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This pocket companion offers rapid, portable access to the most important pathology facts and concepts fromRobbins and Cotran Pathologic Basis of Disease, 9th Edition. It distills the key concepts and principles of pathology into a condensed, at-a-glance format, making it the perfect pocket-sized reference for quick review anytime!
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Companion to
Robbins and
Pathologic Basis
of Disease

Richard N. Mitchell, MD, PhD
Lawrence J. Henderson Professor of Pathology and Health Sciences and
Technology, Department of Pathology, Harvard Medical School, Staff
Pathologist, Brigham and Women’s Hospital, Boston, Massachusetts


Vinay Kumar, MBBS, MD,
Donald N. Pritzker Professor and Chairman, Department of Pathology,
Biologic Sciences Division and the Pritzker School of Medicine, The
University of Chicago, Chicago, Illinois

Abul K. Abbas, MBBS
Distinguished Professor and Chair, Department of Pathology, University
of California San Francisco, San Francisco, California

Jon C. Aster, MD, PhD
Professor of Pathology, Harvard Medical School, Brigham and Women’s
Hospital, Boston, Massachusetts
With illustrations by James A. Perkins, MS, MFA


Table of Contents
Cover image
Title page

General Pathology
1. The Cell as a Unit of Health and Disease
The Genome (p. 1)
Cellular Housekeeping (p. 6)
Cellular Metabolism and Mitochondrial Function (p. 14)
Cellular Activation (p. 15)
Signal Transduction Pathways (p. 16)
Growth Factors and Receptors (p. 18)


Interaction With the Extracellular Matrix (p. 20)
Maintaining Cell Populations (p. 25)

2. Cellular Responses to Stress and Toxic Insults: Adaptation,
Injury, and Death
Introduction (p. 31)
Overview (p. 32)
Causes of Cell Injury (p. 39)
Morphologic Alterations in Cell Injury (p. 40)
Mechanisms of Cell Injury (p. 44)
Examples of Cell Injury and Necrosis (p. 50)
Apoptosis (p. 52)
Intracellular Accumulations (p. 61)
Pathologic Calcification (p. 65)
Cellular Aging (p. 66)

3. Inflammation and Repair
Overview of Inflammation (p. 69)
Acute Inflammation (p. 73)
Mediators of Inflammation (p. 82)
Morphologic Patterns of Acute Inflammation (p. 90)
Outcomes of Acute Inflammation (p. 92)
Summary of Acute Inflammation (p. 93)
Chronic Inflammation (p. 93)
Systemic Effects of Inflammation (p. 99)


Tissue Repair (p. 100)

4. Hemodynamic Disorders, T; hromboembolic Disease, and Shock
Edema and Effusions (p. 113)
Hyperemia and Congestion (p. 115)
Hemostasis, Hemorrhagic Disorders, and Thrombosis (p. 116)
Embolism (p. 127)
Infarction (p. 129)
Shock (p. 131)

5. Genetic Disorders
Genes and Human Diseases (p. 137)
Mendelian Disorders (p. 140)
Complex Multigenic Disorders (p. 158)
Chromosomal Disorders (p. 158)
Single-Gene Disorders With Nonclassic Inheritance (p. 168)
Molecular Genetic Diagnosis (p. 174)

6. Diseases of the Immune System
Hypersensitivity: Immunologically Mediated Tissue Injury (p. 200)
Rejection of Transplant Tissues (p. 231)
Immunodeficiency Syndromes (p. 237)
Amyloidosis (p. 256)

7. Neoplasia


Nomenclature (p. 266)
Characteristics of Benign and Malignant Neoplasms (p. 267)
Epidemiology (p. 275)
Molecular Basis of Cancer: Role of Genetic and Epigenetic Alterations
(p. 280)
Molecular Basis of Multistep Carcinogenesis (p. 320)
Carcinogenic Agents and Their Cellular Interactions (p. 321)
Clinical Aspects of Neoplasia (p. 329)

8. Infectious Diseases
General Principles of Microbial Pathogenesis (p. 341)
Viral Infections (p. 354; Table 8-4)
Bacterial Infections (p. 362; Table 8-5)
Fungal Infections (p. 385)
Parasitic Infections (p. 390; Table 8-6)

9. Environmental and Nutritional Diseases
Environmental Effects on Global Disease Burden (p. 404)
Health Effects of Climate Change (p. 405)
Toxicity of Chemical and Physical Agents (p. 406)
Environmental Pollution (p. 407)
Occupational Health Risks: Industrial and Agricultural Exposures (p.
Effects of Tobacco (p. 414)
Effects of Alcohol (p. 417)
Injury by Therapeutic Drugs and Drugs of Abuse (p. 419)


Injury by Physical Agents (p. 426)
Nutritional Diseases (p. 432)

10. Diseases of Infancy and Childhood
Congenital Anomalies (p. 452)
Prematurity and Fetal Growth Restriction (p. 456)
Perinatal Infections (p. 459)
Fetal Hydrops (p. 461)
Inborn Errors of Metabolism and Other Genetic Disorders (p. 464)
Sudden Infant Death Syndrome (p. 471)
Tumors and Tumorlike Lesions of Infancy and Childhood (p. 473)

Systemic Pathology: Diseases of Organ Systems
11. Blood Vessels
Vascular Structure and Function (p. 483)
Vascular Anomalies (p. 485)
Vascular Wall Response to Injury (p. 485)
Hypertensive Vascular Disease (p. 487)
Arteriosclerosis (p. 491)
Atherosclerosis (p. 491)
Aneurysms and Dissection (p. 501)
Vasculitis (p. 505)
Disorders of Blood Vessel Hyper-Reactivity (p. 513)
Veins and Lymphatics (p. 514)


Vascular Tumors (p. 515)
Pathology of Vascular Intervention (p. 520)

12. The Heart
Cardiac Structure and Specializations (p. 523)
Effects of Aging on the Heart (p. 525)
Overview of Cardiac Pathophysiology (p. 526)
Heart Failure (p. 526)
Congenital Heart Disease (p. 531)
Ischemic Heart Disease (p. 538)
Arrhythmias (p. 550)
Hypertensive Heart Disease (p. 552)
Valvular Heart Disease (p. 554)
Cardiomyopathies (p. 564)
Pericardial Disease (p. 573)
Heart Disease Associated With Rheumatologic Disorders (p. 575)
Tumors of the Heart (p. 575)
Cardiac Transplantation (p. 577)

13. Diseases of White Blood Cells, Lymph Nodes, Spleen, and
Development and Maintenance of Hematopoietic Tissues (p. 579)
Disorders of White Cells (p. 582)
Leukopenia (p. 582)
Reactive Proliferations of White Cells and Lymph Nodes (p. 583)


Neoplastic Proliferations of White Cells (p. 586)
Spleen (p. 623)
Thymus (p. 625)

14. Red Blood Cell and Bleeding Disorders
Anemias (p. 629)
Polycythemia (p. 656)
Bleeding Disorders: Hemorrhagic Diatheses (p. 656)

15. The Lung
Congenital Anomalies (p. 670)
Atelectasis (Collapse) (p. 670)
Pulmonary Edema (p. 671)
Acute Lung Injury and Acute Respiratory Distress Syndrome (Diffuse
Alveolar Damage) (p. 672)
Obstructive and Restrictive Lung Diseases (p. 674)
Obstructive Lung Diseases (p. 674)
Chronic Diffuse Interstitial (Restrictive) Diseases (p. 684)
Diseases of Vascular Origin (p. 697)
Pulmonary Infections (p. 702)
Lung Transplantation (p. 711)
Tumors (p. 712)
Pleura (p. 721)

16. Head and Neck
Oral Cavity (p. 727)


Inflammatory and Reactive Lesions (p. 728)
Infections (p. 729)
Oral Manifestations of Systemic Disease (p. 730)
Precancerous and Cancerous Lesions (p. 731)
Upper Airways (p. 735)
Nose (p. 735)
Nasopharynx (p. 736)
Tumors of the Nose, Sinuses, and Nasopharynx (p. 737)
Larynx (p. 738)
Ears (p. 740)
Inflammatory Lesions (p. 740)
Otosclerosis (p. 740)
Neck (p. 741)
Thyroglossal Duct Cyst (p. 741)
Paraganglioma (Carotid Body Tumor) (p. 741)
Salivary Glands (p. 742)
Inflammation (Sialadenitis) (p. 743)
Neoplasms (p. 743)

17. The Gastrointestinal Tract
Congenital Abnormalities (p. 750)
Diaphragmatic Hernia, Omphalocele, and Gastroschisis (p. 750)
Ectopia (p. 750)
Meckel Diverticulum (p. 751)


Pyloric Stenosis (p. 751)
Hirschsprung Disease (p. 751)
Esophagus (p. 753)
Achalasia (p. 753)
Esophagitis (p. 754)
Barrett Esophagus (p. 757)
Esophageal Tumors (p. 758)
Stomach (p. 760)
Chronic Gastritis (p. 763)
Complications of Chronic Gastritis (p. 766)
Hypertrophic Gastropathies (p. 768)
Gastric Polyps and Tumors (p. 769)
Small Intestine and Colon (p. 777)
Intestinal Obstruction (p. 777)
Ischemic Bowel Disease (p. 779)
Aangiodysplasia (p. 780)
Malabsorption and Diarrhea (p. 781)
Infectious Enterocolitis (p. 785)
Irritable Bowel Syndrome (p. 796)
Inflammatory Bowel Disease (p. 796)
Other Causes of Chronic Colitis (p. 802)
Graft-Versus-Host Disease (p. 802)
Sigmoid Diverticular Disease (p. 803)
Polyps (p. 804)


Adenocarcinoma (p. 810)
Hemorrhoids (p. 815)
Acute Appendicitis (p. 816)
Tumors of the Appendix (p. 816)
Peritoneal Cavity (p. 817)
Tumors (p. 817)

18. Liver and Gallbladder
The Liver and Bile Ducts (p. 821)
Infectious Disorders (p. 830)
Autoimmune Hepatitis (p. 839)
Drug- and Toxin-Induced Liver Injury (p. 840)
Metabolic Liver Disease (p. 845)
Autoimmune Cholangiopathies (p. 858)
Circulatory Disorders (p. 862)
Hepatic Complications of Organ or Hematopoietic Stem Cell
Transplantation (p. 865)
Hepatic Disease Associated With Pregnancy (p. 865)
Nodules and Tumors (p. 867)
Gallbladder (p. 875)

19. The Pancreas
Congenital Anomalies (p. 883)
Pancreatitis (p. 884)
Non-Neoplastic Cysts (p. 889)


Neoplasms (p. 890)

20. The Kidney
Clinical Manifestations of Renal Diseases (p. 898)
Glomerular Diseases (p. 899)
Tubular and Interstitial Diseases (p. 927)
Vascular Diseases (p. 938)
Congenital and Developmental Anomalies (p. 944)
Cystic Diseases of the Kidney (p. 945)
Urinary Tract Obstruction (Obstructive Uropathy) (p. 950)
Urolithiasis (Renal Calculi, Stones) (p. 951)
Neoplasms of the Kidney (p. 952)

21. The Lower Urinary Tract and Male Genital System
The Lower Urinary Tract (p. 959)
Urinary Bladder (p. 961)
Urethra (p. 969)
The Male Genital Tract (p. 970)
Testis and Epididymis (p. 972)
Prostate (p. 980)

22. The Female Genital Tract
Infections (p. 992)
Vulva (p. 995)
Vagina (p. 1000)


Cervix (p. 1001)
Body of Uterus and Endometrium (p. 1007)
Fallopian Tubes (p. 1021)
Ovaries (p. 1022)
Gestational and Placental Disorders (p. 1034)

23. The Breast
Disorders of Development (p. 1044)
Clinical Presentation of Breast Disease (p. 1045)
Inflammatory Disorders (p. 1046)
Benign Epithelial Lesions (p. 1048)
Carcinoma of the Breast (p. 1051)
Types of Breast Carcinoma (p. 1057)

