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General Pathological Anatomy - Comprehensive Study Guide

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1. Circulatory Disorders - Classification. Plethora (Hyperemia). Arterial Plethora.

Classification of Circulatory Disorders

1. Hyperemia (arterial and venous)
2. Ischemia
3. Bleeding/hemorrhage
4. Stasis
5. Thrombosis
6. Embolism
7. Infarction
8. Shock
9. Edema

Hyperemia (Plethora) - General

Arterial Hyperemia (Active Hyperemia)

• Physiological: Working skeletal muscle, skin flushing, post-meal splanchnic engorgement, blush response
• Pathological: Sites of acute inflammation (due to mediators - histamine, prostaglandins causing arteriolar dilation)
• Reactive hyperemia: Hyperemia following a period of ischemia (post-ischemic reperfusion)
• Collateral hyperemia: Develops when a main artery is obstructed and collateral vessels dilate

• Affected tissues are bright red (erythema) due to increased delivery of oxygenated blood
• Microscopically: dilated arterioles and capillaries, engorged with red cells
• Tissue is warm to touch (increased blood flow)

• Usually beneficial - increases oxygen and nutrient delivery
• In inflammation, supports healing
• In pathological conditions (e.g., severe reactive hyperemia), may contribute to reperfusion injury through free radical generation

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2. Venous Hyperemia (Passive Congestion)

General Characteristics

Classification

• Systemic (general) vs. Local
• Acute vs. Chronic
• Systemic: cardiac failure (affects both pulmonary and systemic circulations)
• Local: isolated venous obstruction (e.g., DVT, portal hypertension)

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Venous Congestion in the Pulmonary (Small) Circulation

• Acute: Engorged alveolar capillaries; alveolar septal edema; focal intraalveolar hemorrhage
• Chronic:
  • Septal thickening and fibrosis
  • Alveoli contain hemosiderin-laden macrophages ("heart failure cells") derived from phagocytosed extravasated RBCs
  • Brown induration of the lung (gross appearance - stiff, brown lungs)
  • Diagnosed by Prussian blue stain for hemosiderin

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Venous Congestion in the Systemic (Large) Circulation

• Acute: Central veins and sinusoids distended; centrilobular hepatocytes may undergo ischemic necrosis (most distal from hepatic arterioles); periportal hepatocytes better oxygenated → only develop fatty change
• Chronic:
  • Gross: "Nutmeg liver" - centrilobular regions appear red-brown (congested) and depressed, surrounded by yellow-tan periportal zones (fatty change)
  • Micro: centrilobular congestion, hemorrhage, hemosiderin-laden macrophages, hepatocyte dropout and necrosis
  • Long-standing: cardiac cirrhosis (centrilobular fibrosis)

• Enlarged, tense, dark red
• Microscopically: dilated sinusoids, possible hemorrhagic infarcts

• Edema, stasis dermatitis, venous ulcers in chronic cases

• Edema (increased hydrostatic pressure)
• Ischemic injury and scarring
• Hemorrhagic foci from capillary rupture → hemosiderin deposits
• Fibrosis (cardiac cirrhosis in liver, brown induration in lung)

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Portal Hypertension (Venous Congestion in the Portal System)

1. Prehepatic: Portal vein thrombosis, splenomegaly
2. Intrahepatic (most common): Cirrhosis (alcohol, viral hepatitis, NASH) → regenerative nodules + fibrosis compress intrahepatic veins → increased resistance
3. Posthepatic: Budd-Chiari syndrome (hepatic vein occlusion), right heart failure

• Ascites: Increased hydrostatic pressure in portal capillaries + hypoalbuminemia (cirrhosis) + aldosterone excess → fluid accumulation in peritoneal cavity
• Esophageal and gastric varices: Portosystemic anastomoses dilate (left gastric vein → esophageal veins); risk of catastrophic hemorrhage
• Caput medusae: Dilated periumbilical veins (via paraumbilical veins)
• Hemorrhoids: Inferior mesenteric vein → superior hemorrhoidal plexus
• Splenomegaly (congestive): Can lead to hypersplenism (pancytopenia)
• Hepatic encephalopathy: Due to shunting of portal blood (ammonia) past liver

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3. Ischemia

• Arterial obstruction: atherosclerosis, thrombosis, embolism, vasospasm
• Hypotension/shock
• Venous outflow obstruction (venous ischemia)
• Reduced oxygen-carrying capacity (anemia, CO poisoning)

• Reduced oxygen → shift to anaerobic glycolysis → lactic acidosis, ATP depletion
• ATP depletion → failure of Na+/K+-ATPase → cellular swelling
• Calcium influx → activation of phospholipases, endonucleases, proteases
• Mitochondrial dysfunction → free radical generation (especially on reperfusion)
• If prolonged: irreversible injury → necrosis

