Rapid Review Pathology

Hypoxia: general term for disorders causing inadequate oxy-genation of tissue • Several types of hypoxia produce oxygen 02-related changes reported with arterial blood gas measurements T

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PATHOLOGY

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NOTICE

Pathology is an ever-changing field Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications It

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The Publisher

ISBN-13: 978-0-323-02393-1

ISBN-10: 0-323-02393-2

Acquisitions Editor: William Schmitt

Managing Editor: Susan Kelly

Developmental Editors: Martha Cushman, Carol Vartanian

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Printed in the United States of America

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To my wife, Joyce Without you, my life would truly be incomplete -EFG

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•

Richard M Awdeh Yale University School of Medicine Joy A Baldwin

University of Vermont College of Medicine John Cowden

Yale University School of Medicine Andrew Deak

Northeastern Ohio Universities College of Medicine Tracey DeLucia

Loyola University Chicago Stritch School of Medicine

Acknowledgments

This book is the culmination of more than 22 years of teaching medical

students and almost 10 years of teaching USMLE Step 1 board review

courses in pathology Discussions with colleagues, mentors, and medical

students, both here and abroad, have contributed greatly to the writing of

this book.

I especially thank Ivan Damjanov, who has been a constant source of

inspiration over the years that I have been a student and a teacher of

pathology Many of his photographs are included in the book (and on the

CD-ROM) and exemplify his incredible breadth and depth of knowledge

and experience in the field of pathology Ivan, I truly value your friendship

and support.

Special thanks to Susan Kelly, Managing Editor, and her excellent team

of editors (Martha Cushman and Carol Vartanian) Thank you, Susan, for

providing me with valuable insights that often changed my gibberish

(thoughts) into words that actually made sense.

I also thank Matt Chansky, illustrator, who translated my thoughts into

figures, and my valued friend Karlis Sloka, who helped me write many of

the questions and discussions that are included in the book and on the

CD-ROM.

Edward F Goljan, MD

ix

IV Tissue repair 20

V Laboratory findings associated with inflammation 23

3 Immunopathology 24

I Cells of the immune system 24

II Major histocompatibility complex 25III Hypersensitivity reactions 25

IV Transplantation immunology 27

IV Shock 42

Table of Contents xi

5 Genetic and Developmental Disorders 44

I Mutations 44

II Mendelian disorders 45

III Chromosomal disorders 51

IV Other patterns of inheritance 55

V Disorders of sex differentiation 56

VI Congenital anomalies 57

VII Selected perinatal and infant disorders 59

VIII Diagnosis of genetic and developmental disorders 59

6 Environmental Pathology 60

I Chemical injury 60

II Physical injury 63

III Radiation injury 65

7 Nutritional Disorders 67

I Protein-energy malnutrition 67

II Eating disorders and obesity 67

III Fat-soluble vitamins 69

IV Water-soluble vitamins 72

8 Neoplasia 75

I Nomenclature 75

II Properties of benign and malignant tumors 77

III Cancer epidemiology 81

IV Vessel aneurysms 92

V Venous system disorders 95

VI Lymphatic disorders 96

VII Vascular tumors and tumor-like conditions 97

VIII Vasculitic disorders 97

IX Hypertension 100

10 Heart Disorders 103

I Ventricular hypertrophy 103

II Congestive heart failure 103

III Ischemic heart disease 105

IV Congenital heart disease 109

V Acquired valvular heart disease 112

VI Myocardial and pericardial disorders 117

VII Cardiomyopathy 118

VIII Tumors of the heart 119

Xii Table of Contents

11 Red Blood Cell Disorders 121

12 White Blood Cell Disorders 142

I Benign qualitative white blood cell disorders 142

II Benign quantitative white blood cell disorders 143III Neoplastic myeloid disorders 145