24. The Endocrine System
Pituitary Gland (p. 1074)
Thyroid Gland (p. 1082)
Parathyroid Glands (p. 1100)
The Endocrine Pancreas (p. 1105)
Adrenal Glands (p. 1122)
Pineal Gland (p. 1137)

25. The Skin
The Skin: More Than a Mechanical Barrier (p. 1141)
Disorders of Pigmentation and Melanocytes (p. 1143)


Benign Epithelial Tumors (p. 1151)
Premalignant and Malignant Epidermal Tumors (p. 1154)
Tumors of the Dermis (p. 1158)
Tumors of Cellular Migrants to the Skin (p. 1159)
Disorders of Epidermal Maturation (p. 1161)
Acute Inflammatory Dermatoses (p. 1162)
Chronic Inflammatory Dermatoses (p. 1165)
Blistering (Bullous) Diseases (p. 1167)
Disorders of Epidermal Appendages (p. 1172)
Panniculitis (p. 1174)
Infection (p. 1175)

26. Bones, Joints, and Soft Tissue Tumors
Bones (p. 1180)
Cells (p. 1180)
Development (p. 1181)
Homeostasis and Remodeling (p. 1182)
Developmental Disorders of Bone and Cartilage (p. 1183)
Acquired Disorders of Bone and Cartilage (p. 1187)
Fractures (p. 1193)
Osteonecrosis (Avascular Necrosis) (p. 1194)
Osteomyelitis (p. 1195)
Bone Tumors and Tumorlike Lesions (p. 1196)
Joints (p. 1207)


Osteoarthritis (p. 1208)
Rheumatoid Arthritis (p. 1209)
Juvenile Idiopathic Arthritis (p. 1212)
Seronegative Spondyloarthropathies (p. 1212)
Infectious Arthritis (p. 1213)
Crystal-Induced Arthritis (p. 1214)
Joint Tumors and Tumorlike Lesions (p. 1218)
Soft Tissue Tumors (p. 1219)
Pathogenesis (p. 1219)
Classification (p. 1219)
Tumors of Adipose Tissue (p. 1220)
Fibrous Tumors (p. 1221)
Skeletal Muscle Tumors (p. 1222)
Smooth Muscle Tumors (p. 1223)
Tumors of Uncertain Origin (p. 1223)

27. Peripheral Nerves and Skeletal Muscles
Diseases of Peripheral Nerves (p. 1227)
Specific Peripheral Neuropathies (p. 1230)
Diseases of the Neuromuscular Junction (p. 1235)
Diseases of Skeletal Muscle (p. 1237)
Peripheral Nerve Sheath Tumors (p. 1246)

28. The Central Nervous System
Cellular Pathology of the Central Nervous System (p. 1252)


Cerebral Edema, Hydrocephalus, and Raised Intracranial Pressure
and Herniation (p. 1254)
Malformations and Developmental Disorders (p. 1256)
Perinatal Brain Injury (p. 1258)
Trauma (p. 1259)
Cerebrovascular Diseases (p. 1263)
Infections (p. 1271)
Prion Diseases (p. 1281)
Demyelinating Diseases (p. 1283)
Neurodegenerative Diseases (p. 1286)
Genetic Metabolic Diseases (p. 1302)
Toxic and Acquired Metabolic Diseases (p. 1304)
Tumors (p. 1306)

29. The Eye
Orbit (p. 1320)
Eyelid (p. 1322)
Conjunctiva (p. 1322)
Sclera (p. 1324)
Cornea (p. 1324)
Anterior Segment (p. 1327)
Uvea (p. 1330)
Retina and Vitreous (p. 1332)
Optic Nerve (p. 1340)
The End-Stage Eye: Phthisis Bulbi (p. 1342)




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Knowledge and best practice in this field are constantly changing.
As new research and experience broaden our understanding,
changes in research methods, professional practices, or medical
treatment may become necessary.
Practitioners and researchers must always rely on their own
experience and knowledge in evaluating and using any
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To the fullest extent of the law, neither the Publisher nor the
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contained in the material herein.
Previous editions copyrighted 2012, 2006, 1999, 1995, and 1991.
Library of Congress Cataloging-in-Publication Data
Names: Mitchell, Richard N., author. | Kumar, Vinay, 1944-, author.
| Abbas,
Abul K., author. | Aster, Jon C., author.
Title: Pocket companion to Robbins and Cotran pathologic basis of
disease /
Richard N. Mitchell, Vinay Kumar, Abul K. Abbas, Jon C. Aster ;


illustrations by James A. Perkins
Description: Ninth edition. | Philadelphia, PA : Elsevier, [2017] |
index. | Complemented by: Robbins and Cotran pathologic basis of
disease /
[edited by] Vinay Kumar, Abul K. Abbas, Jon C. Aster. Ninth
Identifiers: LCCN 2016008207| ISBN 9781455754168 (pbk. : alk.
paper) | ISBN
Subjects: | MESH: Pathology | Handbooks
Classification: LCC RB111 | NLM QZ 39 | DDC 616.07--dc23
LC record available at
Content Strategist: William R. Schmitt
Content Development Specialist: Rebecca Gruliow
Publishing Services Manager: Catherine Jackson
Senior Project Manager: Daniel Fitzgerald
Designer: Ryan Cook
Printed in the United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1


Charles E. Alpers, MD
Professor and Vice-Chair, Department of Pathology, University of
Washington School of Medicine
Pathologist, University of Washington Medical Center, Seattle,
The Kidney
Douglas C. Anthony, MD, PhD
Professor, Pathology and Laboratory Medicine, Warren Alpert
Medical School of Brown University
Chief of Pathology, Lifespan Academic Medical Center, Providence,
Rhode Island
Peripheral Nerves and Skeletal Muscles; The Central Nervous System
Anthony Chang, MD, Associate Professor of Pathology, Director
of Renal Pathology, Department of Pathology, The University of
Chicago, Chicago, Illinois
The Kidney
Umberto De Girolami, MD
Professor of Pathology, Harvard Medical School
Neuropathologist, Brigham and Women’s Hospital, Boston,
The Central Nervous System
Lora Hedrick Ellenson, MD
Professor and Director of Gynecologic Pathology, Department of
Pathology and Laboratory Medicine, New York Presbyterian


Hospital-Weill Cornell Medical College
Attending Pathologist, New York Presbyterian Hospital, New York,
New York
The Female Genital Tract
Jonathan I. Epstein, MD
Professor of Pathology, Urology, and Oncology, The Reinhard
Professor of Urologic Pathology, The Johns Hopkins University
School of Medicine
Director of Surgical Pathology, The Johns Hopkins Hospital,
Baltimore, Maryland
The Lower Urinary Tract and Male Genital System
Robert Folberg, MD
Founding Dean and Professor of Biomedical Sciences, Pathology,
and Ophthalmology, Oakland University William Beaumont School
of Medicine, Rochester, Michigan
Chief Academic Officer, Beaumont Hospitals, Royal Oak, Michigan
The Eye
Matthew P. Frosch, MD, PhD
Lawrence J. Henderson Associate Professor of Pathology and
Health Sciences and Technology, Harvard Medical School
Director, C.S. Kubik Laboratory of Neuropathology, Massachusetts
General Hospital, Boston, Massachusetts
The Central Nervous System
Andrew Horvai, MD, PhD, Professor, Department of Pathology,
Associate Director of Surgical Pathology, University of California
San Francisco, San Francisco, California
Bones, Joints, and Soft Tissue Tumors
Ralph H. Hruban, MD, Professor of Pathology and Oncology,
Director of the Sol Goldman Pancreatic Cancer Research Center,
The Johns Hopkins University School of Medicine, Baltimore,
The Pancreas
Aliya N. Husain, MBBS,

Professor, Department of Pathology,


Director of Pulmonary, Pediatric and Cardiac Pathology, Pritzker
School of Medicine, The University of Chicago, Chicago, Illinois
The Lung
Christine A. Iacobuzio-Donahue, MD, PhD
Attending Physician, Department of Pathology
Associate Director for Translational Research, Center for Pancreatic
Cancer Research, Memorial Sloan Kettering Cancer Center, New
York, New York
The Pancreas
Raminder Kumar, MBBS, MD, Chicago, Illinois
Clinical Editor for Diseases of the Heart, Lung, Gastrointestinal Tract,
Liver, and Kidneys
Alexander J.F. Lazar, MD, PhD, Associate Professor,
Departments of Pathology and Dermatology, Sarcoma Research
Center, University of Texas M.D. Anderson Cancer Center,
Houston, Texas
The Skin
Susan C. Lester, MD, PhD
Assistant Professor of Pathology, Harvard Medical School
Chief, Breast Pathology, Brigham and Women’s Hospital, Boston,
The Breast
Mark W. Lingen, DDS, PhD, PRCPath, Professor, Department of
Pathology, Director of Oral Pathology, Pritzker School of Medicine,
The University of Chicago, Chicago, Illinois
Head and Neck
Tamara L. Lotan, MD, Associate Professor of Pathology and
Oncology, The Johns Hopkins Hospital, Baltimore, Maryland
The Lower Urinary Tract and Male Genital System
Anirban Maitra, MBBS, Professor of Pathology and
Translational Molecular Pathology, University of Texas M.D.
Anderson Cancer Center, Houston, Texas


Diseases of Infancy and Childhood; The Endocrine System
Alexander J. McAdam, MD, PhD
Vice Chair, Department of Laboratory Medicine, Medical Director,
Infectious Diseases Diagnostic Laboratory, Boston Children’s
Associate Professor of Pathology, Harvard Medical School, Boston,
Infectious Diseases
Danny A. Milner, MD, MSc, FCAP, Assistant Professor of
Pathology, Assistant Medical Director, Microbiology, Harvard
Medical School, Boston, Massachusetts
Infectious Diseases
Richard N. Mitchell, MD, PhD
Lawrence J. Henderson Professor of Pathology and Health Sciences
and Technology, Department of Pathology, Harvard Medical
Staff Pathologist, Brigham and Women’s Hospital, Boston,
The Cell as a Unit of Health and Disease; Blood Vessels; The Heart
George F. Murphy, MD
Professor of Pathology, Harvard Medical School
Director of Dermatopathology, Brigham and Women’s Hospital,
Boston, Massachusetts
The Skin
Edyta C. Pirog, MD
Associate Professor of Clinical Pathology and Laboratory Medicine,
New York Presbyterian Hospital-Weill Medical College of Cornell
Associate Attending Pathologist, New York Presbyterian Hospital,
New York, New York
The Female Genital Tract
Peter Pytel, MD, Associate Professor, Director of
Neuropathology, Department of Pathology, University of Chicago


School of Medicine, Chicago, Illinois
Peripheral Nerves and Skeletal Muscles
Frederick J. Schoen, MD, PhD
Professor of Pathology and Health Sciences and Technology,
Harvard Medical School
Director, Cardiac Pathology, Executive Vice Chairman, Department
of Pathology, Brigham and Women’s Hospital, Boston,
The Heart
Arlene H. Sharpe, MD, PhD
Professor of Pathology, Co-Director of Harvard Institute of
Translational Immunology, Harvard Medical School
Department of Pathology, Brigham and Women’s Hospital, Boston,
Infectious Diseases
Neil Theise, MD, Departments of Pathology and Medicine,
Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai,
New York, New York
Liver and Gallbladder
Jerrold R. Turner, MD, PhD, Sara and Harold Lincoln Thompson
Professor, Associate Chair, Department of Pathology, Pritzker
School of Medicine, The University of Chicago, Chicago, Illinois
The Gastrointestinal Tract


