the cause of the pain is important because this determines the therapeutic approach. In some cases, a specific factor such as infection or muscle spasm can be treated, leading to pain reduction. Radiation treatment can relieve nerve compression. For analgesics, a stepwise approach is frequently adopted. This involves using mild drugs in low doses initially, then increasing the dose, then changing to a stronger analgesic, and ultimately using morphine. Multiple-drug “cocktails” are often effective as the pain intensity increases. Very high doses of narcotics may be administered as tolerance builds. Self-administration or implanted units providing continuous infusion are helpful in long-term pain control. Dependency is currently less of a concern, but narcotic analgesics do have a number of significant side effects. These include nausea, constipation, drowsiness, and respiratory depression. Other methods for pain relief may be beneficial, as well as measures that reduce fatigue and anxiety, which can aggravate pain. Alternative therapies are sought by many clients in whom the traditional treatments have not been successful. https://ghr.nlm.nih.gov/primer#therapy CHAPTER 20 Neoplasms and Cancer 561 Ovarian Cancer Ovarian cancer has a very poor prognosis, ranking high in mortality rates. The tumor is hidden in the peritoneal cavity; it is a “silent” tumor (see Fig. 20.7). Although there are many histologic types of ovarian cancer, this section deals only with the basic concepts (see Chapter 19). Hormonal and genetic factors appear to play a role in the development of this cancer. Presenting (or first) signs are vague and appear only after the tumor is well advanced and is large enough to cause pressure on the adjacent structures, such as the bladder or intestine, or when an inflammatory exudate forms in the abdominal cavity. These late signs often contribute to a late diagnosis and a delay in treatment. There are tumor markers to assist in early diagnosis and screening, but false-negatives do occur. The marker CA125 is elevated in other conditions as well as ovarian cancer, but is useful in monitoring the effectiveness of treatment. The first indications are usually altered bowel or bladder function or increased abdominal girth. The tumor spreads easily by means of the lymphatic vessels and by seeding as cancer cells pass along the peritoneal membranes or are sloughed into peritoneal fluid, traveling to the liver and other organs. The cancer also invades the uterus and pelvis. Treatment includes surgery, radiation, and che- motherapy. (See Chapter 19 for further discussion.) Brain Cancer Brain tumors may be benign or malignant. Both are space-occupying masses that create pressure inside the skull, and both are serious for this reason. Brain tumors, even when small, can cause death if they are located in the brain stem or cerebellum, where they can interfere In some cases, early diagnosis and treatment limit the extent of the illness in an individual. In other cases, cancer treatment involves a prolonged period of illness with intermittent acute episodes. Information and support for the patient and family are offered by the American Cancer Society as well as cancer clinics and the many other community support groups. The death rates for specific cancers vary. For some types of cancer, such as lung cancer, there has been no significant improvement in the outcome even with aggres- sive treatment. For other cancers, such as certain childhood leukemias and Hodgkin lymphoma, effective treatment has been developed, and survival rates are much improved. Current statistics for specific cancers are available from the American Cancer Society or Canadian Cancer Society. Prognosis in a specific individual is influenced by many factors and so is subject to change. THINK ABOUT 20.9 a. From your knowledge of normal physiology, explain how good nutrition could reduce the complications or additional problems associated with cancer and its treatment. b. Suggest some factors other than clinical test results that could affect the prognosis or outcome for an individual with cancer. Examples of Malignant Tumors These examples are used to illustrate some general aspects of cancer. Additional details are provided in the appropri- ate chapter dealing with the affected system. For specific information on other types of cancer, refer to the body system chapter in which the affected organ/structure is discussed. Skin Cancer Skin cancer is visible, easily diagnosed and treated (by surgery), and develops slowly; therefore most types with the exception of malignant melanoma have an excellent prognosis. Skin cancers have the highest rate of recurrence and usually arise on the head and neck or back, areas exposed to the sun and irritation. They occur more fre- quently in individuals with fair skin who are over 40 years of age and live in southern climates. The number of cases is increasing, resulting in a public education campaign to reduce sun exposure and sun tanning practices. Basal cell carcinoma is the most common form of skin cancer (see Chapter 8 for other skin cancers). The tumor appears as a pearly papule and develops a central ulceration, a “rodent ulcer” (Fig. 20.11). Significant char- acteristics of the lesion include lack of pain or pruritus (itching) and persistence—the lesion remains and grows slowly. The tumor is slowly invasive into the subcutaneous tissues. THINK ABOUT 20.10 Explain several reasons for the good prognosis in skin cancer. FIG. 20.11 Basal cell carcinoma. (From Lookingbill D, Marks J: Principles of Dermatology, ed 3, Philadelphia, 2000, Saunders.) 562 SECTION IV Factors Contributing to Pathophysiology A. Frontal astrocytoma E. Glioblastoma D. Meningioma B. Pituitary adenoma C. Cerebellar tumor A + D. Tumors on surface of brain B. Pituitary tumor causes neurologic dysfunction and hormonal abnormalities C. Cerebellar tumors, even when small, can interfere with vital brain stem function E. Tumors in the interior of the brain shift ventricles and interfere with flow of cerebrospinal fluid F. Multiple metastases E. Glioblastoma F. Metastatic tumor from lung Ventricle FIG. 20.12 Effects of brain tumors in various locations. Large acoustic neurino distorting brainstem an Meningioma invading superior sagittal sinus A B FIG. 20.13 A, Contrast-enhanced MRI showing irregular enhancement with central necrosis in the left temporal lobe. B, Large hemispheric glioblastoma multiforme with central areas of necrosis. Brain distortion. (A From Benjamin I, et al: Cecil Essentials of Medicine, ed 9, Philadelphia, 2016, Elsevier, Saunders. B From Misulis K, Head T: Netter’s Concise Neurology, updated edition, Philadelphia, 2017, Elsevier.) with vital functions such as respiration. Removal of the mass may be fairly easy if it is located on the brain surface but difficult and dangerous if it is located elsewhere (Fig. 20.12). Brain tumors vary histologically, originating from neurons, neuroglial cells, blood vessels, or connective tissue. They can occur in children as well as adults (Fig. 20.13). Early indications of brain tumors are seizures or signs of pressure such as headache, drowsiness, vomit- ing, visual problems, or impaired motor function (see Chapter 14 for information on increased intracranial CHAPTER 20 Neoplasms and Cancer 563 Top 10 Cancer Sites: 2009–2013 (U.S.); Male and Female All Races White Black Asian/Pacific Islander§ American Indian/ Alaska Native§ Hispanic§¶ 1 Female Breast 123.4 Female Breast 124.4 Prostate 194.8 Female Breast 89.1 Female Breast 69.5 Prostate 104.4 2 Prostate 123.2 Prostate 113.3 Female Breast 122.4 Prostate 63.5 Prostate 65.9 Female Breast 92.2 3 Lung and Bronchus 62.5 Lung and Bronchus 63.2 Lung and Bronchus 65.5 Lung and Bronchus 36.0 Lung and Bronchus 43.9 Colon and Rectum 35.6 4 Colon and Rectum 40.6 Colon and Rectum 39.7 Colon and Rectum 48.1 Colon and Rectum 32.2 Colon and Rectum 30.7 Lung and Bronchus 32.7 5 Corpus and Uterus, NOS 25.6 Corpus and Uterus, NOS 26.0 Corpus and Uterus, NOS 24.6 Corpus and Uterus, NOS 18.0 Corpus and Uterus, NOS 16.6 Corpus and Uterus, NOS 21.7 6 Urinary Bladder 20.7 Melanomas of the Skin 23.0 Kidney and Renal Pelvis 17.5 Thyroid 14.2 Kidney and Renal Pelvis 15.6 Non-Hodgkin Lymphoma 17.2 7 Melanomas of the Skin 20.3 Urinary Bladder 22.0 Pancreas 15.4 Liver and Intrahepatic Bile Duct 13.4 Non-Hodgkin Lymphoma 11.1 Kidney and Renal Pelvis 15.9 8 Non-Hodgkin Lymphoma 19.1 Non-Hodgkin Lymphoma 19.7 Non-Hodgkin Lymphoma 14.1 Non-Hodgkin Lymphoma 12.8 Liver and Intrahepatic Bile Duct 9.4 Liver and Intrahepatic Bile Duct 13.0 9 Kidney and Renal Pelvis 16.0 Kidney and Renal Pelvis 16.2 Myeloma 12.8 Stomach 11.0 Urinary Bladder 8.9 Thyroid 12.6 10 Thyroid 14.0 Thyroid 14.6 Urinary Bladder 11.7 Pancreas 9.3 Ovary 8.5 Urinary Bladder 11.4 • This table was taken from: https://nccd.cdc.gov/uscs/toptencancers.aspx. CASE STUDY A Lung Cancer Ms. T., a 65-year-old woman in good health, presents to her family doctor with a chronic cough. She is currently a nonsmoker. A chest x-ray shows a small growth in the right lung. A blood test for lung tumor markers is negative, and a bronchoscopy is scheduled to biopsy the tumor. The pathology report indicates the lung tumor is a secondary tumor from the small intestine. Ms. T. is referred to an oncologist for treatment. 1. What factors in her history indicate a risk of cancer for Ms. T.? 2. What is the significance of a negative test for tumor markers in this case? 3. How did the small intestine tumor cells reach the lungs? 4. What is the probable prognosis for Ms. T.? pressure). Malignant brain tumors do not metastasize outside the central nervous system because the primary tumor is usually fatal before metastasis begins. However, tumors from the breast, lung, or bone can metastasize into the brain, forming secondary tumors. Treatment of brain tumors may be surgery, radiation, or chemotherapy and may cause the loss of some additional brain tissue. Aftereffects of treatment may include loss of specific function and disability. Cancer Incidences In 2016 the Centers for Disease Control and Prevention released information from The United States Cancer Statistics between 1999 and 2013. This resource is the: United States Cancer Statistics: 1999–2013 Incidence and Mortality Web-Based Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2016. Available at www.cdc.gov/uscs. http://www.cdc.gov/uscs https://nccd.cdc.gov/uscs/toptencancers.aspx 564 SECTION IV Factors Contributing to Pathophysiology • Staging of a tumor at the time of diagnosis is based on the size of the primary tumor, the involvement of nearby lymph nodes, and the presence of distant metastases. Staging is used as a guide to treatment and prognosis. • Treatment may involve any or all of surgery, radiation, and chemotherapy. A cancer is considered cured after 5 years without recurrence. • The carcinogenic process is based on exposure, first to initiating factors and later to promoters, each of which contributes to changes in cell DNA, creating a malignant neoplasm. • Carcinogens or risk factors include genetic predisposi- tion and environmental, biologic, and dietary factors. • Radiation therapy may be provided by external sources such as a cobalt machine or by internal implants of material such as radioactive radium. • Chemotherapy frequently consists of a specific com- bination of drugs administered (often intravenously) at intervals over a certain period. Hormones such as prednisone may be added to the regimen. The growth of some tumor cells is hormone dependent, in which case hormones may be provided or removed, as neces- sary. Several new approaches to drug therapy are under development. • Adverse effects of chemotherapy and radiation include bone marrow depression causing leukopenia, anemia, and thrombocytopenia; epithelial damage causing mucosal ulceration and hair loss; and nausea and vomiting. • Basal cell carcinoma is an example of skin cancer related to sun exposure. The prognosis is excellent because the cancer is slow growing, obvious at an early stage, and easily treated. • Ovarian cancer has a poor prognosis because of the tumor’s hidden location and lack of signs until it is large in size or metastasis has occurred, as well as its rapid growth and early spread. • Brain tumors, both benign and malignant, result in pressure inside the skull and may be difficult to remove without causing additional brain damage. C H A P T E R S U M M A R Y In the body, each cell type is distinguished by its indi- vidualized life cycle and pattern of differentiation. Neoplasm means “new growth,” whereby the cells do not follow the normal growth controls. The changes are determined by biopsy and histologic examination. • Benign neoplasms are space-occupying masses of abnormal cells, but they do not spread to distant sites and are not considered life threatening unless located in an area such as the brain. • Malignant neoplasms (cancer) usually consist of more primitive cells that are reproducing more rapidly, and they spread by invasion or metastases. Systemic effects are present. • Local effects relate to the pressure of the mass (e.g., ischemia and necrosis, obstruction, or pain). • Systemic effects of malignant tumors include weight loss, anemia, fatigue, and paraneoplastic syndrome. • Grading of a cancer is determined by the degree of differentiation and indicators of mitoses seen in the tumor cells. S T U D Y Q U E S T I O N S 1. Compare benign and malignant neoplasms, describing three differences. 2. How does the zone of inflammation around the tumor contribute to pain? 3. Explain why metastasis can lead to multiple secondary tumors in different sites. 4. Why may chemotherapy be recommended for a client when a cure is not likely? 5. Explain why severe thrombocytopenia can be life threatening. 6. Explain two reasons why infection may occur with cancer. 7. Describe two potential problems resulting from bleeding. 8. Describe the local effects of radiation. 9. Explain why benign brain tumors are serious. 10. Compare basal cell skin cancer and ovarian cancer by: a. presenting signs b. spread c. prognosis CASE STUDY B Breast Cancer W.R., a 32-year-old woman, felt a small, hard, painless lump in her left breast during regular self-examination. The lump did not disappear during the next few days, so she went to her physician for an examination. Tests followed, and a biopsy confirmed the presence of a malignant tumor. The tumor (1.5 cm) was removed, as well as five lymph nodes, two of which contained malignant cells. No other metastases appeared to be present. Courses of radiation and chemotherapy were recommended after a 6-week recovery period, and the prognosis appeared good. 1. Which activities led to the good prognosis? 2. Why were the lymph nodes checked? 3. Why are radiation and chemotherapy recommended in this case? Describe three possible side effects of treatment. 565565 Congenital and Genetic Disorders C H A P T E R 21 Review of Genetic Control Congenital Anomalies Genetic Disorders Single-Gene Disorders Autosomal-Recessive Disorders Autosomal-Dominant Disorders X-Linked Dominant Disorders X-Linked Recessive Disorders Chromosomal Disorders Multifactorial Disorders Developmental Disorders Diagnostic Tools Genetic Technology Genetic Engineering and Gene Therapy Genetic Diagnosis and DNA Testing Proteomic Research and Designer Drugs Down Syndrome Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Define congenital, genetic, chromosomal, developmental, and multifactorial disorders. 2. Describe the inheritance pattern of autosomal- recessive, autosomal-dominant, and X-linked recessive disorders. 3. Explain the common causes of developmental disorders and their relationship to fetal development. 4. Discuss the importance of proteomics in the development of treatments for genetic disorders. 5. Describe the benefits and risks of genetic screening programs and prenatal testing. 6. Discuss the purposes of genetic engineering, manipulation, and related current concerns. 7. Describe the cause and effect of Down syndrome. L E A R N I N G O B J E C T I V E S allele amniocentesis anomaly autosomes expression gene penetration genotype heterozygous homozygous incomplete dominant karyotype meiosis mitosis mutation neonates organogenesis phenotype polygenic teratogenic trisomy K E Y T E R M S Review of Genetic Control Genetic information for each cell is stored on chromo- somes, of which there are 23 pairs in each human cell. Twenty-two pairs are autosomes, and they are numbered when arranged by size and shape in a diagnostic graphic termed a karyotype (Fig. 21.1). The 23rd pair consists of the pair of sex chromosomes; males have XY, and females have XX chromosomes. A male child receives the X chromosome from his mother and a Y chromosome from his father. A female child receives an X chromosome from each parent. During meiosis in humans, each sperm and each ovum receive only 23 chromosomes, that is, one chromosome from each pair. When the ovum is fertilized by the sperm, the resulting zygote has 46 chromosomes, or 23 pairs, containing an assortment of genetic informa- tion inherited from the parents. Because so many combina- tions of genes are possible, it is most unlikely that any two persons other than identical twins will have the same genes and sequence of DNA (deoxyribonucleic acid). Therefore DNA is considered a unique identifying characteristic for an individual (Fig. 21.2). Chromosomes are made up of many genes, which are matched for a function (allele) at a specific location on 566 SECTION IV Factors Contributing to Pathophysiology is carried forward. Changes can occur because of an error in the process of meiosis or mitosis, but these are relatively rare. Such a mutation, or alteration in genetic material, may be spontaneous or may result from exposure to harmful substances such as radiation, chemicals, or drugs. Research has been directed toward “mapping” all the genes on particular chromosomes and identifying the role of each gene (Fig. 21.3). The International Human Genome Project (HGP) is a worldwide project conducted by geneticists that aims to identify and map all the genes on every chromosome. • The HGP was initiated in 1990. The timeline of research on the human genome can be reviewed at: www.genome.gov • In April 2003, the HGP was completed. • The refining, verifying, and analysis of data and identification and functional determination of indi- vidual genes is an ongoing process and continues the paired chromosomes. A gene is a DNA “file” that contains information about protein synthesis in the cell. All cells in an individual’s body contain the same chro- mosomes and genes for the same traits (genotype), although not all genes are active in each cell. This limited activity is referred to as gene expression. Usually only a small group of genes is controlling protein synthesis in a particular cell at any particular time; gene expression is related to the cell’s specific function. Genes are composed of DNA strands, which determine the function of all cells in the body. RNA (ribonucleic acid) provides the communication link with DNA during the actual synthesis of proteins and helps to maintain control of cell activity. During embryonic and fetal development, when cells are undergoing mitosis (somatic cell division), the chromosomes replicate, and each daughter cell receives a copy of DNA identical to that in the parent cell. Therefore the same genetic information C D A B 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 19 20 X Y21 22 17 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 19 20 X Y21 22 17 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 19 20 X Y MM 21 22 17 18 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 19 20 X Y21 22 17 18 FIG. 21.1 Examples of Karyotypes. A, Normal female (46, XX). B, Normal male (46, XY). C, Male with Down syndrome or trisomy 21 (47, XY, + 21). D, Female with translocation involving chromosomes 14 and 15 (45, XX, t [14q15q]). (Courtesy of Cytogenetics Laboratory, North York General Hospital, Toronto, Ontario, Canada.) http://www.genome.gov/ CHAPTER 21 Congenital and Genetic Disorders 567 S S S S S S P SS S S S S S S S SS S S S S S S S S S S S S S P S P P P P P P P S P P P P P P P P P P P P P P P P P P P P P P T A T C T T G C A A C G C A TA TA C T T C A G G G G FIG. 21.2 DNA replication. (From Applegate E: The Anatomy and Physiology Learning System, ed 2, Philadelphia, 2000, Saunders.) THINK ABOUT 21.1 a. What are the purposes of meiosis? b. Which pair number represents the sex chromosomes? c. Which parent passes on the Y chromosome to the child? d. Describe the structure, location, and function of a gene. e. Why is DNA considered a dependable means of identification for an individual? How might this be used? f. List three ways that genetic control (DNA) could be altered. in many genomic laboratories. For overview and updated information refer to: https://report.nih.gov/ NIHfactsheets/ViewFactSheet.aspx?csid=45 When a specific gene for a pathologic condition is identified, a DNA analysis follows, leading to the development of a simple blood test to screen individuals for the presence of that specific gene. The genetic link to a disease may lead to improved treatment, a cure, or prevention. Many genetic conditions have been determined so far, as well as a large number of genes related to cancer and cardio- vascular disease. Every year, a few more disease-causing genes are located. For some disorders, more than one gene may be responsible; for example, each of four different genes causes four different types of Fanconi anemia. Genes control all physical characteristics, such as eye color or color blindness, and all metabolic processes. The effects, such as shade of eye color, vary with the gene penetration, or frequency of expression of the gene among individuals carrying the gene. Inheritance of many genes for both normal characteristics and disease characteristics follows specific patterns of inheritance termed Mendelian laws or patterns. Mendelian inheritance includes recessive and dominant patterns, and results can be predicted using algebra or Punnett squares (Fig. 21.4). Traditionally recessive genes are represented by lowercase letters and dominant genes by capital letters. Many traits such as eye color and blood type are polygenic, meaning that more than one allele determines the genotype and thus the phenotype of the individual. Congenital Anomalies Congenital anomalies refer to disorders present at birth. Such defects include genetic or inherited disorders as well as developmental disorders. • Genetic disorders may result from a single-gene trait or from a chromosomal defect, or they may be multi- factorial. A few examples are listed in Box 21.1. • Single-gene disorders are caused by a change in one gene within the reproductive cells (ova or sperm); this mutant gene is then transmitted to subsequent genera- tions following the specific inheritance pattern for that gene. Mutations in the body cells other than the reproductive cells may cause dysfunction but are not transmitted to offspring. In some cases, the expression, or effect (phenotype), of an altered gene produces clinical signs that vary in severity depending on the penetration or activity of the gene. Clinical signs of genetic disorders are not always present at birth but may occur months or years later, for example, Huntington disease, which is seen in adults. However, children with genetic disorders do constitute a sig- nificant percentage of those who require hospital and community care. Additional information on children with genetic disorders can be found in any pediatrics textbook. • Chromosomal anomalies usually result from an error during meiosis, when the DNA fragments are displaced or lost, thus altering genetic information (e.g., Down https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45 https://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45 568 SECTION IV Factors Contributing to Pathophysiology Ocular albinism Duchenne muscular dystrophy Turner syndrome Cleft palate Agammaglobulinemia X-linked agammaglobulinemia Hemophilia A Color blindness X CHROMOSOME Emphysema Colorectal cancer Epidermolysis bullosa simplex Diabetes insipidus nephrogenic PKU CHROMOSOME 12 CHROMOSOME 21 Chronic schizophrenia Myeloproliferative disorders (e.g., leukemia with Down syndrome) Myoclonic epilepsy FIG. 21.3 Examples of approximate gene locations on selected chromosomes. BOX 21.1 Examples of Genetic Disorders and Their Inheritance Single-Gene Disorders Autosomal-Dominant Disorders Adult polycystic kidney disease Huntington chorea Familial hypercholesterolemia Marfan syndrome Autosomal-Recessive Disorders Cystic fibrosis Phenylketonuria Sickle cell anemia Tay-Sachs disease X-Linked Dominant Disorders Fragile X syndrome X-Linked Recessive Disorders Color blindness Duchenne muscular dystrophy Hemophilia A Multifactorial Disorders Anencephaly Cleft lip and palate Clubfoot Congenital heart disease Myelomeningocele Schizophrenia Chromosomal Disorders Down syndrome Monosomy X (Turner syndrome) Polysomy X (Klinefelter syndrome) Trisomy 18 (Edwards syndrome) CHAPTER 21 Congenital and Genetic Disorders 569 Chromosomal anomalies are found in approximately 7 in 1000 births. • Other congenital or developmental disorders result from premature birth, a difficult labor and delivery, or exposure to a damaging agent during fetal develop- ment. The defect may be limited to one organ, or it may affect the functions of many organs. Such congenital disorders often do not have a genetic component, but because they manifest at birth, they are termed congenital or developmental. Developmental defects may be spontaneous errors or may result from exposure to environmental factors in utero. The DNA of the embryonic cells may be altered easily because rapid mitosis and differentiation take place normal C C carrier C c carrier C c affected c cc CCARRIER PARENT 25% normal 25% affected 50% carrier Probability Probability Probability Probability CARRIER PARENT AUTOSOMAL RECESSIVE DISORDERS – Example: Cystic fibrosis C c C c C c C cC CNORMAL PARENT AFFECTED PARENT All children carriers (heterozygous) affected normal h h affected H h normal h hNORMAL PARENT 50% affected child AFFECTED PARENT AUTOSOMAL DOMINANT DISORDERS – Example: Huntington chorea HAFFECTED hPARENT AFFECTED PARENT H h H h h h heterozygous homozygous 75% affected 25% normal H h H h H h H H h h female normal female carrier male normal male affected Y XD XD XD XD FATHER C B A NORMAL MOTHER CARRIER X-LINKED RECESSIVE DISORDERS – Example: Duchenne muscular dystrophy AFFECTED FATHER MOTHER CARRIER X d XD Xd XD Y Xd Y Males—50% normal 50% affected Probability Females— 50% normal 50% carriers female carrier female affected male normal male affected X D X d X d Xd XD Xd Xd XD Y Xd Y Males— 50% normal 50% affected Probability Females— 50% carrier 50% affected C c c c Y FIG. 21.4 Inheritance patterns with Punnett squares. syndrome). This may be spontaneous or result from exposure to a damaging substance. During meiosis, genes are often redistributed during the process of “crossover” in which chromosomes may swap portions. There may be an error in chromosomal duplication or reassembly, resulting in abnormal placement of part of the chromosome (a translocation), altered structure (deletion), or an abnormal number of chromosomes. This change is reflected in the expression of genes in the child. These birth defects are more common when the mother is older than age 35. New research has also identified a higher risk in children of older fathers. Such errors are a common cause of spontaneous abortions during the first trimester of pregnancy. 570 SECTION IV Factors Contributing to Pathophysiology FIG. 21.5 Clinical manifestations of Marfan syndrome. Skeletal deformities such as pectus excavatum and abnormal curvature of the thoracic spine are common findings. (From Turnpenny P: Emory’s Elements of Medical Genetics, ed 14, Philadelphia, 2012, Churchill Livingstone.) during the first months of embryonic development. During this period replication of DNA occurs frequently and the possibility of damage is significant. Maternal nutrition may also affect development. For example, low folic acid levels in the mother are a factor in the occurrence of spina bifida in the embryo. • Teratogenic agents—agents that cause damage during embryonic or fetal development—are often difficult to define. Many reports must be collated before a cause is identified. Often the reports do not point to a single factor, and scientific experiments on humans to verify the data are not ethically feasible. For example, the effects of the drug thalidomide were not realized for a long time, and during this time many children were born with missing limbs. Since then, women have been advised to refrain from using any drugs or chemicals during the childbearing years unless recommended by a physician. Teratogenic agents may be present in the workplace; women of childbearing years should be especially careful in following all health and safety recommendations in the workplace. • Multifactorial disorders, affecting approximately 10% of the population, are more complex. They may be polygenic (caused by multiple genes), or they may be the result of an inherited tendency toward a disorder that is expressed after exposure to certain environ- mental factors. A combination of factors is required for the problem to be present, whether at birth or later in life. Frequently the predisposing factors of a disorder such as atherosclerosis (heart and vascular disease), certain cancers (e.g., breast cancer), or schizophrenia (a psychiatric disorder) include a familial tendency, which means that family members have an increased risk of developing the disorder, but not every family member will have the disease. Genetic disorders have social and psychological implica- tions. Decisions about whether or not to bear children when there is a risk of such disorders frequently create ethical dilemmas for families. Social implications of the birth of a child with a genetic disease who requires specialized care and treatment are also a concern. Parents often have difficulty in adjusting to the birth of a child with an unanticipated disorder and may need continued assistance with the care of the child and any associated feelings of guilt. Social resources for the care and educa- tion of children who are disabled by a genetic disorder may not be readily available in the community or may be prohibitively expensive. THINK ABOUT 21.2 a. What translocation and deletion events may occur during chromosomal duplication or assembly? b. Differentiate congenital from genetic defects. c. Differentiate a multifactorial disorder from a chromosomal disorder. Genetic Disorders Single-Gene Disorders More than 6000 abnormalities are known, with a single- gene disorder occurring in 1 : 200 live births. Many dis- orders present few, if any, signs and may not be diagnosed; serious defects usually cause spontaneous miscarriage. Single-gene disorders are commonly classified by inheri- tance pattern, with the major groups being recessive, dominant, and X-linked recessive. Examples are given in Box 21.1. A single gene may control a limited function, such as color blindness, or it may have widespread effects, as in cystic fibrosis or Marfan syndrome (Fig. 21.5). It is also important to realize that certain functions such as hearing may be affected by a number of different genes; for example, deafness in children is linked to approximately 16 genes. When considering the probability that a certain child will be affected, it should be remembered that the risk is calculated individually for each pregnancy. For example, if the first child has Duchenne muscular dystrophy, all CHAPTER 21 Congenital and Genetic Disorders 571 subsequent children will not necessarily be normal because the abnormality has already been expressed. The situation is similar to the probability, approximately 50% with each pregnancy, of having a boy or a girl, even if the parents have already produced four boys! Autosomal-Recessive Disorders Autosomal-recessive disorders include a variety of condi- tions, such as cystic fibrosis, which affects the exocrine glands, primarily the lungs and pancreas; sickle cell disease, which involves defective hemoglobin; and phenylketonuria (PKU), in which a metabolic enzyme is missing. In recessive disorders, both parents must pass on the defective gene (see Fig. 21.4A) to produce an affected (homozygous) child. Male and female children are affected equally. If the child is heterozygous (that is, if one normal gene and one disease gene are present in the pair), then that child is a carrier and shows no clinical signs of disease. In this case, the genotypes of the parents determine the risk of transmitting the defect to the child. In each pregnancy, in which each parent is heterozygous for the recessive disease trait, the probability of inheritance is: • 25% that the child will be born with the unaffected genotype • 50% that the child will be born with the carrier genotype • 25% that the child will be born with the affected or disease genotype If only one parent carries the recessive gene for the disease, there is a 50% probability of the child being a carrier and a 50% probability of having the unaffected genotype. Interestingly, some of these disease-causing genes appear to provide additional resistance to other diseases. For example, carriers of the sickle cell gene have dem- onstrated increased resistance to malaria. Many of these recessive gene disorders involve an enzyme defect that causes toxic metabolites to accumulate inside cells or in the blood and tissues, interfering with cell function and possibly causing death. These disorders may also be called storage disease or inborn errors of metabolism. For example, PKU is defined as a deficiency of the enzyme phenylalanine hydroxylase, an enzyme required to convert phenylalanine into tyrosine, resulting in toxic levels of phenylalanine, which results in brain damage if phenylalanine is present in the diet. Some genes do not wholly fit either the recessive or the dominant pattern. For example, the gene for sickle cell disease is transmitted as a recessive, but may also be referred to as incomplete dominant because hetero- zygotes may display some clinical signs (sickle cell trait), whereas homozygotes show the full range of expression (sickle cell anemia). Further discussion of sickle cell disease may be found in Chapter 10. THINK ABOUT 21.3 a. State the probability as a percentage value of a child of two carrier parents being affected by Tay-Sachs disease. b. State the probability as a percentage value that a child will be the carrier of a recessive gene when the mother is a carrier and the father is normal. Autosomal-Dominant Disorders In autosomal-dominant disorders, the presence of the defect in only one of the alleles produces clinical expres- sion of the disease. An affected parent has a 50% prob- ability of passing the disorder on to each child, regardless of the gender of the child (see Fig. 21.4B). There are no carriers, and unaffected persons do not transmit the disorder. Some of these conditions do not become evident clinically until midlife, and because diagnostic tests are not always available, the defective gene may already have been passed on to the next generation before the disease is diagnosed. A screening program is available to detect the presence of the gene for Huntington disease, a condition in which brain degeneration does not develop until midlife (see Chapter 14). X-Linked Dominant Disorders Fragile X syndrome is the most common cause of mental retardation, cognitive deficit, and learning disorders in North America. One in 4000 boys are affected and 1 in 8000 girls have been identified with the disorder. Social and behavioral problems are often present and may account for the higher identification in males. One-third of affected males exhibit autistic behaviors and one-sixth experience seizures. The mutation responsible for fragile X syndrome is inherited as a dominant allele carried on the X chromosome; thus males and females can be affected. The mutation causes the affected X chromosome to appear constricted or broken. X-Linked Recessive Disorders Alleles for sex-linked recessive disorders are usually carried by the X chromosome. (The Y chromosome does not carry the same genes as does the X.) The genes for X-linked disorders are recessive but are manifested in heterozygous males who lack the matching normal gene on the Y chromosome. Females are carriers (without clinical signs) when they are heterozygous. Examples of X-linked recessive disorders include hemophilia A and Duchenne muscular dystrophy. Carrier females have a 50% chance of producing an affected male child and an equal chance of producing a carrier female child in each pregnancy. An affected male will transmit the defect to all his daughters, who become carriers, whereas his sons will neither be affected nor be carriers. (The male passes only the normal Y chromosome to his sons.) 572 SECTION IV Factors Contributing to Pathophysiology THINK ABOUT 21.4 a. Marfan syndrome is transmitted by a dominant gene. State the probability that a child with an affected parent will have the disorder. b. State the probability of a male child being affected and of a female child being affected if the mother carries a gene for a sex-linked recessive disorder. What if it is the father who carries the gene? c. Hemophilia A is transmitted by an X-linked recessive gene. With an affected father, what is the probability that a child will have the disease? With an affected father and a carrier mother, what is the probability? FIG. 21.6 14-year-old female with Turner syndrome showing the characteristic short stature and webbed neck. (From Moore K, et al: Developing Human: Clinically Oriented Embryology, ed 10, Phila- delphia, 2016, Elsevier.) FIG. 21.7 Typical clinical manifestations of Klinefelter syndrome. (From Moore KL, Persuad TVN: The Developing Human: Clinically Oriented Embryology, ed 8, Philadelphia, 2007, Saunders, pp 466.) THINK ABOUT 21.5 Differentiate a chromosomal disorder from a single-gene disorder. Chromosomal Disorders Down syndrome is an example of a trisomy, in which there are three chromosomes rather than two in the 21 position; it is called trisomy 21 (see Fig. 21.1C). Therefore an individual with Down syndrome has 47 chromosomes. A less common form of Down syndrome exists in which part of a chromosome 21 is attached to another chromo- some (translocation). Trisomy 21 change has marked effects throughout the body. Additional information is provided at the end of the chapter. Monosomy X, or Turner syndrome (Fig. 21.6), occurs when only one sex chromosome, the X chromosome, is present. This person has only 45 chromosomes, resulting in a variety of physical abnormalities and lack of ovaries. In Klinefelter syndrome (Fig. 21.7) or polysomy X, an extra X chromosome is present (XXY), resulting in a total of 47 chromosomes in each cell. Not all males show signs and are diagnosed, but typically, testes are small and sperm are not produced. Other common chromosomal abnormalities occur when parts of chromosomes are rearranged or lost during replication. Multifactorial Disorders Multifactorial disorders involve a number of genes or genetic influences combined with environmental factors. Common examples include cleft palate, congenital hip dislocation, congenital heart disease, type 2 diabetes mellitus, anencephaly, and hydrocephalus. These disorders tend to be limited to a single localized area. The same defect is likely to recur in siblings, but there is no increased risk of occurrence of other defects. If the presence of the mutated gene can be documented, avoidance of certain environmental factors or close monitoring of the individual may minimize the risk of development of the disease. For example, genetic CHAPTER 21 Congenital and Genetic Disorders 573 mutations have been noted in some forms of breast cancer. Frequent periodic breast examinations are recommended in women in families in which such genes have been identified. Familial incidence can be determined by using a family pedigree and tracing the incidence of the disorder through several generations (Fig. 21.8). In colon cancer, which has shown a familial pattern, dietary changes to reduce the risk of development of tumors and early colonoscopy may reduce mortality from the cancer. Carrying a gene for a multifactorial disorder such as a cancer increases the risk of developing the disease; but because penetrance of genes differs, one cannot predict with certainty that the individual will develop cancer. Developmental Disorders Exposure to negative environmental influences during pregnancy and even before pregnancy such as radiation may cause changes in the sperm or ova. Evidence has been gathered about the damaging effects on the fetus of alcohol (fetal alcohol syndrome), cigarette smoking (low birthweight and increased risk of stillbirth), radiation, pharmaceuticals, cocaine abuse, and maternal infections. Chemicals such as mercury in food and water, as well as many drugs, can cross the placental barrier and damage the rapidly dividing cells of the embryo and fetus. TORCH is an acronym applied to routine prenatal screening tests for high-risk maternal infections: Toxoplasmosis, Other (hepatitis B, mumps, rubeola, varicella, gonorrhea, syphilis), Rubella, Cytomegalovirus, and Herpes. Newer Affected male Affected female Unaffected male Unaffected male Female carrier Affected male male Female KEY Female Affected Carrier Unaffected Male or or All unaffected Affected male 1ST GENERATION 2ND GENERATION 3RD GENERATION Affected carrier Unaffected male Female carrier FIG. 21.8 Family pedigree for an X-linked recessive trait. programs provide integrated assessment of the TORCH diseases as well as other significant teratogenic or harmful factors. Because many chemicals and drugs are thought to be possibly teratogenic, and because it is difficult to establish proof of such harm, it is recommended that women avoid unnecessary exposure to drugs, chemicals, or radiation during the childbearing years. In most cases, the damage to the embryo occurs in the early period before a preg- nancy is suspected. A deficit or excess of particular nutrients can also lead to developmental abnormalities. The cause of specific malformations is rarely known. Exposure to harmful influences in the first 2 weeks of embryonic life usually results in the death of the embryo. The most critical time is the first 2 months of development, when the cells are dividing rapidly and differentiating, organogenesis is taking place, and the basic body struc- tures are forming (Fig. 21.9). Changes in the basic cells at this time have far-reaching effects. The effects of exposure depend on the stage of development at the precise time of the exposure. In addition to an anomaly, or a developmental abnormality, exposure to damaging substances such as cocaine may cause premature birth, a high risk of further illness in the infant (low birthweight or increased respiratory problems), and increased risk of sudden infant death syndrome. Cerebral palsy is an example of the kind of brain damage that can occur before, during, or immediately after birth (see Chapter 14). The cause may be insufficient oxygen, the toxic effects of excessive bilirubin in the blood 574 SECTION IV Factors Contributing to Pathophysiology Screening programs are helpful when genetic counseling is available to assist individuals or families make decisions in light of the results. Prenatal diagnosis may offer reassurance to high-risk families; early diagnosis also provides time to plan for the special needs of an affected child or time to make an informed decision about an abortion. Birth defects that may be minor or severe occur in 1 : 28 live births. Prenatal diagnosis does not ensure the birth of a “perfect child” because testing does not eliminate all possibilities of defects; rather, the tests detect certain defects. Examples of prenatal testing include ultrasonography, which can visualize structural anomalies and maternal blood tests such as the triple screen, performed at 16 to 18 weeks. This test measures levels of alpha-fetoprotein (AFP), the beta subunit of human chorionic gonadotropin (hCG), and unconjugated estriol (uE3). In some areas a quadruple screen is used, which also checks levels of inhibin-A. Abnormal levels indicate a high risk of conditions such as spina bifida or Down syndrome. Follow-up amnio- centesis or chorionic villus sampling may confirm the abnormality. Methods of prenatal diagnosis include amniocentesis, or extraction of amniotic fluid from the uterus, and extraction of a sample of the chorionic villus of the fetus so as to examine a sample of fetal tissue. Chromosomal abnormalities can then be detected by growing fetal cells, harvesting them, and then examining the chromosomes or karyotype (see Fig. 21.1). DNA tests, enzyme deficits, and the presence of abnormal constituents such as AFP can also be included in this examination. These are invasive procedures and carry a slight risk to the fetus and mother. One other drawback of prenatal diagnosis is that some tests may not show conclusive results for 4 to 6 weeks and are often not done until approximately Death of zygote and embryo Eyes and ears Area most affected CNS Heart Arms and legs Teeth and palate Death Major abnormalities Minor abnormalities Major effect Minor effect 2 weeks 4 weeks 8 weeks 12 weeks 38 weeksTerm FIG. 21.9 Effects of teratogens during pregnancy. (jaundice), or trauma. The effects may be localized or may involve several areas of the brain. THINK ABOUT 21.6 a. At which stage of pregnancy does the highest risk of central nervous system damage occur? b. State five substances that are thought to be teratogenic. Diagnostic Tools Diagnostic tests that can detect some disease-causing genes or chromosomal abnormalities in carriers during the prenatal period, immediately after birth, or later in life when a disorder is suspected are available. Tests are not available for many disorders because either the cause or a testing procedure may not yet have been identified. Some disorders have such a low incidence rate that research and development of technology to test for the trait have not been feasible. The cost of genetic testing may be very high and thus testing is not universal. Testing is recommended for those who have a family history of a specific disease, those who have previously given birth to a child with an abnormality, and women more than 35 years of age. Screening programs for carriers are available for many disorders, particularly when the disorder has an ethnic basis and therefore a clearly defined population to test. For example, Tay-Sachs disease is common among Ashkenazi Jews, and specific screening programs for this group have been successful in determining the carrier population, reducing the incidence, and offering reas- surance and guidance to many individuals. A simple blood test can also detect carriers of sickle cell disease. CHAPTER 21 Congenital and Genetic Disorders 575 effective gene therapy has generally been slower and more difficult than expected. It is anticipated that new treatments with a genetic basis may be sought for prob- lems in the areas of mental illness, cancer, substance abuse, and criminal behavior. In some of these cases there is not yet a clear indication of a precise genetic component or cause to target with therapy. For more detailed and continued updated information please refer to: http://www.mayoclinic.org/tests-procedures/gene- therapy/home/ovc-20243692 and https://ghr.nlm.nih.gov/primer/therapy/genetherapy For ethical issues please refer to https://ghr.nlm .nih.gov/primer/therapy/ethics---this site is being constantly updated. Genetic Diagnosis and DNA Testing DNA testing for genetic disorders has been used to identify conditions in embryos and newborns. There have been a number of cases in which gene testing was con- ducted on embryos (from in vitro fertilization) to ensure birth of a child whose tissue was compatible with that of an older sibling ill with leukemia. The child then could provide stem cells to the older sibling, saving the child’s life. Preimplantation genetic diagnosis through testing of embryos has also been used to guard against the birth of a child with a serious defect. Another benefit of gene testing is seen in the identifica- tion of individuals who possess genes that place them at high risk of colon cancer (e.g., familial polyposis). These persons can subsequently receive frequent examinations. Women who have had breast cancer but do not possess the genes predisposing to recurrence may not require as extensive chemotherapy and radiation after surgery for the primary cancer. Concern has been expressed about the possible abuse of gene testing and therapy procedures and the risk of unanticipated changes in the expression of genes. In humans, instead of a cure, could altered genes cause other disorders to appear? How dependable is the information? Other concerns relate to access to personal genetic information by insurance companies, who could turn down coverage of persons on a genetic basis, police and the courts, or employers. Legislation has been drafted to protect the genetic rights of the individual, but not all jurisdictions have enacted such protections. DNA testing can be used to identify individuals because DNA is considered a unique characteristic like a “fingerprint,” thereby facilitating the use of genetic markers in blood and other body fluids by forensic scientists. Another forensics application is the analysis of DNA from a crime scene to identify if the individual is male or female or carries any specific characteristics. Many questions concerning the use, possible complications, and potential for abuse of genetic testing procedures still remain to be answered. 16 to 18 weeks into the pregnancy, leaving a long period of uncertainty. Improved equipment and techniques in ultrasonography and blood tests are leading to more rapid and more definitive diagnoses, thus reducing the need for amniocentesis. Neonates can be tested approximately 48 hours after birth, using blood from a heel prick. Most babies do not show signs of metabolic disorders at birth because the maternal kidney and liver have been active up to that time, but permanent damage to tissues can occur quickly thereafter. Mandatory screening after birth is required in many areas for congenital metabolic disorders such as PKU and hypothyroidism, in which prompt treatment can prevent mental retardation in affected children. The number of tests required varies in different areas, but may also include metabolic disorders such as sickle cell anemia, maple syrup urine disease, galac- tosemia, congenital adrenal hyperplasia, biotinidase deficiency, and homocystinuria. The infection congenital toxoplasmosis is frequently included. Many hospitals offer additional optional tests for metabolic disorders. Tests for cystic fibrosis include a check for a pancreatic immunoreactive trypsinogen, which, if positive, is fol- lowed by a DNA test and additional tests. In addition, an infant may be screened for hearing loss before leaving the hospital. Genetic Technology Genetic Engineering and Gene Therapy Genetic engineering refers to the laboratory practices of manipulating genes in living organisms, including microorganisms, plants and animals, and humans. Genes may be altered by changing the sequence of DNA by rearrangement, deletion, or substitution. The ultimate goal of gene manipulation is to remove a defective gene and supply a normal one so as to eliminate genetic defects. Recombinant DNA technology formed an early stepping- stone toward this goal. A chain of DNA was split and either some of the components changed position or a new piece was added, and then the chain was joined together again. This altered DNA then produces identical specific molecules such as insulin or erythropoietin. Gene therapy is a possible way to fix a genetic problem involving its source. Gene therapy can be effective, particularly in humans, where a single gene appears to be responsible for a disease, such as cystic fibrosis, polycystic kidney, or Huntington disease. Gene therapy involves the introduction of normal genes into living target cells, sometimes by means of a harmless virus or bacterium, thus changing the cell activity or replacing missing genes. For example, insertion of a gene to supply an enzyme missing in children with severe combined immunodeficiency disease is under way. Some gene therapies have been withdrawn from clinical trials because of unexpected death; the process of developing safe and http://www.mayoclinic.org/tests-procedures/gene-therapy/home/ovc-20243692 http://www.mayoclinic.org/tests-procedures/gene-therapy/home/ovc-20243692 https://ghr.nlm.nih.gov/primer/therapy/genetherapy https://ghr.nlm.nih.gov/primer/therapy/ethics https://ghr.nlm.nih.gov/primer/therapy/ethics 576 SECTION IV Factors Contributing to Pathophysiology • The mouth tends to hang open, revealing a large, protruding tongue and a high-arched palate. • The hands are small and have a single palmar (simian) crease. • The muscles tend to be hypotonic, the joints are loose, cervical abnormalities and instability are often evident, and stature is short. • Developmental stages are delayed. • All children are cognitively impaired, but the severity of impairment varies with the individual, and early stimulation programs are helpful. • Sexual development is often delayed or incomplete. • Many children have an assortment of other problems, including visual problems (cataracts, strabismus), hearing problems, obstructions in the digestive tract, celiac disease, congenital heart defects, decreased resistance to infection (immune deficit), and a high risk of developing leukemia. As the life of these children has been extended as a result of improved medical care, a marked increase in the development of Alzheimer disease after 40 years of age has been observed. Proteomic Research and Designer Drugs Research has recently turned from identification of base pairs in the DNA of specific genes to the proteins that are elaborated when the gene is activated. This study is termed proteomics and strives to characterize all of the proteins that are significant in the metabolic pathway for expression of a particular allele. Proteomic research is being funded to determine the shape and chemical activity of these crucial proteins so as to develop drugs specific to the metabolic pathway. These research products have been referred to as “designer drugs” in the popular press. Imatinib mesylate (Gleevec), a drug specific to growth proteins in ovarian cancer, and trastuzumab (Herceptin), specific to some growth proteins in breast cancers, are examples of such drug research. Some cur- rently used drugs interact differently in genetically different individuals; proteomic research will help to develop drugs tailored to the individual’s genotype and reduce untoward side effects of commonly used medica- tions. This research is, however, much more complex than the HGP and progress is not expected to be instan- taneous; sequencing DNA base pairs in the HGP was the first of many steps in understanding and treating common diseases that have a genetic component. THINK ABOUT 21.7 a. Explain why it would be helpful to know if one is carrying a gene associated with a disease. b. Briefly describe two methods of prenatal diagnosis and the purpose of each. THINK ABOUT 21.8 a. Explain the meaning of trisomy 21. b. How is prenatal diagnosis of Down syndrome achieved? c. Can diagnostic tests provide full information on the extent of effects of Down syndrome in an individual child at the time of birth? Down Syndrome Down syndrome, or trisomy 21, is a common chromosomal disorder, resulting in numerous defects in physical and mental development. Formerly called Down’s syndrome or mongolism, it is now identified as Down syndrome in North America. The risk of bearing a child with Down syndrome increases with maternal age. For example, a woman at age 30 has a risk of approximately 1 in 1000 of bearing a child with Down syndrome, whereas at age 35 the risk increases to approximately 1 in 500 and at age 40 to 1 in 100. Whether this risk is caused by damage to the oocytes resulting from degeneration with aging or environmental agents or other factors is unknown. Recently it has been suggested that some cases may be of paternal origin. A positive triple screen test on maternal blood followed by amniocentesis can detect the disorder. Characteristics of individuals with Down syndrome include the following (Fig. 21.10): • The head is small and has a flat facial profile. • The eyes are slanted, and the irises contain Brushfield spots. CASE STUDY A Retinoblastoma A.L. is a healthy toddler with a normal perinatal history. Her parents notice a white spot in the pupil of one eye and request a referral to a pediatric ophthalmologist. Examination of the eye suggests that A.L. has developed a retinoblastoma, a cancer in her eye. This cancer occurs in approximately 1 in every 1500 live births, and approximately 250 children are diagnosed each year in the United States. The family is referred for genetic testing and counseling. Retinoblastoma can occur because of a change in chromosome 13 or a mutation in the RB1 gene, which in its normal state prevents abnormal mitosis. A.L.’s tumor results from mutation of the RB1 gene, but neither parent shows this mutation. 1. What is the difference in the cause and inheritance of chromosomal changes compared with the inheritance of a mutation in a specific gene? 2. How did the mutation likely occur in the genes in A.L.’s tumor cells? 3. Testing of A.L.’s blood shows no evidence of the RB1 mutation; how likely is it that A.L. could transmit the mutated gene to her children? 4. How has the mutation caused growth of the tumor in A.L.’s eye? 5. What is the prognosis if the tumor is limited to the intraocular tissues? CHAPTER 21 Congenital and Genetic Disorders 577 disorders by the manipulation and replacement of defective genes. • Proteomics is the science of identifying the proteins associated with the expression of a particular gene so as to design drugs to replace absent proteins or inhibit damaging proteins. • The common patterns of inheritance of single-gene disorders are classified as recessive (e.g., cystic fibrosis) or X-linked recessive (e.g., hemophilia A), dominant (e.g., Huntington disease) or X-linked dominant (fragile X syndrome). • The probability of inheritance can be predicted using Punnett squares. The same probability exists with each pregnancy. E F A B D C FIG. 21.10 Down Syndrome. A, Characteristic facial features with upward-slanting palpebral fissures, epicanthal folds, and flat nasal bridge. B, Brushfield spots. C, Bridged palmar crease seen in some infants with Down syndrome. There are two transverse palmar creases connected by a diagonal line. D, Wide space between first and second toes. E, Short fifth finger. F, Small ears and flat occiput. (From Zitelli BJ, Davis HW: Atlas of Pediatric Physical Diagnosis, ed 4, St. Louis, 2002, Mosby.) C H A P T E R S U M M A R Y Congenital disorders are conditions that are present in an individual at birth but are not necessarily manifested until later in life. Included are inherited genetic disorders and developmental defects resulting from damage to the child in utero or at birth. Genetic disorders are a consequence of changes in the genes that make up the 23 pairs of chromosomes in each human cell. Each gene is a DNA file that controls one or more aspects of cellular activity. • The HGP is a multinational research effort whose goal is to identify the location, DNA sequence, and purpose of every gene so as to reduce the incidence of inherited 578 SECTION IV Factors Contributing to Pathophysiology • Screening programs are available for carriers of specific genetic disorders. Ultrasonography and amniocentesis may detect certain developmental defects in the fetus. A family pedigree will assist in determining the risk of such an occurrence, justifying the testing procedure and genetic counseling. • Down syndrome is presented as an example of a disorder affecting many body components. Abnormali- ties can be found in most systems and include physical appearance, skeletal structure, and intellectual development. • Chromosomal disorders, such as Down syndrome, or trisomy 21, involve an abnormal distribution of the chromosomes or dislocation of a part or loss of a chromosome. A karyotype demonstrates the arrange- ment of the chromosomes from an individual’s cell. • Developmental disorders are caused by damage to one or more body structures during embryonic or fetal development, during labor and delivery, or shortly after birth. The embryonic stage, the time of organogenesis, is the most vulnerable period. Possible factors include hypoxia, viruses, radiation, and expo- sure to drugs or other teratogens. • Multifactorial disorders result from a combination of genetic predisposition and exposure to certain envi- ronmental factors. S T U D Y Q U E S T I O N S 1. Define homozygous and heterozygous. 2. What is the purpose of a pedigree? 3. Explain why teratogens are difficult to identify. 4. Explain why a woman carrying the gene for hemophilia can produce two hemophiliac sons when she is mated to a normal male. 5. Under what conditions does a female acquire an X-linked recessive disorder? 6. Why are X-linked recessive disorders never passed from a father to a son? 7. The pedigree for Queen Victoria of England, a carrier of hemophilia A, shows the transmission to some of her descendants, including members of many royal families in Europe, such as Russia and Spain, but not Germany. Hemophilia A does not affect anyone in the present British royal family. Can you explain why hemophilia A has disappeared from one family and appeared in others? 8. What is the probability that a parent carrying a dominant trait will pass that trait on to each child? 9. How can prenatal diagnosis demonstrate the sex of an unborn child? 10. Describe briefly amniocentesis and its purpose. 11. Which of the following can be identified by an abnormal karyotype? a. Sickle cell disease b. Cystic fibrosis c. Monosomy X d. Tay-Sachs disease e. Huntington chorea 579 Embryonic and Fetal Development Physiologic Changes During Pregnancy Diagnosis of Pregnancy Physiologic Changes and Their Implications Hormonal Changes Reproductive System Changes Weight Gain and Nutrition Digestive System Changes Musculoskeletal Changes Cardiovascular Changes Potential Complications of Pregnancy Ectopic Pregnancy Preeclampsia and Eclampsia: Pregnancy-Induced Hypertension Gestational Diabetes Mellitus Placental Disorders Blood Clotting Disorders Thrombophlebitis and Thromboembolism Disseminated Intravascular Coagulation Rh Incompatibility Infection Adolescent Pregnancy Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Describe the stages of fetal development and discuss the basic effects on the mother. 2. Describe the impact of maternal hormonal changes on the body systems. 