IV Lymphoid leukemias 151

13 Lymphoid Tissue Disorders 153

I Lymphadenopathy 153

II Reactive lymphadenitis 154III Non-Hodgkin's lymphoma 155

IV Hodgkin's lymphoma 156

V Plasma cell dyscrasias 158

VI Langerhans' cell histiocytoses 159VII Mast cell disorders 160

VIII Disorders of the spleen 160

15 Blood Transfusion Disorders 174

I ABO blood groups 174

II Rh and non-Rh antigen systems 174III Blood transfusion therapy 175

IV Hemolytic disease of the newborn 177

16 Respiratory Disorders 180

I Upper airway disorders 180

II Atelectasis 181III Respiratory infections 183

IV Vascular lung lesions 189

V Restrictive lung diseases 191

VI Obstructive lung diseases 194VII Neoplasms 198

VIII Disorders of the pleura 200

17 Gastrointestinal Disorders 201

I Disorders of the oral cavity: mouth and jaw 201

II Salivary gland tumors 202

III Disorders of the esophagus 203

IV Stomach disorders 207

V Disorders of the small and large bowels 210

VI Anorectal disorders 221

VII Acute appendicitis 221

18 Hepatobiliary and Pancreatic Disorders 222

1 Laboratory evaluation in liver cell injury 222

II Viral hepatitis 223

III Other inflammatory hepatic disorders 227

IV Circulatory disorders of the liver 228

V Alcohol-related and drug- and chemical-induced liver disorders 230

VI Cholestatic (obstructive) liver disease 230

VII Cirrhosis 231

VIII Liver tumors 234

IX Gallbladder and biliary tract disorders 235

X Cystic fibrosis 236

XI Pancreatic disorders 237

19 Kidney Disorders 239

1 laboratory studies used to assess renal function 239

II Congenital anomalies and cystic diseases of the kidney 240

III Glomerular disorders 242

IV Disorders affecting tubules and interstitium 251

V Chronic renal failure 254

VI Vascular disorders 255

VII Obstructive disorders 256

VIII Tumors of the kidney 256

20 Lower Urinary Tract and Male Reproductive Disorders 259

I Disorders of the urethra and bladder 259

II Disorders of the penis 260

III Disorders of the scrotum, testis, and epididymis 261

IV Prostate disorders 262

V Male hypogonadism and erectile dysfunction 266

21 Female Reproductive Disorders and Breast Disorders 267

I Sexually transmitted diseases and other genital infections 267

II Disorders of the vulva 269

III Disorders of the vagina 270

IV Disorders of the cervix 271

V Disorders of the uterus 272

VI Fallopian tube disorders: PID 275

VII Disorders of the ovary 275

VIII Gestational disorders 277

IX Breast disorders in females 279

X Breast disorders in males 283

XIV Table of Contents

22 Endocrine Disorders 284

I Overview of endocrine disease 284

II Pituitary gland 284 III Thyroid gland 287

IV Parathyroid glands 292

IV Fungal disorders 314

V Benign noninfectious disorders 315

VI Benign melanocytic disorders 318 VII Neoplastic skin disorders 318

25 Nervous System Disorders 321

I Cerebral edema, herniation, and hydrocephalus 321

II Developmental disorders 322 III Head trauma 324

IV CNS vascular disorders 325

V CNS infections 327

VI Demyelinating disorders 329 VII Degenerative disorders 331 VIII Toxic and metabolic disorders 334

IX CNS tumors 335

X Peripheral nervous system and pineal gland disorders 336

XI Selected eye and ear disorders 337

Tests 339

Table of Common Laboratory Values 340

Test 1 Questions 343 Test 1 Answers and Discussions 357 Test 2 Questions 389

Test 2 Answers and Discussions 403

Index 437

Cell Injury

1 Tissue Flypoxia

A Hypoxia: general term for disorders causing inadequate

oxy-genation of tissue

• Several types of hypoxia produce oxygen (02)-related

changes reported with arterial blood gas measurements

(Table 1-1)

B Ischemia: reduction in arterial blood flow (e.g., occlusion of

arteries, such as coronary artery atherosclerosis)

C Hypoxemia: decrease in the amount of 0 2 dissolved in

plasma; caused by:

1 Respiratory acidosis: due to carbon dioxide (CO 2)

reten-tion in the lungs

2 Ventilation defect: impaired 0 2 delivery to the alveoli

a Perfusion of alveoli without gas exchange

b Produces intrapulmonary shunting of blood

3 Perfusion defect: absence of blood flow to alveoli (e.g.,

pulmonary embolus)

4 Diffusion defect: inability of 0 2 to diffuse through the

alveolar-capillary interface (e.g., interstitial fibrosis)

D Hemoglobin (Hb)-related abnormalities

1 Anemia: reduction in Hb concentration (normal 0 2

dis-solved in the plasma of arterial blood, Pa02; and

normal arterial 0 2 saturation, Sa02)

2 Methemoglobinemia: excessive methemoglobin

(metHb) in the blood

a Oxidized heme groups cannot bind 0 2, decreasing

5a02 without affecting Pa02

b Caused by oxidizing agents (e.g., nitrite- or

sulfur-containing drugs, such as nitroglycerin and prim—sulfamethoxazole) or a deficiency of metHbreductase (normally converts ferric iron, Fe 3+, toferrous iron, Fe2+)

trimetho-Most common cause of hypoxia: coronary artery atherosclerosis

1

2 Pathology

TABLE 1-1 Terminology Associated With Oxygen Transport and Hypoxia

Pa02 Amount of 02

dissolved in plasma

of arterial blood Sa02 Average percentage

of 0 2 bound to Hb

0 2 content Total amount of 02

carried in blood

Percent 0 2 in inspired air, atmospheric pressure, normal

0 2 exchange Pa0 2 and valence of heme iron in each

of the four heme groups

Fe' binds to 0 2 ; Fe3+

does not

Hb concentration in red blood cells (most important factor), Pa0 2 , Sa02

Reduced in emia

hypox-Sa0 2 < 80% produces cyanosis of skin and mucous membranes

Hb is most important carrier of 02

Fee ', ferrous iron; Fe', ferric iron; Hb, hemoglobin; 02, oxygen Pa02, partial pressure of arterial oxygen; Sa02, arterial oxygen saturation

Patients with methemoglobinemia have

chocolate-colored blood and cyanosis; their skincolor does not return to normal after administra-

tion of 0 2 Treatment is methylene blue vates metHb reductase) and ascorbic acid (re-

(3) It causes a left shift in the 0 2-binding curve.

b Causes: automobile exhaust, smoke inhalation

4 Factors causing a left shift in the 02 -binding curve

E Abnormalities in oxidative phosphorylation: decreased synthesis of adenosine triphosphate (ATP) in the inner mito- chondrial membrane

1 Defective oxidative phosphorylation

the electron transport chain, which normally fers electrons to 02

trans-b CN poisoning may result from drugs (e.g., side) and combustion of polyurethane products.

nitroprus-2 Uncoupling of oxidative phosphorylation

a Uncoupling proteins (e.g., thermogenin in brown fat

in newborns) carry protons pumped from the tron transport chain into the mitochondrial matrix,

elec-Treat CO poisoning

with 100% 02_

CO and CN inhibit

cytochrome oxidase.

Chapter 1 Cell Injury 3

bypassing ATP synthase and decreasing ATP

synthesis.

Agents such as alcohol and salicylates act as

mitochondrial toxins They damage the inner

mitochondrial membrane, causing protons tomove into the mitochondrial matrix

b Oxidative energy is released as heat rather than as

ATP, increasing the danger of hyperthermia.

II Consequences of Hypoxic Cell Injury

A Decreased synthesis of ATP: reversible change

1 Anaerobic glycolysis is used for ATP synthesis and is

accompanied by:

a Activation of phosphofructokinase caused by

low citrate levels and increased adenosinemonophosphate

b Decrease in intracellular pH caused by an excess of

lactate

2 Impaired Ne, K+ -ATPase pump, resulting in diffusion

of M.+ and H 20 into cells and causing cellular swelling

3 Impaired calcium (Ca 2+)-ATPase pump, resulting in

in-creased cytosolic Ca2+

4 Decreased protein synthesis, resulting from the

detach-ment of ribosomes from the rough endoplasmic

reticulum

B Increased cytosolic Ca 2+, which leads to:

1 Enzyme activation

a Activates phospholipase: increases cell and

organ-elle membrane permeability

b Activates proteases: damages membrane and

struc-tural proteins

c Activates endonucleases: damages nuclear

chro-matin, causing fading (karyolysis)

2 Reentry of Ca 2+ into mitochondria: increases

mitochon-drial membrane permeability, with release of

cyto-chrome c (activates apoptosis)

[II Free Radical Cell Injury

• Free radicals are compounds with unpaired electrons in the

outer orbit.