• Gross: Pallor, swelling; later infarction (pale/red)
• Micro (early): Cytoplasmic eosinophilia, nuclear pyknosis, karyolysis, karyorrhexis; cell swelling
• Diagnostic methods: EM (mitochondrial swelling, membrane damage); immunohistochemistry (troponin in myocardium); LDH/AST/ALT enzymes in blood; TUNEL stain for DNA fragmentation

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4. Bleeding and Hemorrhage

• Petechiae: Minute (1-2 mm) hemorrhages in skin/mucosa/serosal surfaces
• Purpura: Slightly larger (3 mm or more) hemorrhages
• Ecchymoses: Larger (1-2 cm) subcutaneous hematomas ("bruises"); color changes: red/blue → green (biliverdin) → yellow (bilirubin) → golden-brown (hemosiderin)
• Hematoma: Accumulation of blood in a tissue space
• Hemothorax, hemopericardium, hemoperitoneum, hemarthrosis: Blood in body cavities

1. Vessel wall rupture (hemorrhage per rhexin): Trauma, aneurysm rupture, erosion by tumor/inflammation
2. Diapedesis (hemorrhage per diapedesin): RBCs pass through intact vessel walls in severe congestion, inflammation, or vasculitis
3. Defects in primary hemostasis: Thrombocytopenia, platelet dysfunction, von Willebrand disease
4. Defects in secondary hemostasis: Coagulation factor deficiencies (hemophilias), anticoagulant drugs, DIC
5. Fragile vessels: Scurvy (collagen deficiency), amyloid, vasculitis

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5. Stasis

• Microthrombus formation: Slow flow allows coagulation factors to concentrate and platelets to aggregate
• Rouleaux formation: RBCs stack together, further impeding flow
• Hypoxic injury: Reduced oxygen delivery to tissues
• Leukocyte margination: White cells line up along vessel walls (important in inflammation)
• Viscosity increase: Polycythemia, dehydration, hyperviscosity syndromes
• Venous stasis: Promotes DVT (component of Virchow's triad)

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6. Thrombosis

Local and General Factors (Virchow's Triad)

Thrombus - Types and Morphological Characteristics

• Lines of Zahn: Alternating pale layers (platelets + fibrin) and dark layers (RBCs) - pathognomonic of antemortem thrombus; helps distinguish from postmortem clot
• Red (coagulation) thrombus: Forms in slow flow; rich in RBCs and fibrin
• White (platelet) thrombus: Forms in fast flow (arteries); pale, firm, adherent
• Mixed thrombus: Most common; has head (white, adherent), body (mixed), and tail (red, loosely attached)

• Mural thrombus: In heart chambers or aorta (on wall, non-occlusive)
• Occlusive thrombus: Completely fills vessel lumen (common in veins)
• Vegetations: On cardiac valves (infective endocarditis, non-bacterial thrombotic endocarditis)

Venous Thrombosis

• Most common site: deep veins of lower extremities (DVT) - popliteal, femoral, iliac veins
• Causes: stasis (immobilization, cardiac failure), hypercoagulable states, vessel injury
• Risk: pulmonary embolism (PE)
• Often occlusive, red/dark, may extend proximally

Arterial Thrombosis

• Usually at sites of atherosclerotic plaque disruption (turbulent flow, endothelial injury)
• Common in coronary, cerebral, and femoral arteries
• White/mixed; may be occlusive → acute MI, stroke, limb ischemia

Cardiac Thrombosis

• Atrial: Atrial fibrillation → stasis → clot in left atrial appendage → systemic emboli (stroke)
• Ventricular: Post-MI mural thrombus; akinetic wall segment → stasis
• Valvular: Endocarditis vegetations; non-bacterial thrombotic endocarditis (marantic) in debilitated patients

Outcomes of Thrombosis

1. Resolution/lysis: Fibrinolytic system dissolves small thrombi
2. Organization and recanalization: Fibroblasts and capillaries grow into thrombus; new channels form restoring partial flow (weeks)
3. Propagation: Thrombus enlarges
4. Embolization: Fragment detaches → embolus
5. Calcification: "Phleboliths" (venous calcified thrombi)

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7. Embolism

Types

1. Thromboembolism (most common - >95% of emboli)
2. Fat embolism
3. Air/gas embolism
4. Amniotic fluid embolism
5. Tumor embolism
6. Cholesterol embolism (atherosclerotic)
7. Bone marrow embolism
8. Septic embolism (infected thrombus fragments)

Pulmonary Embolism (PE)

• Over 95% originate from DVT proximal to the popliteal fossa
• Fragments travel through right heart → pulmonary arteries