3. Discuss the potential problems of hypertension, thrombus formation, placental separation, and Rh incompatibility during pregnancy. L E A R N I N G O B J E C T I V E S abortion amniocentesis amnion amniotic fluid auscultation cervical os chorionic villi chorionic villus sampling differentiation embolus embryo fetus gestation gestational age gravidity human chorionic gonadotropin hypotension inner cell mass organogenesis ovum parity placenta sperm supine teratogen trimesters trophoblast viable zygote K E Y T E R M S C H A P T E R 22 Complications of Pregnancy Embryonic and Fetal Development Many natural changes occur in the mother’s body during embryonic and fetal development. In some cases, the mother’s condition affects the child’s development and growth. In other cases, the physiologic changes in the mother can initiate disease or aggravate preexisting conditions. Additional information is available in any obstetrics textbook. Infertility is discussed in Chapter 19 of this text. Conception, or fertilization of the ovum by a sperm, takes place in the oviduct or fallopian tube. During the next few hours, the genetic information contained in the ovum (oocyte) is merged with that contained in the sperm to form the zygote (fertilized ovum), and many mitotic divisions occur as the zygote moves along the fallopian tube toward the uterus. Implantation of the zygote in the uterine wall is completed approximately 1 week after fertilization, and differentiation (specialization) of cells is apparent as the inner cell mass and trophoblast or 580 SECTION IV Factors Contributing to Pathophysiology structures such as the lungs. Elementary functions can be observed as the limbs move and amniotic fluid is swallowed. However, functional impairment, particularly in the CNS, can occur with exposure to teratogens at this stage of development. During the last trimester in utero, the fetus gains weight and organs such as the lungs mature. With improvements in technology and neonatal care, the fetus may be able to survive (remain viable) outside the uterus as early as 22 to 23 weeks after concep- tion. Birth at such a premature age is often accompanied by complex medical problems as the child adapts to life outside the uterus. Monozygotic, or identical, twins form when the developing embryo divides to form two separate, geneti- cally identical embryos. This occurs in approximately 1 : 100 births for unknown reasons. Dizygotic, or fraternal, twins form when two ova are fertilized by two different sperm, resulting in two genetically dissimilar embryos. Physiologic Changes During Pregnancy Pregnancy is a normal, natural process in the life cycle. The standard period for pregnancy is divided into three trimesters, each approximately 3 months long and each involving significant changes in the mother and the developing fetus. In some individuals, these changes may precipitate complications or aggravate preexisting patholo- gies in the mother. Good prenatal care at an early stage and throughout the pregnancy is essential to minimize the risk of potential complications. Diagnosis of Pregnancy Laboratory diagnosis of pregnancy is based on the pres- ence of human chorionic gonadotropin (hCG) in the mother’s plasma or urine, using enzyme-linked immu- nosorbent assay–based tests. The hormone hCG, which is secreted by the chorionic villi (villi that form from the outermost extraembryonic membrane, the chorion) after implantation of the fertilized ovum in the uterus, can be detected by a simple office or home test. Many typical signs of pregnancy, such as nausea or morning sickness, do not provide confirmation of pregnancy because each could result from other causes. The positive (absolute) signs occur later in the pregnancy and include the fetal heartbeat as detected by auscultation (listening to heart sounds with a stethoscope) or ultrasound, fetal movement detected by someone other than the mother, and visualization of the fetus with ultrasound. The estimated date of delivery (EDD) or estimated date of birth (EDB) can be calculated easily using Nägele’s rule if the first day of the last menstrual period (LMP) is known. Three months are subtracted from that date, and then 7 days are added to the resulting figure. For example, if the LMP began on October 20, one would subtract 3 months (July 20) and add 7 days, giving an EDB of July outer cell mass form. The inner cell mass becomes the actual fetus, whereas the outer cell mass gives rise to the embryonic membranes, the amnion and placenta. The period from 3 to 8 weeks is termed the embryonic stage, and this is a critical time in the development of all the organs and structures in the fetal body. During this period, termed organogenesis, cells divide rapidly, move, and differentiate to form the basic functional elements of the various organ systems and external structures such as the limbs and eyes. By the end of 8 weeks, all organs are formed. For example, the primitive fetal heart is beating at 4 weeks. Note all times relate to that which has elapsed since fertilization, thus the central nervous system (CNS) is forming within 1 week of the woman’s first missed menstrual period. Exposure of the embryo to any teratogen (any sub- stance or situation that causes a developmental abnormal- ity; see Chapter 21) during this early stage usually causes major widespread damage to the developing structures and leads to serious congenital abnormalities (see Fig. 21.9, which outlines the effects of teratogens on the organs at various times during the pregnancy). Common terato- gens include drugs, viruses, alcohol, and radiation. It is preferable to avoid all medications, including herbal remedies and those available without prescription, during pregnancy or to consult with a physician to determine a safe alternative. Viruses such as rubella (German measles) and erythema infectiosum (fifth disease) are known to cause damage to the embryo and fetus. For example, during the first trimester, maternal rubella affects infants in 90% of cases, causing spontaneous abortion (loss of the embryo or fetus) or major congenital anomalies. Major abnormalities rarely occur from exposure after 20 weeks. Erythema infectiosum, acquired during the first half of pregnancy, causes severe anemia in the fetus and possible death. Cigarette smoking by the mother usually results in a child with low birth weight and increased irritability and may also result in stillbirth. There is also an increased risk of placenta previa and abruptio placentae with exposure to tobacco. Because alcohol can easily pass through the placental barrier, there is risk of damage to the fetus during the entire pregnancy. Fetal alcohol syndrome, which varies in severity, impairs a child’s neurologic and intellectual development as well as causing unique physical characteristics (e.g., typical facies) and growth retardation. Increased intake of folic acid before and during pregnancy has greatly reduced the incidence of neural tube defects such as spina bifida and anencephaly (see Chapter 14 and Fig. 14.26 for information on spina bifida). After 8 weeks, the term fetus is used, and most organs have completed basic formation. Teratogens have less effect on development during this period because cell damage occurs primarily in certain tissues that are actively differentiating at the time of exposure. Continued growth and development result in completion of many specialized CHAPTER 22 Complications of Pregnancy 581 27. Various charts and wheels are available to provide the dates quickly. For women with longer cycles or irregular menstrual cycles, the formula must be adjusted. First pregnancies are often slightly longer. Gestation refers to the length of time since the first day of the LMP and equals 280 days (40 weeks) or 10 lunar months. Gestational age is 2 weeks longer than the actual age of the child from the time of fertilization—266 days or 38 weeks. Gravidity and parity are terms used to describe a woman’s history of pregnancy and childbirth. Gravidity refers to the number of pregnancies; for example, a primigravida is a woman who is pregnant for the first time. Parity refers to the number of pregnancies in which the fetus has reached viability (approximately 22 weeks of gestation). A multipara has completed two or more pregnancies to the point of fetal viability. Coding systems are available to document histories. For example, a five- digit system records, in sequence, the number of pregnan- cies, the number of deliveries, the number of premature deliveries, the number of abortions of any type, and the number of children living. The history of a woman in her second pregnancy who has one child living and no other experiences would be recorded as 2-1-0-0-1. Amniocentesis is the withdrawal of a small amount of amniotic fluid, including some sloughed fetal cells, from the uterus after 14 weeks. The fluid can be checked for its chemical content and the cells cultured for chromo- some analysis. Amniocentesis is recommended when there are signs of abnormality, perhaps from an early ultrasound examination, maternal blood screening, or a history of genetic disorders; it may also be used when the mother is more than 35 years of age to check for Down syndrome. There are some risks because the test is invasive. This test may also be used later in pregnancy to check fetal lung maturity. An alternative process is chorionic villus sampling, which can take place earlier in pregnancy and is useful for chromosomal examination and diagnosis in high-risk clients. Physiologic Changes and Their Implications Hormonal Changes Levels of estrogen and progesterone in the maternal blood are increased during pregnancy as the placenta increases its production of these hormones, which are essential to the development of the uterus, maintenance of pregnancy, and preparation of the breasts for lactation (milk produc- tion). Hyperplasia of the thyroid gland and increased production of thyroxine also occur (see Chapter 16 for more information on thyroid hormones), which increases the mother’s metabolism. Reproductive System Changes Estrogen causes a tremendous increase in the size of the uterus due to hypertrophy of the muscle cells, some hyperplasia, and an increase in fibrous tissue. The number Lungs Spine Stomach Liver Placenta Urinary bladder Vagina Rectum Colon Intestine FIG. 22.1 Sagittal section of a pregnant woman demonstrating the effects of the expanding uterus. THINK ABOUT 22.1 Explain how the pressure of a large uterus would affect the filling of the bladder and the frequency of urination. How would these changes affect other activities? of blood vessels in the uterus is also greatly increased to ensure the adequacy of the blood supply to the fetus. As the fetus and uterus grow, they exert pressure on the surrounding structures (Fig. 22.1). For example, pressure on the bladder and bowel may alter elimination patterns, and upward pressure on the diaphragm may restrict lung expansion, leading to shortness of breath on exertion. Other changes in the reproductive system include increased vascularity of the cervix and vagina, resulting in a softening of the tissues (Goodell sign) and a typical deeper purplish color of the mucosal lining (Chadwick sign). Cervical mucus is more abundant and thick and forms a cervical plug to protect the uterine contents from foreign material and microbes. Vaginal secretions increase and become more acidic (pH 3.5 to 6.0), which is a deter- rent to some infecting organisms, but when combined with increased glycogen content, predisposes to yeast or monilial infections during pregnancy. The breasts become larger as the ducts and glands develop preparatory to milk production, and fatty deposits in the breast tissue 582 SECTION IV Factors Contributing to Pathophysiology pressure of the expanding uterus interferes with digestive function also. Constipation is common due to decreased gastric motility and iron supplements. If chronic, constipa- tion may lead to hemorrhoids, which are dilated veins in the anal canal. These can become very painful and may bleed or become infected. A diet high in fiber is recommended to avoid constipation and straining during defecation. increase. Bluish veins on the breast surface become more prominent and the breasts are tenderer. Weight Gain and Nutrition The average weight gain during pregnancy is 11 to 14 kg, or 25 to 30 lb, much of which occurs in the last trimester. The increased size of the uterus and its contents (the placenta, amniotic fluid, and fetus), the enlarged breasts, additional blood volume, and stored nutrients or fat all contribute to the weight gain. There is an increased demand for protein, carbohydrate, fat, vitamins, and minerals to promote healthy tissue development during pregnancy. The metabolic rate of the mother increases in the latter half of pregnancy. However, any caloric intake beyond that required is stored as adipose tissue (fat). Extra weight during pregnancy comes from (these are estimates and are somewhat different in each pregnancy): • Baby: ≈8 pounds • Placenta: 2 to 3 pounds • Amniotic fluid: 2 to 3 pounds • Breast tissue: 2 to 3 pounds • Blood supply: 4 pounds • Stored fat for delivery and breastfeeding: 5 to 9 pounds • Larger uterus: 2 to 5 pounds • Total: 25 to 35 pounds The fetus stores iron in the last trimester to provide for its needs during the first few months after delivery. Adequate calcium is required for fetal bones and teeth. It is a myth that calcium is drawn from the mother’s teeth to supply the fetus, but changes in salivary secretions can promote dental caries (see Chapter 17). Food cravings often include foods that are high in sugars; consumption of such snacks can increase the risk of caries. Even beneficial foods such as dried fruits or raisins can be a problem. Prenatal care should include a consultation with a dentist or dental hygienist to ensure good oral hygiene. Digestive System Changes Nausea and vomiting are common in the first trimester because of the hormonal changes that occur in pregnancy. Changes in eating patterns often reduce discomfort. Frequent small meals, avoidance of fatty or spicy foods, and a reduced fluid intake with meals are suggested. Medication is recommended only in severe cases. The combination drug doxylamine-pyridoxine has been studied extensively and appears to be a safe treatment during pregnancy. Severe uncontrollable vomiting, or hyperemesis gravidarum, may lead to dehydration and electrolyte imbalances and may affect nutrition at a critical point in fetal development. Hospital care is often necessary to maintain fluid and electrolyte balance. The relaxation of smooth muscle in the stomach and intestines by progesterone results in decreased motility in the digestive tract, slower emptying of the stomach, reflux of stomach contents into the esophagus (heartburn), and feelings of bloating and abdominal discomfort. The THINK ABOUT 22.2 a. Suggest a reason for maternal weight loss during the first trimester of pregnancy. b. List three potential effects of excessive intake of foods associated with food cravings. THINK ABOUT 22.3 Suggest several ways of reducing or preventing backache during pregnancy. Musculoskeletal Changes Marked postural changes occur in the mother as preg- nancy progresses. The pelvic joints relax or loosen as hormones prepare the pelvis for delivery, resulting in a loss of stability and a waddling gait. The increased abdominal weight leads to a shift in the center of gravity and a tendency toward lordosis, or increased lumbar curvature. These changes may lead to backache, particu- larly if the back and abdominal muscles are weak. Continued regular moderate exercise during pregnancy is helpful in maintaining good posture as well as cardio- vascular fitness. Cardiovascular Changes Blood volume, including the relative volumes of both fluid and erythrocytes, is greatly increased to meet the metabolic needs of the fetus. For example, blood flow to the uterus and kidneys must increase to supply more oxygen to the fetus and uterine tissue and remove wastes. Vascular resistance tends to decrease because smooth muscle in the arterioles is somewhat relaxed as a result of increased progesterone. The heart rate may increase slightly, and blood pressure frequently drops slightly in the first two trimesters but then rises again to normal levels during the last trimester. The increased blood volume leads to congestion and edema in many tissues. For instance, there may be nasal congestion, which affects breathing. Gingivitis, or inflam- mation of the tissues around the teeth/gums (see Chapter 17), is common, causing bleeding. Fatigue or stress may impede daily oral hygiene, resulting in more severe pregnancy gingivitis and caries. The increased production of red blood cells for the fetus requires increased iron intake by the mother. Iron CHAPTER 22 Complications of Pregnancy 583 not possible to maintain a tubal pregnancy to the time the fetus would be viable outside the uterus. Preeclampsia and Eclampsia: Pregnancy-Induced Hypertension Pregnancy-induced hypertension (PIH; see Chapter 12) refers to a state of persistently elevated blood pressure (more than 140/90) that develops after 20 weeks of gestation and returns to normal after delivery. A specific cause has not been determined, although numerous risk factors have been identified. PIH, if not controlled, may lead to damaged blood vessels in tissues such as the kidneys and retina of the eye or to stroke or heart failure. The decreased blood flow to the uterus may cause pre- mature degeneration of the placenta and presents a risk to the fetus. The efficacy of low doses of aspirin (ASA) in controlling PIH continues to be investigated. Preeclampsia and eclampsia are more serious condi- tions in which the blood pressure is higher, and kidney dysfunction is indicated by proteinuria, weight gain, and generalized edema (face, hands, feet, and legs). In some patients with preeclampsia, a complication develops. This condition is known for its manifestations by the acronym HELLP (for Hemolysis, Elevated Liver enzymes, and Low Platelets). In a few cases, HELLP progresses to coagulation disorders such as disseminated intravascular coagulation (DIC), as indicated by excessive bleeding. Also, preeclamp- sia may progress to eclampsia, in which the blood pressure becomes extremely high and generalized seizures (grand mal) or coma develops. Immediate hospitalization is required for adequate treatment of eclampsia. supplements are frequently required. Because of a rela- tively greater increase in fluid, the hematocrit decreases slightly, and the woman appears to have a low hemoglobin level (physiologic anemia). Varicose veins frequently develop during pregnancy (see Chapter 12 and Fig. 12.33 for more information on varicose veins). Either the superficial or the deep veins of the legs may be involved. The superficial veins appear large, distended, and purplish. Varicose veins result from restriction of blood flow in the veins to the heart due to the pressure of the uterus, particularly in women who must stand for long periods or who are predisposed to this condition by defects in the vein walls or valves. Varicosities can cause sensations of heavy or aching legs. Legs should be elevated whenever possible, and restrictive clothing such as tight stockings should be avoided to enhance the flow of venous blood. The risk of dangerous blood clots and emboli to the lungs is increased, particu- larly after delivery. When a pregnant woman lies in a supine position, the inferior vena cava may be compressed by the heavy uterus, resulting in decreased venous return to the heart and less cardiac output, leading to potential hypotension, or low blood pressure. Lying on the left side usually facilitates maternal blood flow back to the heart and increases output to the placenta and the fetus. A supine position will also affect the blood pressure and pulse, giving false readings. THINK ABOUT 22.4 Using your knowledge of normal blood pressure controls, explain why blood pressure does not rise when blood volume increases during pregnancy. THINK ABOUT 22.5 Compare the signs of PIH with those of eclampsia, and explain how eclampsia endangers the pregnant woman and her fetus.Potential Complications of Pregnancy Ectopic Pregnancy Commonly called tubal pregnancy, an ectopic pregnancy occurs when the fertilized ovum (zygote) is implanted outside the uterus. In most cases of ectopic pregnancy, implantation occurs in the fallopian tube. The incidence has been increasing over the past 20 years, perhaps because of an increase in pelvic inflammatory disease that may scar the tube, restricting movement of the zygote to the uterus. Spontaneous abortion may follow in the early stages of pregnancy, or the embryo may continue to develop, eventually causing the tube to rupture. This may lead to severe hemorrhage or peritonitis (a serious infection in the peritoneal cavity; see Chapter 17) with loss of the fallopian tube. The pregnant woman experi- ences severe pelvic or abdominal pain as blood irritates the peritoneal membranes. Ectopic pregnancy is consid- ered a medical emergency and requires prompt treatment, usually surgical removal of the embryo and associated tube, to prevent hemorrhage and shock. It is currently Gestational Diabetes Mellitus Diabetes mellitus develops in 2% to 5% of women during pregnancy (see Chapter 16 for more information on diabetes). This condition involves increased glucose intolerance and leads to increased glucose levels in blood and urine. Glucose levels should be closely monitored in women in whom there is a family history of diabetes or who have previously had high-birthweight infants. Dietary management is important, and insulin may be necessary in some cases. Oral hypoglycemic drugs are contraindicated as potentially teratogenic. There is a higher risk of fetal abnormalities if blood glucose is increased in the first trimester, as well as an increase of other complications and stillbirth. The newborn born to a woman with diabetes is usually larger in size and may experience problems regulating blood glucose immediately after birth. Gestational diabetes may resolve 584 SECTION IV Factors Contributing to Pathophysiology occurs, resulting in diffuse blood clots and excessive consumption of all clotting factors. Diagnosis is confirmed by the low serum levels of clotting factors. This situation leads to hemorrhage as the clotting factors are no longer available for normal clotting. The formation of multiple thrombi in the tissues causes organ damage in later stages, but the signs of DIC are related to hemorrhage in the early stages. Bleeding may occur from the uterus, at injection sites, from the nose or mouth, under the skin (purpura), or internally. after the pregnancy, but in many cases diabetes develops in that individual at a later time. Placental Disorders Placenta previa occurs when the placenta is implanted in the lower uterus or over the cervical os (the passage between the uterus and the cervix). In the case of placenta previa when the uterus expands and contracts near the end of pregnancy, the placenta is torn and bleeding occurs. The sign is bright red bleeding that is painless. Diagnosis is confirmed by ultrasound. Although in some cases the leak may close, any hemorrhage during pregnancy places both mother and fetus at risk and requires immediate assessment and intervention. Abruptio placentae refers to premature separation of the placenta from the uterine wall, resulting in bleeding that may or may not be evident vaginally, depending on where the tear occurs. The blood is often dark red, and abdominal pain is common. Abruptio placentae occurs more commonly during the last trimester. THINK ABOUT 22.6 Using your knowledge of normal cardiovascular function, explain why any hemorrhage is serious for both mother and fetus. THINK ABOUT 22.7 Differentiate the location and effects of a thrombus from an embolus. Blood Clotting Disorders Thrombophlebitis and Thromboembolism Thromboembolisms, or blood clots (see Chapter 10), are common after childbirth and usually develop in the veins of the legs or pelvis (see Chapter 12). To prevent the formation of clots in the legs, the new mother is encour- aged to be up and walking immediately after sedation or anesthesia has worn off even in a cesarean section birth. Thrombus may form spontaneously (phlebothrom- bosis), usually because of stasis of blood or increased coagulability. In some cases, the clot forms over an inflamed area in the vein wall (thrombophlebitis). If a piece of the thrombus breaks away (an embolus), it will flow with the venous blood to the right side of the heart and then into the lungs, where it will lodge in a pulmonary artery or smaller branch, obstructing blood flow in the lungs. This is a pulmonary embolus (see Chapter 13 for more information), which can be very serious and can affect respiratory and cardiovascular function. It is important not to massage a leg that is painful or red until the risk of thrombus has been eliminated. Antiem- bolic stockings and bed rest may be helpful, as well as careful management of the coagulation problem. Disseminated Intravascular Coagulation DIC is not a primary problem, but is a serious complica- tion of events such as abruptio placentae and preeclampsia. In DIC, an increased activation of the clotting mechanism Rh Incompatibility Blood incompatibility can develop when the Rh factor antigens on fetal red blood cells differ from those on maternal red blood cells. Rh incompatibility can be more serious when it leads to hemolytic disease of the newborn (erythroblastosis fetalis). Rh incompatibility results when the mother is Rh negative and the fetus is Rh positive (Fig. 22.2). During the first pregnancy there are usually no problems unless the mother has been exposed to Rh-positive blood at some prior time through a blood product or abortion. At the end of the first pregnancy, when the placenta tears during delivery, some Rh-positive fetal blood enters the maternal circulation, stimulating the formation of antibodies to Rh-positive cells in the mother. During subsequent pregnancies, the maternal Rh antibodies cross the placenta to the fetus. The resulting antigen–antibody reaction in the fetus destroys the fetal red blood cells. Hemolysis of red blood cells leads to severe anemia or low hemoglobin and possible heart failure and death in the child. Hemolysis also causes high serum bilirubin levels in the child, resulting in jaundice (yellow color in the eyes and skin; see Chapter 17) and potential neurologic damage (kernicterus) as bilirubin enters brain tissue. If the fetus experiences severe hemolysis in utero, an early birth or intrauterine transfusion may be recom- mended. After birth, an exchange transfusion may be required. When the neonate is jaundiced, phototherapy (exposure of the newborn’s body to fluorescent or blue light) can reduce serum bilirubin levels by promoting conjugation of bilirubin and excretion in the bile. Routine screening of maternal blood for Rh antibodies (indirect Coombs test) is carried out early in pregnancy and at regular intervals during the pregnancy. If the mother has not become sensitized and developed antibod- ies, for example, during the first pregnancy, she can be given passive immunity at the time of delivery to suppress the immune response temporarily. This is done by administering Rh immunoglobulin (RhoGAM) to the CHAPTER 22 Complications of Pregnancy 585 are vulnerable to infection. Common organisms include group B hemolytic Streptococcus, Escherichia coli, Staphy- lococcus aureus, Mycoplasma, and Chlamydia trachomatis. A predisposition to endometritis (inflammation of the uterine lining) can be caused by the separation of the placenta, which leaves raw tissue open to easy access of organisms from the vagina. Any retained placental frag- ments also promote infection. Signs of infection include fever, vomiting, lower abdominal pain, and foul-smelling discharge from the vagina. The infection may spread to cause pelvic cellulitis (infection in the connective tissues or broad ligament of the pelvis) or peritonitis (infection mother within 72 hours of delivery. This process prevents sensitization of the mother as a result of fetal red blood cells entering her body during labor and delivery. Infection Localized wound infections are usually contained if they are treated quickly. Puerperal infection (childbed fever) is infection of the reproductive tract at any time during the 6 weeks after birth. It may be endogenous (because of vaginal flora) or exogenous (because of causes in the environment). Cervical lacerations or episiotomy repairs Rh FACTOR INCOMPATIBILITY OF MATERNAL–FETAL BLOOD (ERYTHROBLASTOSIS FETALIS, OR HEMOLYTIC DISEASE OF THE NEWBORN) BLOOD TYPES Mother = Rh negative Father = Rh positive Fetus = Rh positive – – – – – – + + + + + ++ + + Fetus Fetus Mother Mother First exposure, e.g., first pregnancy Rh-positive antigen from fetus enters mother’s circulation A+ – – – – + + + + + A+ A+ A+ A+ – – – – + + + A+ A+ A+ A+ A+ A+ Fetus Mother – – – – + + + + Mother A+ A+ A+ Mother forms anti-Rh antibodies RhoGAM injection blocks here Next pregnancy, mother’s anti-Rh antibodies enter the fetal circulation and attach to Rh antigen on fetal RBCs HEMOLYSIS OF CHILD’S RBCs Severe anemia, jaundice, brain damage (kernicterus) FIG. 22.2 Rh incompatibility of maternal and fetal blood. RBCs, red blood cells. 586 SECTION IV Factors Contributing to Pathophysiology C H A P T E R S U M M A R Y Numerous normal changes occur in the mother’s body during pregnancy, related to elevated levels of estrogen and progesterone, as well as to the demands of the developing child. Mild nausea and abdominal discomfort, increased blood volume, relaxation of the pelvic joints, and postural effects are common occurrences. In some cases, however, these changes may exacerbate or pre- cipitate a maternal disorder such as hypertension, or a maternal disease or infection may predispose the fetus to additional risks or disease. • Hyperemesis gravidarum requires medical supervision to prevent dehydration and acidosis. • PIH and preeclampsia developing in the latter part of pregnancy require close monitoring to prevent complications for mother and child. • Blood glucose levels in the mother must be checked to detect gestational diabetes. • Rh incompatibility occurs when an Rh-negative mother carries an Rh-positive child. The consequences (hemolysis of fetal red blood cells) can be avoided by treating the mother at delivery to prevent an immune response and development of maternal antibodies. • Thromboembolism and pulmonary embolus are risks for some women after delivery, particularly those with varicose veins or increased blood clotting tendencies. • Adolescent pregnancy incurs additional risks because of the mother’s immature body. • Teratogens, including drugs, chemicals and alcohol, viruses, and radiation, cause major damage to the embryo during the first 8 weeks, often before pregnancy is suspected. All potential teratogens should be avoided during childbearing years. of the peritoneal membranes) (see Chapter 17). Peritonitis results from infection that spreads directly along the fallopian tubes into the peritoneal cavity and is a serious complication of childbirth. Peritonitis is manifested by severe pain, high fever, tachycardia, and abdominal distention. Scar tissue resulting from infection that involves the fallopian tubes or ovaries may cause infertil- ity. Pelvic abscess, a localized infection, may persist after peritonitis. Adolescent Pregnancy The adolescent period is a time of growth, change, and maturation in many areas of the body (see Chapter 23). The teenager has increased nutritional needs to meet the demands of her own growth, and, in addition, dietary intake, physical activity, and hormonal changes are more erratic during this period. Pregnancy at this time carries an increased risk of complications. The teenage gravida may not seek prenatal care early in the pregnancy, and this results in inadequate nutrition to support the growth needs of the teen and fetus, as well as lack of identification of potential problems of pregnancy. The young woman’s pelvis may be too small to allow for passage of the fetal head, increasing risk during labor and delivery. Anemia is a common problem if prenatal vitamin supplements with iron are not taken. Factors such as maternal smoking, alcohol use, and drug intake are more common in ado- lescent pregnancies and often negatively affect outcomes for the fetus. These should be identified as quickly as possible and support provided for discontinuation of the high-risk behavior. Psychosocial factors are often present and require support and counseling during the pregnancy. Babies born to adolescent mothers frequently weigh less than normal or are preterm, and labor and delivery may be difficult due to the immature pelvic structure. For the mother, PIH (high blood pressure) is a common complication. If the young mother receives and accepts prenatal guidance and support, the pregnancy often progresses with minimal complications. CASE STUDY A Gestational Diabetes Mellitus* C.S. was a healthy, active teenager, other than experiencing irregular menstrual cycles and severe dysmenorrhea (painful menstruation). She had gained weight during her college years. Family history indicated that a paternal great-grandmother had diabetes. Current history included two miscarriages at 3 months’ gestation and one at 5 months after amniocentesis. At age 36, after a course of fertility drugs, C.S. became pregnant, but developed high blood pressure in the first trimester. Routine testing at 3 months’ gestation revealed elevated blood glucose and protein in the urine as a result of gestational diabetes and kidney dysfunction. Insulin injections and daily oral ASA were *This case study is continued in Chapter 16. prescribed, as well as weekly appointments with the obstetrician. A weight loss of 30 pounds occurred during the pregnancy. 1. Using your knowledge of normal physiology, explain how glucose and protein can be present in the urine. 2. List the potential risks with gestational diabetes. 3. Why was insulin prescribed? Delivery was induced 4 weeks before term because of persistent elevated blood pressure. A healthy male child, weighing 5 pounds 11 ounces, was delivered. Postpartum, blood glucose remained high, but was controlled by diet and exercise. A second pregnancy at age 38 again led to elevated blood pressure, proteinuria, and diabetes, which was controlled by insulin injections and close monitoring. 4. Suggest several possible complications of high blood pressure during pregnancy. 5. Why is close monitoring important during these pregnancies? A healthy female child, weighing 8 pounds 5 ounces, was delivered at term. After this pregnancy, blood pressure and blood glucose remained elevated. Treatment included dietary modifica- tions, exercise, and oral hypoglycemic drugs (see Chapter 16). CHAPTER 22 Complications of Pregnancy 587 S T U D Y Q U E S T I O N S 1. State possible signs of pregnancy resulting from physiologic changes in the woman. 2. Suggest some guidelines for fluid and food intake that would optimize fetal development and minimize complications or discomfort for the mother. Include a rationale for each. 3. Explain how a good fitness program is helpful during pregnancy. 4. Differentiate among abruption, previa, and ectopic pregnancy in terms of cause, time of occurrence, and signs. 5. Explain how each of the following affect the pregnant woman and fetus: PIH, eclampsia, and gestational diabetes. 6. Explain why the adolescent gravida is at greater risk of complications of pregnancy. 7. Suggest several signs or symptoms of the development of postpartum infection. 588 Review of Changes During Adolescence Obesity and Metabolic Syndrome Musculoskeletal Abnormalities Kyphosis and Lordosis Scoliosis Osteomyelitis Juvenile Rheumatoid Arthritis Eating Disorders Anorexia Nervosa Bulimia Nervosa Skin Disorders Acne Vulgaris Infection Infectious Mononucleosis Disorders Affecting Sexual Development Chromosomal Disorders Tumors Menstrual Abnormalities Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Identify the body mass index, risk of metabolic syndrome, and potential problems associated with obesity. 2. Describe the changes in the postural abnormalities kyphosis, lordosis, and scoliosis. 3. Discuss the bone infection osteomyelitis and the importance of early treatment. 4. Describe the effects of juvenile rheumatoid arthritis. 5. Compare the eating disorders anorexia nervosa and bulimia nervosa. 6. Explain the cause and potential effects of acne. 7. Describe the disease infectious mononucleosis. 8. Describe the following disorders involving the reproductive system: chromosomal abnormalities, testicular cancer, and menstrual abnormalities. L E A R N I N G O B J E C T I V E S androgens body mass index effusion emaciated epiphyseal plate or disc Epstein Barr virus esophagitis glucose metabolism insulin resistance lipoprotein metabolism metabolic syndrome puberty pustule sebaceous sinus K E Y T E R M S C H A P T E R 23 Complications of Adolescence Review of Changes During Adolescence Adolescence is a time of major physiologic, psychological, and sociologic changes, a time of transition into adulthood. It is also a time when certain diseases, developmental or infectious, tend to develop. The period of adolescence is generally considered to begin with the development of secondary sex characteristics around the age of 10 to 12 years and to continue until physical growth is com- pleted at about age 18. The term puberty indicates the onset of reproductive changes, beginning with the appearance of secondary sexual characteristics and the first menstrual cycle in females. Both the timing and the extent of change vary greatly among individuals. In recent years, perhaps because of improved nutrition, maturation has tended to occur at an earlier age. The biologic changes typical of adolescence result primarily from hormonal activity stimulated by the hypothalamus and pituitary gland. Gonadotropin- releasing hormone (GnRh) from the hypothalamus stimulates and increases the release of gonadotropins from the pituitary. Gonadotropins (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]; see Chapter 19) support the further development of the ovaries and testes. In the female, the ovaries release ova and the sex hormones estrogen and progesterone, and in the male, CHAPTER 23 Complications of Adolescence 589 Obesity and Metabolic Syndrome Research has shown that the ability to burn fat during exercise declines after puberty. This metabolic change along with changes in activity and diet can lead to obesity during adolescence. Not only is obesity a significant factor in the teen’s self-image, it also constitutes a major threat to his or her health and leads to pathophysiologic changes in metabolism that predispose the teen to diabetes and cardiovascular disease as well as permanent joint damage. Overweight refers to an excess amount of body weight that may be a result of muscles, bone, fat, and water. Obesity refers to an excess amount of body fat. Overweight and obesity are due to a caloric imbalance. This imbalance may be due to more calories consumed than expended, and it can also be affected by various genetic, behavioral, and environmental factors. Obesity is determined by calculating the body mass index (BMI). The BMI is an international standard and is calculated based on the child’s or adolescent’s age as well as height and weight. Adolescents are considered clinically obese if the BMI is at the 95th percentile or greater for their age. Adolescents whose BMI is between the 85th percentile and the 94th percentile are clinically “at risk for obesity.” Note that the amount of fat normally differs with gender and age until after age 20, thus adult BMI charts are not applicable to adolescents. Fig. 23.1 illustrates the prevalence of adolescent obesity in the United States over several decades. Alarm has been expressed regarding the increase in obesity in children and teens. In the 6- to 11-year-old age group, the number of obese children doubled between 1980 and 2000, whereas the number in the 12- to 19-year- old group tripled. Obesity in children 6 to 11 years old the testes begin to produce sperm and to release testos- terone. Although the adrenal cortex produces these sex hormones in small quantities during all stages of life, the larger quantities now available from the gonads are responsible for the unique types of growth and develop- ment that are characteristic of the teen years. Linear growth is accelerated during the typical adoles- cent growth spurt. In most males the growth spurt occurs later than in females and usually lasts longer because epiphyseal closure is delayed in males. In recent genera- tions both males and females have achieved a greater average height. Any growth retardation usually is appar- ent before adolescence, but if it is evident at this time it can be confirmed by x-rays illustrating an abnormally thin epiphyseal plate or disc. Other skeletal changes include the development of a broader pelvis in females and an increase in the width of the shoulders and chest in males. Because of the anabolic actions of the male sex hormones (androgens) or testosterone, males develop more skeletal muscle mass than females during puberty. This is obvious in the shoulder and chest areas. In a newer form of substance abuse, some adolescents take synthetic androgens, the “muscle-building” steroids, to improve body image and athletic performance, without regard for dangerous side effects on the heart and liver. The growth changes of adolescence do not occur simul- taneously. Limb growth occurs first, then hip and shoulder development, and the increase in skeletal muscle mass is last. This is why the adolescent may appear awkward and gangly for a time until proportionate and complete maturation is accomplished. Additional factors influencing growth during this period include nutrition, genetic factors, and activity levels. It is most important that calcium and vitamin D intake be adequate during this period. It has become evident that maintaining sufficient calcium intake from childhood and throughout life influences the risk of osteoporosis later in life. Unfortunately, dietary intake often becomes erratic during this period just when demand is higher for iron, protein, and other nutrients. Therefore it is essential for the adolescent to maintain basic nutritional requirements. With increasing body dimensions, there is an associated increase in blood volume and in the strength of cardiac contractions, although the pulse rate diminishes. Both cardiovascular and pulmonary functions reach adult values during adolescence, but usually they do not keep pace with musculoskeletal growth, leading to decreased exercise tolerance and marked fatigue at times in active teens. The basal metabolic rate gradually declines to adult levels during this period. THINK ABOUT 23.1 Predict three factors that could interfere with normal develop- ment during adolescence. P er ce nt 20 15 10 5 0 4 5 4 6 7 5 11 11 16 16 6–11 Age in years 12–19 1963–70 1971–74 1976–80 1988–94 1999–02 NOTE: Excludes pregnant women starting with 1971–74. Pregnancy status not available for 1963–65 and 1966–70. Data for 1963–65 are for children 6–11 years of age; data for 1966–70 are for adolescents 12–17 years of age, not 12–19 years. SOURCE: CDC/NCHS, NHES and NHANES FIG. 23.1 Prevalence of obesity among adolescents in the United States 1963-2002. (From the Centers for Disease Control and Prevention [CDC]/National Center for Health Statistics [NCHS], National Health Examination Survey [NHES], and National Health and Nutrition Examination Survey [NHANES].) 590 SECTION IV Factors Contributing to Pathophysiology The current generation of adolescents may be the first to have a shorter life expectancy than their parents. (in the United States) rose from 7% in 1980 to 18% in 2012. Obesity in the 12- to 19-year-old age group rose from 5% in 1980 to 21% in 2012. Accompanying this significant trend is a marked increase in children and young adults with type 2 diabetes mellitus, elevated blood cholesterol/lipid levels, and increased blood pressure. The prevalence of psychological problems is also higher in obese children. Because many obese children become obese adults, these conditions will lead to a higher incidence of cardiac problems, strokes, and musculoskeletal problems such as osteoarthritis. The increased obesity in children and young adults appears related to an increased intake of high-fat and high-carbohydrate snacks, high-sugar soft drinks, and “fast foods” in conjunction with decreased exercise and activity related to excessive time spent watching television or playing computer games. It is recommended that nutritious, healthy snacks and meals as well as increased regular physical activity be encouraged. This will also promote general health, growth, and development of the body. A child’s BMI calculated from the height and weight should be moni- tored if unusual weight gain is noticed. THINK ABOUT 23.2 What changes in adolescent lifestyle have occurred since the 1960s? How has each affected BMI? Metabolic syndrome is defined in various ways, but three factors are common to all definitions: the presence of significant abdominal fat mass resulting in an increased waistline measurement, changes in glucose metabolism, and changes in lipoprotein metabolism. Changes in cardiac output, hypertension, or type 2 diabetes may also be present. (See Chapter 12 for a discussion of coro- nary artery disease and Chapter 16 for a discussion of diabetes.) Metabolic syndrome occurs in 1% to 4% of children and adolescents and in 49% of significantly and clinically obese young people. Obesity is the primary cause of the syndrome, and any weight loss is significant in preventing complications. The underlying cause of metabolic syndrome is the release of insulin antagonists by adipose tissue. An increased proportion of body fat results in insulin resis- tance, a condition in which the body’s cells become resistant to the effects of insulin and changes in metabolism. Specific changes resulting from insulin resistance are discussed in Chapter 16. These changes are a major risk factor for the development of cardiovascular disease and type 2 diabetes. The incidence of cardiovascular diseases such as hypertension and congestive heart failure is higher in individuals with metabolic syndrome, and onset is as early as the teens in adolescents with the syndrome. The same is true of type 2 diabetes. Earlier onset of cardio- vascular disease or type 2 diabetes leads to earlier complications and a significantly shortened life expectancy. THINK ABOUT 23.3 a. How does obesity and change in self-image affect the teen’s diet and exercise? b. Why does the teen need to consume a balanced diet rather than trying the most recent fad diet? c. How can physical activity be increased in daily life activities without the use of expensive equipment or fitness club memberships? Musculoskeletal Abnormalities During the growth spurt, muscular development lags behind skeletal growth; thus less support is available for the weight-bearing areas. Coordination may be impaired at times. Adequate warm-up before exercise or competitive sports is essential to reduce the risk of injury. Postural abnormalities can easily develop during this growth period. Other factors, such as developmental abnormalities in children with Down syndrome or cerebral palsy, may be further aggravated during this period (see Chapter 14). If a correction of a postural abnormality is not undertaken in the early stage, the curvature will progress throughout the adult years, leading to complications. Kyphosis and Lordosis Kyphosis, often called hunchback or humpback, is an increase in the convexity of the thoracic spine (see Chapter 9, Fig. 9.7). Although it often develops in mature adults secondary to disorders such as osteoporosis (bone demineralization) and tuberculosis, a milder and revers- ible form, commonly of postural origin, occurs during the adolescent growth spurt. Teens frequently hunch over, particularly if they are taller than their peers or are self- conscious about breast development. Also, skeletal muscle support may be temporarily inadequate. Marked kyphosis can interfere with lung expansion and ventilation. Exercise and postural change can usually reverse mild deformities, although severe deformity may require surgery or a brace for correction. Lordosis is an exaggerated concave lumbar curvature, or “swayback.” Again, it may accompany musculoskeletal disease, but frequently it develops because of poor posture during the adolescent growth spurt. Obesity aggravates the tendency toward lordosis because the center of gravity for the body is altered, and postural compensation causes the change in vertebral alignment. Scoliosis Scoliosis is a lateral curvature of the spine affecting either the thoracic or lumbar area, or both, and it may be accompanied by rotation of the vertebrae (see Chapter CHAPTER 23 Complications of Adolescence 591 tissue injury, precedes this condition. A bruise or sprain leaves the area vulnerable to blood-borne organisms from another site, such as a skin boil, an abscess, or sinusitis. In adolescents the common causative organism is Staphylococcus aureus, but any pathogen can be the culprit. The most common site of infection in adolescents is the metaphysis (the area between the end and central shaft of a long bone) of the femur or tibia in the leg. Certain conditions such as sickle cell anemia also predispose adolescents to bone infection, as do, of course, open injuries and fractures. The course of osteomyelitis involves the following phases: • A local accumulation of purulent exudate or pus develops, which destroys the bone in the area (Fig. 23.2). This exudate creates pressure within the rigid bony structure and causes severe pain owing to pressure on the nerves, and the periosteum, or outer covering of the bone, may be lifted or torn off if the pressure becomes excessive. • Stimulation causes the surrounding bone to develop new bone growth around the infected site, walling off an area of infection and necrotic bone, which then becomes more difficult to treat effectively. • If the pressure of the exudate tears the periosteum on the surface of the bone, a sinus or passage through the soft tissue may develop, spreading the infection to adjacent tissue. • Possible joint involvement occurs. Usually the epiphy- seal plate acts as a barrier to joint involvement, although the infection can spread through the joint capsule to cause infectious arthritis. If the epiphyseal plate or periosteum is damaged, the future growth of the child may be affected. Manifestations of osteomyelitis include the local signs of inflammation—swelling, redness, and warmth at the site—and pain that increases with movement. Usually there are systemic signs of infection as well, including fever, leukocytosis, malaise, and irritability. Treatment requires aggressive drug therapy with bone-penetrating antimicrobials appropriate for the causative organism. If chronic infection develops, surgery may be necessary to remove necrotic and infected tissue in order to allow healing. The prognosis improves when treatment takes place in the early stage of infection. 9, Fig. 9.7). The curvature becomes greater during growth spurts. Screening programs, offered in many schools, aid early diagnosis. Otherwise, it may be noticed when clothes do not fit properly, or the uneven shoulder elevation may become apparent when the child bends forward. Scoliosis may be classified as structural or functional. Structural scoliosis is a primary spinal deformity, of which 80% are idiopathic (without known cause), although a genetic factor appears to play a key role. In the idiopathic form, females are more frequently affected than males (5 : 1). Congenital scoliosis results from developmental defects such as hemivertebrae, which is a deformity that alters spinal alignment. Sixty percent of congenital sco- liosis cases occur in girls, some of whom have additional congenital defects such as urinary tract abnormalities. Another form, degenerative scoliosis, may develop in older individuals with osteoporosis or osteoarthritis, which create an unstable vertebral column. Functional, nonstructural, or postural scoliosis is secondary to another problem such as unequal leg length or spinal nerve compression. Unequal spinal muscle supports related to partial paralysis, trauma, muscular dystrophy, cerebral palsy, or spinal tumors may lead to loss of the normal curvature. Early effects of abnormal spinal curvature include the following: • Loss of alignment of the hip and shoulder • Rotation of the vertebrae, which affects the pelvis and thorax. (The ribs can become rigid in an abnormal position; if severe, this rotation and fixation can restrict ventilation.) In teenagers with milder postural scoliosis, exercise and bracing may be helpful in restoring the normal curvature of the back. However, surgical correction with instru- mentation and fusion of the vertebrae is often required, causing restriction of the individual’s activity for long periods of time. Unfortunately, even when corrected, complications, including a return of the abnormal cur- vature, may occur later in life. THINK ABOUT 23.4 a. Compare the abnormal curvatures associated with kyphosis, lordosis, and scoliosis by preparing a chart with a simple line drawing and a brief description of each one. b. Bend your head and shoulders forward and down. Attempt to take a deep breath. What happens? c. Describe the potential complications of scoliosis if it is not treated in the early stage. Osteomyelitis This infection of the bone may occur at any age, most commonly as a complication of trauma such as fractures (see Chapter 9). However, it is common in the adolescent period, associated with minor trauma, particularly in younger males. Often a history of minor trauma, a soft THINK ABOUT 23.5 a. List all the manifestations of osteomyelitis. b. Suggest reasons why osteomyelitis might not be diagnosed in an early stage. c. Give several reasons why early treatment is important. Juvenile Rheumatoid Arthritis Juvenile rheumatoid arthritis (JRA) is a group of autoimmune diseases that cause chronic inflammation in the connective 592 SECTION IV Factors Contributing to Pathophysiology tissue in areas such as the joints in children. It is somewhat similar in pathology to adult rheumatoid arthritis (see Chapter 9), but it has certain distinctive qualities. For example, onset is more marked and large joints, such as knees, wrists, and elbows, are more frequently involved, and more systemic effects are apparent. Juvenile rheumatoid arthritis is classified into three subgroups, depending on the joints affected, the types of antibodies found in the blood, and the other effects. One form is termed Still disease, distinguished by its systemic effects and acute onset with high fever, skin rash, and enlarged spleen. The specific cause is not known, although there is a genetic factor, and links to an infectious agent or envi- ronmental factor have been suggested. A study is in process recording cases occurring in siblings. It affects 1 : 1000 children and is more common in two age groups, children aged 2 to 5 years and those aged 9 to 12 years. Many cases are mild and remain undiagnosed for some time. One or more pairs of joints may be involved, depending on the specific type of JRA that is present. The synovial membrane of the joint is inflamed, result- ing in swelling and effusion (fluid) in the joint with gradual erosion of the cartilage. Affected joints are red and swollen in the initial or acute stage; they are often tender to touch and stiff after rest. Joint pain does not seem to be severe, but mobility is impaired by the per- sistent swelling, stiffness, and occasional muscle spasms. If the inflammation persists, adhesions can form, causing fixation and deformity of the joint. Specific diagnostic tests are helpful but not definitive in JRA because the rheumatoid factor is usually not present in the child’s blood. Joint swelling or discomfort lasting more than 6 weeks is an indicator. General signs of inflammation such as leukocytosis are present and Epiphyseal plate Dead bone (sequestrum) Primary infection Sinus forms through soft tissue, draining pus Periosteum raised off bone and torn New bone growth stimulated on perimeter (involucrum) Bone marrow Compact bone Periosteum B Spongy bone A FIG. 23.2 A, Osteomyelitis. B, Femur with osteomyelitis. Resected femur illustrating draining osteomyelitis. The drainage tract (sinus) in the subperiosteal shell of a new viable bone (involucrum) reveals the necrotic cortex (sequestrum). (B From Kumar V, Abbas AK, Fausto M: Robbins and Cotran Pathologic Basis of Disease, ed 7, Philadelphia, 2005, Saunders.) antinuclear antibodies (ANAs) are frequently found in the blood. Other conditions such as infection or trauma must be ruled out. The course may be marked by remissions and exacerba- tions, or the signs may persist continuously. The disease may last for a few months or for years. Complications such as hip involvement or iridocyclitis (inflammation of the eye) may occur. Treatment includes nonsteroidal antiinflammatory drugs (see Chapter 5) and glucocorticoids if needed. Glucocorticoids may be required for severe inflammation or if organs such as the heart are affected. Disease- modifying antirheumatic drugs (DMARDs) such as methotrexate may be used in small doses to slow the progress of the disease and prevent joint damage. Phys- iotherapy and exercise, particularly swimming, are important to maintain the flexibility, alignment, function, and proper development of the joints. Growth may be impaired during the time of active disease, related to immobility or to glucocorticoid treatment, but often a catch-up growth spurt follows recovery. In some cases unequal limb growth related to joint involvement may occur, and the individual may never reach his or her original growth potential. The prognosis is positive for the majority of children, with more than 50% experiencing complete remission and only a small number developing severe joint deformi- ties and motor disability. THINK ABOUT 23.6 a. Explain several ways in which arthritis affects mobility. b. Explain how long-term arthritis of the legs might affect a child’s growth. CHAPTER 23 Complications of Adolescence 593 Many specialized clinics and support groups have been formed to deal with eating disorders. Bulimia Nervosa Bulimia is also common in females but occurs more frequently in older adolescents. Bulimia is characterized by binge eating, particularly of carbohydrates, followed by purging. Binge eating consists of ingesting huge amounts of food, usually high in calories, within a very short period of time. This is followed by purging by means of self-induced vomiting and an excessive use of laxatives and diuretics. Compulsive exercising is fre- quently associated with the disorder. The cycle may be repeated several times during a day or less frequently. Bulimia and anorexia may often overlap. The bulimic often maintains a relatively normal weight, although appropriate levels of individual nutrients may not be sustained, resulting in problems such as anemia (low hemoglobin levels) and menstrual irregularities. Frequent vomiting causes fluid and electrolyte imbalances, which may cause cardiac arrhythmias, tetany, or severe abdominal pain. Recurrent vomiting leads to erosion of tooth enamel (usually on the lingual surface of the maxil- lary teeth) and increased dental caries, tears and ulcers in the oral mucosa, enlarged parotid and submandibular glands, and chronic esophagitis with sore throat and difficulty in swallowing. Self-induced vomiting may leave visible scars on the fingers or back of the hand used to stimulate the gag reflex. Binge eating disorder is a different condition character- ized by the intake of excessively large amounts of food, but lacks purging. It is often associated with obesity. Depression and guilt feelings are found frequently. Eating Disorders In Western cultures, eating disorders such as anorexia nervosa and bulimia are common problems in adolescents and young adults, primarily females. Because more children now tend to obesity in early childhood and adolescence, increasing numbers of teens are focusing on their bodies and desire to change their bodies. With eating disorders, the major medical concern is the effect of poor nutrition on growth and development and on the child’s general health status. The incidence of eating disorders is increasing, but often the affected person makes a great effort to conceal the problem, making it more difficult to detect and treat in the early stages. In addition to the physical problems, the psychological and behavioral factors in these disorders need to be addressed. The two major problems are anorexia nervosa and bulimia nervosa; they may occur separately or, more frequently, they may overlap. Anorexia Nervosa Anorexia nervosa is an extreme loss of weight because of self-starvation, in the absence of another disease. The onset of anorexia occurs in two peak periods, first in the early teen years (ages 12 to 14) and again later in the 16- to 17-year age range, with females being most often affected. The psychological component is strongly evident in these patients, who typically are young women who are perfectionists and high achievers. This psychological component—combined with other factors that may include a history of family conflict, a confused perception of body image and sexuality, and a morbid fear of “fatness”—leads to anorexia. Research is also focusing on possible hypothalamic abnormalities related to hunger as well as other physiologic dysfunctions. The basic problem in anorexia nervosa is a refusal to eat, resulting in severe malnutrition, including protein and vitamin deficits. The affected person may also induce vomiting, take excessive amounts of laxatives, and exercise strenuously to achieve even further weight loss. The anorexic appears markedly emaciated (thin and wasted). Other manifestations include amenorrhea (lack of menstrual cycles), low body temperature and cold intolerance, low blood pressure and slow heart rate, dry skin and brittle nails, and development of fine body hair (lanugo). It has been demonstrated that low calcium intake at this time can predispose to osteoporosis later in life. In some cases, anorexia nervosa can be life threatening. Dehydration can be severe, affecting kidney and cardio- vascular function (see Chapter 2). Electrolyte imbalances such as hypokalemia and hyponatremia may cause complications such as cardiac arrhythmias (irregular heart rhythms) and cardiac arrest. Hospitalization and long-term psychotherapy with behavioral modification may be necessary to arrest the weight loss and initiate recovery. THINK ABOUT 23.7 Prepare a chart comparing anorexia and bulimia according to eating pattern, body weight, and potential complications. Skin Disorders Acne Vulgaris Acne is a common skin infection that occurs in adolescence and through the teen years, particularly in males, although there is a wide variation between its mild and severe forms. Severe forms can lead to permanent scarring. The lesions of acne affect the sebaceous glands and associated hair follicles on the face, neck, and upper trunk (Fig. 23.3). At puberty these glands increase in activity, resulting in plugged pores and infection. There are two types of lesions. Comedones, often called whiteheads or blackheads, are noninflammatory collec- tions of sebum (the oily glandular secretion), sloughed 594 SECTION IV Factors Contributing to Pathophysiology epithelial cells, and bacteria, which clog the gland and prevent normal drainage. These lesions usually resolve without scarring. The second type of lesion involves a severe inflammatory response and infection. The hair follicles swell and rupture, and Propionibacterium acnes, a bacterial component of normal flora, breaks down the sebum into irritating fatty acids, resulting in inflammation. Staphylococcal organisms invade, creating a pustule (raised red mass containing purulent exudate). The lesion is often aggravated by irritation caused by the individual’s picking at or squeezing the mass. Eventually the lesion ruptures, causing local tissue destruction and possibly spreading to nearby areas. Skin damage and scarring are a common outcome. Identifying predisposing factors that can be modified in the client’s history will help reduce the incidence of new lesions. These include hereditary predisposition, increased androgen levels, premenstrual hormonal fluctuations, the application of oily creams, the use of certain drugs, heavy or irritating clothing, backpacks and helmets, and exposure to increased heat and humidity. Shampooing and cleaning the area more frequently (but avoiding harsh soaps and scrubbing), improving general nutrition, and avoiding oil-based cosmetics are helpful preventive measures. Peeling agents (benzoyl peroxide, tretinoin, and isotretinoin) and antibacterial agents (tetracycline) assist in controlling severe lesions and reducing the cosmetic problem. Dermabrasion may be successful in removing some scars. THINK ABOUT 23.8 a. Describe the development of an acneiform lesion. b. Suggest measures that can reduce the severity of acne. Infection Infectious Mononucleosis Infectious mononucleosis is an acute infection affecting lymphocytes caused by the Epstein-Barr virus (EBV, which is in the herpes group). It is common in adolescents and young adults. The infection is usually mild and self-limiting, but occasionally it is marked by complica- tions. The agent is transmitted by direct contact with infected saliva (hence the term kissing disease), airborne droplets, and blood. Epstein-Barr virus invades epithelial cells in the nasopharynx and oropharynx and penetrates to lymphoid tissue, targeting the B lymphocytes and producing typical antibodies. The incubation period is approximately 4 to 6 weeks. The manifestations include the following: • Sore throat, headache, fever, fatigue, and malaise • Enlarged lymph nodes (lymphadenopathy) and spleen (splenomegaly) • A rash on the trunk • An increase in lymphocytes and monocytes in the blood, and the presence of atypical T lymphocytes (Fig. 23.4) • A positive heterophil antibody test (Monospot test) Possible complications include hepatitis, ruptured spleen, and meningitis. Because no effective treatment for viral infections is available, supportive measures, particularly bed rest, are indicated. As with many viral infections, recovery may be prolonged, and fatigue and malaise may be persistent. Fitness students and trainers should be aware of an important safeguard against rupture of the spleen—that is, ensuring that the spleen has returned to normal size before an individual participates in sports or strenuous exercise programs. FPO FIG. 23.3 Severe acne, including papules, pustules, and nodules. (From Jarvis C: Physical Examination and Health Assessment, ed 7, St. Louis, 2016, Elsevier.) FIG. 23.4 Reactive lymphocytes, such as in infectious mononucleo- sis. (From Rodak, B, Carr J: Clinical Hematology Atlas, ed 5, St. Louis, 2017, Elsevier.) CHAPTER 23 Complications of Adolescence 595 and directly irritate the nerve endings, and to the vascular changes and ischemia in the uterine wall that occur as the endometrium is shed. Dysmenorrhea may be treated with hormones or nonsteroidal antiinflammatory drugs such as ibuprofen (Advil). Popular nonprescription products for dysmenorrhea such as Midol contain aspirin, caffeine, and cinnamedrine, a uterine relaxant. Secondary dysmenorrhea usually is related to infection or other pathologies. CASE STUDY A Obesity M.R., age 12, weighs 26 kg/57 lbs and is 60 in/150 cm tall. She is concerned about her weight but finds it hard to “diet” because her family constantly snacks while watching TV. She enjoys texting friends and using the computer for chats and surfing the latest musical groups. Her father tells her not to worry about her weight, that men like women with some “meat on their bones.” Although she likes swimming, she has stopped going to the local pool since her weight has increased. 1. Why are specific tables used to calculate BMI in children and adolescents rather than a simple formula of mass divided by height used for adults? 2. What family factors are related to M.R.’s weight? 3. What personal factors are related to M.R.’s weight? 4. M.R. is at high risk of developing metabolic syndrome because of her weight. What potential life-threatening health problems may she experience if she does develop this syndrome? 5. When will such health problems most likely occur? 6. What changes in body function occur in metabolic syndrome, and how are these monitored? 7. How can M.R. change her lifestyle to reduce complications? What support would be helpful? Disorders Affecting Sexual Development Chromosomal Disorders Depending on the manifestations, some genetic disorders are diagnosed early in life, and some are not diagnosed until puberty, when the effects on sexual development become apparent. An example is Klinefelter syndrome, which affects males owing to the presence of an addi- tional X chromosome (XXY instead of XY; see Chapter 21). Although mental retardation is a common finding, most boys are diagnosed at puberty because the testes remain small, sperm are not produced, and secondary male sex characteristics do not develop. Turner syndrome, a monosomy X (see Chapter 21) in which one X chromosome is missing, affects sexual development in females and causes other abnormalities as well. Anomalies or malfor- mations commonly occur in the heart and genitourinary system; growth is retarded; and at puberty the growth spurt, development of secondary sex characteristics, and initiation of the menstrual cycle are lacking. Hormone replacement treatment is beneficial in these girls. Tumors Testicular tumors are not common but do affect young adult males in their 20s and 30s. When this tumor develops in the testes of the adolescent, it is usually malignant (see Chapter 19). As early as possible, adolescents should be checked and treated for undescended testes (see Fig. 19.2), because this condition is frequently the predisposing factor. This cancer manifests as a unilateral hard, heavy mass and often is not painful. Serum markers may be present, depending on the type of tumor. Routine testicular self-examination is helpful in achieving early diagnosis and treatment. Surgical removal of the affected testicle is necessary. Removal of one testicle usually does not affect sexual function or fertility. However, if radiation or chemotherapy is required after surgery, sterility is likely. Menstrual Abnormalities Delayed menarche or primary amenorrhea, the absence of menstruation after age 17, is usually caused by an abnormality in the reproductive organs (structural or hormonal) or an abnormality in the pituitary gland or hypothalamus. Consistent strenuous physical activity, such as training for competitive sports, and certain systemic disorders, such as hypothyroid or diabetes, may also delay menarche. Dysmenorrhea refers to the discomfort that occurs in varying degrees during the first or second day of men- struation (see Chapter 19). In some girls the pain is incapacitating, and vomiting or fainting may occur. The cramping pain is related to the increased secretion of uterine prostaglandins, which increase muscle contractility C H A P T E R S U M M A R Y Adolescence generally refers to the period of time between the development of secondary sex characteristics and the completion of physical growth around age 18. The increased secretion of gonadotropins and sex hormones is primarily responsible for musculoskeletal changes and sexual maturation. • Obesity is increasingly common in adolescents and is most often accompanied by changes in metabolism of lipids and glucose leading to metabolic syndrome. Metabolic syndrome leads to cardiovascular disease and type 2 diabetes. Complications occur at an early age and limit life expectancy. • Abnormal spinal curvatures such as lordosis and scoliosis may develop during the adolescent growth spurt. Scoliosis, a lateral curvature of the spine, affects the alignment of the hips, shoulders, and ribs, requiring prompt treatment. 596 SECTION IV Factors Contributing to Pathophysiology • Acne vulgaris is an infection of the hair follicles on the face and neck, which may cause significant scarring. • Infectious mononucleosis is a communicable infectious disease caused by the Epstein-Barr virus, usually with mild signs and symptoms but with a prolonged recovery period. • Chromosomal abnormalities affecting sexual develop- ment, such as Klinefelter syndrome, may become obvious at puberty. • Male adolescents should be checked for maldescended testes, a predisposing factor to testicular cancer. This cancer occurs in men younger than age 30. • Osteomyelitis is a serious infection of the bones that may complicate minor injuries. There is a risk of damage to the periosteum or joint, affecting growth. • Juvenile rheumatoid arthritis is similar in many ways to the adult form, but it affects the large joints more frequently and manifests more systemic effects than does the adult form. Most individuals recover fully. • Anorexia nervosa, characterized by a refusal to eat, and bulimia nervosa, typically binge eating accompa- nied by self-induced vomiting and purging, may occur separately or as a combination in a specific patient. A psychological component is frequently present. Com- plications are common. S T U D Y Q U E S T I O N S 1. Briefly describe five changes that indicate sexual maturation in the female. 