A 02 -derived free radicals

1 Superoxides (02 ): neutralized by superoxide dismutase

2 Hydroxyl ions (OH • ): neutralized by glutathione

peroxidase

3 Peroxides (H 2 02): neutralized by catalase (located in

per-oxisomes) and glutathione peroxidase

B Drug and chemical free radicals: conversion to free radicals

occurs via the cytochrome P-450 system in the liver

Lactate decreases intracellular pH and denatures struc- tural and enzyme proteins.

4 Pathology

1 Free radicals from acetaminophen, which may be tralized by glutathione peroxidase, lead to liver andkidney injury

neu-2 Carbon tetrachloride (CC14) is converted to CC13•,

leading to liver cell necrosis with fatty change.

C Consequences of free radical injury

1 Lipid peroxidation of polyunsaturated fats, leading to

increased permeability of cells and organelles

2 Irreversible injury to nuclear DNA and cytoskeletalproteins

3 Clinical correlations

a Reperfusion injury in the heart after myocardial

infarction: 02i and cytosolic Ca 2+ irreversiblydamage previously injured cells on restoration ofblood flow

b 02 toxicity (levels > 50%): 0 2i may damage retinal

tissue, causing blindness

c Iron overload (e.g., hemochromatosis): intracellular

iron produces OH • , which damages parenchymalcells (e.g., cirrhosis)

IV Injury to Cellular Organelles

A Mitochondria: injury initiates apoptosis resulting from the

release of cytochrome c

B Smooth endoplasmic reticulum (SER)

1 Initiation of the cytochrome P-450 system by drugs or chemicals

a Caused by alcohol, barbiturates, phenytoin, andnicotine

b Results in SER hyperplasia and increased drug

de-toxification, with lower-than-expected therapeuticdrug levels

2 Inhibition of the cytochrome P-450 system

a Caused by histamine receptor blockers (e.g., cimetidine) and proton pump inhibitors

(e.g., omeprazole)

b Results in decreased drug detoxification, with

higher-than-expected therapeutic drug levels

C Lysosomes

1 Primary lysosomes

a Hydrolytic enzymes destined for primary lysosomes

are marked with mannose 6-phosphate in the

Chapter 1 Cell Injury 5

Inclusion (D-cell disease is a rare inherited dition in which lysosomal enzymes lack themannose 6-phosphate marker Therefore, pri-mary lysosomes do not contain the hydrolyticenzymes necessary to degrade complex sub-strates, and undigested substrates accumulate aslarge inclusions in the cytosol Symptoms in-clude psychomotor retardation and early death

con-2 Secondary lysosomes (phagolysosomes): arise from

fusion of primary lysosomes with phagocytic vacuoles:

defective in Chêdiak-Higashi syndrome

D Cytoskeleton

1 Mitotic spindle defects: drugs bind to tubulin in

micro-tubules (e.g., vinca alkaloids, colchicine)

2 Mallory bodies: damaged keratin intermediate filaments

in alcoholic liver disease

3 Rigor mortis: myosin heads become locked to actin

fila-ments due to a lack of ATP

1 Mechanisms of fatty change

a Increased glycerol 3-phosphate

(1) Reduced nicotinamide adenine dinucleotide(NADH) is a product of alcohol metabolism

(2) Increased NADH accelerates enzyme sion of dihydroxyacetone phosphate to glycerol3-phosphate

conver-b Increased fatty acid synthesis (e.g., increased

pro-duction of acetyl coenzyme A, a product of alcoholmetabolism)

c Decreased (3-oxidation of fatty acids (e.g., alcohol,

diphtheria toxin)

d Increased mobilization of fatty acids from adipose

tissue (e.g., starvation, alcohol)

e Decreased synthesis of apolipoprotein B-100 (e.g.,

decreased protein intake in kwashiorkor)

f Decreased hepatic release of very low density

lipo-protein (e.g., alcohol)

2 Morphology

a Gross: normal or enlarged liver with a yellowish

discoloration

b Microscopic: clear space pushing the nucleus of the

hepatocyte to the periphery

B Iron (see Table 1-2)

1 Ferritin: major soluble iron storage protein

Most common cause of fatty change in the liver: alcohol

6 Pathology

TABLE 1-2 Intracellular Accumulations

Substance Clinical Significance

Endogenous Accumulations

Cholesterol Xanthelasma: yellow plaque on eyelid; cholesterol in

macrophages Atherosclerosis: cholesterol-laden smooth muscle cells and macrophages are component of fibrofatty plaque Glycogen Diabetes mellitus: increased glycogen in hepatocyte nuclei

and renal tubule cells Von Gierke's glycogenosis: deficiency of glucose-6- phosphatase; glycogen excess in hepatocytes and renal tubular cells

Melanin Nevus: benign pigmented melanocytic neoplasm of skin Hemosiderin and ferritin

Bilirubin

Iron overload disorders (e.g., hemochromatosis): excess hemosiderin deposition in parenchymal cells, leading to free radical damage and organ dysfunction (e.g., cirrho- sis); increase in serum ferritin

Iron deficiency: decrease in ferritin and hemosiderin Kernicterus: fat-soluble unconjugated bilirubin derived from Rh hemolytic disease of newborn; bilirubin enters basal ganglia nuclei of brain, causing permanent damage

Coal worker's pneumoconiosis: phagocytosis of black anthracotic pigment (coal dust) by alveolar macrophages ("dust cells")