The dramatic revolution in molecular biology, coupled with the
computational ability to make sense of terabytes of data, is
changing the face of medicine. With each passing year (indeed with
almost every passing hour) there is an explosion of new information
that requires digestion, comprehension, and assimilation—all of it
potentially impacting disease diagnosis and therapy. Integrating
and making sense of all the new knowledge is a challenging
proposition—even for seasoned physicians and scientists who
already enjoy a reasonable (and semi-organized) understanding of
pathobiology. However, for the novice student—experiencing the
amazing depth and breadth of human disease for the first (or
second or third) time—the thirst for knowledge can easily get
drowned by a fire hose of information. Robbins and Cotran Pathologic
Basis of Disease (AKA: the Big Book) has long been the fundamental
pathology text for students of medicine, organizing the occasionally
bewildering flood of facts and concepts into a comprehensive yet
manageable, beautifully illustrated, and eminently readable entrée
into the universe of pathobiology. And yet, at more than 1300 pages
(and weighing in at 7 pounds in its dead tree form), the Big Book is
still a daunting tome.
Enter the Pocket Companion. Initially an offspring of the fourth
edition of the Big Book in 1991, the Pocket Companion was born of
the recognition that the immense wealth of knowledge about
human disease could somehow be succinctly organized and made
even more accessible for the overwhelmed medical student and
harried house officer. In addition, students and educators alike are
increasingly reluctant to make a substantial financial commitment


to an opus that is constantly being rewritten, keeping up with the
ever-changing landscape of modern medicine. Thus the Pocket
Companion meets several important needs, being practical and
frugal, yet also immensely (and densely) useful—substantially
more than a simple topical outline or the “Key Concepts” boxes that
are now a prominent feature of the Big Book. In assembling this
update, four major objectives have guided the writing:
• Make the detailed expositions in Robbins and Cotran Pathologic
Basis of Disease easier to digest by providing a condensed
overview and also retaining the most helpful figures and tables.
• Facilitate the use of the Big Book by providing the relevant crossreferenced page numbers.
• Help readers identify the core material that requires their primary
• Serve as a handy tool for quick review of a large body of
In the age of Wikipedia and other online data compendiums, it is
obviously not difficult to just find information; to be sure, the
Pocket Companion is also available in a readily searchable digital
format. However, what the twenty-first century student of
pathology needs is an organized, pithy, and easy-to-digest synopsis
of the pertinent concepts and facts with specific links to the
definitive material in a more expansive volume.
This ninth edition of the Pocket Companion hopefully
accomplishes that end. It has been rewritten from front to back,
reflecting all the innovations and new knowledge encompassed in
the Big Book. Illustrative tables and figures also reduce the
verbiage, although as before, the beautiful gross and histologic
images of the parent volume are not reproduced. Pains have also
been taken to present all the material with the same stylistic voice;
the organization of the material and level of detail is considerably
more uniform between chapters than in previous editions. In doing
so we hope that the Pocket Companion retains the flavor and
excitement of the Big Book—just in a more bite-size format—and
truly is a suitable “companion.”
In closing, the authors specifically wish to acknowledge the
invaluable assistance and editing skills (and infinite patience) of


Rebecca Mitchell and Becca Gruliow; without their help and
collaboration, this edition of the Pocket Companion might still be in
Rick Mitchell
Vinay Kumar
Abul Abbas
Jon Aster


General Pathology
1. The Cell as a Unit of Health and Disease
2. Cellular Responses to Stress and Toxic Insults: Adaptation,
Injury, and Death
3. Inflammation and Repair
4. Hemodynamic Disorders, Thromboembolic Disease, and
5. Genetic Disorders
6. Diseases of the Immune System
7. Neoplasia
8. Infectious Diseases
9. Environmental and Nutritional Diseases
10. Diseases of Infancy and Childhood



The Cell as a Unit of
Health and Disease
Disease pathogenesis is best understood in the context of normal
cellular structure and function and how that can be deranged; this
chapter is a survey of basic principles and recent advances in cell
biology as they apply to the rest of the book.

The Genome (p. 1)
Noncoding DNA (p. 1)
The human genome encodes approximately 20,000 proteins, but the
sequences involved in coding such genes comprise only 1.5% of the
total 3.2 billion DNA base pairs. Up to 80% of the remaining DNA
is functional in that it can bind proteins or otherwise regulate gene
expression. Major classes of functional nonprotein coding
sequences include the following (Fig. 1-1):
• Promoter and enhancer regions providing binding sites for
transcription factors.
• Binding sites for factors that maintain higher-order chromatin
• Noncoding regulatory RNAs. More than 60% of the genome is
transcribed into RNAs that are never translated into protein but
that still regulate gene expression (e.g., microRNAs [miRNAs]
and long noncoding RNAs) (see later discussion).
• Mobile genetic elements (e.g., transposons). One third of the genome
is composed of such “jumping genes” that are implicated in gene


regulation and chromatin organization.
• Special structural regions of DNA (e.g., telomeres [chromosome
ends] and centromeres [chromosome “tethers”]).
Any two individuals share greater than 99.5% of their DNA
sequences; thus person-to-person variation, including disease
susceptibility and responses to environmental stimuli, is encoded in
less than 0.5% of total cellular DNA (15 million base pairs). The two
most common forms of DNA variation are as follows:
• Single-nucleotide polymorphisms (SNPs): These are variants at single
nucleotide positions identified through genome sequencing; they
number approximately 6 million. SNPs occur across the genome
—within exons, introns, and intergenic regions. Only 1% of these
occur in coding regions; SNPs located in noncoding regions may
impact gene expression by influencing regulatory elements. Even
SNPs that are “neutral” (no effect on gene function or expression)
can be useful markers if they are coinherited with a diseaseassociated gene as a result of physical proximity (linkage
disequilibrium). In most cases any given SNP has a relatively
minimal influence on disease; however, combinations of SNPs
may predict risk for complex multigenic disorders (e.g.,

FIGURE 1-1 The organization of nuclear DNA.

At the light microscopic level the nuclear genetic
material is organized into dispersed, transcriptionally
active euchromatin or densely packed, transcriptionally
inactive heterochromatin; chromatin can also be
mechanically connected with the nuclear membrane,
and nuclear membrane perturbation can thus influence


transcription. Chromosomes (as shown) can only be
visualized by light microscopy during cell division.
During mitosis, they are organized into paired
chromatids connected at centromeres; the
centromeres act as the locus for the formation of a
kinetochore protein complex that regulates
chromosome segregation at metaphase. The
telomeres are repetitive nucleotide sequences that cap
the termini of chromatids and permit repeated
chromosomal replication without loss of DNA at the
chromosome ends. The chromatids are organized into
short “P” (“petite”) and long “Q” (“next letter in the
alphabet”) arms. The characteristic banding pattern of
chromatids has been attributed to relative GC content
(less GC content in bands relative to interbands), with
genes tending to localize to interband regions.
Individual chromatin fibers comprise a string of
nucleosomes—DNA wound around octameric histone
cores—with the nucleosomes connected via DNA
linkers. Promoters are noncoding regions of DNA that
initiate gene transcription; they are on the same strand
and upstream of their associated gene. Enhancers are
regulatory elements that can modulate gene
expression over distances of 100 kB or more by
looping back onto promoters and recruiting additional
factors that are needed to drive the expression of premRNA species. The intronic sequences are
subsequently spliced out of the pre-mRNA to produce
the definitive message that is translated into protein—
without the 3′ and 5′ untranslated regions (UTRs). In
addition to the enhancer, promoter, and UTR
sequences, noncoding elements are found throughout
the genome; these include short repeats, regulatory
factor binding regions, noncoding regulatory RNAs,
and transposons.

• Copy number variations (CNVs): These represent different numbers
of repeated sequences of DNA—up to millions of base pairs in
length. Approximately half of CNVs involve gene-coding
sequences; thus CNVs may underlie a large portion of human
phenotypic diversity.
• Epigenetics—heritable changes in gene expression that are not
caused by primary variation in DNA sequence—is also important


in generating genetic diversity (see the following section).

Histone Organization (p. 3)
Although all cells have the same genetic material, terminally
differentiated cells have distinct structures and functions; these are
determined by lineage-specific programs of gene expression driven
by epigenetic factors (Fig. 1-2):
• Histones and histone-modifying factors. Nucleosomes are 147 base pair
segments wrapped around a core of histones; DNA-histone
complexes are joined through DNA linkers and packed together
to form chromatin. Chromatin exists in two basic forms: (1)
cytochemically dense and transcriptionally inactive
heterochromatin and (2) cytochemically dispersed and
transcriptionally active euchromatin (Fig. 1-1). Histones are
dynamic structures:
• Chromatin-remodeling complexes reposition nucleosomes on
DNA, exposing (or obscuring) gene regulatory elements, such
as promoters.
• Chromatin writer complexes make chemical modifications (marks)
on amino acids that include methylation, acetylation, or
phosphorylation. Actively transcribed genes have histone
marks that render DNA accessible to RNA polymerases;
inactive genes have histone marks that enable DNA
compaction into heterochromatin.
• Chromatin erasers remove histone marks; chromatin readers bind
particular marks and thereby regulate gene expression.
• Histone acetylation tends to increase transcription; methylation
and phosphorylation can increase or decrease transcription.
• DNA methylation. High levels of DNA methylation in gene
regulatory elements typically result in transcriptional silencing.
• Chromatin organizing factors are proteins that bind to noncoding
regions and control long-range looping of DNA to regulating the
spatial relationships between gene enhancers and promoters.

MicroRNA and Long Noncoding RNA (p. 4)
miRNA (p. 4) are short RNAs (21 to 30 nucleotides); they do not
encode proteins but rather are involved in posttranscriptional


silencing of gene expression. miRNA transcription produces a
primary miRNA, which is progressively trimmed by the enzyme
DICER, eventually becoming associated with a multiprotein
aggregate called RNA-induced silencing complex (RISC; Fig. 1-3).
Subsequent base pairing between the miRNA strand and its target
mRNA directs the RISC to either induce mRNA cleavage or repress
its translation.
Synthetic small interfering RNAs (siRNAs) are short RNA
sequences that can be introduced into cells, acting in a manner
analogous to endogenous miRNAs. These form the basis for
knockdown experiments to study gene function and are also being
developed as possible therapeutic agents to silence pathogenic

FIGURE 1-2 Histone organization.

A, Nucleosomes are composed of octamers of histone
proteins (two each of histone subunits H2A, H2B, H3,
and H4) encircled by 1.8 loops of 147 base pairs of
DNA; histone H1 sits on the 20- to 80-nucleotide linker
DNA between nucleosomes and helps to stabilize the
overall chromatin architecture. The histone subunits
are positively charged, thus allowing the compaction of
the negatively charged DNA. B, The relative state of
DNA unwinding (and thus access for transcription
factors) is regulated by histone modification (e.g., by
acetylation, methylation, and/or phosphorylation [socalled “marks”]); marks are dynamically written and
erased. Certain marks, such as histone acetylation,
“open up” the chromatin structure, whereas others,
such as methylation of particular histone residues, tend
to condense the DNA and lead to gene silencing. DNA
itself can also be also be methylated, a modification
that is associated with transcriptional inactivation.


FIGURE 1-3 Generation of microRNAs (miRNAs) and their

mode of action in regulating gene function.
miRNA genes are transcribed to produce a primary
miRNA (pri-miRNA), which is processed within the
nucleus to form pre-miRNA composed of a single RNA
strand with secondary hairpin loop structures that form
stretches of double-stranded RNA. After this premiRNA is exported out of the nucleus via specific
transporter proteins, the cytoplasmic Dicer enzyme
trims the pre-miRNA to generate mature doublestranded miRNAs of 21 to 30 nucleotides. The miRNA
subsequently unwinds, and the resulting single strands
are incorporated into the multiprotein RISC. Base
pairing between the single-stranded miRNA and its
target mRNA directs RISC to either cleave the mRNA


target or repress its translation. In either case the
target mRNA gene is silenced posttranscriptionally.

Long noncoding RNA (lncRNA) (p. 5) exceed coding mRNAs by
tenfold to twentyfold and are involved in modulating gene
• lncRNA can restrict RNA polymerase access to specific coding
genes. The best example involves XIST, which is transcribed from
the X chromosome and plays an essential role in physiologic X
chromosome inactivation.
• lncRNA can facilitate transcription factor binding, thus
promoting gene activation.
• lncRNA can facilitate chromatin modification or provide the
scaffolding to stabilize chromatin structure.

