UNIT I Pathophysiologic Processes


UNIT I Pathophysiologic Processes

1 Introduction to Pathophysiology, 1

2 Homeostasis, Allostasis, and Adaptive Responses to Stressors, 12

UNIT II Cellular Function

3 Cell Structure and Function, 26

4 Cell Injury, Aging, and Death, 59

5 Genome Structure, Regulation, and Tissue Differentiation, 77

6 Genetic and Developmental Disorders, 94

7 Neoplasia, 117

UNIT III Defense

8 Infectious Processes, 141

9 Inflammation and Immunity, 158

10 Alterations in Immune Function, 194

11 Malignant Disorders of White Blood Cells, 215

12 HIV Disease and AIDS, 233

UNIT IV Oxygen Transport, Blood Coagulation, Blood Flow, and Blood Pressure

13 Alterations in Oxygen Transport, 259

14 Alterations in Hemostasis and Blood Coagulation, 298

15 Alterations in Blood Flow, 313

16 Alterations in Blood Pressure, 337

UNIT V Cardiac Function

17 Cardiac Function, 354

18 Alterations in Cardiac Function, 382

19 Heart Failure and Dysrhythmias: Common Sequelae of Cardiac Diseases, 411

20 Shock, 434

UNIT VI Respiratory Function

21 Respiratory Function and Alterations in Gas Exchange, 451

22 Obstructive Pulmonary Disorders, 478

23 Restrictive Pulmonary Disorders, 499

UNIT VII Fluid, Electrolyte, and Acid-Base Homeostasis

24 Fluid and Electrolyte Homeostasis and Imbalances, 521

25 Acid–Base Homeostasis and Imbalances, 541

UNIT VIII Renal and Bladder Function

26 Renal Function, 551

27 Intrarenal Disorders, 575

28 Acute Kidney Injury and Chronic Kidney Disease, 593

29 Disorders of the Lower Urinary Tract, 609

UNIT IX Genital and Reproductive Function

30 Male Genital and Reproductive Function, 626

31 Alterations in Male Genital and Reproductive Function, 641

32 Female Genital and Reproductive Function, 656

33 Alterations in Female Genital and Reproductive Function, 671

34 Sexually Transmitted Infections, 689

UNIT X Gastrointestinal Function

35 Gastrointestinal Function, 697

36 Gastrointestinal Disorders, 720

37 Alterations in Function of the Gallbladder and Exocrine Pancreas, 742

38 Liver Diseases, 754

UNIT XI Endocrine Function, Metabolism, and Nutrition

39 Endocrine Physiology and Mechanisms of Hypothalamic-Pituitary Regulation, 783

40 Disorders of Endocrine Function, 799

41 Diabetes Mellitus, 815

42 Nutritional and Metabolic Disorders, 838

UNIT XII Neural Function

43 Structure and Function of the Nervous System, 850

44 Acute Disorders of Brain Function, 891

45 Chronic Disorders of Neurologic Function, 915

46 Alterations in Special Sensory Function, 936

47 Pain, 955

UNIT XIII Neuropsychological Function

48 Neurobiology of Psychotic Illnesses, 971

49 Neurobiology of Nonpsychotic Illnesses, 989

UNIT XIV Musculoskeletal Support and Movement

50 Structure and Function of the Musculoskeletal System, 1001

51 Alterations in Musculoskeletal Function: Trauma, Infection, and Disease, 1020

52 Alterations in Musculoskeletal Function: Rheumatic Disorders, 1042

UNIT XV Integumentary System

53 Alterations in the Integumentary System, 1058

54 Burn Injuries, 1093

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JACQUELYN L. BANASIK, PhD, ARNP Associate Professor College of Nursing

Washington State University Spokane, Washington

LEE-ELLEN C. COPSTEAD, PhD, RN Professor Emerita

Department of Nursing College of Nursing and Health Sciences

University of Wisconsin—Eau Claire Eau Claire, Wisconsin

3251 Riverport Lane St. Louis, Missouri 63043


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Brent A. Banasik, PhD, MA, BS Scientist Chemistry Banasik Consulting Seattle, Washington

Brianne N. Banasik, BS Environmental Science, MS Marine Resources Management

Research Associate Pediatric Vaccinology University of Texas Medical Branch Galveston, Texas

Jacquelyn L. Banasik, PhD, ARNP Associate Professor College of Nursing Washington State University Spokane, Washington

Robin Y. Beeman, BSN, MSN, PhD Chair and Professor Nursing University of Wisconsin—Eau Claire Eau Claire, Wisconsin

Cheryl L. Brandt, PhD, RN, ACNS-BC Professor College of Nursing and Health Sciences University of Wisconsin—Eau Claire Eau Claire, Wisconsin

Ann Futterman Collier, PhD Associate Professor and Chair Psychological Sciences Northern Arizona University Flagstaff, Arizona

Lee-Ellen C. Copstead, PhD, RN Professor Emerita Department of Nursing College of Nursing and Health Sciences University of Wisconsin—Eau Claire Eau Claire, Wisconsin

Carol L. Danning, MD Staff Rheumatologist Rheumatology Department Gundersen Health Systems La Crosse, Wisconsin

Michael R. Diestelmeier, MD Fellow American Academy of Dermatology Dermatologist, Retired Mayo Clinic Health System Eau Claire, Wisconsin

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Roberta J. Emerson, PhD, RN Associate Professor, Retired Washington State University College of Nursing Spokane, Washington

Linda Felver, PhD, RN Associate Professor School of Nursing Oregon Health & Science University Portland, Oregon

Rosemary A. Jadack, PhD, RN Professor Nursing University of Wisconsin—Eau Claire Eau Claire, Wisconsin

Debra A. Jansen, PhD, RN Associate Dean, Professor College of Nursing and Health Sciences University of Wisconsin—Eau Claire Eau Claire, Wisconsin

Marie L. Kotter, PhD, MS, BS Professor Emeritus Health Sciences Weber State University Ogden, Utah

Teresa Grigsby Loftsgaarden, MSN, RN, OCN,ONN-CG

Oncology Nurse Navigator Regional Cancer Center Sacred Heart Hospital Eau Claire, Wisconsin

Joni D. Marsh, BSN, MN Advanced Registered Nurse Practitioner Medical Oncology Summit Cancer Centers Spokane, Washington

Benjamin J. Miller, PhD, ARNP, FNP-C, ACNPC, ENP-C

Assistant Professor Seattle University Seattle, Washington

Sarah Ogle, DO, MS Banner University Medical Center-Phoenix University of Arizona College of Medicine

Phoenix Phoenix, Arizona

Nirav Patel, MD Assistant Professor, Infectious Diseases and

Critical Care Medicine Internal Medicine Saint Louis University School of Medicine; Chief Medical Officer SSM Health Saint Louis University Hospital; Infection Control Officer/Director of

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Faith Young Peterson, BSN, MSN, MPA, CFNP

Family Nurse Practitioner Marsing, Idaho

Cheryl Rockwell, RN, MSN Clinical Assistant Professor Nursing Department Indiana University-Purdue University at

Fort Wayne; Staff/Clinical Nurse Surgical Trauma Intensive Care Unit Parkview Health Systems Fort Wayne, Indiana

Samantha Cody Russell, Psychology, MA Graduate Student Psychological Sciences Northern Arizona University Flagstaff, Arizona

Jeffrey S. Sartin, MD Consulting Physician Infectious Diseases Infectious Disease and Epidemiology

Associates; Consulting Physician Infectious Diseases Nebraska Medicine; Consulting Physician Infectious Diseases CHI Hospitals Omaha, Nebraska

Lorna L. Schumann, PhD Heritage UGM Women and Children’s

Clinic Medical Clinic Heritage Health Coeur d’Alene, Idaho

Susan G. Trevithick, RN, MS, NE-BC Compliance Officer VA Salt Lake City Healthcare System Salt Lake City, Utah

Marvin Van Every, MD Staff Urologist Urology Department Gundersen Health Systems La Crosse, Wisconsin

Linda D. Ward, PhD, FNP-C Assistant Professor College of Nursing Washington State University Spokane, Washington


Brianne N. Banasik, MS Research Associate Pediatric Vaccinology University of Texas Medical Branch Galveston, Texas

Deb Cipali, RN, BSN, MSN, EdD(c) Des Moines Area Community College Nursing Lab Coordinator/Adjunct Professor Ankeny, Iowa

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Maria Fleurdeliz Cuyco, BS Instructor Preferred College of Nursing Los Angeles, California

Abimbola Farinde, PhD Professor Columbia Southern University Orange Beach, Alabama

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Barbara Hunter, RN, MSN School of Nursing, Klamath Falls Campus Oregon Health & Science University Klamath Falls, Oregon

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Clarice Perry, MS Research Associate Pediatric Vaccinology University of Texas Medical Branch Galveston, Texas


Janet Pinkelman, MSN, RNC-Maternal Newborn Nursing

Professor of Nursing Owens Community College Toledo, Ohio

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The pace of scientific discovery in health and medicine continues to transform our understanding of physiology and disease. To be clinically relevant and useful to health care students and professionals, a text must synthesize a vast amount of detailed knowledge into overarching concepts that can be applied broadly. As in previous editions, the goal of the sixth edition of Pathophysiology is to include recent and relevant information on anatomy, biochemistry, cell physiology, genomics, and pathophysiology while not overwhelming the reader. Attention is given to major concepts relevant to clinical practice while still providing enough detail for deep understanding.

ORGANIZATION Pathophysiology uses a systems approach to content, beginning with a review of normal anatomy and physiology, followed by pathophysiology and application of concepts to specific disorders. The text is organized into 15 units, each of which includes a particular body system or group of interrelated body systems and the pertinent pathophysiologic concepts and disorders.