Lead poisoning: lead deposits in nuclei of proximal renal tubular cells (acid-fast inclusion) contribute to nephro- toxic changes in proximal tubule

b Small amounts circulate in serum: decreased serum

ferritin correlates with decreased ferritin stores inbone marrow macrophages

2 Hemosiderin: product of ferritin degradation in

lyso-somes; appears as golden-brown granules in tissue or asblue granules when stained with Prussian blue

C Pathologic calcification

1 Dystrophic calcification: deposition of calcium

phos-phate in necrotic tissue

a Normal serum calcium and phosphate

b Example: calcified atherosclerotic plaque

2 Metastatic calcification: deposition of calcium

phos-phate in normal tissue (e.g., calcification of renal tubular

basement membranes); causes include:

a Hypercalcemia (primary hyperparathyroidism)

b Hyperphosphatemia: phosphate drives calcium into

normal tissue (renal failure)

Serum ferritin is

decreased In iron

deficiency anemia

Chapter 1 Cell Injury 7

side) and the thickened interventricular septum The right ventricle wall (left side) is of normal

thickness.

VI Adaptation to Cell Injury : Growth Alterations

A Atrophy: diminished cell size or loss of cells

1 Causes of diminished cell size

a Decreased hormone stimulation (e.g.,

hypopituita-rism causing atrophy of target organs, such as the thyroid)

b Decreased activity (e.g., muscle atrophy following

loss of lower motor neurons in poliomyelitis)

c Reduced blood flow (e.g., cerebral atrophy)

d Occlusion of secretory ducts

2 Cell loss is caused by apoptosis.

3 Cell and organ effects of atrophy

a Increased catabolism of cell organelles (e.g., chondria) leads to a reduction in tissue mass and

mito-function.

Brown atrophy is a tissue discoloration that

results from lysosomal accumulation of

lipofus-cin ("wear and tear" pigment), which is

associ-ated with free radical damage and tissue atrophy.

Lipofuscin is an indigestible lipid derived from lipid peroxidation of cell membranes.

B Hypertrophy: increase in cell size due to increased demand

1 Causes

a Increased workload (e.g., increased peripheral tance imposed on cardiac muscle in the left ventri- cle in essential hypertension; (Figure I-I)

resis-b Removal of an organ (e.g., removal of one kidney

causes hypertrophy of the remaining kidney)

2 Cell and organ effects of hypertrophy: increased

syn-thesis of cell structural components and organelles leads

to an increase in organ size and function.

Pancreatic exocrine deficiency in cystic fibrosis is due to atrophy of the exo- crine glands.

8 Pathology

C Hyperplasia: increase in the number of normal cells

1 Causes

a Hypersecretion of a trophic hormone (e.g., excess

release of growth hormone in acromegaly)

b Chronic irritation (e.g., bronchial mucous gland

hy-perplasia in smokers)

c Chemical imbalance (e.g., hypocalcemia stimulates

parathyroid gland hyperplasia)

2 Hyperplasia (and hypertrophy) depends on the ative capacity of different types of cells.

regener-a Labile cells (stem cells) divide continuously and

mainly undergo hyperplasia as an adaptation to cellinjury (e.g., stimulation of red blood cell stem cells

by erythropoietin in blood loss)

b Stable cells (resting cells) divide infrequently and

undergo hyperplasia and/or hypertrophy (e.g., plasia of hepatocytes in liver injury; hyperplasia andhypertrophy of smooth muscle cells in the uterusduring pregnancy)

hyper-c Permanent cells (nonreplicating cells) are highly

specialized cells that undergo hypertrophy only (e.g.,cardiac and striated muscle)

3 Cell and organ effects of hyperplasia

a Increase in organ size and function

b Potential for developing cancer if not treated

D Metaplasia: replacement of one fully differentiated tissue by

another

1 Involves reprogramming stem cells in response to

signals, such as hormones (e.g., estrogen); vitamins(e.g., retinoic acid); or chemical irritants (e.g., cigarettesmoke); sometimes reversible

2 Types of metaplasia

a Squamous: replacement of columnar epithelium by

squamous epithelium (e.g., squamous metaplasia

of mainstem bronchus from smoking tobacco)

b Glandular: replacement of squamous epithelium

with intestinal cells (e.g., goblet cells, secreting cells)

mucus-Glandular metaplasia of the distal esophagus

results from injury of the squamous epithelium

by gastric acid in gastroesophageal reflux disease

(Barrett's esophagus) Persistence of acid reflux

may result in gastric adenocarcinoma of thedistal esophagus

E Dysplasia: abnormal tissue development

110 • 'dr

Chapter 1 Cell Injury 9

Figure 1-2 Squamous dysplasia of the cervix, a precursor of squamous cell carcinoma There

is a complete lack of orientation of the squamous cells throughout the full thickness of the

epithelium The arrow points to one of the many atypical nuclei

b Metaplasia (e.g., squamous metaplasia of the stem bronchus in smokers)

main-c Infection (e.g., human papilloma virus type 16,causing cervical dysplasia)

d Ultraviolet light (e.g., solar damage of skin, causing

squamous dysplasia)

2 Microscopic features of dysplasia (Figure 1-2)

a Increased mitotic activity, with normal mitoticspindles

b Disorderly proliferation of cells with loss of cell

maturation as cells progress to the surface

c Nuclear variation in size, shape, and density ofchromatin

3 May be a transitional stage linking neoplasia to

meta-plasia or to hypermeta-plasia; if the irritant is removed (e.g.,cessation of smoking), dysplasia may not progress tocancer

4 Examples

a Squamous dysplasia associated with squamous cell carcinoma (e.g., squamous dysplasia of the main-

stem bronchus in a smoker)

b Glandular dysplasia associated with noma (e.g., Barrett's esophagus, endometrialhyperplasia)

of neoplasia.