Cellular Housekeeping (p. 6)
Cell viability and function depend on fundamental housekeeping
activities (e.g., membrane integrity, nutrient acquisition, communication,
movement, renewal of senescent molecules, molecular catabolism, and
energy generation). Specific activities are often compartmentalized
within membrane-bound intracellular organelles (Fig. 1-4); unique
intracellular environments (e.g., low pH or high calcium) facilitate
specific biochemical pathways and also sequester potentially
injurious enzymes or reactive metabolites.


FIGURE 1-4 Basic subcellular constituents of cells.

The table presents the number of the various
organelles within a typical hepatocyte, as well as their
volume within the cell. The figure shows geographic
relationships but is not intended to be accurate to
scale. (Adapted from Weibel ER, Stäubli W, Gnägi HR, et al: Correlated
morphometric and biochemical studies on the liver cell. I. Morphometric model,
stereologic methods, and normal morphometric data for rat liver. J Cell Biol 42:68,

Plasma Membrane: Protection and Nutrient
Acquisition (p. 7)
Plasma and organellar membranes are fluid bilayers of amphipathic


phospholipids with hydrophilic head groups that face the aqueous
environment and hydrophobic lipid tails that interact to form a
barrier to passive diffusion (Fig. 1-5). Membrane components are
distributed heterogeneously and asymmetrically:
• Phosphatidylinositol on the inner membrane leaflet can be a
phosphorylated scaffold for intracellular proteins, whereas
polyphosphoinositides can be hydrolyzed by phospholipase C to
generate intracellular second signals, such as diacylglycerol and
inositol trisphosphate.
• Phosphatidylserine on the inner face provides a negative charge for
protein interactions; on the extracellular face (in cells undergoing
programmed cell death), it is an “eat me” signal for phagocytes.
• Glycolipids and sphingomyelin are preferentially expressed on the
extracellular face; glycolipids are important in cell-cell and cellmatrix interactions.
• Some membrane components tend to self-associate to form
discrete domains known as “lipid rafts.”
Membrane proteins associate with lipid membranes by one of
several interactions:
• Transmembrane proteins have one or more relatively hydrophobic
α-helical segments that traverse the lipid bilayer.
• Posttranslational attachment to prenyl groups (e.g., farnesyl) or
fatty acids (e.g., palmitic acid) that insert into the plasma
• Posttranslation glycosylphosphatidylinositol (GPI) modification
allow anchorage on the extracellular face of the membrane.
• Peripheral membrane proteins may noncovalently associate with
true transmembrane proteins.
• Many plasma membrane proteins function together as large
complexes; these may be primarily assembled in the rough
endoplasmic reticulum (RER) or form by lateral diffusion in the
plasma membrane; the latter is characteristic of many receptors
that dimerize in the presence of ligand to form functional
signaling units.
Although membranes are laterally fluid, proteins within them
can be confined to discrete domains. Thus inserted proteins have
different intrinsic solubilities in various lipid domains and can
accumulate in different areas (e.g., lipid rafts). Nonrandom protein


distributions can also be achieved through intercellular proteinprotein interactions (e.g., at tight junctions) that establish discrete
boundaries; this strategy is used to maintain cell polarity (e.g.,
top/apical versus bottom/basolateral) in epithelial layers. Unique
membrane domains can also be generated by the interaction of
proteins with cytoskeletal molecules or extracellular matrix (ECM).
The resulting nonrandom distribution of lipids and membrane
proteins is relevant to cell-cell and cell-matrix interactions, as well
as secretory and endocytic pathways.
The extracellular face of the plasma membrane is studded with
carbohydrates on glycoproteins and glycolipids, as well as by
polysaccharide chains attached to integral membrane
proteoglycans. This glycocalyx functions as a chemical and
mechanical barrier and mediates cell-cell and cell-matrix

Passive Membrane Diffusion (p. 9)
Small, nonpolar molecules (O2 and CO2) and hydrophobic
molecules (e.g., steroid-based molecules such as estradiol or
vitamin D) rapidly diffuse across lipid bilayers moving down their
concentration gradients. Small, polar molecules (e.g., water,
ethanol, and urea) can also cross membranes relatively easily,
although large-volume water transport (e.g., renal tubular
epithelium) requires aquaporin proteins.

FIGURE 1-5 Plasma membrane organization and

The plasma membrane is a bilayer of phospholipids,


cholesterol, and associated proteins. The phospholipid
distribution within the membrane is asymmetric due to
the activity of flippases; phosphatidylcholine and
sphingomyelin are overrepresented in the outer leaflet,
and phosphatidylserine (negative charge) and
phosphatidylethanolamine are predominantly found on
the inner leaflet; glycolipids occur only on the outer
face, where they contribute to the extracellular
glycocalyx. Although the membrane is laterally fluid
and the various constituents can diffuse randomly,
specific domains—lipid rafts—can also stably develop.
Membrane-associated proteins may traverse the
membrane (singly or multiply) via α-helical hydrophobic
amino acid sequences; depending on the membrane
lipid content and the hydrophobicity of protein
domains, such proteins may have nonrandom
distributions within the membrane. Proteins on the
cytosolic face may associate with membranes through
posttranslational modifications (e.g., farnesylation or
addition of palmitic acid). Proteins on the
extracytoplasmic face may associate with the
membrane via glycosylphosphatidylinositol linkages. In
addition to protein-protein interactions within the
membrane, membrane proteins can also associate
with extracellular and/or intracytoplasmic proteins to
generate large, relatively stable complexes (e.g., the
focal adhesion complex). Transmembrane proteins can
translate mechanical forces (e.g., from the
cytoskeleton or ECM) as well as chemical signals
across the membrane. Similar organizations of lipids
and associated proteins occur within the various
organellar membranes.

Carriers and Channels (p. 9)
Polar molecules >75 daltons (e.g., sugars and nucleotides) and all
ions require specialized protein transporters to cross cell
membranes (plasma or organellar); each solute typically has a
highly specific transporter (e.g., a given protein will transport
glucose but not galactose) (Fig. 1-6).
• Channel proteins create hydrophilic pores, which, when open,
permit rapid movement of solutes (restricted by size and charge).


Concentration and/or electrical gradients drive the solute
movement; plasma membranes typically have an electrical
potential difference across them, with the inside negative relative
to the outside.
• Carrier proteins bind their specific solute and undergo a
conformational change to transfer the ligand across the
membrane. Active transport of certain solutes against a
concentration gradient can thus be accomplished by carrier
molecules (not channels) using energy released by adenosine
triphosphate (ATP) hydrolysis or a coupled ion gradient.
Because membranes are freely permeable to small polar
molecules, water will move across membranes following the
relative solute concentrations. Thus extracellular salt in excess of
that in the cytosol (hypertonicity) causes a net movement of water
out of cells, whereas hypotonicity causes a net movement of water
into cells. Because the cytosol is rich in charged metabolites and
protein species that attract a large number of counterions that tend
to increase the intracellular osmolarity, cells need to constantly
pump out small inorganic ions (e.g., Na+ and Cl−) to prevent
overhydration. This is accomplished through the activity of the
membrane sodium-potassium ATPase; thus loss of the ability to
generate energy (e.g., in a cell injured by toxins or ischemia) will
result in osmotic swelling and eventual rupture of cells. Similar
transport mechanisms regulate intracellular and intraorganellar pH;
most cytosolic enzymes have pH optima (and therefore work best)
around pH 7.4, whereas lysosomal enzymes function best at pH 5
or less.

Receptor-Mediated and Fluid-Phase Uptake (Fig. 1-6)
(p. 9)
Endocytosis allows the import of macromolecules >1000 daltons:
Select molecules can be taken up by invaginations of the plasma
membrane called caveolae, whereas others are internalized via
pinocytic vesicles after binding to specific cell-surface receptors.
• Caveolae-mediated endocytosis. Caveolae (“little caves”) are
noncoated plasma membrane invaginations associated with GPIlinked molecules, cyclic adenosine monophosphate (cAMP)
binding proteins, SRC-family kinases, and the folate receptor.


Internalization of caveolae with any bound molecules and
associated extracellular fluid is called potocytosis—literally
“cellular sipping.” Although caveolae deliver some molecules to
the cytosol (e.g., folate), they also regulate transmembrane
signaling and/or cellular adhesion by internalizing receptors and
• Pinocytosis (“cellular drinking”) is a fluid-phase process in which
the plasma membrane invaginates and is pinched off to form a
cytoplasmic vesicle; endocytosed vesicles can recycle back to the
plasma membrane for another round of ingestion. Pinocytosis
and receptor-mediated endocytosis (see later) begin at a
specialized region of the plasma membrane called the clathrincoated pit, which invaginates and pinches off to form a clathrincoated vesicle; trapped within the vesicle is a gulp of the
extracellular milieu and receptor-bound macromolecules (see
later). The vesicles then uncoat and fuse with acidic intracellular
structures called early endosomes where the contents can be
partially digested before further passage to the lysosome.

FIGURE 1-6 Movement of small molecules and larger

structures across membranes.
The lipid bilayer is relatively impermeable to all but the
smallest and/or most hydrophobic molecules. Thus the
import or export of charged species requires specific
transmembrane transporter proteins; the internalization
or externalization of large proteins, complex particles,


or even cells requires encircling them with segments of
the membrane. Small charged solutes can move
across the membrane using either channels or
carriers; in general each molecule requires a unique
transporter. Channels are used when concentration
gradients can drive the solute movement. Carriers are
required when solute is moved against a concentration
gradient. Receptor-mediated and fluid-phase uptake of
material involves membrane-bound vacuoles.
Caveolae endocytose extracellular fluid, membrane
proteins, and some receptor-bound molecules (e.g.,
folate) in a process driven by caveolin proteins
concentrated within lipid rafts (potocytosis).
Pinocytosis of extracellular fluid and most surface
receptor-ligand pairs involves clathrin-coated pits and
vesicles. After internalization the clathrin dissociates
and can be reused, while the resulting vesicle
progressively matures and acidifies. In the early and/or
late endosome, ligand can be released from its
receptor (e.g., iron released from transferrin bound to
the transferrin receptor) with receptor recycling to the
cell surface for another round. Alternatively, receptor
and ligand within endosomes can be targeted to fuse
with lysosomes (e.g., epidermal growth factor bound to
its receptor); after complete degradation the late
endosome-lysosome fusion vesicle can regenerate
lysosomes. Phagocytosis involves the nonclathrinmediated membrane invagination of large particles—
typically by specialized phagocytes (e.g., macrophages
or neutrophils). The resulting phagosomes eventually
fuse with lysosomes to facilitate the degradation of the
internalized material. Transcytosis involves the
transcellular endocytotic transport of solute and/or
bound ligand from one face of a cell to another.
Exocytosis is the process by which membrane-bound
vesicles fuse with the plasma membrane and
discharge their contents to the extracellular space.

• Receptor-mediated endocytosis is the major uptake mechanism
for certain macromolecules (e.g., transferrin and low-density
lipoprotein [LDL]). After binding to receptors localized in
clathrin-coated pits, LDL and transferrin are endocytosed in
vesicles. In acidic environments LDL and transferrin release their


cargo (cholesterol and iron, respectively), which can be
discharged into the cytoplasm. The LDL and transferrin receptors
are resistant to the degradation, allowing them to be recycled
back to the plasma membrane. Defects in receptor-mediated
uptake or processing of LDL can be responsible for familial
hypercholesterolemia (see Chapter 5).
Cellular export of large molecules from cells is called exocytosis;
proteins synthesized and packaged within the RER and Golgi
apparatus are concentrated in secretory vesicles, which then fuse
with the plasma membrane to expel their contents. Transcytosis is
the movement of endocytosed vesicles between the apical and
basolateral compartments of cells; this allows transfer of large
amounts of intact proteins across epithelial barriers (e.g., ingested
antibodies in maternal milk across intestinal epithelia) or for the
rapid movement of large volumes of solute.