FEATURES An understanding of normal structure and function of the body is necessary for any detailed understanding of its abnormalities and pathophysiology. The first chapter in most units includes a fully illustrated review of normal physiology. Age-related concepts are highlighted in boxes titled Geriatric Considerations and Pediatric Considerations.

Each chapter opens with Key Questions, which are designed to alert the reader to important conceptual questions that will be discussed in the chapter. Although the chapters are meant to be read from beginning to end to develop an understanding of the material, the text also serves as a reference for looking up specific content. Chapter Outlines are included at the beginning of each chapter to help the reader locate specific content. Within every chapter, Key Points are identified at the end of every major discussion and are presented in short bulleted lists. These recurring summaries help readers to focus on the main points.

Nearly 900 illustrations elucidate both normal physiology and pathophysiologic changes. The entire book is in full color, with color

used generously in the illustrations to better explain pathophysiologic concepts.

A study of pathophysiology requires a new vocabulary, and many of these terms are defined in a comprehensive Glossary, which appears at the end of the text. Common prefixes and suffixes as well as root words are included in the back matter to help with basic understanding of the language of pathophysiology.

ANCILLARIES Student Learning Resources on Evolve The student section of the book’s website hosted on Evolve offers nearly 700 Student Review Questions in a variety of question formats, an Audio Glossary, Animations to help readers visualize pathophysiologic processes, Case Studies with questions, and Key Points Review. Visit the Evolve website at http://evolve.elsevier.com/Banasik/pathophysiology.

Study Guide Pathophysiology can be a daunting subject for students because of the large volume of factual material to be learned. The student Study Guide is designed to help students focus on important pathophysiologic concepts. Questions to check recall of normal anatomy and physiology are included for each chapter. A number of activities that help the student focus on similarities and differences between often-confused pathologic processes are included. More than 1500 self-assessment test questions with answers are included to help students check their understanding and build confidence for examinations. Case studies, with more than 250 questions including rationales for correct and incorrect answers, are used to help students begin to apply pathophysi- ologic concepts to clinical situations.

Instructor Learning Resources on Evolve The Instructor Learning Resources on Evolve provide a number of teaching aids for instructors who require the text for their students. The materials include a Test Bank presented in Exam View with approximately 1200 test items, a Teach for Nurses instructor manual detailing the resources available to instructors for their lesson planning, a PowerPoint lecture guide with more than 4000 slides with integrated case studies and audience response questions to facilitate classroom presentations, and an Image Collection of more than 900 color images from the text.



Revising this 6th edition of the text has been possible because of the tremendous dedication of authors, artists, reviewers, and editors. Sincere gratitude goes to all who helped with this and previous editions. In particular, grateful appreciation is extended to all of the contributing authors who have given exhaustively of their time over many editions over the decades. Thank you to the many thoughtful experts who gave their time to read and critique manuscripts and help ensure excellence in chapter content throughout the text.

Grateful recognition is made to the staff at Elsevier: Kellie White, Executive Content Strategist; Jennifer Wade, Content Development Specialist; Jeffrey Patterson, Publishing Service Manager; Carol O’Connell, Book Production Specialist; Renee Duenow, Book Designer; and Vikraman Palani, Multimedia Producer.

We would like to recognize those who provided a foundation for the revised text through their contributions to earlier editions: Arnold A. Asp, Donna Bailey, Barbara Bartz, Linda Belsky-Lohr, Tim Brown, Carolyn Spenee Cagle, Karen Carlson, Katherina P. Choka, Arnold Norman Cohen, Cynthia F. Corbett, Lorri Dawson, Leslie Evans, Patricia Garber, Jane Georges, Karen Groth, Christine M. Henshaw, Carolyn Hoover, Jo Annalee Irving, Marianne Genge Jagmin, Debby Kaaland, Naomi Lungstrom, Rick Madison, Anne Roe Mealey, David Mikkelsen, Carrie Miller, Linda Denise Oakley, Maryann Pranulis, Mark Puhlman, Edith Randall, Bridget Recker, Cleo Richard, Dawn Rondeau, Mary Sanguinetti-Baird, Billie Marie Severtsen, Jacqueline Siegel, Gary Smith, Sheila Smith, Martha Snider, Pam Springer, Angela Starkweather, Patti Stec, Julie Symes, Lorie Wild, and Debra Winston-Heath.




UNIT I Pathophysiologic Processes

1 Introduction to Pathophysiology, 1 Lee-Ellen C. Copstead

Framework for Pathophysiology, 2 Etiology, 2 Pathogenesis, 2 Clinical Manifestations, 3 Treatment Implications, 3

Concepts of Normality in Health and Disease, 4 Statistical Normality, 4 Individual Factors Influencing Normality, 5

Patterns of Disease in Populations, 6 Concepts of Epidemiology, 6

2 Homeostasis, Allostasis, and Adaptive Responses to Stressors, 12 Debra A. Jansen and Roberta J. Emerson

Homeostasis and Allostasis, 12 Homeostasis, 12 Allostasis, 13

Stress as a Concept, 13 The General Adaptation Syndrome and

Allostasis, 14 Stressors, Gender and Developmental Influences,

and Risk Factors, 16 Neurohormonal Mediators of Stress and

Adaptation, 17 Catecholamines: Norepinephrine and

Epinephrine, 17 Adrenocortical Steroids: Cortisol and

Aldosterone, 18 Endorphins, Enkephalins, and Immune

Cytokines, 19 Sex Hormones: Estrogen, Testosterone, and

Dehydroepiandrosterone, 19 Growth Hormone, Prolactin, and

Oxytocin, 19 Adaptation, Coping, and Illness, 20

Adaptation, Coping, and Resilience, 20 Allostatic Overload and Illness, 21

UNIT II Cellular Function

3 Cell Structure and Function, 26 Jacquelyn L. Banasik and Brianne N. Banasik

Plasma Membrane, 27 Membrane Structure, 27 Lipid Bilayer, 27 Membrane Proteins, 29

Organization of Cellular Compartments, 30 Cytoskeleton, 30 Nucleus, 30 Endoplasmic Reticulum, 31 Golgi Apparatus, 32 Lysosomes and Peroxisomes, 33 Mitochondria, 34

Cellular Metabolism, 34 Glycolysis, 36 Citric Acid Cycle, 36 Oxidative Phosphorylation, 36

Functions of the Plasma Membrane, 39 Membrane Transport of Macromolecules, 39 Membrane Transport of Small Molecules, 40 Cellular Membrane Potentials, 45

Intercellular Communication and Growth, 48 Cell Signaling Strategies, 48 Cell Surface Receptor–Mediated Responses, 49 Intracellular Receptor–Mediated Responses, 53 Regulation of Cellular Growth and Proliferation, 54

4 Cell Injury, Aging, and Death, 59 Jacquelyn L. Banasik

Reversible Cell Injury, 59 Hydropic Swelling, 60 Intracellular Accumulations, 60

Cellular Adaptation, 63 Atrophy, 63 Hypertrophy, 63 Hyperplasia, 63 Metaplasia, 63 Dysplasia, 64

Irreversible Cell Injury, 64 Necrosis, 64 Apoptosis, 66

Etiology of Cellular Injury, 68 Ischemia and Hypoxic Injury, 68 Nutritional Injury, 70 Infectious and Immunologic Injury, 70 Chemical Injury, 72 Physical and Mechanical Injury, 72

Cellular Aging, 74 Cellular Basis of Aging, 74 Physiologic Changes of Aging, 75

Somatic Death, 75 5 Genome Structure, Regulation, and Tissue

Differentiation, 77 Jacquelyn L. Banasik

Structure and Function of DNA, 78 Structure of DNA, 78 DNA Replication, 79 Genetic Code, 80 Transcription, 81 Translation, 82

Regulation of the Genome, 84 Transcriptional Controls, 84

Differentiation of Tissues, 86 Cell Diversification and Cell Memory, 86 Mechanisms of Development, 86 Differentiated Tissues, 87

6 Genetic and Developmental Disorders, 94 Linda D. Ward

Principles of Inheritance, 95 DNA Mutation and Repair, 96

xii CoNTeNTs

GENETIC DISORDERS, 98 Chromosomal Abnormalities, 99

Aberrant Number of Chromosomes, 99 Abnormal Chromosome Structure, 100 Examples of Autosomal Chromosome

Disorders, 100 Examples of Sex Chromosome Disorders, 101

Mendelian Single-Gene Disorders, 102 Autosomal-Dominant Disorders, 103 Autosomal-Recessive Disorders, 104 Sex-Linked (X-Linked) Disorders, 106

Nonmendelian Single-Gene Disorders, 107 Anticipation, 109 Mitochondrial Gene Mutations, 109 Genomic Imprinting, 110

Polygenic and Multifactorial Disorders, 110 Environmentally Induced Congenital

Disorders, 111 Periods of Fetal Vulnerability, 111 Teratogenic Agents, 111 Other Disorders of Infancy, 113

Diagnosis, Counseling, and Gene Therapy, 113 Prenatal Diagnosis and Counseling, 113 Genetic Analysis and Therapy, 114 Recombinant DNA Technology, 114

7 Neoplasia, 117 Jacquelyn L. Banasik

Benign Versus Malignant Growth, 118 Characteristics of Benign and Malignant

Tumors, 118 Tumor Terminology, 118 The Malignant Phenotype, 118

Epidemiology and Cancer Risk Factors, 120 Tobacco Use, 120 Nutrition, 120

Genetic Mechanisms of Cancer, 123 Proto-Oncogenes, 124 Tumor Suppressor Genes, 127

Multistep Nature of Carcinogenesis, 129 Initiation, 129 Promotion, 131 Progression, 131

Metastasis, 132 Patterns of Spread, 132 Angiogenesis, 133 Grading and Staging of Tumors, 134

Effects of Cancer on the Body, 136 Cancer Therapy, 137

Surgery, 137 Radiation Therapy, 138 Drug Therapy, 138 Immunotherapy, 138 Gene and Molecular Therapy, 138 Stem Cell Transplantation, 139