A B

10 Pathology

the right foot shows coagulation necrosis The dark black area of gangrene is bordered by the light-colored, parchment-like skin The tip of the third toe has early signs of gangrene Wet gangrene (B) involving the hallux area of the left foot shows liquefactive necrosis caused by a superimposed infection of anaerobic bacteria, usually Clostridium perfringens The taut skin and areas of ulceration extend from the metatarsal head to the lateral border of the big toe

VII Cell Death

• Cell death occurs when cells or tissues are unable to adapt toinjury

A Necrosis: death of groups of cells, often accompanied by aninflammatory infiltrate

1 Coagulation necrosis: preservation of the structuraloutline of dead cells

a Mechanism: denaturation of enzymes and tural proteins by intracellular accumulation oflactate or heavy metals (e.g., lead, mercury); inacti-vation of intracellular enzymes prevents dissolu-tion (autolysis) of the cell

struc-b Infarcts: gross manifestations of coagulation necrosissecondary to the sudden occlusion of a vessel

(1) Usually wedge-shaped and occur when omously branching vessels (e.g., pulmonaryartery) are occluded

dichot-(2) Pale (ischemic): increased density of tissue(e.g., heart, kidney, spleen) prevents red bloodcells from diffusing through necrotic tissue

Dry gangrene of the toes in individuals

with diabetes mellitus is a form of

infarc-tion that results from ischemia

Coagula-tion necrosis is the primary type of

necro-sis present in the dead tissue (Figure 1-3, A)

(3) Hemorrhagic (red): loose-textured tissue (e.g.,lungs, small bowel) allows red blood cells todiffuse through necrotic tissue

Chapter 1 Cell Injury 11

Figure 1-4 Acute myocardial infarction (MI) showing coagulation necrosis This section of

myocardial tissue is from a 3-day-old acute MI The outlines of the myocardial fibers are intact;

however, they lack nuclei and cross-striations A neutrophilic infiltrate is present between

some of the dead fibers

c Microscopic features (Figure 1-4)

(1) Indistinct outlines of cells within dead tissue(2) Absent nuclei or karyolysis (fading of nuclearchromatin)

2 Liquefactive necrosis: necrotic degradation of tissue

that softens and becomes liquified

a Central nervous system infarction: autocatalytic

effect of hydrolytic enzymes generated by neuroglialcells produces a cystic space

b Abscess in a bacterial infection: hydrolytic enzymes

generated by neutrophils liquefy dead tissue

Wet gangrene of the toes of individuals with

diabetes mellitus is a superimposed anaerobic

infection of dead tissue Liquefactive necrosis is

the primary type of necrosis present in the dead

tissue (Figure 1-3, B).

3 Caseous necrosis: variant of coagulation necrosis

associ-ated with acellular, cheese-like (caseous) material

a Gaseous material is formed by the release of lipid

from the cell walls of Mycobacterium tuberculosis and systemic fungi (e.g., Histoplasma) after destruction by

4 Enzymatic fat necrosis: peculiar to adipose tissue located

around an acutely inflamed pancreas

Most common cause of caseous necrosis:

tuberculosis

Enzymatic fat crosis is associated with acute

ne-pancreatitis.

12 Pathology

a Mechanisms (1) Activation of pancreatic lipase (e.g., alcohol

excess): hydrolysis of triacylglycerol in fat cells

(2) Conversion of fatty acids into soap

(saponifi-cation): combination of fatty acids and calcium

b Gross appearance: chalky yellow-white deposits

are primarily located in peripancreatic andomental adipose tissue

c Microscopic appearance: pale outlines of fat cells

filled with basophilic-staining calcified areas

d Distinction from traumatic fat necrosis: occurs in

fatty tissue (e.g., female breast tissue) as a result oftrauma; is not enzyme-mediated

5 Fibrinoid necrosis: limited to small muscular arteries, terioles, venules, and glomerular capillaries

ar-a Mechanism: deposition of pink-staining

proteina-ceous material in damaged vessel walls

b Associated conditions: immune vasculitis (e.g.,

Henoch-SchOnlein purpura), malignant hypertension

B Apoptosis: genetically controlled, enzyme-dependent death

of individual cells

1 Events in apoptosis

a Signals that initiate the process

(1) Binding of tumor necrosis factor to its receptor(2) Injurious agents: viruses, radiation, free radicalsthat damage DNA

(3) Withdrawal of growth factors or hormones

b Modulators that control cell response to the signal

(1) TP53 (p53) suppressor gene: temporarily

arrests the cell cycle to repair DNA damage(aborts apoptosis) or promotes apoptosis if DNA

damage is too great by activating the BAX

apoptosis gene

(2) BCL2 gene family: manufactures gene products

that inhibit apoptosis by preventing dria) leakage of cytochrome c into the cytosol

mitochon-c Enzymatic cell death beginning with activation of

the caspases (group of cysteine proteases)

(1) Activation of endonuclease leads to nuclear

pyknosis ("ink dot" appearance) andfragmentation

(2) Activation of protease leads to the breakdown

of the cytoskeleton

d Formation of cytoplasmic buds on the cell

mem-brane, which contain nuclear fragments, dria, and condensed protein fragments

mitochon-e Formation of apoptotic bodies by the breaking off of

Chapter 1 Cell Injury 13

TABLE 1-3 Enzyme Markers of Cell Death

Aspartate aminotransferase

(AST)

Alanine aminotransferase (ALT)

Creatine kinase MB (CK-MB)

Amylase and lipase

Marker of diffuse liver cell necrosis (e.g., viral hepatitis)

Mitochondrial enzyme preferentially increased in alcohol-induced liver disease

Marker of diffuse liver cell necrosis (e.g., viral hepatitis)

More specific for liver cell necrosis than AST Isoenzyme elevated in acute myocardial infarction or myocarditis

Marker enzymes for acute pancreatitis Lipase more specific than amylase for pancreatitis Amylase also increased in salivary gland inflamma- tion (e.g., mumps)

b Deeply eosinophilic-staining cytoplasm

c Pyknotic, fragmented, or absent nucleus

d Minimal or no inflammatory infiltrate surrounding

the cell

3 Examples

a Programmed destruction of cells during

embryo-genesis (e.g., loss of mullerian structures in malefetus)

b Hormone-dependent atrophy of tissue (e.g.,

endo-metrial cell breakdown after withdrawal of gen and progesterone in the menstrual cycle)

estro-c Death of tumor cells by cytotoxic T cells

C Enzyme markers of cell death

1 Tissues release certain enzymes that indicate the type of

tissue involved and extent of injury

2 Table 1-3 lists clinically significant enzyme markers

A Cardinal signs of inflammation

1 Rubor (redness): histamine-mediated vasodilation of

2 Vasodilation of arterioles: mast cells release histamine,

which acts on vascular smooth muscle and causes creased blood flow

in-3 Increased permeability of venules: histamine contractsendothelial cells of the vessels, causing movement of a

transudate into interstitial tissue.