• 60-80%: Small, clinically silent; undergo organization → incorporated into vessel wall (bridging fibrous webs)
• Large (saddle embolus): Sudden death, acute right heart failure (cor pulmonale), or cardiovascular collapse when >60% of pulmonary circulation is occluded
• Medium: Usually do NOT cause infarction (dual supply: pulmonary + bronchial arteries); but if bronchial circulation is compromised (left heart failure), pulmonary hemorrhage or infarction occurs
• Small end-arteriolar: Hemorrhage or infarction in periphery
• Recurrent/multiple: Pulmonary hypertension + right ventricular failure

Acute Pulmonary Heart Disease (Acute Cor Pulmonale)

• Sudden obstruction of major pulmonary arteries → acute rise in pulmonary vascular resistance → acute right ventricular dilation and failure
• ECG: S1Q3T3, right axis deviation, right bundle branch block
• Can be immediately fatal

Thromboembolic Syndrome

• Pattern of recurrent thromboemboli in the context of hypercoagulable states (Virchow's triad)
• DVT + PE is the classic presentation
• Associated with: immobility, surgery, malignancy (Trousseau syndrome - migratory thrombophlebitis), pregnancy, oral contraceptives, hereditary thrombophilias
• Morphologically: organizing thrombi in vessels at different stages; pulmonary hypertension in recurrent PE; potential for paradoxical embolism through patent foramen ovale

Other Emboli

• Fat embolism: After long bone fractures or soft tissue trauma; fat globules in vasculature. Fat embolism syndrome: pulmonary insufficiency, neurologic symptoms, anemia, thrombocytopenia, petechial rash; onset 1-3 days post-injury
• Air embolism: Iatrogenic (IV lines), decompression sickness (nitrogen bubbles); >100 mL air can cause fatal cardiac dysfunction; treat with hyperbaric oxygen
• Amniotic fluid embolism: Entry of amniotic fluid into maternal circulation during delivery; fetal squames and mucin in pulmonary vessels; presents as sudden dyspnea, cyanosis, DIC

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8. Shock

Types and Mechanisms

Stages of Shock

1. Compensated (non-progressive) stage: Reflex mechanisms maintain perfusion (catecholamines, renin-angiotensin, ADH); tachycardia, peripheral vasoconstriction, oliguria
2. Progressive (decompensated) stage: Perfusion falls despite compensation; metabolic acidosis, lactic acidosis; widespread cellular injury; may worsen tissue injury through reperfusion
3. Irreversible stage: Irreversible cell/organ damage; multi-organ dysfunction syndrome (MODS); death

Morphological Characteristics (in various organs)

• Brain: Hypoxic encephalopathy; "watershed" (boundary zone) infarcts
• Heart: Subendocardial hemorrhagic necrosis; coagulative necrosis (ischemic necrosis)
• Kidney: Acute tubular necrosis (ATN) - patchy tubular epithelial necrosis; shock kidney
• Adrenals: Lipid depletion from cortex (adrenal exhaustion)
• Liver: Central hemorrhagic necrosis; "shock liver"
• GI tract: Hemorrhagic/ischemic enteropathy; mucosal ulcers
• Lungs: Diffuse alveolar damage (ARDS - adult respiratory distress syndrome): hyaline membrane formation, interstitial and alveolar edema

Septic Shock Pathogenesis

• Bacterial components (LPS/endotoxin, peptidoglycan, lipoteichoic acid) activate macrophages and endothelium via TLRs
• Massive cytokine release (TNF, IL-1, IL-6, IL-12)
• Endothelial activation → coagulopathy (DIC), increased vascular permeability, vasodilation
• iNOS upregulation → nitric oxide → profound vasodilation

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9. Dystrophy - Definition, Mechanisms, Classification

Mechanisms of Development

1. Infiltration: Accumulation of substances from blood/extracellular space into cells
2. Perversion (perverse synthesis): Abnormal substances produced within cells
3. Transformation: Normal metabolites converted into abnormal products
4. Decomposition (phanerosis): Breakdown of normal organelle-associated lipoproteins releasing visible lipid or protein droplets

Classification

• Protein dystrophies (dysproteinoses)
• Lipid dystrophies (lipidoses)
• Carbohydrate dystrophies
• Mineral dystrophies (calcification, gout)

• Parenchymatous (intracellular): In parenchymal cells of organs
• Stromal-vascular (extracellular/mesenchymal): In connective tissue stroma and vessel walls
• Mixed

• General (systemic)
• Local (focal)

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10. Parenchymatous Protein Dystrophies (Dysproteinoses)