2. Differentiate structural from functional scoliosis, and give an example of a cause of each type. 3. Explain how the signs of osteomyelitis differ from the signs of JRA. 4. How do anorexia and bulimia differ from each other? 5. Explain how anorexia and bulimia can have serious consequences. 6. Explain how scars may develop from acne. 7. Describe the cause and transmission of infectious mononucleosis. 8. Why should undescended testes not go untreated? 9. Describe the cause and significance of metabolic syndrome. 597 The Aging Process Physiologic Changes With Aging Hormonal Changes Reproductive System Changes Changes in the Skin and Mucosa Cardiovascular System Changes Musculoskeletal System Changes Osteoporosis Osteoarthritis Herniated Intervertebral Disc Other Changes Respiratory System Changes Nervous System Changes Digestive System Changes and Nutrition Urinary System Changes Other Factors Multiple Disorders Case Studies Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Describe the metabolic and structural changes in tissues. 2. Discuss the effects of hormonal changes as women and men age. 3. Describe the common changes in the heart and the arteries. 4. Explain the causes and effects of osteoporosis and osteoarthritis in older individuals. 5. Discuss the common changes in nervous system function. 6. Describe common changes in the digestive system and the urinary system. 7. Explain the increased incidence of inflammation, infections, and cancer. 8. Explain how multiple system disorders can interact and cause complications. L E A R N I N G O B J E C T I V E S cholesterol frequency neurofibrils neurotransmitter plaques sedentary senescence K E Y T E R M S C H A P T E R 24 Complications of Aging The Aging Process Aging begins at birth but becomes more evident at about 30 years of age. The process is irreversible, but the rate and effects of aging vary greatly among individuals and do not necessarily match chronologic age. The typical changes in various organs do not occur at the same time or in any particular order. The extent of the changes also depends on the individual’s genetic makeup, lifestyle, and health status. Many diverse research projects are taking place into the physiologic changes related to aging with the goal of delaying changes or reversing them. Much of this research is in developmental biology and includes the study and expression of various genes that have been identified in normal development. Research on various stem cells and their potential as methods of treatment for a number of medical issues involving aging is ongoing. Senescence refers to the period of life from old age to death. Overall, women live longer than men. In general the average life span is increasing, creating a higher proportion of older individuals in the population. This trend occurs largely because of improved social and living standards, better nutrition, and advancements in health care. Physical exercise that occurs on a routine basis and increases cardiac output and ventilation may slow tissue changes associated with senescence by providing improved nutrition and oxygenation to the 598 SECTION IV Factors Contributing to Pathophysiology Physiological Changes With Aging Hormonal Changes Generally hormone secretions remain relatively constant with advancing age, but the number of tissue receptors may decrease, thus diminishing the body’s response to hormones. This effect is apparent in disorders such as type 2 diabetes mellitus, which is common in older persons. In this condition, sufficient insulin is produced, but because the number of cell receptors is reduced, glucose does not enter the cells (see Chapter 16). In the absence of any specific pathology, the pituitary, thyroid, parathyroids, adrenals, and pancreas appear to maintain relatively normal function, producing hormones in adequate quantities. The major natural hormonal change occurs in women at about age 50, when the ovaries cease to produce estrogen and progesterone; subsequently, serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) rise in response to natural feedback mechanisms (see Chapter 19). The effects of the decreased estrogen and progesterone are described in the following sections. Although there is a gradual decrease in testos- terone levels in the male, the testes do not totally cease to function. Testosterone levels in males peak during teenage years and early adulthood. After the age of 30 testosterone levels decrease about 1% a year. The decline is usually not obvious until later in life. Reproductive System Changes Menopause is the term given to the change that occurs in women at around age 50, when the ovaries cease to respond to FSH and LH, resulting in lack of ovulation, cessation of the menstrual cycle, and declining estrogen and progesterone levels. The decreased levels of sex hormones lead to changes such as thinning of the mucosa, loss of elasticity, and decreased glandular secretions in the vagina and cervix. These changes may cause inflam- mation and dyspareunia, or painful sexual intercourse (see Chapter 19). The effects can be minimized by topical (local) administration of estrogen creams. There are risks associated with oral hormone replacement therapy; therefore individual case assessment is necessary. The pH of the vaginal secretions becomes more alkaline, thus predisposing older women to recurrent vaginal infections. Breast tissue also decreases in volume. These changes in hormone levels in the early stage of menopause frequently tissues. Cognitive activities requiring problem solving such as card games, puzzles, and reading seem to reduce senescence in the central nervous system. Social interaction during exercise or games is also significant in maintaining function. With aging, a general reduction in function occurs throughout the body at the cellular and organ level, and the body is characterized by a decreased capacity to adapt to change. Aging is a natural process, but it is affected by many pathologic processes. Degenerative changes associated with aging may predispose an individual to certain pathologies, and pathologic changes can hasten aging. Of particular concern are the organs and tissues that cannot regenerate, such as the brain and myocardium. This chapter covers only some of the more significant effects of aging that are linked to pathologic problems. For additional information, a gerontology reference should be consulted. There are different theories about the causes of aging. One theory suggests that aging is programmed genetically through the cells and that this control directly limits the cells’ reproductive capacity (see Chapter 1). Predetermined cell death is termed apoptosis. Other possible factors include wear and tear, cellular damage resulting from accumulated wastes and altered protein (amyloid) or lipid (lipofuscin) components, and increased degenerative changes in collagen and elastin fibers. In addition, random errors may occur during cell mitosis. Some theories suggest that aging is related to resident latent viruses or increased autoimmune reactions in which the body rejects its own tissues or to environmental agents that affect cells. One concern relates to free radicals such as peroxides, reactive chemicals produced during cell metabolism. Free radicals are known to damage nucleic acids and cells, leading to cancer and other diseases. It is likely that many factors contribute to the aging process, and that these factors vary in individuals. Changes in the tissues are obvious. Cells assume less regular arrangements in tissues later in life. Elastic fibers become less numerous or are lost almost entirely and the number of collagen cross-linkages or other abnormal structures in tissues and organs increases. Mitosis, or cellular reproduction, gradually slows down, partly in response to the slower metabolic rate, resulting in decreased tissue repair. Some cells such as neurons and muscle cells cannot replicate, and when they die function is reduced in these tissues. Certain cells appear to have limits on the number of times they can replicate, and therefore they are not replaced in older individuals. Other cells accumulate wastes or are altered by environmental factors and become less functional or die, ultimately leading to organ failure. It has become evident that prolonged exposure to numerous environmental factors such as radiation, viral infections, and chemicals over the years increases the risk of cancer and other diseases in older people. Many of these changes also occur in younger individuals, so they are not unique to the aging process. THINK ABOUT 24.1 a. List changes in the tissues of the body that occur with aging. b. List the signs of aging you have noted in individuals at 30, 50, and 80 years of age. CHAPTER 24 Complications of Aging 599 Cardiovascular System Changes Age-related changes occur in the cardiac muscle fibers and the connective tissues in the heart. Fatty tissue and collagen fibers accumulate in the heart muscle with aging and may eventually interfere with impulse conduction and cardiac muscle contraction. The size and number of cardiac muscle cells declines, reducing the strength of cardiac contractions. In the absence of any pathologic changes, the left ventricle appears smaller, because demand is also reduced. Cardiac muscle fibers do not undergo mitosis and cannot be replaced. Heart valves often thicken and therefore become less flexible and efficient. In some individuals, vascular degeneration causes a decrease in the oxygen supply to the heart muscle and reduces the ability of the heart muscle to use oxygen. Thus cardiac output and cardiac reserve are diminished, decreasing the maximum cardiac output possible with stress. Adequate fluid intake is important to maintain cardiovascular function, as the percentage of fluid in the body declines in older individuals. Again, a regular fitness program is most helpful in maintaining cardiac function. The common pathologies of the cardiovascular system are associated with degenerative changes in the arteries, both in the heart and throughout the body (see Chapter 12). Loss of elasticity and the accumulation of collagen in the arterial walls result in thickening of the arterial walls, thus limiting expansion of the large arteries and obstructing the lumina of smaller arteries. This leads to arteriosclerosis (see Chapter 12) and elevated blood pressure. Also, degenerative changes promote the accumulation of cholesterol and lipid in the walls of large arteries, the condition known as atherosclerosis (see Chapter 12), particularly when the individual has elevated blood lipid levels. These lipid plaques obstruct blood flow and predispose to thrombus formation. Atherosclerosis is a common cause of angina, myocardial infarctions (heart attacks), peripheral vascular disease in the legs, and strokes. Dietary changes, including reduced cholesterol intake, and regular exercise programs assist in lowering blood lipid and cholesterol levels and lessen the risk of vascular degeneration and high blood pressure. lead to systemic signs such as “hot flashes,” which involve periodic sweating or vascular disturbances. Also head- aches, irritability, and insomnia are common manifesta- tions. The effects of menopause may be felt for short or long periods of time (several years) and are more marked in some women than others. Approximately 25% of women experience significant effects. If surgical removal of the ovaries is necessary before menopause occurs naturally, similar effects will be evident. In males, testosterone levels decline gradually, the testes decrease in size, sperm production is somewhat reduced, and the glandular secretions of the prostate are decreased, but the older male is capable of fathering a child. The common problem in older males is benign prostatic hypertrophy (BPH) (see Chapter 19), in which the central part of the gland around the urethra hypertrophies, resulting in some degree of obstruction of the urethra. If urinary flow is significantly impaired, surgery may be necessary. Cancer of the reproductive organs is more common in both males (prostatic cancer) and females (uterine and breast cancer) in later years and may be related to altered hormonal levels. Frequent examinations by a physician in addition to routine self-examination and testing (eg, mammograms) are essential to lessen the risk of advanced malignancy. THINK ABOUT 24.2 a. Compare the changes in reproductive hormones and structures that occur in older males and females. b. Using your knowledge of the normal actions of the sex hormones, suggest some effects of decreased secretion of sex hormones on various body tissues and structures. (You may refer to Chapter 24 for help with hormonal actions.) Changes in the Skin and Mucosa Some changes in the skin are related to genetic factors; many are based on exposure to sun and weather. With aging, both the skin and mucous membranes become thin and fragile. The dermis is thinner and subcutaneous tissue is diminished. Fewer capillaries are present and cell prolifera- tion is decreased, resulting in slower wound healing and atrophy of the glands. The numbers of sensory receptors in the skin and mucosa decline. These factors increase susceptibility to injury, bruising occurs frequently, and the mucosal membranes become inflamed or ulcerated. The skin is often dry and appears wrinkled as elastic fibers are reduced and collagen fibers become less flexible. Obvious lesions include skin tags (small projections of skin) on the neck and axillary areas, keratoses (rough raised masses, often dark in color) over the body, and lentigines or liver spots (dark flat macules), often on the hands and face. The hair becomes gray as melanocytes are reduced in number, and thinning occurs as the number of hair follicles decreases. THINK ABOUT 24.3 a. Based on your general knowledge, can you suggest ways of restricting the diet to reduce the risk of cardiovascular problems? b. Suggest different types of exercise appropriate for older individuals, and explain how regular exercise can delay the onset of degenerative changes. c. Explain how the reduced blood supply may affect the skin and mucosa. d. Describe the outcome of a blocked artery. 600 SECTION IV Factors Contributing to Pathophysiology such as the vertebrae and pelvis (Fig. 24.2). Spontaneous vertebral fractures result in decreased height and kyphosis with increased age (see Chapter 9 and Fig. 9.7, which illustrates kyphosis). As the thoracic curvature increases, the individual compensates by increasing the cervical curvature and tilting the head, leading to a typical hunchback posture (dowager’s hump) and a shuffling gait. This impairs ventilation and mobility. Recommendations to reduce the risk and the progres- sion of osteoporosis with aging include the following: • Increased calcium intake plus adequate vitamin D for all age groups (the current recommendation for the daily calcium intake for those older than 50 years is 1500 mg, plus 800 IU vitamin D) • Walking and other weight-bearing exercise, physio- therapy, or a rehabilitation program • Drugs such as the bisphosphonates (eg, alendronate sodium [Fosamax]), which inhibit bone resorption • Individualized hormonal therapy, including selective estrogen receptor modulators (eg, raloxifene/[Evista]), estrogen/progestin replacement therapy, or synthetic calcitonin (Miacalcin) or parathyroid hormone Osteoarthritis Degeneration of the cartilage in the joints is a common problem that results in osteoarthritis (see Chapter 9). In this condition, the articular cartilage becomes thin and erosions occur, impairing joint movement and causing pain, particularly in the large weight-bearing joints such as the knees and hips. In some cases, bone spurs or overgrowths develop at points of stress, further restricting Musculoskeletal System Changes Osteoporosis The important change in bone with aging is loss of calcium and bone mass, which leads to osteoporosis. This condition may occur for many reasons, but the high incidence in postmenopausal women is a concern because of the serious consequences (see Chapters 9 and 25 for additional information on osteoporosis). Fractures of the spine, pelvis, and limbs are common occurrences, requiring hospitalization and limiting mobility. It is recommended that older women have a routine bone density test to check for the “silent” development of osteoporosis. It is now apparent that many men, approximately 1:8, also lose bone mass. Several risk factors are associated with osteoporosis in older persons, including the following: • Hereditary predisposition • Decreased estrogen levels • Decreased weight-bearing activity or stress on bone (sedentary or inactive lifestyle or immobility) • Decreased intake of calcium, vitamins C and D, at all ages, including childhood • Decreased intestinal absorption of calcium • Decreased osteoblastic activity, which is an increased risk with glucocorticoid/cortisol use Deposition of new bone is reduced, leading to decreased bone mass and density. Note the reduction in the outer layer of compact bone in the metacarpal bone in Fig. 24.1. The bones are often porous and brittle, thus precipitating frequent fractures (see Chapter 9) in areas BA FIG. 24.1 A, Normal metacarpal bone. B, Osteoporotic metacarpal bone. (From Helms CA: Fundamentals of Skeletal Radiology, ed 3, Philadelphia, 2005, Saunders.) CHAPTER 24 Complications of Aging 601 Young normal Osteoporotic Lumbar Spine FIG. 24.2 Three-dimensional reconstruction of a lumbar spinal sample for a young adult woman and a postmenopausal woman with osteoporosis. (From Benjamin E, et al: Cecil Essentials of Medicine, ed 9, Philadelphia, 2016, Elsevier, Saunders.) movement. Pain increases with walking and other move- ments. Joint replacement may be necessary. Herniated Intervertebral Disc The fibrocartilage in the intervertebral discs in the spine degenerates with age, and a sudden stress on the back may result in herniation of a disc. This herniation causes pressure on the spinal nerves and results in severe back pain (see Chapter 14). If the pressure is not relieved, permanent damage to the nerves can result. Also, as the intervertebral discs become thinner, loss of height becomes apparent. Other Changes • Skeletal muscle mass declines with aging owing to both atrophy and a decreased number of fibers. Skeletal muscle fibers cannot be replaced. Loss of muscle and subcutaneous tissue leads to an increased susceptibility to skin breakdown and pressure-related ulcers because of the reduced cushion between skin and bone. Also, there is less “insulation” to retain heat in the body and less “cushioning” against falls or pressure. • The strength of muscle contractions decreases some- what, but this also depends on the activity level of the individual. • Flexibility is reduced as elastic fibers degenerate throughout the body. • Often movements become slower, stiffness becomes evident, and coordination and balance are reduced. These changes are associated with changes in the musculoskeletal structures as well as in the neurologic components. Dressing, walking, food preparation, and many other daily activities require a longer time to complete. Regular moderate, low-impact exercise, such as swim- ming or tai chi, helps to maintain mobility and flexibility, both by increasing the efficiency and activity of muscle and bone and by improving the circulation of blood to the tissues. Good nutrition, particularly protein, minerals, and vitamins, is also important in maintaining the integrity of the basic structures in older people. THINK ABOUT 24.4 a. Using your knowledge of normal physiology, suggest how improved circulation with exercise could slow the onset of degenerative changes in the musculoskeletal system. b. How does pain from osteoarthritis affect the ability to exercise and maintain an appropriate body mass? c. Why would severe trauma to skeletal muscle, such as a crush injury, have permanently disabling effects? Respiratory System Changes In aging individuals, ventilation, both inspiration and expiration, is limited for several reasons: • Elasticity in the lung tissue is reduced. • The costal cartilage between the ribs and the sternum calcifies, reducing rib movement. 602 SECTION IV Factors Contributing to Pathophysiology feel chilled owing to poor blood circulation, decreased metabolism, and decreased activity levels. Often there is reduced temperature sensitivity in the skin when touching hot or cold surfaces. Changes usually occur in the special senses as well. In the eye, the iris and its associated muscles degenerate, resulting in decreased adaptation by the pupil to light and possible obstruction of flow of aqueous humor, leading to increased intraocular pressure and glaucoma (see Chapter 15). The lens tends to become yellow and less transparent, interfering with color perception, especially blue hues. Night vision is impaired, and many elderly people are unable to drive safely when it is dark. The lens eventually may become opaque as cataracts (see Chapter 15) develop. If vision is lost, surgery may be required to remove the cataract. The lens also becomes larger and less elastic, causing presbyopia (farsightedness, see Chapter 15) and possibly cataracts. Vascular degenera- tion may affect the retina of the eye, which contains the nerve cells for receiving images, and this condition causes permanent visual loss. Hearing loss associated with aging is usually caused by degenerative changes in the inner ear in either the nerve receptor cells of the cochlea or the nerve fibers supplying the ear. In noisy surroundings, it may become difficult to discriminate among sounds, impairing com- munication and deterring socialization. The senses of taste and smell often diminish with aging. Taste may be altered by reduced salivary secretions or decreased perception within the central nervous system. The ability to discriminate among odors is reduced. Diminished powers of taste and smell may impair appetite and nutrition. • Skeletal muscle (eg, intercostal muscles) atrophies and weakens. • Any skeletal change (eg, rib shape) may reduce thoracic movement. Expiration is reduced, and residual volume is increased (see Chapter 13). The more restricted lung movements lead to decreased expansion for deep breathing and coughing. Weaker skeletal muscles also reduce cough effectiveness. When the capability for initiating an effective cough is impaired, secretions tend to accumulate, and the risk of pneumonia increases. Vascular degeneration in the lungs leads to decreased perfusion and reduced gas exchange in the alveoli. There tends to be a reduced oxygen level rather than an increased carbon dioxide level. Regular physical exercise is effective in maximizing ventilation and circulation. Breathing exercises and oxygen therapy may assist respiratory function in those with respiratory pathologies and sup- porting physical activity. Nervous System Changes Because neurons are not replaced after birth, a natural reduction in brain mass occurs with aging. This does not affect cognitive function in many individuals because there is a considerable reserve of neurons. Loss may occur in different areas of the brain, at different times and to varying degrees. Maintenance of high activity levels and stimulation of the nervous system in the later years appear to assist in maintaining brain function. Exposure to toxic materials such as lead tends to hasten the degeneration. Some of the degenerative changes observed in the brain tissue include lipid accumulations in the neurons, loss of the myelin sheath, and the development of abnormal neurofibrils (masses of tiny, tangled fibrils) and plaques on the cells. Vascular impairment such as arteriosclerosis hastens the degenerative process. Neu- rofibrils and plaques are present in much higher numbers in those who become mentally incompetent through organic brain syndrome, a condition that includes senile dementia and Alzheimer disease (see Chapter 14). There also appears to be a decreased cellular response in the brain to neurotransmitter chemicals such as norepineph- rine, leading to delays in synaptic transmission. General changes in function commonly noticed in older persons include slower response time, decreased reflexes, and short-term memory lapses. However, past experiences can greatly facilitate decision making and the learning process. It has been documented that the elderly can learn new information and skills, although the process is slower because the individual incorporates more information and uses more functions of the brain rather than learning by rote. The autonomic nervous system does not always provide adequate adaptation, resulting in decreased tolerance to extreme hot or cold temperatures. The elderly THINK ABOUT 24.5 Describe four neurologic changes that can be expected to occur in an older individual. Digestive System Changes and Nutrition Maintenance of good nutrition is a problem in many elderly. Sometimes the older person feels that less food is needed and components such as meat (protein) are unnecessary at this stage of life. In the mouth, loss of teeth because of periodontal disease (inflammation and infection in the tissue surrounding the teeth, see Chapter 17) and decreased salivary secretions frequently restrict dietary choices as the older person experiences difficulty in chewing many foods. Often dentures are not satisfactory for chewing as the gums and bone recede. The mucosa thins and blood flow is reduced. The fragile tissues in the mouth are easily irritated by ill-fitting dentures or accumulated food particles. Xerostomia, or dry mouth (see Chapter 17), is common because the amount of saliva is reduced. Decreased saliva may also result from use of CHAPTER 24 Complications of Aging 603 compensate for rapid changes in electrolyte and acid levels and may have a reduced capacity to secrete drugs into the urine, resulting in excessively high levels of drugs in the blood. A major complication of aging is reduced control of bladder function as the muscles of the urethra and bladder become weaker. Reduced bladder capacity and incomplete bladder emptying result in frequency, nocturia (frequent urination during the night), and infection. In women, the pelvic floor muscles have often been stretched and weakened by childbirth, reducing the ability of the external sphincter to restrict urinary outflow. Also, decreased estrogen levels may decrease smooth muscle tone. Sensory perception of a full bladder is reduced, and this problem, combined with a weakened urethral sphincter, often results in incontinence (involuntary voiding of urine). Incontinence usually results in incom- plete emptying of the bladder, which leads to residual urine and frequent urinary tract and bladder infections (cystitis) (see Chapter 18). Other Factors Infections are common in the elderly, in whom poor circula- tion impairs the normal defense mechanisms, and tissue healing is delayed owing to the reduced rate of mitosis. Although the antibody pool is large, the immune response to new microbes is less effective because lymphocytes are slower to respond to antigens and are less active in the later years. Skin breakdown and ulcers may predispose those with immune-deficient states to infection. Surveys of chronic care facilities indicate a high incidence of urinary tract infections. Men are at risk because of prostatic obstruction and women because of bladder prolapse, incontinence, and thinner mucosa in the bladder. Both sexes tend to have more frequent catheterizations or instrumentation, predisposing to infection. Cancer is more common in the elderly because the immune system becomes a less effective surveillance unit, and older people have had a higher cumulative exposure to carcinogens (see Chapter 20). The incidence of breast cancer in women and prostate cancer in men rises dramati- cally with increasing age. Older people are more subject to autoimmune disorders and more degenerative pathologies related to wear and tear, many of which are chronic progressive disorders. Adaptation to stressors is slower in the elderly and more difficult because the systems may be unable to respond to the increased demands. Multiple Disorders Multiple disorders are common in the older population. Osteoarthritis may lead to obesity and diabetes; cardiovascular disease may lead to changes in sexual function, cognitive deficits, or respiratory problems. It certain drugs or from the mouth-breathing associated with many respiratory problems. Swallowing difficulties resulting from neurologic causes or mechanical obstruc- tions such as scar tissue or hiatal hernia may develop (see Chapter 17). The need for a soft diet and other factors such as lack of socialization, fatigue, restricted mobility, or financial concerns may also limit food choices and interfere with nutritional status. Obesity is common in some older individuals, par- ticularly those who lead sedentary lives. The basal metabolic rate (BMR) decreases significantly as one ages. This reduction must be accompanied by a decrease in the intake of fats and carbohydrates to maintain an appropriate weight. In some cases, excessive carbohydrate and fat intake may mask the signs of protein, fiber, or vitamin deficits. Obesity increases cardiac workload as well as the likelihood of atherosclerosis and hypertension. Gallstones are also a complication of obesity, as is osteo- arthritis affecting the weight-bearing joints. Insulin resistance caused by obesity is an important factor in metabolic syndrome leading to altered glucose and lipid metabolism as well as type 2 diabetes. Atrophy of the mucosa and glands of the digestive tract frequently reduces digestive secretions and absorp- tion of essential nutrients. Absorption of vitamin B12, calcium, and iron may be impaired but can be replaced by vitamin B12 injections plus more easily absorbed forms of calcium and iron. Decreased mucus secretion and thinning of the mucosa predisposes the older person to peptic ulcer development. Unfortunately, signs of ulcers are vague or may be masked by self-medication in the early stages. Older individuals are predisposed to malignancies in the digestive tract, particularly in the stomach and colon, which may be related to hereditary factors as well as to dietary intake. Carcinogenic substances in the diet are more hazardous when they are associated with constipa- tion because of the prolonged exposure of the tissues to these substances during transit through the gut. Constipa- tion is common in the elderly. Many factors contribute to it, including decreased activity, low fiber and fluid intake, and excessive use of laxatives. Chronic constipation frequently leads to hemorrhoids. THINK ABOUT 24.6 a. Using your knowledge of normal physiology, list the factors that lead to constipation. b. Describe several possible pathologic conditions involving the digestive tract in older people. c. Explain why obesity is undesirable in the elderly. Urinary System Changes Kidney function is reduced with aging owing to loss of glomeruli and degeneration of the tubules and blood vessels. The kidneys have a diminished ability to 604 SECTION IV Factors Contributing to Pathophysiology CASE STUDY B Alzheimer’s Disease Mr. J. is a 75-year-old widower and quite active. He has a history of elevated blood pressure, which he controls effectively with diet and exercise at the local community center. Recently he has been neglecting his appearance and hygiene, and his friends at the community center have noted his absence from many activities. He has missed appointments with his nurse practitioner at the local clinic stating that he thought the appointments were “next week.” While playing cards with friends, he becomes angry and throws his cards down, saying, “This is a stupid game!” His adult daughter visits him while on a business trip in a nearby city and notes his confusion and irritability. When the nurse practitioner refers him to a gerontology assessment unit, a preliminary diagnosis of early Alzheimer disease is made. 1. What are the possible causes of Mr. J.’s irritability? 2. How will early Alzheimer disease affect his ability to control his weight and blood pressure as he has done in the past? 3. What problems does Mr. J. face if medication is prescribed for his elevated blood pressure? 4. What potential complications could occur if Mr. J.’s weight increases to 20% over the desirable weight? CASE STUDY C Multiple Disorders of Aging Mrs. B.N. is 67 years of age and has had a long history of arthritis, which is treated with antiinflammatory medication. Her doctor has prescribed a drug to protect her stomach, but the drug is very expensive. She has chosen to take the “arthritis pills” without the “stomach pills” because her stomach feels fine. Recently she has had indigestion, which is relieved somewhat by eating. She also noticed hard, black tarlike stools. The indigestion becomes very painful, and she vomits several times one morning. She is weak and lies down to rest, but her nausea and vomiting continue. When her heart begins to beat as though it “is trying to run away with me,” she calls a friend to take her to the hospital. She is examined and a diagnosis of acute gastritis and irregular heartbeat is made. Treatment is started. 1. What fluid and electrolyte imbalances can be caused by vomiting? How are these imbalances related to Mrs. B.N.’s irregular heartbeat? 2. Mrs. B.N. has experienced an irregular heartbeat that reduces cardiac output and may cause blood to pool in the atria of the heart. What are two potential problems that Mrs. B.N. may experience from the altered function of the heart? 3. What has caused the change in Mrs. B.N.’s stools, and what potential problem can occur if this continues? CASE STUDY A Complications of Aging Mrs. H., age 85, is living alone in her family home after the death of her spouse 6 years ago. Recently, she has been using a cane to walk because of “stiff joints” in her knees and hips. Before this, she usually walked for 1 to 2 hours per day in her small community neighborhood, but she finds it too tiring and painful these days. She has lost 22 lb (10 kg) and states that she finds it difficult to shop and cook for herself. She states that she takes a vitamin pill each day, but usually has tea and a few cookies or toast when she is hungry. Blood tests reveal hemoglobin of 90 g/L, elevated electrolytes, and elevated hematocrit. She is diagnosed with anemia and dehydration as well as osteoarthritis in several joints. Her physician indicates she is not healthy enough to consider joint replacement at this time. 1. What is the probable cause of Mrs. H.’s anemia, and how does anemia affect her health? 2. How might Mrs. H.’s malnutrition affect her ability to fight infection or maintain tissue integrity? 3. What role has pain played in the development of Mrs. H.’s malnourished state? 4. Why does Mrs. H. have an elevated hematocrit and elevated electrolytes? 5. Mrs. H. does not want to take any medications for her joint pain, stating that “I am old and pain is to be expected.” How is control of her joint pain related to prevention of future malnutrition? THINK ABOUT 24.7 Suggest three ways by which the changes common to aging may be delayed to some extent. is important to ensure that the older adult with multi- system disorders is treated for all the interacting problems by all health care workers. If one problem is ignored, it may well lead to exacerbation of the problem and further complications. Many elderly people take a large number of medications, both prescribed drugs and over-the-counter (OTC—no prescription required) medications and herbal remedies. These combinations increase the possibility of undesirable drug interactions, particularly if an individual is consult- ing several doctors (see Chapter 3). Sometimes patients become confused regarding dosage; therefore written instructions and a system to monitor timing are essential to prevent a missed dose or an overdose. Other problems with medications in the elderly include a higher risk of idiosyncratic or unexpected reactions; toxic effects caused by unpredictable absorption, distribution, and elimination of drugs; and impaired function such as lethargy or lack of coordination. Noncompliance may be an issue. As the tissue receptors and body mass change in the elderly, it is often necessary to adjust the dosage and combinations of medications. C H A P T E R S U M M A R Y Aging begins after birth, but the effects vary considerably with the individual, not with chronologic age. With aging, a general reduction occurs in cell and organ function. CHAPTER 24 Complications of Aging 605 S T U D Y Q U E S T I O N S 1. Describe appropriate guidelines for a healthy diet for an older individual. 2. Explain the different ways in which regular moderate exercise can benefit an older person. 3. Suggest some reasons why the aging process varies among different individuals. 4. Why are infections more common in elderly individuals? Possible factors contributing to the aging process include apoptosis, effects of “wear and tear,” metabolic products accumulating in cells, and increased autoimmune reactions in the body. • Hormones other than the sex hormones normally continue to be secreted at normal levels. Women demonstrate some tissue degeneration in the reproduc- tive structures. Most men develop some degree of benign prostatic hypertrophy. • Cancer frequently develops in the reproductive systems of men and women. • Skin and mucosal membranes become thinner and blood flow is reduced. • The major change in the cardiovascular system involves arterial degeneration. • Osteoporosis develops frequently in postmenopausal women related to factors such as decreased estrogen levels, a more sedentary lifestyle and diet, as well as genetic predisposition. • Osteoarthritis or herniated intervertebral disc impairs mobility in many older individuals. • Ventilation capacity is reduced in the elderly. • Older persons may experience slower neurologic response times and reflexes, but past experience and acquired knowledge facilitate decision making and learning. • Degenerative changes in the eyes and ears often impair vision and hearing. • Many individuals do not receive adequate nutrition. • The kidneys are not as capable of retaining fluid, and bladder control may be less effective. 606 Immobility and Associated Problems S E C T I O N V Environmental Factors and Pathophysiology C H A P T E R 25 Factors Involving Immobility Musculoskeletal System Effects Cutaneous Effects Cardiovascular System Effects Respiratory System Effects Digestive System Effects Urinary System Effects Neurologic/Psychological Effects Effects of Immobility on Children Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Describe the possible effect of immobility on skeletal muscle, bone, and joints. 2. Discuss the development of decubitus ulcers. 3. Explain the changes in blood pressure and potential thrombus formation. 4. List the potential problems related to respiratory function. 5. Discuss the common effects of immobility on appetite, bowel function, and urinary tract function. 6. Discuss the potential effects of immobility on the nervous system and psychological implications. 7. Describe the potential effect of immobility on a child’s growth. L E A R N I N G O B J E C T I V E S basal metabolic rate decubitus ulcers diplegia extensor flexor hemiplegia orthostatic hypotension paraplegia quadriplegia stasis supine K E Y T E R M S Factors Involving Immobility Immobility, or lack of movement, may involve only one part of the body such as a fractured arm in a cast. A part of the body may be affected, as occurs with paralysis: one side of the body (hemiplegia), the lower half of the body (paraplegia), or the trunk and all four limbs (quadriplegia). Diplegia refers to symmetric paralysis in any area of the body. When one is in a coma or during an acute illness the entire body may be immobilized. The effects of such inactivity depend on the extent of the immobilization and its duration. Physiotherapy or passive exercise imposed on the involved area of the body can minimize the effects of lack of voluntary movement. Respiratory therapy is significant in preventing infections such as pneumonia. When the body is supine (lying on the back), the loss of the force of gravity affects many of its natural functions, CHAPTER 25 Immobility and Associated Problems 607 in cardiac output, which may cause dizziness or fainting when changing position. Bone deteriorates with inactivity. Bone is a “living” tissue in which new bone is constantly forming (osteo- blastic activity; see Chapter 9) and other bone is being resorbed (osteoclastic activity; see Chapter 9). Bone demineralization occurs because the lack of weight bearing and muscle action reduces osteoblastic activity or bone formation; however, osteoclastic activity continues. This process leads to loss of bone mass and osteoporosis with the potential for spontaneous fractures if undue stress is placed on the bones (see Chapters 9 and 24). The breakdown of muscle and bone tissue initially results in elevated serum levels of nitrogen wastes such as creatinine and in elevated serum calcium. Hypercal- cemia may cause renal calculi or kidney stones if fluid intake is inadequate and the urine becomes too concen- trated (see Chapter 18). Also a high serum calcium level can further impede muscle activity because it decreases muscle tone and leads to flaccidity or loss of muscle tone. Passive range-of-motion exercises and weight bearing if tolerated on a regular basis are helpful in preventing these complications. Tendons and ligaments that connect the muscles to bone and maintain joint structure also require movement to maintain their structure and functionality. After 4 to 6 days of immobility these forms of connective tissue begin to shorten and the density of the tissue increases, limiting flexibility and range of motion. primarily in the intestines and urinary tract. Other notice- able effects result from the lack of stress normally exerted on bone by skeletal muscle and the decreased circulation of blood. Bed rest also alters respiratory function, metabo- lism, and digestive and renal function. Musculoskeletal System Effects Inactive muscle loses strength, endurance, and mass quickly. Perhaps you have seen an arm or a leg shriveled due to atrophied muscle (often called disuse atrophy) after it has been confined to a cast for several weeks. Loss of muscular strength due to immobility progresses at a rate of about 12% each week. After 3 to 5 weeks of immobility due to bed rest, almost half of the muscular strength is lost. Correct positioning and reduction of abnormal stress on immobilized muscles and joints are important because these structures may stretch or shorten, resulting in abnormal fixation of a joint, altering biomechanics. For example, an ankle may develop contractures when a tight, heavy blanket or improper positioning puts excessive and inappropriate pressure on the foot (Fig. 25.1). Gener- ally flexor muscles are stronger than the opposing extensor muscles (which atrophy more than the flexor muscles), and this imbalance may allow an inactive joint to take an abnormal position if flexibility is not maintained by range-of-motion exercises. With inactivity, tendons and ligaments shorten and lose elasticity. Prolonged immobil- ity causes fibrous tissue to replace muscle cells, leading to muscle wasting and weakening, decreased flexibility, further possibly irreversible deformity (contracture; see Chapter 5), and loss of function. The lack of muscular activity impairs venous return, which causes pooling of blood in dependent areas of the body, development of dependent edema, and a decrease FIG. 25.1 Contracture of the feet in a patient with muscular dystrophy. (From Jahss MH: Disorders of the Foot and Ankle, vol. 1, ed 2, Philadelphia, 1991, Saunders.) THINK ABOUT 25.1 a. Explain the effects of immobility on posture and joints. b. Explain how immobility can lead to osteoporosis. Cutaneous Effects The skin breaks down easily when its circulation is impaired and cell regeneration is reduced. Blood supply is often reduced in places where the skin is stretched over bony projections and there is little fatty or muscular tissue to cushion the weight of the body. Areas that are particularly vulnerable to poor blood perfusion include the ischial tuberosities, the sacrum, the greater trochanter of the hip, the heels, and the elbows. Pressure at these points causes ischemia and necrosis of tissue (Fig. 25.2), leading to decubitus ulcers (pressure sores or bedsores). Other factors that promote skin breakdown and the development of decubiti include the following: • Poor general circulation or anemia • Edema • Inadequate subcutaneous tissue in the elderly or debilitated person • Loss of sensation • Prolonged static positioning 608 SECTION V Environmental Factors and Pathophysiology is subject to orthostatic hypotension with short periods of dizziness or fainting, pallor and sweating, and rapid pulse whenever the body position is quickly changed. Normally skeletal muscle contractions as part of regular activity assist in returning the venous blood to the heart (“skeletal muscle pump”). Also when the body position changes from supine to upright, reflex vasoconstriction occurs in the skin and viscera to promote venous return. Adequate venous return ensures sufficient cardiac output to supply the brain and prevent a drop in blood pressure and fainting. When a patient becomes mobile after a prolonged period of bed rest, it may take several weeks for the reflex controls to return to normal, ensuring adequate circulation. Other problems occur when the blood pools in dependent areas. The increased volume of blood in these areas leads to increased capillary pressure and edema (see Chapter 2). A persistent increase in inter- stitial fluid (edema) leads to reduced arterial flow and capillary exchange of nutrients in that dependent area, thus predisposing the person to tissue necrosis, ulcers, and infection in the area. Even if a small area such as an arm is immobilized, the limb should be elevated to reduce edema. The stasis or pooling of blood associated with immobility promotes thrombus formation in the veins, particularly in the legs. In addition to sluggish blood flow and decreased venous return, blood clots may be encouraged by compression or damage to blood vessels resulting from pressure related to the body position in bed or a wheelchair. Action of skeletal muscles, such as the contractions of the calf muscles, compresses the major veins in the legs aiding in the venous flow back to the heart. Blood clotting is also encouraged in patients with dehydration or cancer by the increased coagulabil- ity of the blood associated with these conditions. The combination of three factors—venous stasis, hyperco- agulability, and blood vessel damage—is known as the Virchow triad; when present, these factors dramatically increase the chances of a deep vein thrombosis. Thrombi are a threat because a thrombus may break away with movement or massage, resulting in a pulmonary embolus, which has serious consequences for respiratory and cardiovascular function (see Chapter 13). Depending on the primary problem, antiembolic stockings, exercises, or anticoagulant therapy may be helpful prophylactic measures. Respiratory System Effects Initially when a person is immobilized, there is less demand for oxygen because metabolism is decreased, unless some factor such as infection is increasing the resting rate of metabolism or basal metabolic rate (BMR); therefore the respiratory system can easily meet the body’s requirements. Usually respirations become slow and shallow. FIG. 25.2 Decubitus ulcer. (From Callen J, Greer K, Hood A, et al: Color Atlas of Dermatology, Philadelphia, 1993, Saunders.) THINK ABOUT 25.2 a. Explain why an elderly person confined to a wheelchair might develop decubitus ulcers. b. Suggest several specific ways of reducing the risk of skin breakdown and ulceration. • Mechanical irritation or friction by clothing, braces, or other equipment • Excessive moisture from perspiration or urine • Poor personal hygiene • Inadequate nutrition or hydration • Trauma to the skin due to friction against clothing or sheets if a patient is moved without due care or slides down in bed, or if skeletal muscle spasms occur; adhesive tape may irritate the skin directly or indirectly when it is removed Pressure ulcers are difficult to heal unless the predisposing conditions can be removed. The affected area first appears red, and then superficial skin breakdown is apparent. Ulceration follows, and the area may become a purplish red color if the damage is deep. Eventually necrosis destroys deeper tissue, and a large open area develops with full-thickness damage. Local infection is common. The risk of skin breakdown can be reduced if sensitive areas are protected by sheepskin pads or flotation devices and the patient’s position is changed frequently to avoid prolonged pressure in certain areas, thereby maintaining adequate circulation. Cardiovascular System Effects Initially when a person is fully immobilized, the horizontal body position leads to more blood returning to the heart from the legs. Blood pools in the trunk, especially in the lungs. Initially this increased venous return leads to an increased intracardial pressure, increasing the heart rate and stroke volume. With prolonged immobility and bed rest, venous return and cardiac output are reduced, and the patient CHAPTER 25 Immobility and Associated Problems 609 When a person is inactive, appetite is often reduced, leading to decreased dietary intake. This may result in a negative nitrogen balance (protein deficit), especially when muscle tissue is breaking down. The protein imbal- ance contributes to a low hemoglobin level and delays in healing. Unfortunately, the decreased food intake usually aggravates fatigue and depression, which further decrease appetite and ultimately may cause malnutrition and further delays in healing and recovery. New liquid products to deliver adequate calories and nutrients are somewhat easier for the immobilized person to consume. If normal nutrition cannot be maintained orally, it may be necessary to use total parenteral nutrition (TPN), in which the required nutrient solution is administered directly into a vein or via a nasogastric tube. In some cases immobility can lead to obesity. When a person is inactive, caloric intake can quickly exceed the energy expended. Also there may be an increase in snacking as a result of stress and discomfort. Urinary System Effects Stasis of urine in the kidneys or bladder frequently causes infection or renal calculi (stones) to develop in the urinary tract (see Chapter 18). A supine position leads to residual urine in the calyces of the kidney in the dependent area because normal drainage by gravity into the ureter is impeded. It is also difficult to empty the bladder com- pletely into a bedpan when one is supine or the muscles are weakened. Renal calculi are more likely to develop in people with hypercalcemia caused by prolonged immobility or with reduced fluid intake. Bladder infection (cystitis) is common in immobilized people if calculi form or catheters are used to drain the urine. Another potential effect on the urinary system involves an increase of diuresis, leading to dehydration. A blood shift into the thorax can potentially stimulate release of atrial natriuretic peptide (ANP) from the heart, which acts as a powerful diuretic. This blood shift can also stretch the aortic arch and receptors in the carotid sinus, which reduces antidiuretic hormone (ADH) release. This reduction in ADH will reduce the reabsorption of water by the kidneys, which further increases the diuretic effect of the ANP and increases the overall urine output, which can lead to dehydration. Neurologic/Psychological Effects Prolonged pressure on the skin and underlying tissue as well as resultant tissue damage can activate pain sensations, as sense receptors such as exteroceptors, mechanoceptors, or nociceptors are stimulated. Over time the continued pressure can cause serious local tissue damage that can destroy the nerves, resulting in a new sensation of tingling in the affected area and eventually a total loss of feeling in the area. Damage to the nerves and innervation of the muscles can also result in spasms. When the person is supine in bed, deep breathing and coughing become more difficult because body weight and the upward pressure of the abdominal contents against the diaphragm restrict chest expansion. Gas exchange is decreased as thoracic capacity is reduced and ventilation is diminished. Any muscle weakness will impair the effectiveness of respiratory efforts. Many drugs, including sedatives (to promote sleep and reduce anxiety) and analgesics (to control pain), depress neuromuscular activity and the respiratory control center, leading to slowed, shallow respirations. When a person is immobilized, secretions build up in the airways and are difficult to remove because the cough mechanism is less effective. Ciliary action may be reduced if nutrition is impaired or the patient is a smoker. Other factors leading to increased secretions in the lungs include more-viscous mucus due to dehydration and inflammation due to instrumentation, related to surgery or testing procedures. Increased fluids in the lungs further impair lung expansion. Stasis of secretions predisposes the patient to serious respiratory complications. The increased mucous secretions frequently lead to infection (hypostatic pneumonia; see Chapter 13) or obstruction of the airway and collapse of the lung (atelectasis). Pneumonia and atelectasis may also result from aspiration of food or water intake, which occurs more easily when the patient is immobilized or in a supine position. Normally in the upright position, gravity assists the rapid movement of food down the esophagus. Respiratory therapy, including breathing exercises, may be helpful and are frequently part of the preoperative preparation. Personal respirometers provide an incentive for patients to improve their ventilation capacity before and after surgery. THINK ABOUT 25.3 Explain why pneumonia is a common occurrence in immobilized persons. Digestive System Effects The major problem associated with immobility and the gastrointestinal tract is constipation. Elimination is affected by the slower passage of feces through the intestine due to muscle inactivity and body position, which results in a harder stool. In people who are ill, the intake of food, fiber, and fluid is often reduced, leading to reduced peristalsis in the intestine and more water absorption from the fecal mass. Weakened muscles make defecation more difficult, as does the awkwardness of using a bedpan in a supine position. The elderly patient is particularly vulnerable to bowel complications. In addition to using appropriate laxatives, an increase in fiber and fluid intake will reduce the problem of constipation in the patient with decreased activity. 610 SECTION V Environmental Factors and Pathophysiology C H A P T E R S U M M A R Y Immobility may involve one part of the body (eg, a limb) or a major portion of the body, and it may be temporary or permanent. • Effects on muscle and bone develop within a short period. Skeletal muscle atrophies with loss of strength and mass, osteoporosis occurs, and contractures may arise. • Skin breakdown or decubitus ulcers develop easily, particularly where pressure causes ischemia after the person remains in one position for a long time. • Orthostatic hypotension and thromboembolism are two problems associated with cardiovascular function. • Deep breathing and cough effectiveness may be restricted by immobility, predisposing to stasis of secretions in the lungs, followed by pneumonia. • Reduced peristalsis associated with immobility fre- quently leads to constipation. • Immobility may predispose to urinary stasis, renal calculi, infection, and dehydration • Immobility can cause the stimulation of sensory recep- tors in the skin and affected tissue leading to pain. • Growth in children is frequently delayed during periods of immobility. In addition to the psychological effects of pain, the person’s lack of control over his or her environment can have negative psychological effects. These effects include depression, anxiety, confusion, and forgetfulness. The overall increased levels of stress involved in immobility has been linked to the release of stress hormones such as corticosteroids, which can result in widespread physi- ologic changes affecting an individual’s overall health. THINK ABOUT 25.4 Explain how immobility may affect the urinary system to produce a systemic as well as local effect. CASE STUDY A Trauma and Immobility L.D. is a 27-year-old man who has no chronic health problems. He prides himself on keeping fit and enjoys “living on the edge.” Last weekend he was thrown from his motorcycle when it spun out on a wet patch of pavement. In the emergency department, he was diagnosed with fractures of the left tibia and ribs. He reported being in pain and having difficulty breathing. He was discharged with a full leg cast and medication for pain to be taken every 4 hours as needed. He was told not to bear any weight on his affected leg and was shown how to walk with crutches. 1. How will L.D.’s broken ribs affect his respiration, and what potential problem may occur if L.D. does not follow instructions to breathe deeply and cough? 2. How does the pain medication affect his ability to deep-breathe and move? 3. How will L.D.’s lifestyle, health habits, and age affect healing of the damaged tissues? 4. L.D.’s pain medication makes him nauseated. Why is it important for him to maintain a diet high in calcium, protein, and vitamins C and D? 5. L.D.’s skin itches under the cast, and he finds this very irritating. On one very hot day, he resorts to inserting his mother’s knitting needle under the cast to scratch the skin. Why are skin breakdown and infection greater risks in the cast limb? 6. After 4 weeks L.D.’s cast seems quite loose and it is replaced with a new walking cast. L.D. is distressed to see that the leg is thinner than it was. What is the cause of the change in the size and shape of L.D.’s fractured leg? 7. What problems is L.D. likely to experience when the cast is finally removed from his leg? Effects of Immobility on Children When children are immobilized for an extended period of time, normal growth is often delayed because the physical movement to stimulate bone and muscle develop- ment is lost. Catch-up growth may be possible when mobility returns. Depending on the underlying condition, deformities involving the hips, spine, hands, and feet may develop. Other developmental delays are common when sensory and experiential stimulations are decreased. S T U D Y Q U E S T I O N S 1. Explain how immobility affects the circulation. 2. Give several reasons why healing may be delayed during a period of immobility. 3. Explain how frequent changes of position would affect the following: a. the amount of interstitial fluid in an area b. respiratory function c. the skin 611 Review of the Stress Response Stress and Disease Potential Effects of Prolonged or Severe Stress Coping With Stress Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Describe the stress response. 2. Explain how the stress response is related to diseases. 3. Describe how severe stress may lead to acute renal failure, stress ulcers, or infection. 4. Suggest positive coping strategies. L E A R N I N G O B J E C T I V E S bronchodilation endorphins homeostasis lipolysis maladaptive physiologic K E Y T E R M S C H A P T E R 26 Stress and Associated Problems Review of the Stress Response The stress response is a generalized or systemic response to a change (stressor), internal or external. The response may be modified or altered in specific situations. The role of stress in disease became more firmly established in the 20th century, when Hans Selye, in 1946, defined the general adaptation syndrome (GAS), or “fight or flight” concept. His work revealed that the body constantly responds to minor changes in its needs or environment, such as altered food take or activity level, and thus maintains homeostasis. The body has built-in mechanisms that quickly compensate for physiologic changes in fluid balance or blood pressure. Minor fluctuations in body functions are normal. A stressor is any factor that creates a significant change in the body or environment. It may be physical or psy- chological or a combination of the two. A stressor may be a real, anticipated, or imagined short-term or long-term factor. Possible stressors include pain, exposure to cold temperatures, trauma, anxiety or fear, a new job, infection, or, indeed, even a joyous occasion. Stress is considered to occur when an individual’s status is altered by his or her reaction to a stressor. The stress response is the generic but complex response made by the body to any stressor. The body’s physiologic response to different types of stressors is the same, although the response may vary in intensity and effects in a given situation or person. An additional, specific response may occur with certain stressors; for example, infection may initiate a fever. Each person may perceive stressors differently. A certain stressor for one individual may be mildly exciting or stimulating, but for someone else the same stressor may be deeply depressing. It may even cause illness in another person. If the individual can cope with the stressor, the body returns to its normal status, but if the person cannot adapt, harmful effects may result from the stress. This may be termed distress. Stressors are a normal component of life and can be a positive influence on the body when appropriate coping mechanisms function well. Stressors may stimulate growth and development in many ways. Without any changes or stressors in life, a person would merely exist in a dull, inert, unresponsive form. But if a stressor is extremely severe or is perceived as a very negative influence, or when multiple factors effect change at one time, the body’s adaptive mechanisms may not suffice. Then the body systems become more disrupted, maladaptive or 612 SECTION V Environmental Factors and Pathophysiology These activities increase the general level of function in critical areas of the body such as the brain, the heart, and the skeletal muscles by mechanisms such as increasing oxygen levels, increasing circulation, and increasing the rate of cell metabolism. Short-term stressors, mild or moderate, appear to enhance cognitive function and short-term memory. The stress response also increases the release of endorphins, which act as pain-blocking agents (see Chapter 4). In most cases, the body responds positively, the stressor is dealt with, the stress response diminishes, and body activity returns to normal. Additional distress results if the state of stress is severe or prolonged, or if the indi- vidual’s adaptive mechanisms are impaired for some reason. In some cases, when an illness requires additional treatment, such as hospitalization or physiotherapy, extra stressors are added that may overwhelm the patient. For example, hospitalization may give rise to fear and pain or to anxiety associated with separation from the family or job, change in routine and diet, and loss of privacy and control over one’s life. In other cases, hospitalization may offer positive relief from the burden of illness. With major or prolonged stress, intellectual function and memory are frequently disrupted. One factor related to the change is the large number of glucocorticoids released because memory impairment has been shown to occur in persons taking large doses of glucocorticoids. inappropriate behavior can occur, and homeostasis is not possible for that person. Factors such as aging or pathologic disorders may interfere with an individual’s ability to respond adequately to a stressor. A vicious cycle may develop when the original stressor remains, and the effects of this stressor prevent the body from coping with new stressors. In some cases, more damage results, adding to the stress and lessening the person’s coping capabilities even further, thereby decreasing the probabil- ity of a return to normal status. In the same way, maladap- tive behaviors such as ignoring the stressor or eating unwisely are likely to add additional problems without removing the original stressful factor. THINK ABOUT 26.1 a. Give examples of nonphysical stressors that can result in physiologic responses. b. Describe several coping mechanisms that can be used in dealing with physical stressors. c. Describe several coping mechanisms that can be used in dealing with psychological stressors. THINK ABOUT 26.2 a. Using your knowledge of normal physiology, explain the probable source of the increased glucose level in the blood with stress. b. Name the organs in which vasoconstriction occurs and blood flow diminishes during a stress response. Name the areas that have increased blood flow. c. State two ways by which oxygen supplies to the brain may increase during a stress response. d. List the hormones released during the stress response and two significant actions for each one. Selye originally defined three stages in the stress response (GAS): • In the alarm stage, the body’s defenses are mobilized by activation of the hypothalamus, sympathetic nervous system, and adrenal glands. • In the second, or resistance stage, hormonal levels are elevated, and essential body systems operate at peak performance. • The final stage, or stage of exhaustion, occurs when the body is unable to respond further or is damaged by the increased demands. Extensive research into various aspects of stress has followed Selye’s work. It has been found that the stress response involves an integrated series of actions, including the hypothalamus and the pituitary gland, the sympathetic nervous system, the adrenal medulla, and the adrenal cortex. The locus ceruleus, a collection of norepinephrine- secreting cells in the brain stem, provides the rapid response in the nervous system. Any type of stressor immediately initiates a marked increase in adrenocorti- cotropic hormone (ACTH) secretion, followed by a great increase in cortisol secretion. The major actions are summarized in Fig. 26.1. Significant effects of the stress response include the following: • Elevated blood pressure and increased heart rate • Bronchodilation and increased ventilation • Increased blood glucose levels (resulting from glycogenolysis and gluconeogenesis in the liver and protein catabolism in muscle as well as lipolysis) • Arousal of the central nervous system • Decreased inflammatory and immune responses (cortisol reduces the early and later stages) Stress and Disease Greater than 40% of all adults experience adverse effects from stress, and 75% to 90% of doctor’s office visits are for stress-related problems and complaints. Stress may cause a specific problem such as a headache, which may develop during a stress response or, in some persons, as the stressor is relieved. Prolonged vasoconstriction may cause inflammation and necrosis that result in stomatitis (ulcers in the mouth) and necrotizing periodontal disease (Fig. 26.2), or nausea. More severe complications may arise if reduced blood supply impairs function or causes necrosis in the gastrointestinal tract or kidneys. In some patients who have preexisting pathologic conditions, a stress response may become an additive or exacerbating CHAPTER 26 Stress and Associated Problems 613 life crisis, which suggests that the immune system has been depressed. In many chronic disorders stress is an exacerbating factor. The stressor may be physical or emotional. For example, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, asthma, acne, ulcerative colitis, and eczema are some conditions that usually become more acute when a stressor is present. It is important for a person with a chronic illness to develop improved coping mechanisms and an adequate support system to delay exacerbations or progressive degeneration in chronic illness. PROCESS POSSIBLE COMPLICATIONS STRESSOR CNS ACTIVATED HYPOTHALAMUS LIMBIC SYSTEM CEREBRAL CORTEX Norepinephrine released at SNS nerve endings ADRENAL MEDULLA Norepinephrine Epinephrine (catecholamines) released into circulation activates SNS nerve endings CRF ANTERIOR PITUITARY POSTERIOR PITUITARY ACTH ADRENAL CORTEX Cortisol (glucocorticoids) OTHER FEEDBACK MECHANISMS ADH • Water reabsorbed • Blood volume • BP Hypertension Tension headache Insomnia Diabetes mellitus Infection Heart failure Peptic ulcer Fatigue CNS stimulation STABILIZE CVS • Enhance catecholamine action Allergic response decreased EFFECTS Norepinephrine Epinephrine Heart rate + force increased • BP Vasodilation Skeletal muscle • Function Glycogenolysis Lipolysis Gluconeogenesis • Blood glucose CNS stimulation • More alert • Muscle tone Vasoconstriction • Skin — Pallor • Viscera — Kidneys — GFR — GI mucosa — Nausea • BP Bronchodilation • O2 Aldosterone (mineralocorticoid) • Retain Na+ and water • Blood volume • BP Gastic secretion Ulcers Protein catabolism Gluconeogenesis • Blood glucose • Serum amino acids • Delayed healing Inflammatory response decreased • WBC Immune response decreased • Atrophy of lymphoid tissue • Lymphocytes • Antibody production SNS FIG. 26.1 The stress response. ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; BP, blood pressure; CNS, central nervous system; CRF, corticotropin-releasing factor; CVS, car- diovascular system; GFR, glomerular filtration rate; GI, gastrointestinal; SNS, sympathetic nervous system; WBC, white blood cell. factor, creating an acute complication or adding to the severity of the original disorder. For example, elevation of blood pressure or cardiac dysrhythmia (irregular heart rate) resulting from a stress response may seriously aggravate the condition of an individual with a damaged heart. Stress has been shown to be a precipitating factor in several disorders. Chronic infections such as herpes simplex (cold sores) often erupt when the person is stressed. Acute asthma attacks or a seizure may be trig- gered in some individuals by a stressful situation. The onset of cancer or an infection frequently follows a serious 614 SECTION V Environmental Factors and Pathophysiology BOX 26.1 A Selection of Stress-Related Disorders Gastrointestinal System Peptic ulcer, stress ulcers Ulcerative colitis Regional ileitis Nausea, diarrhea Stomatitis, periodontitis Nervous System Multiple sclerosis Seizures Depression Cardiovascular accident (CVA; stroke) Respiratory System Asthma Musculoskeletal System Rheumatoid arthritis Cardiovascular System Hypertension Angina Congestive heart failure Skin Herpes simplex Eczema Acne Urinary System Acute renal failure Cirrhosis due to alcohol abuse Other Cancer Infection Autoimmune disorders Obesity FIG. 26.2 A possible effect of stress in the oral cavity: inflammation and necrosis (necrotizing periodontal disease seen in young adults at academic examination time). (Courtesy of Evie Jesin, RRDH, BSc, George Brown College, Toronto, Ontario, Canada.) In some diseases such as hypertension, coronary artery disease, and diabetes mellitus, stress is thought to be an etiologic factor. It has been noted that serum cholesterol is elevated during stress, and the reactive vasoconstriction affects blood pressure and blood vessels when stress is sustained. A brief selection of stress-related disorders is presented in Box 26.1. Potential Effects of Prolonged or Severe Stress Severe stress may lead to a variety of serious complica- tions, such as renal failure or perforating stomach ulcers. Acute renal failure results from prolonged severe vaso- constriction and reduced blood supply to the kidney. Reduced blood supply causes tubular necrosis, obstruction of filtrate flow, and cessation of glomerular filtration or shutdown (see Chapter 18). In some cases, permanent kidney damage results. Stress ulcers may develop with severe trauma; a good example is a Curling ulcer, which is associated with burns. Stress ulcers are multiple gastric ulcers, often asymptomatic, but nevertheless dangerous because they frequently manifest with gastric hemorrhage (see Chapter 17). Several factors in the stress response contribute to ulcer formation. Intense vasoconstriction in the gastric mucosa decreases mucosal regeneration and mucus production, decreased motility causes stasis of chyme in the stomach, and the catabolic effects of glucocorticoids delay tissue regeneration—all of which contribute to ulcer formation. When possible, preventive measures are taken to reduce the risk of complications from severe stress. For example, to prevent acute renal failure, caregivers promote fluid flow through the kidneys by encouraging increased hydration, and physicians order drugs that dilate the renal arterioles and thus protect renal function. To guard against stress ulcers, medications may be administered to protect the gastric mucosa and reduce acid secretions, thereby preventing ulcer development. Another potential complication of severe stress is infection, which is related to depression of the inflamma- tory response and the immune system by increased cortisol secretion. Because these body defense mechanisms are reduced, opportunistic infections may develop, and the person becomes susceptible to infection by unusual organisms that are not normally pathogenic (see Chapter 7). The lack of an inflammatory response may mask the signs of infection until it is well established. In time, lymphoid tissue atrophies, and the circulating leukocytes are reduced in number and function. The increased incidence and growth of malignant tumors associated with severe stress have also been linked with the decreased efficiency of the surveillance function of the immune system. Continued stress may impede the healing of tissue following trauma or surgery. Two major factors are involved. First, the increased amounts of cortisol reduce CHAPTER 26 Stress and Associated Problems 615 • A relatively constant blood supply to the brain prevents mood swings and reduces irritability • Engaging in distracting activities for a time and then assessing the problem more objectively • Counseling and support services • Using relaxation techniques, imagery, biofeedback therapy, and music and art therapy • Using antianxiety medications (minor tranquilizers such as lorazepam [Ativan] for a short period of time) (These medications must be used with caution because even low doses can have adverse side effects such as drowsiness, memory loss, impaired judgment, confu- sion, nausea, and lack of energy.) • Undertaking a methodical approach, assessing options or goals, and making immediate decisions Just as each person perceives stressors differently, each must develop an individualized set of coping mechanisms, and these skills will probably have to be modified periodically. It is a good idea to recognize any tendency toward maladaptive behavior at an early stage in the response to stress. Avoiding sleep, eating junk food, drinking too much coffee, and smoking constantly are behaviors that are more likely to add stress than to alleviate it. protein synthesis and tissue regeneration; second, the increased catecholamine levels lead to vasoconstriction, reduced blood supply, and reduced delivery of nutrients to the traumatized area. In some cases, these effects lead to an increased risk of infection and increased amounts of scar tissue at the site of the trauma or the surgery. Posttraumatic stress disorder (PTSD) has been recog- nized as a serious consequence of a major disaster. It was first recognized in war veterans and now has been diagnosed in individuals involved in catastrophic events or personal trauma. This syndrome usually occurs within 3 months of the event, but it may cause symptoms years later. Three categories of symptoms may occur: revisiting or reliving the event, avoidance of certain activities and a lack of emotional response, and a dissociative state in which the person is nonresponsive. There is also a high risk of the person with PTSD developing a dependence on drugs or alcohol. With treatment, symptoms usually resolve in 6 months, but in some cases symptoms persist or reoccur for several years. THINK ABOUT 26.3 Explain how reduced blood flow in an area can interfere with healing and increase the risk of infection. Coping With Stress To prevent stress from becoming a negative influence on the body, it is important for each individual to recognize stress-inducing factors and discover the best way to deal with them, both emotionally and behaviorally. People must take appropriate action to solve the problem or develop improved coping mechanisms if the stressor cannot be removed. For many people, this is easier to say than to do, especially when a stressor becomes overwhelming or when multiple stressors develop. Fatigue, age, inadequate nutrition, insufficient knowledge, and lack of emotional support are among the factors that may interfere with an appropriate response. A support system, even short term, is essential to minimize the risk of developing pathologic effects caused by stress. Strategies may include the following: • Ensuring adequate rest and a healthy diet • Changing one’s lifestyle in order to adapt to the new situation • Adopting a regular moderate exercise program that assists in controlling stress, particularly if it is under- taken at a time when stress levels are high: • Aerobic exercise such as cycling, swimming, or running is useful to release muscle tension and improve circulation as well as to provide a distraction • During aerobic exercise, the body uses more fats for energy, and therefore blood sugar levels remain more stable CASE STUDY A Situational Stress Response L.D. is a 13-year-old healthy teenager who is very anxious about getting her wisdom teeth removed by the dentist. She is afraid that the dentist will use a needle to “freeze” her mouth. In the past, she has felt light headed and dizzy when receiving routine immunizations in the doctor’s office. Her mother thinks that L.D.’s anxious behavior is silly and tries to reassure L.D. on the drive to the dental office that everything will be fine. The dental office is quite busy and the receptionist states that the dentist has had an emergency patient and there will be a delay before L.D. will be seen. L.D. waits 30 minutes for her appointment. 1. What stressors are present for L.D.? 2. How will the delay affect L.D.’s stress response? What could reduce L.D.’s stress during the wait? 3. When L.D. is finally called by the receptionist, she gets up and immediately feels like she is going to faint. Which change in the nervous system is responsible for her hypotension? Is this part of the usual response to stressors? 4. She is sweating and her pupils are dilated. What specific changes have occurred to cause these manifestations? 5. L.D.’s mother tells her to “calm down” and “be brave.” How would this likely affect the stress L.D. is experiencing? The dentist reassures L.D. that she will use a mask to deliver the anesthetic rather than a needle, and L.D. agrees to go ahead with the procedure. L.D. has four teeth extracted and is sent home. At home she experiences pain and stiffness in her jaws. 1. How will continued pain and stiffness affect tissue healing and recovery? 2. What can L.D. do to reduce her stress the next time an invasive procedure is scheduled? 616 SECTION V Environmental Factors and Pathophysiology C H A P T E R S U M M A R Y The basic stress response is the same in all situations, with variations depending on the specific stressor or cause. Stressors are a normal part of life. • The stress response is considered to include three stages—alarm, resistance, and exhaustion—involving the activities of the hypothalamus, pituitary, sympa- thetic nervous system, and adrenal glands. • Stress may cause minor problems such as headache, may precipitate a more serious problem such as a seizure or cancer, or may exacerbate a chronic illness such as ulcerative colitis. • Severe prolonged stress or multiple stressors may have serious consequences such as the development of a peptic ulcer or acute renal failure. • An individual can resolve stressful situations in a positive manner and return to a normal state using appropriate coping mechanisms. S T U D Y Q U E S T I O N S 1. List the factors or mechanisms in the stress response that contribute to increased oxygen supplies for the cells, and explain how each factor contributes to the stress response. 2. Describe a recent stressor in your life and the stress response that followed it. 3. List some disorders that are stress related. 4. Describe two potential complications of severe stress. 5. Why are maladaptive coping mechanisms such as excessive eating or alcohol intake not helpful? 617 Terminology Predisposing Factors Environmental/Behavioral Risk Factors Indications/Recognition of Abuse Potential Complications of Substance Abuse Overdose Withdrawal Effects on Pregnancy Cardiovascular Problems Infection Neurologic/Psychological Effects Alcohol Cirrhosis (Laënnec Cirrhosis) Nervous System Damage Treatment for Substance Abuse Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Use the appropriate terminology. 2. Discuss the factors predisposing to substance abuse. 3. Identify possible signs of substance abuse. 4. Describe the problems of drug overdose, withdrawal, pregnancy, psychological effects, and infection. L E A R N I N G O B J E C T I V E S chemical dependency depressant euphoria hallucinogens hepatotoxin perception stimulant synergism tolerance K E Y T E R M S C H A P T E R 27 Substance Abuse and Associated Problems Substance abuse, or chemical dependency, is a newer term used to cover the older concepts of addiction, including alcoholism. Substance abuse is a matter of concern to all health care workers. A recent estimate suggests 22.6 million persons use illicit drugs, with marijuana being used by the most people; 17.6 million people experience alcohol abuse problems or alcohol dependency. In the United States in 2009 there were 37,485 drug deaths, which exceeded the number of motor vehicle deaths. The World Health Organization estimates that for every dollar spent in substance abuse treatment, there is a $7 savings in related health care. Social and economic costs are also reduced as people return to productive work in their communities. These statistics do not include individuals abusing legally acquired drugs. This chapter provides a brief introduction to the topic of substance abuse. The World Health Organization has taken substance abuse into its global health priorities and defines it as the harmful or hazardous use of psychoactive substances, including alcohol and illicit drugs. Abuse of chemicals, whether prescribed or illicit, leads to changes in behavior, sleep patterns, and interpersonal relationships. Employ- ment is often precarious as the individual focuses on obtaining the drug as a priority. Most of these chemicals cause serious health problems or death if abuse is not addressed. For example, alcohol- ism leads to cirrhosis of the liver and brain damage. Cocaine causes damage to the heart and brain. Anabolic steroids cause heart disease. People using intravenous drugs can contract hepatitis or human immunodeficiency virus (HIV). Children born to substance abusers are directly and indirectly affected as a result of the par- ent’s substance abuse. Many babies are born addicted and must be supported as they experience withdrawal from the agent. Family dynamics threaten the physical and mental health of the developing child, and there is a higher incidence of substance abuse among children 618 SECTION V Environmental Factors and Pathophysiology • Addiction is an older term but is still in common use and is employed for the most serious form of substance abuse—the uncontrollable compulsion to use a sub- stance, often with serious consequences for the indi- vidual, the family, and society. Substance abuse at this level often involves increased use of the substance and loss of control over use, leading to multidimen- sional issues including health, social, psychological, occupational, and legal problems. of drug abusers. Complications can easily arise in the health care of substance abusers because their diagnostic tests may be distorted and general assessment clouded, unwanted drug interactions may occur, and pathologic processes may be initiated or aggravated by the inap- propriate use of drugs. Substance abuse has implications for the family and employer of the individual as well as for society. Because access to drugs may be facilitated in the work environment, health care workers themselves may be directly involved in substance abuse. Early recognition of dependency can lead to more successful treatment of the problem. Many professional groups, including the health professions, now provide counseling and therapy for those affected by substance abuse in the workplace. Terminology Terminology frequently changes in the area of substance abuse, and there may also be overlap or lack of clarity in some definitions. • Substance abuse, or chemical dependency, is a broad term that refers to the inappropriate or unnecessary (nonmedical) use of drugs or chemicals that impairs a person’s function in some way to some extent. The individual desires the substance because it may cause euphoria, a sense of pleasure (“high”), or may alter one’s perception of reality or decrease one’s awareness of people and the environment. Essentially the drug interferes with the brain’s reward system, increasing the craving for the drug as well as promoting tolerance and dependence. Substance abuse is not limited to illegal or street drugs but may include prescribed drugs or other readily available substances. • Habit means a practice, often involuntary, of using drugs or other substances at regular and frequent intervals. Habit may be associated with either common customs such as constant coffee drinking or cigarette smoking or the use of illegal or street drugs. These terms do not apply to the occasional use on social occasions of a substance such as alcohol when the user feels no need to consume a large amount or to have a drink at regular short intervals. • Dependence includes both physiologic and psychological cravings for the substance. • Physiologic dependence means that the body has adapted to the presence of the drug or chemical so that discontinuing the drug results in withdrawal signs such as tremors or abdominal cramps. • Psychological dependence refers to a continuing desire to take the drug to be able to function. • Tolerance implies that because the body adapts to the substance, in time, the amount of the substance taken must be increased to achieve the same effect. The client who has tolerance to a substance will experience withdrawal if use of the substance is discontinued. THINK ABOUT 27.1 Define the terms tolerance and physiologic dependence. Abused substances may be classified in many ways, including mode of action and source. Under mode of action, commonly abused psychoactive substances include the following: 1. Central nervous system depressants or tranquilizers, such as alcohol 2. Narcotics or painkillers, which cause euphoria and drowsiness 3. Stimulants, such as coffee or amphetamines 4. Psychedelics or hallucinogens, which alter a person’s perception and awareness and produce illusions Some chemicals actually manifest both stimulant and depressant effects. For example, alcohol is really a central nervous system (CNS) depressant, although initially it appears to be a stimulant because it first depresses the higher brain centers used for judgment or the inhibitory neurons. Abused drugs are also classified by source. They include legally prescribed medications. These include but are not limited to tranquilizers or sedatives that are prescribed and used long after the need for them has passed, medica- tions shared with another person, prescriptions acquired from several sources, and medications combined with other substances such as alcohol or nonprescription drugs to achieve the desired effect. The surge in drug deaths has recently been fueled by the increased availability and abuse of prescription painkillers (such as OxyContin) and antianxiety drugs. Prescribed drugs that are consid- ered more addictive or dangerous are restricted by government agencies and are available only for research or with a signed written prescription without refill provi- sions. Heroin and morphine are regulated this way, as are stimulants such as those prescribed for attention deficit hyperactivity disorder. Many psychoactive substances are readily available without restrictions, such as sleep-inducing or wake-up pills; cough syrups; spray paints; decongestants; alcohol- based hair lotions; or glues, nail polish removers, aerosols, and solvents for sniffing or inhaling. These generally provide a short “high” followed by depression and disorientation. Such substances are frequently misused CHAPTER 27 Substance Abuse and Associated Problems 619 Individuals who abuse substances such as alcohol often crave risk or excitement and participate in activities that are inherently dangerous. Driving under the influence or in an impaired state is an example of such behavior. Approximately 40% of all traffic-related deaths are related to alcohol use/abuse. Social limits on behavior are often dampened by the depressive effects of many chemicals leading to impaired judgment and difficulty controlling feelings of anger. Interaction with law enforcement or emergency medical personnel may be unpredictable and carry increased danger to first responders. and have been responsible for a number of suicides and accidental deaths. As a result, substances of this type are kept behind the counter in stores and must be requested. Illegal or street drugs are widely available and are both costly and more dangerous for the user because their content is unpredictable. Usage often leads to overdose or toxic effects caused by adulterating sub- stances. Many street drugs are better known by their common names than by their medical or chemical names. For example, “speed” or “uppers” is the term used for amphetamines, “angel dust” for phencyclidine (PCP), and “snow” or “powder” for cocaine. Methamphetamine is a highly addictive, easily manufactured stimulant and is known as “crank,” “ice,” or “crystal.” It can be sniffed, injected, smoked, or taken orally. It stimulates the body by increasing dopamine levels in the brain but subse- quently damages dopamine-producing neurons in the brain. A high dose causes elevated body temperature and seizures. Heroin is commonly known on the street as “blow.” “Ecstasy” or MDMA, a stimulant, is a designer drug, chemically modified to provide special effects and avoid legal restrictions. Ecstasy imparts a feeling of euphoria and energy. A high dose leads to hyperthermia and heart failure. It is commonly known as “X,” “K,” or “Special K.” A new group of psychoactive drugs has recently appeared on the scene and is referred to as “bath salts.” Not to be confused with harmless bathing type salts, these synthetic cathinones are marketed as cheaper, “safer” substitutes for other stimulants such as meth and cocaine. Deaths have been recorded as a result of cathinone intoxication, and it has been shown, through laboratory testing, to be addictive. The market for illegal drugs has become a matter of concern both economically and socially because of the increased criminal activity and violence associated with drug trafficking. Many street drugs are easily manufac- tured from inexpensive chemicals in simple “laboratories.” Regulations to restrict access to the precursor chemicals required to produce the popular street drugs have been enacted in many countries in an effort to control the source of street drugs. Street drugs are often diluted with contaminants that may be toxic; this practice is done to increase profits and or to make the substance more marketable on the street. It is important that screening is done for both the primary compound as well as known contaminants when treating a drug-induced emergency. Discussion continues about the medical benefits compared with the abuse potential, and the legal versus illegal status of marijuana. An active ingredient, dronabi- nol (Marinol), or delta-9-tetrahydrocannabinol, is available for the controlled treatment of nausea, vomiting, and wasting associated with cancer chemotherapy or AIDS. It is not effective in all patients. Other less definitive areas involve tobacco smoking and the social use of alcohol, for which the concepts of addiction and health risks are not well defined. THINK ABOUT 27.2 Differentiate the effects of stimulants from those of psychedelic drugs. Predisposing Factors Theories regarding the etiology or cause of substance abuse focus on psychological imbalances, personality deficits, biologic abnormalities, dysfunctional interper- sonal relationships, or a combination of these factors. Research considers the role of gender differences in addiction, particularly with respect to women. Questions center on whether the abuse of substances is related to physiologic or socioeconomic factors facing women. Substance abuse has been attributed to the following: • Heredity or genetics • Family systems and practices • Disease • The ready availability of drugs • Stress and increased medical use of antianxiety agents • Increased acceptance of alcohol or marijuana as a recreational tool in all age groups Environmental/Behavioral Risk Factors Unfortunately, substance abuse is becoming more common in young adolescents. The public receives mixed mes- sages about substance abuse from the media. In many publications, both advertising and articles on drug use by high-profile personalities lend a glamorous facade to the abuse. This aura of glamour and excitement influences young people, who respond to peer pressure and the need to express independence among their contemporaries. Recent developments among teens include “M and M” parties in which the contents of parents’ medicine cabinets are raided and combined at the party. Surveys have shown that 55% of those age 12 and older who used prescription drugs for nonmedicinal problems obtained them from friends or family. A handful of the mixture of drugs is taken without any knowledge of what is being consumed. This risk behavior is particu- larly challenging for health care workers because the 620 SECTION V Environmental Factors and Pathophysiology effect than one substance, and combinations also tend to cause more toxic effects. The effects of an individual drug depend on the clas- sification of the drug. Depressants usually decrease the level of CNS function, whereas stimulants increase CNS activity. Generally drugs impair neurologic function in some way—for example, by slowing the reflexes, reducing coordination and judgment, or impairing sensitivity and perception. Information about specific drugs can be found in reference texts on substance abuse or pharmacology. The method of administration may also indicate drug abuse in some people; for example, intravenous use leaves injection marks on the body. General indications of substance abuse include changes in behavior, appearance (eg, eyes), personality, daily living patterns, or work habits. In adolescents, this may include a change in friends, academic achievement, interest in sports, or increase in risk-taking behaviors. Frequently, the person may be defensive, angry, or embarrassed if he or she is questioned about drug intake. The pattern of behavior is that any stress will immediately require a “helpful” pill or a drink. Often a cycle develops in which the person takes a depressant to relax or sleep and then needs a stimulant to wake up. As the need for drug support increases, more secretive behavior may ensue and there may be less personal care of clothes and appear- ance, more excuses for time and performance lapses, stronger efforts to acquire substitute drugs, and eventually criminal activity. Some individuals may become mal- nourished or may develop anemia or infection and ignore normal health needs. It is important for any health care worker to be sensitive to the issue of substance abuse. Caution is advisable when strangers request specific drugs for pain relief—for example, in a dental office. Drugs, including samples and prescription order forms, should not be visible or readily available to clients. Potential Complications of Substance Abuse Overdose Overdose is a common acute problem. Some drugs have a relatively small safety margin, and an increased dose may cause toxic effects or death. Street drugs may be contaminated by other substances, thereby causing unanticipated effects. A common emergency situation develops when a combination of drugs, often including alcohol, results in a stronger reaction (synergism) than the individual components normally cause. Many hospital emergency rooms list alcohol-drug combinations as their major overdose cases and the primary cause of brain damage and death. The barbiturates, which induce sleep, and the narcotics morphine and heroin depress the CNS and compromise respiratory function. These substances may depress respiratory effort to a critical level (very slow and shallow respirations), leading to respiratory combined affects make treatment difficult. Educational measures to reduce substance abuse have not been effective, and both peer pressure and the curiosity factor remain problems in the abuse of substances by young people. The rapid changes and increased complexity of society, the increase in family breakdown, and economic factors including homelessness and job loss have also contributed to the increase in substance abuse. Some individuals use drugs to cope with anxiety and stress because drugs alter one’s mood or perception of reality. Evidence supports the correlation between increased stress and increased substance abuse, and a return to addiction after a period of withdrawal. People who take narcotic analgesics for prolonged periods of time risk becoming dependent because the drugs are addictive, creating a state of euphoria while relieving pain. Narcotics are helpful when medically treating severe pain, particularly in patients with terminal illnesses. Heroin is rarely used medically because of its strong tendency to produce dependency. Research on substance abuse continues in an effort to find not only its cause but also factors related to it and improved methods of prevention and treatment. A more recently developed category of abused sub- stances involves the synthetic anabolic steroids, similar to testosterone, taken by some athletes and bodybuilders. Substance abuse among athletes in competitive sports has been well publicized, and it has spread into the high schools. Abuse also involves many different groups in the general population and increasingly includes females. Some individuals with eating disorders ingest anabolic steroids in order to build muscle mass and enhance performance. Unfortunately, these drugs cause mood disorders, high blood pressure, serious cardiac damage, and liver cancer. There are effects on sexual function, fertility, and appearance as well. Date rape drugs have become another form of sub- stance abuse in which the person who administers the drug gets a rush from the illicit behavior and the abused person may experience physical and psychological trauma. Alcohol is mixed with certain drugs such as flunitrazepam (Rohypnol); gamma-hydroxybutyrate, an easy drug to manufacture; or lorazepam, which depresses the CNS and rapidly causes a deep sleep. No memory of the events after administration is retained. For this reason, it is difficult to bring charges against the abuser or to institute treatment. Indications/Recognition of Abuse Recognizing substance abuse is difficult because the pattern of consumption can vary. A substance may be taken consistently and frequently or in large amounts periodically (such as occurs with binge drinkers). Some individuals are affected by relatively small amounts, whereas others can function quite well with a high intake. Combinations of chemicals usually exert a more marked CHAPTER 27 Substance Abuse and Associated Problems 621 infant after birth. Drugs such as cocaine and barbiturates lead to addiction in the newborn, who then must undergo withdrawal therapy after birth. Cocaine causes maternal hypertension, decreasing the placental blood supply to the fetus and resulting in developmental defects or premature birth. Cardiovascular Problems Cocaine and other stimulants such as amphetamines affect the cardiovascular system, causing irregular heartbeat and increased blood pressure. This may lead to heart attacks, strokes, or heart failure at a young age. Infection Systemic infections such as hepatitis B and HIV are common in drug abusers who share needles and other materials when injecting drugs. Local lesions can also form due to local infection of injection sites. These lesions can later become gangrenous, leading to potential systemic infections. Neurologic/Psychological Effects Hallucinogenic or psychedelic drugs such as lysergic acid diethylamide and PCP lead to an increased but unreal and distorted interpretation of sensory input into the brain with little control over the experience. The user hopes for a pleasant, euphoric experience (a “high”) but may have an unpleasant episode with a combination of acute fear, panic, and depression, increasing the risk of suicide. Many hallucinogens also have physical effects, including increased blood pressure, nausea, and tremors. Ecstasy (MDMA) increases basal metabolism and body temperature and is associated with dehydration and electrolyte imbalances that can lead to cardiac arrest. These drugs also impair memory and distort perceptions and judgment, presenting a high risk to those who operate machinery or drive an automobile while under the influ- ence of the drug. Alcohol Cirrhosis (Laënnec Cirrhosis) Alcoholic liver disease, or Laënnec cirrhosis, develops in persons with chronic alcoholism or long-term excessive alcohol intake. In 2010 there were 15,990 liver disease deaths due to alcoholism. Alcohol is a hepatotoxin, an irritant that causes metabolic changes in the liver cells, leading first to lipid accumulation in the cells (fatty liver), then to inflammation and necrosis (alcoholic hepatitis), and finally to fibrosis or scar tissue formation (see Chapter 17 for a discussion of cirrhosis). Destruction of the liver takes place insidiously, with only mild signs and symptoms until the condition is well advanced and irreversible. failure or cardiac arrest. Antidotes such as naloxone (Narcan), which is given for narcotic overdose, can stimulate the respiratory drive. Although the antianxiety drugs such as diazepam do not cause respiratory depres- sion when used alone, they may cause brain damage and coma when combined with alcohol. Other stimulant drugs, such as Ecstasy, cause marked elevations in blood pressure that frequently result in brain damage. Withdrawal Discontinuing a drug on which the body has become physically dependent results in withdrawal symptoms. The signs of withdrawal may be mild or severe depending on the specific drug used and the amount of drug to which the body cells have adapted. Common signs of withdrawal include irritability, tremors, nausea, vomiting and stomach cramps, high blood pressure, psychotic episodes, and convulsions. It is safer to experience withdrawal under medical supervision in a hospital or detoxification center than on one’s own. THINK ABOUT 27.3 Differentiate between overdose and withdrawal and include their causes and effects. Effects on Pregnancy The pattern of neglect of health and nutrition established in the female substance abuser usually continues during pregnancy, creating serious prenatal concerns for both the woman and her fetus. Many women who are abusing substances do not seek prenatal care because of fear of detection or lack of funds. They often are admitted to the hospital in labor with no prior history of care and generally have a higher risk of perinatal complications. Many chemical substances, including alcohol, can affect the fetus, resulting in congenital defects. Fetal alcohol syndrome is a serious example of fetal damage. The incidence of fetal alcohol syndrome increases with the dose of alcohol consumed and with any nutritional deficits. No safe level of alcohol consumption during pregnancy has been determined, and generally pregnant women are encouraged to restrict or avoid consumption. The newborn child of a woman who has abused alcohol during pregnancy has characteristic physical and facial abnormalities and is cognitively delayed. Alcohol con- sumption late in pregnancy is likely to cause cognitive and behavioral abnormalities more commonly than physical defects in the child. Both cigarette smoking and exposure to second-hand smoke decrease blood flow through the placenta. The consequences of maternal exposure to cigarette smoke include an increase in stillbirths, low birth weight for gestational-age babies, and increased irritability in the 622 SECTION V Environmental Factors and Pathophysiology C H A P T E R S U M M A R Y Substance abuse or chemical dependency in an individual complicates health care because diagnostic tests may be inaccurate, disease may be masked or aggravated, and drug interactions are likely to develop. • Dependency may be psychological, physiologic, or a combination of these factors. • Categories of abused substances include illegal street drugs, prescribed medications, alcohol, and household substances. • Effects of substances include CNS stimulation or depression or hallucinations. • Some indicators of substance abuse are behavioral changes; decreased regard for appearance, family, or work responsibilities; or specific physical characteristics. Nervous System Damage Chronic alcoholism may cause serious nerve damage in the brain owing to a combination of neurotoxicity and malnutrition. A combination of Wernicke syndrome, manifested by confusion, disorientation, and loss of motor coordination, and Korsakoff psychosis, which involves altered personality and amnesia, can occur with long-term abuse. Treatment for Substance Abuse A person suffering an overdose or toxic effect should be treated immediately in an emergency room. Withdrawal from an abused substance should be handled in a medical facility, preferably one with experience in dealing with this problem (eg, a drug detoxification center). Supportive care is required to prevent complications. Clients fre- quently benefit from psychiatric intervention. Family support services and follow-up are also beneficial. Second- ary medical problems such as cirrhosis or pregnancy also require medical supervision. Treatment for any addiction must be individualized and include a holistic approach to all of the individual’s problems. Long-term therapy and support are usually required to maintain abstinence or a significant decrease in use. Therapy may include methadone maintenance pro- grams for heroin dependency. Methadone is a synthetic opioid that prevents withdrawal symptoms, improves function, and lessens the craving for narcotics in depen- dent persons. Methadone is administered in prescribed doses in a controlled situation. Methadone programs have been successful in reducing crimes associated with heroin abuse. Newer treatment for opiate addiction may be administered in oral tablets that can be used without daily clinic attendance. Such programs include monthly monitoring of treatment. Disulfiram (Antabuse) is a deterrent to alcohol use. The drug is taken on a daily basis and causes unpleasant reactions (severe headache, vomiting, difficulty in breath- ing, and visual problems) when the patient ingests even a small amount of alcohol. Initially observed drug therapy may be employed to establish compliance with the treat- ment program. In many persons requiring treatment for substance abuse, malnutrition, particularly protein and vitamin B deficits, is a problem that requires treatment. Counseling and behavior modification therapy are ongoing require- ments. Some corporations have developed rehabilitation programs to assist employees with drug dependency, and some of the health professions have established self-help groups for their own members. Support groups such as Alcoholics Anonymous and Narcotics Anonymous are available for those with dependency problems, as are groups for families of affected persons (such as Al-Anon). In addition, many community agencies can provide guidance and resources. CASE STUDY A Alcohol Abuse Mr. M. is a 40-year-old salesperson with a wife and three teenaged children. He recently began to have a beer at lunch and a few drinks after work to reduce his work-related stress. An economic downturn in the housing industry has reduced the need for new home appliances, and his income and sales record was affected. Several other salespeople were laid off at his firm. He was told that if his sales and attendance records did not improve, he would be fired. He and his wife were constantly arguing about finances and the children’s increasing demands for money. His drinking increased to several beers at lunch and continued drinking after dinner. When he returned to work one day with alcohol on his breath, he was dismissed from his job. He continues to consume alcohol during the day as he attempts a job search. His wife is very concerned, as are his teenaged children. 1. What is the action of alcohol on the CNS, and how has alcohol abuse affected Mr. M.’s ability to deal with customers and his coworkers? 2. Mr. M. states he is a social drinker and “can stop at any time.” How accurate is his self-assessment? 3. What stressors are present in Mr. M.’s case? 4. Why does Mr. M. continue to increase his alcohol intake? 5. What changes in liver function can Mr. M. expect if he continues to drink large amounts of alcohol? 6. Mr. M. complains to his wife that all the stress is causing “indigestion.” How do stress and alcohol consumption affect gastrointestinal function? 7. Why is Mr. M. at greater risk for trauma? Mr. M. is convinced to see his doctor and is referred to a center that helps alcoholics to recover and remain sober. He recovers over the following year and successfully completes job retraining at a local college. Mr. M. is assisted in his job search and settles into work with new colleagues. His relationship with his family improves, and he makes several friends among his coworkers. He celebrates his second year of sobriety with his wife. 8. What behaviors increase the risk of Mr. M. reverting to alcohol abuse? 9. What is the long-term prognosis for Mr. M.? CHAPTER 27 Substance Abuse and Associated Problems 623 • Children of substance abusers are frequently born with congenital defects and a dependency to the substance. • Potential complications for substance abusers include infection, liver disease, malnutrition, CNS damage, and cardiovascular disorders. • Overdose or toxicity is a frequent outcome because the safety margin in the dose is often small, street drugs may be contaminated, and combinations of chemicals are dangerous. • Withdrawal is best accomplished with medical support. S T U D Y Q U E S T I O N S 1. List several factors that are considered to predispose a person to substance abuse. 2. Describe several signs that may indicate the presence of substance abuse. 3. Describe two potential health problems resulting from substance abuse. 4. Explain several reasons why withdrawal requires medical attention. 624 Chemicals Heavy Metals Acids/Bases Inhalants Asbestos Pesticides Physical Agents Temperature Hazards Hyperthermia Hypothermia Radiation Hazards Ionizing Radiation Light Energy Noise Hazards Food and Waterborne Hazards Biologic Agents Bites and Stings Case Study Chapter Summary Study Questions C H A P T E R O U T L I N E After studying this chapter, the student is expected to: 1. Name the sources and types of hazardous materials in the environment. 2. Compare the causes and manifestations of hyperthermia and hypothermia. 3. Describe the effects of different types of radiation. 4. Name the required safety measures in the workplace. 5. Give examples of dangerous insects and animals. 6. Discuss the possible effects of contaminated food and water. L E A R N I N G O B J E C T I V E S demyelination detoxification ecosystems encephalopathy hemolytic anemia leukemia neuritis occlusion paralysis particulate pica seizures solvents syncope tinnitus toxicology tympanic membrane vectors K E Y T E R M S C H A P T E R 28 Environmental Hazards and Associated Problems Many agents in the environment can cause damage to cells and organs in the human body. Frequently the damage occurs slowly as the agent accumulates in the body. Sufficient documentation may have been gathered to enable researchers to discern the correct cause only years later, after signs and symptoms have become apparent. For example, evidence linking cigarette smoking and secondhand smoke to the occurrence of lung cancer has led to widespread bans against smoking in public areas. The substantial increase in childhood cancers and hypersensitivities, including asthma and anaphylaxis, is cause for serious concern about the environment. The National Center for Health Statistics indicates 6.5 million children and 16 million adults in the United States were diagnosed with asthma in 2005. This constitutes almost 8% of the population in the United States and its terri- tories. Puerto Ricans experienced an incidence rate 125% greater than that in non-Hispanic whites and 80% greater than in non-Hispanic blacks. In the 0- to 17-year age group, boys are affected 30% more frequently than are girls; in adults, this relationship is reversed, with 40% more women than men experiencing asthma. The overall death rate for asthma in the United States is 1.4 deaths per 100,000 people, and these deaths match incidence data closely. Hypersensitivities to new chemical substances in the environment have greatly increased. The increased number of chemicals in food processing, synthetic materi- als in buildings and furnishings, and cosmetics and CHAPTER 28 Environmental Hazards and Associated Problems 625 disturbed by the use of pesticides, including those of microorganisms, some of which may become pathogenic, or disease causing. The increased availability of organi- cally grown fruits and vegetables has provided an opportunity for consumers to reduce their exposure to chemicals ingested in food. Tissue damage may result from a large dose in a single incident, or, more often, damage results from repeated exposure to small amounts of the unwanted material. The chemical may cause damage at the site of entry, or it may enter the blood and circulate to other sites in the body. Frequently this process occurs without the knowl- edge of the individual. Normally the liver is responsible for detoxification, or inactivation and removal of foreign chemicals from the body. In many cases, however, these chemicals bypass the liver and are stored in certain tissues, gradually accumulating to dangerous levels over years of exposure. Usually there are no obvious signs of this accumulation. For example, hexachlorophene was widely used in hospitals as well as in homes as an antiseptic in soaps and powders until it was discovered that it was absorbed through the skin, particularly broken skin. Heavy use eventually caused brain damage. Now the use of hexachlorophene is restricted. However, new types of antibacterial soaps are being used extensively, and it may be some years before the effects of these new chemicals are documented. Currently there is increasing concern about children’s exposure to plastics in the environment. Chemicals such as phthalates are used to soften plastics and prevent shattering. Toys, bottle nipples, and soothers made of phthalates have been withdrawn from the market in the United States and Canada, but products manufactured overseas may still contain the banned product. Bisphenol A (BPA) is a hardening agent used in plastic baby bottles and water bottles. This chemical has been classified as a toxin by the Canadian government. The concern about such plastics relates to their ability to mimic hormones such as estrogen and act physiologically within the tissues. It is thought that such endocrine disrupters can lead to infertility and promote the growth of endocrine-sensitive cancers. There is also increasing concern about chemicals and regulation of the menstrual cycle and reproduction in women. Surveys link exposure to solvents to increased risks in women for altered menstrual cycles, spontaneous abortions (miscarriages), and stillbirths. Chemicals may affect the body in different ways. Chemical substances often injure cells directly by damag- ing the cell membrane and causing swelling and eventual rupture of the cell. This results in inflammation and necrosis in the tissue. Some chemicals alter the metabolic pathways in the cell, leading to degenerative changes. Many chemicals are carcinogenic—that is, they cause mutations of the cell and lead to the onset of cancers such as leukemia. A few examples of dangerous chemicals are described in the following section. toiletries is of concern. The security of water and food supplies from chemical and microbial contamination is of concern in all areas of the world. Many of these chemicals cannot be metabolized in the body, increasing the level of toxins in the cells. Physical factors also play a role in environmental disease; awareness of the role of sun exposure in combination with chemical exposure is increasing. Only in recent years have additional safety procedures been instituted in the workplace and the environment to protect individuals from some of these hazards. Regula- tions have been established for the different work environ- ments to include health care facilities and various industrial facilities. The Occupational Safety and Health Administration (OSHA) in the United States has made great advances to ensure safe work environments. In Canada, the federal government has instituted mandatory training about hazardous materials in the workplace (Workplace Hazardous Materials Information System [WHMIS]) and the precautions required for storage, handling, and use. These regulations cover areas such as infection control, protective equipment, exposure to harmful substances, and hazardous material. For example, improved ventilation systems may be required in factories, or soil in certain areas may be tested for contaminants before new housing is constructed. In many places, safety-monitoring groups have been established, and unions and workers cooperate in providing training programs that supply information about the standard symbols used for hazardous materials and the precautions recommended for handling them. To increase awareness of the role of these agents in pathologic processes, a few examples of diseases arising from environmental hazards are presented here. Additional information can be found in toxicology texts or environmental references. Every worker should feel free to question potential risk factors in the workplace or living environment. Chemicals Unwanted chemicals may be ingested in contaminated food or water, inhaled into the lungs, or absorbed through the skin. Exposure may occur in the workplace, at home, or during travel. Industrial wastes may have contaminated food and water; for example, freshwater fish may absorb mercury in lakes and rivers. It now appears that farmed salmon may contain toxic chemicals contained in feed. Some water processing plants test for more than 300 chemicals, including PCBs, DDT, and dioxin, as well as lead and mercury. It is not unusual for chemical wastes to remain in the original dangerous form; alternatively, they may undergo transformation into more toxic materi- als or break down into harmless substances. For example, although pesticides may remain in the environment for a long time, some, such as DDT, do not break down into harmless chemicals, and therefore high levels gradually accumulate in the environment. Many ecosystems are 626 SECTION V Environmental Factors and Pathophysiology be found in numerous household products as well as in labs and manufacturing facilities. In addition to acids and bases, strong oxidizers, reducing agents, and solvents can also cause chemical burns. Treatment will depend on the specific chemical causing the burn. In general first aid involves rinsing off the chemical with water or a neutralizing solution. In some cases involving lipophilic chemicals such as hydrofluoric acid, the burn symptoms may not be immediately obvious but may appear hours later. Inhalants Inhalants can be classified as particulate, such as asbestos and silica, or gaseous, such as sulfur dioxide and ozone; or they may arise from solvents, such as carbon tetra- chloride. Although local irritation of the eyes and nose is often noticeable when exposure occurs, the inflamma- tion of the respiratory tract and the effect on the central nervous system are not immediately apparent. Some inhaled or aspirated solvents such as carbon tetrachloride diffuse into the circulation and eventually cause inflam- mation of the liver cells and irreversible hepatic damage as well as pneumonitis. Other inhalants affect the lung tissues directly. Sources of toxic inhalants include factories, laboratories, mines, insecticides, and aerosols. Paints, glues, furniture, and floor coverings supply irritants in the home. Smog is visible air pollution that contains both noxious gases, such as hydrogen sulfide, and particles from dust and smoke. Beginning in the late 1990s, the poor ventilation in crowded airplanes raised concerns about risks to passengers and crew from inhaled substances and infec- tious agents as well as lower oxygen levels. Many office and apartment buildings do not supply sufficient fresh air to the interior. Iron oxide and silica are examples of inhaled particles that frequently cause lung damage in workers in mines or other industries using these substances. These chemicals can cause episodes of acute inflammation, or they may lead to low-grade chronic inflammation, resulting in fibrosis in the lung. More information on chronic lung disease is found in Chapter 13. Also, chronic cough and frequent infections result from the irritation and inflam- mation of the respiratory mucosa and may lead to additional damage. Geographic areas with heavy pollution demonstrate an increased incidence of chronic lung disease. Many of these particles are carcinogenic and increase the risk of lung cancer. Many gases such as sulfur dioxide also cause inflam- mation in the lungs. Carbon monoxide, which results from incomplete combustion (eg, automobile exhaust), is not a threat in small amounts for healthy people; but because it displaces oxygen from hemoglobin, it can be dangerous for individuals with cardiovascular or respiratory disease. Carbon monoxide remains bound to hemoglobin for significant periods of time and can lead to a fatal decrease in oxygen supply if exposure is Heavy Metals Lead and mercury are examples of heavy metals that can accumulate in the tissues with long-term exposure. Lead can be ingested in food or water or inhaled and is then stored in bone. Lead is heavily used in industry and is found in lead pipes and batteries. It is also a common childhood poison because children tend to chew on items covered with lead-based paint, such as toys or furniture, and they ingest paint flakes from walls or woodwork. There have been widespread recalls of common toys manufactured offshore because of the use of lead paints. Lead has been found to vaporize over time from some imported (and unregulated) vinyl window blinds. Individuals with pica (the craving for nonfood substances such as clay) may also develop high blood levels of lead. The toxic effects of lead include the following: • Hemolytic anemia (destruction of erythrocytes leading to low hemoglobin levels) (Fig. 28.1). • Inflammation and ulceration of the digestive tract (lead colic). • Inflammation of the kidney tubules. • Damage to the nervous system such as neuritis (inflam- mation and demyelination of peripheral nerves) and encephalopathy (edema and degeneration of neurons in the brain). Children manifest lead toxicity with seizures or convulsions, delayed development, and intellectual impairment. Even low doses of lead can cause irreversible brain damage. Lead poisoning can be detected by bone defects or “lead lines” in the bone as well as on the gingiva or gums adjacent to the teeth. Acids/Bases Acids and bases can cause corrosive damage to living tissue, which is classified as a chemical burn. The clas- sification of the type of chemical burn follows the same standard system as thermal burns. Acids and bases can FIG. 28.1 Red blood cell showing lead poisoning. (From Stevens ML: Fundamentals of Clinical Hematology, Philadelphia, 1997, Saunders.) CHAPTER 28 Environmental Hazards and Associated Problems 627 occur as a result of the drainage of commercial products into creeks, rivers, and other bodies of water. Depending upon the uses of the body of water, this contamination may cause problems through the ingestion of the water, eating fish that are caught/harvested, or exposure to the body through recreational activities such as swimming or boating. During infancy and childhood, the organs and body systems are still in the process of development. Therefore infants and small children are especially sensitive to health risks that can arise due to exposure to pesticides. Signs of acute exposure problems include diarrhea, nausea, vomiting, pinpoint pupils, rashes, headaches, and irritation of the eyes, skin, or throat. Chronic exposure can, with some chemicals, lead to the aggravation of asthma problems, cause damage to the immune system, as well as increase the risk of certain cancers and birth defects. Treatment for a pesticide illness will usually depend on the specific chemical(s) involved. prolonged. Carbon monoxide monitors are available to warn of the presence of the colorless and tasteless gas. Cigarette smoking predisposes the smoker to lung disease, including emphysema, bronchitis, and lung cancer, and also to bladder cancer, peptic ulcers, and cardiovascular disease. Smoking impairs fertility, and during pregnancy it also affects fetal development, leading to stillbirth or low-birth-weight infants and an increased risk of complications. These concerns have led to social and political action concerning cigarette smoking and secondhand smoke exposure. Many areas across the country now have laws banning smoking in the workplace and any indoor place other than the home. Asbestos Asbestos is still found in older buildings, where it was used for insulation. Exposure of the lungs to asbestos can cause a severe acute inflammation and subsequent scarring, which could lead to chronic problems such as mesothe- lioma. Malignant mesothelioma is a rare form of lung cancer that develops in the mesothelium and is often caused by exposure to asbestos (Fig. 28.2). Other asbestos- related diseases include asbestosis, pleural plaques, and pleural thickening. Chronic asbestos-related diseases often take a long time to manifest, which leads to delayed diagnosis and a poor prognosis for recovery. Pesticides Pesticide illness is a group of diseases and complications that can be caused by some type of exposure to pesticides. Depending on the type of pesticide and amount of exposure, these chemicals can cause a variety of both acute and chronic adverse health effects. Problems often FIG. 28.2 Lung asbestosis. (From Damjanov, I, Linder J: Pathology: A Color Atlas, St. Louis, 1999, Mosby.) THINK ABOUT 28.1 a. Explain why chronic lung disease such as bronchitis occurs more frequently in highly industrialized regions. b. Describe two possible effects of chemical toxicity in the body, giving an example of each one. c. Explain why young children are at greater risk of pathologic changes resulting from exposure to hazardous chemicals such as pesticides. Physical Agents Temperature Hazards Hyperthermia Although the body has mechanisms such as vasodilation and diaphoresis for adapting to temperature extremes, hyperthermia, an excessive elevation in body temperature, can occur when the environmental temperature is unusu- ally high, preventing effective cooling of the body. Also, strenuous activity that generates excessive body heat on a hot day or inadequate replacement of the fluid and salt lost in perspiration may lead to hyperthermia. Because of less effective physiologic compensation mechanisms, older people, infants, and cardiac patients are most at risk for overheating, as demonstrated in a severe heat wave in Chicago during the summer of 1995 that resulted in more than 100 fatalities. A number of syndromes are associated with hyperthermia: • Heat cramps with skeletal muscle spasms caused by loss of electrolytes. • Heat exhaustion, with sweating, headache, nausea, and dizziness or syncope (fainting), the most common problem, resulting from a loss of water and sodium leading to hypovolemia. • Heat stroke, with shock, coma, and very high core body temperature, the most serious complication. Heat 628 SECTION V Environmental Factors and Pathophysiology Radiation Hazards Ionizing Radiation Ionizing radiation, much of it arising from natural sources such as the sun and radioactive minerals in the soil, is an ongoing hazard. Increasing concern has been voiced regarding the change in the protective ozone layer in the earth’s atmosphere and the resultant risk of more radia- tion. However, the expanded exposure to radiation—in homes (eg, radon gas, a by-product of the natural decay of uranium in the earth, can seep into a house through soil or water), industry and defense systems, nuclear reactors for the generation of electricity, and medicine for diagnostic procedures such as x-ray and tracer studies as well as for treatment—presents the primary risk of exposure for workers and clients. Health care workers who are at risk of exposure to radiation must use lead shields and wear monitoring devices to check individual exposure. Ionizing radiation includes x-rays and gamma rays as well as particles such as protons and neutrons. These rays and particles differ both in energy levels and their ability to penetrate body tissue, clothing, or lead. Increased distance from the source lessens the amount of radiation to which a person is exposed. Radiation emissions are measured in roentgens. The amount of radiation absorbed by the body is measured in radiation-absorbed doses known as rads. Radiation primarily affects cells that undergo rapid mitosis, such as epithelial tissue, bone marrow, and the gonads (ovaries and testes). With small doses of radiation, cells can sometimes repair the ruptured DNA strands. With larger doses, DNA is altered and often cross-linkages form, leading to mutations in the cell and the development of cancer (see Chapter 20 for a discussion of carcinogenesis). The cells may be destroyed. Exposure to large amounts of radiation leads to radiation sickness, resulting in damage to the bone marrow, diges- tive tract, and central nervous system. Without intensive care and bone marrow replacement, most victims of radiation sickness die within a few days. Radiation damage may occur with a single large exposure, usually accidental, or may accumulate with repeated small exposures. The effects of repeated small doses of radiation have not been well studied and there is far less information about the resulting pathology than for massive exposure, such as occurred when atomic bombs were used against cities in Japan in 1945 and in the 1986 nuclear meltdown of the Chernobyl nuclear reactor in Ukraine. Light Energy Exposure to both visible light and ultraviolet (UV) rays can cause damage to skin and eyes. Cumulative damage is manifested by the development of skin cancers resulting from ultraviolet rays related to sun exposure, as seen frequently in older individuals. The UV damages the nucleotides in the cell’s DNA. Reducing exposure and stroke occurs commonly in the elderly, infants, or debilitated persons. Early signs include red, dry skin; headache; dizziness; and a rapid, weak pulse. It is caused by general vasodilation, a marked decrease in circulating blood volume, and damage to the heart. Prompt cooling and fluid and electrolyte replacement in persons with these syndromes are essential to prevent brain damage or cardiac failure. Hypothermia Exposure to cold temperatures may have localized or systemic effects. There has been an increase in serious cases of hypothermia in colder climates as the number of homeless individuals in these areas has escalated. Children are also vulnerable, because they may not understand the risks. Localized frostbite usually affects the fingers, toes, ears, or exposed parts of the face. Wet clothing increases the danger. In these areas, vascular occlusion occurs quickly and may lead to necrosis and gangrene. Usually sensation is lost early, and the individual may not be aware of the danger. Close observation of exposed areas for color changes, particularly whitish or bluish spots, is important. Gradual warming of the area without rubbing can mini- mize the damage. Systemic exposure to cold temperatures may occur with submersion in cold water, lack of adequate clothing in cold weather, or wet clothing on a windy day, particularly if body movement is reduced. Low temperatures can affect many body tissues, depending on the length of time of the exposure and the actual temperature. Shivering occurs initially in an effort to generate more body heat, and then the body feels numb. Lethargy and confusion become marked. The pulse and respirations become slower, and the person becomes unresponsive. Reflex vasoconstriction and increased blood viscosity lead to ischemia and reduced metabolism. When the core body temperature drops, the capillaries and cell membranes are damaged. This leads to abnormal shifts of fluid and sodium and ultimately to hypovolemic shock (low blood pressure) and cell necrosis ensues. Rewarming must be done slowly and cautiously and must be accompanied by fluid replacement to maintain adequate circulation and minimize cell damage. Often the brain is protected against edema by the administration of corticosteroid drugs during the return to normal body temperature. THINK ABOUT 28.2 a. Compare the effects of hypothermia and hyperthermia on the circulation. b. Suggest some reasons why it would be difficult for a person submerged in an icy lake to continue swimming. c. How does hypothermia affect cell metabolism and oxygen requirements of the brain? CHAPTER 28 Environmental Hazards and Associated Problems 629 runoff drains through cattle pastures. Antibiotic-resistant pathogens, originating from humans or animals treated with antibiotics, have also been found in lakes and rivers. Generally water in deep wells has been filtered under- ground and is considered safe. However, heavily con- taminated water may seep into the water table and wells, where untreated water may cause widespread illness. In the 1990s, several extremely toxic strains of E. coli emerged and have continued to cause serious illness, including deaths from kidney damage. Hemolytic uremic syndrome develops when specific strains of E. coli invade the bloodstream and cause damage to renal tubules. Many serious outbreaks have occurred in North America. It is imperative that any meat products that have been ground and processed be cooked thoroughly to the recommended temperature. Institutions frequently have outbreaks of Salmonella infection associated with contaminated poultry products or with food handlers who are carriers (a person who is a reservoir for the organism and can spread it but shows no clinical signs of infection). Widespread infection may also occur in nurseries or day care centers when careful handwashing and other infection control techniques have not been maintained. Stool cultures can be used to identify the responsible organism. In many cases such infections are self-limiting, but infants and elderly people are at increased risk and may become dehydrated quickly. Other pathogens that have been identified in foodborne outbreaks include Listeria and Shigella. Listeria is most common in processed meat products such as sausage or ham and is common in the environment. This makes control extremely difficult. Shigella causes dysentery, a bloody diarrhea that is extremely dangerous. Shigella is a bacterium that is transmitted primarily through unwashed hands; only a small loading dose of organisms is needed to cause serious infection. Melamine is a plastic that has been added to food and milk in some areas of the world to allow dilution of the food with water. Melamine reacts as a protein when tested and can go unnoticed in milk or other food unless specific testing is carried out. Food is adulterated to increase profit margins. The result of ingestion of melamine is acute renal failure and possible death. Biologic Agents Bites and Stings Bites and stings may cause disease and other physical complications: 1. By direct injection of animal toxin into the human body. Examples of toxins involved in bites include the neurotoxins produced by poisonous snakes or spiders that affect the nervous system, causing paralysis and respiratory failure or seizures. 