4 Swelling of tissue: outflow of fluid surpasses lymphaticability to remove fluid

5 Reduced blood flow: caused by outflow of fluid from

blood vessels

C Cellular events

1 Margination: red blood cells (RBCs) aggregate into

rou-leaux ("stacks of coins") in venules, with the neutrophilspushed to the periphery

2 Rolling: selectin molecules on the cell surfaces cause theneutrophils to "roll" along the endothelium or toadhere to it temporarily

3 Adhesion: neutrophils adhere to endothelial cells

Neutrophils are the

primary

leuko-cytes in acute

inflammation

14

Chapter 2 Inflammation and Repai r 15

a Activation of adhesion molecules on neutrophils(CD11/CD18 integrins) is mediated by C5a and leu-kotriene B4 (LTB4)

b Activation of adhesion molecules on endothelial cells

is mediated by interleukin-1 (IL-1) and tumor sis factor (TNF)

necro-4 Transmigration: neutrophils move through the

base-ment membrane of venules and release type IV nase, producing an exudate in the interstitial tissue

collage-Leukocyte adhesion molecule defect prevents

neu-trophil adhesion and transmigration into tissue,causing failure of the umbilical cord to separate afterbirth Histologic sections of the umbilical cord do notshow margination or transmigration by neutrophilsinto the connective tissue matrix

5 Chemotaxis: neutrophils migrate toward bacteria.

a Chemical mediators (e.g., C5a, LTB4) bind to

neu-trophil receptors

b Binding causes the release of calcium, increasing trophil motility

neu-6 Phagocytosis: neutrophils ingest opsonized bacteria.

a Opsonization: IgG and C3b attach to bacteria.

b Ingestion: neutrophils with membrane receptors for

IgG and C3b engulf and then trap bacteria inphagocytic vacuoles

c Phagolysosome formation: primary lysosomes

empty hydrolytic enzymes into phagocytic vacuoles

In Chediak-Higashi syndrome, a defect in

mi-crotubule polymerization inhibits phagocytosisand chemotaxis The lysosomes are packed withenzymes and appear as large azurophilic granules

in leukocytes

7 Bacterial killing by neutrophils

a 02-dependent myeloperoxidase system (Figure 2-1) (1) Production of superoxide free radicals (0 2 i ):

reduced nicotinamide adenine dinucleotide

phosphate (NADPH) oxidase in the neutrophil

cell membrane converts molecular 02 to 02iusing NADPH (pentose phosphate pathway);

the resulting release of energy is called the

res-piratory (oxidative) burst.

(2) Production of peroxide (H202): superoxide

dismutase converts 0 2i to H 202, which is tralized by glutathione peroxidase

de-Most potent bicidal system: 02-dependent myeloperoxidase system

mIcro-C3b receptor'

Or. GSH GSSG

NADP+ NADPH G6-P 6PG

Glucose-6-phosphate dehydrogenase

16 Pathology

Figure 2 - 1 Oxygen-dependent myeloperoxidase system A series of biochemical reactions occurs in the

phagolyso-some, resulting in the production of hypochlorous free radicals (bleach; HOC• that destroy bacteria, GSH, reduced glutathione; G6-P, glucose 6-phosphate; GSSG, oxidized glutathione; H2 02, peroxide; MPO, myeloperoxidase; oxidized form of nicotinamide adenine dinucleotide phosphate; NADPH, reduced nicotinamide adenine dinucleotide phosphate; 6PG, 6-phosphogluconate; SOD, superoxide dismutase

(3) Production of bleach (HOC1 • ): dase combines H2 0 2 with chloride (a-) to formhypochlorous free radicals (HOC1 •), which killbacteria

myeloperoxi-Chronic granulomatous disease of hood, an X-linked recessive disorder, is

child-characterized by deficient NADPH oxidase

in the cell membranes of neutrophils and monocytes The reduced production of 02i results in an absent respiratory burst.

Catalase-positive organisms that produce

H20 2 (e.g., Staphylococcus aureus) are

in-gested but not killed, because the catalase

degrades H 202 Myeloperoxidase is present, but HOC1 • is not synthesized because of the

absence of H 20 2 Catalase-negative

organ-isms (e.g., Streptococcus species) are gested and killed when myeloperoxidase

Chapter 2 Inflammation and Repair 17

Myeloperoxidase deficiency, an autosomal

re-cessive disorder, differs from chronic tous disease in that both 0 2: and H202 areproduced (normal respiratory burst) The ab-sence of myeloperoxidase prevents synthesis ofHOC1•

granuloma-b 02-independent system (e.g., lysosomal enzymes;

lactoferrin, which binds iron)

D Chemical mediators (Table 2-1)

1 Histamine: vasoactive amine; acts as a key mediator in

acute inflammation

2 Serotonin: vasoactive mediator, with actions similar to

histamine

3 Arachidonic acid mediators (Figure 2-2)

a Arachidonic acid is released from membrane

phos-pholipids by phospholipase A2 and is

synthe-sized from linoleic acid (o)6 essential fatty acid).

b Compounds synthesized from arachidonic acid:

prostaglandins; thromboxane A2 (TXA2); leukotrienes(LT B,, LTC 4, LTD 4 , LTE4)