Types

• Most common; reversible
• Cause: any cellular injury (hypoxia, toxins, fever, infections)
• Pathogenesis: cell membrane injury → Na+ influx → cellular swelling; ER swells; protein denaturation
• Gross: organs enlarged, pale, dull, "boiled" appearance; tissue crumbles on cutting
• Micro: cytoplasm filled with fine eosinophilic granules (swollen mitochondria and dilated ER); nuclear changes minimal
• Outcome: reversible if cause removed

• More severe; may be irreversible
• Cause: hypoxia, viral infections (hepatitis), hypokalemia, toxic damage
• Pathogenesis: severe Na+/K+-ATPase failure → massive water influx → large cytoplasmic vacuoles
• Gross: enlarged, pale, flabby organs
• Micro: large clear cytoplasmic vacuoles ("balloon cells"); nucleus pushed to periphery
• Outcome: can progress to coagulative necrosis

• Protein droplets appear as eosinophilic, homogeneous intracellular inclusions
• Seen in: renal tubular cells (reabsorption of proteins - nephrotic syndrome); liver cells (Mallory-Denk bodies in alcoholic hepatitis - aggregates of keratin intermediate filaments)
• Diagnostic: PAS stain (pink droplets in tubular cells); hematoxylin-eosin shows bright pink droplets
• Outcome: cell death if severe

• Accumulation of keratinous material in epithelium

• H&E staining (eosinophilic granules/droplets)
• PAS stain (glycoproteins)
• Oil Red O/Sudan III (excludes lipid)
• Electron microscopy (ultrastructural changes)

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11. Stromal-Vascular Dysproteinoses

Stages of Stromal Disorganization (Connective Tissue Disorganization)

• Ground substance imbibes water → reversible; collagen fibers spread apart
• Metachromasia with toluidine blue (accumulation of glycosaminoglycans)
• Seen early in rheumatic diseases, hypertension

• Collagen fibers undergo fibrinoid transformation (lose cross-striations, become homogeneous, deeply eosinophilic, resembling fibrin)
• Fibrinogen + gamma-globulins infiltrate from plasma
• MSB stain (Masson): fibrinoid stains red; PAS-positive
• Irreversible; progression from mucoid swelling

• Complete destruction of collagen architecture; necrosis of connective tissue cells
• Seen in: arterial walls in hypertension, rheumatic nodules, immune complex vasculitis

• Organization of necrotic material → fibrosis → hyalinosis

Types of Fibrinoid

1. Coagulative fibrinoid - with fibrin (fibrinogen from plasma)
2. Metachromatic fibrinoid - with glycosaminoglycans
3. Collagenolytic fibrinoid - destruction of own collagen

Role in Disease Morphogenesis

• Rheumatic diseases (SLE, rheumatoid arthritis, etc.): Immune complex deposition in vessel walls and connective tissue → complement activation → fibrinoid necrosis → vasculitis; Aschoff bodies in rheumatic fever (granulomatous foci with fibrinoid necrosis)
• Glomerulonephritis: Immune complexes deposited in mesangium and basement membrane → fibrinoid necrosis of glomerular capillary walls → crescentic GN
• Gastric/duodenal ulcers: Fibrinoid necrosis at ulcer base; perpetuates ulceration
• Arterial hypertension: Hyaline arteriolosclerosis (benign); fibrinoid necrosis of arterioles (malignant hypertension)

Hyalinosis (Hyaline Dystrophy)

• Vascular hyalinosis: Hyaline arteriolosclerosis (benign hypertension, DM) - homogeneous pink material replaces vessel wall; lumen narrows
• Connective tissue hyalinosis: Old scars, keloids, cardiac valve thickening
• Intracellular hyaline: Russell bodies (immunoglobulin in plasma cells), Mallory-Denk bodies

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12. Parenchymatous Lipidoses (Fatty Degeneration)

Causes and Pathogenesis

• Causes: severe anemia, hypoxia (e.g., diphtheria toxin - blocks beta-oxidation), alcoholism, myocarditis
• Two patterns:
  • "Tigroid heart" (tabby cat pattern): Alternating yellow (fat-laden) and red-brown (normal) streaks under endocardium, due to patchy hypoxia; groups of myocytes with lipid droplets alternating with normal cells
  • Diffuse: Uniform fatty change in all myocytes; yellow, flabby heart
• Micro: small lipid vacuoles (Sudan III/Oil Red O positive, cleared in H&E) in myocyte cytoplasm; nuclei usually intact

• Most common cause: alcohol (inhibits beta-oxidation, increases fatty acid synthesis, impairs VLDL export)
• Other causes: obesity, DM type 2, malnutrition (kwashiorkor), toxins (CCl4), drugs (corticosteroids, methotrexate), pregnancy
• Pathogenesis: imbalance between fat delivery/synthesis and export/oxidation - excess triglycerides accumulate
• Gross: enlarged (up to 3-4x normal weight), yellow, greasy, soft
• Micro: Large clear cytoplasmic vacuoles displacing nucleus to periphery (macrovesicular) or multiple small droplets (microvesicular); H&E shows cleared vacuoles; Oil Red O/Sudan confirms fat
• Outcome: Reversible if cause removed. Can progress: steatohepatitis → fibrosis → cirrhosis