Cytoskeleton and Cell-Cell Interactions (p.
Cell shape, polarity, intracellular trafficking, and motility depend on
intracellular cytoskeleton proteins (Fig. 1-7):
• Actin microfilaments: Five- to nine-nanometer-diameter fibrils
formed from globular actin (G-actin), the most abundant
cytosolic protein; G-actin monomers noncovalently polymerize
into filaments (F-actin) forming double-stranded helices with
defined polarity; new globular subunits are added (or lost) at the
“positive” end of the strand. In nonmuscle cells, actin-binding
proteins organize actin into bundles and networks that control
cell shape and movement. In muscle cells, contraction occurs
through ATP-driven myosin ratcheting along actin filaments.
• Intermediate filaments: Large and heterogeneous family of 10-nmdiameter fibrils, with characteristic cell- and tissue-specific
patterns of expression.
• Lamin A, B, and C: Nuclear lamina of all cells
• Vimentin: Mesenchymal cells (fibroblasts, endothelium)
• Desmin: Scaffold in muscle cells allowing actin and myosin
• Neurofilaments: Axons of neurons, imparting strength and


• Glial fibrillary acidic protein: Glial cells around neurons
• Cytokeratins: At least 30 distinct varieties, subdivided into acidic
(type I) and neutral/basic (type II)
Intermediate filaments exist predominantly in a polymerized
form and do not actively reorganize like actin; they are ropelike
fibers that bear mechanical stress and form the major structural
proteins of skin and hair. Nuclear lamins maintain nuclear
morphology and regulate nuclear transcription.

FIGURE 1-7 Cytoskeletal elements and cell-cell interactions.

Interepithelial adhesion involves several different
surface protein interactions, including through tight
junctions and desmosomes; adhesion to the ECM
involves cellular integrins (and associated proteins)
within hemidesmosomes.


• Microtubules: Twenty-five-nanometer-thick fibrils composed of
noncovalently polymerized dimers of α- and β-tubulin.
Microtubules are dynamically changing hollow tubes with a
defined polarity; the ends are designated “+” or “−”; the “−” end
is embedded in a microtubule-organizing center (MTOC, or
centrosome) near the nucleus associated with paired centrioles,
whereas the “+” end elongates or recedes by adding or
subtracting tubulin dimers. Microtubules are connecting cables
that motor proteins “walk” along to move vesicles and organelles
around cells: kinesins are motor proteins for anterograde (− to +)
transport, whereas dyneins are for retrograde (+ to −) transport.
Microtubules also participate in sister chromatid separation
during mitosis and have been adapted to form motile cilia (e.g.,
in bronchial epithelium) or flagella (in sperm).
Cell-cell interactions (p. 11). Cells interact and communicate via
junctional complexes (Fig. 1-7):
• Occluding junctions (tight junctions) seal adjacent cells together to
create a continuous barrier that restricts the paracellular (between
cells) movement of ions and other molecules. The junctions are
formed from multiple transmembrane proteins, including
occludin, claudin, zonulin, and catenin. In addition to a highresistance barrier to solute movement, this zone is also the
boundary between apical and basolateral domains of cells,
helping to maintain cellular polarity. Tight junctions are dynamic
structures that can dissociate and reform as required to facilitate
epithelial proliferation or inflammatory cell migration.
• Anchoring junctions (desmosomes) mechanically attach cells—and
their intracellular cytoskeletons—to other cells or to the ECM.
• Spot desmosomes (macula adherens) are small, rivetlike adhesions
between cells; similar rivetlike attachments to the ECM are
called hemidesmosomes, whereas broad intercellular adhesion
domains are called belt desmosomes.
• Desmosomes are formed by homotypic association of
transmembrane glycoproteins called cadherins. In spot
desmosomes the cadherins are linked to intracellular
intermediate filaments to distribute extracellular forces over
multiple cells; in belt desmosomes the cadherins are associated
with intracellular actin microfilaments, which can influence cell


shape and motility.
• In hemidesmosomes the transmembrane connector proteins are
called integrins; these attach to intracellular intermediate
filaments, and thus functionally link the cytoskeleton to the
• Focal adhesion complexes are large (>100 proteins)
macromolecular complexes that localize to hemidesmosomes
and include proteins that can generate intracellular signals
when cells are subjected to mechanical forces (e.g.,
endothelium in the bloodstream or cardiac myocytes in a
failing heart).
• Communicating junctions (gap junctions) mediate the passage of
chemical or electrical signals between cells. These junctions are
dense planar arrays of 1.5- to 2-nm pores (called connexons)
formed by hexamers of transmembrane proteins called connexins.
The permeability of gap junctions is reduced by acidic pH or
increased intracellular calcium. Gap junctions play a critical role
in cell-cell communication; in cardiac myocytes, cell-to-cell
calcium fluxes through gap junctions allow the myocardium to
behave like a functional syncytium.

Biosynthetic Machinery: Endoplasmic
Reticulum and Golgi (p. 12)
All cell constituents are constantly renewed and degraded, although
every type of molecule has a distinct half-life.
• Endoplasmic reticulum (ER). Membrane proteins and lipids, as well
as molecules destined for export, are all synthesized within the
ER. The ER is composed of distinct domains, distinguished by the
presence (RER) or absence (smooth ER or SER) of ribosomes (Fig. 15).
• RER: Membrane-bound ribosomes of the RER translate mRNA
into proteins that are extruded into the ER lumen or become
integrated into the ER membrane; the process is directed
through signal sequences on the N-termini of nascent proteins. If
proteins lack a signal sequence, translation occurs on free
ribosomes in the cytosol, and the vast majority of such proteins
remain in the cytoplasm. Proteins inserted into the ER fold and


can form polypeptide complexes (oligomerize); in addition,
disulfide bonds are formed, and N-linked oligosaccharides (sugar
moieties attached to asparagine residues) are added. Chaperone
molecules retain proteins in the ER until these modifications are
complete and the proper conformation is achieved. If a protein
fails to appropriately fold or oligomerize, it is retained and
degraded within the ER. Excess misfolded proteins—exceeding
the capacity of the ER to edit and degrade them—leads to the
ER stress response (also called the unfolded protein response
[UPR]), which triggers cell death through apoptosis (see Chapter
• SER: The SER in most cells is relatively sparse and primarily
exists as the transition zone from RER to transport vesicles
moving to the Golgi (see later discussion). However, in cells
that synthesize steroid hormones (e.g., in the gonads or
adrenals) or that catabolize lipid-soluble molecules (e.g., in the
liver), the SER may be abundant. Indeed, repeated exposure to
compounds that are metabolized by the SER (e.g.,
phenobarbital catabolism by the cytochrome P-450 system) can
lead to a reactive SER hyperplasia. The SER also sequesters
intracellular calcium; subsequent release from the SER into the
cytosol can mediate a number of responses to extracellular
signals (including apoptotic cell death). In muscle cells,
specialized SER called sarcoplasmic reticulum is responsible for
the cyclical release and sequestration of calcium ions that
regulate muscle contraction and relaxation, respectively.
• Golgi apparatus. From the RER, proteins and lipids destined for
other organelles or for extracellular export are shuttled into the
Golgi apparatus. This organelle consists of stacked cisternae that
progressively modify proteins in an orderly fashion from cis
(near the ER) to trans (near the plasma membrane);
macromolecules are shuttled between the various cisternae
within membrane-bound vesicles. As molecules move from cis to
trans, the N-linked oligosaccharides originally added to proteins in
the ER are pruned and further modified in a step-wise fashion; Olinked oligosaccharides (sugar moieties linked to serine or
threonine) are also appended. Some of this glycosylation is
important in directing molecules to lysosomes (via the mannose-6-


phosphate [M6P] receptor); other glycosylation adducts may be
important for cell-cell or cell-matrix interactions or for clearing
senescent cells. The cis-Golgi network recycles proteins back to the
ER, whereas the trans-Golgi network sorts proteins and lipids and
dispatches them to other organelles (including the plasma
membrane) or to secretory vesicles destined for extracellular

Waste Disposal: Lysosomes and
Proteasomes (p. 13)
Cellular constituent degradation involves lysosomes or proteasomes (Fig.
• Lysosomes are membrane-bound organelles containing acid
hydrolases, including proteases, nucleases, lipases, glycosidases,
phosphatases, and sulfatases. Many of these are M6P-modified
proteins, which are targeted to lysosomes via binding to M6P
receptors on trans-Golgi vesicles. Other macromolecules destined
for lysosomes arrive via three pathways (Fig. 1-8):
• Material internalized by fluid-phase pinocytosis or receptormediated endocytosis passes through various endosomes en
route to lysosomes. The early endosome is the first acidic
compartment encountered, whereas proteolytic enzymes only
begin significant digestion in the late endosome; late
endosomes mature into lysosomes. During the maturation
process the organelle becomes progressively more acidic.
• Senescent organelles and large, denatured protein complexes
enter lysosomes via autophagy. Obsolete organelles are
encircled by a double membrane derived from the ER, forming
an autophagosome that fuses with lysosomes. In addition to
facilitating the turnover of aged and defunct structures,
autophagy is also used to preserve cell viability during nutrient
depletion (see Chapter 2).
• Phagocytosis of microorganisms or large fragments of matrix or
debris occurs primarily in professional phagocytes
(macrophages or neutrophils). The material is engulfed to form
a phagosome that subsequently fuses with lysosomes.


FIGURE 1-8 Intracellular catabolism.

A, Lysosomal degradation. In heterophagy (right side),
lysosomes fuse with endosomes or phagosomes to
facilitate the degradation of their internalized contents
(Fig. 1-6). The end products may be released into the
cytosol for nutrition or discharged into the extracellular
space (exocytosis). In autophagy (left side), senescent
organelles or denatured proteins are targeted for
lysosome-driven degradation by encircling them with a
double membrane derived from the ER and marked by
LC3 proteins (microtubule-associated protein 1A/1Blight chain 3). Cell stressors, such as nutrient depletion
or certain intracellular infections, can also activate the
autophagocytic pathway.B, Proteasome degradation.
Cytosolic proteins destined for turnover (e.g.,
transcription factors or regulatory proteins), senescent
proteins, or proteins that have become denatured due
to extrinsic mechanical or chemical stresses can be
tagged by multiple ubiquitin molecules (through the
activity of E1, E2, and E3 ubiquitin ligases). This marks
the proteins for degradation by proteasomes, cytosolic


multisubunit complexes that degrade proteins to small
peptide fragments. High levels of misfolded proteins
within the ER trigger a protective unfolded protein
response—engendering a broad reduction in protein
synthesis, but specific increases in chaperone proteins
that can facilitate protein refolding. If this is inadequate
to cope with the levels of misfolded proteins, apoptosis
is induced.

• Proteasomes are multisubunit protease complexes that degrade
cytosolic proteins, including denatured or misfolded proteins, as
well as other macromolecules whose lifespan must be regulated
(e.g., transcription factors) (Fig. 1-8). Many proteins destined for
proteasome destruction are covalently bound to a small protein
called ubiquitin; polyubiquitinated proteins are then funneled into
the proteasome “cylinder of death,” where they are digested into
small (6 to 12 amino acids) fragments that can further degrade to
their constituent amino acids.