UNIT III Defense

8 Infectious Processes, 141 Brent A. Banasik

Host–Microbe Relationship, 142 The Human Microbiome, 142

Host Characteristics, 142 Pathogen Characteristics, 144

Transmission of Infection, 147 Routes of Transmission, 148 Emerging Infectious Diseases, 148 Weapons of Bioterrorism, 149

Types of Pathogenic Organisms, 149 Bacteria, 149 Viruses, 150 Fungi, 151 Parasites, 152

9 Inflammation and Immunity, 158 Jacquelyn L. Banasik


Epithelial Barriers, 159 Mononuclear Phagocyte System, 159 Lymphoid System, 160

Primary Lymphoid Organs, 160 Secondary Lymphoid Organs, 161

Leukocytes, 162 Neutrophils, 162 Eosinophils, 163 Basophils and Mast Cells, 164 Monocytes and Macrophages, 164 Dendritic Cells, 165 Lymphocytes, 165

Chemical Mediators of Immune Function, 167 Complement, 167 Kinins, 169 Clotting Factors, 169 Cytokines and Chemokines, 169


Increased Vascular Permeability, 171 Emigration of Leukocytes, 172 Phagocytosis, 172 Chronic Inflammation, 174

Healing, 174 Inflammatory Exudates, 175 Systemic Manifestations of Inflammation, 175 SPECIFIC ADAPTIVE IMMUNITY, 176 Major Histocompatibility Complex, 176 Antigen Presentation by MHC, 176

MHC Class I Presentation, 177 MHC Class II Presentation, 177

Mechanisms of Cell-Mediated Immunity, 178 T Helper Cells (CD4+), 178 Cytotoxic T Cells (CD8+), 181

Mechanisms of Humoral Immunity, 181 Antigen Recognition by B Cells, 181

Antibody Structure, 183 Class Switching and Affinity Maturation, 185 Antibody Functions, 186

Passive and Active Immunity, 187 Passive Immunity, 187 Active Immunity, 187


Integrated Response to Microbial Antigen, 189 Integrated Response to Viral Antigen, 191 Regulation of Immune Function, 192

CoNTeNTs xiii

10 Alterations in Immune Function, 194 Faith Young Peterson


Genetic Factors, 196 Environmental Triggers, 196 Pharmacotherapies, 197

Hypersensitivity, 198 Type I Hypersensitivity, 199 Type IIa Hypersensitivity, 201 Type IIb Hypersensitivity, 204 Type III Hypersensitivity, 204 Type IV Hypersensitivity, 207

DEFICIENT IMMUNE RESPONSES, 210 Primary Immunodeficiency Disorders, 210

B-Cell and T-Cell Combined Disorders, 210 T-Cell Disorders, 211 B-Cell Disorders, 212

Secondary Immunodeficiency Disorders, 212 11 Malignant Disorders of White Blood Cells, 215

Marie L. Kotter and Jacquelyn L. Banasik Classification of Hematologic Neoplasms, 215 Etiology of Myeloid and Lymphoid Neoplasms, 216 General Principles of Management, 217

Diagnosis of Hematologic Neoplasms, 217 Principles of Treatment, 218 Prevention and Management of Complications, 219

Myeloid Neoplasms, 221 Chronic Myeloid Leukemia, 221 Acute Myeloid Leukemia, 222

Lymphoid Neoplasms, 223 Chronic Lymphoid Leukemia, 223 Acute Lymphoblastic Leukemia/Lymphoma, 223 Hairy Cell Leukemia, 224 Plasma Cell Myeloma (Multiple Myeloma), 224 Hodgkin Disease, 227 B-Cell, T-Cell, and NK-Cell Lymphoma

(Non-Hodgkin), 229 12 HIV Disease and AIDS, 233

Faith Young Peterson Epidemiology, 234

History, 234 Types of HIV, 234 Transmission, 236 Prevention of Transmission, 238

Etiology, 239 HIV Structure, 239 HIV Binding and Infection, 239

Pathogenesis, 242 Effect of HIV on Immune Cells at the Cellular

Level, 242 Viral Production and Cell Death, 242 Progression of HIV Infection From Seroconversion

to AIDS, 244 CDC HIV Classification System, 245

Diagnostic Testing, 245 Monitoring the Progression of HIV, 246 Clinical Manifestations, 248

Systemic Manifestations, 248 Gastrointestinal Manifestations, 249 Pulmonary Manifestations, 249 Mucocutaneous Manifestations, 250

Gynecologic Manifestations, 251 Neurologic Manifestations, 252 Ocular Manifestations, 253 Cardiovascular Manifestations, 253 Manifestations in Other Systems, 253 Manifestations in Children, 254

Treatment, 254 Antiretroviral Therapy Recommendations, 254 Nucleoside Reverse Transcriptase Inhibitors, 255 Nucleotide Reverse Transcriptase Inhibitors, 255 Nonnucleoside Reverse Transcriptase

Inhibitors, 255 Protease Inhibitors, 257 Fusion Inhibitors, 257 CCR5 Inhibitors, 257 Integrase Strand Transfer Inhibitors, 257 Other Treatments and Vaccines, 257

UNIT IV Oxygen Transport, Blood Coagulation, Blood Flow, and Blood Pressure

13 Alterations in Oxygen Transport, 259 Susan G. Trevithick

Composition of Blood, 260 Organic and Inorganic Components, 261 Cellular Components, 261

Structure and Function of Red Blood Cells, 262 Hematopoiesis, 263 Hemoglobin Synthesis, 265 Nutritional Requirements for Erythropoiesis, 266 Energy and Maintenance of Erythrocytes, 267 Red Cell Production, 267 Red Cell Destruction, 268

Gas Transport and Acid–Base Balance, 268 Oxygen Transport, 268 Carbon Dioxide Transport, 270 Alterations in Oxygen Transport, 270

Anemia, 272 General Effects of Anemia, 272

Anemia Related to Decreased Red Cell Production, 277 Aplastic Anemia, 277 Anemia of Chronic Renal Failure, 277 Anemia Related to Vitamin B12 (Cobalamin)

or Folate Deficiency, 278 Iron Deficiency Anemia, 279

Anemia Related to Inherited Disorders of the Red Cell, 279 Thalassemia, 279 Sickle Cell Anemia, 281 Hereditary Spherocytosis, 282 Glucose-6-Phosphate Dehydrogenase

Deficiency, 282 Anemia Related to Extrinsic Red Cell Destruction or

Loss, 284 Hemolytic Disease of the Newborn, 284 Antibody-Mediated Drug Reactions, 284 Acute Blood Loss, 285 Other Extrinsic Abnormalities, 285

Transfusion Therapy, 286 Polycythemia, 286

xiv CoNTeNTs

Polycythemia Vera, 286 Secondary Polycythemia, 292 Relative Polycythemia, 293

14 Alterations in Hemostasis and Blood Coagulation, 298 Cheryl Rockwell

The Process of Hemostasis, 298 Stages of Hemostasis, 298 Platelets, 299 Blood Coagulation Factors, 299 Fibrin Clot, 299 Fibrinolysis, 301

Evaluation of Hemostasis and Coagulation, 301 Clinical Assessment, 301 Laboratory Tests, 304

Vascular and Platelet Disorders, 304 Vascular Disorders, 304 Platelet Disorders, 306

Coagulation Disorders, 308 15 Alterations in Blood Flow, 313

Teresa Grigsby Loftsgaarden Organization of the Circulatory and Lymphatic

Systems, 315 Vessel Structure, 315 Lymphatic Structure, 317

Principles of Flow, 317 Hemodynamics of the Circulatory System, 317

Control of Flow, 322 Control of Blood Flow, 322 Control of Lymphatic Flow, 323

General Mechanisms That Cause Altered Flow, 323 Blood Vessels: Obstructions, 323 Blood Vessels: Structural Alterations, 325 Lymphatic Vessels, 326

Alterations in Arterial Flow, 326 Arteriosclerosis/Atherosclerosis, 326 Thromboangiitis Obliterans (Buerger Disease), 330 Raynaud Syndrome, 330 Aneurysms, 330 Acute Arterial Occlusion, 331

Alterations in Venous Flow, 332 Valvular Incompetence, 332 Varicose Veins, 332 Chronic Venous Insufficiency, 333 Deep Vein Thrombosis, 333

Alterations in Lymphatic Flow, 333 Lymphedema, 333

16 Alterations in Blood Pressure, 337 Benjamin J. Miller

Arterial Blood Pressure, 337 Determinants of Systemic Blood Pressure, 337 Measurement of Blood Pressure, 338

Mechanisms of Blood Pressure Regulation, 341 Short-Term Regulation of Systemic Blood

Pressure, 341 Long-Term Regulation of Systemic Blood Pressure, 341 Normal Fluctuations in Systemic Blood Pressure, 343

Hypertension, 343 Definition and Classification, 343 Primary Hypertension, 344 Secondary Hypertension, 348 Hypertensive Emergencies and Urgency, 349

Low Blood Pressure, 350

UNIT V Cardiac Function

17 Cardiac Function, 354 Jacquelyn L. Banasik

Cardiovascular Anatomy, 355 Heart, 355 Circulatory System, 356

Cardiac Cycle, 358 Isovolumic Contraction, 359 Ventricular Ejection, 360 Isovolumic Relaxation, 360 Atrial Events, 360 Aortic and Pulmonary Artery Events, 360

Coronary Circulation, 360 Anatomy of the Coronary Vessels, 360 Regulation of Coronary Blood Flow, 361

Cardiac Myocytes, 363 Myocyte Structure, 363 Structure of the Contractile Apparatus, 363 Characteristics of Contractile Filaments, 365

Molecular Basis of Contraction, 366 Overview of Contraction, 366 Sliding Filament/Cross-Bridge Theory of Muscle