• Causes: nephrotic syndrome (lipid reabsorption by tubular cells), DM, severe anemia, toxins
• Proximal tubular epithelium most affected
• "Lipoid nephrosis" - tubules filled with lipid droplets
• Gross: pale, yellowish cortex
• Micro: vacuolated tubular cells (cleared on H&E); Sudan III/Oil Red O positive
• Also: lipid casts in tubular lumens and collecting ducts

• Oil Red O / Sudan III/IV: Stain neutral fats red/orange in frozen sections
• Osmic acid: Stains lipids black
• Sudan Black B: Stains phospholipids
• H&E alone: lipids dissolved during processing - leaves clear vacuoles

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13. Obesity

• By BMI: Grade I (30-34.9), Grade II (35-39.9), Grade III / morbid obesity (>40)
• By fat distribution:
  • Android (central/visceral): Intra-abdominal fat; "apple shape"; higher cardiovascular/metabolic risk (waist circumference: >102 cm men, >88 cm women)
  • Gynoid (peripheral/subcutaneous): Gluteofemoral fat; "pear shape"; lower metabolic risk
• By etiology:
  • Primary (dietary excess, sedentary lifestyle, genetic predisposition)
  • Secondary (Cushing syndrome, hypothyroidism, insulinoma, hypothalamic damage)

• Adipose tissue: Hypertrophy and hyperplasia of adipocytes; macrophage infiltration in visceral fat; chronic low-grade inflammation (adipokine dysregulation - increased TNF, IL-6, leptin resistance; decreased adiponectin)
• Liver: Steatosis/NASH (non-alcoholic steatohepatitis)
• Cardiovascular: Left ventricular hypertrophy; epicardial fat infiltration; cardiomegaly; atherosclerosis
• Lungs: Obesity hypoventilation syndrome; sleep apnea (pharyngeal fat compresses airway)
• Joints: Osteoarthritis (weight-bearing joints)
• Pancreas: Islet hyperplasia → insulin resistance → T2DM; lipotoxicity to beta cells

• Type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease (MI, stroke), NASH/cirrhosis, obstructive sleep apnea, certain cancers (endometrial, breast, colon), osteoarthritis, venous thromboembolism

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14. Pigment (Chromoprotein) Metabolism Disorders

Lipofuscin Disorders

• Morphology: Fine, golden-brown granular cytoplasmic deposits, particularly perinuclear
• Brown atrophy: Organ atrophy (particularly heart) with prominent lipofuscin accumulation in old age or cachexia
• Significance: Marker of oxidative stress and aging; generally not harmful itself
• Stains: PAS-positive, autofluorescent, Ziehl-Neelsen weakly positive

Melanin Disorders

• Hyperpigmentation:
  • Addison disease (adrenal insufficiency): elevated ACTH/MSH → diffuse hyperpigmentation of skin and mucosae
  • Cafe-au-lait spots (neurofibromatosis); freckles; nevi; melanoma
  • Chloasma (melasma): pregnancy/oral contraceptives
• Hypopigmentation:
  • Vitiligo: autoimmune destruction of melanocytes → patches of depigmentation
  • Albinism: absence of tyrosinase → no melanin synthesis; photosensitivity, risk of skin cancer

Hemoglobin Metabolism Disorders

• Localized accumulation at sites of prior hemorrhage
• Old bruise, pulmonary congestion ("heart failure cells"), hepatic congestion
• Consequence of local RBC breakdown and iron storage in macrophages

• Widespread hemosiderin deposits throughout the reticuloendothelial system (liver, spleen, bone marrow, lymph nodes)
• Causes: hemolytic anemias, multiple transfusions, increased iron absorption
• Iron stored mainly in macrophages; parenchymal cells relatively spared
• Usually does NOT cause organ dysfunction (unlike hemochromatosis)

• Severe systemic iron overload with iron accumulation in parenchymal cells (hepatocytes, pancreatic acini, myocardium, joints, skin, pituitary)
• Primary (hereditary): HFE gene mutations (most common: C282Y homozygous); impaired hepcidin regulation → excessive duodenal iron absorption
• Secondary: Multiple transfusions, ineffective erythropoiesis (beta-thalassemia)
• Morphology: liver - hemosiderin deposits; cirrhosis; pancreas - fibrosis (diabetes); myocardium - cardiomyopathy; skin - bronze pigmentation (melanin + hemosiderin); joints - arthropathy; pituitary - hypogonadism
• "Bronze diabetes" = classic triad of cirrhosis + DM + bronze skin
• Outcome: cirrhosis, hepatocellular carcinoma, cardiomyopathy, diabetes
• Diagnosis: serum ferritin, transferrin saturation, liver biopsy (Prussian blue), HFE genotyping