4 Nitric oxide (NO): free radical gas

5 Cytokines: IL-1 and TNF

6 Bradykinin

7 Complement

E Outcome of acute inflammation

1 Complete resolution: only mild injury to labile and

stable cells

2 Tissue destruction and scar formation: extensive injury

(e.g., abscess) or damage to permanent cells

3 Progression to chronic inflammation

II Chronic Inflammation

• Inflammation of prolonged duration (weeks to years) most often

results from persistence of an injury-causing agent

A Injurious agents include infectious diseases (e.g., hepatitis C,

tuberculosis) and alcohol

B Morphology

1 Cell types: monocytes and/or macrophages,

lympho-cytes and/or plasma cells, eosinophils, fibroblasts,

endo-thelial cells

2 Necrosis: not as prominent a feature as in acute

inflammation

3 Destruction of parenchyma: loss of functional tissue,

with repair by fibrosis

C Granulomatous inflammation

1 Causes

a Infectious agents include tuberculosis and systemic

fungal infection; usually associated with caseousnecrosis

Histamine is the main chemical medi- ator of acute inflammation.

Bradykinin induces cough and angio- edema in patients taking ACE inhibitors.

Monocytes and/or macrophages are the primary leuko- cytes in chronic inflammation.

Thromboxane A 2 (TXA2 ) Platelets

Converted from PGH, by thromboxane synthase

Leukotrienes (LTs) Converted from arachidonic acid by

lipoxygenase-mediated hydroxylation

Vasodilation, increased permeability Vasodilation, increased permeability

PGE 2 : vasodilation, pain, fever

PGI 2 : vasodilation; inhibition of platelet aggregation

Vasoconstriction, platelet aggregation, bronchoconstriction

LTB 4 : chemotaxis and adhesion phil molecule activation

neutro-LTC 4 , LTD,, LTE 4 : vasoconstriction, increased vessel permeability, bronchoconstriction

Vasodilation, bactericidal

Initiate PGE 2 synthesis in anterior thalamus, leading to production of fever

hypo-Activate endothelial cell adhesion molecules

Increase liver synthesis of acute-phase reactants, such as ferritin, coagulation factors (e.g., fibrinogen), and

perme-C5a: activation of neutrophil adhesion molecules, chemotaxis

C5–C9 (membrane attack complex): cell lysis

Mast cells, basophils, platelets

Leukocytes, endothelial cells, platelets PGH 2 : major precursor of PGs and thromboxanes

PGG 2 : converted from arachidonic acid

Product of kinin system activation by activated factor XII

Synthesized in liver

b Noninfectious causes include sarcoidosis and

Crohn's disease; associated with noncaseating

•

Chapter 2 Inflammation and Repair 19

Cell membrane phospholipids

Figure 2-2 Arachidonic acid metabolism Arachidonic acid is released from membrane

phospholipids It is converted into prostaglandins (PGs), thromboxane A2 (TXA2), and

leukotrienes (LTs).

Figure 2-3 Caseous tuberculous granuloma in the lung showing the well-circumscribed

nature of the granuloma Granular, acellular material in the center of the lesion represents

caseous necrosis The arrow indicates a multinucleated giant cell The majority of cells

represent activated macrophages (epithelioid cells) and activated TH1 cells.

(2) Cell types: epithelioid cells (activated

macro-phages), mononuclear (round cell) infiltrate(CD4 helper T cells, or T H cells of the TH 1 type)

(3) Multinucleated giant cells: fusion of

epitheli-oid cells; nuclei usually at the periphery

3 Pathogenesis of a tuberculous granuloma (Box 2-1)

[II Patterns of Inflammation

A Suppurative (purulent) inflammation

1 Localized proliferation of pus-forming organisms, such as

Staphylococcus aureus (e.g., skin abscess)

2 S aureus contains coagulase, which cleaves fibrinogen

into fibrin and traps bacteria and neutrophils

B Cellulitis

1 Proliferation of bacteria (e.g., Streptococcus pyogenes)

through subcutaneous tissue (e.g., erysipelas)

20 Pathology

BOX 2-1 Sequence of Formation of a Tuberculous Granuloma

1 The tubercle bacillus Mycobacterium tuberculosis undergoes phagocytosis

by alveolar macrophages (processing of bacterial antigen).

2 Macrophages present antigen to CD4 T cells in association with class II

5 Lipids from killed tubercle bacillus lead to caseous necrosis

6 Activated macrophages fuse and become multinucleated giant cells.

2 S pyogenes contains hyaluronidase, which hydrolyzes the extracellular matrix (ECM), causing bacteria to spread.

C Pseudomembranous inflammation

• Bacterial toxin-induced damage of the mucosal lining, ducing a shaggy membrane composed of necrotic tissue (e.g., pseudomembranes associated with Clostridium difficile

F Fistula

• Inflammatory reaction producing a passage between two hollow organs (e.g., bowel-to-bowel fistulas in Crohn's disease)

IV Tissue Repair

A Factors involved in tissue repair

2 Repair by connective tissue (fibrosis)

B Parenchymal cell regeneration

1 Depends on the ability of cells to replicate

a Labile cells (e.g., stem cells in epidermis) and stable

cells (e.g., hepatocytes, fibroblasts) are able to licate (see Chapter 1).

rep-b Permanent cells are unable to replicate.

(1) Cardiac and striated muscle are replaced by scar

tissue (fibrosis).

2 Requires factors that stimulate parenchymal cell tion (e.g., growth factors, hormones, loss of tissue)

regenera-3 Restoration to normal (e.g., first-degree burn) requires

preservation of the basement membrane and a

Chapter 2 Inflammation and Repair 21

relatively intact connective tissue infrastructure

(e.g., collagen, adhesive proteins).

C Repair by connective tissue (fibrosis)

1 Occurs when injury to parenchymal cells, basement

membranes, and connective tissue infrastructure is severe

or persistent (e.g., third-degree burn)

2 Requires neutrophil transmigration to liquefy injured

tissue and then macrophage transmigration to remove

the debris

3 Depends on the formation of granulation tissue in

the ECM

a Granulation tissue is highly vascular and composed

of newly formed blood vessels and fibroblasts

b It requires fibronectin, whose functions include:

(1) Chemotaxis of fibroblasts, which synthesize

collagen, and endothelial cells, which form

new blood vessels (angiogenesis)

(2) Binding of collagen and other components to

glycoproteins on the cell surface (integrins)

c It accumulates in the ECM and eventually produces

dense fibrotic tissue (scar).