Contraction, 366 Role of Calcium in Muscle Contraction, 367 Energy of Muscle Relaxation, 367

Cardiac Energy Metabolism, 368 Oxygen Utilization, 368 Substrate Utilization, 369

Cardiac Electrophysiology, 369 Cardiac Resting Potential, 369 Cardiac Action Potential, 369 Rhythmicity of Myocardial Cells, 370 Specialized Conduction System of the Heart, 371 Autonomic Regulation of Rhythmicity, 372

Electrocardiography, 372 Determinants of Cardiac Output, 374

Determinants of Heart Rate, 374 Determinants of Stroke Volume, 375 Cardiac Workload, 376

Endocrine Function of the Heart, 376 Tests of Cardiac Function, 376

Electrocardiography, 376 Magnetic Resonance Imaging and Computed

Tomography, 378 Echocardiography, 378 Nuclear Cardiography, 379 Cardiac Catheterization/Coronary

Angiography, 379 18 Alterations in Cardiac Function, 382

Jacquelyn L. Banasik Coronary Heart Disease, 383

Etiology of Coronary Heart Disease, 383 Risk Factors and Mechanisms of Coronary

Atherosclerosis, 383 Pathophysiology of Ischemia, 385 Clinical Features and Management of Coronary

Syndromes, 388 Endocardial and Valvular Diseases, 394

Disorders of the Mitral Valve, 394 Disorders of the Aortic Valve, 397 Diseases of the Endocardium, 398

CoNTeNTs xv

Myocardial Diseases, 399 Myocarditis, 399 Cardiomyopathy, 400

Pericardial Diseases, 402 Pericardial Effusion, 402 Pericarditis, 402

Congenital Heart Diseases, 403 Embryologic Development, 403 Etiology and Incidence of Congenital Heart

Disease, 404 Pathophysiology of Congenital Heart

Disease, 405 Acyanotic Congenital Defects, 406 Cyanotic Congenital Defects, 408

19 Heart Failure and Dysrhythmias: Common Sequelae of Cardiac Diseases, 411 Benjamin J. Miller and Jacquelyn L. Banasik

Heart Failure, 412 Pathogenesis and Diagnosis, 412 Compensatory Mechanisms, Remodeling,

and Progression, 413 Clinical Manifestations, 417 Class and Stage of Heart Failure, 420 Treatment, 421

Cardiac Dysrhythmias, 421 Dysrhythmia Mechanisms, 421 Dysrhythmia Analysis, 423 Abnormal Rates of Sinus Rhythm, 424 Abnormal Site of Impulse Initiation, 425 Conduction Pathway Disturbances, 428 Treatment, 431

20 Shock, 434 Benjamin J. Miller

Pathogenesis of Shock, 434 Impaired Tissue Oxygenation, 435 Compensatory Mechanisms and Stages of

Shock, 437 Types of Shock, 439

Cardiogenic Shock, 439 Obstructive Shock, 441 Hypovolemic Shock, 442 Distributive Shock, 443

Assessment and Hemodynamic Monitoring, 447 Cardiac Output, 447 Arterial Oxygen Content, 447 Distribution of Blood Flow, 448 Hemodynamic Monitoring, 448

Complications of Shock, 449 Acute Respiratory Distress Syndrome, 449 Disseminated Intravascular Coagulation, 449 Acute Renal Failure, 449 Multiple Organ Dysfunction Syndrome, 449

UNIT VI Respiratory Function

21 Respiratory Function and Alterations in Gas Exchange, 451 Lorna L. Schumann

Functional Anatomy, 452 Development of the Pulmonary System, 452 Upper Airway Structures, 452

Lower Airway Structures, 453 Pulmonary Circulation, 457 Age-Related Variations, 457

Ventilation, 460 Lung Volumes and Capacities, 460 Dead Space, 460 Minute Ventilation, 460 Alveolar Ventilation/Oxygenation, 461 Mechanics of Breathing, 461 Airway Resistance, 461 Lung Compliance, 462 Distribution of Ventilation, 462 Neurologic Control of Ventilation, 462

Pulmonary Blood Flow, 465 Pulmonary Vasculature, 465 Distribution of Blood Flow, 465 Ventilation–Perfusion Ratios, 465 Hypoxic Vasoconstriction, 466

Diffusion and Transport of Respiratory Gases, 466 Barriers to Diffusion, 466 Oxygen Transport, 467 Carbon Dioxide Transport, 467

Alterations in Pulmonary Function, 468 Hypoventilation and Hyperventilation, 468 Hypoxemia and Hypoxia, 468 Acute Respiratory Failure, 469

Diagnostic Tests, 471 Pulmonary Function Testing, 471 Bronchial Provocation Tests, 472

Alterations in Pulmonary Vasculature, 472 Pulmonary Hypertension, 472 Pulmonary Venous Thromboembolism, 473

Pulmonary Malignancies, 475 Etiology, 475 Pathogenesis, 475 Clinical Manifestations, 476 Diagnosis, 476 Treatment, 476

22 Obstructive Pulmonary Disorders, 478 Benjamin J. Miller and Lorna L. Schumann

Obstruction From Conditions in the Wall of the Lumen, 479 Asthma, 479 Acute Bronchitis, 483 Chronic Bronchitis, 485

Obstruction Related to Loss of Lung Parenchyma, 488 Emphysema, 488

Obstruction of the Airway Lumen, 491 Bronchiectasis, 491 Bronchiolitis, 493 Cystic Fibrosis, 494 Acute Tracheobronchial Obstruction, 495 Epiglottitis, 496 Croup Syndrome, 496

23 Restrictive Pulmonary Disorders, 499 Lorna L. Schumann and Benjamin J. Miller

Lung Parenchyma Disorders, 500 Fibrotic Interstitial Lung Diseases, 500

Atelectatic Disorders, 504 Pleural Space Disorders, 508

xvi CoNTeNTs

Neuromuscular, Chest Wall, and Obesity Disorders, 511 Neuromuscular Disorders, 511 Chest Wall Deformities, 511 Disorders of Obesity, 513

Infection or Inflammation of the Lung, 514

UNIT VII Fluid, Electrolyte, and Acid-Base Homeostasis

24 Fluid and Electrolyte Homeostasis and Imbalances, 521 Linda Felver

Body Fluid Homeostasis, 522 Fluid Intake and Absorption, 522 Fluid Distribution, 523 Fluid Excretion, 524 Fluid Loss Through Abnormal Routes, 524

Fluid Imbalances, 525 Extracellular Fluid Volume, 525 Body Fluid Concentration, 526 Both Volume and Concentration, 528 Interstitial Fluid Volume, 528

Principles of Electrolyte Homeostasis, 529 Electrolyte Intake and Absorption, 529 Electrolyte Distribution, 531 Electrolyte Excretion, 531 Electrolyte Loss Through Abnormal Routes, 531

Electrolyte Imbalances, 531 Plasma Potassium, 531 Plasma Calcium, 533 Plasma Magnesium, 534 Plasma Phosphate, 535

25 Acid–Base Homeostasis and Imbalances, 541 Linda Felver

Acid–Base Homeostasis, 541 Buffers, 542 Respiratory Contribution, 542 Renal Contribution, 543

Acid–Base Imbalances, 545 Mixed Acid–Base Imbalances, 549

UNIT VIII Renal and Bladder Function

26 Renal Function, 551 Jacquelyn L. Banasik

Renal Anatomy, 552 Renal Parenchyma, 552 Renal Lymphatics and Innervation, 552 Renal Blood Supply, 553

Overview of Nephron Structure and Function, 554 Glomerulus, 555 Proximal Convoluted Tubule, 557 Loop of Henle, 558 Distal Convoluted Tubule, 559 Collecting Duct, 559

Regulation of Glomerular Filtration, 560 Physics of Filtration, 560 Factors Affecting Filtration Pressure, 562 Tubuloglomerular Feedback, 563

Effects of Glucose and Amino Acids, 563 Role of Mesangial Cells, 564

Transport Across Renal Tubules, 565 Reabsorption of Glucose, 565 Regulation of Acid–Base Balance, 565 Secretion of Potassium, 566

Regulation of Blood Volume and Osmolality, 567 Antidiuretic Hormone, 567 Aldosterone, Angiotensin II, Natriuretic

Peptides, Urodilatin, Uroguanylin, and Guanylin, 568

Diuretic Agents, 569 Endocrine Functions, 570

Erythropoietin, 570 Vitamin D, 570

Age-Related Changes in Renal Function, 570 Infant, 570 Adult and Elderly, 570

Tests of Renal Structure and Function, 570 Urine and Blood Studies, 570 Diagnostic Tests, 572

27 Intrarenal Disorders, 575 Jacquelyn L. Banasik and Roberta J. Emerson

Common Manifestations of Kidney Disease, 575 Pain, 575 Abnormal Urinalysis Findings, 576 Other Diagnostic Tests, 576

Congenital Abnormalities, 577 Renal Agenesis and Hypoplasia, 577 Cystic Kidney Diseases, 578

Neoplasms, 579 Infection, 581 Obstruction, 583 Glomerular Disorders (Glomerulopathies), 586

Glomerulonephritis, 587 Nephrotic Syndrome, 589

28 Acute Kidney Injury and Chronic Kidney Disease, 593 Cheryl Rockwell and Robin Y. Beeman

Acute Kidney Injury, 593 Etiology and Pathophysiology, 594 Clinical Presentation of Acute Kidney Injury, 596

Chronic Kidney Disease, 601 Risk Factors, 601 Pathophysiology of Progression of Chronic

Kidney Disease, 602 Stages of Chronic Kidney Disease, 602 Complications of Chronic Kidney Disease, 602