• Pre-hepatic (hemolytic): excess unconjugated bilirubin
• Hepatic (hepatocellular): both fractions elevated
• Post-hepatic (obstructive/cholestatic): conjugated bilirubin elevated

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15. Pathological Calcification (Calcinosis)

Types

• Definition: Calcium deposition in dead or dying tissues with normal serum calcium levels
• Mechanism: Cell death → release of phospholipids from membranes → precipitation of calcium phosphate; cellular debris acts as a nidus; alkaline phosphatase activity; mitochondrial calcium accumulation
• Sites: Atherosclerotic plaques (calcified vessels), old caseous necrosis (tuberculosis - "Ghon complex"), fat necrosis, dead parasites (cysticercosis), old infarcts, thrombi (phleboliths), aging cardiac valves ("porcelain" lesions)
• Gross: Hard, gritty, chalk-white deposits
• Micro: Initially, granular basophilic deposits; later, dense acellular masses; bone may even form (heterotopic ossification)
• Significance: Can cause valve dysfunction (aortic stenosis), vessel rigidity

• Definition: Calcium deposition in normal living tissues due to hypercalcemia
• Mechanism: Elevated Ca2+ or phosphate overwhelms normal tissue buffering
• Causes of hypercalcemia:
  • Hyperparathyroidism (primary, secondary in renal failure)
  • Destruction of bone (metastases, multiple myeloma)
  • Hypervitaminosis D
  • Milk-alkali syndrome
  • Sarcoidosis (ectopic 1α-hydroxylase)
• Sites: Interstitial tissues of kidney (nephrocalcinosis), stomach, lungs, arterial walls, cornea - tissues that excrete acid (interstitial pH is relatively alkaline)
• Significance: Can impair organ function; nephrocalcinosis → renal failure

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16. Necrosis - Causes, Mechanisms, Macro/Micro Characteristics

Causes

• Hypoxia/ischemia (most common)
• Physical agents (radiation, trauma, temperature extremes)
• Chemical toxins and drugs
• Infectious agents (bacteria, viruses, fungi, parasites)
• Immune reactions (complement, cytotoxic T cells)
• Nutritional deficiencies

Mechanisms

1. ATP depletion → Na+/K+-ATPase failure → cell swelling, Ca2+ influx
2. Ca2+ overload → activation of:
   • Phospholipases → membrane breakdown
   • Proteases (calpains) → cytoskeletal disruption
   • Endonucleases → DNA fragmentation
   • ATPases → further energy depletion
3. Free radical injury: ROS from reperfusion, mitochondria; lipid peroxidation; protein oxidation; DNA oxidation
4. Lysosomal rupture: Autolytic enzymes released → self-digestion

Macroscopic Characteristics (by type - see below)

• Coagulative necrosis: firm, pale
• Liquefactive: soft, liquified, cavity
• Caseous: cheesy, white-gray
• Fat: chalky white
• Gangrenous: black, wet or dry

Microscopic Characteristics

• Pyknosis: Nuclear shrinkage and increased basophilia (chromatin condensation)
• Karyorrhexis: Fragmentation of pyknotic nucleus
• Karyolysis: Fading of nucleus (DNase activity)

• Increased eosinophilia (protein denaturation, loss of RNA)
• Cell outlines may persist (coagulative) or be lost (liquefactive)
• "Ghost cells" - cell shapes visible but no organelle detail

• Loss of tissue architecture
• Inflammatory infiltrate (neutrophils first, then macrophages)

Necrosis vs. Apoptosis - Morphological Differences

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17. Clinical and Morphological Forms of Necrosis

1. Coagulative Necrosis

• Most common form; architecture preserved ("ghost outlines")
• Pathogenesis: Protein denaturation predominates over enzymatic digestion; acidic pH inactivates lysosomal enzymes
• Causes: Ischemia (virtually all organs except brain), toxins
• Morphology: Firm, pale, opaque area; cell outlines preserved microscopically for days/weeks; nuclei disappear
• Classic example: Renal infarct, myocardial infarction (first days)

2. Liquefactive Necrosis

• Enzymatic digestion dominates → liquid mass
• Pathogenesis: Rich in lysosomal enzymes (brain has little connective tissue framework); neutrophil enzymes (bacterial infections)
• Causes: Brain infarct (ischemia/stroke); bacterial abscesses (pyogenic bacteria release powerful enzymes)
• Morphology: Soft, yellow-gray, viscous; cystic cavity in brain; pus (neutrophils + dead cells + fluid) in abscess
• Examples: Cerebral infarct, lung abscess