2. By transmission of infectious agents through animal or insect vectors to humans. An example of an infection routine use of skin lotions that block damaging ultraviolet rays, both UVA and UVB, are recommended to reduce the risk of skin cancer. Exposure of the eyes to strong UV radiation can also cause permanent damage depend- ing on the specific wavelength involved. The shorter wavelengths can cause corneal cell damage, UVA and UVB rays can cause lens damage, and the longer wave- lengths have been implicated in macular degeneration and retinal tissue damage (see Chapter 15). Visible laser light can also cause severe damage to the eyes. Two types of eye damage that can be caused by a laser beam are tissue thermal burns, affecting structures such as the cornea, and photochemical damage to the retina. Powerful lasers can also cause thermal damage to unprotected skin. THINK ABOUT 28.3 a. Epithelial tissue is very sensitive to radiation. List specific structures that include epithelial tissue likely to be damaged by radiation. b. Give several specific examples of radiation sources in your community and workplace. Noise Hazards Hearing impairment may result from excessive noise; for example, a single loud noise such as a gunshot or a variety of noise intensities can cause cumulative damage. A sudden, extremely loud noise may rupture the tympanic membrane (eardrum) or damage the nerve cells in the inner ear (see Chapter 15). Inner ear damage involving the nerves is usually irreversible. Cumulative damage caused by noise may result directly from noise in the workplace but is often associated with higher noise levels in urban areas and recreational sources such as rock music. Ear protection (eg, plugs) is now required in most noisy work environments. Because only soft or high-pitched sounds are lost initially, the effects of such trauma are often gradual and go unnoticed until they are well advanced. In some cases, the individual may notice tinnitus, or ringing in the ears, which is a more obvious warning of the problem. Food and Waterborne Hazards Contaminated food and water are common sources of gastroenteritis, or vomiting and diarrhea. This topic is covered in Chapter 17. Infection can be spread in many ways. Organisms such as Escherichia coli, part of normal intestinal flora, are transmitted by the oral-fecal route when personal hygiene or community sanitation is not up to standard. So-called traveler’s diarrhea is an example of this type of infection. In some regions a high risk of infection is associated with swimming in areas where adequate sewage treatment is not maintained or water 630 SECTION V Environmental Factors and Pathophysiology C H A P T E R S U M M A R Y Increased awareness of medical problems arising from water and air pollution, contaminated food, and industrial exposure to dangerous substances has sparked increased concern for environmental issues. • Common chemicals with harmful effects include heavy metals and pesticides, which are appearing in consumer goods manufactured offshore. • Inhalants such as asbestos are classified as particulates, whereas sulfur dioxide and carbon tetrachloride are gaseous. These substances cause respiratory tract inflammation and may also be absorbed into the circulation to cause damage elsewhere in the body. • Hyperthermia may cause heat cramps, heat exhaustion, or heat stroke, depending on the rise in body temperature. • Exposure to cold temperatures may cause localized frostbite with tissue necrosis or generalized hypother- mia affecting the circulation and cell function. • Radiation damage may result from a single exposure or may be cumulative. Radiation damages DNA, particularly in cells undergoing mitosis. • Bites and stings cause disease in three ways: by injection of toxins, transmission of infectious agents, or allergic reactions. • Ingested toxins cause food poisoning, liver damage, and other manifestations. transmitted by an animal bite is rabies or hydrophobia, which is caused by an RNA virus. Rabies is caused primarily by the bites of wild animals, such as raccoons or skunks, but also occasionally by bites from domes- ticated animals (cats or dogs) that have been bitten by infected wild animals. Following any bite, the animal is usually impounded and monitored for infection. Rabies leads to nerve paralysis and death if it is not treated quickly. In certain regions, ticks and mosquitoes are threats because they transmit infections such as rickettsial Rocky Mountain spotted fever and Lyme disease, caused by a spirochete also transmitted by ticks. 3. By an allergic reaction to the insect’s secretion. An example of an allergic reaction is the response of some individuals to bee or wasp stings: an anaphylactic reaction—a sudden and severe life-threatening hyper- sensitivity or circulatory allergic reaction. Anaphylaxis is identifiable by respiratory difficulty and shock in someone who has just been bitten (see Chapter 7). CASE STUDY A Occupational Hazards of Fighting Forest Fires E.C. is a 24-year-old professional firefighter in a western region that has had severe forest fires because of hot, dry, windy weather. He has worked overtime for several weeks and is experiencing continual shortness of breath, fatigue, and exercise intolerance, which are unusual for him. E.C. complies with health and safety requirements, including wearing appropriate protective equip- ment. Community support agencies are onsite to provide water, food, and support as needed. Fighting forest fires exposes workers to extreme heat, fatigue from working on uneven terrain, toxins used in fire suppression, insecticides, pesticides, particulate matter, and carbon monoxide. Protective equipment reduces exposure to toxic substances but is not used in down time when exposure can also occur because of wind currents and close proximity to the fire sites. 1. What factors in E.C.’s work situation increase the risk of health problems? S T U D Y Q U E S T I O N S 1. Explain the potential benefits of reducing the use of pesticides and insecticides. 2. List examples of the dangerous gaseous and particulate components of chemical inhalants. 3. Describe the potential effects of chemicals on the respiratory tissues. 4. Explain how skin cancer is linked to sun exposure. 5. Give several examples of excessive noise in your environment. 6. Name a biologic agent and the associated problem for each of the following: a. Transmission of an infection through a bite b. Hypersensitivity reaction c. Injection of a toxin 7. Define a carrier. 8. Define fecal-oral transmission of infection, and give an example. 2. What role do the support agencies play in reducing health problems for firefighters? 3. What are possible causes of E.C.’s exercise intolerance and fatigue? 4. How may the toxins in smoke affect lung function if they irritate the lung tissues? 5. What long-term risks exist for firefighters exposed to smoke from woodland fires? 631 Appendices Ready Reference 1 Body Planes, Cavities, Regions, and Fluid Compartments The following terms are useful in describing body position and movement as well as the location of structures in the body. Body Planes (Fig. RR1.1) coronal a line from side to side, dividing the front and back halves of the body midsagittal a line from superior to inferior along the midline, dividing the right and left halves of the body sagittal a vertical line from superior to inferior at any point that divides the body into right and left parts transverse a line dividing the upper and lower halves of the body Body Cavities (Fig. RR1.2) abdominal cavity below the diaphragm; contains the stomach, intestines, pancreas, and liver dorsal cavity cranial cavity and vertebral cavity pelvic cavity most inferior cavity, containing the urinary bladder, rectum, and uterus thoracic cavity above the diaphragm; contains the heart, lungs, esophagus, trachea, aorta, and venae cavae ventral cavity thoracic cavity and abdominopelvic cavity Body Regions (Figs. RR1.3 and RR1.4) Body Fluid Compartments (Fig. RR1.5) Several fluid compartments within the body are significant in understanding fluid and electrolyte dynamics. It is Inferior Cranial (superior) Frontal (coronal) plane Midsagittal plane Transverse plane Posterior (dorsal) Anterior (ventral) Right side Left side FIG. RR1.1 Body planes. (From Solomon EP: Understanding human anatomy and physiology, Philadelphia, 1987, WB Saunders.) Cranial cavity Spinal cavity Diaphragm Imaginary point of division Dorsal cavity Ventral cavity Abdominal cavity Pelvic cavity Thoracic cavity FIG. RR1.2 Body cavities. (From Leonard PC: Building a medical vocabulary, ed 5, Philadelphia, 2001, WB Saunders.) 632 A p p e n d i c e s FIG. RR1.3 Body regions. (From Dowd SB, Wilson BG: encyclopedia of radiographic positioning, Philadelphia, 1995, WB Saunders.) FIG. RR1.4 Body regions. (From Dowd SB, Wilson BG: encyclopedia of radiographic positioning, Philadelphia, 1995, WB Saunders.) Body Weight 60 kg Total Body Water (TBW) 36 L Intracellular Fluid (ICF) 24 L Cell membrane Extracellular Fluid (ECF) 12 L Interstitial Fluid 9L Plasma 3L x 0.6 2/3 1/3 3/4 1/4 Capillary wall FIG. RR1.5 Body fluid compartments. (Netter Anatomy Illustration Collection, copyright Elsevier, Inc. All rights reserved.) A p p e n d i c e s 633 Ready Reference 2 Anatomic Terms Prefix or Root (Combining Form) Used in Anatomic Terms ab away from ad toward adeno gland ante before, forward anti opposed auto self bi two caud lower part or tail cephal top or head cervic, cervico neck circum around contra opposite, against crani head en, endo in epi over, above ex, exo out hemi half inter between intra within mega large mono one poly many post after, behind retro behind sub below or under super, supra above version to turn Directional Terms afferent moving toward anterior front or abdominal surface contralateral opposite side distal far from the center or point of attachment dorsal back surface efferent moving away external outside inferior lower part, beneath internal inside ipsilateral same side lateral toward the side medial toward the midline posterior toward the back prone lying on the abdominal surface proximal near the center or point of attachment superior above, upper part supine lying flat on the back ventral front or abdominal surface important not to confuse these physiologic compartments with cavities that are anatomic structures. The fluid compartments contain differing proportions of total body water and differing concentrations of specific electrolytes (Tables RR1.1 and RR1.2). Intracellular Fluid Compartment the compartment and fluid within cells and bounded by cell membranes Extracellular Fluid Compartment the compartment outside of cells, including: •  Interstitial Fluid Compartment the fluid between cells •  Vascular Fluid Compartment the fluid within lymph capillaries and blood vessels Common Body Movements (Fig. RR1.6) TABLE RR1.1 Fluid Volumes of Fluid Compartments in the Adult Compartment Volume (liters) % of Body Weight (varies with BMI) intracellular (icF) 28 40 interstitial (isF) 11 15 intravascular 3 5 Total Body Water (TBW) 42 60 TABLE RR1.2 Distribution of Electrolytes in Body Fluids in mEq/L Electrolyte Intravascular Interstitial (ISF) Intracellular (ICF) Bicarbonate 25 27 12 calcium 4 3 4 chloride 112 118 4 Magnesium 1 1 34 phosphate 2 2 40 potassium 4 4 150 protein 17 Trace to absent 54 Other 6 7 90 634 A p p e n d i c e s G. Plantar flexion A. Extension and flexion (elbow) Flexion Extension B. Flexion (neck) D. Supination and pronation E. Adduction and abduction C. Hyperextension F. Dorsiflexion H. Eversion and inversion Supination Pronation Inversion AbductionAdduction Eversion FIG. RR1.6 common body movements. A p p e n d i c e s 635 Ready Reference 3 Conversion Tables (Tables RR3.1 and RR3.2) TABLE RR3.1 Measurement Conversion Table Common Units nano one billionth nanogram ng 10−9 g micro (µ) one millionth microgram µg 10−6 g milli one thousandth milligram mg 10−3 g kilo one thousand kilogram kg 103 g centi one hundredth centimeter cm 10−2 m millimeter mm 10−3 m Conversion Factors To Convert Multiply By centimeters to inches 0.39 inches to centimeters 2.54 meters to feet 3.28 feet to meters 0.305 fluid ounces to milliliters 30 milliliters to fluid ounces 0.03 liters to quarts 1.06 quarts to liters 0.95 gallons (Us) to liters 4.4 grams to ounces 0.035 ounces to grams 28 pounds to grams 453.6 kilograms to pounds 2.2 grains to grams 0.065 calories to joules 0.23 Equivalents 1 grain (apothecary) = 65 mg (metric) = 0.035 ounce 15 grains = 1 g 437.5 grains = 28.3 g = 1 ounce 453.6 g = 1 pound or 16 oz 1 kg = 35.2 ounces or 2.2 pounds 1 dram (apothecary) = 4 mL 30 mL = 1 fluid ounce 1 liter = 2.1 pints or 1 quart Equivalents for Household Measures 1 teaspoon = 4 mL 1 tablespoon = 15 mL or 0.5 fluid ounce 1 cup = 240 mL = 8 fluid ounces = 0.5 pint 1 quart = 960 mL = 4 cups = 2 pints 1 fluid ounce = 30 mL 1 liter = 1.06 quart 1 inch = 2.5 cm TABLE RR3.2 Temperature Conversion Chart To Convert Fahrenheit to Celsius: subtract 32 from the number of °F and multiply by 5/9: (X° F − 32) × 5/9 = Y °c To Convert Celsius to Fahrenheit: Multiply the number of °c by 9/5 and add 32: (Y °c × 9/5) + 32 = X° F Equivalents °F °C 95.0 35.0 96.0 35.5 97.0 36.1 98.0 36.7 normal body temperature 98.6 37.0 99.0 37.2 100.0 37.8 101.0 38.3 102.0 38.9 103.0 39.4 104.0 40.0 1°c = 1.8°F 0°c = 32°F (freezing point of water) 20°c = 68°F (room temperature) 100°c = 212°F (boiling point of water) Ready Reference 4 Common Abbreviations and Acronyms ABGs arterial blood gases ABO blood types, A, B, and O ACE angiotensin-converting enzyme ACh acetylcholine ACTH adrenocorticotropic hormone ADH antidiuretic hormone ADLs activities of daily living AED automatic external defibrillator AFP alpha-fetoprotein AIDS acquired immune deficiency syndrome ALL acute lymphocytic leukemia ALS amyotrophic lateral sclerosis ANA antinuclear antibodies aPTT or APTT activated partial thromboplastin time ARDS adult respiratory distress syndrome ARF acute renal failure ASA aspirin, acetylsalicylic acid ATP adenosine triphosphate BBB bundle branch block (heart) BM bowel movement BMR basal metabolic rate BP blood pressure BPH benign prostatic hypertrophy BSA body surface area BSE breast self-examination 636 A p p e n d i c e s IgG immunoglobulin G (gamma globulin) INR international normalized ratio (prothrombin time) IOP intraocular pressure IRDS infant respiratory distress syndrome ISF interstitial fluid JRA juvenile rheumatoid arthritis K+ potassium ion LDL low-density lipoprotein LLQ left lower quadrant LMP last menstrual period LOC level or loss of consciousness LP lumbar puncture MAOI monoamine oxidase inhibitor (antidepressant drug) MD muscular dystrophy MHC major histocompatibility complex MI myocardial infarction (heart attack) MMR measles, mumps, and rubella vaccine MRI magnetic resonance imaging (test) MS multiple sclerosis Na+ sodium ion NaCl sodium chloride, salt NIDDM non–insulin-dependent or type 2 diabetes mellitus NMR nuclear magnetic resonance test NPO no food or fluid (nothing) by mouth NSAID nonsteroidal antiinflammatory drug OA osteoarthritis OD overdose or right eye OS left eye OTC over-the-counter (availability of drugs, e.g., AsA [aspirin]) PaO2 partial pressure of oxygen in arterial blood PCO2 partial pressure of carbon dioxide pH hydrogen ion concentration (acidity) PID pelvic inflammatory disease PKU phenylketonuria PMN polymorphonuclear leukocyte (polys, neutrophil) PMS premenstrual syndrome PSA prostate specific antigen PT prothrombin time, pro time PTCA percutaneous transluminal coronary angioplasty PTT partial thromboplastin time PVC premature ventricular contraction PVD peripheral vascular disease RAS reticular activating system RBC red blood cell (erythrocyte) RFA radiofrequency ablation (destruction) RLQ right lower quadrant ROM range of motion SIDS sudden infant death syndrome SLE systemic lupus erythematosus SOB shortness of breath STD/STI sexually transmitted disease/infection T&A tonsillectomy and adenoidectomy TB tuberculosis TBC thrombocyte (platelet) count TBW total body water TIA transient ischemic attack TMJ temporomandibular joint CA cancer Ca++ calcium ion CABG coronary artery bypass graft CAD coronary artery disease CAT or CT scan computerized axial tomography or computed tomography CBC complete blood count CCU coronary care unit CDC centers for disease control and prevention, UsA CEA carcinoembryonic antigen CF cystic fibrosis CHF congestive heart failure Cl− chloride ion CNS central nervous system COPD chronic obstructive pulmonary disease (also cOLd, chronic obstructive lung disease) CPR cardiopulmonary resuscitation CRP c-reactive protein C&S culture and sensitivity test CSF cerebrospinal fluid CVA cerebrovascular accident (stroke) CVP central venous pressure D5W intravenous solution of 5% glucose in water D&C dilation and curettage of the uterus DIC disseminated intravascular coagulation DNA deoxyribonucleic acid DNR do not resuscitate DPT diphtheria, pertussis, and tetanus vaccine Dx diagnosis EBV epstein–Barr virus ECF extracellular fluid ECG electrocardiogram ECT electroconvulsive therapy EEG electroencephalogram ELISA enzyme-linked immunosorbent assay (antibody or antigen test) EPS extrapyramidal signs ESR erythrocyte sedimentation rate ESWL extracorporeal shockwave lithotripsy FUO fever of undetermined origin GABA gamma-aminobutyric acid (neurotransmitter) GFR glomerular filtration rate GVHD graft-versus-host disease Hb or Hgb hemoglobin HbA hemoglobin A HbA1c glycosylated hemoglobin A HbF fetal hemoglobin HBV hepatitis B virus HCG human chorionic gonadotropin HCl hydrochloric acid HDL high-density lipoprotein HIV human immunodeficiency virus HLA human leukocyte antigen HPV human papillomavirus HSV herpes simplex virus IBD inflammatory bowel disease ICF intracellular fluid I&O intake and output of fluids ICP intracranial pressure IICP increased intracranial pressure ICU intensive care unit IDDM insulin-dependent diabetes mellitus A p p e n d i c e s 637 endoscopic examinations include bronchoscopy, gastros- copy, cystoscopy, proctosigmoidoscopy, arthroscopy, and laparoscopy. Imaging Studies Radiograph or X-Ray Film Ionizing radiation provides an image on film of bones and soft tissues that varies in density with the absorption of the x-rays striking the tissues (see Fig. 9.3 and Fig. RR5.1). • Plain x-ray films are used as a preliminary screen for problems such as fractures or pneumonia. • Contrast medium may be used (e.g., barium swallow or barium enema) to illustrate digestive tract abnormali- ties in more detail. In angiography various contrast media are used to examine the blood vessels. Myelo- grams utilize a dye to visualize the spinal cord and nerve roots. • In mammography, low-dose x-ray films are used to detect lesions in breast tissue. • In bone density scanning (DEXA), two x-ray beams are used simultaneously to measure the thickness of bone. The dose rate of radiation is much less than a plain x-ray. Computed Tomography (Ct Scan, Formerly Computerized Axial Tomography or Cat Scan) A cross-section of tissues is provided by a scanning machine taking x-ray films in a series of shots from all directions (360 degrees); these measure differences in tissue density. A computer processes and compiles the readings to produce an image (Fig. RR5.2). Ultrasonography (Ultrasound) High-frequency sound waves that bounce off body structures are used to obtain images by ultrasonography (Fig. RR5.3). The echoes reflect differences in the struc- tures, which are analyzed and then visualized. This test is useful because it does not involve radiation, is nonin- vasive, is considered safe during pregnancy (can be used to measure fetal size and development), and is relatively inexpensive. It is limited by the fact that sound waves cannot penetrate deeply. • Doppler ultrasound assesses the blood flow in arteries and veins by measuring sound waves reflected from moving red blood cells. • Echocardiography measures the efficiency of heart valves and heart function (see Fig. 12.25). Magnetic Resonance Imaging (MRI) MRI makes use of a magnetic field surrounding the body and the hydrogen (water) content of the body. Radio waves provide the energy source. Relative tissue densities are calculated by computer to produce an image. MRI is noninvasive and safe because it does not use ionizing radiation or injected contrast media. It provides more detailed visualization and can project past bone; therefore it is particularly useful for TPA tissue plasminogen activator TPN total parenteral nutrition TPR temperature, pulse, respiration URI upper respiratory infection UTI urinary tract infection VS vital signs WBC white blood cell (leukocyte) WHO World Health Organization Common Pharmaceutical Abbreviations Rx take M or mitte send (amount) sig label ac before meals cc with meals pc after meals PO by mouth, orally SL sublingual, dissolve under tongue IM intramuscular injection SC or SubQ subcutaneous injection IV intravenous injection stat immediately bid twice daily tid three times daily qid four times daily hs bedtime prn as needed q4h every four hours q8h every eight hours OD right eye OS left eye gtt drop tab tablet cap capsule Ready Reference 5 Common Diagnostic Studies and Tests The diagnostic tests described in this section are basic tests that are usually available and most often used to diagnose and monitor diseases and the effectiveness of treatment. A brief description is included for some of the procedures. Additional specialized tests may be offered in certain institutions. New techniques and more accurate equipment are constantly being developed. Test results are now available more rapidly with the use of multiple analyzers and computers. However, older procedures and equipment may be used by some centers. Endoscopic Examination Endoscopy is used to visualize lesions or structures directly by inserting a tube into the body through an opening (e.g., trachea) or through the body wall. This procedure may facilitate a diagnosis or be used to obtain a specimen (tissue or fluid) for further examination and diagnosis (e.g., a biopsy) or perform simple surgery (e.g., remove cartilage debris from a knee joint). Examples of 638 A p p e n d i c e s A, X-ray of chest shows air under the diaphragm, which has leaked out of a ruptured stomach; heart and lungs are normal (frontal view). (Courtesy of Dr. Christine MacAdam, Department of Medical Imaging, North York General Hospital, Toronto, Ontario, Canada.) B, X-ray of the spine (frontal plane) shows evidence of calcification from previous pancreatitis. (Courtesy of Dr. Christine MacAdam, Department of Medical Imaging, North York General Hospital, Toronto, Ontario, Canada.) Lung Heart Diaphragm Air under diaphragm A B Spine Calcified pancreatitis FIG. RR5.1 X-rays. Liver Gallbladder Kidney Fatty tissue Spine Spleen Aorta Adrenal gland Pancreas FIG. RR5.2 computed tomography (cT) scan shows cross-section of organs. (Courtesy of Dr. Christine MacAdam, Department of Medical Imaging, North York General Hospital, Toronto, Ontario, Canada.) A p p e n d i c e s 639 phosphate, is labeled with a very small amount of radioactive material and administered (orally, by injec- tion, by inhalation) to the patient. A scanning procedure traces gamma ray emissions as it follows the radioactive material through the body to the appropriate tissue; for example, iodine to the thyroid gland or phosphate to bone. Abnormalities of distribution of the tracer substance or of tissue function can be detected by this process. A computer transforms the scan into an image. For example, a “hot spot” indicates increased uptake of the radioactive material and could be used to identify an overactive thyroid or the presence of a metastatic bone cancer. By contrast, a malignant thyroid tumor is usually “cold” with less radioactivity. An embolus obstructing blood flow would be illustrated by an area without radioactivity in the lung or heart (radioactive thallium scan). The radioactive material is soon excreted by the patient. Positron Emission Tomography (PET) PET involves radioisotopes used with a scanner and computer to provide a cross-sectional functional image of a tissue such as the brain. This method is used to determine biochemical changes in the tissue and thus functional changes such as oxygen uptake in the tissue. Determinations of Electrical Activity Electrocardiogram (ECG, EKG) By attaching electrodes to the chest and limbs of a patient, the conduction system of the heart can be assessed. The rate, rhythm, and characteristics of the contractions can be recorded by the machine. Typical abnormal patterns assist in the diagnosis of myocardial infarctions, cardiac dysrhythmias, electrolyte imbalances, and digoxin toxicity (see Fig. 12.17). Holter monitoring uses a portable ECG device to monitor cardiac activity in ambulatory patients while they perform and keep a log of their daily activities. The patient wears a small recording device attached to electrodes on the chest for a 24-hour period, and any cardiac abnormalities can be correlated with the daily routine. Stress Test (Exercise Electrocardiography) Electrocardiographic measurements and blood pressure are monitored during a period of controlled exercise on a treadmill or stationary bicycle to determine the cardiac response to increased workload. The test is useful in detecting early coronary artery disease, checking post-MI cardiac function, and assessing the effectiveness of medication. It may also be used before establishing an individual’s fitness or exercise program. Electroencephalogram (EEG) The electrical activity of the neurons in the brain is determined by electrodes attached to the scalp; the activity is then recorded as waves by the machine. visualization of neurologic and cardiovascular abnormalities (Fig. RR5.4). Nuclear Scanning Nuclear medicine tests involve tracking the distribution of a radioactive tracer substance (radiopharmaceutical, radionuclide, or radioisotope) in the body. A substance that is normally used in the body, such as iodine or Gallbladder FIG. RR5.3 Ultrasound of gallbladder and liver. (Courtesy of Dr. Christine MacAdam, Department of Medical Imaging, North York General Hospital, Toronto, Ontario, Canada.) FIG. RR5.4 Magnetic resonance image (MRi) of the kidneys (frontal plane). (Courtesy of Dr. Christine MacAdam, Department of Medical Imaging, North York General Hospital, Toronto, Ontario, Canada.) 640 A p p e n d i c e s factors (e.g., fibrinogen). These tests may be used to determine deficits of individual factors or monitor anticoagulant treatment. • Hemoglobin electrophoresis is used to detect the presence of abnormal hemoglobin (e.g., HbS). • Serum-ferritin level indicates the level of iron storage. Blood Chemistry Tests Automated electronic systems are now in widespread use. They make use of computerized multiple analyzers that can run a number of tests rapidly. Depending on the outcome, additional tests may be required in specific situations. Blood chemistry tests evaluate: • Arterial blood gases (ABGs) for acid–base balance or oxygen levels, including serum pH, PO2, PCO2, SO2 (oxygen saturation), CO2 and O2 content, bicarbonate, base excess and base deficit, and serum pH • Serum hormone levels (e.g., ACTH or thyroid—T3 and T4) • Lipid levels, including serum cholesterol and triglyc- erides, lipoproteins such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL) • Serum electrolytes (e.g., K+, Na+, Cl+) • Glucose (fasting blood sugar or glucose tolerance test) • Serum enzymes and isoenzymes (to determine the site of infarction or inflammation or to monitor the spread of a malignant tumor) • Serum levels of bilirubin (direct, indirect, and total) • Urea or ammonia to check kidney and liver functions Special methods such as chromatography may be used for amino acid determinations. Immunodiagnostic Tests Major changes are occurring in the area of immunodi- agnostic testing as improved methods are developed to assess serum antigen and antibody levels. Current methods make use of precipitation or agglutination reactions, immunofluorescence tests, or enzyme-linked immunosorbent assay (ELISA). Immunologic testing is used for many purposes, such as the diagnosis and monitoring of the course of hepatitis, diagnosis of HIV infection, screening for infection during pregnancy (the TORCH test), ABO blood typing, and assistance in the diagnosis of diseases resulting from immunologic abnor- malities (e.g., antinuclear antibodies in systemic lupus erythematosus or rheumatoid factor in rheumatoid arthritis). Skin tests, scratch, or patch tests, are simple local tests based on immune responses. They are used to check for specific allergies or exposure to microbes (e.g., Mantoux test for tuberculosis). Abnormal patterns may result from seizure disorders, tumors, or injuries. Absence of electrical activity in all parts of the brain may be used to confirm brain death. Pulmonary Function Tests Both pulmonary volumes and capacities (e.g., tidal volume, total lung capacity—see Fig. 13.3 and Table 13.1) can be measured using a spirometer, a machine into which the patient breathes through a mouthpiece. These tests assist in diagnosing specific respiratory disorders, response to treatment, or progression of chronic disorders. Blood Tests Hematology Testing Blood is checked for its components and its blood clot- ting capability (hemostasis). Depending on the particular test, blood may be procured from a vein or a small puncture on the fingertip (see tables in the inside front cover). • Complete blood count (CBC) is used to check the count and characteristics of all formed elements or cells (erythrocytes, leukocytes, and thrombo- cytes) as well as hemoglobin and hematocrit. This examination is useful in the diagnosis of anemias or leukemias. • Hemoglobin (Hgb) indicates the amount of hemoglobin in the blood for oxygen transport, independent of the number of red blood cells. • Glycosylated hemoglobin (HBA1c) measures the amount of glucose bound to hemoglobin. This reflects the blood glucose levels over a period of time (e.g., months). It is used to monitor control of diabetes mellitus over the past 90 to 120 days. • Hematocrit (HCT) indicates the percentage of erythro- cytes in a specific volume of blood. The number of white blood cells (WBCs) is not significant in measuring the cell volume. Hematocrit can indicate fluid imbal- ance or anemia. • White blood cell differential count, often referred to as a “differential count,” determines whether there has been a change in the proportions of leukocytes and may provide a clue to the cause of a problem. For example, an increase in eosinophils usually indicates an allergic response. • Bone marrow aspiration may be used to confirm abnormalities related to the production of blood cells such as megaloblastic anemia or leukemia. Specimens may be taken from the anterior iliac crest or sternum. • Blood culture and sensitivity may be per- formed if bacteremia or unknown infection is present. • Blood clotting tests evaluate various clotting times (e.g., prothrombin time) and serum levels of the clotting A p p e n d i c e s 641 Microbiologic Tests Any body fluids or exudates from lesions may be exam- ined for the presence of microorganisms, which then may be identified. Body fluids may include sputum, blood, urine, stool, semen, gastric aspirate, or cervical scrapings. Microscopy may involve the use of different types of microscopes (dark-field, phase-contrast, electron), depend- ing on the site from which the sample was obtained and the type of microbe suspected. Stains such as Gram stain may be used to assist with identification. Cultures, using a medium suitable for the specific organism, and sensitiv- ity tests to determine the most effective drugs are common procedures (see Figs. 6.2 and 6.17). Organisms such as viruses require living tissue for culture, a more complex and time-consuming procedure. Ready Reference 6 Example of a Medical History The purpose of a medical history is to obtain information regarding a patient’s health status and then to assess the implications of this information for planning and implementing health care interventions. Goals include the: • Establishment of general considerations required for treatment of an individual • Identification of any medical condition that could be complicated by actions of the health care provider • Identification of a medical condition, medication, or other treatment that might require special precautions or modified treatment on the part of the health care provider • Identification of any condition that could create a risk for staff or other patients • Assurance that any changes in the patient’s condition or treatment are recorded • Promotion of accurate and effective communication among all parties • Need to cover any legal requirements concerning risk factors for each patient Many different forms are available for a medical history. These may be modified to meet the needs of a particular health profession. There are essentially three parts to a medical history. First, a basic form is often completed by the patient before the first appointment. Then, the health care professional may ask questions, record observations, and make notes regarding specific items in the patient’s history or regarding the patient’s current complaint. The patient’s responses may prompt more questions, or additional information may be needed. Lastly, a section for updating records may be included. A typical form is shown in Fig. RR6.1. Chromosomal and Genetic Analysis Chromosome analysis, including techniques used in cytogenetics and molecular biology, is used to examine the chromosomes and/or DNA to determine chromosome or genetic abnormalities in affected individuals or carriers, to determine paternity, or in forensic science. DNA identification is used routinely, and information is being recorded in computer data banks. Gene mapping and subsequent development of tests for various genetic defects is a current major project. White blood cells are commonly used for this type of testing, but other sources of cells, such as fetal cells in amniotic fluid, may also be used. Therapeutic Drug Monitoring Serum drug levels are checked in patients in whom there is a narrow therapeutic range of a drug and risk of toxicity or who have severe renal or liver disease or potential drug interactions. Examples of drugs monitored are digoxin, lithium, lidocaine, and phenobarbital. Urine Tests Routine urinalysis is used to check the physical and chemi- cal characteristics of a freshly collected urine specimen. Physical examination of the specimen includes its appear- ance and specific gravity. Color of urine may be altered by drugs or diet. Chemical analysis includes pH and presence of abnormal constituents such as protein or ketones, as well as electrolyte levels and wastes such as urea. Microscopic examination determines the presence of cells or urine casts. Tests such as creatinine clearance are used to determine the glomerular filtration rate. Pregnancy tests make use of urine levels of human chorionic gonadotropin. Patients who have diabetes mellitus or are on certain diets may monitor their own urine for ketones. Cerebrospinal Fluid Tests Cerebrospinal fluid is collected by means of a lumbar puncture (see Fig. 14.11). The pressure is measured, and the fluid is examined for appearance, protein and glucose levels, and the presence of cells or microorganisms. Fecal Tests or Stool Analysis A fecal specimen is checked for its physical characteristics such as color and consistency. Presence of occult blood is determined by the guaiac test. Stool cultures are used to check for parasites as well as other microbial content. Chemical tests include tests for lipids, enzymes such as trypsin, or mucus. Microscopic examination assesses factors such as the presence of leukocytes (abnormal). 642 A p p e n d i c e s Please check any conditions you have experienced SEX F M DATE OF BIRTH: When did you last see your family doctor? Date of last physical examination? Date of last chest x-ray? Last hospitalization. Purpose Date List any medical condition you are currently being treated for List any drugs you are taking List any other treatments you may be taking at this time List any allergies Angina Heart attack High blood pressure Other heart problem Any blood or bleeding problems Frequent infections Stroke Seizures Eye problems Hearing problems Dizziness, vertigo Mobility problems Headaches Cough, sinus problems Breathing problems MARITAL STATUS OCCUPATION FAMILY PHYSICIANS NAME PHONE NUMBER ADDRESS DATEPATIENT:NAME TELEPHONE NUMBER: HOME BUSINESS FIG. RR6.1 Medical history form. A p p e n d i c e s 643 Tuberculosis Peptic ulcer Intestinal disorder Liver disease, jaundice Any dietary restrictions Recent weight loss/gain Diabetes Thyroid Other hormonal problems Kidney or bladder problems Arthritis and joint problems Osteoporosis Skin rashes or lesions Cancer Pregnancy Smoker Other concerns: SUGGESTIONS FOR ADDITIONAL QUESTIONS How long have you had this condition? What medications or treatment are you receiving? Do you have a specialist for this? Name? Phone? Current disorder and treatment How long have you been taking this medication? Do you have any unwanted effects from this drug? Do you take any “over-the-counter” medications, such as vitamins, pain killers, laxatives, or herbal remedies? Drugs Chest pain (do you have chest pain, when(triggers?), how long does it last? how long have you been having this? do you take nitroglycerin, do you have nitroglycerin with you?) Heart attack (When, how long were you hospitalized, bypass surgery, drug treatment such as anticoagulants, any special precautions now?) High blood pressure (controlled? what is it now? do you take it yourself? medication, any dizziness or fainting?) Irregular heart rate (when? medication? do you have a pacemaker?) Heart valves (Have you had rheumatic fever, congenital heart defect, artificial valve, take “blood thinners”?) Heart failure (breathing problems, can you climb stairs? Are you uncomfortable lying down? do you need extra pillows for sleeping, legs swelling?) Blood problems (Do you have anemia? Type?, Bleeding problems?, frequent infections) Do you take penicillin before a dental appointment? (Information on prophylactic drugs to prevent infective endocarditis and the high risk groups is published by the American Heart Association—www.americanheart.org) Other concerns? Heart: Stoke—How long ago? Whar residual effects did it have? Eg. mobility, speech, memory Seizures (type, frequency, precipitating events, medication?) Mental health—(specific disorder, treatment) Visual problems (glaucoma, cataract, glasses or contact lenses?) Hearing problems (hearing aid?) Dizziness, vertigo (when, predisposing factors?) Headaches (type, when, medication?) Fainting (when?) Nervous System FIG. RR6.1, cont’d Continued 644 A p p e n d i c e s Recurrent cough/cold; sinus Asthma (frequency of acute attacks, precipitating factors, inhaler?) Smoker (for how long? amount?) Chroinc respiratory disorders—asthma, bronchitis, emphysema (for how long? medication, effects?) Tuberculosis (when, how diagnosed, active, medication) Respiratory Problems Appetite (is it good, snacks, fluid intake) Diet (any restrictions?) Recent significant weight gain/loss Peptic ulcer (discomfort, diet, medication) Intestinal disorder (type, chronic diarrhea, colitis) Liver disease (hepatitis, cirrhosis, jaundice) Gastrointestinal System Diabetes (type, controlled by, acute and chronic complications, when was last meal and insulin taken) Thyroid (hypo or hyperthyroid, treatment?) Take glucocorticoids regularly? Other hormonal problems? Endocrine function Kidneys (disorder? control?) Bladder (frequency, infections?) Urinary system Arthritis—rheumatoid, osteoarthritis, gout, ankylosing spondylitis (where, therapy) Artificial joint (type, when?) Osteoporosis (cause, complications, treatment) Mobility—limitations, stairs Musculoskeletal Skin rashes—contact/irritants (tape), allergies Infections (Herpes) Chronic disorders (Eczema, psoriasis, other, factors, treatment) Skin General infections (current, recurrent or chronic, frequency? type? STD, fungal, viral) Immunizations (Have you had all recommended immunizations? Influenza?) Cancer (site, when, chemotherapy, radiation) Other concerns or observations Pregnancy (any problems, limitations?) Surgery—what, when, any problems Precautions Concerns and Precautions Date Changes in health status RECORD UPDATE FIG. RR6.1, cont’d A p p e n d i c e s 645 Ankylosing spondylitis A progressive inflammatory condition involving the spine, leading to fibrosis and ankylosis; Chapter 9 Anorexia nervosa An eating disorder in which extreme weight loss results from self-starvation; Chapter 23 Aortic aneurysm A localized dilation in the aorta, which may rupture; Chapter 12 Aphasia A group of speech and language disorders resulting from brain damage; Chapter 14 Appendicitis Obstruction and inflammation in the appendix with possible rupture; Chapter 17 Arteriosclerosis Degeneration of small arteries causing hardening of the walls and narrowing of the lumen with decreased blood flow; Chapter 10 Aspiration Liquids and solids may cause obstruction and inflammation in the airway; Chapter 13 Atelectasis The collapse or nonaeration of part or all of a lung; Chapter 13 Atherosclerosis Development of lipid plaques with attached thrombi in large arteries, causing obstruction; Chapter 10 Atopic dermatitis (eczema) Chronic inflammatory skin condition related to genetic and hypersensitivity factors; Chapter 7 Basal cell carcinoma Skin cancer, slow growing, com- monly on exposed areas of the body; Chapter 20 Benign prostatic hypertrophy Hyperplasia of prostatic tissue compressing the urethra; Chapter 19 Bladder cancer An invasive tumor in the bladder wall, often related to exposure to chemicals or recurrent infec- tions; Chapter 18 Brain tumor Benign and malignant tumors are space- occupying lesions, resulting in increased intracranial pressure; Chapters 14 and 20 Breast cancer A common malignant tumor in women, frequently metastasizing at an early stage; Chapters 19 and 20 Bronchiectasis A secondary respiratory problem in which dilated bronchial walls allow pooling of secretions and recurrent infections; Chapter 13 Bronchiolitis A viral infection in the bronchioles and small bronchi in young children; Chapter 13 Bronchitis Chronic inflammation and recurrent bacterial infections damage bronchial walls, leading to obstructions and hypoxia (COPD); Chapter 13 Bulimia nervosa An eating disorder characterized by binge eating, followed by purging; Chapter 23 Burns A thermal (heat) or nonthermal (chemical or electrical) injury to the body causing acute inflammation and tissue destruction; Chapter 5 Cancer, oral cavity Squamous cell carcinoma commonly on the floor of the mouth or tongue; Chapter 17 Candidiasis Common fungal infection, which may involve the mouth, esophagus, vagina, or skin; Chapters 7, 17, 19, and 27 Ready Reference 7 Disease Index Acne vulgaris A staphylococcal infection involving the sebaceous glands and hair follicles, common in teenagers; Chapter 23 Acromegaly Caused by increased secretion of growth hormone in the adult and resulting in broader bones and soft tissue growth; Chapter 16 Acute necrotizing fasciitis Rapidly invasive and destruc- tive multimicrobial infection of soft tissue; Chapter 8 Acute respiratory failure The end stage of many respira- tory problems when severe hypoxemia and/or respiratory acidosis results, interfering with nervous system function; Chapter 13 Addison’s disease A deficit of adrenocortical hormones leads to hypotension, hypoglycemia, and cardiac arrhyth- mias; Chapter 16 AIDS Active infection with HIV that meets the criteria established by the Centers for Disease Control (CDC) and World Health Organization (WHO); Chapters 7, 10, and 14 Allergic rhinitis Hay fever, an allergic response to inhal- ants causes sneezing and profuse watery nasal discharge; Chapter 7 Alzheimer’s disease A form of dementia, with progressive loss of cognitive function and personality changes; Chapter 14 Amenorrhea Absence of menstruation, which may result from many factors; Chapter 19 Amyotrophic lateral sclerosis A progressive degenera- tive condition involving loss of upper motor neurons in the cerebral cortex and lower motor neurons in the brainstem and spinal cord leading to paralysis; Chapter 14 Anaphylaxis Life-threatening, systemic hypersensitivity reaction causing circulatory shock and airway obstruction; Chapter 7 Anemia, aplastic Bone marrow failure results in pancy- topenia, with resultant anemia, increased bleeding tenden- cies, and high risk of infection; Chapter 10 Anemia, iron deficiency Decreased hemoglobin produc- tion (microcytic, hypochromic erythrocytes) due to iron deficit; Chapter 10 Anemia, pernicious Autoimmune reaction leads to decreased absorption of vitamin B12 due to lack of intrinsic factor. This results in megaloblastic red blood cells (RBCs) that are prematurely destroyed; Chapter 10 Anemia, sickle cell A genetic defect in hemoglobin causes sickling and hemolysis of red blood cells (RBCs) under hypoxic conditions. This causes multiple thrombi and infarctions throughout the body; Chapter 10 Angina pectoris Transient chest pain resulting from myocardial hypoxia when demands on the heart increase or if oxygen supply to the heart is impaired; Chapter 12 646 A p p e n d i c e s Cystic fibrosis Genetic disorder affecting the exocrine glands, causing thick mucus to obstruct the bronchioles in the lungs, pancreatic, and biliary ducts. Respiratory infections are common; Chapter 13 Cystitis Infection of the bladder usually due to E. coli; Chapter 18 Dental caries Tooth decay caused by bacterial action on sugars; Chapter 18 Depression A group of mood disorders based on changes in neurotransmitter activity; Chapter 14 Detached retina A tear in the retina deprives retinal cells of nutrients that, if prolonged, may cause permanent loss of vision; Chapter 15 Diabetes insipidus A deficit of antidiuretic hormone resulting in excessive loss of fluid and dehydration; Chapter 16 Diabetes mellitus A relative deficit of insulin leads to hyperglycemia and multiple metabolic abnormalities; Chapter 16 Dislocation The separation of two bones at a joint with loss of articulation and deformity; Chapter 9 Disseminated intravascular coagulation (DIC) A com- plication of many disorders, DIC causes excessive blood coagulation and consumption of clotting factors, leading to hemorrhage; Chapters 10 and 22 Diverticular disease Outpouching of the intestinal wall, often multiple, which may become inflamed or infected and may cause obstruction; Chapter 17 Down syndrome A chromosome disorder, trisomy 21, causing multiple defects in physical and intellectual development; Chapter 21 Dumping syndrome Removal of the pyloric sphincter results in uncontrolled gastric emptying, which leads to intestinal distention and hypovolemia after meals; Chapter 17 Dwarfism May be caused by a deficit of growth hormone; Chapter 16 Dysmenorrhea Painful menstruation, both primary and secondary; Chapter 19 Dysphagia Difficulty in swallowing due to neurologic or structural problems; Chapter 17 Eczema (atopic dermatitis) Chronic inflammatory skin condition related to genetic and hypersensitivity factors; Chapter 7 Emphysema The destruction of alveolar walls decreases oxygen diffusion, and loss of elasticity in the lungs impedes expiration, leading to overinflated lungs (COPD); Chapter 13 Endometrial cancer Carcinoma of the uterus is usually indicated by bleeding in older women; Chapter 28 Endometriosis Endometrial tissue is present outside the uterus and responds to hormonal changes; Chapter 19 Epiglottitis Bacterial infection and inflammation may obstruct the airway; Chapter 13 Epispadias Urethral opening on the dorsal surface of the penis; Chapter 19 Cardiac arrhythmias Abnormalities in the conduction system of the heart cause irregular rhythms and decreased cardiac output; Chapter 12 Cataracts Progressive clouding of the lens of the eye; Chapter 15 Celiac disease A malabsorption disorder related to intolerance to gluten and atrophy of the intestinal villi; Chapter 17 Cellulitis Infection, often staphylococcal, of the dermis and subcutaneous tissue; Chapter 8 Cerebral aneurysm A dilated area on the circle of Willis that may rupture and cause brain damage; Chapter 14 Cerebral palsy A group of disorders caused by brain damage during the perinatal period and classified by the type of motor impairment; Chapter 14 Cerebrovascular accident A CVA or stroke is an infarction of brain tissue resulting from a thrombus, embolus, or hemorrhage causing permanent loss of brain tissue; Chapter 14 Cervical cancer An invasive cancer linked to viral infec- tions of the cervix. It can be diagnosed in situ by a Pap test; Chapter 19 Chlamydial infection A common sexually transmitted disease that may cause pelvic inflammatory disease (PID) in women; Chapter 19 Cholelithiasis Formation of gallstones, consisting of cholesterol or bilirubin, which may obstruct the biliary tract; Chapter 17 Cirrhosis Gradual destruction of liver tissue with loss of function and ultimately liver failure; Chapter 17 Cleft lip and palate Developmental defects of the mouth and nose caused by failure of tissues to fuse at the midline; Chapter 17 Colorectal cancer A tumor, signs of which depend on the location. Signs may be occult blood in the stool, change in bowel habits, or obstruction; Chapter 17 Condylomata acuminata (genital warts) A sexually transmitted disease caused by human papillomavirus; Chapter 19 Congestive heart failure (CHF) Inability of the heart to pump sufficient blood to meet the needs of the body. This may result from heart damage or increased demands on the heart. Cardiac output is reduced, and backup congestion in the tissues or organs develops; Chapter 12 Conjunctivitis Inflammation or infection of the conjunc- tiva of the eye; Chapter 15 Contact dermatitis Skin rash resulting from hypersensitiv- ity reaction or direct irritation after direct exposure to a substance; Chapters 7 and 8 Creutzfeldt–Jakob disease A type of dementia caused by an infectious prion; Chapter 14 Cryptorchidism Maldescent of the testes after birth; Chapter 19 Cushing syndrome Excessive glucocorticoids in the body cause catabolic effects on tissues, increased risk of infec- tion, and hypertension; Chapter 16 A p p e n d i c e s 647 Hemophilia Classic hemophilia is a genetic disorder characterized by excessive bleeding resulting from a deficit of clotting factor VIII; Chapter 10 Hepatitis, infectious Viral infection of the liver by one or more of the hepatitis virus group, causing inflammation and necrosis; Chapter 17 Hepatitis, toxic Inflammation and necrosis of the liver due to chemicals or drugs; Chapter 17 Herniated intervertebral disc Rupture or stretching of the annulus fibrosis of the disc causes pressure on spinal nerves and pain; Chapters 14 and 25 Herpes simplex Recurrent, viral infection usually around the mouth (HSV-1) or genitalia (HSV-2); Chapters 8, 17, and 19 Herpes zoster Infection in adults by varicella virus involving a unilateral cranial or spinal nerve; Chapter 14 Hiatal hernia Part of the stomach protrudes above the diaphragm, either temporarily or permanently, causing reflux and inflammation; Chapter 17 Histoplasmosis A fungal infection frequently in the lungs that may spread to other sites; Chapter 13 HIV infection Presence of human immunodeficiency virus (HIV) and antibodies in the blood, without signs of active infection; Chapter 7 Hodgkin lymphoma A malignancy involving the T lymphocytes that first develops in a single lymph node and then spreads in an orderly fashion; Chapter 11 Huntington disease An inherited disorder with onset in adulthood where progressive atrophy of the brain affects motor and cognitive functions; Chapter 14 Hydrocele Excessive fluid around the testes; Chapter 19 Hydrocephalus Excessive cerebrospinal fluid accumulates, compressing the brain tissue; Chapter 14 Hydronephrosis A disorder secondary to obstructions in the urinary tract, causing backup of urine and compres- sion of renal tissue; Chapter 18 Hyperparathyroidism Often due to an adenoma, it causes hypercalcemia and osteoporosis; Chapter 16 Hypertension, essential Consistently elevated blood pressure of unknown origin; Chapter 14 Hypertension of pregnancy Elevated blood pressure, proteinuria, and edema occurring in pregnancy. For- merly termed preeclampsia or eclampsia; Chapters 12 and 22 Hyperthyroidism Increased secretion of thyroid hormones causes hypermetabolism; Chapter 16 Hypoparathyroidism Hypocalcemia causes weak cardiac contractions and tetany; Chapter 16 Hypospadias Urethral opening on the ventral surface of the penis; Chapter 19 Hypothyroidism If severe and untreated, causes cretin- ism in the infant and child, myxedema in the adult; Chapter 16 Impetigo Highly contagious staphylococcal infection around the mouth, commonly occurring in children; Chapter 8 Esophageal cancer Squamous cell carcinoma frequently caused by chronic irritation; Chapter 17 Fibrocystic breast disease Nodules in breast tissue that change with cyclic hormonal levels. Some types should be monitored; Chapter 19 Fibromyalgia A syndrome of symptoms, including chronic pain in soft tissues of the body, sleep interruptions, fatigue, and in some cases depression; Chapter 9 Flail chest injury Multiple rib fractures cause loss of chest wall rigidity and paradoxical movements of the flail section during ventilation, resulting in hypoxia and circulatory impairment; Chapter 13 Fracture A break in a bone, of which there are various patterns; Chapter 9 Furuncle (boil) Staphylococcal infection in a hair follicle; Chapter 8 Gastric cancer An ulcerative cancer often arising in the mucous glands; Chapter 17 Gastritis, acute Inflammation or infection of the gastric mucosa causing nausea or vomiting, sometimes with pain; Chapter 17 Gastritis, chronic Chronic irritation causes atrophy of the gastric mucosa, including loss of secretory glands; Chapter 17 Gastroenteritis Acute inflammation or infection of the stomach and intestines causing pain, vomiting and diar- rhea; Chapter 17 Gastroesophageal reflux Intermittent flow of gastric contents into the esophagus related to an incom- petent sphincter or increased abdominal pressure; Chapter 17 Glaucoma Increased intraocular pressure due to increased aqueous humor. May damage the retina and optic nerve; Chapter 15 Glomerulonephritis (acute poststreptococcal) Anti- streptococcal antibodies cause inflammation in the glomeruli of the kidney causing increased perme- ability and decreased glomerular filtration rate (GFR); Chapter 18 Goiter Enlargement of the thyroid gland associated with both hyperthyroid and hypothyroid conditions; Chapter 16 Gonorrhea A common sexually transmitted disease that may cause pelvic inflammatory disease (PID) in women; Chapter 19 Gout Deposits of uric acid and urate in the joint cause inflammation and damage to the cartilage; Chapter 9 Guillain–Barré syndrome Reversible inflamma- tion and degeneration of the spinal nerves, causing paralysis and loss of function in an ascending pattern; Chapter 14 Hay fever (allergic rhinitis) An allergic reaction involving the nasal mucosa, causing increased watery secretions and sneezing; Chapter 7 Head injury Various types of injury may damage brain tissue directly or through increased intracranial pressure; Chapter 14 648 A p p e n d i c e s Malignant melanoma A skin cancer typically arising from a nevus or mole, which metastasizes at an early stage; Chapter 8 Metabolic syndrome Obesity, hypertension, type 2 diabetes, and lipid abnormalities that together are associ- ated with early mortality; Chapters 12, 16, and 23 Ménière syndrome Periodic episodes of excess endolymph formation in the inner ear, causes loss of hearing and vertigo, eventually permanent damage; Chapter 15 Meningitis An infection of the meninges covering the brain and spinal cord causing increased intracranial pressure; Chapter 14 Multiple myeloma A form of cancer involving the plasma cells, which invade the bone marrow, destroying bone in the vertebrae, ribs, pelvis, and skull; Chapter 10 Multiple sclerosis A group of chronic progressive dis- orders, resulting from demyelination in the brain, spinal cord, and cranial nerves; Chapter 14 Muscular dystrophy A group of inherited disorders causing progressive degeneration of skeletal muscle; Chapter 9 Myasthenia gravis An autoimmune disorder that inter- feres with the neuromuscular junctions, commencing in the face and neck; Chapter 14 Myocardial infarction (MI, heart attack) Obstruction of a coronary artery causes necrosis of heart tissue, impairing pumping ability and/or conduction; Chapter 12 Nephrosclerosis Degenerative changes in the arterioles cause ischemia and necrosis of kidney tissue as well as increased blood pressure; Chapter 18 Nephrotic syndrome A kidney disorder secondary to many systemic disorders, as well as kidney dis- eases, that causes marked proteinuria and lipiduria; Chapter 18 Non-Hodgkin lymphoma A malignancy involving primarily B lymphocytes with multiple lymph node involvement; Chapter 11 Osteoarthritis Noninflammatory, progressive degen- eration of the articular cartilage in joints, particularly the knees and hips. Impairs mobility; Chapters 9 and 24 Osteomyelitis Infection of the bone, often associated with trauma; Chapter 23 Osteoporosis Loss of bone density and mass leading to fragile bones and spontaneous fractures; Chapter 9 Osteosarcoma Malignant tumor in bone of child or young adult; Chapter 9 Otitis media Infection of the middle ear cavity; Chapter 15 Otosclerosis Fixation by abnormal bone growth of the stapes to the oval window in the middle ear, causing progressive loss of hearing; Chapter 15 Ovarian cancer Asymptomatic hidden tumor usually diagnosed after metastasis; Chapters 19 and 20 Ovarian cyst Various types and sizes of cysts may form on the ovaries; Chapter 19 Inappropriate ADH syndrome Excess antidi- uretic hormone (ADH) causes retention of fluid; Chapter 16 Infant respiratory distress syndrome Insufficient sur- factant production in premature infants prevents adequate lung expansion, resulting in severe hypoxia and fluid accumulating in the alveoli; Chapter 13 Infectious arthritis Infection and inflammation, some- times destructive, and usually involving a single joint; Chapter 9 Infectious mononucleosis A viral infection affecting lymphocytes, common in adolescents and young adults; Chapter 23 Infectious rhinitis (common cold) Viral infection (rhi- novirus, adenovirus) of the upper respiratory tract; Chapter 13 Infective endocarditis Microorganisms damage heart valves, both previously deformed and normal; Chapter 12 Influenza Viral infection involving the upper and lower respiratory tract, frequently complicated by pneumonia; Chapters 6 and 13 Intestinal obstruction May be structural or functional (paralytic ileus) and manifested by pain and vomiting; Chapter 17 Juvenile rheumatoid arthritis A group of autoimmune diseases causing inflammation in joints and other con- nective tissue in children; Chapters 9 and 23 Kaposi sarcoma A skin cancer now frequently associated with AIDS; Chapter 8 Keratitis Inflammation or infection of the cornea of the eye; Chapter 15 Keratoses Benign skin lesions associated with aging or sun damage; Chapter 8 Kyphosis Increased convexity of the thoracic spine; Chapter 23 Laryngotracheobronchitis (croup) Viral infection of the upper respiratory tract, including the larynx, in young children, causing a characteristic barking cough; Chapter 13 Leiomyoma (fibroid) Benign tumor of the uterus; Chapter 19 Leukemia A form of cancer in which one or more leu- kocytes is an immature, nonfunctional neoplastic cell developing in the bone marrow and peripheral blood, leading to increased risk of infection and hemorrhage; Chapter 10 Liver cancer Secondary tumors are common; the primary cancer is usually hepatocellular cancer related to hepatitis or cirrhosis; Chapter 17 Lung cancer Primary and secondary cancers are common in the lungs. Primary cancer is predis- posed by cigarette smoking and insidious in onset; Chapter 13 Macular degeneration Age-related degeneration of the macula lutea in the retina of the eye causes loss of vision in older persons; Chapter 15 A p p e n d i c e s 649 Polycystic kidney A group of genetic disorders in which gradually enlarging cysts progressively destroy kidney tissue; Chapter 18 Polycythemia vera Increased production of erythrocytes causing increased blood volume, viscosity, and blood pressure; Chapter 10 Preeclampsia Elevated blood pressure and kidney dysfunction during pregnancy; Chapter 22 Premenstrual syndrome A group of manifestations present the week before onset of menses; Chapter 19 Primary fibromyalgia syndrome Group of idiopathic disorders affecting muscles and tendons, causing pain and stiffness; Chapter 9 Prostate cancer Usually adenocarcinoma of the prostate gland, common in older men; Chapter 19 Prostatitis Inflammation or bacterial infection of the prostate gland; Chapter 19 Psoriasis Chronic inflammatory skin condition, character- ized by rapid cellular proliferation; Chapter 8 Pulmonary edema Fluid collecting in the alveoli and interstitial spaces for many different reasons, interfering with oxygen diffusion and lung expansion; Chapter 13 Pulmonary embolus Thrombus or other material traveling through the venous circulation to block blood flow through the lung, interfering with respiratory function or circulation; Chapter 13 Pyelonephritis Ascending infection of one or both kidneys; Chapter 18 Pyloric stenosis A developmental defect or acquired obstruction involving the pyloric sphincter, preventing gastric emptying; Chapter 17 Rabies Viral infection of the central nervous system (CNS) caused by a bite by a rabid animal; Chapter 14 Regional ileitis (Crohn disease) Chronic inflammatory disorder affecting the ileum, interfering with absorption of nutrients and a potential cause of obstructions; Chapter 17 Renal cell carcinoma Adenocarcinoma usually first indicated by painless hematuria; Chapter 18 Renal failure, acute Sudden loss of all kidney function, potentially reversible, resulting in anuria, acidosis, and elevated serum urea; Chapter 18 Renal failure, chronic Gradual permanent loss of neph- rons from primary kidney disease, with end-stage azo- temia, acidosis, and fluid–electrolyte imbalance affecting many systems; Chapter 18 Repetitive strain injury Repeated forceful movements damage muscles, tendons, or nerves; Chapter 9 Reye syndrome Cerebral edema and liver dysfunction, usually after viral infections treated with ASA in children; Chapter 14 Rheumatic fever A systemic inflammatory disorder resulting from an immune reaction, causing permanent damage to heart valves and sometimes the cardiac conduc- tion system; Chapter 12 Rheumatic heart disease Damaged heart valves and dysrhythmias caused by rheumatic fever. Impairs cardiac function; Chapter 12 Paget disease Progressive replacement of bone by fibrous tissue and abnormal bone in older persons; Chapter 9 Pancreatic cancer Adenocarcinoma often causes inflam- mation and obstruction of the ducts; Chapter 17 Pancreatitis Severe inflammation of the pancreas and surrounding tissues associated with autodigestion by pancreatic enzymes; Chapter 17 Panic disorder An anxiety disorder in which attacks occur with increased neuronal activity or changes in neurotrans- mitters; Chapter 14 Parkinson disease A progressive degenerative condition affecting mobility that results from loss of extrapyramidal function; Chapter 14 Pediculosis Infection by lice on the body, scalp, or pubic area; Chapter 8 Pelvic inflammatory disease Ascending infection of the female reproductive tract involving the fallopian tubes and ovaries; Chapter 19 Pemphigus An autoimmune disorder causing blisters to form on the skin; Chapter 8 Peptic ulcer Erosions in the mucosa of the stomach or proximal duodenum because of decreased tissue resistance or increased gastric secretions; Chapter 17 Pericarditis Inflammation or infection of the pericardium, causing effusion and impaired filling of the heart, or painful friction rub; Chapter 12 Periodontal disease Infection and damage to the gingiva, bone, and ligaments around the teeth; Chapter 17 Peritonitis Inflammation or infection of the peritoneal membranes leading to hypovolemia, pain, and possibly septicemia; Chapter 17 Pheochromocytoma A benign tumor of the adrenal medulla that causes increased secretion of catecholamines and hypertension; Chapter 16 Pituitary adenoma A benign tumor affecting the secretion of one or more pituitary hormones and increases intra- cranial pressure; Chapter 16 Pleural effusion Fluid collects in the pleural cavity due to inflammation, infection, or trauma, reducing lung expansion; Chapter 13 Pneumoconioses Chronic progressive restrictive lung disorders with fibrosis caused by chronic expo- sure to environmental irritants such as asbestos; Chapter 13 Pneumonia Infection in the lung by pneumococcus, viruses, or other microbes. Congestion interferes with oxygen diffusion and ventilation; Chapter 13 Pneumothorax Air in the pleural cavity results from injury or spontaneous tears in the pleura, causing atelectasis. Various types of pneumothorax may affect circulation and the unaffected lung; Chapter 13 Poliomyelitis A viral infection involving motor neurons in the spinal cord and medulla, often causing weakness or paralysis. Postpolio syndrome is now symptomatic in many persons with a history of polio in childhood; Chapter 14 650 A p p e n d i c e s and unoxygenated blood in the systemic circulation and thus systemic hypoxia and cyanosis; Chapter 12 Thalassemia A genetic defect in hemoglobin causes premature hemolysis of red blood cells (RBCs) and severe anemia; Chapter 10 Thrombophlebitis Inflammation in a leg vein often associated with thrombus formation; Chapters 12 and 22 Tinea Fungal infection of the feet, scalp, or body; Chapter 8 Torsion of the testes Rotation of the testes on the sper- matic cord; Chapter 19 Transient ischemic attacks (TIAs) Result from temporary reduction of blood supply in an area of the brain, causing brief loss of function; Chapter 14 Trichomoniasis A sexually transmitted infection that remains localized; Chapter 19 Ulcerative colitis Chronic inflammation and ulceration of the rectum and colon with remissions and exacerba- tions; Chapter 17 Urolithiasis (renal calculi) Kidney stones most frequently composed of calcium or uric acid, which may obstruct flow of urine; Chapter 18 Urticaria (hives) Skin rash resulting from hypersensitivity to ingested substances; Chapter 8 Uterine prolapse Various degrees of descent of the cervix or uterus into the vagina; Chapter 19 Varicose veins Dilated and tortuous areas of superficial or deep veins in the legs. May cause edema and impaired arterial circulation; Chapter 12 Variocele Dilated vein in the spermatic cord; Chapter 19 Ventricular septal defect A congenital