4 Requires the initial production of type III collagen

a Collagen is the major fibrous component of

connec-tive tissue

b It is a triple helix of cross-linked a-chains; lysyl

oxidase cross-links points of hydroxylation (vitamin

C—mediated) on adjacent a-chains

c Cross-linking increases the tensile strength of

collagen

d Type I collagen in skin, bone, and tendons has

greater tensile strength than type III collagen in the

early phases of tissue repair

Ehlers-Danlos syndrome consists of a group of

mendelian disorders characterized by defects oftype I and type III collagen synthesis and struc-ture Clinical findings include hypermobilejoints, aortic dissection (most common cause ofdeath), bleeding into the skin (ecchymoses), andpoor wound healing

5 Dense scar tissue produced from granulation tissue must

be remodeled.

a Remodeling increases the tensile strength of scar

tissue

b Metalloproteinases (collagenases) replace type III

collagen with type I collagen, increasing tensile

strength to approximately 80% of the original

An intact basement membrane is es- sential for normal cell proliferation and repair.

Granulation tissue

is essential for normal connective tissue repair.

22 Pathology

Primary intention Day 1: fibrin clot (hematoma) develops Neutrophils infiltrate the

wound margins There is increased mitotic activity of basal cells of mous epithelium in the apposing wound margins.

squa-Day 2: squamous cells from apposing basal cell layers migrate under the

fibrin clot and seal off the wound after 48 hours Macrophages

emi-grate into the wound.

Day 3: granulation tissue begins to form Initial deposition of type III

collagen begins but does not bridge the incision site Macrophages replace neutrophils.

Days 4-6: granulation tissue formation peaks, and collagen bridges the

replace-Secondary intention: typically, these wounds show:

More intense inflammatory reaction than primary healing Increased amount of granulation tissue formation than in primary healing

Wound contraction caused by increased numbers of myofibroblasts

6 Wound healing (Box 2-2)

a Healing by primary intention: approximation of

wound edges by sutures; used for clean surgicalwounds

b Healing by secondary intention: wound remainsopen; used for gaping or infected wounds

D Factors that impair healing

1 Persistent infection

2 Metabolic disorders (e.g., diabetes mellitus): ity to infection caused by impaired circulation and in-creased glucose

susceptibil-3 Nutritional deficiencies: decreased protein, vitamin C deficiency, trace metals (zinc; cofactor in type III

collagenase)

4 Glucocorticoids: interfere with collagen formation and

decrease tensile strength; occasionally used with ics to prevent scar formation (e.g., bacterial meningitis)

antibiot-Keloids, the raised scars caused by excessive synthesis

of type III collagen, are common in African cans and may occur as the result of third-degree

Ameri-burns Microscopically, keloids appear as irregular, thick collagen bundles that extend beyond the con- fines of the original injury.

Infections that

in-terfere with healing

are most

com-monly caused by

S auteus.

Chapter 2 Inflammation and Repair 23

Figure 2 - 4 Absolute cytosis with left shift Arrows

leuko-point to band (stab) neutrophils, which exhibit prominence of the azurophilic granules (toxic granu- lation) Vacuoles in the cytoplasm represent phagolysosomes

•

• V Laboratory Findings Associated With Inflammation

• A Leukocytes 1 Acute inflammation (e.g., bacterial infection)

• (Figure 2-4) a Absolute neutrophilic leukocytosis: accelerated

medi-ated by IL-1 and TNF

b Left shift: > 10% band (stab) neutrophils or the

pres-a ence of earlier precursors (e.g., metamyelocytes)

c Toxic granulation: prominence of azurophilic

• 2 Chronic inflammation (e.g., tuberculosis): absolute monocytosis

• B Erythrocyte sedimentation rate (ESR)

• • ESR is the rate of settling of RBCs in a vertical tube in

mm/h.

• 1 ESR is elevated in acute and/or chronic inflammation

(e.g., multiple myeloma)

• 2 Plasma factor or RBC factors that promote rouleaux

for-• mation increase the ESR.

a Plasma factor: increase in fibrinogen (acute-phase

promot-• b RBC factors: anemia promotes rouleaux formation. ing rouleaux formation.

• C C-reactive protein: acute-phase reactant; general scavenger

molecule

• 1 Sensitive indicator of acute inflammation (e.g.,

inflamma-• 2 Monitor of disease activity (e.g., rheumatoid arthritis) tory atherosclerotic plaques, bacterial infection)

•••

Immunopathology IFFP-w

I Cells of the Immune System (Table 3-1)

TABLE 3-1 Types of Immune Cells

Bone marrow stem cells

Bone marrow stem cells Conversion of mono- cytes into macro- phages in connective tissue

Bone marrow stem cells

Peripheral blood and bone marrow, thymus, pare- cortex of lymph nodes, Peyer's patches

Peripheral blood and bone marrow, germinal follicles

in lymph nodes, Peyer's patches

Peripheral blood (large granular lymphocytes) Connective tissue; organs (e.g., alveolar macro- phages, lymph node sinuses)

Skin (Langerhans' cells), germinal follicles

CD4 cells: secrete cytokines (IL-2 proliferation of CD8 T cells; 7-interferon

—> activation of phages); help B cells become antibody- producing plasma cells CD8 cells: kill virus-infected, neoplastic, and donor graft cells

macro-Differentiate into plasma cells that produce im- munoglobulins to kill encapsulated bacteria (e.g., Streptococcus pneumoniae)

Act as APCs that interact

with CD4 cells Kill virus-infected and neoplastic cells

Involved in phagocytosis and cytokine production Act as APCs

Act as APCs

APC, antigen-presenting cell; IL, interleukin

24