3. Caseous Necrosis

• "Cheesy" appearance; specific to granulomatous infections
• Pathogenesis: Mixture of coagulative and liquefactive necrosis + immune-mediated injury; waxy lipid coat of mycobacteria contributes
• Morphology: Gross - white, soft, crumbly ("cottage cheese"); Micro - amorphous, structureless, eosinophilic granular debris; NO preserved cell outlines (unlike coagulative); surrounded by granulomatous reaction
• Examples: Tuberculosis (classic), fungal infections (histoplasmosis)

4. Fat Necrosis

• Specific to adipose tissue
• Pathogenesis: Release of pancreatic lipases (acute pancreatitis) → enzymatic saponification of fat; fatty acids released react with calcium → calcium soaps
• Morphology: Gross - chalky white deposits in adipose tissue (peritoneal, omental fat); Micro - necrotic fat cells (shadowy outlines), basophilic calcium deposits, surrounding inflammation
• Example: Acute pancreatitis, breast trauma (traumatic fat necrosis)

5. Fibrinoid Necrosis

• In blood vessel walls
• Pathogenesis: Immune complex deposition + complement activation → destruction of vessel wall; deposits of plasma proteins (fibrin, immunoglobulins)
• Morphology: Hyper-eosinophilic, smudgy deposits in vessel walls; MSB stain: deep red
• Examples: Malignant hypertension, polyarteritis nodosa, immune complex vasculitis, rheumatic diseases

6. Gangrenous Necrosis

• Not a specific type - usually coagulative necrosis with secondary bacterial infection
• Dry gangrene: Coagulative necrosis predominates; no bacterial infection; limb becomes dry, black, mummified; sharp demarcation
• Wet gangrene: Liquefactive superimposed; secondary bacterial infection; putrefaction; foul odor; no clear border; spreads rapidly
• Gas gangrene: Clostridium perfringens infection; gas bubbles in tissue

Outcomes of Necrosis

1. Organization: Granulation tissue replaces necrotic area → scar (fibrosis)
2. Regeneration: If parenchymal cells regenerate (liver, tubular epithelium)
3. Encapsulation/calcification: Dystrophic calcification
4. Cavity formation: Liquefaction (brain cyst, abscess)
5. Sequestration: Dead tissue separates (bone sequestrum in osteomyelitis)
6. Ulceration: Necrotic surface tissue sloughs off
7. Mutations: Rarely, surviving cells near necrotic zone may undergo mutational changes

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18. Infarction

Morphological Characteristics by Type

• Occur in solid organs with end-arterial (non-collateral) supply
• Sites: Kidney, spleen, heart
• Mechanism: occlusion → ischemia; hemorrhage cannot fill compact solid tissue
• Morphology: wedge-shaped (base at surface, apex toward hilus), pale/white-yellow; surrounded by dark hyperemic zone; histologically: coagulative necrosis with preserved ghost outlines
• Myocardial infarction (MI):
  • Day 0-4: coagulative necrosis; hyperemic border; irreversible injury at 20-40 minutes of ischemia; histologically: eosinophilic "wavy fibers," loss of nuclei, contraction bands
  • Day 1-3: neutrophilic infiltrate
  • Day 5-10: macrophage infiltrate (phagocytosis)
  • 2-8 weeks: granulation tissue → fibrosis (scar)
  • Complications: arrhythmia, cardiogenic shock, rupture (day 3-7), mural thrombus, pericarditis, Dressler syndrome

• Occur in: (a) venous occlusions; (b) loose tissue (lung) where blood can re-enter; (c) tissues with dual blood supply; (d) reperfused areas
• Sites: Lung (arterial embolism + dual supply), intestine (venous occlusion), testis (torsion), brain (venous)
• Morphology: dark red, wedge-shaped; microscopically - coagulative or liquefactive necrosis with hemorrhage
• Pulmonary infarct: Wedge-shaped hemorrhagic area at pleural surface; firm, red-brown → yellow-white as infarct ages → scar

• Ischemic stroke: Most commonly from atherothrombosis or cardioembolism
• Initially: coagulative necrosis (first 12-24h); but brain undergoes liquefactive necrosis (rich in lipid, lacks connective tissue)
• Within days: neutrophils, then macrophages (foam cells)
• Weeks-months: cystic cavity lined by gliosis (astrocytic scarring)
• Reperfusion injury: Conversion to hemorrhagic (red) infarct common in embolic strokes