deformity; a hole in the septum between the ventricles that results in a left-to-right shunt of blood; Chapter 12 Verrucae (warts) A skin lesion caused by human papil- lomavirus, often on the hands or feet; Chapter 8 Wilms tumor A congenital tumor of the kidney occurring in young children. It presents as a large abdominal mass; Chapter 18 Ready Reference 8 Drug Index Acetaminophen (Tylenol) Analgesic for mild pain, antipyretic; Chapter 4 Acetylsalicylic acid (ASA, Aspirin) Antiinflammatory, analgesic for mild pain; antipyretic; reduces platelet adhesion and blood clotting; Chapters 4, 5, 12, and 9 Acyclovir (Zovirax) Antiviral agent—herpes simplex; Chapters 8 and 17 Albuterol (Ventolin) Bronchodilator, inhaler; Chapter 13 Alendronate (Fosamax) Inhibits bone resorption in osteoporosis; Chapters 9 and 24 Almotriptan (Axert) Analgesic in the treatment of migraine; Chapter 22 Rheumatoid arthritis A systemic inflammatory disorder, considered to be of autoimmune origin, causing progres- sive damage to joints; Chapter 9 Rh incompatibility When the mother is Rh negative and the fetus is Rh positive, the antigen–antibody reaction causes hemolysis of fetal erythrocytes; Chapter 22 Rickets Soft bone and leg deformity in a child due to lack of vitamin D and phosphate; Chapter 9 Scabies Invasion of the skin by a mite; Chapter 8 Schizophrenia A group of mental disorders character- ized by typical alterations in the brain and behavior; Chapter 14 Scleroderma A progressive skin disorder with possible systemic effects, characterized by collagen deposits and inflammation; Chapter 8 Scoliosis Lateral curvature of the spine, often developing in adolescence; Chapter 23 Seizure disorders A group of disorders characterized by different types of recurrent localized or generalized seizures that result from sudden excessive uncontrolled neuronal activity in the brain; Chapter 14 Severe acute respiratory syndrome (SARS) An emerg- ing viral infection (coronavirus) that causes severe congestion in the lungs and hypoxia. Mortality is high; Chapter 13 Shock Decreased circulating blood volume because of impaired pumping by the heart, loss of blood volume, or general vasodilation. This leads to decreased blood pressure and general hypoxia; Chapter 12 Sinusitis Bacterial infection of one or more paranasal sinuses; Chapter 13 Spermatocele A cyst between the testis and epididymis; Chapter 19 Spina bifida Congenital defect in which the posterior spinous processes of the vertebrae do not fuse, in many cases allowing the meninges, cerebrospinal fluid (CSF), and nerve tissue to protrude; Chapter 14 Spinal cord injury The effects depend on the level of injury and the extent of the permanent damage to the spinal cord; Chapter 14 Squamous cell carcinoma A skin cancer usually related to sun exposure; Chapter 8 Stress ulcers Multiple gastric ulcers resulting from severe ischemia; Chapter 17 Syphilis A sexually transmitted disease with systemic manifestations; Chapter 19 Systemic lupus erythematosus (SLE) A chronic auto- immune disease causing inflammation and damage in multiple systems; Chapter 7 Testicular cancer A rare tumor affecting young males; Chapter 19 Tetanus An infection by a spore-forming bacillus that causes severe, possibly fatal, muscle spasms; Chapter 14 Tetralogy of Fallot A congenital heart defect that includes four cardiac abnormalities: pulmonary stenosis, ventricular septal defect, dextroposition of the aorta, and right ventricular hypertrophy. Leads to mixing of oxygenated A p p e n d i c e s 651 Lorazepam (Ativan) Antianxiety drug; Chapter 26 Meperidine (Demerol) Narcotic analgesic; Chapter 4 Metformin (Glucophage) Oral hypoglycemic; Chapter 16 Metoprolol (Lopressor) Antihypertensive, antianginal, antiarrhythmic; Chapter 12 Nifedipine (Adalat) Antihypertensive, antianginal, peripheral vasodilator; Chapter 12 Nitrofurantoin (Furadantin) Antibacterial; urinary tract infections; Chapter 18 Nitroglycerin Prevent and treat angina; Chapter 12 Nystatin (Mycostatin) Antifungal agent; Chapter 17 Omeprazole (Prilosec) Reduces gastric acid secretion; Chapter 17 Oseltamivir (Tamiflu) Antiviral—influenza; Chapter 6 Pancrelipase (Cotazym) Pancreatic enzyme replacement (e.g., cystic fibrosis); Chapter 13 Penicillin Antibacterial, primarily gram-positive microbes; Chapter 6 Phenobarbital Sedative; Chapter 14 Phenytoin (Dilantin) Anticonvulsant; Chapter 14 Prednisone Glucocorticoid, antiinflammatory, reduces allergic reaction; Chapter 5 Pregabalin (Lyrica) Central-acting analgesic for fibro- myalgia; Chapter 9 Promethazine (Phenergan) Sedative, antihistamine, antiemetic; Chapters 7, 17, and 26 Propantheline (Pro-Banthine) Gastrointestinal antispas- modic; Chapter 17 Pyridostigmine (Mestinon) Treat myasthenia gravis; Chapter 14 Psyllium hydrophilic mucilloid (Metamucil) Laxative— bulk; Chapter 17 Ramipril (Altace) Antihypertensive; Chapter 12 Ribavirin (Virazole) Antiviral agent—hepatitis C; Chapter 17 Selegiline (Eldepryl) Treat Parkinson disease; Chapter 23 Simvastatin (Zocor) Decrease cholesterol and low-density lipoprotein LDL levels; Chapter 12 Spironolactone (Aldactone) Potassium-sparing diuretic; Chapter 18 Streptokinase (Streptase) Thrombolytic agent; Chapters 12, 13, and 14 Sulfasalazine (Salazopyrin) Antiinflammatory/ antibacterial; Chapter 17 Tamoxifen (Nolvadex) Blocks estrogen receptors; Chapter 19 Tetrabenazine (Xenazine) Reduces choreiform move- ments; Chapter 14 Tetracycline Antibacterial, broad spectrum; Chapter 6 Timolol Reduces intraocular pressure in glaucoma; Chapter 15 Trifluoperazine (Stelazine) Antipsychotic; Chapter 14 Trimethoprim-sulfamethoxazole (Bactrim) Antibacterial; Chapter 18 Amantadine (Symmetrel) Antiviral, influenza; Chapters 6 and 13 Amitriptyline (Elavil) Antidepressant; Chapter 14 Amoxicillin (Amoxil) Antibacterial, prophylaxis for endocarditis; Chapters 6 and 12 Amphotericin B (Fungizone) Antifungal drug; Chapter 13 Atorvastatin (Lipitor) Cholesterol-lowering agent; Chapter 12 Azathioprine (Imuran) Immunosuppressant; Chapter 7 Azithromycin (Zithromax) Antimicrobial; Chapter 19 Captopril (Capoten) Antihypertensive; Chapter 12 Cefotaxime sodium (Cefotaxime) Third-generation cephalosporin, antimicrobial; Chapter 6 Celecoxib (Celebrex) Nonsteroidal antiinflammatory analgesic; Chapter 9 Cimetidine (Tagamet) Decrease gastric acid secretion in peptic ulcer; Chapter 17 Ciprofloxacin (Ciloxan) Antibacterial; Chapter 6 Clarithromycin (Biaxin) Antibacterial; Chapter 17 Clindamycin (Dalacin) Antibacterial; Chapter 6 Codeine For moderate pain; Chapter 4 Cyclobenzaprine (Flexeril) Skeletal muscle relaxant; Chapter 9 Diazepam (Valium) Antianxiety, antiepileptic, relief of skeletal muscle spasm; Chapters 9, 14 and 26 Digoxin Congestive heart failure, antiarrhythmic; Chapter 12 Diltiazem (Cardizem) Reduce cardiac conduction and contractility; Chapter 12 Dimenhydrinate (Dramamine, Gravol) Antiemetic; Chapter 17 Diphenhydramine (Benadryl) Antihistamine, reduce allergic reactions; Chapter 7 Docusate sodium (Colace) Stool softener, laxative; Chapter 17 Donepezil (Aricept) Treat early stages of Alzheimer disease; Chapter 14 Enalapril (Vasotec) Antihypertensive; Chapter 12 Eletriptan (Relpax) Analgesic for migraine; Chapter 22 Epinephrine General vasoconstrictor, increases heart rate and force, bronchodilator; Chapters 7, 12, and 13 Fluoxetine (Prozac) Antidepressant; Chapter 14 Furosemide (Lasix) Diuretic, for edema; Chapter 12 Glyburide (DiaBeta) Oral hypoglycemic; Chapter 16 Griseofulvin (Fulvicin) Antifungal; Chapter 6 Haloperidol (Haldol) Antipsychotic agent; Chapter 14 Heparin Anticoagulant; Chapters 10 and 12 Hydrochlorothiazide (Hydro DIURIL) Diuretic, antihy- pertensive; Chapter 18 Ibuprofen (Advil, Motrin) Relieves pain and inflamma- tion (NSAIDs); Chapters 3 and 4 Isoniazid (INH) Antitubercular drug; Chapter 13 Levodopa (Sinemet, Larodopa) Relief of Parkinson disease; Chapter 14 Loperamide (Imodium) Antidiarrheal; Chapter 17 652 A p p e n d i c e s Warfarin (Coumadin) Anticoagulant, prophylaxis for thrombi; Chapter 12 Zanamivir (Relenza) Antiviral—influenza; Chapter 13 Zidovudine (Retrovir) Antiretroviral agent (HIV); Chapter 6 Ready Reference 9 Additional Resources Specific resources are listed below. T E X T B O O K S Anatomy and Physiology Applegate EJ: The anatomy and physiology learning system, ed 4, Philadelphia, 2011, WB Saunders. Guyton AC, Hall JE: Textbook of medical physiology, ed 12, Philadelphia, 2011, WB Saunders. Thibodeau GA, Patton KT: Structure and function of the body, ed 14, St Louis, 2012, Mosby. Tortora GJ, Derrickson BH: Principles of anatomy and physiology, ed 13, New York, 2011, Wiley. Pathophysiology Copstead-Kirkson LE, Banasik JL: Pathophysiology, ed 5, Philadelphia, 2013, WB Saunders. Kumar V, Abbas AK, Fausto N: Robbins and Cotran pathologic basis of disease, ed 8, Philadelphia, 2010, WB Saunders. McCance KL, Huether SE: Pathophysiology: the biologic basis for disease in adults and children, ed 6, St Louis, 2010, Mosby. Medicine Abrams WB: The Merck manual of geriatrics, ed 3. Online at http://www.merck.com/mkgr/mmg/home.jsp. Andreoli TE, et al: Andreoli and Carpenter’s Cecil essentials of medicine, ed 8, Philadelphia, 2011, WB Saunders. Porter RS: The Merck manual of diagnosis and therapy, ed 19, Whitehouse Station, NJ, 2012, Merck & Co. Callen JP, Greer KE, Paller AS, Swinyer LJ: Color atlas of dermatology, ed 2, Philadelphia, 2000, WB Saunders. Heymann DL: Control of communicable diseases manual, ed 19, Washington, DC, 2009, American Public Health Association. Kliegman RM, Behrman RE: Nelson textbook of pediatrics, ed 19, Philadelphia, 2012, WB Saunders. Kliegman RM, Marcdante K, Jensen HB, Behrman RE: Nelson essentials of pediatrics, ed 6, Philadelphia, 2011, WB Saunders. Papadakis M, et al: Current medical diagnosis and treatment 2014, ed 53, New York, 2014, Lange Medical Books/ McGraw-Hill. Perkin GD: Mosby’s color atlas and text of neurology, ed 2, London, 2002, Mosby. Pharmacology Burnham T: Drug facts and comparisons, St. Louis, Facts and Comparisons (drug index with monthly updates). Favaro MKA, Favaro J: Introduction to pharmacology, ed 12, Philadelphia, 2012, WB Saunders. Gillis MC: Compendium of pharmaceuticals and specialties, Ottawa, Ontario, Canada, Canadian Pharmacists Association (annual). Haveles EB: Applied pharmacology for the dental hygienist, ed 6, St Louis, 2011, Mosby. Krinsky DL, LaValle JB, Hawkins EB, et al: Natural therapeutics pocket guide, ed 2, Hudson, OH, 2003, Lexi-Comp. Mosby’s drug consult 2007, St Louis, 2007, Mosby. Skidmore-Roth L: Mosby’s 2013 nursing drug reference, St Louis, 2013, Mosby. Skidmore-Roth L: Mosby’s handbook of herbs and natural supplements, ed 4, St Louis, 2010, Mosby. Other Topics Bergquist LM, Pogosian B: Microbiology: principles and health science applications, Philadelphia, 2000, WB Saunders. Engelkirk Pand Burton G: Burton’s microbiology for the health sciences, ed 9, Philadelphia, 2010, Lippincott Williams & Wilkins. Greenwood D, Slack RC, Peutherer JF: Medical microbiology: a guide to microbial infections: pathogenesis, immunity, laboratory diagnosis and control, ed 17, New York, 2007, Churchill Livingstone. Little JW, Falace D, Miller CS, Rhodus NL: Little and Falace’s dental management of the medically compromised patient, ed 8, St Louis, 2013, Mosby. Mahon CR, Manuselis G: Textbook of diagnostic microbiology, ed 4, Philadelphia, 2011, WB Saunders. Malarkey LM, McMorrow ME: Saunders nursing guide to laboratory and diagnostic tests, ed 2, Philadelphia, 2012, WB Saunders. Pagana KD, Pagana TJ: Mosby’s diagnostic and laboratory test reference, ed 11, St Louis, 2013, Mosby. Dictionaries and Medical Terminology Chabner DE: The language of medicine, ed 9, Philadelphia, 2011, WB Saunders. Dorland’s illustrated medical dictionary, ed 32, Philadelphia, 2011, WB Saunders. Miller-Keane MT, O’Toole M: Miller-Keane encyclopedia and dictionary of medicine, nursing and allied health, ed 7, Philadelphia, 2005, WB Saunders. Mosby’s medical, nursing and allied health dictionary, ed 9, St Louis, 2013, Mosby. Journals American Scientist; Published by Sigma Xi, The Scientific Research Society, Research Triangle Park, NC. Heart and Lung: Journal of Critical Care. Journal of Allergy and Clinical Immunology. Journal of the American Medical Association (JAMA). http://www.merck.com/mkgr/mmg/home.jsp A p p e n d i c e s 653 Journal of Bacteriology. Journal of Clinical Oncology. Journal of Emergency Medicine. Lancet. Nature: International Journal of Science, London, England. New England Journal of Medicine. Scientific American. Journals Published by Professional Groups American Journal of Nursing. American Journal of Occupational Therapy. Clinical Acupuncture and Oriental Medicine. Clinics in Sports Medicine. Journal of the American Dietetic Association. Journal of Dental Hygiene. Physical Medicine and Rehabilitation Clinics. Respiratory Care Clinics. Web Sites http://www.ama-assn.org: American Medical Association. http://www.americanheart.org: American Heart Association. http://www.amsci.org: American Scientist Journal. http://www.asha.org: American Speech-Language-Hearing Association. http://www.asm.org: American Society for Microbiology. http://www.cancer.org: American Cancer Society. http://www.cdc.gov: Centers for Disease Control and Prevention. http://www.fda.gov: United States Food and Drug Administration. http://www.healthfinder.gov: United States Department of Health and Human Services. http://www.lungusa.org: American Lung Association. http://jama.ama-assn.org: The Journal of the American Medical Association. http://www.mayoclinic.com: Mayo Clinic. http://aip.completeplanet.com. http://www.nci.nih.gov: National Cancer Institute. http://content.nejm.org: The New England Journal of Medicine. http://www.nhlbi.nih.gov: National Heart, Lung, and Blood Institute. http://www.niaid.nih.gov: National Institute of Allergy and Infectious Diseases. http://www.niams.nih.gov: National Institute of Arthritis and Musculoskeletal and Skin Diseases. http://www.niddk.nih.gov: National Institute of Diabetes and Digestive and Kidney Diseases. http://www.nih.gov/icd: National Institutes of Health (research site). http://www.nlm.nih.gov/medlineplus: United States National Library of Medicine. http://www.sciam.com: Scientific American (journal). http://www.scienceonline.org: Science (journal). http://www.who.int: World Health Organization. http://www.wfnals.org: World Federation of Neurology. http://www.ama-assn.org/ http://www.americanheart.org/ http://www.amsci.org/ http://www.asha.org/ http://www.asm.org/ http://www.cancer.org/ http://www.cdc.gov/ http://www.fda.gov/ http://www.healthfinder.gov/ http://www.lungusa.org/ http://jama.ama-assn.org/ http://www.mayoclinic.com/ http://aip.completeplanet.com/ http://www.nci.nih.gov/ http://content.nejm.org/ http://www.nhlbi.nih.gov/ http://www.niaid.nih.gov/ http://www.niams.nih.gov/ http://www.niddk.nih.gov/ http://www.nih.gov/icd http://www.nlm.nih.gov/medlineplus http://www.sciam.com/ http://www.scienceonline.org/ http://www.who.int/ http://www.wfnals.org/ 654 Glossary Abscess a localized pocket of infection or purulent exudate surrounded by inflammation. Accommodation the lens of the eye adjusts its shape for distance. Acetylcholine (Ach) a neurotransmitter. Achlorhydria lack of hydrochloric acid in the gastric secretions. Acidosis an increased number of hydrogen ions; a blood pH of less than 7.4. Acute a disease with sudden onset of signs and short course. Adenocarcinoma malignant tumor arising from glandular epithelial cells. Adenoma benign tumor made up of glandular epithelial cells. Adhesion a band of fibrous scar tissue forming an abnormal connection between two surfaces or structures (e.g., binding two loops of intestine together). Adrenergic related to the sympathetic nervous system transmitters norepinephrine (noradrenaline) and epinephrine (adrenaline). Afferent toward the center; for example, afferent nerves carry impulses toward the central nervous system. Agenesis lack of an organ or structure because of a developmental error. Agglutination clumping together of cells or particles. AIDS (acquired immunodeficiency syndrome) a chronic infectious disease caused by HIV, which destroys helper T-lymphocytes, causing a loss of immune response. Albumin a plasma protein responsible for maintaining osmotic pressure of the blood. Aldosterone a mineralocorticoid hormone that increases the reabsorption of sodium and water in the renal tubules. Alkalosis a decreased number of hydrogen ions; a blood pH greater than 7.4. Allele one of two forms of a gene at corresponding sites on a chromosome pair; the code for phenotype or characteristic manifested in an individual. Allergen an antigen that can initiate an allergic reaction. Alopecia hair loss. Amenorrhea the absence of menstrual periods. Amnesia loss of memory. Amniocentesis removal of a small amount of amniotic fluid from around the fetus for examination and diagnosis. Amputation the removal of a body part, often a limb or part of a limb, to remove a tumor, prevent spread of infection, or relieve pain. Anabolism the building up or synthesis of complex compounds from simple molecules. Anaerobic metabolism and function without oxygen. Analgesic a substance that relieves pain. Anaphylaxis a life-threatening systemic allergic or hypersensitivity reaction, with respiratory obstruction and decreased blood pressure. Anaplasia undifferentiated primitive cells of variable size and shape, associated with cancer. Anasarca severe generalized edema. Anastomosis a connection between two blood vessels or tubes. Androgen steroid hormone that enhances male characteristics (e.g., testosterone). Anemia a decrease in circulating hemoglobin and oxygen-carrying capacity in the blood because of decreased erythrocyte production, decreased hemoglobin production, excessive hemolysis, or loss of blood. Anencephaly congenital condition where most of the brain and skull are absent. Anesthetic a substance that reduces sensation, locally or systemically. Aneurysm an outpouching or abnormal dilated area in a blood vessel. Angiogenesis the development of new capillaries. G los s a ry 655 Athetoid involuntary writhing movement of limbs and body. Atopic inherited tendency to hypersensitivities. Atresia blind end to a tube; loss of the lumen. Atrophy degeneration and wasting of tissue, organs, or muscle due to decrease in cell size. Atypical unusual, not characteristic. Aura a sensation (e.g., visual or auditory), usually preceding a seizure or migraine headache. Auscultation listening for sounds, perhaps with a stethoscope, within the body (e.g., lungs, heart, intestines). Autoantibody antibodies to self-antigens such as cells or DNA. Autoclave an appliance to sterilize instruments or materials with steam at high temperature and pressure. Autodigestion abnormal destruction of tissues by activated digestive enzymes. Autoimmune the development of antibodies to self-antigens. Autoinoculation the spread of infection (e.g., by fingers) from one site to a second site on the body. Autopsy an examination of part or all of a body, including organs, after death (postmortem) to determine the cause of illness and death. Autoregulation automatic regulation or reflex control of blood flow in an area depending on the local needs. Azotemia excess urea and other nitrogen wastes in the blood, as in renal failure. Bacteremia bacteria present in the circulating blood. Bactericidal chemical that destroys bacteria. Bacteriostatic substance that reduces the growth and reproduction of bacteria. Baroreceptor a sensory nerve receptor that is stimulated by a change in pressure, perhaps blood pressure. Basal Metabolic Rate (BMR) the amount of energy (measured by oxygen requirements) to maintain essential function in the body at rest. Benign nonthreatening, mild, or nonmalignant. Bifurcation the division of a tube or vessel into two channels or branches. Bilirubin a product from the breakdown of hemoglobin, excreted in bile. Biopsy the removal of a small piece of living tissue for microscopic examination to determine a diagnosis. Bolus a round mass of food ready to be swallowed; a dose of concentrated drug administered intravenously all at once. Borborygmus the rumbling or gurgling sounds from gas in the intestine. Bradycardia abnormally slow heart rate. Bradykinin a chemical mediator released during inflammation causing vasodilation. Angiography an examination of blood vessels using radiographs with a contrast medium. Angioplasty repair of a blood vessel. Angiotensin-Converting Enzyme (ACE) an enzyme that converts angiotensin I to angiotensin II, a potent general vasoconstrictor and stimulus for aldosterone secretion. Anion a negatively charged ion such as chloride, Cl−. Ankylosis fixation or immobility at a joint. Anomaly an abnormal structure, often congenital. Anorexia loss of appetite. Antagonism opposing action. Antibiotic a substance derived from microorganisms that is used to treat infection. Antidiuretic Hormone (ADH) increases absorption of water in the renal tubules. Antigen a substance that causes the production of antibodies. Antimicrobial an agent that kills or inhibits growth and reproduction of microorganisms. Antineoplastic a substance or process that destroys neoplastic cells. Antioxidant a substance such as vitamin E that reduces oxygenation and production of damaging “free radicals” during cell metabolism. Antiseptic reduces the number of microorganisms on the skin. Anuria absence of urine production. Aphasia loss of the ability to communicate, speak coherently, or understand speech. Apnea lack of breathing. Apoptosis normal programmed cell death in tissues. Arrhythmia loss of normal heart rate and rhythm; dysrhythmia. Arteriosclerosis hardening and loss of elasticity of the arterial wall with narrowing of the lumen. Arthroscopy examination and possible treatment of a joint through insertion of a small instrument. Aschoff Bodies localized lesions in the heart muscle that may interfere with conduction. Ascites abnormal accumulation of fluid in the abdominal cavity. Asepsis the absence of pathogens. Aspiration inhaling liquid or solid material into the lungs or withdrawing fluid or tissue from a cavity or organ. Asymptomatic no signs or symptoms. Asystole absence of cardiac contractions; cardiac arrest or standstill. Ataxia impaired coordination, imbalance, staggering gait. Atelectasis collapse and nonaeration of part or all of a lung. Atherosclerosis development of obstruction by cholesterol plaques and thrombus on the walls of large arteries. 656 G los s a ry Broca’s Area area of the left frontal lobe of the brain in which the output of words, both written and verbal, is coordinated. Bronchoconstriction contraction of smooth muscle in the bronchioles, narrowing the airways. Bronchodilation relaxation of smooth muscle in the bronchioles, widening the airway. Bruit an abnormal sound heard by auscultation (e.g., blood flow in an aneurysm). Cachexia extreme loss of weight and body wasting associated with serious illness. Calcification deposits of calcium in tissues. Calculus a stone developing in the body (e.g., kidney or bile). Carcinogen a substance that causes cancer by changing normal cells. Cardiomegaly a heart that is larger than normal size. Caries (dental) destruction of the tooth surface; a cavity or erosion in the enamel surface of a tooth. Carpopedal Spasm a strong muscle contraction of the hand or foot. Carrier a person hosting an infectious pathogen who shows no signs of the disease but could transmit the infection to others. Catabolism the breakdown of complex molecules into simple molecules during metabolism. Cataract an opacity of the lens of the eye. Catheter a small tube inserted into the bladder to remove urine; a tube inserted into a blood vessel or other structure to allow drainage or maintain an opening. Cation a positively charged ion such as sodium, Na+. Chemical Mediator a chemical released in the body during an inflammatory response or immune response. Chemoreceptor a sensory nerve receptor stimulated by chemical changes such as pH. Chemotaxis the movement of cells toward or away from an area of the body in response to chemical signals (e.g., phagocytic cells move to an area of tissue injury). Cholestasis obstructed flow of bile in the liver or biliary tract. Chorea involuntary repeated jerky movements of face and limbs. Chorionic Villus part of the placenta that can be tested for genetic defects in the fetus. Choroid Plexus infoldings of blood vessels of the pia mater that secrete cerebrospinal fluid. Chromosome made up of genes, the genetic code of the living cell, consisting of DNA. Chronic a condition with insidious or slow onset, mild but continuous manifestations, and long-lasting, often progressive, effects. Chyme thick, semifluid mixture of partially digested food passing out of the stomach into the duodenum. Clonic Movements consisting of rapid, alternating contraction and relaxation of skeletal muscle. Coagulation the process of changing a liquid into a solid (e.g., blood forming a thrombus). Cognitive intellectual abilities, for example, memory, thinking, problem solving, judgment, initiative. Cohesion tendency to stick together or be attracted. Colic sharp severe pain resulting from strong, smooth muscle contraction (e.g., intestinal). Collagen the common protein making up connective tissue and bone. Collagenase an enzyme that breaks down collagen fibers. Colostomy surgical creation of an artificial opening from the colon onto the abdominal surface. Coma unconscious state; person cannot be aroused. Communicable Disease a disease that can be transmitted from an infected person, directly or indirectly, to other susceptible hosts. Complement a series of inactive proteins circulating in the blood; when activated, they can destroy bacteria or antigens or participate in the inflammatory response. Compliance the ability of the lungs to expand and recoil or the patient’s willingness to follow a prescribed treatment. Congenital present at birth. Contamination the presence of a pathogen on a body, clothing, or inanimate object. Contracture shortening of a muscle or scar tissue causing immobility and deformity of a joint or structure. Contraindications any condition that renders a particular treatment improper or undesirable. Contralateral opposite side of the body. Contusion tissue injury or bruise; bleeding into tissues. Corticosteroid the steroid hormones from the adrenal cortex, including the glucocorticoids (cortisol) and mineralocorticoids (aldosterone). C-reactive Protein (CRP) appears in the blood with inflammation and necrosis. Crepitus the noise heard when the ends of a broken bone rub together or when fluid is present in the lung. Culture growth of microorganisms on a specific nutritious medium in a laboratory. Cyanosis bluish color of skin and mucosa that occurs when a large proportion of hemoglobin is unoxygenated. Cyst a closed sac or capsule lined with epithelium, containing fluid. Cytology the study of cells. Cytotoxic a substance that damages or destroys cells. Débridement surgical removal of dead tissue and foreign material from a wound. Decubitus (Ulcer) skin breakdown from prolonged pressure on skin and tissue over a bony prominence leading to compressed blood vessels and ischemia. G los s a ry 657 Dehydration a deficit of water in the body. Dementia progressive loss of intellectual function, loss of memory, personality change. Demyelination loss of the myelin sheath from a nerve surface, interfering with conduction. Denude stripping off skin, leaving bare. Dermatome an area of skin innervated by a specific spinal nerve. Detoxification the removal of a toxic or poisonous material and/or neutralization of its effects on a person. Dialysis a procedure to remove wastes and excess fluid or adjust blood to normal values in cases of renal failure. Diapedesis the passage of leukocytes through intact capillary walls to a site of inflammation. Diaphoresis excessive perspiration. Differential Count the proportion of each type of leukocyte in a blood sample. Differentiation increased specialization of cells for certain functions. Diffusion the movement of molecules from an area of high concentration to low concentration. Diplopia double vision. Disinfectant a chemical that may destroy or inhibit the growth and reproduction of microorganisms. Disorientation mental confusion with inadequate or incorrect awareness of time, place, and person. Diuresis excessive amount of urine. Dosage determination of the size, frequency, and number of doses. Dose a quantity to be administered at one time. Dyscrasia abnormality of the blood or bone marrow; abnormal cell characteristics or numbers. Dysentery severe diarrhea, often bloody, with cramps. Dyspareunia pain or discomfort in the pelvis during sexual intercourse. Dysphagia painful or difficult swallowing. Dysplasia disorganized cells that vary in size and shape with large nuclei. Dyspnea difficulty breathing. Dysuria painful urination. Ecchymoses reddish blue discoloration of skin or mucosa because of bleeding. Ectopic away from the normal position, displaced. Edema the accumulation of excess fluid in cells, tissue, or a cavity, resulting in swelling. Efferent moving away from the center; for example, efferent nerve fibers carry motor impulses to muscles. Effusion the accumulation of fluid leaking from a blood vessel into a cavity or potential space. Electrocardiogram (ECG) a record of conduction in the heart. Embolus a mass (e.g., blood clot, air, fat, tumor cells) that breaks away into the circulation and obstructs a blood vessel. Embryo the early stage of an organism’s life; in humans, the developmental stage between implantation in the uterus and 8 weeks. Encephalopathy impaired function of the brain. Endarterectomy removal of the intima and any obstructive material in an artery. Endemic a disease that is always present in a specific region. Endogenous originating from within the body. Endorphins morphinelike substances produced in the body that block pain stimuli at sites in the brain and spinal cord. Endoscope an illuminated optic instrument that can be inserted into a body cavity, tube, or organ to visualize any changes (bronchoscope, cystoscope, laparoscope). Endospore (Spore) a latent form that certain bacteria can assume under adverse conditions, in order to survive extreme temperatures, drying, or chemicals. Endotoxin a toxin released from the walls of certain gram-negative bacteria after lysis. Enteric related to the intestine. Enterotoxin a toxin from certain bacteria that damages the intestinal mucosa. Enzyme-Linked Immunosorbent Assay (ELISA) a test to detect certain antibodies. Eosinophilia the formation and accumulation of an abnormally large number of eosinophils in the blood. Epidemic a disease occurring in higher numbers than usual in a certain population within a given period. Epistaxis nose bleed. Epstein-Barr Virus (EBV) a virus that causes infectious mononucleosis. Erythema redness and inflammation of the skin or mucosa due to vasodilation. Erythrocyte Sedimentation Rate (ESR) the rate at which red blood cells (RBCs) settle out of a blood specimen (containing anticoagulant); an elevation in ESR is a general characteristic of inflammation. Etiology cause or origin of a disease or abnormality. Euphoria an exaggerated feeling of well-being or unrealistic elation. Eupnea normal, regular, quiet breathing. Exacerbation an acute episode or increased severity of manifestations. Excoriation an abrasion or injury to the skin. Exogenous originating from outside the body. Exteroreceptors sensory receptors located close to the body surface and are sometimes referred to as cutaneous receptors. Exotoxin toxin excreted by a bacterium (e.g., neurotoxin or enterotoxin). Exudate a fluid that accumulates and may leak from tissue, for example, a serous exudate due to allergy, a purulent exudate, or pus associated with infection. Fascia sheet of fibrous connective tissue separating and supporting muscle. 658 G los s a ry Fecalith a hard mass of feces, often impacted, in the intestine. Ferritin a storage form of iron. Fetus the human child in utero between 8 weeks and birth. Fibrinogen the plasma protein that is formed into solid fibrin strands during the clotting process. Fibrinolysis the breakdown of fibrin. Fibrosis growth of fibrous or scar tissue related to collagen deposits. Fimbria a hairlike projection on some bacteria. Fissure a crack or split in the surface of skin or mucous membrane. Fistula an abnormal tube or passage formed between structures, for example, between the esophagus and trachea or between the rectum and skin. Flaccidity lack of tone in muscle; weakness and softness. Foramen an opening in bone or membrane. Free Radical a byproduct of cell metabolism that damages cell membranes, proteins and DNA. Fulminant rapid, severe, uncontrolled progress of a disease or infection. Ganglion a collection of nerve cell bodies, usually outside the central nervous system. Gangrene necrotic tissue infected by bacteria. Gene a unit of DNA (a nucleic acid sequence) in a particular location on a specific chromosome. Genetic inherited. Genotype the genetic makeup of a cell or individual. Gestation the time between conception and birth. Gingivitis inflammation of the gums in the mouth. Globulin a group of proteins in the blood. Glucocorticoid the steroid hormones from the adrenal cortex, for example, cortisol (hydrocortisone), that increase blood glucose levels and act to decrease inflammation and allergic reactions. Gluconeogenesis the production of glucose from protein or fat. Glucosuria glucose in the urine. Glycemic Index the rate at which an ingested carbohydrate elevates blood glucose levels. Glycogen a polysaccharide, made up of glucose molecules, stored in skeletal muscle or the liver. Glycoprotein a combination of protein and carbohydrate. Gram Stain a stain for bacteria that differentiates the cell walls of gram-positive bacteria from that of gram-negative bacteria; used for identification and choice of drug treatment. Granulation Tissue newly developed fragile tissue, consisting of fibroblasts and blood vessels, formed during healing. Granuloma a nodular destructive mass associated with some chronic inflammation or infection. Gynecomastia abnormal breast enlargement in men. Hallucination a sensory perception (e.g., visual or auditory) that is not real but results from nervous system excitation. Hemarthrosis bleeding into a joint cavity. Hematemesis vomiting blood; may be called “coffee- grounds” vomitus because it appears brown and granular. Hematocrit percentage of erythrocytes in a blood sample. Hematoma a blood clot formed after bleeding into a tissue or organ. Hematuria blood in the urine; may be microscopic (small amount) or gross (large amount, darkening the color). Hemiparesis weakness on one side of the body. Hemiplegia paralysis on one side of the body. Hemolysis destruction of erythrocytes with release of hemoglobin. Hemoptysis frothy sputum containing streaks of blood, usually bright red; spitting up blood. Hemostasis blood clotting or controlling bleeding. Heparin a substance present in the body to prevent blood clotting. Hepatomegaly enlarged liver. Hepatotoxin a substance that damages the liver. Hering-Breuer Reflex a reflex that prevents excessive lung expansion. Heterozygous having two different alleles at corresponding points on a chromosome pair. Hirsutism excessive body hair in a male pattern. Histamine a chemical released from mast cells and basophils during immune reactions; causes vasodilation and bronchoconstriction. Holistic an approach to health care that includes the physical, mental, emotional, and spiritual needs of the patient. Homeostasis a relatively stable or constant environment in the body, including blood pressure, temperature, and pH, maintained by the various control mechanisms. Homozygous having two identical alleles at corresponding points on a chromosome pair. Hypercapnia increased level of carbon dioxide (CO2) in the blood. Hyperemia increased blood flow in an area, resulting in a warm, red area. Hyperkalemia abnormally high level of potassium ions (K+) in the blood. Hypernatremia abnormally high level of sodium ions (Na+) in the blood. Hyperplasia an abnormal increase in the number of cells resulting in an increased tissue mass. Hyperreflexia excessive reflex responses. Hypertension a persistent elevation of blood pressure. Hypertonic a solution with a greater concentration of solutes or higher osmotic pressure than that inside the cells present in the solution. G los s a ry 659 Hypertrophy increased size of an organ or muscle due to increased size of individual cells. Hyperuricemia excessive uric acid in the blood. Hyphae filamentous or threadlike outgrowths produced by some fungi and bacteria. Hypoalbuminemia abnormally low serum albumin levels. Hypoproteinemia abnormally low level of plasma protein in the blood. Hypotension low blood pressure and decreased tissue perfusion. Hypovolemia decreased blood volume. Hypoxemia insufficient oxygen in the arterial blood. Hypoxia a decreased or insufficient level of oxygen in the tissues. Iatrogenic caused by a treatment, procedure, or error. Ictal related to a seizure (postictal—after a seizure). Icterus jaundice. Idiosyncrasy an unusual reaction by an individual to a normally harmless substance. Idiopathic no known cause. Immunocompetent a person who can produce a normal immune response. Immunodeficiency (Immunocompromised, Immunosuppressed) reduced ability of the immune system to produce an immune response to defend the body. Immunoglobulin a protein with antibody activity. Incidence the number of new cases of a disease in a certain population within a given period. Incontinence lacking voluntary control over urination or defecation. Incubation Period the time between the initial exposure to the infectious agent and the appearance of the first signs of infection. Infarct, Infarction an area of dead tissue caused by lack of blood supply. Inflammation the response to tissue damage, indicated by redness, swelling, warmth, and pain. Insidious a disease whose onset is marked only by vague or mild general signs. In Situ cell growth and reproduction, such as cancer, remaining at the original site, not invasive or spreading. Interferons a group of antiviral glycoproteins produced by viral-infected cells. Interleukin protein (cytokine) primarily produced by T cells, active in the inflammatory and immune responses and leukocyte communication. Intraarticular into the joint cavity or joint space. Intractable resistant to treatment (e.g., pain) that cannot be relieved by drugs. Ipsilateral same side of the body. Ischemia decreased blood supply to an organ or tissue. Isoenzymes cell enzymes specific to certain organs that differ slightly in structure but have similar functions. Jaundice yellow color of the sclera of the eye and skin due to excessive bilirubin in the body fluids for any reason. Karyotype a visual demonstration of the pairs of cell chromosomes arranged in order of size. Keloid abnormal healing causes overgrowth of collagen and mass of fibrous tissue. Ketone or Ketoacid chemical byproduct of lipid metabolism. Kyphosis increased convex curvature of the spine in the thoracic region; “hunchback.” Labile unstable, changing. Laryngospasm closure of the larynx obstructing the airway. Latent present but hidden and inactive. Lesion an abnormality in the structure of a tissue or organ. Leukocytosis an above-normal number of leukocytes (white blood cells [WBCs]) in the blood. Leukopenia a decreased number of leukocytes in the blood. Lichenification hardening and thickening of the skin; leatherlike. Lithiasis presence or formation of stones or calculi (e.g., cholelithiasis—gallstones). Lordosis exaggerated concave curve of the lumbar region of the spine. Lymphadenopathy a disease affecting the lymph nodes. Lymphoma malignant neoplasm of lymphoid tissue. Lysis destruction of a cell. Lysosome a membrane-bound vesicle in a cell containing digestive or lytic enzymes, including lysozyme. Lysozyme enzymes found in some cells and in body fluids such as tears, sweat, or saliva, which can destroy some microorganisms. Macroangiopathy degenerative changes in the walls of large arteries. Macule a discolored skin lesion that is not elevated above the skin surface. Malabsorption impaired absorption of nutrients from the intestines. Malaise a general feeling of discomfort or unease or of being unwell. Mast Cells located in the tissues, they release chemicals such as histamine, heparin, and bradykinin in response to injury or foreign material. Mediastinum the area of the thoracic cavity between the lungs in which is located the trachea, esophagus, and large blood vessels. Megaloblast abnormally large, nucleated, immature erythrocytes. Melena black, tarry stool caused by bleeding in the digestive tract. Metabolic Syndrome syndrome associated with obesity, including hypertension, type 2 diabetes, and hyperlipidemia. 660 G los s a ry Metabolism the chemical processes occurring in living cells, consisting of anabolism (synthesis or building up of new compounds) and catabolism (breakdown of complex substances). Metaplasia replacement of one mature cell type by another mature cell type. Metastasis spread of cancer cells to distant sites by the blood or lymphatics; secondary malignant tumor. Microcirculation blood flow in the very small blood vessels (e.g., capillaries). Micrometastasis spread of malignant cells not yet detectable. Microorganism very small living organism, not visible to the naked eye, usually single-celled. Microscopic visible only when magnified by lenses in a microscope. Micturition voiding of the urinary bladder; urination. Mitosis a process of cell reproduction resulting in two daughter cells with the same DNA as the parent cell. Morbidity the rate at which a disease occurs; the proportion of a group affected by a disease. Morphologic the physical size, form, structure, and shape of cells or organs. Mortality the number of deaths in a group for a specific disease. Murmur an abnormal sound heard in the heart, caused by a defective valve or opening in the heart. Mutation a change in the genetic makeup (DNA) of a cell, which will be inherited. Mycosis fungal infection. Necrosis death or destruction of tissue. Neonate newborn child. Neoplasm abnormal growth of new cells, benign or malignant. Neuritis inflammation of a nerve. Neuropathy degeneration of nerve fibers. Neurotoxin a bacterial toxin that affects the nervous system function. Neurotransmitter a chemical released upon stimulation from vesicles at the end of the axon of a neuron in order to stimulate the receptor site. Neutropenia a deficit of neutrophils in the blood. Nevus a darkly pigmented lesion on the skin; a mole. Nidus the focus or point of origin of a morbid process. Nociceptor receptors for pain stimuli. Nocturia urination required during sleep at night. Nosocomial an infection acquired while hospitalized. Nuchal Rigidity a stiff neck, often associated with meningitis or brain hemorrhage. Nystagmus involuntary rhythmic movements of the eyes in any direction. Occlusion an obstruction or blockage. Occult hidden, difficult to detect. Occurrence the incidence and prevalence of disease. Oliguria abnormally small volume of urine output. Oncogenic a substance or situation that causes cancer. Oncology the study of cancer. Opioid natural or synthetic substance that binds to opioid receptors in the central nervous system, relieving pain; related to opium derivatives such as morphine or codeine. Opportunist a microorganism, normally nonpathogenic, that causes infectious disease when the person’s resistance is reduced, microbial balance is upset, or the microbe is transferred to another part of the body. Organogenesis the formation and differentiation of organs and systems during embryonic development. Orthopnea difficult or labored breathing when recumbent that is usually relieved by an upright position. Orthostatic Hypotension a drop in blood pressure occurring when a person rises from a supine to a standing position. Osmosis the force that draws water through a semipermeable membrane from a solution of lower solute concentration to a solution of higher concentration. Osmoreceptors sensory nerve receptors stimulated by changes in fluid and electrolyte concentrations. Osteodystrophy a general defect in bone development related to altered calcium and phosphate metabolism. Ototoxic a substance causing damage to the inner ear or auditory nerve. Palliative providing comfort and relieving pain and other symptoms of a disease without effecting a cure. Pancytopenia decrease in all blood cells, erythrocytes, leukocytes, and thrombocytes. Pandemic a worldwide increase in the numbers of people affected by a disease. Paraneoplastic Syndrome additional disorders such as Cushing syndrome resulting from some malignant tumors. Paraplegia paralysis of the lower limbs. Parasite an organism that lives on or in another living organism. Parenteral the injection of substances into the body (e.g., intramuscularly or intravenously). Paresis muscle weakness or mild paralysis. Paresthesia abnormal sensations. Paroxysmal Nocturnal Dyspnea awakening in severe respiratory distress, usually associated with pulmonary edema. Pathogen a disease-causing microorganism. Pathogenesis the early stages in the development of a disease. Pathogenicity ability of microorganism to cause disease. Perforation a hole through the wall of a tube or hollow structure. Perfusion the flow of blood in the microcirculation to supply oxygen and nutrients to cells. G los s a ry 661 Periodontal Disease inflammation and damage to the structures anchoring the teeth, including the periodontal ligament, gingiva, and alveolar bone. Periodontitis an inflammatory reaction of the tissues surrounding the tooth. Permeable Membrane permits certain substances to pass through. Petechiae tiny, pinpoint hemorrhages under the skin. Phagocyte a cell that can surround, ingest, and destroy microorganisms, cell debris, or foreign substances (e.g., a macrophage). Phenotype the characteristics manifested by a person depending on genetic and environmental factors. Phlebotomy incision into a vein and collecting of blood. Photophobia increased sensitivity of the eyes to light. Pili hairlike appendages on some bacteria for adhesion to tissue and transfer of DNA. Placebo a medication that lacks active ingredients, prescribed for psychological effect or as part of research studies. Plaque a flat, raised covering or scale. Plasma the liquid portion of blood after cells are removed. Polysaccharide a carbohydrate made up of many sugars (e.g., glycogen, starch). Polyuria an abnormally large volume of urine excreted within a given period. Potentiate to increase the strength or effect. Precursor a substance that can be used to form other materials. Prevalence the total number of new and existing cases of a disease in a specific population at a given time. Prion an infectious abnormal protein particle; does not contain DNA. Probability the likelihood or chance of occurrence. Prodromal the initial period in the development of disease before acute symptoms occur. Prognosis the probable outcome of a disease. Prophylactic a measure or drug to prevent disease. Proprioceptors receptors that provide information about body movement, orientation, and muscle stretch. Prostaglandins (PGs) a group of chemical substances in the body that can exert a variety of effects, such as vasodilation, muscle contraction, and inflammation. Prosthesis an artificial replacement for a body part (e.g., a limb or heart valve). Protease an enzyme that breaks down a protein into amino acids. Proteinuria an abnormality whereby protein is found in the urine. Pruritus itching sensation. Pseudohypertrophy abnormal enlargement of tissue or organ due to excessive fat and fibrous tissue. Ptosis drooping eyelid. Pulse Pressure the difference between systolic and diastolic pressures. Pulsus Paradoxus abnormal decrease in systolic pressure during inspiration. Purpura reddish-blue discoloration of the skin due to bleeding; bruise. Purulent like pus (microbes, white blood cells [WBCs], and cell debris); thick, yellowish material in tissue often resulting from bacterial infection. Pyrexia fever. Pyrogen a substance that causes fever, a rise in body temperature. Pyuria pus in the urine. Radioisotope a radioactive form of an element giving off radiation (beta or gamma) in the body, used in diagnosis and therapy. Radiosensitive responsive such as cells damaged by radiation. Radiotherapy treatment of cancer with radiation from an external source (gamma rays), such as radioactive cobalt or an internal implant of radioactive material. Rales a bubbly or crackling sound in the lungs caused by air mixing with fluid in the airways. Reflux backward movement of fluid, for example, from the stomach into the esophagus and mouth. Regeneration tissue repair through replacement by identical functioning cells. Regurgitation a reverse flow to the normal (e.g., vomiting). Reservoir a site where pathogens can survive or multiply. Resident Flora (also called microflora, indigenous flora, normal flora, microbiota) the variety of nonpathogenic microorganisms that normally permanently colonize various parts of the body. Residual volume the volume of air remaining in the lungs after maximum expiration. Retroperitoneal behind the peritoneal membrane against the abdominal wall. Retrovirus a virus containing RNA and the enzyme reverse transcriptase, required to convert RNA to DNA that is then integrated with host cell DNA. Rhonchus a harsh noise heard in the lungs resulting from air passing through partial obstruction by thick mucus or exudates. Sclerosis abnormal hardening of tissue. Scotoma a defect in the visual field. Sedative a substance that exerts a calming effect on a person. Sedentary inactive lifestyle. Seizure (Convulsion) sudden, involuntary movement with loss of awareness, caused by uncontrolled neuronal discharge in the brain. Senescence related to aging, growing old. 662 G los s a ry Septicemia, Sepsis systemic infection arising from bacterial toxins in the circulating blood or bacteria reproducing and spreading through the circulating blood. Serous watery secretion. Serum the liquid portion of the blood, lacking cells and clotting factors. Spasm a strong, involuntary muscle contraction. Splenectomy removal of the spleen. Splenomegaly enlarged spleen. Stasis slowing of the normal flow of fluid. Steatorrhea fatty, bulky stool resulting from malabsorption. Stem Cell a basic cell that may divide to give rise to a variety of specialized cells (e.g., the blood cells). Stenosis narrowing of a tube, valve, or opening (stricture). Sterile absence of all forms of microorganisms. Steroid hormones based on a cholesterol structure produced in the adrenal cortex or gonads. Stomatitis inflammation and ulceration in the mouth. Stricture abnormal narrowing of a duct or tube. Stridor an abnormal high-pitched, crowing sound caused by obstruction in the trachea or larynx. Stupor a state of extreme lethargy, unawareness, and unresponsiveness. Subluxation partial dislocation of a joint. Substernal Retraction the chest wall under the sternum moves inward during inspiration. Supine lying down on the back. Syncope fainting, temporary loss of consciousness. Syndrome a group of signs and symptoms characteristic of a specific disorder. Synergism a combination of substances or agents that produce an effect greater than expected. Tachycardia excessively rapid heartbeat. Tachypnea rapid, shallow respirations. Tenesmus spasms or straining associated with forced or painful elimination of urine or stool. Teratogen a substance or condition that impairs normal development of the embryo or fetus in utero, causing a congenital abnormality. Tetany repeated skeletal muscle contractions or spasms, seen in the extremities and face, related to increased irritability of the nerves, often associated with hypocalcemia. Therapeutic beneficial treatment. Thrombocytopenia abnormally low number of thrombocytes or platelets. Thrombus a blood clot attached inside a blood vessel. Tinnitus abnormal ringing sound or noise in the ears. Total Parenteral Nutrition (TPN) administration of a nutritionally complete fluid (protein, glucose, vitamins, etc.) into the superior vena cava. Toxin a substance that can harm the body or interfere with its function; poisonous. Transcutaneous Electrical Nerve Stimulation (TENS) electrical stimulation of nerve endings through electrodes placed on the skin, for relief of pain. Transillumination the passage of light through a structure to determine if an abnormality is present. Trisomy Cells contain an extra chromosome, for a total of 47; named for the pair where the extra chromosome occurs (e.g., trisomy 21). Troponins a complex of muscle proteins that inhibits contraction. Turgor indicates tension of the skin based on pressure within the cells; a measure of dehydration. Ulcer an open, craterlike lesion on the skin or mucous membranes. Ulcerogenic producing or aggravating ulcers. Universal Precautions safety precautions at two levels, recommended to protect health care workers from infection, based on the assumption that all patients and all body fluids are sources of infection. Uremia the end result of renal failure when waste products accumulate in the blood and fluid/electrolyte imbalance develops. Uveitis inflammation of the uveal tract of the eye (iris, ciliary body, and choroid). Vaccine attenuated or killed microorganisms administered to induce antibody production. Vector an animal or insect that transmits disease. Verrucae a wart. Vesicle a small thin-walled sac containing fluid (e.g., a blister). Viable ability to sustain life. Virulence the degree of pathogenicity or disease that a microbe is capable of causing. Visceroceptors receptors that are located internally and provide information about the environment around the viscera. Vital Capacity the maximum amount of air that can be moved in and out of the lungs. Wernicke’s Area an integration center in the brain that comprehends language, both spoken and written. Wheeze a high-pitched whining sound typical of obstruction in the bronchioles and small bronchi. Xerostomia dry mouth with reduced saliva secretion. 663 Index A Abnormal menstrual bleeding, 527 Abnormal spinal curvatures, 173–174, 174f ABO blood groups, 193, 194t Abortion, 580 Abruptio placentae, 584 Abscess, 150 brain, 351–352, 352f definition of, 71 pancreatic, 468 Staphylococcus, 106f Absence seizures, 368 Absorption, 434–435 Accommodation, 386–387 Acetaminophen, 74 Acetylcholine (ACh), 164, 164f, 335 Acetylsalicylic acid (ASA), 61–62, 73–74 ACh. see Acetylcholine. Achalasia, 446–447 Achlorhydria, 197 Acid-base balance, 24 Acid-base imbalances, 29–36, 32t, 282, 438 acidosis, 33–35 alkalosis, 35–36 compensation and, 32 concepts and processes related to, 29–30 decompensation and, 32–33 pH and, 30–32 types of, 32 Acidosis, 32t, 33–35, 267 causes of, 33–35 effects of, 35 examples of, 34–35, 37t Acid pump inhibitor, 440–441 Acids, 626 Acini, 523 Acne, 150 Acne vulgaris, 593–594, 594f Acquired immunity, 120–121, 120t Acquired immunodeficiency, 131–132 Acquired immunodeficiency syndrome (AIDS), 132–139, 133f agent, 134–135, 134f–135f case study on, 139b–140b children with, 137 clinical signs and symptoms of, 136, 137f–138f course of, 134f diagnostic tests for, 136 history of, 132–134 people over age of 50 with, 137–139 stages of, 133f T cells and, 118 transmission, 135–136 treatment of, 137–139 tuberculosis and, 138–139 women with, 137 Acquired seizures, 368 Acromegaly, 415–416, 417f ACTH. see Adrenocorticotropic hormone. Actinic keratoses, 157 Actinobacillus actinomycetemcomitans, 444 Activated partial thromboplastin time (APTT), 204 Active artificial immunity, 120–121 Active natural immunity, 120 Active transport, 489 Acupuncture, 50 Acute appendicitis, 475f Acute asthma, 300, 301f, 321b Acute coronary syndrome, 233–242. see also Coronary artery disease. Acute disease, 6 Acute endocarditis, 257 Acute gastritis, 449 Acute infections, 106 Acute inflammation, 69–72 diagnostic tests for, 71–72 local effects of, 70–71 pathophysiology and general characteristics of, 69–70 potential complications with, 72 systemic effects of, 71 Acute lymphocytic leukemia (ALL), 209, 209f–210f case study on, 211b Acute myelogenous leukemia (AML), 209 Acute necrotizing fasciitis, 151–152 Acute necrotizing ulcerative gingivitis (ANUG), 444 Acute neurologic problems, 344–363 brain injuries, 354–358 brain tumors, 344–345 infections, 350–354 spinal cord injuries, 358–363 vascular disorders, 345–350 Acute pancreatitis, 468–469, 468f Acute period of infection, 105 Acute poststreptococcal glomerulonephritis, 500–502 Acute pulmonary edema, 248–249 Acute renal failure, 507–509, 508f, 509t, 614 Acute respiratory distress syndrome (ARDS), 266–267, 319–320, 319f Acute respiratory failure (ARF), 320 Acute rheumatic mitral valvulitis, 256f Acute tissue/organ transplant rejection, 122 Acyclovir, 109 Addiction, 618 Addison disease, 421–423, 423t Adenocarcinomas, 296 Adenoma, 403. see also Benign tumors. ADH. see Antidiuretic hormone. Adhesions, 79f, 592 scar formation and healing, complications with, 78 Adolescence changes during, 588–589 complications of, 588–596 eating disorders during, 593 infection during, 594 metabolic syndrome during, 589–590 musculoskeletal abnormalities during, 590–592 obesity during, 589–590, 589f pregnancy during, 586 sexual development during, disorders affecting, 595 skin disorders during, 593–594 Adrenal cortex, 421–423 Adrenal gland disorders, 420–423 Adrenaline, 335–337 Adrenal medulla, 420 Adrenergic-blocking drugs, 232 Adrenergic fibers, 335–337 Adrenergic receptors, 225, 337 Adrenocorticotropic hormone (ACTH), 75 Adriamycin, 558–559 Adult polycystic kidney, 507, 507f Adult respiratory distress syndrome (ARDS), 319–320, 319f AEDs. see Automated external defibrillators. Aerobic exercise, 165 Aerobic respiration, 165 Aerosol transmission, 100 Afferent arterioles, 491, 494f Afferent fibers, 54–55, 330 AFP. see Alpha-fetoprotein. Afterload, 228 Age-related macular degeneration (AMD), 393, 393f Agenesis, 506 Agglutination, 193 Aging process, 597–598 cancer and, 603 cardiovascular system and, 599 complications of, 597–605 digestive system and, 602–603 flexibility and, 601 herniated intervertebral disc and, 601 hormones and, 598 infections and, 603 mucosa and, 599 multiple disorders and, 603–604 muscles and, 601 musculoskeletal system and, 600–601 nervous system and, 602 nutrition and, 602–603 osteoarthritis and, 600–601 osteoporosis and, 600 physiologic changes with, 598–603 reproductive system and, 598–599 skeletal muscles and, 601 skin and, 599 urinary system and, 603 Agnosia, 341 Agraphia, 341 AIDS. see Acquired immunodeficiency syndrome. AIDS dementia, 377. see also Acquired immunodeficiency syndrome. Air trapping, 301 Alanine aminotransferase (ALT), 72 Albinism, 143 Alcohol. see also Substance abuse. case study on abusing, 622b nervous system, damage to, 622 potential complications of, 621–622 Alcoholic hepatitis, 463 Alcoholic liver disease, 463–464, 621. see also Cirrhosis. Aldosterone, 15 Alendronate, 172 Alexia, 341 Algae, 99 Page numbers followed by “f” indicate figures, “t” indicate tables, and “b” indicate boxes. 