Clinical Management, 604 29 Disorders of the Lower Urinary Tract, 609

Cheryl L. Brandt Lower Urinary Tract, 609

Functional Anatomy, 609 Physiology of Micturition, 610 Diagnostic Tests, 611

Lower Urinary Tract Symptoms and Syndromes, 611

Neurogenic Bladder, 614 Congenital Disorders, 615 Neoplasms, 617 Inflammation and Infection, 619 Obstruction, 622

Lower Urinary Tract Calculi, 622

CoNTeNTs xvii

UNIT IX Genital and Reproductive Function

30 Male Genital and Reproductive Function, 626 Marvin Van Every

Anatomy, 626 Upper Genitourinary Tract, 626 Lower Genitourinary Tract, 627 Auxiliary Genital Glands, 628 External Genitalia, 629

Embryology, 632 Nephric System, 632 Vesicourethral Unit, 633 Gonads, 633 Genital Duct System, 633 External Genitalia, 633

Male Reproductive Physiology, 633 Hypothalamic-Pituitary-Testicular Axis, 633 Spermatogenesis, 637 Anatomy of Spermatozoa, 637 Transport of Spermatozoa, 637

31 Alterations in Male Genital and Reproductive Function, 641 Marvin Van Every

Disorders of the Penis and Male Urethra, 641 Congenital Anomalies, 641 Acquired Disorders, 643 Infectious Disorders, 645 Neoplastic Disorders, 647

Disorders of the Scrotum and Testes, 647 Congenital Disorders, 647 Acquired Disorders, 648 Infectious Disorders, 650 Neoplastic Disorders, 650

Disorders of the Prostate, 651 32 Female Genital and Reproductive Function, 656

Rosemary A. Jadack Reproductive Structures, 656

Organization of the Female Reproductive Organs, 656

Menstrual Cycle, 659 Breast, 662

Structure of the Breast, 662 Breast Development, 662 Lactation, 663

Pregnancy, 663 Early Human Development, 663 Implantation, 663 Fetal Membranes and Placenta, 663 Development of the Human Embryo and Fetus, 664 Parturition, 665 Response of the Mother’s Body to Pregnancy, 667

Menopause, 668 33 Alterations in Female Genital and Reproductive

Function, 671 Rosemary A. Jadack

Menstrual Disorders, 672 Alterations in Uterine Position and Pelvic

Support, 674 Inflammation and Infection of the Female

Reproductive Tract, 676 Benign Growths and Aberrant Tissue of the Female

Reproductive Tract, 678

Cancer of the Female Genital Structures, 679 Disorders of Pregnancy, 681 Disorders of the Breast, 682

Reactive-Inflammatory Breast Disorders, 682 Benign Breast Disorders, 683 Malignant Disorder of the Breast, 684

34 Sexually Transmitted Infections, 689 Rosemary A. Jadack

Urethritis, Cervicitis, Salpingitis, and Pelvic Inflammatory Disease, 690

Diseases With Systemic Involvement, 691 Diseases With Localized Lesions, 694

Ulcerative Lesions, 694 Nonulcerative Lesions, 694

Enteric Infections, 695

UNIT X Gastrointestinal Function

35 Gastrointestinal Function, 697 Jeffrey S. Sartin

Structure and Organization of the Gastrointestinal Tract, 698 Embryology, 698 Functional Anatomy, 699

Gastrointestinal Motility, 704 Characteristics of the Intestinal Wall, 704 Neural Control, 704 Hormonal Control, 706 Movement in the Gastrointestinal Tract, 706 Movement of Nutrients, 707

Secretory Function, 712 Secretion of Gastrointestinal Juices, 712 Gastrointestinal Hormones, 712

Digestion and Absorption, 712 Digestion of Carbohydrates, 713 Digestion of Lipids, 713 Digestion of Proteins, 714 Absorption, 715

Gastrointestinal Function Across the Life Span, 717 Maturation, 717 Age-Related Changes, 717

36 Gastrointestinal Disorders, 720 Jeffrey S. Sartin

Manifestations of Gastrointestinal Tract Disorders, 721 Dysphagia, 721 Esophageal Pain, 721 Abdominal Pain, 721 Vomiting, 723 Intestinal Gas, 723 Alterations in Bowel Patterns, 723


Oral Infections, 724 Esophageal Disorders, 724 ALTERATIONS IN THE INTEGRITY OF


Inflammation of the Stomach and Intestines, 726

xviii CoNTeNTs

Inflammatory Bowel Disease, 728 Enterocolitis, 731 ALTERATIONS IN MOTILITY OF THE

GASTROINTESTINAL TRACT, 733 Motility Disorders, 733 Disorders of Malabsorption, 735 Mucosal Disorders, 735 Malabsorption Disorders After Surgical


TRACT, 737 Esophageal, Gastric, and Small Intestinal

Cancers, 737 Colonic Polyps and Colon Cancer, 738 Psychosocial Aspects of Gastrointestinal

Disorders, 739 Stress of Lifestyle Changes, 739

37 Alterations in Function of the Gallbladder and Exocrine Pancreas, 742 Jeffrey S. Sartin

Structure and Function of the Pancreaticobiliary System, 742

Embryology of the Pancreaticobiliary System, 743

Physiology of Bile, 743 Functional Anatomy of the Pancreas, 744 Disorders of the Gallbladder, 744

Pathophysiology of Cholesterol Gallstone Formation, 744

Cholelithiasis and Cholecystitis, 745 Disorders of the Pancreas, 748

Pancreatitis, 748 38 Liver Diseases, 754

Jeffrey S. Sartin Structure and Function of the Liver, 755 General Manifestations of Liver Disease, 755

Hepatocellular Failure, 755 Portal Hypertension, 759 Portal Systemic Encephalopathy, 763 Complications of Advanced Liver

Disease, 764 Disorders of the Liver, 767

Hepatitis, 767 Chronic Hepatitis, 772

Cirrhosis, 773 Alcoholic Liver Disease, 773

Toxic Liver Disorders, 774 Metal Storage Diseases, 774 Toxic Metabolic Agents, 775

Other Structural Liver Conditions, 775 Transplantation, 776

Evaluation of the Transplantation Patient, 777

Posttransplantation Management, 777 Age-Related Liver Disorders, 778

Liver Diseases and Pediatric Considerations, 778 Abnormal Bilirubin Metabolism in the Neonatal

Period, 778 Infectious and Acquired Hepatitides in

Children, 778 Congenital Liver Disease, 779

Liver Diseases and Geriatric Considerations, 780

UNIT XI Endocrine Function, Metabolism, and Nutrition

39 Endocrine Physiology and Mechanisms of Hypothalamic-Pituitary Regulation, 783 Jacquelyn L. Banasik

Hormone Structure and Action, 784 Chemical Structure of Hormone Classes, 784 Mechanisms of Hormone Action, 784

Hormone Regulation, 786 Hormone Synthesis, Secretion, and

Metabolism, 786 Regulation of Receptor Responses, 787

Hypothalamic-Pituitary Endocrine System, 788 Hormones of the Posterior Pituitary Gland, 788 Hormones of the Hypothalamus and Anterior

Pituitary Gland, 790 Thyroid Hormones, 793

Thyroid Hormone Synthesis and Secretion, 793 Thyroid Action on Target Cells, 793

Steroid Hormones, 794 Steroid Hormone Synthesis and Secretion, 794 Steroid Action on Target Cells, 795

Categories of Endocrine Disease, 797 Hyposecretion, 797 Hypersecretion, 797 Hyporesponsiveness, 797

40 Disorders of Endocrine Function, 799 Jacquelyn L. Banasik

Basic Concepts of Endocrine Disorders, 799 Etiology of Endocrine Disorders, 799 Classification of Endocrine Disorders, 800

Growth Hormone Disorders, 801 Thyroid Hormone Disorders, 803 Adrenocortical Hormone Disorders, 806 Adrenal Medulla Disorder, 810 Parathyroid Gland Disorders, 811

Regulation and Actions of Parathyroid Hormone, 811

Antidiuretic Hormone Disorders, 812 41 Diabetes Mellitus, 815

Benjamin J. Miller Regulation of Glucose Metabolism, 816

Hormonal Regulation, 816 Neural Regulation, 817 Exercise, 818 Stress, 818

Glucose Intolerance Disorders, 820 Classification of Glucose Intolerance

Disorders, 820 Prediabetes, 820 Diabetes Mellitus, 821 Screening for Diabetes, 824

Clinical Manifestations and Complications, 825 Acute Hyperglycemia, 825 Diabetic Ketoacidosis, 825 Nonketotic Hyperglycemic Hyperosmolar

Syndrome, 826 Chronic Hyperglycemia, 826 Vascular Complications, 826 Neuropathic Complications, 827 Complications in Pregnancy, 827

CoNTeNTs xix

Treatment and Education, 827 Nutrition, 828 Obesity and Eating Disorders, 828 Exercise, 829 Pharmacologic Agents, 829 Stress Management, 831 Assessment of Efficacy, 831

Pediatric Considerations, 833 Goals of Therapy, 834 Acute Complications, 834 Chronic Complications, 834 Treatment, 834

Geriatric Considerations, 834 Goals of Therapy, 835 Acute Complications, 835 Chronic Complications, 835 Treatment, 835

42 Nutritional and Metabolic Disorders, 838 Brent A. Banasik

Metabolic Processes, 838 Anabolism and Catabolism, 839 Metabolic Rate, 839

Nutrient Metabolism, 839 Carbohydrates, 839 Lipids, 840 Proteins, 841

Regulation of Appetite and Nutrient Metabolism, 841 Role of Genetics, Epigenetics, and

Environment, 841 Hormonal Regulation of Nutrient Intake and

Appetite, 842 Hormonal Regulation of Nutrient Storage,

Distribution, and Metabolism, 843 Obesity and Metabolic Syndrome, 844

Obesity, 844 Metabolic Syndrome, 844

Metabolic Responses to Starvation and Physiologic Stress, 844 Starvation and Protein-Energy Malnutrition, 845 Physiologic Stress, 845

