Posted: October 27th, 2022

Week 8: Discussion: Share Your Knowledge

 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.

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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

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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 pr