664 I n d e x Alkalosis, 32t, 35–36 ALL. see Acute lymphocytic leukemia. Allele, 565–566, 571 Allergen, 123 Allergic dermatitis, 146 Allergic reactions, 123–125. see also Allergies. anaphylactic shock as, 125 anaphylaxis as, 125 to antibacterial drugs, 108–109 causative mechanism of, 123 clinical signs and symptoms of, 123–125 Allergic rhinitis, sign of allergic reaction, 123 Allergies, 123. see also Allergic reactions. Allograft, 121–122 Alopecia, 559 Alosetron, 440 Alpha-fetoprotein (AFP), 365, 574 Alpha receptors, 337 ALS. see Amyotrophic lateral sclerosis. ALT. see Alanine aminotransferase. Alveolar ducts, 274 Alveoli/alveolus, 274, 279f Alzheimer’s disease, 375–377, 376f, 602 AMD. see Age-related macular degeneration. Amebas, 97–98 Ameboid action, 191 Amenorrhea, 526, 593 American Sign Language (ASL), 395 Amitriptyline, 379 AML. see Acute myelogenous leukemia. Amlodipine, 231–232 Amnesia, 354 Amniocentesis, 574–575, 581 Amnion, 579–580 Amniotic fluid, 581 Amoxicillin, 500 Amphiarthroses, 166 Ampulla, 515 Amyotrophic lateral sclerosis (ALS), 373–374 Anabolic hormone, 404 Anabolic steroids, 165 Anaerobic metabolism, 9, 265 Anaerobic respiration, 165 Analgesic effect, 73–74 Analgesics, 61t, 560 Anaphylactic shock, 125, 267 Anaphylaxis, 125, 125t, 126f case study on, 139b emergency treatment for, 125b Anaplasia, 8 ANAs. see Antinuclear antibodies. Anasarca, 502 Anastomoses, 226, 331, 490–491 Androgens, 589 Anemia, 195–203, 203t, 496. see also specific types of. aplastic, 199–200 bulimia nervosa and, 593 Cooley, 203 Fanconi, 200 hemolytic, 200–203, 626, 626f iron deficiency, 196, 196f–197f megaloblastic, 197–199 pernicious, 198f pernicious anemia-vitamin B12 deficiency as, 197–199 sickle cell, 200, 202f from tumors, 549 Anencephaly, 365, 580 Anesthesia, for pain, 62, 63t Aneurysms aortic, 261–262, 262f “berry”, 349 cerebral, 349–350, 349f dissecting, 261 Angina pectoris, 238–239, 239b, 239f Angiogenesis, 76, 548 Angiogenesis inhibitor drug, 560 Angiotensin-converting enzyme inhibitors (ACE inhibitors), 232 Anion, 28 Ankylosing spondylitis, 181–182, 181f Ankylosis, 178 Ann Arbor staging system, 218 Anopheles mosquito, 97 Anorexia nervosa, 435 during adolescence, 593 hypokalemia, effect of, 24 inflammation, systemic effect of, 71 ANP. see Atrial natriuretic peptide. Antacids, 439–440 Antagonism, 42 Antagonistic hormones, 402 Antagonists, 165 Anterior cavity of eye, 387 Anterior cerebral artery, 331 Anterior communicating artery, 331 Anthrax, 293–294 Antibacterial drugs, 91f, 108–109, 440 Antibiotics, 108 Antibodies antinuclear, 129, 180 B cells and, 118 immune system and, 120–121 specific, 115 titer of, 119 Anticholinergic drugs, 440 Anticoagulant drugs, 192f, 205 Anticoagulants, 232 Antidiarrheals, 440 Antidiuretic hormone (ADH), 15, 416 Antiemetic drugs, 559 Antifungal agents, 109–110 Antigenic blood types, 193–194, 194f, 194t Antigens carcinoembryonic, 477 HLA-B27, 181 human leukocyte, 195, 200 immune system and, 115 prostate specific, 520 type A, 193 type B, 193 Antihelminthic agents, 110 Antihistamine drugs, 125 Antihypertensive drugs, 232 Antiinflammatory analgesic aspirin (ASA), 180 Antimicrobial drugs, 108 classification of, 108 guidelines for using, 107–108 modes of action of, 108–110 for treating infections, 107–110 Antineoplastic drugs, 558 Antinuclear antibodies (ANAs), 129, 180 Antiprotozoal agents, 110 Antipyretic effect, 73–74 Antiseptics, 104–105 Antistreptokinase (ASK), 496 Antistreptolysin O (ASO), 496 Antiviral agents, 109, 109f ANUG. see Acute necrotizing ulcerative gingivitis. Anuria, 507 Aortic aneurysms, 261–262, 262f Aphasia, 340–341, 341t Aphthous ulcers, 442 Apical pulse, 228 Aplastic anemia, 199–200 Apnea, 318 Apocrine glands, 144 Apoptosis, 9, 546, 598 Appendages, 144 Appendicitis, 473–475, 474f–475f APTT. see Activated partial thromboplastin time. Aqueous humor, 387 Arachnoid, 327 Arachnoid mater, 327 Arachnoid villi, 327 ARDS. see Acute respiratory distress syndrome; Adult respiratory distress syndrome. ARF. see Acute respiratory failure. Aromatherapy, 49 Arrhythmias, 225, 593. see also Cardiac dysrhythmias. Arterial blood gas determination, 231 Arterial circulation, 20 Arterial disorders, 258–262 aortic aneurysms as, 261–262 atherosclerosis as, 261 hypertension as, 258–260 peripheral vascular disease as, 261 Arteries, 185, 188f anterior cerebral, 331 anterior communicating, 331 basilar, 331 internal carotid, 331 interventricular, 226 left anterior descending, 226 left circumflex, 226 major, 186f middle cerebral, 331 posterior cerebral, 331 posterior communicating, 331 vertebral, 331 Arterioles, 185 Arteriosclerosis, 233–238, 599 Arthritis gouty, 180–181 infectious, 180 rheumatoid, 178–180, 179f, 182b septic, 180 Arthroscopy, 166–167 Arthus reaction, 127 Articular capsule, 166 Articular cartilage, 166, 600–601 Articulation, 162 Artificial blood, 195 Artificial kidney, 497 ASA. see Acetylsalicylic acid; Antiinflammatory analgesic aspirin. Asbestos, 627, 627f Ascaris, 99 Aschoff bodies, 255 Ascites, 18–19, 249, 464–465, 466f Asian concepts, of disease and healing, 49–51 ASK. see Antistreptokinase. ASL. see American Sign Language. ASO. see Antistreptolysin O. Aspartate aminotransferase (AST), 72 Aspiration, 298–299 emergency treatment for, 300b in lungs, 430–431 vomiting and, 435 Aspiration pneumonia, 287 Association area, 329 AST. see Aspartate aminotransferase. Asthma, 300–302 acute, 300, 301f allergic reaction, sign of, 124–125 extrinsic, 300 intrinsic, 300 obstructive lung diseases and, 300–302 Astigmatism, 388 Astrocytoma, 345f Asystole, 245 Ataxic cerebral palsy, 366 Atelectasis, 312–313, 313f compression, 312 contraction, 312 obstructive, 312 postoperative, 312 resorption, 312 Atheromas, 234, 346 Atherosclerosis, 234f, 236f–237f, 261, 346, 599 as arterial disorder, 261 as coronary artery disease, 233–238 Athetoid, 366 Atopic, defined, 147 Atopic dermatitis, 147–148, 148f allergic reaction, sign of, 124 case study on, 159b Atopic hypersensitivity reactions, 123 Atorvastatin, 232–233 Atresia, 364, 447–448 Atrial conduction abnormalities, 243–244 Atrial fibrillation, 243f, 244 Atrial flutter, 244 Atrial natriuretic peptide (ANP), 16 Atrioventricular (AV) node block, ECG of, 243f Atrioventricular (AV) valves, 224 Atrioventricular node abnormalities, 244 Arterial disorders (Continued) I n d e x 665 Atrophied muscles, 607 Atrophy, 8–9 disuse, 607 of muscle, 165 Atypical cells, 546–547 Auditory tubes, 273 Aura, 368 Auscultation, 228, 580 Autoantibodies, 128 Autoclaving, 104 Autodigestion, 468 Autoimmune disorders, 128–131 example of, 128–131, 130f. see also Systemic lupus erythematosus. mechanism of, 128, 130f Autoinoculation, 151 Automated external defibrillators (AEDs), 241, 245, 245f Autonomic dysreflexia, 361–362, 362f Autonomic nervous system, 335–337, 337t parasympathetic nervous system within, 337 sympathetic nervous system within, 335– 337 Autopsy, 5 Autoregulation, 185, 238, 331, 491 Autosomal-dominant disorders, 568b, 571 Autosomal-recessive disorders, 568b, 571 Autosomes, 565 AV. see Atrioventricular (AV) valves. Avodart, 519 Avulsion, 170–171 Ayurveda, 51 Azathioprine, 122 Azidothymidine (AZT), 4, 138 Azotemia, 510 B Bacilli, 90 Bacteremia, 106 Bacteria binary fission of, 92 Gram-negative, 90 Gram-positive, 90 microorganism, as type of, 90–92 morphology of, 89f spores in, 94f structure of, 90, 91f Bacterial infections, 538–541. see also Bacterial skin infections. chlamydial infections as, 538–539 gonorrhea as, 539 local signs of, 106t syphilis as, 539–541 systemic signs of, 106t Bacterial skin infections, 150–152. see also Bacterial infections. acute necrotizing fasciitis as, 151–152 cellulitis as, 150, 151f furuncles as, 150–152, 151f impetigo as, 151 leprosy as, 152 Bactericidal drugs, 108 Bacteriostatic drugs, 108 Bacteroides forsythus, 444 Bacteroides oralis, 444 Balance tests, 398 Balanitis, 518 BAPP. see Beta-amyloid precursor protein. Baroreceptors, 225, 342 Bartholin glands, 523 Basal cell carcinoma, 561, 561f Basal ganglia, 330 Basal metabolic rate (BMR), 603, 608 Basal nuclei, 330 Bases, 626 Basilar artery, 331 Basilar fractures, 354–355 Basophils, 191 B cells, 118. see also B lymphocytes. BCG. see Calmette-Guérin (BCG) vaccine. Becker muscular dystrophy, 175f Beclomethasone dipropionate, 75 Benign prostatic hypertrophy (BPH), 518–519, 519f, 599 Benign tumors, 546–547 of breast, 548f characteristics of, 547, 547t, 548f in female reproductive system, 530–532 Bergey’s Manual, 89 “Berry” aneurysms, 349 Beta-amyloid precursor protein (BAPP), 376 Beta-blockers, 231, 337 Beta receptors, 337 Bevacizumab, 533, 560 Bicarbonate, 189 chloride and, 28, 29f maintenance of, 30, 31f Bicarbonate-carbonic acid buffer system, 30 Bifurcation, 277, 349 Bile ducts, 294 Biliary cirrhosis, 463 Bilirubin, 190–191, 584 Binary fission of bacteria, 92 Binge eating disorder, 593 Biologic agent hazards, 629–630 Biologic response modifiers, 559–560 Biopsy of bladder, 496 definition of, 5 of kidney, 496 of skin, 146 of tumors, 550 Biosynthetic skin substitutes, 84 Bioterrorism, immunity from, 121 Bisphosphonates, 172 Bites, 629–630 Bladder, 492–493 biopsy of, 496 cancer of, 505 exstrophy of, 516 Bleeding, abnormal menstrual, 527 Bleomycin, 559 Blindness, color, 387 Blocks, in heart, 244 Blood, 186–195. see also Circulatory system. antigenic types of, 193–194, 194f, 194t artificial, 195 brain, supply to, 331 cells in, 188–193. see also Hematopoiesis. clotting of, 193, 193f composition of, 187, 189f, 489t dyscrasias of, 195–208. see also Blood disorders. frank, 437 inflammation and, changes in, 72t occult, 437 one-way flow of, 224 therapies for, 195 whole, 195 Blood-brain barrier, 328 Blood cells, 191f Blood-cerebrospinal fluid barrier, 328 Blood clotting, 193, 193f. see also Blood-clotting disorders. Blood-clotting disorders, 204–207 disseminated intravascular coagulation as, 206–207, 206f hemophilia A as, 205 during pregnancy, 584 thrombophilia as, 207 von Willebrand disease as, 206 warning signs of, 204b Blood disorders anemias as, 195–203 blood-clotting disorders as, 204–207 myelodysplastic syndrome as, 207–208 neoplastic, 208–211 Blood groups, ABO, 194t Blood pressure, 229–230, 229f, 491 Blood tests, 231 for endocrine disorders, 404 for infection, 107 for skin, 146 troponin, 231 for urinary system disorders, 495–496 “Blood thinners”, 232 Blood types, antigenic, 193–194, 194f, 194t Blood urea nitrogen (BUN), 495 Blood vessels, 185 “Blue babies”, 253 B lymphocytes, 116 BMI. see Body mass index. BMR. see Basal metabolic rate. Body defenses, 66–67 mechanical barrier, 66 nonspecific, 66–67 specific, 66–67 Body louse, 156 Body mass index (BMI), 439, 589 Body surface area (BSA), 80 Boil. see Furuncles. Bolus, 430–431 Bone disorders, 172–174 abnormal curvatures of spine as, 174f bones tumors as, 174 osteomalacia as, 173 osteomyelitis as, 173 osteoporosis as, 172–173 Paget disease as, 173 rickets as, 173 Bone marrow, 195 Bones, 162–163, 163f cancellous, 162 compact, 162 dislocations of, 170, 170f fractures of, 167–170, 167f, 182b healing of, 168–170, 169f shape of, 162 spongy, 162 structure of, 162, 163f trauma to, 167–171 tumors of, 174 Bony callus, 168 Bony orbit, 386 Booster, 120–121 Borrelia burgdorferi, 352 Boyle’s law, 275 BPH. see Benign prostatic hypertrophy. Brachytherapy, 557 Bradycardia, 225, 243, 243f Brain, 326–331 abscess in, 351–352, 352f blood supply to, 331 cancer of, 561–563 cranial nerves in, 330–331 functional areas of, 328–331, 329f, 330t injuries to, 354–358, 355f. see also Head injuries. protection for, 326–328 tumors of, 344–345, 345f, 380b–381b, 561–563, 562f Brain attack, 348b. see also Cerebrovascular accidents. Brain death, 338–339 Brain stem, 330–331 Breast, 525f cancer of, 553b carcinoma of, 532–534 fibrocystic disease of, 530–532 metastasis of, 552f tumors of, 548f Breath sounds, 282 Breathing patterns, 281–282, 281f Broad spectrum, 108 Broca area, 329 Bronchiectasis, 307–308 Bronchiolitis, 285t, 286 Bronchitis, chronic, 322 Bronchoalveolar cell carcinomas, 296 Bronchoconstriction, 123 Bronchodilation, 274, 612 Bronchogenic carcinoma, 296, 297f Bronchopneumonia, 287t, 288–289, 288f Brudzinski sign, 350 BSA. see Body surface area. Buffer systems, 30 Bulbourethral glands, 515 Bulimia nervosa, 436, 593 BUN. see Blood urea nitrogen. Bundle branch block, 244 Burns, 78 assessment of, 80, 82f case study on, 86b in children, 80, 86 classifications of, 79–86, 80f deep partial-thickness, 81f 666 I n d e x effects of, 82–83 emergency treatment for, 82b fourth-degree, 79–80 full thickness, 79–80, 81f granulation tissue in, 78f healing of, 84 infections from, 84f partial thickness, 79, 80f–81f scar from, 79f second-degree, 79 third-degree, 79 Burow solution, 146 Bursae, 166 Bursitis, 182 “Butterfly rash”, 128, 130f C CABG. see Coronary artery bypass graft. Cachexia, 549 Café coronary, 299 Calcitonin, 172 Calcium, 26, 164 for clot formation, 193 parathyroid hormone and, 413–414, 415f supplements for, 172 Calcium channel blockers, 231–232 Calcium imbalances, 26–27, 27t hypercalcemia, 27 hypocalcemia, 27 signs of, 27t Calcium stones, 503–504 Calculi, 498–499, 503–504, 504f. see also Kidney stones. Calmette-Guérin (BCG) vaccine, 292, 559–560 Canal of Schlemm, 387 Cancellous bone, 162 Cancer, 545–564. see also Malignant tumors; specific types of. aging process and, 603 bladder, 505 breast, 553b cervical, 535f colorectal, 476–478, 477f–478f, 560 esophageal, 448 exocrine, 469 gastric, 454–455 incidences of, 563 liver, 467 lung, 296–298 of oral cavity, 445–446 ovarian, 537, 551, 553f, 561 pancreatic, 469 prostate, 519–520 sites of, 563t skin, 561 staging of, 552–553 of testes, 520–521, 521f warning signs of, 549b Cancer suppressor genes, 555 Candida, 83, 97 Candida albicans, 353 Candidiasis, 412f, 442, 527–528 Capillaries, 185 Capillary permeability, 19 Capsule, 90–91 Captopril, 232 Carbapenems, 500 Carbohydrates, complex, 434–435 Carbon dioxide, transport of, 279–280 Carbon monoxide poisoning, 282 Carbuncles, 151 Carcinoembryonic antigen (CEA), 439, 477 Carcinogenesis, 553–555 Carcinomas. see also Tumors; specific types of. basal cell, 561, 561f of breast, 532–534 bronchoalveolar cell, 296 bronchogenic, 296, 297f of cervix, 534–536, 535f, 551f endometrial, 536–537 hepatocellular, 467, 467f large cell, 296 “oat cell”, 296 renal cell, 505, 505f small cell, 296 squamous cell, 157, 158f of uterus, 536–537 Cardiac arrest, 245 Cardiac catheterization, 230–231 Cardiac control center, 225 Cardiac cycle, of heart, 227–228, 227f Cardiac dysrhythmias, 24, 242–245, 244t asystole and, 245 atrial conduction abnormalities and, 243–244 atrioventricular node abnormalities and, 244 cardiac arrest and, 245 sinus node abnormalities and, 243 standstill and, 245 treatment of, 245 ventricular conduction abnormalities and, 244 Cardiac output, 228, 229f Cardiac reserve, 228 Cardiac tamponade, 257–258 Cardiogenic shock, 242, 264 Cardiomegaly, 247 Cardiovascular disorders, 223–271. see also Cardiovascular disorders; Heart; Vascular disorders. acute coronary syndrome as, 233–242 cardiac dysrhythmias as, 242–245 congenital heart defects as, 250–255 congestive heart failure as, 245–249 coronary artery disease as, 233–242 ischemic heart disease as, 233–242 shock and, 264 treatment of, 231–233, 233t Cardiovascular function, 231, 589 Cardiovascular system. see also Cardiovascular disorders; Heart. aging process and, 599 blood pressure and, 229–230, 229f immobility, effects of, 608 pregnancy, changes during, 582–583 substance abuse, problems in, 621 Caries, 444, 582, 593 Carpopedal spasm, 27 Carrier, 100 Case fatality rate, 102 Case studies on acromegaly, 424b–425b on acute lymphocytic leukemia, 211b on acute pain, 63b on acute poststreptococcal glomerulonephritis, 511b on aging complications of, 604b multiple disorders of, 604b on AIDS, 139b–140b on alcohol abuse, 622b on Alzheimer’s disease, 382b, 604b on anaphylaxis, 139b on asthma, 321b on atopic dermatitis, 159b on benign prostatic hypertrophy, 542b on brain tumor, 380b–381b on breast cancer, 543b, 564b on burns, 86b on chronic pain, 63b on chronic renal failure, 511b on cirrhosis, 485b on colon cancer, 485b on congenital deafness, 399b on Crohn disease, 485b on cystic fibrosis, 322b on diabetes mellitus type 1, 423b on diabetes mellitus type 2, 423b–424b on diarrhea, 38b on emphysema, 321b on essential hypertension, 269b on fractures, 182b on gastroenteritis, 484b on gestational diabetes mellitus, 424b, 586b on glaucoma, 398b on gonorrhea, 543b on hepatitis B, 485b on HIV, 139b–140b on Hodgkin disease, 222b on hypersensitivity, 139b on immobility, 610b on increased intracranial pressure, 381b on influenza, 321b on lung cancer, 563b on malignant melanoma, 159b on Ménière’s syndrome, 398b–399b on multiple sclerosis, 382b on myocardial infarction, 269b on nephrosclerosis, 511b on nephrotoxicity, 511b–512b on obesity, 595b on occupational hazards of fighting forest fires, 630b on pain therapies, 51b on pelvic inflammatory disease, 543b on peptic ulcer, 484b–485b on peritonitis, 484b–485b on pituitary adenoma, 424b–425b on pneumonia, 321b on retinoblastoma, 576b on rheumatoid arthritis, 182b on spinal cord injury, 381b on stress response, 615b on systemic lupus erythematosus, 139b on trauma, 86b on upper respiratory infection, 112b on viral gastroenteritis, 112b on vomiting, 37b–38b Caseation necrosis, 290–291 Castleman disease, 221–222 Catabolism, 405 Cataracts, 392–393, 392f, 413, 602 Catecholamines, 335 Catheter, 494 Cation, 21 Cavitation, 291, 292f CCK. see Cholecystokinin. CEA. see Carcinoembryonic antigen. Celecoxib, 74 Celiac disease, 469, 470f Celiac sprue. see Celiac disease. Cell-mediated/delayed hypersensitivity, 127–128, 129f Cell-mediated immunity, 116–117, 117f Cell membrane, 90 Cells. see also specific types of. abnormal growth patterns of, 9f atypical, 546–547 B, 118 blood, 188–193, 191f. see also Hematopoiesis. changes in, 8–12 cycle of, 558, 558f cytotoxic CD8 positive T-killer, 116–117 damage and necrosis to, 9–12 differentiation in, 546, 579–580 dysplastic, 547 enzyme in, 71–72 epithelial, 76, 428 glial, 334 immune system and, 115 immunocompetent, 116 lupus erythematosus, 129 mast, 123 mastoid air, 394 morphologic changes in, 10 natural killer, 118 neuroglial, 334 normal, 546 osmoreceptor, 15 osteoprogenitor, 162 prokaryotic, 89 Reed-Sternberg, 217–218, 219f stem, 116–117, 188, 195 T, 116–117 T-killer, 116–117 terms used for, 8–9 wall, 90 Cellulitis, 70f, 150 Central chemoreceptors, 277 Central venous pressure, 230–231 Cephalosporins, 500 Cerebellum, 331 Cerebral aneurysm, 349–350, 349f Carcinomas (Continued) Case studies (Continued)Burns (Continued) I n d e x 667 Cerebral edema, 347 Cerebral hemispheres, 328–330, 329f Cerebral ischemia, 342 Cerebral palsy (CP), 365–367, 366t Cerebrospinal fluid (CSF), 15, 329t, 343, 344f Cerebrovascular accidents (CVA), 346–348, 346t, 347f. see also Stroke. emergency first aid for, 348b warning signs of, 348b Cervical os, 584 Cervicitis, 527 Cervix cancer, 535f carcinoma of, 534–536, 535f, 551f CF. see Cystic fibrosis. CFTR gene, 295 Chadwick sign, 581–582 Chancre, 539–540 Chemical dependency, 617 Chemical hazards, 625–627 acids as, 626 asbestos as, 627, 627f bases as, 626 heavy metals as, 626 inhalants as, 626–627 leukemia caused by, 625 pesticides as, 627 Chemical irritation, 144–145 Chemical mediators, 69, 69t, 116t, 118 Chemical peritonitis, 453 Chemoreceptors, 277, 278f, 342, 386 central, 277 peripheral, 277 Chemotaxis, 69–70 Chemotherapy, 556, 558–559, 558f Chest x-ray films, 230 Chewing, 430 CHF. see Congestive heart failure. Children with acquired immunodeficiency syndrome, 137 bronchiolitis in, 285t burns in, 80, 86 congenital deafness in, 395 with congestive heart failure, 249–250 epiglottitis in, 285t immobility in, 610 laryngotracheobronchitis in, 285, 285t pain and, 57 respiratory infections in, 285t Chiropractic medicine, 49 Chlamydiae, 94, 96f Chlamydial infections, 538–539 Chlamydial pneumonia, 289 Chlamydia pneumoniae, 289 Chlamydia trachomatis, 389, 585 Chloasma, 143 Chloride, 28–29, 29f Chloride shift, 28 Chlorpheniramine, 125 Cholangitis, 456 Cholecystitis, 456 Cholecystokinin (CCK), 433–434 Choledocholithiasis, 456 Cholelithiasis, 456 Cholestasis, 463 Cholesteatoma, 397 Cholesterol, 599 Cholesterol-lowering drugs, 232–233 Cholinergic fibers, 335–337 Chondrosarcomas, 174 Chordee, 516 Choreiform, 366 Chorionic villi, 580 Chorionic villus sampling, 581 Choroid, 386 Christmas disease, 205. see also Hemophilia B. Chromosomal disorders, 568b, 572, 595 Chromosomes, 546 Chronic bronchitis, 322 Chronic degenerative disorders, 370–375 amyotrophic lateral sclerosis as, 373–374 Huntington disease as, 374–375 multiple sclerosis as, 370–372 myasthenia gravis as, 374 Parkinson disease as, 372–373, 372f Chronic disease, 6 Chronic gastritis, 451 Chronic glaucoma, 391 Chronic infections, 106 Chronic inflammation, 72–73 Chronic inflammatory bowel disease, 469–473 Chronic lymphocytic leukemia (CLL), 209 Chronic myelogenous leukemia (CML), 209 Chronic obstructive lung disease (COLD), 302–303. see also Chronic obstructive pulmonary disease. Chronic obstructive pulmonary disease (COPD), 302–308, 303t bronchiectasis, 307–308 chronic bronchitis, 322 emphysema, 303–307 Chronic renal failure, 509–511, 509t, 510f Chronic tissue/organ transplant rejection, 122 Chronologic age, 597 Chylomicrons, 434 Chyme, 431 Ciliary muscle, 386 Ciprofloxacin, 294 Circle of Willis, 331 Circulating fluids, 21 Circulatory system. see also Blood. anatomy of, 185 blood vessels of, 185 components of, 185 disorders of, 184–212 structures of, 185 Cirrhosis, 463–466, 463f, 467f alcohol, complication of consuming, 621 biliary, 463 case studies on, 485b end-stage, 464 postnecrotic, 463 CJD. see Creutzfeldt-Jakob disease. CK-MB enzyme, 72 Classic hemophilia, 205 Clearance tests, 496 Cleft lip and palate, 441–442, 441f Clitoris, 521–523 CLL. see Chronic lymphocytic leukemia. Clonic stage, 368 Closed fracture, 167, 168f Closed head injury, 354 Closed pneumothorax, 314 Clostridium difficile, 101, 450 Clostridium tetani, 353 “Clot-busting agents”, 348 Clot formation, 193. see also Coagulation. Clubbed fingers, 282 Clubbing, 282 CML. see Chronic myelogenous leukemia. Coagulation, 193 Coagulative necrosis, 10, 11f Cocaine, 617–618 Cocci, 90 Cochlear implants, 395–396, 396f Cognitive decision, 330 Cohesion, 275 COLD. see Chronic obstructive lung disease. Cold, common, 283–285 Cold sores. see Herpes simplex virus. Colfosceril, 318–319 Collagen, 76, 598 Collateral circulation, 226 Colles fracture, 167, 168f Colloidal oatmeal, 146 Color blindness, 387 Colorectal cancer, 476–478, 477f–478f Colostomy, 473, 479f Coma, 338 Comminuted fractures, 167, 168f Common cold, 283–285 Communicable diseases, 7 Communicating hydrocephalus, 363 Compact bone, 162 Compartment syndrome, 169 Compensation, 32 Complement system, 118 Complementary/alternative therapies, 49–51, 560 Complete fracture, 167 Complex carbohydrates, 434 Compliance, 43–44, 275 Complications, definition of, 7 Compound fractures, 354 Compression atelectasis, 312 Compression fracture, 167, 168f Concussion, 354 Conduction deafness, 395 Conduction of impulses, 334–335 Conduction system, of heart, 224–225, 242 Condylomata acuminata, 542 Cones, 387 Congenital anomalies, 567–570 Congenital atresia, 447–448 Congenital deafness, 395 Congenital defects, oral cavity disorders and, 441–442 Congenital disorders, 565–578 Congenital heart defects, 250–255 tetralogy of Fallot as, 253–255 valvular defects as, 253 ventricular septal defect as, 252–253 Congenital neurologic disorders, 363–367 cerebral palsy, 365–367 hydrocephalus, 383 spina bifida, 364–365 Congenital syphilis, 540–541 Congenital urinary system disorders, 506–507 Congestion, 287 Congestive heart failure (CHF), 242, 245–249, 246f, 247t, 248f children with, 249–250 Conjunctiva, 386 Conjunctivitis, 389 Consciousness, levels of, 338–339 Consolidation, 287 Constipation, 437 Constituents in urine, abnormal, 495 Contact dermatitis, 127, 146–147, 147f Contact lenses, 389 Continuous mucosa, 498 Continuous mucous membrane, 394 Continuous positive airway pump (CPAP), 300 Contraction atelectasis, 312 Contractures, 78, 607 Contraindications, 41 Contralateral side, 329 Contrecoup injury, 355 Contusion, 354 Convalescence, 7 Convulsions. see Seizures. Cooley anemia, 203 Coombs test, 119 Cooties, 156 COPD. see Chronic obstructive pulmonary disease. Cordotomy, 62 Cornea, 386 Coronary angiography, 231, 231f Coronary angioplasty, 238 Coronary arteries, 226, 226f Coronary artery bypass graft (CABG), 238, 238f Coronary artery disease, 233–242 angina pectoris as, 238–239 arteriosclerosis as, 233–238 atherosclerosis as, 233–238 myocardial infarction as, 240–242 Coronary circulation, 226–227 Cor pulmonale, 247, 249f, 303 Cortex, 329, 489 Corticospinal tracts, 332 Corticosteroids, 74 Cotransport, 489 Coughing, 281 Cough reflex, 281 Cowper glands, 515 COX-2 (cyclooxygenase-2), 180 CP. see Cerebral palsy. CPAP. see Continuous positive airway pump. Cranial nerves, 331, 332t Craniosacral therapy, 51 C-reactive protein (CRP), 71–72, 235 Crepitus, 170 Cretinism, 420 Creutzfeldt-Jakob disease (CJD), 99, 377 Crohn disease, 470–472, 471f 668 I n d e x Cromolyn sodium, 302 Croup, 285 CRP. see C-reactive protein. Cryptorchidism, 516–517, 516f CSF. see Cerebrospinal fluid. Culture, 90, 90f Culture and sensitivity studies, 496 Culture and staining techniques, 107 Curative treatment, 556 Curling ulcers, 454 Cushing syndrome, 421, 421f–423f, 423t Cushing ulcers, 454 Cutaneous effects of immobility, 607–608 CVA. see Cerebrovascular accidents. Cyanosis, 282 Cyanotic appearance, 208 Cyclosporine, 122 Cystic fibrosis (CF), 294–296, 294f–295f Cystitis, 499–500 Cystocele, 525–526 Cystoscopy, 496 Cytokines, 69, 76 Cytologic tests, 550 Cytoplasm, 91, 546 Cytotoxic CD8 positive T-killer cells, 116–117 Cytotoxic hypersensitivity, 126–127, 127f D Dacarbazine, 559 Dalton’s law, 278 Dead space, 277 Deafness, congenital, 395 Decerebrate posturing, 339, 340f Decompensated metabolic acidosis, 405–406 Decompensation, 32–33 Decorticate posturing, 339, 340f Decubitus ulcer, 607–608 Deep partial-thickness burn, 81f Deep vein thrombosis (DVT), 309 Defecation reflex, 433 Defective platelet function, 204 Defense mechanisms, of body, 66–67, 66f Deficit of fluid, 19t Deglutition, 430–431 Dehydration, 20–21, 437 causes of, 21 effects of, 19t, 21 third-spacing and, 21 Delayed hypersensitivity, 127–128 Delayed menarche, 595 Delta virus, 462 Dementia, 377 AIDS, 377 Alzheimer’s disease as, 375–377 Creutzfeldt-Jakob disease as, 377 vascular, 377 Demyelination, 197–199, 626 Dental problems, 443–444, 445f caries as, 443–444 gingivitis as, 444 periodontal disease as, 444 periodontitis as, 444 Denuded areas, 149 Deoxyhemoglobin, 188–189 Deoxyribonucleic acid (DNA), 565, 567f genetic diagnosis, testing of, 575 proteomic research on, 576 Dependence, 618 Depolarization, 225, 334 Depressants, 620 Depressed fracture, 167, 168f, 354 Depression, 378–379 Dermatitis allergic, 146 atopic, 147–148, 148f, 159b contact, 146–147, 147f Dermatomes, 55, 333, 360f Dermatophytoses, 154 Dermis, 144 Designer drugs, 576, 619 Detached retina, 393 Detoxification, 625 Developmental disorders, 573–574 Dexamethasone, 75, 559 Diabetes acute complications of, 407–409 controlling, 405 initial stage of, 405 insulin replacement for, 407 oral medications for, 406–407 type I, 404–405, 404t type II, 404t, 405 vascular problems with, 410t Diabetes mellitus, 413f. see also Diabetes. gestational, 583–584 insulin and, 404–413 with nodular glomerulosclerosis, 412f Diabetic ketoacidosis, 408–409, 409f, 410t Diabetic nephropathy, 410 Diabetic retinopathy, 411f Diagnosis, definition of, 5 Diagnostic and Statistical Manual of Mental Disorders (DSM), 377 Diagnostic tests for acquired immunodeficiency syndrome, 136 for acute inflammation, 71–72 for cardiovascular function, 230–231 definition of, 6–7 for digestive system disorders, 439 for eye, 388 for genetic disorders, 574–575 for immunity, 119 for malignant tumors, 550 for musculoskeletal system disorders, 166–167 for neurologic dysfunction, 344 for respiratory disorders, 280 for thyroid disorders, 420 for urinary system disorders, 494–496 Dialysate, 497–498 Dialysis, 497–498, 497f Diapedesis, 69–70, 191 Diaphysis, 162, 163f Diarrhea, 436–437 case study on, 38b fatty, 437 large-volume, 437 traveler’s, 629 Diarthroses, 166 Diastole, 227–228 Diastolic hypertension, 258 Diastolic pressure, 229 DIC. see Disseminated intravascular coagulation. Diclofenac sodium, 74 Diencephalon, 330 Diet, for controlling diabetes, 406 Differential count, 71–72, 192 Differentiation in cells, 546, 579–580 Diffusion of sodium, 21 DiGeorge syndrome, 131 Digestion, 434–435 Digestive system, 428–435. see also Digestive system disorders. absorption in, 434–435 anatomy of, 429f digestion in, 434–435 functions of, 428–433 hormonal controls in, 433–434, 434t neural controls in, 433–434 obstruction of, 479–482 pregnancy, changes during, 582 structures of, 428–433 Digestive system disorders, 427–487. see also Digestive system. anorexia, 435–436 bulimia, 435–436 constipation, 437 diagnostic tests for, 439 diarrhea, 436–437 drugs used in, 440t electrolyte imbalances, 437–438 fluid imbalances, 437–438 liver disorders, 456–469 lower gastrointestinal tract disorders, 469–484 malnutrition, 438–439 manifestations of, 435–439 pain, 438 prevention of, 439–441 therapies for, 439–441 upper gastrointestinal tract disorders, 441–456 vomiting, 435 Digoxin, 232, 242 Dimenhydrinate, 440 Diphenhydramine, 125 Diplegia, 606 Diplopia, 340, 388 Direct contact, 100 Directly Observed Therapy (DOT) program, 292–293 Disc diffusion method, 107 Discoid lupus erythematosus, 128 Disease. see also specific types of. acute, 6 causes of, 6 characteristics of, 6–7 chronic, 6 communicable, 7 health and, 2 iatrogenic, 6 idiopathic, 6 incidence of, 7 latent, 6 manifestations of, 6 notifiable, 7–8 occurrence of, 7, 8f onset of, 6 predisposing factors for, 6 prevention of, 2–3, 3b reportable, 7–8 signs of, 6 silent, 6 stress caused by, 612–615 subclinical, 6 symptoms of, 6 Disease-modifying antirheumatic drugs (DMARDs), 592 Disinfectants, 104 Disk diffusion, 107f Dislocations, 170, 170f Dissecting aneurysms, 261 Disseminated intravascular coagulation (DIC), 206–207, 206f, 267, 584 Distributive shock, 267 Disulfiram, 622 Disuse atrophy, 165, 607 Diuretic drugs, 23, 496, 496t Diuretics, 232 Diverticular disease, 475–476. see also Diverticulosis. Diverticulitis, 475 Diverticulosis, 475, 476f. see also Diverticular disease. Diverticulum, 475 DMARDs. see Disease-modifying antirheumatic drugs. DNA. see Deoxyribonucleic acid. Dominant hemisphere, 329 Doppler studies, 231 Dorsal horn, 332 Dosage, 42 Dose, 42 DOT. see Directly Observed Therapy (DOT) program. Down syndrome, 572, 576, 577f. see also Trisomy 21. Droplet transmission, 100 Drugs, 41. see also Nonsteroidal antiinflammatory drugs; specific types of. administration and distribution of, 42–45, 43f, 44t, 45f adrenergic-blocking, 232 angiogenesis inhibitor, 560 antibacterial, 91f, 108–109 anticholinergic, 440 anticoagulant, 192f, 205 antiemetic, 559 antihistamine, 125 antimicrobials, 108 antineoplastic, 558 bactericidal, 108 for cardiovascular system disorders, treatment of, 231–233, 233t cholesterol-lowering, 232–233 Digestive system disorders (Continued) I n d e x 669 classifications and prescriptions of, 46–47 designer, 619 for digestive system disorders, treatment of, 439, 440t disease-modifying antirheumatic, 592 diuretic, 23 effects of, 41–42 first-generation, 108 immunosuppressive, 122 for inflammation, treatment for, 73–75, 74t lipid-lowering, 232–233 mechanisms and receptors of, 45, 46f nomenclature of, 47t ototoxic, 395 prophylactic antimicrobial, 132 resistance to, 107–108 responses, 46 dose effects, 46 time effects, 46 toxicity, 46 second-generation, 108 steroidal antiinflammatory, 74 ulcerogenic, 449 variability of, 46 DSM. see Diagnostic and Statistical Manual of Mental Disorders. Duchenne muscular dystrophy, 175 Ductus deferens, 515 Dumping syndrome, 455–456, 455f Duodenal ulcers, 451–454 Dura mater, 326–327 DVT. see Deep vein thrombosis. Dwarfism, 414 Dysarthria, 341 Dyscrasia, 188 Dyskinetic disease, 366 Dysmenorrhea, 526–527, 595 Dyspareunia, 525, 598–599 Dysphagia, 446–448, 447f Dysplasia, 8, 534 Dysplastic cells, 547 Dyspnea, 195, 248, 282 Dysrhythmias, 24, 225, 242–245, 244t Dysuria, 500 E EAggEC. see Enteroaggregative E. coli. Ear, 394–398 chronic disorders of, 398 disorders of, 385–399 external, 394 function of, 394–395 hearing loss in, 395–396 infections in, 396–398 inner, 394 middle, 394 parts of, 394 semicircular canals in, 395 sound pathway in, 394–395 structure of, 394–395, 394f Eating disorders, during adolescence, 593 EB. see Elementary body. Ecchymoses, 207 Eccrine glands, 144 ECF. see Extracellular compartment fluid. ECG. see Electrocardiogram. Echocardiography, 230 Eclampsia, 583 ECOG. see Electrocochleography. Ecosystems, 625 “Ecstasy”, 619 ECT. see Electroconvulsive therapy. Ectopic kidney, 507 Ectopic pregnancy, 583 Ectopic site, 241–242 Eczema, 124, 147, 148f. see also Atopic dermatitis. EDB. see Estimated date of birth. EDD. see Estimated date of delivery. Edema, 16–20 causes of, 18–19, 18f cerebral, 347 definition of, 17–18 effects of, 19–20, 19t pitting, 19, 20f third-spacing and, 21 Efferent arteriole, 491, 494f Efferent fibers, 55, 330 Effusion, 257, 592 EHEC. see Enterohemorrhagic E. coli. EIEC. see Enteroinvasive E. coli. Electrocardiogram (ECG), 225, 243f arrhythmias on, 230, 242 of atrial fibrillation, 243f of AV node block, 243f of bradycardia, 243f of potassium imbalance, 24, 26f of premature atrial contraction, 243f of tachycardia, 243f of ventricular fibrillation, 243f Electrocochleography (ECOG), 398 Electroconvulsive therapy (ECT), 379 Electrodes, 225 Electrolyte imbalances, 21–29, 437–438 calcium, 26–27 chloride, 28–29 magnesium, 28 phosphate, 28 sodium, 21–24 Electrolytes, 434–435, 438, 496 distribution of, 22t movement of, 16, 17f Electromyograms (EMGs), 166–167 Electronystagmography (ENG), 398 Elementary body (EB), 94 Elephantiasis, 221, 221f ELISA. see Enzyme-linked immunosorbent assay. Emaciated appearance, 593 Embolus, 346–347, 584 Embryo, 580 Emergency treatment for anaphylaxis, 125b for angina pectoris, 239b for aspiration, 300b for brain attack, 348b for burns, 82b for cardiac arrest, 245b for cerebrovascular accidents, 348b for flail chest, 317b for fracture, 170b for hypoglycemic shock, 408b for insulin shock, 408b for pneumothorax, 315b for seizure, 369b for shock, 267b for stroke, 348b Emerging infectious disease, 121 Emetic reflex, 436f EMGs. see Electromyograms. Emphysema, 303–307, 304f, 306f Empyema, 287 Enalapril, 232 Enamel, 444 Encephalitis, 352 Encephalopathy, 136, 626 Endarterectomy, 261 Endemic goiter, 417, 419f Endemic infection, 100 Endocarditis, 255 Endocardium, 224 Endocrine glands, 400 Endocrine system, 400–403, 401f. see also Endocrine system disorders. Endocrine system disorders, 400–426. see also Endocrine system. of adrenal glands, 420–423 of antidiuretic hormone, 416 diabetes mellitus, 404–413 of growth hormone, 414–416, 417f of parathyroid hormone, 413–414 of pituitary hormone, 414–416 of thyroid, 417–420 Endogenous environment, 10 Endometrial adenocarcinoma, 536f Endometrial carcinoma, 536–537, 536f Endometriosis, 527, 528f Endometritis, 585–586 Endomysium, 164 Endorphins, 56–57, 612 Endospores, 91–92, 93f Endosteum, 162–163 Endothelial injury, 235 Endotoxins, 91 End-stage cirrhosis, 464 End-stage renal failure, 497 Endurance exercise, 165 Enemas, 440 ENG. see Electronystagmography. Entamoeba histolytica, 97–98, 98f Enteroaggregative E. coli (EAggEC), 450–451 Enterogastric reflex, 433 Enterohemorrhagic E. coli (EHEC), 451 Enteroinvasive E. coli (EIEC), 450 Enteropathogenic E. coli (EPEC), 450 Enterotoxigenic E. coli (ETEC), 450 Environmental hazards, 624–630 of biologic agents, 629–630 of chemicals, 625–627 of physical agents, 627–629 Enzyme defect, 571 Enzyme-linked immunosorbent assay (ELISA), 119, 580 Enzymes, 91 in cell, 71–72 CK-MB, 72 lysosomal, 10 in saliva, 430, 430t Eosinophilia, 147 Eosinophils, 191 EPEC. see Enteropathogenic E. coli. Epidemics, 7, 100 Epidemiology, 7 Epidermis, 143 Epididymis, 515 Epididymitis, 539, 540f Epidural hematoma, 356 Epiglottitis, 285, 285t Epimysium, 164 Epinephrine, 125, 335 Epiphyseal plate or disc, 589 Epiphysis, 162 Epispadias, 516 Epithelial cells, 76, 428 Epoetin alfa, 195 EPS. see Extrapyramidal system. Epstein-Barr virus, 594 Eroded cartilage, 178 Erysipelas, 70f Erythema, 125 Erythrocytes, 188, 195, 201f. see also Red blood cells. circulation path of, 224f hypochromic, 196 microcytic, 196 Erythrocyte sedimentation rate (ESR), 71–72 Erythrocytosis, 208 Erythropoietin, 188 Escharotomy, 79–80 Escherichia coli (E. coli), 102, 267, 350, 450–451, 585, 629 Esophageal cancer, 448 Esophageal diverticula, 448 Esophageal varices, 464, 465f Esophagitis, 593 Esophagus, 430–431 cancer of, 448 squamous cell carcinoma of, 448f stomach and, 431 ESR. see Erythrocyte sedimentation rate. Essential hypertension, 258 Estimated date of birth (EDB), 580–581 Estimated date of delivery (EDD), 580–581 ETEC. see Enterotoxigenic E. coli. Etiology, definition of, 5 Euphoria, 618 Eupnea, 281–282 Eustachian tubes, 273 Evidence-based research findings, 3 Ewing sarcoma, 174 Exacerbations, 7 Excess fluid, 19t Excoriations, 156 Exercise, for controlling diabetes, 406 Drugs (Continued) Edema (Continued) 670 I n d e x Exercise stress tests, 230 Exocrine cancer, 469. see also Pancreas. Exocrine pancreas, 431 Exogenous environment, 10 Exogenous estrogen, 533 Exophthalmos, 418, 420f Exotoxins, 91 Expanding uterus, 581, 581f Expansion disorders, 312–320 acute respiratory failure as, 320 adult or acute respiratory distress syndrome as, 319–320 atelectasis as, 312–313 flail chest as, 315–317 infant respiratory distress syndrome as, 317–319 pleural effusion as, 313–314 pneumothorax as, 314–315 Expectorant medication, 281 Expiration, 275–276, 276f Expression, 567 Expressive aphasia, 341 Exstrophy of bladder, 516 Extensor muscles, 607 External auditory meatus, 394 External ear, 394 Exteroceptors, 385 Extracellular compartment fluid (ECF), 15 Extracellular fluid, 15t Extradural hematoma, 356 Extrapulmonary tuberculosis, 291 Extrapyramidal motor system, 372 Extrapyramidal system (EPS), 330 Extrapyramidal tracts, 332 Extrinsic asthma, 300 Extrinsic muscles, 386 Exudate definition of, 70–71 fibrinous, 70 purulent, 70–71 serous, 70 Exudative effusions, 314 Eye, 386–393 age-related macular degeneration in, 393 anterior cavity of, 387 cataracts in, 392–393 detached retina in, 393 diagnostic tests for, 388 disorders of, 385–399 eyeball in, 386–387 fluids in, 387–388 function of, 386–388 glaucoma in, 390–392, 391f infections in, 389–390, 390f posterior cavity of, 387 protection for, 386 refraction of, 386–387 defects of, 389f structural defects of, 388–389 structure of, 386–388, 387f trauma to, 389–390 visual pathway of, 388 Eyeball, 386–387 F Facial ecchymoses, 204f Fallopian tube, 579–580 “False” ribs, 275 Familial tendency, 570 Fanconi anemia, 200 Fascia, 169, 220–221 Fat emboli, 169 Fatigue, 549 Fat necrosis, 10, 11f Fats, 234–235, 434 Fat-soluble vitamins, 434 Fatty liver, 463 Fecalith, 473 Fecal tests for occult blood (FOBT), 476 Female reproductive system, 521–524 function of, 521–523 hormones of, 523–524 infections in, 527–530 inflammation in, 527–530 menstrual cycle and, 523–524 pregnancy, changes during, 581–582 structure of, 521–523, 522f tumors in, 530–532 Female reproductive system disorders, 521–537. see also Reproductive system disorders. menstrual disorders, 526–527 Ferritin, 190 Fertilization, 581 Fetal alcohol syndrome, 580 Fetal hemoglobin (HbF), 201–202 Fetus, 579–580 passive natural immunity in, 121 pregnancy, development during, 579–580 viable, 580 Fever, 71, 71f characteristics of, 106 hemorrhagic, 205 inflammation, systemic effect of, 71 rheumatic, 255–256, 255f Rocky Mountain spotted, 94, 629–630 Scarlet, 286, 286f typhus, 94 West Nile, 352 Fibrillation, 244 Fibrin, 193 Fibrin mesh, 193 Fibrinogen, 71–72, 193 Fibrinolysis, 193 Fibrinous exudate, 70 Fibroblasts, 72–73 Fibrocartilaginous callus, 168 Fibrocystic breast disease, 530–532 Fibroids, 530, 531f Fibromyalgia syndrome, primary, 176 Fibrosis, 178 Fibrous capsule, 166 “Fight or flight” concept, 611 Filariasis, 221 Filtrate, composition of, 489t Filtration, 16, 489 Fimbriae, 91 First aid. see Emergency treatment. First-degree heart block, 244 First-degree muscle tears, 171 First-generation drug, 108 Flaccidity, 339 Flaccid paralysis, 373 Flagella, 91 Flail chest, 315–317, 317f Flesh-eating disease, 151–152. see also Acute necrotizing fasciitis. Flexibility, aging process and, 601 Flexor muscles, 607 “Floaters”, 387 Flu. see Influenza. Fluent aphasia, 341 Fluid compartments, 15, 15t Fluid imbalances, 15–21, 437–438 concepts and processes related to, 15–16 deficit fluids, 20–21. see also Dehydration. excess fluids, 16–20 third-spacing and, 21 Fluids amniotic, 581 circulating, 21 deficiency of, 19t. see also Dehydration; Fluid imbalances. excess, 16–20, 19t. see also Edema; Fluid imbalances. extracellular, 15t in eye, 387–388 interstitial, 15, 69 intracellular, 15t loss of, 20 synovial, 166 Fluoride, 444 FOBT. see Fecal tests for occult blood. Focal infections, 106 Folic acid, 197, 202–203 Follicle-stimulating hormone (FSH), 516, 598 Food, hazards of, 629 Food allergies, sign of allergic reaction, 123–124 Foramina, 326 Forced inspiration, 275 Forest fires, occupational hazards of fighting, 630b Fosfomycin, 500 Fourth-degree burns, 79–80 Fovea centralis, 387 Fractures, 167–170, 167f aging and, 600 basilar, 354–355 case study on, 182b closed, 167 Colles, 167 comminuted, 167, 354 complete, 167 compound, 167, 354 compression, 167 depressed, 167, 354 emergency treatment for, 170b greenstick, 167 healing process of, 168–170 impacted, 167 incomplete, 167 linear, 167, 354 oblique, 167 open, 167 pathologic, 167 Pott, 167 segmental, 167 simple, 167 spiral, 167 stress, 167 transverse, 167 Fragile X syndrome, 571 Frank blood, 437 Frequency, 603 Friction rub, 282 Frostbite, 628 FSH. see Follicle-stimulating hormone. Full thickness burns, 79–80, 81f Fulminant, definition of, 350 Functional obstructions, 479 Functional scoliosis, 591 Fungal infections, 154–155 Fungi, 94–97 Furosemide, 232 Furuncles, 150–152, 151f Fusion, of two kidneys, 507 G GABA. see Gamma-aminobutyric acid. Gait, 582 Gallbladder disorders, 456–457, 456f Gallstones, 456–457, 456f, 603 Gamma-aminobutyric acid (GABA), 335 Ganglion, 333 Gangrene, 10–12, 11f GAS. see General adaptation syndrome. Gas, 437 Gas diffusion, 278 Gas exchange, 278 carbon dioxide and, 278 gas diffusion and, 278 oxygen and, 279–280 Gastrectomy, 199, 454 Gastric cancer, 454–455 Gastric ulcers, 451–454 Gastrin, 431, 433 Gastritis, 449–451 acute, 449 chronic, 451 gastroenteritis and, 449–451 Gastroenteritis, 449–451 case study on, 484b Escherichia coli infection and, 450–451 viral, 112b Gastroesophageal reflux disease (GERD), 449 Gene expression, 565–566 Gene penetration, 567 General adaptation syndrome (GAS), 611 Generalized seizures, 368–369, 368b Gene therapy, 560, 575 Genetic control, 565–567 Genetic disorders, 568b, 570–573. see also Genetics. chromosomal disorders as, 572 designer drugs for, 576 diagnostic tools for, 574–575 Female reproductive system (Continued) I n d e x 671 DNA testing for, 575 multifactorial disorders as, 572–573 single-gene disorders as, 570–571 Genetic engineering, 575 Genetics. see also Deoxyribonucleic acid; Genetic disorders. technology for, 575–576 Genital herpes, 541–542, 541f Genital warts, 154, 542 Genomics, 109 GERD. see Gastroesophageal reflux disease. Gestation, 581 Gestational age, 581 Gestational diabetes mellitus, 405, 583–584 GFR. see Glomerular filtration rate. Ghon complexes, 290–291 Gigantism, 414, 417f Gingival hyperplasia, 369f Gingivitis, 444, 582 Glasgow coma scale, 338, 339t Glaucoma, 390–392, 391f, 602 Glaucomatous cup, 392f Glial cells, 334 Gliomas, 344 Global aphasia, 341 Glomerular capillaries, 491 Glomerular filtration rate (GFR), 16, 491 Glomerulonephritis, 500–502, 501f–502f Glossitis, 196 Glottis, 273 Glucocorticoids, 74, 122, 125, 421 Gluconeogenesis, 421, 431 Glucose, 495 Glucose metabolism, 590 Glucosuria, 405, 489 Glutaraldehyde, 104 Gluten, 469 Gluten enteropathy. see Celiac disease. Glyburide, 407 Glycine, 335 Glycogen, 165, 431 Glycoproteins, 115 GnRh. see Gonadotropin releasing hormone. Goiter, 417–418, 419f Goitrogens, 417–418 Gonadotropin releasing hormone (GnRh), 588–589 Gonadotropins, 588–589 Gonads, 400, 588–589 Gonioscopy, 388 Gonococcal conjunctivitis, 390f Gonorrhea, 539 Goodell sign, 581–582 “Goose bumps”, 144 Gout, 180–181, 181f Gouty arthritis, 180–181, 181f Gower maneuver, 175, 175f Gram-negative bacteria, 90 Gram-positive bacteria, 90 Gram stain, 90 Grand mal seizures, 368–369 Granulation tissue, 76, 78f Granuloma, 72–73, 298, 299f Graves disease, 418–420 Gravidity, 581 Greenstick fractures, 167 Gross hematuria, 495 Growth hormone disorders, 414–416, 417f Guillain-Barré syndrome, 118, 354 Gynecomastia, 521 Gyri, 328 H H2. see Histamine2 (H2) receptors. HAART. see Highly active antiretrovirus therapy. Habit, 618 Haemophilus influenzae, 103, 350, 397 Hair follicles, 144 Hallucinogens, 618 Hand, transmission through, 100 Hansen disease. see Leprosy. Hashimoto’s thyroiditis, 420 Haversian systems, 162 Hay fever, sign of allergic reaction, 123 HbA. see Hemoglobin A. HbF. see Fetal hemoglobin. HbS. see Hemoglobin S. hCG. see Human chorionic gonadotropin. HD. see Huntington disease. Headache, 59–60, 342 Head injuries, 354–358, 355f–356f. see also Brain. Head louse, 156 Healing, 75–78 of bones, 168–170 example of, 78–86. see also Burns. factors affecting, 76 factors delaying, 77b factors promoting, 77b of fractures, 168–170 inflammation and, 65–87, 73f process of, 76, 77f scar formation and complications with, 78 types of, 75–76 Health disease and, 2 steps to, 2b World Health Organization, defined by, 2 Health care workers, 127–128 Hearing aids, 395 Hearing loss, 395–396, 602 Heart, 224–228 anatomy of, 224 blocks in, 244 cardiac cycle of, 227–228, 227f conduction system of, 224–225, 225f control of, 225–226 coronary circulation of, 226–227 disorders of, 230–258 inflammation and infection of, 255–258 sounds of, 228 Heart attack, warning signs of, 241b Heartburn, 449, 582 Heart valve defects, 250f Heat cramps, 627 Heat exhaustion, 627 Heat stroke, 627–628 Heavy metals, 626 Heberden node, 177, 177f Heimlich maneuver, 300b Helicobacter pylori, 451–452 HELLP, 583 Helminths, 99 Helper CD4 positive T cell, 116–117 Hemarthrosis, 205 Hematemesis, 435 Hematocrit, 82, 187 Hematoma, 167–168, 169f epidural, 356 extradural, 356 intracerebral, 357 subdural, 356, 357f types of, 357f Hematopoiesis, 83, 162–163, 188–193, 190f Hematuria, 205, 495 Hemianopia, 339–340, 340f Hemiplegia, 606 Hemochromatosis, 190 Hemodialysis, 497–498, 497f Hemoglobin, 188–189, 191f, 200–201, 201f Hemoglobin A (HbA), 200–201 Hemoglobin S (HbS), 200 Hemolink, 195 Hemolysis, 190–191, 584 Hemolytic anemia, 200–203, 626, 626f sickle cell anemia as, 200, 202f Hemolytic streptococcus, 90f, 91 Hemophilia A, 205, 205f Hemophilia B, 205 Hemophilia C, 205 Hemoptysis, 248–249, 281 Hemopure, 195 Hemorrhage intracerebral, 347 subarachnoid, 356–357 of tumors, 414 Hemorrhagic fever, 205 Hemosiderin, 190 Hemostasis, 192–193, 192f Hemothorax, 314 Heparin, 193 Hepatic encephalopathy, 464 Hepatitis, 458–463 alcoholic, 463 infectious, 458 non-A-non-B, 462 nonviral, 463 serologic changes seen with, 461f toxic, 463 types of, 460t viral, 458–462 Hepatitis A, 458 Hepatitis B, 458–462, 462f Hepatitis C, 462 Hepatitis D, 462 Hepatitis E, 462 Hepatocellular carcinoma, 467, 467f Hepatocytes, 431 Hepatomegaly, 203, 208 Hepatotoxin, 463, 621 Herbal medicine, 49 Herd immunity, 121 Hernia hiatal, 448–449, 448f with infarcted intestine, 482f paraesophageal, 448 rolling, 448 sliding, 448 Herniated intervertebral disc, 380, 380f, 601 Herniation, 343–344 Heroin, 619 Herpes labialis, 442–443 Herpes simplex encephalitis, 352 Herpes simplex virus, 153f Herpes simplex virus type 1 (HSV-1), 442–443 Herpes zoster, 353 Herpetic stomatitis, 442–443 Herpetic whitlow, 443, 443f Heterozygous, definition of, 571 HGP. see International Human Genome Project. Hiatal hernia, 448–449, 448f Highly active antiretrovirus therapy (HAART), 138 Hirsutism, 530 Histamine2 (H2) receptors, 433, 440 Histamines, 69, 335 Histoplasma, 97 Histoplasma capsulatum, 293 Histoplasmosis, 97, 293 Hives, 147, 147f HLA. see Human leukocyte antigen. Hodgkin disease, 222b Hodgkin lymphoma, 217–219, 219f Holistic approach, to disease, 49 Holter monitor, 230 Homeopathy, 49 Homeostasis, 2, 611 Homonymous hemianopia, 339–340 Homozygous, definition of, 571 H1N1 influenza virus, type A, 110, 111f Hordeolum, 389 Hormone disorders antidiuretic, 416 growth, 414–416 parathyroid, 413–414 Hormones, 401, 402t. see also specific types of. aging process and, 598 anabolic, 404 in digestive system, 433, 434t follicle-stimulating, 516, 598 gonadotropin releasing, 588–589 luteinizing, 516, 598 of male reproductive system, 516 menstrual cycle and, 523–524, 524f pregnancy, changes during, 581 reabsorption of, 489 sex, 559 thyroid, 418f tropic, 404 Hospital-acquired pneumonia, 287 Host defenses, 555 Host resistance, 101–102, 101b HPV. see Human papillomavirus. HSV-1. see Herpes simplex virus type 1. Genetic disorders (Continued) 672 I n d e x Human chorionic gonadotropin (hCG), 574, 580 Human leukocyte antigen (HLA), 115, 195, 200 Human papillomavirus (HPV), 4–5, 93 Humoral immunity, 117f, 118 Humpback. see Kyphosis. Hunchback. see Kyphosis. Huntington disease (HD), 374–375, 375f Hyaline membrane disease, 317–318 Hydrocele, 517, 517f Hydrocephalus, 363–364, 364f, 383 Hydrochloric acid, 431 Hydrochlorothiazide, 232, 496 Hydrogen, 24, 25f, 29–30, 29f Hydronephrosis, 503–505, 504f Hydrophobia, 352–353 Hydropneumothorax, 314 Hydrostatic pressure, 16, 67 Hydrothorax, 314 Hydroxyurea, 202–203 Hyperacute tissue/organ transplant rejection, 122 Hyperbilirubinemia, 201, 457 Hypercalcemia, 27, 414 Hypercapnia, 277–278 Hypercholesterolemia, 235 Hyperemesis gravidarum, 582 Hyperemia, 69 Hyperglycemia, 405 Hyperkalemia, 25–26 Hyperkeratosis, 444 Hypermagnesemia, 28 Hypermetabolism, 83 Hypernatremia, 23–24 Hyperopia, 388 Hyperosmolar hyperglycemic nonketotic coma, 409 Hyperparathyroidism, 414 Hyperplasia, 8 Hyperreflexia, 339, 361, 366 Hypersensitivity, 41, 139b cytotoxic, 126–127 immune complex, 127, 128f Hypersensitivity reactions, 122–128, 123t. see also Allergic reactions; Hypersensitivity. atopic, 123 type I, 116t, 123–125, 124f type II, 126–127 type III, 127, 128f type IV, 127–128, 129f Hypertension, 259f as arterial disorders, 258–260 diastolic, 258 essential, 259 and kidney, 506f malignant, 258 primary, 258 resistant, 258 secondary, 258 systolic, 258 uncontrolled, 260f Hyperthermia, 627–628 Hyperthyroidism, 418–420, 420f, 420t Hypertonic/hyper-osmolar fluid, 16 Hypertrophic scar tissue, 78, 79f–80f Hypertrophy, 8, 165, 518–519, 519f Hyperuricemia, 180, 208 Hypervolemia, 18–19 Hyphae, 97 Hypocalcemia, 27, 413 Hypochromic erythrocytes, 196 Hypodermis, 144 Hypogammaglobulinemia, 131 Hypoglycemia, 406 Hypoglycemic shock, emergency treatment for, 408b Hypokalemia, 24 Hypomagnesemia, 28 Hyponatremia, 22–23, 23f effects of, 23 Hypoparathyroidism, 27, 413 Hypoplasia, 506–507 Hypoproteinemia, 131 Hypospadias, 516 Hypotension, 583. see also Shock. Hypothalamus, 15, 55, 330, 400 Hypothermia, 628 Hypothyroidism, 420, 420t Hypotonic/hypo-osmolar fluid, 16 Hypovolemia, 20, 437 Hypovolemic shock, 267 Hypoxemia, 277 Hypoxia, 9, 188, 282 Hypoxic drive, 277 I Iatrogenic conditions, 421 Iatrogenic disease, 6 Iatrogenic effects, 41 IBD. see Inflammatory bowel disease. IBS. see Irritable bowel syndrome. Ibuprofen, 74 ICF. see Intracellular compartment fluid. ICP. see Intracranial pressure. Icterus, 457. see also Jaundice. Idiopathic disease, 6 Idiopathic seizures, 368 Idiosyncratic reactions, 41 IF. see Intrinsic factor. IL-3. see Interleukin-3. Ileostomy, 473 Imatinib mesylate, 576 Imbalances. see also specific types of. acid-base, 29–36, 282, 438 calcium, 26–27 electrolyte, 21–29, 437–438 fluid, 15–21 potassium, 24–26 sodium, 21–24 treatment of, 36–37 Immature neutrophils, 71–72 Immobility, 606–610 cardiovascular system effects of, 608 case study on, 610b in children, effects of, 610 cutaneous effects of, 607–608 digestive system effects of, 609 gastrointestinal effects of, 609 musculoskeletal system effects of, 607 neurologic effects of, 609–610 psychological effects of, 609–610 respiratory system effects of, 608–609 urinary system effects of, 609 Immune complex hypersensitivity, 127, 128f Immune response, 118–120, 120f Immune system, 115–121. see also Immunity. components of, 115, 115f, 116t elements of, 115–118 functions of, 115, 116t structures of, 115, 115f Immunity, 114–141. see also Immune system. acquired, 120–121, 120t from autoimmune disorders, 128–131 bioterrorism, 121 cell-mediated, 116–117, 117f, 127–128, 129f diagnostic tests for, 119 herd, 121 humoral, 116, 117f, 118 hypersensitivity reactions, 122–128, 123t immune response, 118–119 immunodeficiency and, 131–139 from infectious disease, 121 innate, 120 natural, 120 passive artificial, 121 tissue/organ transplant rejection and, 121–122 Immunocompetent cells, 116 Immunodeficiency, 131–139 acquired immunodeficiency syndrome, 132–139, 133f causes of, 131–132, 131t effects of, 132 primary, 131 secondary, 131–132 Immunogens. see Antigens. Immunoglobulin, 118, 119t Immunosuppression, 122 Impacted fracture, 167, 168f Impaction, 437 Impaired neurologic function, 407 Impetigo, 151 Impulses, conduction of, 334–335 Inappropriate antidiuretic hormone syndrome, 416 Inborn errors of metabolism, 571 Incidence, of disease, 7 Incomplete dominant genes, 571 Incomplete fracture, 167 Incontinence, 493–494, 516, 603 Increased capillary hydrostatic pressure, 18–19 Incubation period, 6, 105 Indigenous normal flora. see Resident (normal) flora. Indirect contact, 100 Infant respiratory distress syndrome (IRDS), 317–318, 318f–319f Infantile paralysis, 353 Infarction, 10, 414 Infections, 88–113. see also specific types of. acute, 106 acute neurologic problems and, 350–354 acute period, 105 during adolescence, 594 aging process and, 603 blood tests for, 107 from burns, 83, 84f chronic, 106 control of, 103–105 cycle, 103f, 104–105 diabetes, acute complication of, 412 diagnosis of, 107 of ear, 396–398 endemic, 100 example of, 110–111. see also Influenza. of eye, 389–390, 390f in female reproductive system, 527–530 focal, 106 host resistance to, 101–102 inflammation and, 72 local, 106 in male reproductive system, 518 microbiology and, 89–100 mixed, 106 nosocomial, 101 onset and development of, 105–106, 105f opportunistic, 99–100 oral cavity disorders and, 442–443 patterns of, 106 physiology of, 105–111 during pregnancy, 585–586 primary, 106 principles of, 100–105 puerperal, 585–586 radiologic examination for, 107 secondary, 106 signs and symptoms of, 106 subclinical, 100, 106 substance abuse and, 621 systemic, 106 transmission of, 100–101 transmitted by food and water, 450t treatment of, 107–110 Infectious agents, 101f Infectious arthritis, 180 Infectious disease emerging, 121 immunity from, 121 outcome of, 121 reemerging, 121 respiratory disorders and, 283–294 Infectious hepatitis, 458 Infectious mononucleosis, 594 Infectious rhinitis, 283–285 Infective endocarditis, 256–257 Infertility, 537–538 Infiltration, 547 Inflammation acute, 69–72 blood with, changes in, 72t cardinal signs of, 70 causes of, 67 chronic, 72–73 definition of, 10, 67 example of, 78–86. see also Burns. in female reproductive system, 527–530 healing and, 65–87 infection and, 72, 73f I n d e x 673 interstitial, 302–303 in male reproductive system, 518 normal capillary exchange, 67 physiology of, 67–69 steps of, 67–69 treatment of, 73–75, 74t Inflammatory bowel disease (IBD), 470t Inflammatory lesions, of oral cavity, 442 Inflammatory response, 67, 68f cellular elements in, 69–70, 70t chemical mediators in, 69, 69t Influenza, 110–111 Infratentorial lesions, 338 Inhalants, 626–627 Initiating factors, 553 Innate immunity, 120 Inner cell mass, 579–580 Inner ear, 394 INR. see International normalized ratio. Insertion, 165 Inspiration, 275–276, 276f Insulin, 404–413 Insulin deficit, 404, 410t Insulin resistance, 590 Insulin shock, 407, 408f Interactions, 42 Interferons, 66–67, 101–102 Interleukin-3 (IL-3), 191 Intermittent claudication, 261 Internal carotid artery, 331 International Human Genome Project (HGP), 566–567, 568f International normalized ratio (INR), 195 Interoceptors, 385 Interstitial fluid (ISF), 15, 69 Interstitial inflammation, 302–303 Interstitial pneumonia, 287t Interventricular artery, 226 Intestinal obstruction, 479–482, 480f–481f Intracellular compartment fluid (ICF), 15 Intracellular fluid, 15t Intracerebral hematoma, 357 Intracerebral hemorrhage, 347 Intracranial headaches, 60 Intracranial pressure (ICP), 341–343, 342f, 381b cerebrospinal fluid and, 343 early signs of, 341–342 effects of, 342t vital signs and, 342–343, 343f Intractable pain, 62 Intrahepatic jaundice, 457 Intrauterine device (IUD), 529–530 Intravascular fluid (IVF), 15 Intrinsic asthma, 300 Intrinsic factor (IF), 197, 431 Invasion, 551 Ionizing radiation, 557, 628 Ipsilateral weakness, 339 Irbesartan, 232 IRDS. see Infant respiratory distress syndrome. Iris, 386 Iron deficiency anemia, 196, 196f–197f Irregular bones, 162 Irritable bowel syndrome (IBS), 473 Ischemia, 9, 53–54, 169 Ischemic heart disease, 233–242. see also Coronary artery disease. Ischemic pain, 61 ISF. see Interstitial fluid. Isoenzyme, 72 Isotonic/iso-osmolar fluid, 16 IUD. see Intrauterine device. IVF. see Intravascular fluid. J Jaundice, 190–191, 457–458, 460f, 584 Joint disorders, 176–182 ankylosing spondylitis as, 181–182, 181f gouty arthritis as, 180–181, 181f infectious arthritis as, 180 juvenile rheumatoid arthritis as, 180 osteoarthritis as, 176–178, 177f–178f rheumatoid arthritis as, 178–180, 179f JRA. see Juvenile rheumatoid arthritis. Juvenile rheumatoid arthritis (JRA), 180, 591–592 K Kaposi sarcoma, 158–159, 446 Karyotype, 565, 566f Keloid, 78, 80f Keratin, 143 Keratinization, 143 Keratinocytes, 143 Keratitis, 390 Keratoses, 157 Kernig sign, 350 Ketoacidosis, 405 Ketones, 405, 495 Ketonuria, 405 Kidney, 489–490 blood pressure and, 491 cortex of, 489 ectopic, 507 hypertension and, 506f internal structure of, 491f Kidney stones, 498–499, 503–504. see also Urolithiasis. Kirby-Bauer method, 107 Kissing disease, 594 Klebsiella, 83 Klebsiella pneumoniae, 267, 287 Klinefelter syndrome, 572, 572f, 595 Kussmaul respirations, 282 Kyphosis, 172, 590, 600 L Labia majora, 521–523 Labia minora, 521–523 Labyrinth, 394 Lacrimal gland, 386 Lactation, 523, 581 Lactobacillus, 443–444, 523 Lacunae, 162 Laënnec’s cirrhosis, 621. see also Cirrhosis. Language disorders, 340–341 Lapatinib, 533 Large intestine, 432–433 Large-volume diarrhea, 437 Larvae, 155–156 Laryngospasm, 27 Laryngotracheobronchitis, 285 Larynx, 273 Last menstrual period (LMP), 580–581 Latent disease, 6 Lateral horns, 332 Laxatives, 440 LDL. see Low-density lipoprotein. LDLT. see Liver from a suitable living donor. Lecithin-sphingomyelin (L/S) ratio, 318 Left anterior descending artery, 226 Left circumflex artery, 226 Left coronary artery, 226 Left hemisphere, 338 Legionnaires disease, 286–287, 289 Leiomyoma, 530, 531f Lens, 386 Leprosy, 152 LES. see Lower esophageal sphincter. Lesion, 6 Lethargy, 342, 420 Leukemias, 208–211, 209t chemical hazards caused by, 625 Leukocytes, 66–67, 69–70, 116, 191 Leukocytosis, 71–72, 107, 194 Leukopenia, 107, 194, 550 Leukoplakia, 444, 446f Leukopoiesis, 191 Leukorrhea, 523 Leukotrienes, 69, 301 LH. see Luteinizing hormone. Lice, 156, 156f Lichenification, 147 Light energy, 628–629 Limbic system, 55, 330 Linear fractures, 167, 168f, 354 Linear growth, 589 Lipid-lowering drugs, 232–233 Lipids, 234–235, 434 Lipolysis, 612 Lipoprotein metabolism, 590 Lipoproteins, 234–235, 234f Liquefaction necrosis, 10, 11f Listeria, 629 Liver, 431–432. see also Liver disorders. cancer, 467 disease of, 204 with metastatic tumors, 553f Liver disorders, 456–469. see also Liver. cirrhosis, 463–466 fatty, 463 of gallbladder, 456–457 hepatitis as, 458–463 jaundice as, 457–458, 459f–460f manifestations of, 464t Liver from a suitable living donor (LDLT), 466 Living fetus, 580 LMP. see Last menstrual period. Lobar pneumonia, 287–288, 287t, 289f Local administration, 43 Local anesthesia, 62 Local infections, 106 Local signs, of infection, 106 Localized frostbite, 628 Locked-in syndrome, 338 Lockjaw, 353 Long bones, 162 Lordosis, 173, 174f, 582, 590 Losartan, 232 Loss of function, 78 Lou Gehrig disease, 373 Low-density lipoprotein (LDL), 232–233 Lower esophageal sphincter (LES), 449 Lower gastrointestinal tract, 432–433. see also Lower gastrointestinal tract disorders. large intestine in, 432–433 small intestine in, 432 Lower gastrointestinal tract disorders, 469–484 appendicitis as, 473–475 celiac disease as, 469 chronic inflammatory bowel disease as, 469–473 colorectal cancer as, 476–478 Crohn’s disease as, 470–472 diverticular disease as, 475–476 intestinal obstruction as, 479–482 irritable bowel syndrome as, 473 ulcerative colitis as, 472–473 Lower motor neurons, 332 Lower respiratory tract, 274–275. see also Lower respiratory tract infections. Lower respiratory tract infections, 286–294 anthrax as, 293–294 bronchiolitis as, 286 histoplasmosis as, 293 pneumonia as, 286–289 severe acute respiratory syndrome as, 289–290 tuberculosis as, 290–293, 291f L/S. see Lecithin-sphingomyelin (L/S) ratio. Lubiprostone (Amitiza), 440 Lumbar puncture, 343, 344f Lund and Browder chart, 80 Lungs, 275 aspiration, 430–431 cancer of, 296–298 obstructive diseases of, 294–302 restrictive disorders of, 308–309 Luteinizing hormone (LH), 516, 598 Lyme disease, 352, 629–630 Lymph composition and production of, 215 definition of, 215 lymphatic circulation of, 215 Lymph capillaries, 213–215, 214f Lymphadenopathy, 106, 209 Lymphatic capillaries, 215, 217f Lymphatic circulation, 19, 215, 218f Lymphatic system, 213–215, 214f, 217f. see also Lymph; Lymphatic system disorders. structures and function of, 213–215 Lymphatic system disorders, 213–222. see also Lymphatic system. Castleman disease as, 221–222 elephantiasis as, 221, 221f Inflammation (Continued) 674 I n d e x lymphedema as, 220–221 lymphomas as, 217–220 multiple myeloma as, 220f Lymphatic vessels, 213–215, 214f Lymphedema, 220–221 Lymphocytes, 116, 191 B, 116 T, 116–117, 191 Lymphomas, 217–220 definition of, 217 Hodgkin disease/Hodgkin, 217–219, 219f non-Hodgkin, 220 Lysis, 10 Lysozyme, 386 M Macroangiopathy, 410–411, 412f Macrocytes, 197–199 Macrophages, 66–67, 71, 115–116, 191 Macular degeneration, age-related, 393, 393f Macules, 152 Magnesium, 28 Major depression, 378 Major histocompatibility complex (MHC), 115 Malabsorption syndrome, 27, 196 Maladaptive behavior, 611–612 Malaise, 71 Male reproductive system, 515–516. see also Reproductive system disorders. function of, 515–516 hormones of, 516 infections in, 518 inflammation in, 518 structure of, 515–516, 515f tumors in, 518–521 Male reproductive system disorders, 515–521 of penis, 516 of scrotum, 516–517 of testes, 516–517 Malignant hypertension, 258 Malignant melanoma, 157–158, 158f, 159b Malignant tumors, 546–547. see also Cancer. characteristics of, 547, 547t, 548f diagnostic tests for, 550 effects of, 549 etiology of, 553–555 examples of, 561–563 in female reproductive system, 532–537 host defenses and, 555 pathophysiology of, 547–553 prevention of, 555 prognosis and, 560–561 risk factors of, 555, 555t spread of, 550–551 systemic effects of, 549–550 treatment of, 555–560, 556f Malnutrition, 438–439 Malunion, 169 Mammography, 533–534, 534f Manifestations, of disease, 6 MAO. see Monoamine oxidase (MAO) inhibitors. Maple syrup urine disease, 575 Marfan syndrome, 570, 570f Mast cells, 123 Mastication, 430 Mastoid air cells, 394 MD. see Muscular dystrophy. MDMA, 619 MDS. see Myelodysplastic syndrome. Meatus, 521–523 Mechanical barriers, 66 Mechanical obstructions, 479 Mechanoreceptors, 386 Meconium ileus, 294 MEDEK (CME) program, 367 Mediastinal flutter, 314–315 Mediastinum, 224, 275 Medical history, in pathophysiology, 4 Medulla oblongata, 330–331 Medullary cavity, 162–163 Megaloblastic anemia, 197–199 Megaloblasts, 197–199 Meiosis, 565 Melamine, 629 Melanin, 143 Melanoma, 158b Melasma, 143 Melena, 437 Menarche, 523, 595 Mendelian laws, 567 Ménière’s syndrome, 398 Meninges, 326–327, 328f Meningitis, 350–351, 351f Meningocele, 365 Meningococcus, 350 Menisci, 166 Menopause, 598–599 Menorrhagia, 527 Menstrual bleeding, abnormal, 527 Menstrual cycle, 523–524, 524f abnormalities of, 526–527 during adolescence, abnormalities of, 595 Mental disorders, 377–379 Meperidine, 62 MEq. see Milliequivalent. Meridians, 50 Mesentery, 429 Mesh skin graft, 84, 85f Metabolic acidosis, 33f, 318, 438, 495 Metabolic alkalosis, 34f, 35–36, 438 “Metabolic factory”, 431 Metabolic needs, 83 Metabolic syndrome, 405, 589–590 Metabolism anaerobic, 265 glucose, 590 inborn errors of, 571 lipoprotein, 590 Metaphysis, 162, 591 Metaplasia, 8 Metastasis, 551, 552f–553f Metformin, 406–407 Methamphetamine, 619 Methicillin-resistant Staphylococcus aureus (MRSA), 101 Methylprednisolone, 75 Metrorrhagia, 527 MHC. see Major histocompatibility complex. MI. see Myocardial infarction. MIC. see Minimum inhibitory concentration (MIC) method. Microangiopathy, 410, 411f Microbiology, 89–100 algae and, 99 helminths and, 99 microorganisms and, 89–90 prions and, 99 resident flora and, 99–100, 100t Microcirculation, 265 Microcytic erythrocytes, 196 Micrometastases, 533, 551 Microorganisms, 89–90 comparison of, 89t definition of, 10 opportunistic, 122 types of, 89f, 90–98 virulence and pathogenicity of, 101b, 101t, 102 Microscopic level, 5 Microvilli, 432 Micturition, 493 Middle cerebral artery, 331 Middle ear, 394 Migraine headache, 60 Mild traumatic brain injury (MTBI), 354 Miliary tuberculosis, 291 Milliequivalent (mEq), 22 Minerals, 434–435 Minimal change disease, 502 Minimum inhibitory concentration (MIC) method, 107 Mitosis, 546, 566 Mitral stenosis, 253, 254f, 256f Mitral valve prolapse, 253 Mixed infections, 106 Monoamine oxidase (MAO) inhibitors, 379 Monocytes, 115–116, 192 Monocytosis, 107 Mononuclear phagocytic system, 115–116 Monosomy X, 572, 572f, 595. see also Turner syndrome. Monospot test, 594 Mons pubis, 521–523 Morbidity, 7 Morbidity and Mortality Weekly Report, 102 Morphologic changes, in cells, 10 Morphology, defined, 194 Mortality, 7 Motor aphasia, 341 Motor dysfunction, 339 Motor unit, 164 Moxibustion, 50 MP4, 195 MRSA. see Methicillin-resistant Staphylococcus aureus. MS. see Multiple sclerosis. MTBI. see Mild traumatic brain injury. Mucosa, 599 Mucus, 428 Multifactorial disorders, 568b, 572–573 Multipara, 581 Multiparity, 457 Multiple myeloma, 220f Multiple sclerosis (MS), 370–372, 370f–371f, 382b Multistage carcinogenesis, 554f Mumps, 446, 446f Mural thrombus, 242 Murmurs, 228, 230, 257 Muscle cramp, 165 Muscle sense, 385 Muscle spasm, 165, 169 Muscle tears, 171 Muscle tissue, 164 Muscles atrophied, 607 ciliary, 386 extensor, 607 extrinsic, 386 flexor, 607 radial, 386 skeletal, 164–166 Muscular dystrophy (MD), 175, 175t, 607f Musculoskeletal system adolescence, abnormalities during, 590–592 aging process and, 600–601 immobility, effects of, 607 pregnancy, changes during, 582 Musculoskeletal system disorders, 161–183. see also Musculoskeletal system. of bone, 162–163, 163f diagnostic tests for, 166–167 of joint, 176–182 of joints, 166 of ligaments, 175–176 of muscle, 164–166, 175–176 of tendons, 175–176 Mutation, 102, 546, 566 Myasthenia gravis, 374 Myasthenic crisis, 374 Mycelium, 97 Mycobacterium, 290 Mycobacterium bovis, 291 Mycobacterium leprae, 152 Mycobacterium tuberculosis, 103, 291 Mycoplasma, 585 Mycoplasma pneumoniae, 289 Mycoplasmas, 94 Myelodysplastic syndrome (MDS), 200, 207–208 Myeloma, 220f Myelomeningocele, 365 Myelotoxins, 199 Myocardial infarction (MI), 240–242, 240f–241f case study on, 269b silent, 241 Myocarditis, 255 Myofibrils, 164 Myopia, 388 Myxedema, 420 Myxovirus, 286 N NAA. see Nucleic acid amplification. Nadir, 559 Naloxone, 620–621 Lymphatic system disorders (Continued) I n d e x 675 Narcotics, 62, 618 Narrow-angle glaucoma, 390–391 Narrow spectrum, 108 Nasopharynx, 273 Natural immunity, 120 active, 120 artificial, 120–121 passive, 121 Natural killer cells, 118 Naturopathy, 49 Necrosis, 9 caseation, 290–291 Necrotizing periodontal disease, 444, 612–613, 614f Negative feedback, 401, 403f Neisseria gonorrhoeae, 103, 389 Neisseria meningitidis, 350 Neonatal respiratory distress syndrome (NRDS), 317–318 Neonates, 575 Neoplasia, 8–9 Neoplasms, 545–564 Neoplastic blood disorders, 208–211 leukemias as, 208–211 polycythemia as, 208 Nephroblastoma, 507 Nephrons, 489, 492f Nephropathy, diabetic, 410 Nephrosclerosis, 505–506 Nephrosis, 502–503 Nephrotic syndrome, 502–503 Nephrotoxins, 507–509, 508f Nerve damage, 169 Nerve impulses, 21, 22f Nerves, 166 cranial, 331, 332t spinal, 333 Nervous system. see also Neurologic disorders. aging process and, 602 anatomy and physiology of, review of, 326–337 autonomic, 335–337, 337t brain in, 326–331 conduction of impulses in, 334–335 disorders of, 325–384 neurons in, 334 neurotransmitters in, 335 overview of, 327f parasympathetic, 337 spinal cord in, 331–334 spinal nerves in, 333 substance abuse, effects on, 622 sympathetic, 335–337 synapses in, 335 Neuralgias, 60–61 Neuritis, 626 Neuroborreliosis, 352 Neurofibrils, 602 Neurogenic shock, 267 Neuroglial cells, 334 Neuroleptanesthesia, 62 Neurologic disorders. see also Nervous system. acute neurologic problems, 344–363 chronic degenerative disorders, 370–375 congenital neurologic disorders, 363–367 dementia, 377 mental disorders, 377–379 neurologic dysfunction, 338–344 seizure disorders, 367–370 Neurologic dysfunction, 338–344 diagnostic tests for, 344 focal effects of, 338 herniation and, 344–363 increased intracranial pressure and, 341–343 infratentorial lesions in, 338 language disorders and, 340–341 in left and right hemispheres, 338 level of consciousness and, 338–339 local effects of, 338 motor dysfunction and, 339 seizures and, 341 sensory deficits and, 339 supratentorial lesions and, 338 visual loss and, 339–340 Neurons, 334 Neuropathic pain, 60–61 Neuropathy, 411–412 Neuropeptides, 60 Neurotransmitter substance P, 56–57 Neurotransmitters, 335, 336f Neutropenia, 107 Neutrophils, 66–67, 71–72, 191 Nidus, 503 Nifedipine, 231–232 Nitrofurantoin, 500 Nociceptors, 54, 386 Nocturia, 500, 603 Noise hazards, 629 Nomenclature, of tumors, 546–547 Non-A-non-B hepatitis, 462 Non-Hodgkin lymphomas, 220 Non-nucleated red blood cells, 188, 190f Noncommunicating hydrocephalus, 363 Noncontact therapeutic touch, 49 Nonfluent aphasia, 341 Nonspecific defense mechanisms, 66–67 Nonsteroidal antiinflammatory drugs (NSAIDs), 60–62, 74 Nonsteroids, 401 Nonunion, 169 Nonviral hepatitis, 463 Nonvolatile metabolic acids, 29–30 Norepinephrine, 335 Normal capillary exchange, 67, 68f Normal expiration, 275 Nosocomial infection, 101 Nosocomial pneumonia, 287 Notifiable disease, 7–8 NovoSeven, 195 Nplate, 195 NRDS. see Neonatal respiratory distress syndrome. NSAIDs. see Nonsteroidal antiinflammatory drugs. Nuchal rigidity, 349 Nuclear imaging, 230 Nuclear medicine studies, 230 Nucleic acid amplification (NAA), 292 Nutrition, 48 aging process and, 602–603 malignant tumors and, treatment of, 560 during pregnancy, 582 Nystagmus, 388 Nystatin, 442 O OA. see Osteoarthritis. “Oat cell” carcinoma, 296 Obesity, 589–590, 589f. see also Metabolic syndrome. Obligate intracellular parasite, 93 Oblique fracture, 167, 168f Obstructions partial, 301 scar formation and healing, complications with, 78 total, 301 by tumors, 549, 549f Obstructive atelectasis, 313f Obstructive hydrocephalus, 363 Obstructive lung diseases, 294–302 aspiration as, 298–299 asthma as, 300–302 cystic fibrosis as, 294–296 lung cancer as, 296–298 obstructive sleep apnea as, 300 Obstructive shock, 267 Obstructive sleep apnea, 300 Occipital lobes, 388 Occlusion, 628 Occult blood, 437 Occupational hazards of fighting forest fires, 630b Occupational therapy, 48 for RSI, 171 Oligomenorrhea, 527 Oliguria, 507 Omentum, 429 Oncology, 547 Ondansetron, 559 One-way flow of blood, 224 One-way valve effect, 315 Oocyte, 579–580 Open-angle glaucoma, 391 Open fracture, 167, 168f Open head injury, 354 Open pneumothorax, 314 Open reduction, 170 Ophthalmoscope, 388 Opiate receptors, 56–57 Opiates, 60 Opioids, 56–57 Opportunistic infection, 99–100 Opportunistic microorganism, 122 Optic disc, 388 Optic nerve, 388 Oral candidiasis, 442 Oral cavity, 430, 430f. see also Oral cavity disorders. cancer of, 445–446 squamous cell carcinoma in, 445, 446f Oral cavity disorders, 441–446 congenital defects as, 441–442 dental problems as, 443–444 hyperkeratosis as, 444 infections and, 442–443 inflammatory lesions as, 442 salivary gland disorders as, 446 Oral medications, for diabetes, 406–407 Organ of Corti, 394 Organogenesis, 573, 579–580 Orthopnea, 248, 282 Orthostatic hypotension, 496, 608 Oseltamivir, 111, 285–286 Osler nodes, 257 Osmoreceptors, 15, 386 Osmosis, 16, 489 Osmotic pressure, 16, 67 Osteoarthritis (OA), 176–178, 177f–178f, 603–604 Osteoblasts, 162, 607 Osteoclasts, 162, 607 Osteocytes, 162 Osteodystrophy, 510, 511f Osteomalacia, 173 Osteomyelitis, 173, 591, 592f Osteopathy, 48 Osteoporosis, 162, 172–173, 600f, 607 in adolescence, 590 aging process and, 600, 601f Osteoprogenitor cells, 162 Osteosarcoma, 174, 174f Otitis externa, 398 Otitis media, 396–397 Otosclerosis, 398 Ototoxic drugs, 395 Ovarian cancer, 537, 551, 553f, 561 Ovarian cysts, 530, 532f Overdose, 620–621 Overflow incontinence, 493–494 Oviduct, 579–580 Ovum, 579–580 Oxycodone, 62 Oxygen, transport of, 279–280 Oxyhemoglobin, 188–189 Oxyhemoglobin dissociation curve, 280f P PAB. see Premature atrial beats. PAC. see Premature atrial contraction. Pacemaker, 224–225, 245, 245f Packed platelets, 195 Packed red blood cells, 195 Paget disease, 173 Pain, 53–64 acute, 59, 59t, 63b basic classifications of, 59–61 burns, effects of, 83 cancer-related, 61 central, 60 characteristics of, 57–59 chronic, 59, 59t, 63b control, 55–57, 56f, 61–62 digestive system disorders and, 438 etiology of, 53–54 headache and, 59–60 intractable, 62 ischemic, 61 676 I n d e x methods of managing, 61–62 mild, 61–62 moderate, 62 neuropathic, 60–61 pathways, 54–55, 54f perception and response to, 57–59 phantom, 57 physiology of, 55–57 pleural, 282 referred, 57, 58f, 438 severe, 62 signs and symptoms of, 57 somatic, 54, 438 source of, 53–54 structures of, 54–55 threshold, 54 tolerance, 54 from tumors, 549 visceral, 54, 438 young children and, 57 Painkillers, 618 Palatine, 215 Palatine tonsils, 273 Palliative treatment, 556 Pallor, 195 Palpebrae, 386 Pancreas, 294, 432 exocrine, 431 Pancreatic cancer, 469 Pancreatitis, acute, 468–469, 468f Pancrelipase, 296 Pancytopenia, 199 Pandemic, 7 Panic attack, 379 Panic disorder, 379 Pannus formation, 178, 179f PAP. see Primary atypical pneumonia. Papilledema, 342, 343f Paraesophageal hernia, 448 Paralysis, 329 bites and stings, 629 infantile, 353 spastic, 339, 366 Paralysis agitans, 372–373 Paralytic ileus, 479 Paraneoplastic syndromes, 550 Paraplegia, 361, 606 Parasympathetic nervous system (PNS), 337, 433 Parathyroid gland, 400 Parathyroid hormone (PTH) calcium and, 413–414, 415f disorders of, 413–414 imbalances of, 414, 416f Parenteral injection, 43 Paresis, 329 Paresthesias, 24, 346 Parietal peritoneum, 428 Parietal pleura, 275 Parity, 581 Parkinson disease, 372–373, 372f Paroxysmal nocturnal dyspnea, 248–249, 282 Partial heart block, 244 Partial obstruction, 301 Partial pressure of carbon dioxide (PaCO2), 277 Partial seizures, 367 Partial thickness burns, 79, 80f–81f Partial thromboplastin time (PTT), 195 Particulate, 626 Passive artificial immunity, 121 Passive natural immunity, 121 Pathogenesis, definition of, 6 Pathogenicity, 102 Pathogens, defined, 89–90 Pathologic fracture, 167, 168f Pathophysiology, 1–13 cellular changes in, 8–12. see also Cells. concept of, 2–4 definition of, 1–8 heath and disease in, 2 medical history in, 4 new developments and trends in, 4–5 scope of, 2–4 studying, purpose of, 1–8 terminology of, 5–8 Patient-controlled analgesia (PCA), 62 PCOS. see Polycystic ovarian syndrome. PCP. see Phencyclidine; Pneumocystis carinii pneumonia. PCR. see Polymerase chain reaction. Pediculosis, 156–157 Pediculus humanus capitis, 156, 156f Pediculus humanus corporis, 156 Pediculus pubis, 156 PEG. see Polyethylene glycol. Pegaptanib, 393 Pelvic cellulitis, 585–586 Pelvic inflammatory disease (PID), 528–530, 529f Pelvic relaxation, 525 Pemphigus, 149 Penis, 516 Pepsinogen, 431 Peptic ulcer, 451–454, 452f–453f Peptides, 434 Perception, 618 Percutaneous nephrolithotomy, 504 Perforation, 73, 453 Perfusion, 278–279, 305f Pericardial effusion, 258f Pericardial sac, 224 Pericarditis, 255, 257–258 Perimysium, 164 Perindopril, 232 Periodontal disease, 412, 412f, 444, 602–603, 612–613, 614f Periodontitis, 444 Periosteum, 162, 591 Peripheral resistance, 229 Peripheral vascular disease, 261 Peritoneal cavity, 428 Peritoneal dialysis, 498 Peritoneum, 428 Peritonitis, 267, 453, 482–484, 583, 585–586 development of, 483f Peritubular capillaries, 491 Permanent pacemaker, 245, 245f Permeability, 69 Pernicious anemia, 198f Pernicious anemia-vitamin B12 deficiency, 197–199 