Nutritional Considerations for Aging and Altered Health States, 846 Aging, 846 Infection, Sepsis, and Fever, 846 Surgery, 848 Trauma, 848 Burns, 848 Cancer, 848 Immobility, 848

UNIT XII Neural Function

43 Structure and Function of the Nervous System, 850 Jacquelyn L. Banasik

STRUCTURAL ORGANIZATION, 851 Central Nervous System, 851

Support and Protection of the Central Nervous System, 851

The Brain, 853 The Spinal Cord, 861

Peripheral Nervous System, 863 Cranial Nerves, 863 Spinal Nerves, 864

Autonomic Nervous System, 867 NEURONAL STRUCTURE AND FUNCTION, 868 Neurons and Supportive Cells, 868

Neurons, 868 Glia, 868

Neuronal Communication, 872 Membrane Potentials, 872 Synaptic Transmission, 874 Neurotransmitters, 875 Neuronal Circuits, 880

Neural Development, Aging, and Injury, 880 Development, 880 Aging, 881 Injury, 881

SENSORY FUNCTION, 882 Sensory Receptors, 882 Sensory Pathways, 883 Somatosensory Cortex, 883 MOTOR FUNCTION, 883 Motor Neurons, 884 Spinal Reflexes, 884 Central Control of Motor Function, 885 CONSCIOUSNESS, MEMORY, AND SLEEP, 886 Consciousness and Memory, 886 Sleep, 888

44 Acute Disorders of Brain Function, 891 Joni D. Marsh and Jacquelyn L. Banasik

Mechanisms of Brain Injury, 892 Ischemia and Hypoxia, 892 Increased Intracranial Pressure, 895

Manifestations of Brain Injury, 900 Level of Consciousness, 900 Glasgow Coma Scale, 900 Cranial Nerve Reflexes, 901

TRAUMATIC BRAIN INJURY, 902 Epidemiology, 902 Types of Traumatic Brain Injury, 903 Primary Injury, 903

Intracranial Hematomas, 903 Secondary Injury, 905 Treatment, 905 CEREBROVASCULAR DISEASE AND

STROKE, 905 Epidemiology, 906 Ischemic Stroke, 906 Hemorrhagic Stroke, 906 Treatment, 906 Stroke Sequelae, 908

Motor and Sensory Deficits, 908 Language Deficits, 908 Cognitive Deficits, 908


Cerebral Aneurysm, 909 Etiology, 909 Pathogenesis and Manifestations, 910 Treatment, 910

Arteriovenous Malformation, 911 Etiology, 911

xx CoNTeNTs

Pathogenesis and Manifestations, 911 Treatment, 911


Etiology, 911 Pathogenesis and Clinical Manifestations, 911 Treatment, 911

Encephalitis, 912 Etiology, 912 Pathogenesis and Manifestations, 912 Treatment, 912

Brain Abscess, 912 Etiology, 912 Pathogenesis and Manifestations, 912 Treatment, 913

45 Chronic Disorders of Neurologic Function, 915 Joni D. Marsh

Brain and Cerebellar Disorders, 916 Seizure Disorder, 916 Dementia, 918 Parkinson Disease, 920 Cerebral Palsy, 922 Hydrocephalus, 923 Cerebellar Disorders, 924

Spinal Cord and Peripheral Nerve Disorders, 925 Multiple Sclerosis, 925 Spina Bifida, 927 Amyotrophic Lateral Sclerosis, 928 Spinal Cord Injury, 928 Guillain-Barré Syndrome, 931 Bell Palsy, 932

46 Alterations in Special Sensory Function, 936 Joni D. Marsh

HEARING AND BALANCE, 937 Structure and Function of the Ear, 937

External Ear, 937 Middle Ear, 937 Inner Ear, 937 Balance, 938

General Manifestations of Hearing Impairment, 938 Hearing Impairment Disorders, 939

Conductive Hearing Impairment, 939 Sensorineural Hearing Impairment, 939

Otitis Media, 941 Interventions for Individuals With Hearing

Impairment, 942 VISION, 942 Structure of the Eye, 942 Visual Pathways, 943 General Manifestations of Visual Impairment, 944 Disorders of the Eye, 944

Errors of Refraction, 944 Age-Related Disorders, 945 Retinopathy, 947 Glaucoma, 948 Visual Field Deficits, 950

Interventions for Individuals With Vision Impairment, 950

SMELL AND TASTE, 952 47 Pain, 955

Joni D. Marsh Physiology of Pain, 955

Transduction, 956 Transmission, 956 Perception, 958 Modulation, 958

TYPES OF PAIN, 960 Acute Pain, 961

Headache, 962 Chronic Pain, 962

Fibromyalgia Syndrome, 963 Cancer-Related Pain, 964 Neuropathic Pain, 964

Trigeminal Neuralgia, 965 Diabetic Neuropathy, 965 Postherpetic Neuralgia, 966

Ischemic Pain, 966 Referred Pain, 966 Physiologic Responses to Pain, 967 Pain in the Young and the Elderly, 967 TREATMENT MODALITIES, 967 Pharmacologic and Nonpharmacologic Pain

Management, 967 Interrupting Peripheral Transmission of Pain, 968 Modulating Pain Transmission at the Spinal

Cord, 968 Altering the Perception and Integration of

Pain, 968

UNIT XIII Neuropsychological Function

48 Neurobiology of Psychotic Illnesses, 971 Ann Futterman Collier and Samantha Cody Russell

Schizophrenia, 972 Etiology and Neurobiology, 972 Clinical Manifestations, 976 Pharmacologic Treatment, 976 Nonpharmacologic Treatment, 977

Major Depressive and Persistent Depressive Disorders, 978 Etiology and Neurobiology, 979 Clinical Manifestations, 980 Pharmacologic Treatment, 981 Nonpharmacologic Treatment, 981

Bipolar Disorder, 982 Etiology and Neurobiology, 982 Clinical Manifestations, 983 Pharmacologic Treatment, 983 Nonpharmacologic Treatment, 984

Population Considerations, 984 Women and Mental Illness, 984 Cultural Considerations, 984 Geriatric Considerations, 984

49 Neurobiology of Nonpsychotic Illnesses, 989 Ann Futterman Collier and Samantha Cody Russell

Anxiety Disorders, 989 Panic Disorder, 990 Generalized Anxiety Disorder, 991 Obsessive-Compulsive Disorder, 992 Posttraumatic Stress Disorder, 994

Neurodevelopmental Disorders, 995 Attention-Deficit/Hyperactivity Disorder, 996 Autism Spectrum Disorder, 997

CoNTeNTs xxi

UNIT XIV Musculoskeletal Support and Movement

50 Structure and Function of the Musculoskeletal System, 1001 Carol L. Danning

Structure and Function of Bone, 1002 Composition, 1002 Functional Properties, 1003 Response to Injury, Stress, and Aging, 1004

Structure and Function of Joints, 1006 Synarthroses, 1007 Diarthroses, 1007

Structure and Function of Articular Cartilage, 1011 Composition, 1011 Functional Properties, 1011 Response to Injury, Stress, and Aging, 1012

Structure and Function of Tendons and Ligaments, 1012 Composition, 1012 Functional Properties, 1013 Response to Injury, Stress, and Aging, 1013

Structure and Function of Skeletal Muscle, 1013 Composition, 1014

Mechanics of Muscle Contraction, 1015 Sliding Filament Theory, 1015 Role of Calcium, 1015 Electromechanical Coupling, 1015 Types of Muscle Contraction, 1016 Mechanical Principles, 1017 Response to Movement and Exercise, 1017

51 Alterations in Musculoskeletal Function: Trauma, Infection, and Disease, 1020 Carol L. Danning

SOFT TISSUE INJURIES, 1021 Inert Soft Tissue Injuries, 1021

Ligament Injuries, 1021 Joint Capsule Injuries, 1022 Internal Joint Derangement, 1023 Injuries to Fasciae and Bursae, 1023 Injuries to Nerves, Nerve Roots, or Dura

Mater, 1023 Contractile Soft Tissue Injuries, 1023

Injury to Tendons, 1023 Muscle and Tendon Strains, 1024 Blunt Trauma, 1024 Compartment Syndrome, 1024 Soft Tissue Healing After Trauma, 1024

BONE INJURIES AND INFECTIONS, 1026 Bone and Joint Trauma, 1026

Types of Bone, 1026 Fracture, 1026 Dislocations and Subluxations, 1030

Infections of the Bone, 1031 Osteomyelitis, 1031 Tuberculosis, 1032


Bone Structure Disorders, 1032 Scoliosis, 1032

Metabolic Bone Diseases, 1033

Osteoporosis, 1033 Rickets and Osteomalacia, 1035 Paget Disease, 1035

Bone Tumors, 1036 Benign Tumors, 1036 Malignant Bone Tumors, 1037

DISEASES OF SKELETAL MUSCLE, 1038 Idiopathic Inflammatory Myopathy, 1038

Polymyositis and Dermatomyositis, 1038 Muscular Dystrophy, 1039

Duchenne Muscular Dystrophy, 1039 Becker Muscular Dystrophy, 1039 Facioscapulohumeral Muscular Dystrophy, 1039 Myotonic Dystrophies, 1039

OTHER DISORDERS OF MUSCLE, 1039 Myasthenia Gravis, 1039

Treatment, 1039 Chronic Muscle Pain, 1040

Fibromyalgia Syndrome, 1040 52 Alterations in Musculoskeletal Function: Rheumatic

Disorders, 1042 Carol L. Danning

Local Disorders of Joint Function, 1042 Osteoarthritis, 1042 Infectious Arthritis, 1045 Lyme Disease, 1045

Systemic Disorders of Joint Function, 1046 Immune-Mediated Disorders, 1046 Postinfectious Systemic Disorders, 1052