Cellular Metabolism and
Mitochondrial Function (p. 14)
Mitochondria evolved from ancestral prokaryotes; that origin
explains why mitochondria contain their own DNA (1% of total
cellular DNA), encoding approximately 1% of total cellular proteins
and one fifth of the proteins involved in oxidative phosphorylation.
The mitochondrial translational machinery is similar to present-day
bacteria; mitochondria initiate protein synthesis with Nformylmethionine and are sensitive to antibacterial antibiotics. The
ovum contributes the vast majority of cytoplasmic organelles to the
fertilized zygote; thus mitochondrial DNA is virtually entirely
maternally inherited. Nevertheless, because the protein constituents
of mitochondria derive from both nuclear and mitochondrial genes,
mitochondrial disorders can be X-linked, autosomal, or maternally
inherited. Mitochondria are constantly turning over, with half-lives
ranging from 1 to 10 days.
Each mitochondrion has two separate membranes surrounding a
core matrix containing most mitochondrial metabolic enzymes (e.g.,


those involved in the citric acid cycle). The inner membrane
contains the enzymes of the respiratory chain folded into cristae; the
outer membrane contains porin proteins that form aqueous channels
permeable to small (<5000 daltons) molecules. Larger molecules
(and even some smaller polar species) require specific transporters.
Between these membranes is the intermembrane space, which is the
site of ATP synthesis. Mitochondria have several roles (Fig. 1-9).

Energy Generation (p. 14)
Most cell energy derives from metabolism in mitochondria;
substrates are oxidized to CO2, transferring the high-energy
electrons from the original molecule (e.g., sugar) to molecular
oxygen and generating the low-energy electrons of water. The
oxidation of various metabolites drives proton pumps that transfer
H+ from the core matrix into the intermembrane space. As the H+
ions flow back down their electrochemical gradient, the energy
released is used to synthesize ATP.
Electron transport does not always generate ATP. Thermogenin,
an inner membrane protein present in high levels in certain tissues
(e.g., brown fat), uncouples the process, generating heat instead of
ATP. As a natural by-product of substrate oxidation and electron
transport, mitochondria are also an important source of reactive
oxygen species (e.g., oxygen free radicals, hydrogen peroxide);
hypoxia, injury, or even mitochondrial aging can lead to
significantly increased levels of intracellular oxidative stress.


FIGURE 1-9 Roles of the mitochondria.

In addition to the efficient generation of ATP from
carbohydrate and fatty acid substrates, mitochondria
have an important role in intermediary metabolism,
serving as the source of molecules used to synthesize
lipids and proteins, and are also centrally involved in
cell death pathways.

Intermediate Metabolism (p. 14)
Oxidative phosphorylation produces abundant ATP, but also
“burns” glucose to CO2 and H2O, leaving no carbon moieties
suitable for synthesizing lipids and proteins. Thus rapidly growing
cells (both benign and malignant) increase glucose and glutamine
uptake and decrease their production of ATP per glucose molecule,
a phenomenon called the Warburg effect (aerobic glycolysis; see
Chapter 7). Instead of being used to make ATP, intermediates are
“spun-off” to make lipids, nucleic acids, and proteins.

Cell Death (p. 15)
Mitochondria also regulate the balance of cell survival and death.
There are two major pathways of cell death (see Chapter 2):
• Necrosis: External cellular injury (toxin, ischemia, trauma) can
damage mitochondria, causing formation of mitochondrial
permeability transition pores in the outer membrane that (1)


dissipate the proton gradient, (2) prevent ATP generation, and (3)
cause cell death.
• Apoptosis: Programmed cell death can be triggered by extrinsic
signals (including cytotoxic T cells and inflammatory cytokines)
or intrinsic pathways (including DNA damage and intracellular
stress); mitochondria play a central role in the intrinsic pathway
of apoptosis. If mitochondria are damaged or the cell cannot
synthesize adequate amounts of survival proteins (because of
deficient growth signals), mitochondria leak cytochrome c into
the cytosol where it forms a complex with other proteins to
activate caspases (see Chapter 2).

Cellular Activation (p. 15)
Cell communication controls a variety of functions, including
activation, differentiation, and cell death. Loss of effective cellular
communication can potentially lead to unregulated growth (cancer)
or inappropriate response to stress (shock).

Cell Signaling (p. 15)
Cells can respond to the following extrinsic signals:
• Pathogens and damage to neighboring cells. In addition to microbes,
cells can sense and respond to damaged cells (danger signals); see
Chapters 3 and 6.
• Contact with neighboring cells, mediated through adhesion
molecules and/or gap junctions—the latter through second
messenger molecules, such as cAMP.
• Contact with ECM, mediated through integrins (see Chapter 3).
• Secreted molecules, for example, growth factors (see later
discussion), cytokines (mediators of inflammation and immune
responses; see Chapters 3 and 6), and hormones (see Chapter 24).
Cell-cell signaling pathways are classified as
• Paracrine: Only cells in the immediate vicinity are affected;
signaling molecules have minimal diffusion and are rapidly
degraded, taken up by other cells, or trapped in the ECM.
• Autocrine: When molecules secreted by a cell affect that same cell;
this allows entraining groups of cells undergoing synchronous


differentiation (e.g., during development) or can be used to
autoamplify or feedback inhibit a response.
• Synaptic: Neurons secrete neurotransmitters at specialized cell
junctions (synapses) onto target cells.
• Endocrine: Mediator is released into the bloodstream and acts on
target cells at a distance.
Signaling molecules (ligands) bind their respective receptors and
initiate a cascade of intracellular events. Receptors typically have
high affinities for their cognate ligands and at physiologic
concentrations bind receptors with exquisite specificity. Receptors
can be intracellular or on the cell surface (Fig. 1-10):
• Intracellular receptors are transcription factors activated by lipidsoluble ligands that readily cross plasma membranes. Such
ligands include vitamin D and steroid hormones, which can bind
and activate nuclear receptors to drive specific gene transcription.
Signaling ligands can also diffuse into adjacent cells; thus nitric
oxide produced in one cell (e.g., endothelium) diffuses into
neighboring cells (e.g., medial smooth muscle cells) where it
activates the enzyme guanylyl cyclase to generate cyclic
guanosine monophosphate (GMP), an intracellular second signal
for smooth muscle cell relaxation.
• Cell-surface receptors are generally transmembrane proteins with
extracellular ligand-binding domains. Ligand binding can then
(1) open ion channels (e.g., at the synapse between electrically
excitable cells), (2) activate an associated guanosine triphosphate
(GTP)-binding regulatory protein (G protein), (3) activate an
endogenous or associated enzyme, often a tyrosine kinase, or (4)
trigger a proteolytic event or a change in protein binding or
stability that activates a latent transcription factor.

Signal Transduction Pathways (p. 16)
Ligand binding to surface receptors mediates signaling by inducing
clustering of the receptor (receptor cross-linking) or by other types of
physical perturbations; these trigger intracellular biochemical
changes, ultimately activating transcription factors that enter the
nucleus to alter gene expression (Fig. 1-10):
• Receptors associated with kinase activity. Alterations in receptor


geometry elicit intrinsic receptor protein kinase activity or promote
the enzymatic activity of recruited intracellular kinases—
resulting in the addition of charged phosphate residues to target
molecules. Tyrosine kinases phosphorylate specific tyrosine
residues, serine/threonine kinases add phosphates to distinct serine
or threonine residues, and lipid kinases phosphorylate lipid
substrates. For example, receptor tyrosine kinases (RTKs) are
integral membrane proteins that—upon activation—have the
capacity to phosphorylate tyrosine residues; these include
receptors for insulin, epidermal growth factor, and plateletderived growth factor. For every phosphorylation event,
phosphatases exist to remove the phosphate residue and thus
modulate signaling.
• Several receptors have no intrinsic catalytic activity (e.g., immune
receptors, some cytokine receptors, and integrins). For these,
separate intracellular proteins—nonreceptor tyrosine kinases—
phosphorylate specific motifs on the receptor or other proteins.
SRC is the prototype for these; it contains functional domains
called Src-homology 2 (SH2) and Src-homology 3 (SH3). SH2
domains typically bind to receptors phosphorylated by another
kinase, allowing the aggregation of multiple enzymes. SH3
domains mediate other protein-protein interactions, often
involving proline-rich regions.


FIGURE 1-10 Receptor-mediated signaling.

A, Categories of signaling receptors: receptors that
use a nonreceptor tyrosine kinase; receptor tyrosine
kinases; nuclear receptors that bind ligand and
influence transcription; a seven-transmembrane
receptor linked to heterotrimeric G proteins; Notch,
which is cleaved yielding an intracellular fragment that
enters the nucleus and influences target gene
transcription; and Wnt/Frizzled pathway in which
activation releases intracellular β-catenin from a
protein complex that normally drives its constitutive
degradation. The released β-catenin can then migrate
to the nucleus and act as a transcription factor. Lowdensity lipoprotein receptor-related protein 5 (Lrp5)
and Lrp6 are homologous coreceptors for Wnt/Frizzled


signaling. B, Signaling downstream of tyrosine kinase
receptor-ligand interactions. Ligand binding causes
receptor dimerization and autophosphorylation of
tyrosine residues. Attachment of adapter (or bridging)
proteins couples the receptor to inactive, GDP-bound
RAS, allowing the GDP to be displaced in favor of GTP
and yielding activated RAS. Activated RAS interacts
with and activates RAF (also known as MAP kinase
kinase kinase). This kinase then phosphorylates
mitogen-activated protein kinase (MAPK); in turn,
activated MAPK phosphorylates other cytoplasmic
proteins and nuclear transcription factors, generating
cellular responses. The phosphorylated tyrosine kinase
receptor can also bind other components, such as
phosphatidyl 3-kinase (PI3 kinase), which activates
additional signaling systems. The cascade is turned off
when the activated RAS eventually hydrolyzes GTP to
GDP, converting RAS to its inactive form. Mutations in
RAS that lead to delayed GTP hydrolysis can thus lead
to augmented proliferative signaling. GDP, Guanosine
diphosphate; GTP, guanosine triphosphate; mTOR,
mammalian target of rapamycin.

• G-protein coupled receptors characteristically traverse the plasma
membrane seven times (seven-transmembrane receptors). After
ligand binding, the receptor associates with an intracellular GTPbinding protein (G protein) that contains guanosine diphosphate
(GDP). Such G-protein interactions lead to their activation
through the exchange of GDP for GTP, with downstream
generation of cAMP and inositol-1,4,5-triphosphate (IP3); the
latter releases calcium from the ER.
• Ligand binding to Notch receptors leads to proteolytic cleavage of
the receptor, with nuclear translocation of the cytoplasmic piece
to form a transcription complex.
• Wnt protein ligands signal through transmembrane Frizzled
family receptors to regulate intracellular β-catenin levels.
Normally, β-catenin is degraded by proteasomes; however, Wnt
binding to Frizzled (and other coreceptors) recruits Disheveled
proteins that disrupt the degradation-targeting complex. The
stabilized pool of β-catenin molecules then translocates to the
nucleus to form a transcriptional complex.


Modular Signaling Proteins: Hubs and Nodes
(p. 18)
The traditional linear view of signaling through an orderly sequence
of biochemical intermediates is oversimplified. Any initial signal
causes multiple diverging effects, each contributing in varying
degrees to the final outcome. Thus even specific phosphorylation of
a single protein can allow it to associate with multiple different
molecules—with multiple consequences. Adapter proteins play a key
role in organizing intracellular signaling pathways, functioning as
molecular linkers to promote complex assembly. Signal
transduction can therefore be visualized as a kind of networking
phenomenon with protein-protein complexes forming nodes and the
biochemical events feeding into or emanating from these nodes
being hubs (so-called systems biology).

Transcription Factors (p. 18)
Most signal transduction pathways ultimately influence cellular
function by modulating gene transcription. Conformational
changes of transcription factors (e.g., following phosphorylation)
can allow their translocation into the nucleus or can expose specific
DNA or protein binding motifs. Transcription factors
characteristically have distinct binding domains that allow them to
bridge select DNA sequences with proteins, such as the RNA
polymerase complex, histone-modifying enzymes, and chromatinremodeling complexes. MYC and JUN are growth-inducing
transcription factors, whereas p53 typically leads to growth arrest.