Pesticides, 627 Petechiae, 204f, 207 Petechial rash, 351f Petit mal seizures, 368 Peyer patches, 432 pH buffer systems of, 30 control of, 30–32, 31f maintenance of, 30 range of, 29, 29f in renal system, 31–32 in respiratory system, 31 Phagocytosis, 66–67 Phantom pain, 57 Pharmacodynamics, 41 Pharmacokinetics, 41 Pharmacology, 40–47 basic principles of, 40–41 Pharmacotherapeutics, 41 Pharmacy, 41 Pharyngeal tonsils, 215, 273 Pharynx, 273 Phencyclidine (PCP), 619 Phenotype, 567 Phenylketonuria (PKU), 571 Pheochromocytoma, 420 Phlebitis, 263 Phlebothrombosis, 263–264 Phlebotomy, 208 Phosphate, 28 Photophobia, 349, 390 Photoreceptors, 386 Physical agent hazards, 627–629 food hazards as, 629 noise hazards as, 629 radiation hazards as, 628–629 temperature hazards as, 627–628 waterborne hazards as, 629 Physiologic changes, 611 Physiologic dependence, 618 Physiologic jaundice, 457 Physiology, of infection, 105–111 Physiotherapy, 48 Pia mater, 327, 328f Pica, 626 PID. see Pelvic inflammatory disease. Pig heart valve, 254f Pili, 91 Pineal gland, 400 Pinna, 394 Pinworm, 99, 99f Piroxicam, 74 Pituitary gland, 400 PKU. see Phenylketonuria. Placebo, 47 Placenta, 121, 579–580 Placenta previa, 584 Placental disorders, 584 Plaques, 370, 602 Plasma, 187, 195 Plasma membrane, 546 Plasma proteins, loss of, 19 Plasmodium falciparum, 97, 103 Plasmodium vivax, 97 Plethoric appearance, 208 Pleural effusion, 313–314 Pleural membrane, 275 Pleural pain, 282 Pleurisy, 287, 313–314 Pleuritis, 287, 313 Pluripotential hematopoietic stem cell, 188 PMNs. see Polymorphonuclear leukocytes. PMS. see Premenstrual syndrome. Pneumococcal pneumonia, 287 Pneumoconioses, 308–309, 308t Pneumocystis carinii, 97 Pneumocystis carinii pneumonia (PCP), 289 Pneumonia, 286–289, 550 aspiration, 287 bronchopneumonia as, 288–289 case study on, 321b chlamydial, 289 classification of, 286–287 hospital-acquired, 287 interstitial, 287t Legionnaires disease as, 289 lobar, 287–288, 287t, 289f mycoplasma, 289 nosocomial, 287 pneumococcal, 287 pneumocystis carinii pneumonia (PCP), 289 primary atypical, 287t, 289 streptococcal, 289f viral, 289 Pneumothorax, 314–315, 315b, 315t, 316f PNS. see Parasympathetic nervous system. Poliomyelitis, 353 Polycystic ovarian syndrome (PCOS), 530, 532f Polycythemia, 208 Polydipsia, 405 Polyethylene glycol (PEG), 195 Polygenic disorders, 570 Polymenorrhea, 527 Polymerase chain reaction (PCR), 134–135 Polymorphonuclear leukocytes (PMNs), 69–70 Polyphagia, 405 Polyuria, 405, 509 Poor turgor, 21f Porcine heart valve, 254f Porphyromonas gingivalis, 444 Posterior cavity, of eye, 387 Posterior cerebral arteries, 331 Posterior communicating arteries, 331 Postganglionic fiber, 335 Posthepatic jaundice, 457 Postictal period, 369 Postmortem examination, 7 Postnecrotic cirrhosis, 463 Postoperative atelectasis, 312 Postpolio syndrome (PPS), 353 Poststreptococcal glomerulonephritis, 501f–502f Posttraumatic stress disorder (PTSD), 615 Potassium imbalance, 24–26, 25t nerve impulses, role in conduction of, 21, 22f Pain (Continued) I n d e x 677 Potentiation, 42 Pott fracture, 167, 168f PPS. see Postpolio syndrome. Precipitating factor, 7 Predisposing factors, for disease, 6 Prednisone, 75, 122 Preeclampsia, 583 Prefrontal cortex, 329–330 Pregabalin, 176 Preganglionic fiber, 335 Pregnancy adolescent, 586 blood clotting disorders during, 584 cardiovascular changes during, 582–583 complications of, 583–586 diabetes, acute complication of, 413 diagnosis of, 580–581 digestive changes during, 582 ectopic, 583 embryonic development during, 579–580 fetal development during, 579–580 gestational diabetes mellitus during, 583–584 hormonal changes during, 581 hypertension induced by, 583 infection during, 585–586 musculoskeletal changes during, 582 nutrition during, 582 physiological changes during, 580–583 reproductive system changes during, 581–582 Rh incompatibility during, 584–585 teratogens during, 573, 574f weight gain during, 582 Pregnancy gingivitis, 582 Pregnancy-induced hypertension, 583 Prehepatic jaundice, 457 Prehypertension, 258 Preload, 228 Premature atrial beats (PAB), 244 Premature atrial contraction (PAC), 243f, 244 Premature ventricular contractions (PVCs), 241–242, 244 Premenstrual syndrome (PMS), 527 Presbycusis, 395 Presbyopia, 388, 602 Pressoreceptors, 331 Prevention, of disease, 2–3 Primary atypical pneumonia (PAP), 287t, 289 Primary fibromyalgia syndrome, 176 Primary hypertension, 258 Primary immune response, 120 Primary infections, 106 Primary prevention of disease, 3b Primary tumor, 550–551 Primigravida, 581 Prions, 99 Probability, definition of, 7–8 Prodromal period, 6, 105, 368 Prognosis, definition of, 7–8 Projectile vomiting, 435 Prokaryotic cells, 89 Prolonged stress, 612 Promoters, 553–555 Prophylactic treatment, 556 Prophylaxis, 6 Propionibacterium acnes, 593–594 Proprioceptors, 385 Prostaglandins, 69 Prostate cancer, 519–520, 520f, 559 Prostate gland, 515 Prostate specific antigen (PSA), 520 Prostatitis, 518 Proteases, 303 Proteins, 434 Proteinuria, 495 Proteomic research, on DNA, 576 Prothrombin, 193 Proton pump inhibitor, 440–441 Protozoa, 97–98 Protozoan infections, 542 Pruritic area, 123 Pruritus, 144, 457–458 PSA. see Prostate specific antigen. Pseudohypertrophic muscular dystrophy, 175 Pseudomonas, 267 Pseudomonas aeruginosa, 83, 84f, 287 Psoriasis, 148–149, 149f Psychedelics, 618 Psychological dependence, 618 PTH. see Parathyroid hormone. Ptosis, 343, 389 PTSD. see Posttraumatic stress disorder. PTT. see Partial thromboplastin time. Puberty, 588 Puerperal infection, 585 Pulmonary capillary wedge pressure, 230–231 Pulmonary circulation, 185 Pulmonary edema, 248–249, 309, 310f Pulmonary embolus, 309–312, 311f, 584, 608 Pulmonary function, 589 Pulmonary tuberculosis, 12f Pulmonary valve stenosis, 253 Pulmonary volume, 276–277, 276t, 277f Pulse, 228, 228f Pulse deficit, 228 Pulse pressure, 229, 342 Pulsus paradoxus, 302 Punnett squares, 569f Purulent exudate, 70–71 Pustule, 593–594 PVCs. see Premature ventricular contractions. Pyelonephritis, 500, 508f Pyloric stenosis, 456 Pyloroplasty, 454 Pyramidal tracts, 332 Pyrexia, 71, 106 Pyrogens, 71 Pyrosis, 449 Pyuria, 495 Q QA. see Quality Assurance (QA) program. Quadriplegia, 361, 606 Quality Assurance (QA) program, 6–7 Quiet inspiration, 275 R RA. see Rheumatoid arthritis. Rabies, 352–353, 629–630 Radial muscles, 386 Radiation, 557 Radiation hazards, 628–629 Radiation therapy, 557–558 Radiofrequency ablation (RFA), 298, 557 Radioisotope, 550, 557 Rales, 282 Raloxifene, 172 Ramipril, 232 RAS. see Reticular-activating system. RB. see Reticulate body. RBCs. see Red blood cells. Reabsorption, 489 Receptive aphasia, 341 Rectocele, 525–526 Recurrence, 550 Red blood cells (RBCs), 188, 584, 585f. see also Erythrocytes. non-nucleated, 188 packed, 195 Reduced hemoglobin, 188–189 Reed-Sternberg cell, 217–218, 219f Reermerging infectious diseases, 121 Referred pain, 57, 58f, 438 Reflex response, 55 Reflexes, 333–334 Reflexology, 50–51 Refraction of eye, 386–387 Regeneration, 75–76 Regional anesthesia, 62 Regional enteritis, 470–472 Regional ileitis, 470–472, 471f Registered massage therapy, 48 Rehabilitation, 7 Reinfection tuberculosis, 291 Remissions, 7, 560 Renal arteries, 490–493 Renal cell carcinoma, 505, 505f Renal colic, 504 Renal failure, 507–511 acute, 614 Renal insufficiency, 509 Renal pelvis, 489 Renal system, serum pH in, 31–32 Renin-angiotensin-aldosterone, 491 Repaglinide, 407 Repetitive strain injury (RSI), 171 Replacement, 76 Repolarization, 334 Reportable disease, 7–8 Reproductive system. see also Reproductive system disorders. aging process and, 598–599 pregnancy, changes during, 581–582 Reproductive system disorders, 514–544. see also Reproductive system. female, 521–524 infertility and, 537–538 male, 515–521 Reservoir, 104 Resident microbiota. see Resident (normal) flora. Resident (normal) flora, 99–100, 100t, 144, 273 Residual volume, 276 Resistant hypertension, 258 Resolution, 75 Respiratory acidosis, 33–34, 35f, 318 Respiratory alkalosis, 35, 36f Respiratory disorders. see also Respiratory system. chronic obstructive pulmonary disease as, 302–308 diagnostic tests for, 280 expansion disorders and, 312–320 general manifestations of, 281–282 infectious diseases as, 283–294 obstructive lung diseases as, 294–302 restrictive lung disorders as, 308–309 treatments for, 283 vascular disorders and, 309–312 Respiratory distress syndrome, 299 Respiratory mucosa, 273 Respiratory problems, as effects of burn injury, 82–83 Respiratory syncytial virus (RSV), 286 Respiratory system. see also Respiratory disorders. aging process and, 601–602 gas exchange and, 278–280 immobility, effects of, 608–609 organization of, 273 purpose of, 273 structures of, 273–275, 274f ventilation and, 275–278 Respiratory system disorders, 272–324 in children, 285t treatments for, 283t Restrictive lung disorders, 308–309 Reticular-activating system (RAS), 55, 330 Reticular formation, 55, 330 Reticulate body (RB), 94 Reticulocyte, 195 Retina, 339–340, 387, 602 Retinoblastoma, 576b Retinopathies, 388, 410 Retraction, 282 Retroperitoneal organs, 430 Retroperitoneally, defined, 489 Retrovirus, 134 Reye syndrome, 73–74, 353 RF. see Rheumatoid factor. RFA. see Radiofrequency ablation. Rh immunoglobulin (RHoGAM), 584–585 Rh incompatibility, 584–585, 585f Rheumatic fever, 255–256 Rheumatic heart disease, 255–256, 255f–256f Rheumatic mitral valvulitis, 256f Rheumatoid arthritis (RA), 178–180, 179f, 182b Rheumatoid factor (RF), 178 Rhinitis, infectious, 283–285 Rhizotomy, 62 RHoGAM. see Rh immunoglobulin. Rhonchi, 282 RICE approach, 75 Rickets, 173 Rickettsiae, 94 Right coronary artery, 226 Right hemispheres, 338 678 I n d e x Right-sided heart failure, 249 RNA viruses, 110 Rocky Mountain spotted fever, 94, 629–630 “Rodent ulcer”, 561 Rods, 387 Rolling hernia, 448 Rosenthal’s hemophilia, 205. see also Hemophilia C. Roundworms, 99 Routes, for drug administration, 44t RSI. see Repetitive strain injury. RSV. see Respiratory syncytial virus. Rugae, 431 Rule of nines, 80 S SA. see Sinoatrial (SA) node. Saliva, enzymes in, 430, 430t Salivary glands, 294–295 SARS. see Severe acute respiratory syndrome. SARS-CoV (SARS-associated coronavirus), 290 Scabies, 155–156, 156f Scar from burns, 84, 85f exudate, risk of, 70 formation, 78 Scar tissue, 84 Scarlet fever, 286, 286f Schedules of controlled substances, 47t Schizophrenia, 378 Sclera, 386 Scleroderma, 149–150, 150f Scoliosis, 172–173, 590–591 Scotoma, 370–371 Scrotum, 515, 517f Sebaceous glands, 144, 593 Seborrheic keratoses, 157 Sebum, 144, 593–594 Second-degree burns, 79 Second-degree heart block, 244 Second-degree muscle tears, 171 Second-generation drug, 108 Secondary hypertension, 258 Secondary immune response, 120 Secondary infections, 106 Secondary pneumothorax, 314 Secondary prevention of disease, 3b Secondary tuberculosis, 291 Secondary tumors, 550–551 Secretin, 433–434 Secretion, 489 Sedatives, 62 Seeding, 551 Segmental fracture, 167, 168f Seizures. see also Seizures disorders. emergency treatment for, 369b heavy metals and, 626 infection, sign of, 106 neurologic dysfunction and, 341 Seizures disorders, 367–370, 368b. see also Seizures. Selective serotonin reuptake inhibitors (SSRIs), 379 Self-antigens, 128 Selye, Hans, 611 Semen, 515 Semicircular canals, in ear, 395 Seminal vesicles, 515 Seminiferous tubules, 515 Senescence, 597–598 Sensorineural impairment, 395 Sensory aphasia, 341 Sensory deficits, 339 Sensory receptors, 385–386. see also Ear; Eye. Septal defects, 250, 251f–252f Septic shock, 267 Septicemia, 106 Septum, 224 Sequelae, 7 Serotonin, 56–57, 69, 335 Serotonin-norepinephrine reuptake inhibitors (SNRIs), 379 Serous exudate, 70 Serum, 187 Serum glutamic-oxaloacetic transaminase (SGOT), 72 Serum hepatitis, 458–459 Serum pH. see pH. Serum sickness, 127 Severe acute respiratory syndrome (SARS), 102, 289–290 Severe combined immunodeficiency disease, 575 Severe pain, 62 Severe stress, 614–615 Sex hormones, 559 Sexual development, during adolescence, disorders affecting, 595 Sexually transmitted diseases (STDs), 538–542, 539t bacterial infections, 538–541 protozoan infections, 542 viral infections, 541–542 SGOT. see Serum glutamic-oxaloacetic transaminase. Shiatsu, 50 Shigella, 629 Shingles, 353. see also Herpes zoster. Shock, 264–268 anaphylactic, 125, 267 cardiogenic, 242, 267 in cardiovascular system, 264t, 265f–266f, 268f, 268t distributive, 267 as effects of burn injury, 82, 83f emergency treatment for, 267b hypovolemic, 267 neurogenic, 267 obstructive, 267 septic, 267 vasogenic, 267 Short bones, 162 Sialadenitis, 446 Sick sinus syndrome, 243 Sickle cell anemia, 200, 202f Side effects, 41 Sign language, 395 Silent myocardial infarction, 241 “Silent stage,” of disease, 6 Simple fracture, 167, 168f Simple pneumothorax, 314 Simvastatin, 232–233 Single-gene disorders, 568b, 570–571 autosomal-dominant disorders as, 568b, 571 autosomal-recessive disorders as, 568b, 571 X-linked dominant disorders as, 568b, 571 X-linked recessive disorders as, 568b, 571 Single-photon emission computed tomography (SPECT), 230 Sinoatrial (SA) node, 224–225 Sinus, 591 Sinus headaches, 59 Sinus node abnormalities, 243 Sinus rhythm, 225 Sinusitis, 274f, 285 Sinusoids, 431 Skeletal muscle, 164–166, 601 Skeletal muscle spasms, 72 Skin aging process and, 599 cancer, warning signs for, 157b disorders of, 142–160, 593–594 infections of, 150–157 bacterial, 150–152 inflammatory disorders of, 146–150 atopic dermatitis, 147–148, 148f contact dermatitis, 146–147, 147f pemphigus, 149 psoriasis, 148–149, 149f scleroderma, 149–150, 150f urticaria, 147, 147f lesions of, 144–146, 145f, 146t normal, 143, 143f tumors of, 157–159 Kaposi sarcoma, 158–159 keratoses, 157 malignant melanoma, 157–158, 158f squamous cell carcinoma, 157, 158f turgor, 21 Skin graft, mesh, 84, 85f Skip lesions, 470, 471f SLE. see Systemic lupus erythematosus. Sleep apnea, obstructive, 300 Sliding hernia, 448 Slime layer, 90–91 Small intestine, 432 Sneezing, 281–282 SNRIs. see Serotonin-norepinephrine reuptake inhibitors. SNS. see Sympathetic nervous system. Sodium, 21–22 diffusion of, 21 excessive levels of, 19 imbalance of, 21–24, 23t nerve impulses, role in conduction of, 21, 22f Solvents, 626 Somatic pain, 54, 438 Sores, cold. see Herpes simplex virus. Sounds breath, 282 ear, pathway in, 394–395 waves of, 395 Spastic paralysis, 339, 366 Specific antibodies, 115 Specific defense mechanisms, 66–67 Speech/language pathology, 48 Sperm, 579–580 Spermatic cord, 515 Spermatocele, 517 Spermatogenesis, 515–516 Spina bifida, 364–365, 365f, 580 Spina bifida occulta, 365 Spinal anesthesia, 62 Spinal cord, 331–334 disorder, 380 functional areas of, 333f injuries to, 358–363, 359f, 361f, 381b Spinal nerves, 333 Spinal shock, 360 Spiral fracture, 167, 168f Spirals, 90 Spleen, 215 Splenectomy, 131 Splenomegaly, 201, 464 Spontaneous pneumothorax, 314 Sprain, 170–171 Sputum, 281 Squamous cell carcinoma, 157, 158f Squamous-columnar junction, 523 SSRIs. see Selective serotonin reuptake inhibitors. St. Louis encephalitis, 352 Staghorn calculus, 503 Standstill, 245 Staphylococcus abscess, 106f Staphylococcus aureus, 83, 90f, 103, 256, 389, 585, 591 Stasis, 608 Status asthmaticus, 301 Status epilepticus, 368 STDs. see Sexually transmitted diseases. Steatorrhea, 295, 437 Stein-Leventhal syndrome, 530 Stem cells, 116–117, 188, 195 Stenosis, 78, 448 Sterilization, 104 Steroidal antiinflammatory drugs, 74 Steroids, 401 Still disease, 591–592 Stimulants, 618 Stimulation tests, 404 Stings, 629–630 Stokes-Adams attack, 244 Stomach, 431 Stomatitis, 195 Storage disease, 571 Strabismus, 388 Strain, 170–171 Stratum basale, 143 Stratum corneum, 143 Stratum granulosum, 143 Stratum lucidum, 143 Stratum spinosum, 143 “Strawberry” tongue, 286, 286f Strep throat, 284–285, 284f Streptococcal pneumonia, 289f I n d e x 679 Streptococci, 102 Streptococcus, 255, 585 Streptococcus mutans, 443–444 Streptococcus pneumoniae, 103, 284–285, 350 Streptococcus pyogenes, 286 Streptococcus viridans, 256 Streptokinase, 193 Stress, 611–616 body response to, 611, 613f coping with, 615 diseases caused by, 612–615 disorders related to, 614b prolonged, effects of, 614–615 severe, effects of, 614–615 Stress fracture, 167, 168f Stress incontinence, 493–494 Stress reduction, 439 Stress response, 611–612 Stress ulcers, 454, 454f, 614 Stressor, 611 Stricture, 448 Stridor, 282 Stroke, 346–348. see also Cerebrovascular accidents. heat, 627–628 warning signs of, 348b Stroke volume, 228 Structural scoliosis, 591 Studying pathophysiology, purpose of, 3 Stye, 389 Subarachnoid hemorrhage, 356–357 Subarachnoid space, 327 Subclinical infections, 100, 106 Subclinical state, 6 Subcutaneous tissue, 144 Subdural hematoma, 356, 357f Subdural space, 327 Subluxation, 170 Substance abuse, 617–623. see also Alcohol. behavioral risk factors for, 619–620 cardiovascular system and, 621 environmental risk factors for, 619–620 indications for, 620 infection and, 621 neurologic effects of, 621 potential complications of, 620–622 predisposing factors for, 619 psychological effects of, 621 recognition of, 620 terminology for, 618–619 treatment for, 622 withdrawal and, 621 Substance P, 56–57 Substantia nigra, 372 Sucking wound, 314 Sucralfate, 440 Sulci, 328 Sulcus, 226 “Sunset sign”, 364 “Superbugs”, 102 Superficial burns, 79 Superinfection, 108 Supine position, 583, 609 Suppression tests, 404 Supratentorial lesions, 338 Surface tension, 274–275 Surfactant, 274–275 Surgery, for malignant tumors, treatment of, 557 Suspensory ligament, 386–387 Sutures, 326 Swallowing, 430–431 Sweat glands, 144, 294–295 Swimmer’s ear, 398 Sympathetic nervous system (SNS), 225, 335–337 Synapses, 335, 336f Synarthroses, 166 Syncope, 196, 244, 627 Syndrome, 6 Syndrome of inappropriate antidiuretic hormone, 416 Synergism, 42, 620–621 Synergistic factors, 235 Synovial fluid, 166 Synovial joints, 166 Synovial membrane (synovium), 166 Synovitis, 178, 182 Synthesized drugs, 41 Syphilis, 443, 539–541, 540f Systemic administration, 43 Systemic backup, 249 Systemic circulation, 185 Systemic exposure, 628 Systemic infections, 106 Systemic lupus erythematosus (SLE), 128–131, 130f, 139b clinical signs and symptoms, 129, 131t diagnostic tests, 129, 130f pathophysiology of, 129 treatment of, 129–131 Systemic signs, of infection, 106 Systemic vasoconstriction, 342 Systole, 227–228 Systolic hypertension, 258 Systolic pressure, 229 T Tachycardia, 195, 225, 243–244, 243f Tapeworm, 99, 99f TB. see Tuberculosis. TCAs. see Tricyclic antidepressants. T cells, 116–117, 215, 216f. see also T-lymphocytes. Tears, 386 Temperature, hazards of, 627–628 Temporomandibular joint (TMJ) syndrome, 60 Temporomandibular (TMJ) joint, 166 Tendinitis, 182 Tendon, 165 Tenesmus, 472 Tension headaches, 59 Tension pneumothorax, 315 Teratogen, 580 Teratogenic agents, 570 Teratogenic effects, 42 Teratogens during pregnancy, 573, 574f Tertiary prevention of disease, 3b Testes, 515 cancer of, 520–521, 521f disorders of, 516–517 undescended, 516f Testosterone, 516 Tetanus, 353 Tetany, 27, 165–166 Tetralogy of Fallot, 253–255 Tetraplegia, 361 Thalamus, 55, 330 Thalassemia alpha, 203 Thalassemia beta, 203 Therapeutic effects, 41 Therapeutic interventions, 7 Therapy definition of, 7 traditional forms of, 48–49 Thermoreceptors, 386 Third-degree burns, 79–80 Third-degree heart block, 244 Third-degree muscle tears, 171 Third-spacing, 21 Thorax, 275 Thrombin, 193 Thrombocytes, 192 Thrombocytopenia, 200, 550 Thromboembolism, 242, 584 Thrombophilia, 207 Thrombophlebitis, 263–264, 584 Thrombus, 193, 193f, 584 Thrush, 97f, 132, 442, 443f Thymus gland, 116–117, 215, 216f, 400 Thyroid disorders, 417–420 diagnostic tests for, 420 goiter as, 417–418 hyperthyroidism as, 418–420 hypothyroidism as, 420 Thyroid gland, 400, 418f Thyroid storm, 418 Thyrotoxic crisis, 418 Tinea, 154–155, 155f Tinea pedis, 97 Tinnitus, 395, 629 Tissue engineering, 76 Tissue/organ transplant rejection, 121–122 acute, 122 chronic, 122 hyperacute, 122 process of, 122 treatment and prevention of, 122 types, 122t Tissue perfusion, 264 Tissue plasminogen activator (tPA), 193, 348 Titer of antibodies, 119 T-killer cells, 116–117 T-lymphocytes, 116–117, 191, 594, 594f. see also T cells. TNM. see Tumor size-node involvement-metastases. Tolerance, 618 Tomographic studies, 230 Tonic-clonic seizures, 368–369 Tonometry, 388 Tonsils, 215, 273 Tophus, 181 TORCH, 573 Tositumomab, 560 Total heart block, 244 Total obstructions, 301 Total parenteral nutrition (TPN), 560, 609 Toxemia, 106 Toxic goiter, 418 Toxic hepatitis, 463 Toxic megacolon, 472 Toxic substances, 91 Toxicology, 41, 625 Toxins, 91, 120–121 Toxoid, 120–121 Toxoplasma gondii, 100, 353 tPA. see Tissue plasminogen activator. TPN. see Total parenteral nutrition. Trachea, 274 Trachoma, 389–390 Traction, 170 Tranquilizers, 618 Transcellular fluids, 15 Transcutaneous electrical nerve stimulation (TENS), 55 Transformation zone, 523 Transfusion, 194t Transient ischemic attacks, 346 Transillumination, 365 Transmission aerosol, 100 control of, 103–105 droplet, 100 of infectious agents, 101f through hand, 100 vector-borne, 100 Transport maximum, 489 Transudates, 314 Transverse fracture, 167, 168f Trastuzumab, 533, 560, 576 Trauma to bones, 167–171 case study on, 86b to eye, 389–390 Traveler’s diarrhea, 629 Trench mouth, 444 Treponema pallidum, 100, 443, 539 Triamcinolone, 75 Trichomonas vaginalis, 97, 98f, 542 Trichomoniasis, 542 Trichophyton rubrumis, 155 Tricyclic antidepressants (TCAs), 379 Trigone, 492–493 Trimesters, 580 Trimethoprim-sulfamethoxazole, 500 Triptans, for severe migraines, 60 Trisomy 21, 572, 576, 577f Trophoblast, 579–580 Trophozoite, 97–98 Tropic hormones, 404 Troponin blood test, 231 True vocal cords, 273 Trypanosoma, 98f Tubercle, 290–291 Tuberculin test, 127 680 I n d e x Tuberculosis (TB), 290–293, 291f extrapulmonary, 291 miliary, 291 reinfection, 291 secondary, 291 Tubular maximum, 489 Tubules, 489 Tumor markers, 550 Tumor size-node involvement-metastases (TNM), 296–297 Tumors. see also Carcinomas; specific types of. during adolescence, 595 anemia from, 549 benign, 546–547 biopsies of, 550 of bone, 174 brain, 344–345, 345f, 561–563, 562f of breast, 548f in female reproductive system, 530–532 grading of, 548 local effects of, 549 in male reproductive system, 518–521 malignant, 546–547 nomenclature, 547, 547t obstruction by, 549 primary, 550–551 prognosis of, 552 secondary, 550–551 as urinary tract obstruction, 505 Tunica adventitia, 185 Tunica intima, 185 Tunica media, 185 Tunica vaginalis, 515 Turner syndrome, 572, 572f, 595 Tympanic cavity, 394 Tympanic membrane, 394, 629 with otitis media, 397f Type 1 diabetes, 404–413, 404t Type 2 diabetes, 404–413, 404t, 590 Type A antigens, 193 Type A H1N1 influenza virus, 110, 111f Type B antigens, 193 Typhus fever, 94 U uE3. see Unconjugated estriol. Ulceration, 78 Ulcerative colitis, 472–473, 472f Ulcerogenic drugs, 449 Ulcers, 72 aphthous, 442 Curling, 454 Cushing, 454 decubitus, 607–608, 608f duodenal, 451–454 gastric, 451–454 peptic, 451–454, 452f–453f rodent, 561 stress, 454, 454f, 614 Ultrafiltration, 497–498 Ultraviolet (UV) rays, 628–629 UMNs. see Upper motor neurons. Unconjugated estriol (uE3), 574 Uncontrolled hypertension, 260f Undescended testis, 516f Unicellular, defined, 90 Universal donors, 193–194 Universal precautions, 104 Upper gastrointestinal tract, 430–431. see also Upper gastrointestinal tract disorders. oral cavity in, 430, 430f Upper gastrointestinal tract disorders, 441–446 dumping syndrome as, 455–456 dysphagia as, 446–448 esophageal cancer as, 448 gastric cancer as, 454–455 gastritis as, 449–451 gastroesophageal reflux disease as, 449 hiatal hernia as, 448–449 oral cavity disorders as, 441–446 peptic ulcer as, 451–454, 452f–453f pyloric stenosis as, 456 Upper motor neurons (UMNs), 329, 332 Upper respiratory tract, 273. see also Upper respiratory tract infections. Upper respiratory tract infections, 283–286 case study on, 112b common cold as, 283–285 epiglottis as, 285 influenza as, 285–286 laryngotracheobronchitis as, 285 Scarlet fever as, 286, 286f sinusitis as, 285 Upper right quadrant (URQ) of abdomen, 431 Ureter, obstruction of, 504 Urethra, 493 Urethritis, 499–500 Urgency, 500 Uric acid, 180 Uric acid stones, 504 Urinalysis, 494–495, 495f Urinary casts, 495 Urinary system, 489. see also Urinary system disorders. aging process and, 603 anatomy of, 489–493, 490f immobility, effects of, 609 structures of, 489–493 tests for, 496 Urinary system disorders, 488–513. see also Urinary system. blood tests for, 495–496 congenital, 506–507 diagnostic tests for, 494–496 dialysis for, 497–498, 497f diuretic drugs for, 496 incontinence, 493–494 inflammatory, 500–503 renal failure, 507–511 urinary tract infections, 498–500 urinary tract obstructions, 503–505, 503f vascular disorders, 505–506 Urinary tract infections (UTIs), 498–500 causes of, 499f cystitis, 499–500 pyelonephritis, 500 urethritis, 499–500 Urinary tract obstructions, 503–505, 503f hydronephrosis as, 504–505 tumors as, 505 urolithiasis as, 503–504 Urine appearance of, 495 composition of, 489t constituents in, abnormal, 495 culture and sensitivity studies on, 496 formation of, 493f retention of, 494 Urolithiasis, 503–504. see also Kidney stones. URQ. see Upper right quadrant (URQ) of abdomen. Urticaria, 147, 147f Uterine displacement, 525 Uterine prolapse, 525 Uterus carcinoma of, 536–537 expanding, 581, 581f structural abnormalities of, 525–526, 526f UTIs. see Urinary tract infections. UV. see Ultraviolet (UV) rays. Uvea, 386 Uveitis, 180 V Vaccine, defined, 120–121 Vaginitis, 527 Valvular defects, 253 Varicella-zoster virus (VZV), 353 Varicocele, 517, 517f Varicose veins, 262–263, 263f, 583 Vasa recta, 491 Vasa vasorum, 185 Vascular dementia, 377 Vascular disorders, 258–264, 309–312, 345–350 arterial disorders, 258–262 cerebral aneurysms, 349–350 cerebrovascular accidents, 346–348 diabetes, 410–411, 410t pulmonary edema as, 309 pulmonary embolus as, 309–312 transient ischemic attacks, 346 in urinary system, 505–506 Vascular thrombosis, 414 Vasoconstriction, 612–613 Vasodilation, 69 Vasodilators, 231 Vasogenic shock, 267 Vasopressin disorders, 416 Vasospasm, 349 Vector-borne transmission, 100 Vectors, 629–630 Vegetative state, 338 Veins, 185, 490–493 arteries, comparison of, 188f major, 187f varicose, 262–263, 263f, 583 Venous disorders, 262–264 phlebothrombosis as, 263–264 thrombophlebitis as, 263–264 varicose veins as, 262–263 Ventilation, 275–278, 276f control of, 277–278 expiration and, 275–276 inspiration and, 275–276 pulmonary volumes and, 276–277, 277f Ventilation-perfusion ratio (V̇a/Q̇), 279 Ventral horn, 332 Ventricular conduction abnormalities, 244 Ventricular fibrillation, 243f Ventricular septal defect, 252–253 Venules, 185 Verapamil, 231–232 Verrucae, 154, 154f, 255 Vertebral artery, 331 Vesicles, 123 Vesicoureteral reflux, 506 Viable fetus, 580 Villi, 432, 580 Vinblastine, 559 Viral gastroenteritis, 112b Viral hepatitis, 458–462 Viral infections, 152–154 condylomata acuminata as, 542 genital herpes as, 541–542 herpes simplex, 153f verrucae, 154, 154f Viral pneumonia, 289 Viremia, 106 Viridans Streptococcus, 442 Virion, 93 Viruses. see also specific types of. microorganism, as type of, 93 RNA, 110 shape of, 93, 95f types of, 93, 93t Visceral pain, 54, 438 Visceral peritoneum, 428 Visceral pleura, 275 Visceroceptors, 385 Visual acuity, 388 Visual field tests, 388 Visual loss, 339–340, 340f. see also Hemianopia. Visual pathway, of eye, 388 Vital capacity, 306 Vital signs, 342–343, 343f Vitamin B12 deficiency, 199f Vitamin D, 26b Vitamin K, 432 Vitamin K deficiency, 204 Vitiligo, 143 Vitreous humor, 387 Vocal cords, true, 273 Vomiting, 342, 435 Vomiting reflex, 435 von Willebrand disease, 206 V̇a/Q̇. see Ventilation-perfusion ratio. Vulva, 521–523 VZV. see Varicella-zoster virus. W Waddling gait, 582 Warfarin, 205, 207, 232 “Wasting syndrome”, 438 Vascular disorders (Continued) I n d e x 681 Water, 15 sources and losses of, 15t “Water pills”, 232, 496 Water-recycling system, 15 Water-soluble vitamins, 434–435 “Water waves”, 395 Waterborne hazards, 629 Waterhouse-Friderichsen syndrome, 351f WBCs. see White blood cells. “Wear and tear” joint disease. see Osteoarthritis. Weight gain, during pregnancy, 582 Weight loss, 549 Wellness, state of, 2 Wernicke area, 329 West Nile fever, 352 Western equine encephalitis, 352 Wheezing, 282 White blood cells (WBCs), 71 Whole blood, 195 Wilms tumor, 507 Windpipe, 274 Withdrawal, 621 X X-linked dominant disorders, 568b, 571 X-linked recessive disorders, 568b, 571, 573f Xerostomia, 444, 602–603 Y Yoga, 50 Z Zanamivir, 111 Zika virus, 5b Zygote, 579–580 HANDY TABLES Conventional Units SI Units Arterial Blood Gases PaO2 95-100 mm Hg PaCO2 35-42 mm Hg pH 7.35-7.45 Bicarbonate (HCO3−) 22-26 mEq/L Base excess −2.4 to +2.3 mEq/L Arterial O2 saturation (SaO2) 96%-98% Cells Red blood cells (erythrocytes, RBCs) 4.2-5.9 million (106)/mm3 4.2-5.9 × 1012/L Platelets (thrombocytes) 150,000-350,000/mm3 150-350 × 109/L White blood cells (leukocytes, WBCs) 4500-10,500/mm3 4.5-10.5 × 109/L Differential Neutrophils (57%-70%) 2000-7500/mm3 Lymphocytes (20%-25%) 2000-4000/mm3 Eosinophils (2%-4%) 400-450/mm3 Monocytes (3%-8%) 500-1000/mm3 Basophils (0.5%-1%) 40-100/mm3 Hemoglobin Male 13.5-18 g/100 mL (135-180 g/L) 8.1-11.2 mmol/L Female 12-16 g/100 mL (120-160 g/L) 7.4-9.9 mmol/L Reticulocytes 0.5%-2.5% erythrocytes Hematocrit Male 45%-52% 0.45-0.52 Female 37%-48% 0.37-0.48 Erythrocyte sedimentation rate (ESR) Male 1-13 mm/hr Female 1-20 mm/hr Red cell volume 25-35 mL/kg body weight Mean corpuscular volume 86-98 µm3 Electrolytes Sodium (Na+) 135-142 mEq/L 135-142 mmol/L Potassium (K+) 3.8-5 mEq/L 3.8-5 mmol/L Calcium (Ca2+) 4-5 mEq/L 2-2.6 mmol/L Magnesium (Mg2+) 3 mEq/L 1.25-1.75 mmol/L Chloride (Cl−) 95-102 mEq/L 95-102 mmol/L Nutrients Amino acids (total) 35-65 mg/dL 1.5-2.5 mmol/L Glucose (fasting) 70-110 mg/dL 3.9-5.6 mmol/L Iron (total) 60-150 µg/dL 11-27 µmol/L Lipids (total) 400-800 mg/dL 4-8 g/L Cholesterol 150-250 mg/dL 4-6.5 mmol/L HDL >40 mg/dL
LDL <180 mg/dL Fatty acids (total) 8-20 mg/dL 0.08-0.2 g/L Triglycerides 75-160 mg/dL 0.85-1.9 mmol/L Phospholipids 150-380 mg/dL 1.5-3.8 g/L Vitamin B12 150-900 pg/ mL 150-670 pmol/L Proteins Albumin 3.2-4.5 g/dL 32-45 g/L Fibrinogen 200-400 mg/dL 2-4 g/L Immunoglobulins 0.5-1.5 g/dL 5-16 g/L IgG 640-1350 mg/100 mL 6.4-13.5 g/L IgM 85-350 mg/100 mL 0.8-3.5 g/L IgA 70-300 mg/100 mL 0.7-3 g/L IgE 3-150 mg/100 mL 0.03-1.5 g/L IgD 0-8 mg/100 mL 0 Hormones Adrenocorticotropin (ACTH) 15-70 pg/ mL 3.3-15.4 pmol/L Cortisol 8 AM 5-25 µg/100 mL 0.14-0.69 µmol/L 8 PM <10 µg/100 mL 0-0.28 µmol/L Triiodothyronine (T3) 75-95 ng/100 mL 1.16-3 nmol/L Wastes Bilirubin (direct) maximum 0.3 mg/dL 5 µmol/L Bilirubin (indirect) 0.1-1.0 mg/dL 1.7-17 µmol/L Creatinine 0.6-1.2 mg/dL 53-105 µmol/L Nonprotein nitrogen 20-35 mg/dL 14.3-25 mmol/L Urea nitrogen 8-22 mg/dL 2.9-8 mmol/L Uric acid 2-6 mg/dL 0.12-0.36 mmol/L It may be noted that the normal values presented in various texts differ somewhat. Institutions publish a specific set of normal values to be used as a baseline reference by individuals using that laboratory. Always check the reported values against these norms. Blood HANDY TABLESpH 4.5-8 (av. 6)Sodium 75-200 mg/24 hr Potassium 25-100 mEq/L Ammonia 20-70 mEq/L Creatinine 1-2 g/24 hr Urea 25-35 g/24 hr Uric acid 0.6-1 g/24 hr Glucose 0 Protein 0-150 mg/24 hr (trace) Acetone 0 Bilirubin 0 Hemoglobin/cells 0 Casts 0 Bacteria <10,000/ mL Appearance clear, pale yellow Urine Appearance clear, colorless Pressure 70-180 mm H2O Albumin 11-48 mg/100 mL Glucose 50-75 mg/100 mL Cells occasional WBC Bilirubin 0 Cerebrospinal Fluid (CSF) Bleeding time 4-8 minutes Duke: earlobe 1-3 minutes Clotting time 5-15 minutes (Lee White, room temperature) INR Values vary with lab technology and with anticoagulation therapy Prothrombin time 11-16 seconds Prothrombin/International normalized ratio (PT/INR) 1.5-2.5 seconds Activated partial thromboplastin time (APTT) 25-38 seconds Clot retraction time begins in 30-60 minutes 50% complete in 2 hours Blood Clotting Times Factor Name Information I Fibrinogen Plasma protein synthesized in liver: forms fibrin II Prothrombin Plasma protein synthesized in liver (vitamin K required): forms thrombin III Tissue thromboplastin Released from damaged tissue (extrinsic pathway) and platelets (intrinsic pathway); phospholipid involved in activation of clotting process IV Calcium ions Required for many stages of coagulation process V and VI Proaccelerin; labile factor or accelerator globulin Synthesized in liver: used in prothrombin activation VII Proconvertin; serum prothrombin conversion accelerator (SPCA) Synthesized in liver (vitamin K required); used in extrinsic pathway VIII Antihemophilic factor (AHF) Deficit causes hemophilia A IX Plasma thromboplastin component (PTC), Christmas factor, antihemophilic factor B Synthesized in liver (vitamin K required) X Stuart factor Synthesized in liver (vitamin K required); required for both extrinsic and intrinsic pathways XI Plasma thromboplastin antecedent (PTA), antihemophilic factor C Synthesized in liver; used for activation of intrinsic pathway XII Hageman factor Required in activation of intrinsic pathway XIII Fibrin stabilizing factor (FSF) From platelets—cross-links fibrin to stabilize clot Blood Coagulation Factors pH Scale Pancreatic secretion pH 8.0 Bile pH 7.6-8.6 More alkaline (basic) Fewer hydrogen ions Blood pH 7.35-7.45 Saliva pH 6-7.4 (av. 6.9) Urine pH 5-8 (av. 6) Gastric fluids pH 2 14 7-Neutral 0 More hydrogen ions More acidic Serum Enzymes and Isoenzymes and Markers Alanine aminotransferase (ALT, formerly SGPT) Elevated in damage to liver, heart, muscle, pancreas, kidneys Prostatic acid phosphatase (PAP) Elevated with metastatic prostatic cancer Alkaline phosphatase (ALP) Elevated in bone disease, liver damage Aspartate aminotransferase (AST, formerly SGOT) Elevated in damage to liver, heart, and muscle C-reactive protein Elevated with inflammation Cardiac specific troponin Elevated in myocardial infarction Creatine kinase (CK, formerly CPK) Elevated with heart and skeletal muscle damage CK MB2 (isoenzyme) Elevated with MI Gamma-glutamyl-transferase (GGT) Elevated with liver damage due to alcohol Lactate dehydrogenase (LDH) Elevated with liver, heart, kidney, lung damage LDH1 and LDH2 (isoenzymes) Elevated with MI Alpha-fetoprotein (AFP) A marker for some ovarian tumors, some liver tumors Carcinoembryonic antigen (CEA) A marker for intestinal tumors Prostate-specific antigen (PSA) A marker for recurrent prostatic cancer Front Cover Inside Front Cover Half title page Evolve page Gould's Pathophysiology for the Health Professions Copyright Page Dedication Reviewers Preface Organization Section I—Basic Concepts of Disease Processes Section II—Defense/Protective Mechanisms Section III—Pathophysiology of Body Systems Section IV: Factors Contributing to Pathophysiology Section V: Environmental Factors and Pathophysiology Appendices—additional information: Format and Features What’s New? Guidelines for Users Resources Acknowledgments Table Of Contents I Pathophysiology: Background and Overview 1 Introduction to Pathophysiology Chapter Outline Learning Objectives Key Terms What Is Pathophysiology and Why Study It? Understanding Health and Disease Concept and Scope of Pathophysiology Beginning the Process: A Medical History New Developments and Trends Basic Terminology of Pathophysiology The Disease Process Etiology-Causes of Disease Characteristics of Disease Disease Prognosis Introduction to Cellular Changes Terms Used for Common Cellular Adaptations Cell Damage and Necrosis Chapter Summary Study Questions 2 Fluid, Electrolyte, and Acid-Base Imbalances Chapter Outline Learning Objectives Key Terms Fluid Imbalance Review of Concepts and Processes Fluid Compartments Movement of Water Fluid Excess: Edema Causes of Edema Effects of Edema Fluid Deficit: Dehydration Causes of Dehydration Effects of Dehydration Third-Spacing: Fluid Deficit and Fluid Excess Electrolyte Imbalances Sodium Imbalance Review of Sodium Hyponatremia Causes of Hyponatremia Effects of Hyponatremia Hypernatremia Causes of Hypernatremia Effects of Hypernatremia Potassium Imbalance Review of Potassium Hypokalemia Causes of Hypokalemia Effects of Hypokalemia Hyperkalemia Causes of Hyperkalemia Effects of Hyperkalemia Calcium Imbalance Review of Calcium Hypocalcemia Causes of Hypocalcemia Effects of Hypocalcemia Hypercalcemia Causes of Hypercalcemia Effects of Hypercalcemia Other Electrolytes Magnesium Hypomagnesemia Causes of Hypomagnesemia Effects of Hypomagnesemia Hypermagnesemia Cause of Hypermagnesemia Effects of Hypermagnesemia Phosphate Causes of Hypophosphatemia Effects of Hypophosphatemia Causes of Hyperphosphatemia Effects of Hyperphosphatemia Chloride Causes of Hypochloremia Effects of Hypochloremia Causes of Hyperchloremia Effects of Hyperchloremia Acid-Base Imbalance Review of Concepts and Processes Control of Serum pH Buffer Systems Bicarbonate–Carbonic Acid Buffer System and Maintenance of Serum pH Respiratory System Renal System Acid-Base Imbalance Compensation Decompensation Acidosis Causes of Acidosis Effects of Acidosis Alkalosis Effects of Alkalosis Treatment of Imbalances Chapter Summary Study Questions 3 Introduction to Basic Pharmacology and Other Common Therapies Chapter Outline Learning Objectives Key Terms Pharmacology Basic Principles Drug Effects Administration and Distribution of Drugs Drug Mechanisms and Receptors Responses Dose Effects Time Effects Variability Toxicity Drug Classifications and Prescriptions Traditional Forms of Therapy Physiotherapy Occupational Therapy Speech/Language Therapy Nutrition/Diet Registered Massage Therapy Osteopathy Chiropractic Complementary or Alternative Therapies Noncontact Therapeutic Touch Naturopathy Homeopathy Herbal Medicine Aromatherapy Asian Concepts of Disease and Healing Acupuncture Shiatsu Yoga Reflexology Craniosacral Therapy Ayurveda Chapter Summary Study Questions 4 Pain Chapter Outline Learning Objectives Key Terms Etiology and Sources of Pain Structures and Pain Pathways Physiology of Pain and Pain Control Characteristics of Pain Signs and Symptoms Young Children and Pain Referred Pain Phantom Pain Pain Perception and Response Basic Classifications of Pain Acute Pain Chronic Pain Headache Central Pain Neuropathic Pain Ischemic Pain Cancer-Related Pain Pain Control Methods of Managing Pain Anesthesia Chapter Summary Study Questions II Defense/Protective Mechanisms 5 Inflammation and Healing Chapter Outline Learning Objectives Key Terms Review of Body Defenses Review of Normal Capillary Exchange Physiology of Inflammation Definition Causes Steps of Inflammation Acute Inflammation Pathophysiology and General Characteristics Local Effects Systemic Effects Diagnostic Tests Potential Complications Chronic Inflammation Pathophysiology and General Characteristics Potential Complications Treatment of Inflammation Drugs First Aid Measures Other Therapies Healing Types of Healing Healing Process Factors Affecting Healing Complications Due to Scar Formation Loss of Function Contractures and Obstructions Adhesions Hypertrophic Scar Tissue Ulceration Example of Inflammation and Healing Burns Classifications of Burns Effects of Burn Injury Shock Respiratory Problems Pain Infection Metabolic Needs Healing of Burns Children and Burns Chapter Summary Study Questions Inflammation Healing Burns 6 Infection Chapter Outline Learning Objectives Key Terms Review of Microbiology Microorganisms Types of Microorganisms Bacteria Viruses Chlamydiae, Rickettsiae, and Mycoplasmas Fungi Protozoa Other Agents of Disease Helminths Prions Algae Resident Flora (Indigenous Normal Flora, Resident Microbiota) Principles of Infection Transmission of Infectious Agents Host Resistance Virulence and Pathogenicity of Microorganisms New Issues Affecting Infections and Transmission Control of Transmission and Infection Physiology of Infection Onset and Development Patterns of Infection Signs and Symptoms of Infection Local Signs Systemic Signs Methods of Diagnosis Treatment and Antimicrobial Drugs Guidelines for Use Classification Mode of Action Example of Infection: Influenza (Flu) Chapter Summary Study Questions 7 Immunity Chapter Outline Learning Objectives Key Terms Review of the Immune System Components of the Immune System Elements of the Immune System Antigens Cells Antibodies or Immunoglobulins Complement System Chemical Mediators Immune Response Diagnostic Tests Process of Acquiring Immunity Outcome of Infectious Disease Emerging and Reemerging Infectious Diseases and Immunity Bioterrorism Tissue and Organ Transplant Rejection Rejection Process Treatment and Prevention Hypersensitivity Reactions Type I: Allergic Reactions Causative Mechanism Clinical Signs and Symptoms Hay Fever or Allergic Rhinitis Food Allergies Atopic Dermatitis or Eczema Asthma Anaphylaxis or Anaphylactic Shock ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Type II: Cytotoxic Hypersensitivity Type III: Immune Complex Hypersensitivity Type IV: Cell-Mediated or Delayed Hypersensitivity Autoimmune Disorders Mechanism Example: Systemic Lupus Erythematosus ■ Pathophysiology ■ Clinical Signs and Symptoms ■ Diagnostic Tests ■ Treatment Immunodeficiency Causes of Immunodeficiency Effects of Immunodeficiency ■ Treatment Acquired Immunodeficiency Syndrome History Agent Transmission ■ Diagnostic Tests ■ Clinical Signs and Symptoms Women With AIDS Children With AIDS People Over 50 With HIV/AIDS ■ Treatment Chapter Summary Study Questions III Pathophysiology of Body Systems 8 Skin Disorders Chapter Outline Learning Objectives Key Terms Review of the Skin Resident Microbial Flora Skin Lesions ■ Diagnostic Tests ■ General Treatment Measures Skin Inflammatory Disorders Contact Dermatitis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Urticaria (Hives) ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Atopic Dermatitis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Psoriasis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Pemphigus ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Scleroderma ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Skin Infections Bacterial Infections ■ Pathophysiology Cellulitis ■ Signs and Symptoms ■ Treatment Furuncles ■ Signs and Symptoms ■ Treatment Impetigo ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Acute Necrotizing Fasciitis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Leprosy ■ Treatment Viral Infections Herpes Simplex ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Verrucae (Warts) ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Fungal Infections Tinea ■ Pathophysiology ■ Signs and Symptoms ■ Treatment ■ Signs and Symptoms ■ Treatment Other Infections Scabies ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Pediculosis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Skin Tumors Keratoses Squamous Cell Carcinoma ■ Pathophysiology ■ Signs and Symptoms Malignant Melanoma ■ Pathophysiology ■ Treatment Kaposi Sarcoma ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Chapter Summary Study Questions 9 Musculoskeletal System Disorders Chapter Outline Learning Objectives Key Terms Review of the Musculoskeletal System Bone Skeletal Muscle Joints Diagnostic Tests Trauma Fractures ■ Pathophysiology Factors Affecting the Healing of Bone ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Dislocations Sprains and Strains Other Injuries Muscle Tears Repetitive Strain Injury Bone Disorders Osteoporosis Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Rickets and Osteomalacia Paget Disease (Osteitis Deformans) Osteomyelitis ■ Pathophysiology and Etiology ■ Signs and Symptoms ■ Treatment Abnormal Curvatures of the Spine ■ Pathophysiology and Etiology ■ Treatment Bone Tumors Disorders of Muscle, Tendons, and Ligaments Muscular Dystrophy ■ Pathophysiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Primary Fibromyalgia Syndrome ■ Pathophysiology ■ Diagnosis ■ Signs and Symptoms ■ Treatment Joint Disorders Osteoarthritis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Rheumatoid Arthritis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Juvenile Rheumatoid Arthritis Infectious (Septic) Arthritis Gout (Gouty Arthritis) Ankylosing Spondylitis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Other Inflammatory Joint Disorders Chapter Summary Study Questions 10 Blood and Circulatory System Disorders Chapter Outline Learning Objectives Key Terms Review of the Circulatory System and Blood Anatomy, Structures, and Components Blood Vessels Blood Composition of Blood Blood Cells and Hematopoiesis Hematopoiesis Blood Clotting Fibrinolysis Antigenic Blood Types Diagnostic Tests Blood Therapies Blood Dyscrasias Anemias Iron Deficiency Anemia ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Pernicious Anemia–Vitamin B12 Deficiency (Megaloblastic Anemia) ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Aplastic Anemia ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Hemolytic Anemias Sickle Cell Anemia ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Thalassemia ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Blood-Clotting Disorders Hemophilia A ■ Pathophysiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment von Willebrand Disease ■ Pathophysiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Disseminated Intravascular Coagulation ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Thrombophilia ■ Pathophysiology ■ Signs and Symptoms ■ Diagnosis ■ Treatment Myelodysplastic Syndrome Neoplastic Blood Disorders Polycythemia ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Leukemias ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Chapter Summary Study Questions 11 Lymphatic System Disorders Chapter Outline Learning Objectives Key Terms Review of the Lymphatic System Structures and Function Composition and Production of Lymph Lymphatic Circulation Lymphatic Disorders Lymphomas Hodgkin Disease/Hodgkin Lymphoma ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Non-Hodgkin Lymphomas Multiple Myeloma or Plasma Cell Myeloma ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Lymphedema ■ Physiology and Etiology ■ Signs and Symptoms ■ Treatment Elephantiasis (Filariasis) ■ Etiology ■ Signs and Symptoms ■ Diagnosis ■ Treatment Castleman Disease ■ Pathophysiology and Etiology ■ Signs and Symptoms ■ Diagnosis ■ Treatment Chapter Summary Study Questions 12 Cardiovascular System Disorders Chapter Outline Learning Objectives Key Terms Review of the Cardiovascular System Heart Anatomy Conduction System Control of the Heart Coronary Circulation Cardiac Cycle Blood Pressure Heart Disorders Diagnostic Tests for Cardiovascular Function General Treatment Measures for Cardiac Disorders Coronary Artery Disease, Ischemic Heart Disease, or Acute Coronary Syndrome Arteriosclerosis and Atherosclerosis ■ Etiology ■ Diagnostic Tests ■ Treatment Angina Pectoris ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Myocardial Infarction ■ Pathophysiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Complications ■ Treatment Cardiac Dysrhythmias (Arrhythmias) Sinus Node Abnormalities Atrial Conduction Abnormalities Atrioventricular Node Abnormalities: Heart Blocks Ventricular Conduction Abnormalities Treatment of Cardiac Dysrhythmias Cardiac Arrest or Standstill (Asystole) Congestive Heart Failure ■ Pathophysiology ■ Etiology ■ Signs and Symptoms Young Children With Congestive Heart Failure ■ Diagnostic Tests ■ Treatment Congenital Heart Defects ■ Pathophysiology ■ Etiology ■ Compensation Mechanisms ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Ventricular Septal Defect Valvular Defects Tetralogy of Fallot Inflammation and Infection in the Heart Rheumatic Fever and Rheumatic Heart Disease ■ Pathophysiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Infective Endocarditis ■ Pathophysiology ■ Etiology ■ Diagnostic Tests ■ Signs and Symptoms ■ Treatment Pericarditis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Vascular Disorders Arterial Disorders Hypertension ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Peripheral Vascular Disease and Atherosclerosis ■ Pathophysiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Aortic Aneurysms ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Venous Disorders Varicose Veins ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Thrombophlebitis and Phlebothrombosis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Shock ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Chapter Summary Study Questions 13 Respiratory System Disorders Chapter Outline Learning Objectives Key Terms Review of Structures of the Respiratory System Purpose and General Organization Structures in the Respiratory System Upper Respiratory Tract Lower Respiratory Tract Ventilation The Process of Inspiration and Expiration Pulmonary Volumes Control of Ventilation Gas Exchange Factors Affecting Diffusion of Gases Transport of Oxygen and Carbon Dioxide Diagnostic Tests General Manifestations of Respiratory Disease Common Treatment Measures for Respiratory Disorders Infectious Diseases Upper Respiratory Tract Infections Common Cold (Infectious Rhinitis) ■ Pathophysiology and Etiology ■ Signs and Symptoms Sinusitis ■ Pathophysiology and Etiology ■ Signs and Symptoms Laryngotracheobronchitis (Croup) Epiglottitis Influenza (Flu) Scarlet Fever Lower Respiratory Tract Infections Bronchiolitis (Respiratory Syncytial Virus Infection) Pneumonia Classification of the Pneumonias Lobar Pneumonia Bronchopneumonia Legionnaires Disease Primary Atypical Pneumonia Pneumocystis carinii Pneumonia Severe Acute Respiratory Syndrome Tuberculosis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Histoplasmosis ■ Pathophysiology and Etiology ■ Signs and Symptoms Anthrax ■ Pathophysiology and Etiology ■ Signs and Symptoms Obstructive Lung Diseases Cystic Fibrosis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Lung Cancer ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Aspiration ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Prevention and Treatment Obstructive Sleep Apnea ■ Pathophysiology and Etiology ■ Signs, Symptoms, and Complications ■ Treatment Asthma ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Chronic Obstructive Pulmonary Disease Emphysema ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Chronic Bronchitis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Bronchiectasis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Restrictive Lung Disorders Pneumoconioses ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Vascular Disorders Pulmonary Edema ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Pulmonary Embolus ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnosis ■ Treatment Expansion Disorders Atelectasis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Pleural Effusion ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Pneumothorax ■ Signs and Symptoms Flail Chest ■ Pathophysiology Infant Respiratory Distress Syndrome ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Adult or Acute Respiratory Distress Syndrome ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Acute Respiratory Failure ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Chapter Summary Study Questions 14 Nervous System Disorders Chapter Outline Learning Objectives Key Terms Review of Nervous System Anatomy and Physiology Brain Protection for the Brain Meninges Cerebrospinal Fluid Blood-Brain Barrier and Blood-Cerebrospinal Fluid Barrier Functional Areas Cerebral Hemispheres Diencephalon Brain Stem Cerebellum Blood Supply to the Brain Cranial Nerves Spinal Cord Spinal Cord Spinal Nerves Reflexes Neurons and Conduction of Impulses Neurons Regeneration of Neurons Conduction of Impulses Synapses and Chemical Neurotransmitters Autonomic Nervous System Sympathetic Nervous System Parasympathetic Nervous System General Effects of Neurologic Dysfunction Local (Focal) Effects Supratentorial and Infratentorial Lesions Left and Right Hemispheres Level of Consciousness Motor Dysfunction Sensory Deficits Visual Loss: Hemianopia Language Disorders Seizures Increased Intracranial Pressure Early Signs Vital Signs Visual Signs Changes in Cerebrospinal Fluid Herniation Diagnostic Tests Acute Neurologic Problems Brain Tumors ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Vascular Disorders Transient Ischemic Attacks ■ Pathophysiology ■ Signs and Symptoms Cerebrovascular Accidents (Stroke) ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Cerebral Aneurysms ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Infections Meningitis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Brain Abscess Encephalitis Other Infections Infection-Related Syndromes Herpes Zoster (Shingles) Postpolio Syndrome Reye’s Syndrome ■ Signs and Symptoms ■ Treatment. Guillain-Barré Syndrome ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Brain Injuries Types of Head Injuries ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Spinal Cord Injury ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Congenital Neurologic Disorders Hydrocephalus ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Spina Bifida ■ Pathophysiology ■ Diagnostic Tests ■ Etiology ■ Signs and Symptoms ■ Treatment Cerebral Palsy ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Seizure Disorders ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Generalized Seizures. ■ Partial Seizures. ■ Diagnostic Tests ■ Treatment Chronic Degenerative Disorders Multiple Sclerosis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Parkinson’s Disease (Paralysis Agitans) ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Amyotrophic Lateral Sclerosis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Myasthenia Gravis ■ Pathophysiology ■ Diagnostic Tests ■ Signs and Symptoms ■ Treatment Huntington’s Disease ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Dementia Alzheimer’s Disease ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Other Forms of Dementia Vascular Dementia Creutzfeldt-Jakob Disease Pathophysiology/Etiology Signs/Symptoms AIDS Dementia Mental Disorders Schizophrenia ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Depression ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Panic Disorders ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Spinal Cord Disorder Herniated Intervertebral Disc ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Chapter Summary Increased Intracranial Pressure Vascular Problems Infections Injuries Congenital Neurologic Disorders Chronic Degenerative Diseases Mental Disorders Spinal Cord Study Questions 15 Disorders of the Eyes, Ears, and Other Sensory Organs Chapter Outline Learning Objectives Key Terms Sensory Receptors The Eye Review of Structure and Function Protection for the Eye The Eyeball Fluids in the Eye The Visual Pathway Diagnostic Tests Structural Defects Infections and Trauma Conjunctivitis Trachoma Keratitis Glaucoma ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Cataracts Detached Retina Macular Degeneration ■ Treatment The Ear Review of Structure and Function Parts of the Ear Pathway for Sound The Semicircular Canals Hearing Loss Ear Infections Otitis Media ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Otitis Externa Chronic Disorders of the Ear Otosclerosis Ménière’s Syndrome Chapter Summary The Eye The Ear Study Questions 16 Endocrine System Disorders Chapter Outline Learning Objectives Key Terms Review of the Endocrine System Endocrine Disorders Diagnostic Tests Treatment Insulin and Diabetes Mellitus Type 1 and Type 2 Diabetes ■ Pathophysiology Initial Stage Progressive Effects ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Diet Exercise Oral Medications Insulin Replacement Complications Acute Complications Hypoglycemia (Insulin Shock) ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Diabetic Ketoacidosis (DKA). ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Hyperosmolar Hyperglycemic Nonketotic Coma. Chronic Complications Vascular Problems. Neuropathy. Infections. Cataracts. Pregnancy. Parathyroid Hormone and Calcium Pituitary Hormones Growth Hormone Antidiuretic Hormone (Vasopressin) ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Inappropriate Antidiuretic Hormone Syndrome ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Thyroid Disorders Goiter ■ Pathophysiology ■ Treatment Hyperthyroidism (Graves Disease) ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Hypothyroidism Diagnostic Tests Adrenal Glands Adrenal Medulla Adrenal Cortex Cushing Syndrome Addison Disease ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Chapter Summary Insulin Parathyroid Hormone Pituitary Hormones Thyroxine and Triiodothyronine (T3 and T4) Adrenal Glands Study Questions 17 Digestive System Disorders Chapter Outline Learning Objectives Key Terms Review of the Digestive System Structures and Their Functions Upper Gastrointestinal Tract Oral Cavity Esophagus Stomach Liver Pancreas Lower Gastrointestinal Tract Small Intestine Large Intestine Neural and Hormonal Controls Digestion and Absorption Common Manifestations of Digestive System Disorders Anorexia, Vomiting, and Bulimia Diarrhea Constipation Fluid and Electrolyte Imbalances Pain Malnutrition Basic Diagnostic Tests Common Therapies and Prevention Upper Gastrointestinal Tract Disorders Disorders of the Oral Cavity Congenital Defects Inflammatory Lesions Infections Candidiasis Herpes Simplex Type 1 Infection Syphilis Dental Problems Caries Periodontal Disease Gingivitis Periodontitis Hyperkeratosis Cancer of the Oral Cavity Salivary Gland Disorders Dysphagia Esophageal Cancer Hiatal Hernia Gastroesophageal Reflux Disease Gastritis Acute Gastritis ■ Signs and Symptoms Gastroenteritis Escherichia coli Infection Chronic Gastritis Peptic Ulcer Gastric and Duodenal Ulcers ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Stress Ulcers Gastric Cancer ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Dumping Syndrome Pyloric Stenosis Disorders of the Liver and Pancreas Gallbladder Disorders ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Jaundice Hepatitis Viral Hepatitis ■ Pathophysiology ■ Etiology Hepatitis A. Hepatitis B. Hepatitis C. Hepatitis D. Hepatitis E. ■ Signs and Symptoms ■ Treatment Toxic or Nonviral Hepatitis Cirrhosis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Liver Cancer Acute Pancreatitis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Pancreatic Cancer Lower Gastrointestinal Tract Disorders Celiac Disease Chronic Inflammatory Bowel Disease Crohn Disease (Regional Ileitis or Regional Enteritis) ■ Pathophysiology ■ Signs and Symptoms Ulcerative Colitis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment of Irritable Bowel Diseases Irritable Bowel Syndrome ■ Pathophysiology ■ Signs and Symptoms ■ Diagnosis ■ Treatment Appendicitis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Diverticular Disease ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Colorectal Cancer ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Intestinal Obstruction ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Peritonitis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Chapter Summary Upper Gastrointestinal Tract Liver and Pancreas Lower Gastrointestinal Tract Study Questions 18 Urinary System Disorders Chapter Outline Learning Objectives Key Terms Review of the Urinary System Structures and Anatomy Kidneys Renal Arteries and Veins Incontinence and Retention Diagnostic Tests Urinalysis Appearance Abnormal Constituents (Present in Significant Quantities) Blood Tests Other Tests Diuretic Drugs Dialysis Disorders of the Urinary System Urinary Tract Infections ■ Etiology Cystitis and Urethritis ■ Pathophysiology ■ Signs and Symptoms Pyelonephritis ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Inflammatory Disorders Glomerulonephritis (Acute Poststreptococcal Glomerulonephritis) ■ Pathophysiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Nephrotic Syndrome (Nephrosis) ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Urinary Tract Obstructions Urolithiasis (Calculi, or Kidney Stones) ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Hydronephrosis Tumors Renal Cell Carcinoma Bladder Cancer Vascular Disorders Nephrosclerosis ■ Pathophysiology ■ Treatment Congenital Disorders Adult Polycystic Kidney Wilms Tumor (Nephroblastoma) Renal Failure Acute Renal Failure ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Chronic Renal Failure ■ Pathophysiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Chapter Summary Urinary Tract Infections Inflammatory Disorders Obstructions Renal Failure Study Questions 19 Reproductive System Disorders Chapter Outline Learning Objectives Key Terms Disorders of the Male Reproductive System Review of the Male Reproductive System Structure and Function Hormones Congenital Abnormalities of the Penis Epispadias and Hypospadias Disorders of the Testes and Scrotum Cryptorchidism Hydrocele, Spermatocele, and Varicocele Inflammation and Infections Prostatitis ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Balanitis Tumors Benign Prostatic Hypertrophy ■ Pathophysiology ■ Signs and Symptoms ■ Treatment Cancer of the Prostate ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Cancer of the Testes ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Diagnostic Tests ■ Treatment Disorders of the Female Reproductive System Review of the Female Reproductive System Structure and Function Hormones and the Menstrual Cycle Structural Abnormalities Menstrual Disorders Menstrual Abnormalities Endometriosis Infections and Inflammation Candidiasis Pelvic Inflammatory Disease ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Benign Tumors Leiomyoma (Fibroids) Ovarian Cysts Polycystic Ovarian Syndrome Fibrocystic Breast Disease Malignant Tumors Carcinoma of the Breast ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Carcinoma of the Cervix ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Carcinoma of the Uterus (Endometrial Carcinoma and Uterine Sarcomas) ■ Pathophysiology ■ Etiology ■ Signs and Symptoms ■ Treatment Ovarian Cancer Infertility Sexually Transmitted Diseases Bacterial Infections Chlamydial Infection Gonorrhea Syphilis Viral Infections Genital Herpes Condylomata Acuminata (Genital Warts) Protozoan Infection Trichomoniasis Chapter Summary Disorders of the Male Reproductive System Disorders of the Female Reproductive System Infertility and Sterility Sexually Transmitted Diseases Study Questions IV Factors Contributing to Pathophysiology 20 Neoplasms and Cancer Chapter Outline Learning Objectives Key Terms Review of Normal Cells Benign and Malignant Tumors Nomenclature Characteristics of Benign and Malignant Tumors Malignant Tumors: Cancer Pathophysiology Effects of Malignant Tumors Local Effects of Tumors Systemic Effects of Malignant Tumors Diagnostic Tests Spread of Malignant Tumors Staging of Cancer Etiology Carcinogenesis Risk Factors and Prevention Host Defenses Treatment Surgery Radiation Therapy Chemotherapy Other Drugs Gene Therapy Nutrition Complementary Therapies Prognosis Examples of Malignant Tumors Skin Cancer Ovarian Cancer Brain Cancer Cancer Incidences Chapter Summary Study Questions 21 Congenital and Genetic Disorders Chapter Outline Learning Objectives Key Terms Review of Genetic Control Congenital Anomalies Genetic Disorders Single-Gene Disorders Autosomal-Recessive Disorders Autosomal-Dominant Disorders X-Linked Dominant Disorders X-Linked Recessive Disorders Chromosomal Disorders Multifactorial Disorders Developmental Disorders Diagnostic Tools Genetic Technology Genetic Engineering and Gene Therapy Genetic Diagnosis and DNA Testing Proteomic Research and Designer Drugs Down Syndrome Chapter Summary Study Questions 22 Complications of Pregnancy Chapter Outline Learning Objectives Key Terms Embryonic and Fetal Development Physiologic Changes During Pregnancy Diagnosis of Pregnancy Physiologic Changes and Their Implications Hormonal Changes Reproductive System Changes Weight Gain and Nutrition Digestive System Changes Musculoskeletal Changes Cardiovascular Changes Potential Complications of Pregnancy Ectopic Pregnancy Preeclampsia and Eclampsia: Pregnancy-Induced Hypertension Gestational Diabetes Mellitus Placental Disorders Blood Clotting Disorders Thrombophlebitis and Thromboembolism Disseminated Intravascular Coagulation Rh Incompatibility Infection Adolescent Pregnancy Chapter Summary Study Questions 23 Complications of Adolescence Chapter Outline Learning Objectives Key Terms Review of Changes During Adolescence Obesity and Metabolic Syndrome Musculoskeletal Abnormalities Kyphosis and Lordosis Scoliosis Osteomyelitis Juvenile Rheumatoid Arthritis Eating Disorders Anorexia Nervosa Bulimia Nervosa Skin Disorders Acne Vulgaris Infection Infectious Mononucleosis Disorders Affecting Sexual Development Chromosomal Disorders Tumors Menstrual Abnormalities Chapter Summary Study Questions 24 Complications of Aging Chapter Outline Learning Objectives Key Terms The Aging Process Physiological Changes With Aging Hormonal Changes Reproductive System Changes Changes in the Skin and Mucosa Cardiovascular System Changes Musculoskeletal System Changes Osteoporosis Osteoarthritis Herniated Intervertebral Disc Other Changes Respiratory System Changes Nervous System Changes Digestive System Changes and Nutrition Urinary System Changes Other Factors Multiple Disorders Chapter Summary Study Questions V Environmental Factors and Pathophysiology 25 Immobility and Associated Problems Chapter Outline Learning Objectives Key Terms Factors Involving Immobility Musculoskeletal System Effects Cutaneous Effects Cardiovascular System Effects Respiratory System Effects Digestive System Effects Urinary System Effects Neurologic/Psychological Effects Effects of Immobility on Children Chapter Summary Study Questions 26 Stress and Associated Problems Chapter Outline Learning Objectives Key Terms Review of the Stress Response Stress and Disease Potential Effects of Prolonged or Severe Stress Coping With Stress Chapter Summary Study Questions 27 Substance Abuse and Associated Problems Chapter Outline Learning Objectives Key Terms Terminology Predisposing Factors Environmental/Behavioral Risk Factors Indications/Recognition of Abuse Potential Complications of Substance Abuse Overdose Withdrawal Effects on Pregnancy Cardiovascular Problems Infection Neurologic/Psychological Effects Alcohol Cirrhosis (Laënnec Cirrhosis) Nervous System Damage Treatment for Substance Abuse Chapter Summary Study Questions 28 Environmental Hazards and Associated Problems Chapter Outline Learning Objectives Key Terms Chemicals Heavy Metals Acids/Bases Inhalants Asbestos Pesticides Physical Agents Temperature Hazards Hyperthermia Hypothermia Radiation Hazards Ionizing Radiation Light Energy Noise Hazards Food and Waterborne Hazards Biologic Agents Bites and Stings Chapter Summary Study Questions Appendices Ready Reference 1 Body Planes, Cavities, Regions, and Fluid Compartments Body Planes (Fig. RR1.1) Body Cavities (Fig. RR1.2) Body Regions (Figs. RR1.3 and RR1.4) Body Fluid Compartments (Fig. RR1.5) Common Body Movements Ready Reference 2 Anatomic Terms Prefix or Root (Combining Form) Used in Anatomic Terms Directional Terms Ready Reference 3 Conversion Tables Ready Reference 4 Common Abbreviations and Acronyms Common Pharmaceutical Abbreviations Ready Reference 5 Common Diagnostic Studies and Tests Endoscopic Examination Imaging Studies Radiograph or X-Ray Film Computed Tomography (Ct Scan, Formerly Computerized Axial Tomography or Cat Scan) Ultrasonography (Ultrasound) Magnetic Resonance Imaging (MRI) Nuclear Scanning Positron Emission Tomography (PET) Determinations of Electrical Activity Electrocardiogram (ECG, EKG) Stress Test (Exercise Electrocardiography) Electroencephalogram (EEG) Pulmonary Function Tests Blood Tests Hematology Testing Blood Chemistry Tests Immunodiagnostic Tests Chromosomal and Genetic Analysis Therapeutic Drug Monitoring Urine Tests Cerebrospinal Fluid Tests Fecal Tests or Stool Analysis Microbiologic Tests Ready Reference 6 Example of a Medical History Ready Reference 7 Disease Index Ready Reference 8 Drug Index Ready Reference 9 Additional Resources Textbooks Anatomy and Physiology Pathophysiology Medicine Pharmacology Other Topics Dictionaries and Medical Terminology Journals Journals Published by Professional Groups Web Sites Glossary Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Handy Tables