Joint Dysfunction Secondary to Other Diseases, 1053 Psoriatic Arthritis, 1053 Enteropathic Arthritis, 1053 Neuropathic Osteoarthropathy, 1054 Hemophilic Arthropathy, 1054 Gout, 1054 Adult-Onset Still Disease, 1055

Pediatric Joint Disorders, 1056 Nonarticular Rheumatism, 1056 Hypermobility of Joints, 1056 Juvenile Idiopathic Arthritis, 1056

UNIT XV Integumentary System

53 Alterations in the Integumentary System, 1058 Lee-Ellen C. Copstead, Ruth E. Diestelmeier, and Michael R. Diestelmeier

Age-Related Changes, 1059 Epidermis, 1060 Dermis and Subcutaneous Tissue, 1060 Appendages, 1061

Evaluation of the Integumentary System, 1061 Primary and Secondary Lesions, 1061 Lesion Descriptors, 1062

Selected Skin Disorders, 1063 Infectious Processes, 1064

Viral Infections, 1064 Fungal Infections, 1065 Bacterial Infections, 1067

Inflammatory Conditions, 1069 Allergic Skin Responses, 1072 Parasitic Infestations, 1075

xxii CoNTeNTs

Other Disorders of the Dermis, 1076 Scleroderma, 1076 Sunburn and Photosensitivity, 1077 Ulcers, 1078 Altered Cell Growth: Epidermal Proliferation, 1078 Pigmentation Alterations, 1080

Special Characteristics of Dark Skin, 1081 Integumentary Manifestations of Systemic

Disease, 1083 Skin, 1083 Hair, 1084 Nails, 1084

Treatment Implications, 1086 Topical Treatment, 1086 Intralesional Injection, 1086 Selection of a Delivery System, 1087 Corticosteroids, 1087

Developmental Considerations, 1087 Infancy, 1087 Childhood Skin Disorders, 1088 Adolescence and Young Adulthood, 1090 Geriatric Considerations, 1090

54 Burn Injuries, 1093 Sarah Ogle and Nirav Patel

Thermal Injury, 1094 Etiology, Incidence, and Mortality, 1094

Risk Factors, 1094 Integument Effects, 1094 Depth Classification, 1096 Extent of Injury, 1097 Severity Classification, 1097 Acute Management, 1097 Assessment, 1099 Burn Shock and Acute Resuscitation, 1099 Organ Dysfunction, 1101 Metabolic Changes, 1102 Cellular Changes, 1102 Immune Response, 1103 Elements of Burn Injury Survival, 1103 Rehabilitation Phase, 1106

Electrical Injury, 1107 Incidence and Mortality, 1107 Pathophysiology, 1107 Management and Complications, 1108

Chemical Injury, 1109 Management and Complications, 1109 Common Agents and Treatment, 1109

Special Populations, 1110 Introduction, 1110

Glossary, 1114 Index, 1143


Introduction to Pathophysiology Lee-Ellen C. Copstead

UNIT I Pathophysiologic Processes


K E Y Q U E S T I O N S • What is pathophysiology? • How are etiology and pathogenesis used to predict clinical

manifestations and response to therapy? • How are normal and abnormal physiologic parameters defined?

C H A P T E R O U T L I N E Framework for Pathophysiology, 2

Etiology, 2

Pathogenesis, 2

Clinical Manifestations, 3

Stages and Clinical Course, 3

Treatment Implications, 3

Concepts of Normality in Health and Disease, 4 Statistical Normality, 4

Reliability, Validity, and Predictive Value, 5 Individual Factors Influencing Normality, 5

Cultural Considerations, 5

• What general factors affect the expression of disease in a particular person?

• What kinds of information about disease can be gained through understanding concepts of epidemiology?

Pathophysiology derives from the intersection of two older, related disciplines: pathology (from pathos, suffering) and physiology (from physis, nature). Pathology is the study and diagnosis of disease through examination of organs, tissues, cells, and bodily fluids. Physiology is the study of the mechanical, physical, and biochemical functions of living organisms. Together, as pathophysiology, the term refers to the study of abnormalities in physiologic functioning of living beings.

Pathophysiology seeks to reveal physiologic responses of an organism to disruptions in its internal or external environment. Because humans exhibit considerable diversity, healthy structure and function are not precisely the same in any two individuals. However, discovering the common and expected responses to abnormalities in physiologic func- tioning is useful, and it allows a general prediction of clinical progression, identification of possible causes, and selection of interventions that are

most likely to be helpful. Thus pathophysiology is studied in terms of common, or “classic,” presentations of disorders.

Historically, descriptions of diseases were based on observations of those individuals who attracted medical attention because they exhibited abnormal signs or complained of symptoms. Over time, cases with similar presentations were noted and treatments that had been successful before were used again. In some cases, similarities among individuals pointed to possible common causes. With the advent of more sophis- ticated measurements of physiologic and biochemical function, such as blood pressure measurements, blood chemistry values, x-ray images, and DNA analysis, the wide variability in the expression of diseases and disorders in the population became apparent, as did the opportunity to discover diseases at earlier stages, before they were clinically obvious. Screening programs that evaluated large segments of the population

Age Differences, 6 Gender Differences, 6 Situational Differences, 6 Time Variations, 6

Patterns of Disease in Populations, 6 Concepts of Epidemiology, 6

Endemic, Pandemic, and Epidemic Diseases, 7 Aggregate Factors, 7 Levels of Prevention, 9

http://evolve.elsevier.com/Banasik/pathophysiology/ • Review Questions and Answers • Glossary (with audio pronunciations for selected terms) • Animations

• Case Studies • Key Points Review

2 UNIT I Pathophysiologic Processes

present, it is termed a risk factor. The identification of risk factors is important for disease prevention, and various levels of prevention provide a focus for the epidemiology section at the end of this chapter.

Some diseases are closely linked with etiologic factors, such that they are said to be the causative agents in the disease. For example, microbial pathogens are considered to be causative agents for infectious diseases: Ebola virus disease—a rare and deadly disease—is caused by infection with a virus of the family Filoviridae, genus Ebolavirus (Fig. 1.1); human immunodeficiency virus causes HIV disease, and Myco- bacterium tuberculosis causes pulmonary tuberculosis. These diseases do not occur unless the pathogen is present in the body; however, this does not mean that the infection will have the same consequences in each case, because many host factors affect the clinical course.

Even when the link between disease and etiologic agent is strong, only a portion of the population exposed to the factor may develop the disease. For example, in persons who consume large quantities of alcohol and develop liver cirrhosis, it is the alcohol consumption that is considered to be the cause, yet only a portion of persons who drink heavily will develop cirrhosis. Thus categorizing the probable etiologies for diseases is a long, difficult research process and, not surprisingly, the exact causes of most disorders remain incompletely understood. Several classification schemes have been proposed to categorize diseases according to etiology. Box 1.1 summarizes an example of an etiologic classification system. No classification system is truly comprehensive, and some diseases fall into multiple categories. Some diseases may receive different designations in the future, as further research reveals new data.

Pathogenesis Pathogenesis refers to the development or evolution of a disease, from the initial stimulus to the ultimate expression of the manifestations of the disease. The sequence of physiologic events that occurs in response to an etiologic agent is a dynamic interplay of changes in cell, tissue, organ, and systemic function. As the ways in which intricate intercellular communication networks control physiologic function are discovered,

revealed the complexity and diversity of disease expression, even in persons with the same genetic defect. Thus although the study of pathophysiology is necessarily a study of the usual and expected responses of the body to a given disruption, individuals often vary significantly from a classic presentation, making the diagnostic process complex and challenging.

Advances in genomic and epigenomic characterization, innovative technologies, and revolutionary approaches to the analysis of genetic variation and function have made studies and treatments possible that were not even imaginable just a few years ago. As a result, definitions of the living world have been virtually transformed and permeate every branch of biological science. Benefits of this new biology include a deeper understanding of evolution, greater insights into immune mechanisms, and advances against cancer and AIDS.

Genetic manipulation also raises sensitive and complex ethical and moral questions that did not exist half a century ago. Scientists are able to experiment with genetic manifestations and their mechanisms of action, dramatically altering medical practice, especially the management of inherited diseases. New capabilities have led to experimental treatments such as gene therapy–molecular surgery powerful enough to cure and alter the next generation. The study of pathophysiology assumes even greater significance as genetic research shows fresh insights and hopeful new treatments for human diseases.

Pathophysiology examines disturbances of normal mechanical, physical, and biochemical functions, either caused by a disease or resulting from a disease or abnormal syndrome or condition. For example, the study of a toxin released by a bacterium has evolved from the science of infectious diseases, as well as the harmful effects of that toxin on the body, with one possible result being sepsis. Another example is the study of the chemical changes that take place in body tissue as the result of inflammation.

Although individual study of specific diseases undertaken in medical pathology textbooks helps students identify subtle differences between similar diseases, the study of pathophysiology is dynamic and conceptual, seeking to explain processes and relationships common to a number of pathologies. For example, the pathophysiology of inflammation, hypotension, fluid volume deficit, hypoxia, and ischemia is important to the understanding of a large number of different pathologies, but each separate process is not necessarily a specific disease.

Pathophysiology includes four interrelated topics: etiology, patho- genesis, clinical manifestations, and treatment implications—the framework used throughout this textbook. Specific diseases will be used as illustrative examples of conditions in which particular pathophysiologic processes may occur.