Growth Factors and Receptors (p. 18)
Growth factor activity is mediated through binding to specific
receptors, leading to the expression of genes that
• Promote entry into the cell cycle
• Relieve blocks on cell cycle progression
• Prevent apoptosis
• Enhance biosynthesis of cellular constituents
• Drive a host of nongrowth activities, including migration,


differentiation, and synthetic capacity
Growth factors are involved in the proliferation of cells at steady
state as well as after injury to replace damaged cells. Many growth
factor pathway genes are proto-oncogenes; uncontrolled proliferation
can result when growth factor production is dysregulated or when
growth factor signaling pathways become constitutively active.
Table 1-1 summarizes selected growth factors; although all these
bind to receptors with intrinsic kinase activity, other growth factors
can signal through any of the pathways shown in Figure 1-10.
Growth Factors Involved in Regeneration and Repair
Growth Factor
growth factor
growth factor-α
growth factor
(HGF) (scatter
growth factor
growth factor

Activated macrophages,
salivary glands,
keratinocytes, and many
other cells
Activated macrophages,
keratinocytes, many
other cell types
Fibroblasts, stromal cells
in the liver, endothelial

Mitogenic for keratinocytes and fibroblasts;
stimulates keratinocyte migration; stimulates
formation of granulation tissue

Mesenchymal cells

Stimulates proliferation of endothelial cells;
increases vascular permeability

Stimulates proliferation of hepatocytes and
many other epithelial cells
Enhances proliferation of hepatocytes and other
epithelial cells; increases cell motility

Platelets, macrophages,
endothelial cells, smooth
muscle cells,

Chemotactic for neutrophils, macrophages,
fibroblasts, and smooth muscle cells; activates
and stimulates proliferation of fibroblasts,
endothelial, and other cells; stimulates ECM
protein synthesis
Fibroblast growth Macrophages, mast cells, Chemotactic and mitogenic for fibroblasts;
factors (FGFs),
endothelial cells, many
stimulates angiogenesis and ECM protein
including acidic
other cell types
(FGF-1) and basic
Platelets, T lymphocytes, Chemotactic for leukocytes and fibroblasts;
growth factor-β
stimulates ECM protein synthesis; suppresses
endothelial cells,
acute inflammation
keratinocytes, smooth
muscle cells, fibroblasts
Stimulates keratinocyte migration, proliferation,
growth factor
and differentiation
(KGF) (i.e., FGF-7)

ECM, Extracellular matrix.


Epidermal growth factor (EGF) and transforming growth factor (TGF)-α
(p. 19). These both bind to the same receptors, explaining why
they share many biologic activities; they are produced by
macrophages and epithelial cells and are mitogenic for multiple
cell types. The EGF receptor family includes four membrane
receptors with intrinsic tyrosine kinase activity. EGFR1 (ERBB1)
mutations and/or amplification occur frequently in lung, head
and neck, breast, and brain tumors. The ERBB2 receptor (also
known as HER2) is overexpressed in a subset of breast cancers.
Hepatocyte growth factor (HGF) (p. 19) has mitogenic effects on
hepatocytes and most epithelial cells. HGF acts as a morphogen in
embryonic development (i.e., it influences the pattern of tissue
differentiation), promotes cell migration, and enhances
hepatocyte survival. HGF is produced by fibroblasts and most
mesenchymal cells, endothelium, and nonhepatocyte liver cells. It
is synthesized as an inactive precursor (pro-HGF) that is
proteolytically activated by serine proteases released at sites of
injury. MET is the receptor for HGF; it has intrinsic tyrosine
kinase activity and is frequently overexpressed or mutated in
tumors, particularly renal and thyroid papillary carcinomas.
Platelet-derived growth factor (PDGF) (p. 19) represents a family of
closely related dimeric proteins. Although originally isolated
from platelets (hence the name), it is also produced by activated
macrophages, endothelium, smooth muscle cells, and a variety of
tumors. All PDGF isoforms exert their effects by binding to two
cell-surface receptors (PDGFR α and β), both having intrinsic
tyrosine kinase activity. PDGF induces fibroblast, endothelial,
and smooth muscle cell chemotaxis, proliferation, and matrix
Vascular endothelial growth factor (VEGF) (p. 20) comprises a family of
homodimeric proteins. VEGF-A is generally referred to simply as
VEGF; it is the major angiogenic factor after injury and in tumors.
VEGF-B and placental growth factor are involved in embryonic
vessel development, and VEGF-C and -D stimulate both
angiogenesis and lymphatic development (lymphangiogenesis).
VEGFs are also involved in the maintenance of normal adult
endothelium, with the highest expression in epithelial cells
adjacent to fenestrated epithelium (e.g., podocytes in the kidney,


pigment epithelium in the retina, and choroid plexus in the
brain). VEGF induces angiogenesis by promoting endothelial cell
migration, proliferation (capillary sprouting), and formation of
the vascular lumen; it also induces increased vascular
permeability. Hypoxia is the most important inducer of VEGF
production (mediated through intracellular hypoxia-inducible
factor), in addition to PDGF and TGF-α produced at sites of
inflammation or wound healing.
VEGFs bind to a family of RTKs; VEGFR-2 is highly expressed in
endothelium and is the most important for angiogenesis. AntiVEGF antibodies are used to limit angiogenesis in certain
malignancies, “wet” age-related macular degeneration, and the
retinopathy of prematurity. Anti-VEGF also reduces the leakiness
of vessels that causes diabetic macular edema. Increased levels of
soluble versions of VEGFR-1 (s-FLT-1) in pregnant women can
cause preeclampsia (hypertension and proteinuria) by “sopping
up” the free VEGF required to maintain normal endothelium.
Fibroblast growth factor (FGF) (p. 20) is a family of >20 growth
factors; they associate with heparan sulfate in the ECM, serving
as a reservoir for inactive factors that can be released through
proteolysis (e.g., at sites of wound healing). FGFs contribute to
wound healing responses, hematopoiesis, and development;
basic FGF has all the activities necessary for angiogenesis.
Transforming growth factor-β (TGF-β) (p. 20) has three isoforms (β1β3), each belonging to a family of approximately 30 members that
includes bone morphogenetic proteins (BMPs), activins, inhibins,
and müllerian inhibiting substance. TGF-β1 (more commonly
referred to as TGF-β) has the most widespread distribution; it is a
homodimeric protein produced by multiple cell types as a
precursor that requires proteolysis to yield the biologically active
protein. There are two TGF-β receptors, both with
serine/threonine kinase activity that phosphorylate downstream
Smad transcription factors. TGF-β has multiple and often
opposing effects (called pleiotropic) depending on the target tissue
and concurrent signals. However, primarily TGF-β drives scar
formation and applies brakes on the inflammation that
accompanies wound healing.


Interaction With the Extracellular
Matrix (p. 20)
ECM is a network of interstitial proteins; it is constantly remodeled,
with synthesis and degradation accompanying morphogenesis,
tissue regeneration and repair, chronic fibrosis, and tumor invasion
and metastasis. Cell interactions with ECM are critical for
development and healing, as well as for maintaining normal tissue
architecture (Fig. 1-11):
• Mechanical support: Allowing cell anchorage, cell migration, and
maintenance of cell polarity.
• Control of cell proliferation: ECM binds growth factors that can be
released/activated by proteolysis; ECM can also signal through
cell integrins.
• Scaffolding for tissue renewal: Integrity of the basement membrane
and the stroma of parenchymal cells is critical for the organized
regeneration of tissues.
• Establishment of tissue microenvironments: Basement membrane is
not just a passive support between epithelium and connective
tissue; it can also have functionality (e.g., forming part of the
filtration apparatus in the kidney).
ECM occurs in two basic forms: interstitial matrix and basement
membrane (Fig. 1-12).
• Interstitial matrix is synthesized by mesenchymal cells (e.g.,
fibroblasts); it is present in the spaces between cells in connective
tissue and between parenchymal epithelium and the underlying
support structures. Its major constituents are fibrillar and
nonfibrillar collagens, as well as fibronectin, elastin,
proteoglycans, and hyaluronate.


FIGURE 1-11 Interactions of ECM and growth factor–

mediated cell signaling.
Cell surface integrins interact with the cytoskeleton at
focal adhesion complexes (protein aggregates that
include vinculin, α-actinin, and talin). This can initiate
the production of intracellular messengers or can
directly transduce signals to the nucleus. Cell-surface
receptors for growth factors can activate signal
transduction pathways that overlap with those
mediated through integrins. Signals from ECM
components and growth factors can be integrated by
the cells to produce a given response, including
changes in proliferation, locomotion, and/or


FIGURE 1-12 Main components of the ECM, including

collagens, proteoglycans, and adhesive glycoproteins.
Both epithelial and mesenchymal cells (e.g.,
fibroblasts) interact with ECM via integrins. Basement
membranes and interstitial ECM have different
architecture and general composition, although certain
components are present in both. For the sake of
clarity, many ECM components (e.g., elastin, fibrillin,
hyaluronan, and syndecan) are not included.

• Basement membrane is synthesized from the overlying epithelium
and underlying mesenchymal cells, forming a planar mesh
(although labeled as a membrane, it is quite porous). The major
constituents are amorphous nonfibrillar type IV collagen and
Components of the ECM (p. 21) fall into three groups of proteins:
• Fibrous structural proteins, such as collagens and elastins, that
confer tensile strength and recoil
• Water-hydrated gels, such as proteoglycans and hyaluronan, that
permit compressive resistance and lubrication
• Adhesive glycoproteins that connect ECM elements to cells and each
Collagens (p. 23) are composed of three separate polypeptide
chains braided into a ropelike triple helix; approximately 30
collagen types have been identified.
• Fibrillar collagens: Some collagen types (e.g., types I, II, III, and V)
form linear fibrils stabilized by interchain hydrogen bonding;
these form a major proportion of the connective tissue in
structures such as bone, tendon, cartilage, blood vessels, and


skin, as well as in healing wounds and particularly scars. The
tensile strength of the fibrillar collagens derives from lateral
cross-linking of the triple helices, formed by covalent bonds
facilitated by the activity of lysyl oxidase (vitamin C is a
necessary cofactor).
• Nonfibrillar collagens: These contribute to the structures of planar
basement membranes (type IV collagen), help to regulate
collagen fibril diameters or collagen-collagen interactions via socalled fibril-associated collagen with interrupted triple helices
(FACITs, such as type IX collagen in cartilage), or provide
anchoring fibrils to basement membrane beneath stratified
squamous epithelium (type VII collagen).
Elastin (p. 23) allows tissues to recoil and recover their shape after
physical deformation; this is especially important in cardiac valves
and for large blood vessels (to accommodate pulsatile flow), as well
as in the uterus, skin, and ligaments.
Proteoglycans and hyaluronan (p. 23). Proteoglycans form highly
hydrated gels that resist compressive forces; in joint cartilage,
proteoglycans also provide a layer of lubrication between adjacent
bony surfaces. Proteoglycans consist of long polysaccharides called
glycosaminoglycans (GAGs) attached to a core protein; these are then
linked to a long hyaluronic acid polymer called hyaluronan, in a
manner reminiscent of the bristles on a test tube brush. The
negatively charged sulfated sugars of the GAGs attract cations
(mostly sodium) that in turn osmotically attract water; the result is
a viscous, gelatin-like matrix. In addition to providing
compressibility to tissues, proteoglycans also serve as reservoirs for
growth factors secreted into the ECM (e.g., FGF and HGF).
Adhesive glycoproteins and adhesion receptors (p. 24) are structurally
diverse molecules involved in cell-cell adhesion, cell-ECM, and
ECM-ECM interactions (Fig. 1-13). These include:
• Fibronectin. A large disulfide-linked heterodimer that exists in
tissue and plasma forms; it is synthesized by a variety of cells.
Fibronectin has specific domains that can bind to different ECM
components (e.g., collagen, fibrin, heparin, and proteoglycans), as
well as integrins (Fig. 1-13). In healing wounds, tissue and
plasma fibronectin provide the scaffolding for subsequent ECM
deposition, angiogenesis, and re-epithelialization.