FRAMEWORK FOR PATHOPHYSIOLOGY Etiology Etiology, in its most general definition, is the study of the causes or reasons for phenomena. A description of etiologic process includes the identification of those causal factors that, acting in concert, provoke a particular disease or injury. When the cause is unknown, a condition is said to be idiopathic. If the cause is the result of an unintended or unwanted medical intervention, the resulting condition is said to be iatrogenic. Most disorders are multifactorial, having several different etiologic factors that contribute to their development. For example, coronary heart disease is a result of the interaction of genetic predisposi- tion, diet, exposure to cigarette smoke, elevated blood pressure, and perhaps numerous other lifestyle and hormonal factors acting in concert. None of these individual factors can be said to cause the disease. When the link between an etiologic factor and development of a disease is less than certain but the probability is increased when the factor is

FIG 1.1 Colorized scanning electron micrograph of filamentous Ebola virus particles (blue) budding from a chronically infected VERO E6 cell (yellow-green). (From National Institute of Allergy and Infectious Diseases at http://flickr.com/photos/54591706@N02/14440817981. March 20, 2017.)

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CHAPTER 1 Introduction to Pathophysiology 3

different stages. Knowledge of the possible stages of a disease is helpful in making an appropriate diagnosis and anticipating the clinical course.

Stages and Clinical Course Early in the development of a disease, the etiologic agent or agents may provoke a number of changes in biological processes that can be detected by laboratory analysis, although no recognition of these changes by the patient has occurred. The interval between exposure of a tissue to an injurious agent and the first appearance of signs and symptoms may be called a latent period or, in the case of infectious diseases, an incubation period. The prodromal period, or prodrome, refers to the appearance of the first signs and symptoms indicating the onset of a disease. Prodromal symptoms often are nonspecific, such as headache, malaise, anorexia, and nausea. During the stage of manifest illness, or the acute phase, the disease reaches its full intensity, and signs and symptoms attain their greatest severity. Sometimes during the course of a disease, the signs and symptoms may become mild or even disappear for a time. This interval may be called a silent period or latent period. For example, in the total-body irradiation syndrome, a latent period may occur between the prodrome and the stage of manifest illness. Another example is syphilis, which may have two latent periods: one occurring between the primary and secondary clinical stages and another occurring between the secondary and tertiary stages.

A number of diseases have a subclinical stage, during which the patient functions normally, although the disease processes are well established. It is important to understand that the structure and function of many organs provide a large reserve or safety margin, so that functional impairment may become evident only when organ damage has become advanced. For example, chronic renal disease can completely destroy one kidney and partly destroy the other before any symptoms related to a decrease in renal function are perceived.

The clinical course of a disease is often classified as acute or chronic. An acute condition has relatively severe manifestations but runs a short course measured in hours, days, or a few weeks. A chronic condition lasts for months to years. Sometimes chronic disease processes begin with an acute phase and become prolonged when the body’s defenses are insufficient to overcome the causative agent or stressor. In other cases, chronic conditions develop insidiously and never have an acute phase.

Some diseases (e.g., some types of autoimmune diseases) follow a course of alternating exacerbations and remissions. An exacerbation is a relatively sudden increase in the severity of a disease or any of its signs and symptoms. A remission is an abatement or decline in severity of the signs and symptoms of a disease. If a remission is permanent (sometimes defined as longer than 5 years), the person is said to be cured.

Convalescence is the stage of recovery after a disease, injury, or surgical operation. Occasionally a disease produces a subsequent pathologic condition called a sequela (plural: sequelae). For example, the sequela of an inflammatory process might be scarring. The sequelae of acute rheumatic inflammation of the heart might be scarring and deformation of cardiac valves. In contrast, a complication of a disease is a new or separate process that may arise secondarily because of some change produced by the original problem. For example, bacterial pneumonia may be a complication of viral infection of the respiratory tract.

Treatment Implications An understanding of the etiology, pathogenesis, and clinical consequences of a particular disorder may suggest, or “imply,” that certain treatments could be helpful. For example, understanding that a person with septic shock has excessive dilation of blood vessels that contributes to

pathogenesis is being increasingly understood on the cellular level. One of the best examples of this communication network is the immune system and its interactions with essentially every other cell in the body. A disruption in the delicate system of checks and balances between immune tolerance of normal cells and immune surveillance for abnormal cells and foreign antigens is at the root of a large number of degenerative and inflammatory diseases.

Pathologic disruptions in cellular behavior lead, in turn, to changes in organ and system function that may be detected by clinical or labora- tory examination. Most pathophysiology texts take a systems approach to presenting information. This approach builds on the way in which students learn anatomy and physiology and has its roots in medical specialization. Usually the clinical examination of a patient is also conceptualized by a systems approach. Although the division into systems is useful for dividing the content into conceptual pieces, it is important to remember that the organism functions as an integrated whole and the intercellular communication networks are not confined within single systems. In summary, pathogenesis is a description of how etiologic factors are thought to alter physiologic function and lead to the develop- ment of clinical manifestations that are observed in a particular disorder or disease.

Clinical Manifestations Manifestations of disease that are observed are termed signs of disease. Such objective data may be gathered by clinical examination or by biochemical analysis, diagnostic imaging, and other laboratory tests. The subjective feelings of an abnormality in the body are termed symptoms. By definition, symptoms are subjective and can only be reported by the affected individual to an observer. For example, the feeling of nausea is a symptom, whereas vomiting is objectively observed and is a sign. Some signs and symptoms, such as fever and headache, are nonspecific and, although they designate that something is amiss, they do not indicate a specific cause. In this case further examination and, often, laboratory tests are needed to focus on the possible causes of the signs and symptoms. Many diseases and disorders are characterized by a particular constellation of signs and symptoms, the knowledge of which is essential for accurate detection and diagnosis. When the etiology of a particular set of signs and symptoms has not yet been determined, the disorder may be termed a syndrome. For example, AIDS was originally detected as a set of signs and symptoms related to a deficiency of helper T cells of unknown cause, now known to be a late stage of HIV infection.

The clinical manifestations of some diseases may change significantly over time, resulting in a completely different clinical presentation at

Congenital (inborn) diseases or birth defects Degenerative diseases Iatrogenic diseases Idiopathic diseases Immunologic diseases Infectious diseases Inherited diseases Metabolic diseases Neoplastic diseases Nutritional deficiency diseases Physical agent–induced diseases Psychogenic diseases

BOX 1.1 Etiologic Classification of Diseases

4 UNIT I Pathophysiologic Processes

CONCEPTS OF NORMALITY IN HEALTH AND DISEASE The ability to measure numerous structural, physiologic, biochemical, and genetic parameters in an individual allows the evaluation of information that is helpful in the diagnosis and monitoring of clinical diseases. Many of these same measures are commonly used to screen for disease or to evaluate the risks of a disease occurring in the future. To determine whether a certain finding is indicative of disease or “abnormal,” it must be compared with what is “normal.” The obviousness of this statement belies the difficulty in determining what is normal and the degree of deviation from normal that would be considered abnormal. Many clinical parameters are evaluated by direct observation by the examiner. Skin color and warmth, quality of pulses, briskness of pupil reactions to light, mental acuity, muscle strength, joint mobility, heart sounds, lung sounds, bowel sounds, balance, psychological affect, and level of consciousness are but a few examples of assessments that are subjectively interpreted based on the examiner’s observations. Deciding whether a clinical finding is normal, a normal variation, or an abnormality indicative of a disorder is essential. Reliability of data obtained from observation is dependent on the examiner’s skill and experience. Often the clinical examination is not sufficient to determine definitively the underlying pathophysiologic processes, and diagnostic testing is undertaken to provide more information.

Statistical Normality Some of the variables that are measured to diagnose disease are relatively easy to declare as normal or abnormal because they occur in only two states; for example, a bone is either broken or not broken on x-ray examination. However, most diagnostic variables occur in the population according to a “bell curve,” or normal distribution. This means that a large enough sample taken from the population should give a good estimate of the range of values in the population. Statistics are often used to determine the standard deviation of the variable in question, and then a normal range is suggested as the mean ±2 standard deviations. This means that 95% of the values in the population are expected to fall in the normal range and 5% will be either higher or lower (Fig. 1.2). The “population” chosen to serve as the normal reference population

hypotension implies that fluid administration would likely be helpful. In contrast, most patients with cardiogenic shock have fluid overload, and hypotension in this case is unlikely to improve with fluid administra- tion. Care must be taken not to rely on theoretical implications when evidence-based treatment recommendations are available. When subjected to evaluation by rigorous randomized clinical trials, many treatments that seem as though they should help based on pathophysiology fail to pass the test of application.

The treatment implications discussed in pathophysiology texts usually are general statements rather than specific prescriptions. For example, the pathophysiology of heart failure is characterized by fluid overload, which implies that diuretic therapy would be useful; however, the exact selection of a drug and the dosing schedule would depend on a number of factors particular to the individual patient. Specific treatment recom- mendations are beyond the scope of a pathophysiology text and can be found in pharmacology and clinical practice textbooks.

KEY POINTS • Pathophysiology includes four interrelated topics: etiology, pathogenesis,

clinical manifestations, and treatment implications. • Etiology refers to study of the proposed cause or causes of a particular

disease process. Etiology is a complex notion because most diseases are multifactorial, resulting from interplay between genetic constitution and environmental influences.

• Pathogenesis refers to the proposed mechanisms whereby an etiologic stimulus leads to typically observed clinical manifestations. Pathogenesis describes the direct effects of the initiating event, as well as the usual physiologic responses and compensatory mechanisms.

• Clinical manifestations describe the signs and symptoms that typically accompany a particular pathophysiologic process. Manifestations may vary depending on the stage of the disorder, individual variation, and acuity or chronicity.

• An understanding of the etiology, pathogenesis, and clinical consequences of a particular disorder implies that certain treatments may be helpful.

Normal mean

Mean in those with disease

95% of values Variable values

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FIG 1.2 Representative example of a normal bell curve for a physiologic variable. Many physiologic variables are normally distributed within the population, so the mean ±2 standard deviations include 95% of the normal values in the sample. Approximately 2.5% of values will be above the normal range and 2.5% will be below it. There may be overlap between the values in a normal sample and those in the population with a disease, making interpretation difficult in some cases.

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