FIGURE 1-13 Cell and ECM interactions: adhesive

glycoproteins and integrin signaling.
A, Fibronectin consists of a disulfide-linked dimer, with
several distinct domains that allow binding to ECM and
to integrins, the latter through arginine-glycine-aspartic
acid (RGD) motifs. B, The cross-shaped laminin
molecule is one of the major components of basement
membranes; its multidomain structure allows
interactions between type IV collagen, other ECM
components, and cell-surface receptors. C, Integrins
and integrin-mediated signaling events at focal
adhesion complexes. Each α-β heterodimeric integrin
receptor is a transmembrane dimer that links ECM and
intracellular cytoskeleton. It is also associated with a
complex of linking molecules (e.g., vinculin, and talin)
that can recruit and activate kinases that ultimately
trigger downstream signaling cascades.

• Laminin. The most abundant glycoprotein in basement
membrane, it is a cross-shaped heterotrimer that connects cells to
underlying ECM components such as type IV collagen and
heparan sulfate (Fig. 1-13); it can also modulate cell proliferation,
differentiation, and motility.
• Integrins. A large family of transmembrane heterodimeric
glycoproteins (composed of α- and β-subunits) that allow cells to
attach to ECM constituents, such as laminin and fibronectin—
functionally and structurally linking the intracellular
cytoskeleton with the ECM. Integrins on the surface of leukocytes
mediate firm adhesion and transmigration across endothelium at


sites of inflammation (see Chapter 3), and they play a critical role
in platelet aggregation (see Chapter 4). Integrins attach to ECM
components via a tripeptide arginine-glycine-aspartic acid motif
(abbreviated RGD); binding through the integrin receptors can
also trigger signaling cascades (Fig. 1-13).

Maintaining Cell Populations (p. 25)
Proliferation and the Cell Cycle (p. 25)
Cell proliferation is fundamental to development, maintaining
steady-state tissue populations, and replacing dead or damaged
cells. The key elements that occur during cell cycle proliferation are:
• Accurate DNA replication
• Coordinated synthesis of all other cellular constituents (e.g.,
• Equal apportionment of DNA and other cellular constituents to
daughter cells
The cell cycle consists of (Fig. 1-14):
• G1 (presynthetic growth)
• S (DNA synthesis)
• G2 (premitotic growth)
• M (mitotic) phases
Quiescent cells that are not actively cycling are in the G0 state;
cells can enter G1 either from the G0 quiescent cell pool or after
completing a round of mitosis (e.g., for continuously replicating
cells). Each stage requires completion of the previous step, as well
as activation of necessary factors (see later); nonfidelity of DNA
replication or cofactor deficiency results in arrest at one of the
transition points.
The cell cycle is regulated by activators and inhibitors; progression
through the cell cycle is driven by the following (Fig. 1-15):
• Proteins called cyclins—named for the cyclic nature of their
production and degradation
• Cyclin-associated enzymes called cyclin-dependent kinases (CDKs)
CDKs acquire kinase activity (i.e., the ability to phosphorylate
protein substrates) by forming complexes with the relevant cyclins.
Transiently increased synthesis of a particular cyclin leads to


increased kinase activity of its CDK binding partner; as the CDK
completes its round of phosphorylation, the associated cyclin is
degraded and the CDK activity abates. Thus as cyclin levels rise
and fall, the activity of associated CDKs likewise waxes and wanes.
Cyclins D, E, A, and B appear sequentially during the cell cycle and
bind to one or more CDKs.

FIGURE 1-14 Cell cycle showing phases (G0, G1, G2, S, and

M), the location of the G1 restriction point, and the G1/S and
G2/M cell cycle checkpoints.
Cells from labile tissues, such as the epidermis and the
gastrointestinal (GI) tract, may cycle continuously;
stable cells, such as hepatocytes, are quiescent but
can enter the cell cycle; permanent cells, such as
neurons and cardiac myocytes, have lost the capacity
to proliferate. (Modified from Pollard TD, Earnshaw WC: Cell Biology.
Philadelphia, Saunders, 2002.)


FIGURE 1-15 Role of cyclins, CDKs, and CDK inhibitors in

regulating the cell cycle.
The shaded arrows represent the phases of the cell
cycle during which specific cyclin-CDK complexes are
active. As illustrated, cyclin D-CDK4, cyclin D-CDK6,
and cyclin E-CDK2 regulate the G1-to-S transition by
phosphorylating the Rb protein (pRb). Cyclin A-CDK2
and cyclin A-CDK1 are active in the S phase. Cyclin BCDK1 is essential for the G2-to-M transition. Two
families of CDK inhibitors can block activity of CDKs
and progression through the cell cycle. The so-called
INK4 inhibitors, composed of p16, p15, p18, and p19,
act on cyclin D-CDK4 and cyclin D-CDK6. The other
family of three inhibitors, p21, p27, and p57, can inhibit
all CDKs.

Throughout the cell cycle, surveillance mechanisms assess for
DNA damage. These quality controls act at checkpoints to ensure
that cells with genetic defects do not complete replication.


• The G1-S checkpoint monitors the integrity of DNA before
irreversibly committing cellular resources to DNA replication.
• The G2-M restriction point ensures that there has been accurate
genetic replication before the cell actually divides.
When cells do detect DNA imperfections, checkpoint activation
delays cell cycle progression and triggers DNA repair mechanisms.
If the genetic derangement is too severe to be repaired, the cells will
undergo apoptosis; alternatively, cells can enter a nonreplicative
state called senescence—primarily through p53-dependent
mechanisms (see later).
Enforcing the cell cycle checkpoints is the job of CDK inhibitors
(CDKIs); they accomplish this by modulating CDK-cyclin complex
activity. There are several different CDKIs:
• One family—composed of three proteins called p21 (CDKN1A),
p27 (CDKN1B), and p57 (CDKN1C)—broadly inhibits multiple
• The other family of CDKI proteins has selective effects on cyclin
CDK4 and cyclin CDK6; these proteins are called p15 (CDKN2B),
p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D).
Defective CDKI checkpoint proteins allow cells with damaged
DNA to divide, resulting in mutated daughter cells capable of
developing into malignant tumors.

Stem Cells (p. 26)
• During development, stem cells give rise to the various
differentiated tissues.
• In the adult organism, stem cells replace damaged cells and
maintain tissue populations.
• Stem cells are characterized by two important properties:
• Self-renewal, which permits stem cells to maintain their
• Asymmetric division, in which one daughter cell enters a
differentiation pathway and gives rise to mature cells, while
the other remains undifferentiated and retains its self-renewal
• There are fundamentally just two varieties of stem cells:
• Embryonic stem cells (ES cells) are the most undifferentiated.


Derived from the blastocyst inner cell mass, they have virtually
limitless cell renewal capacity and are totipotent (i.e., can give
rise to every cell in the body) (Fig. 1-16).
• Tissue stem cells (also called adult stem cells) have a limited
repertoire of differentiation; they can usually only produce
cells that are normal constituents of the particular tissue they
are found in. Adult stem cells are usually protected within
specialized tissue microenvironments called stem cell niches;
other cells and soluble factors within the niches keep the stem
cells quiescent until there is a need for
Hematopoietic stem cells are the best characterized; they
continuously replenish all the cellular elements of the blood.
Although rare, they can be purified based on cell surface markers
and can be used to repopulate marrows depleted after
chemotherapy (e.g., for leukemia) or to provide normal precursors
to correct various blood cell defects (e.g., sickle cell disease).
The bone marrow (and other tissues such as fat) also contains a
population of mesenchymal stem cells—multipotent cells that can
differentiate into a variety of stromal cells, including chondrocytes
(cartilage), osteocytes (bone), adipocytes (fat), and myocytes
• Induced pluripotent stem cells (iPS cells) can be created in the
laboratory by introducing a relative handful of genes into somatic
cells (e.g., skin fibroblasts). These genes reprogram the cells to
achieve the “stemness” of ES cells, and the resulting iPS cells can
then be differentiated into multiple lineages. Researchers also
have the capacity to “edit” genetic defects in cells using a Cas9
nuclease and CRISPR guide RNAs. In this way it is hoped that
host cells can be rewired and used to replace defective or
degenerated tissues—opening up the field of regenerative medicine
(p. 28).


FIGURE 1-16 Embryonal stem cells.

The zygote, formed by the union of sperm and egg,
divides to form blastocysts, and the inner cell mass of
the blastocyst generates the embryo. The pluripotent
cells of the inner cell mass, known as embryonic stem
(ES) cells, can be induced to differentiate into cells of
multiple lineages. In the embryo, pluripotent stem cells
can asymmetrically divide to yield a residual stable
pool of ES cells in addition to generating populations
that have progressively more restricted developmental
capacity, eventually generating stem cells that are
committed to just specific lineages. ES cells can be
cultured in vitro and be induced to give rise to cells of
all three lineages.



Cellular Responses to
Stress and Toxic
Adaptation, Injury, and Death
Introduction (p. 31)
Pathology is the study of the structural and functional causes of
human disease. The four aspects of a disease process that form the
core of pathology are as follows:
• The cause of a disease (etiology)
• The mechanism(s) of disease development (pathogenesis)
• The structural alterations induced in cells and tissues by the
disease (morphologic change)
• The functional consequences of the morphologic changes (clinical

Overview (p. 32)
Normal cell function requires a balance between physiologic
demands and the constraints of cell structure and metabolic
capacity; the result is a steady state, or homeostasis. Cells can alter
their functional state in response to modest stress to maintain the


steady state. More excessive physiologic stresses, or adverse
pathologic stimuli (injury), result in (1) adaptation, (2) reversible
injury, or (3) irreversible injury and cell death (Fig. 2-1, Table 2-1).
These responses may be considered a continuum of progressive
impairment of cell structure and function.
• Adaptation occurs when physiologic or pathologic stressors induce
a new state that changes the cell but otherwise preserves its
viability in the face of the exogenous stimuli. These changes
include the following:
• Hypertrophy represents increased cell size (p. 34) often in
response to increased workload. Induced by growth factors
produced in response to mechanical stress or other stimuli; will
increase overall organ size as well.
• Hyperplasia is increased cell number (p. 35) often secondary to
hormones and other growth factors. Occurs in tissues whose
cells are able to divide or contain abundant tissue stem cells.
• Atrophy represents decreased cell size (p. 36); this will also
diminish the overall organ size. Can occur secondary to disuse
or decreased nutrient supply and is associated with decreased
synthesis of cellular building blocks and/or increased
breakdown of cellular organelles, involving proteasome
degradation or autophagy.
• Metaplasia is change from one mature cell type to another (p.
37), often secondary to chronic inflammation. This occurs
through an altered differentiation pathway of tissue stem cells
and can adversely affect tissue function and/or predispose to
malignant transformation.


FIGURE 2-1 Stages of the cellular response to stress

and injurious stimuli.

Cellular Responses to Injury
Nature of Injurious Stimulus
Altered physiologic stimuli; some nonlethal,
injurious stimuli
Increased demand, increased stimulation (e.g., by
growth factors, hormones)
Decreased nutrients, decreased stimulation
Chronic irritation (physical or chemical)
Reduced oxygen supply; chemical injury; microbial
Acute and transient

Metabolic alterations, genetic or acquired; chronic
Cumulative, sublethal injury over long life span


Cellular Response
Cellular adaptations
Hyperplasia, hypertrophy
Cell injury
Acute reversible injury, cellular
swelling, fatty change
Irreversible injury → cell death
Intracellular accumulations;
Cellular aging

• Reversible injury denotes pathologic cell changes that can be
restored to normalcy if the stimulus is removed or if the cause of
injury is mild.
• Irreversible injury occurs when stressors exceed the capacity of the
cell to adapt (beyond a point of no return) and denotes permanent
pathologic changes that cause cell death.
• Cell death occurs primarily through two morphologic and
mechanistic patterns, necrosis and apoptosis (Table 2-2). Although
necrosis always represents a pathologic process, apoptosis may
also serve a number of normal functions (e.g., in embryogenesis)
and is not necessarily associated with cell injury.
Features of Necrosis and Apoptosis