Factors Influencing Infarct Development

• Nature of blood supply (end-arterial vs. dual)
• Rate of occlusion (gradual → collateral development)
• Tissue vulnerability to hypoxia (neurons: 3-5 min; myocardium: 20-40 min; fibroblasts: hours)
• Oxygen-carrying capacity of blood
• Presence of underlying disease (prior vascular disease)

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19. Inflammation - Definition, Etiology, Phases, Classification

• Eliminates causative agent (phagocytosis, killing)
• Limits tissue damage
• Initiates repair
• BUT: may become harmful if excessive (ARDS, septic shock, chronic inflammatory diseases)

• Microbial infections (bacteria, viruses, fungi, parasites)
• Physical agents (trauma, heat, cold, radiation, foreign bodies)
• Chemical agents (toxins, acids, alkalis, drugs)
• Tissue necrosis (ischemic, traumatic)
• Immune reactions (hypersensitivity, autoimmunity)

Phases

• Primary alteration: direct damage by causative agent
• Secondary alteration: cellular and tissue changes; release of vasoactive amines (histamine from mast cells/platelets), prostaglandins, leukotrienes, cytokines

• Vascular changes: Transient vasoconstriction → sustained vasodilation (arterioles) → increased permeability → increased hydrostatic pressure → edema. Classic signs: rubor (redness), calor (heat), tumor (swelling), dolor (pain), functio laesa (loss of function)
• Cellular events:
  • Margination → pavementing → emigration (diapedesis) of leukocytes through vessel walls
  • Chemotaxis (directed migration to injury site)
  • Phagocytosis: recognition (opsonins - IgG, C3b), engulfment, killing (ROS, MPO, defensins)
  • Mediators: complement (C3a, C5a), cytokines (TNF, IL-1, IL-8/CXCL8), PAF, prostaglandins

• Removal of exudate and necrotic debris
• Parenchymal regeneration (if tissue retains regenerative capacity and stroma is intact)
• Connective tissue repair (granulation tissue → scar)

• By duration: Acute (days-weeks) vs. Chronic (weeks-months-years)
• By exudate type: Serous, fibrinous, purulent/suppurative, hemorrhagic, mixed
• By extent: Local vs. systemic
• Productive/Proliferative: Predominantly cellular proliferation

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20. Acute Inflammation - Exudative Forms

Types

• Exudate: watery, protein-poor fluid (transudate-like but from inflammation)
• Examples: Skin blisters (burns, vesicle virus), pleural/pericardial effusion in early inflammation, peritonitis (early)
• Micro: sparse leukocytes; diluted proteins
• Outcome: Usually resolves completely

• Exudate: rich in fibrinogen → precipitates as fibrin strands/meshwork
• Examples: Fibrinous pericarditis ("bread and butter" or "cor villosum"), fibrinous pleuritis (pneumonia), diphtheria (pseudomembranous laryngitis)
• Micro: pink fibrin network with leukocytes
• Outcome: Organization → fibrosis → adhesions/pericardial constriction; or resolution if fibrinolysis sufficient

• Exudate: pus - abundant neutrophils (dead and dying = pyocytes) + necrotic debris + fluid
• Caused by pyogenic bacteria (Staph., Strep., Pseudomonas, etc.)
• Abscess: Focal collection of pus in solid tissue; surrounded by pyogenic membrane (wall of granulation tissue)
• Phlegmon (cellulitis): Diffuse purulent inflammation spreading through tissue planes
• Empyema: Pus in preformed cavity (empyema thoracis, pyopericardium)
• Outcome: Abscess may rupture, drain, organize; chronic inflammation if unresolved

• Exudate: bloody; vessel walls severely damaged
• Examples: anthrax, plague, severe viral infections (hanta, Ebola), hemorrhagic pancreatitis
• Poor prognosis

• Mucous membranes: excessive mucus production
• Examples: common cold (rhinitis), catarrhal bronchitis, gastritis

• Fibrinopurulent exudate firmly adherent to mucosal surface
• Examples: Diphtheria (pharynx - gray pseudomembrane), pseudomembranous colitis (C. difficile)
• Removal of membrane leaves bleeding ulcerated surface

Outcomes of Acute Inflammation

1. Resolution: Complete return to normal (small exudate, no necrosis)
2. Healing by fibrosis/scarring: Significant tissue damage
3. Abscess formation: Contained purulent focus
4. Chronic inflammation: If cause persists or immune response is involved

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21. Chronic Inflammation and Productive Inflammation

• Persistent infections with organisms resistant to destruction (TB, leprosy, viral infections, parasites)
• Prolonged toxic agent exposure (silica → silicosis)
• Autoimmune diseases (rheumatoid arthritis, SLE, inflammatory bowel disease)
• Foreign bodies (implants, sutures)
• Failure to resolve acute inflammation

• Macrophages central: activated by T lymphocytes (via IFN-γ) and other stimuli; secrete mediators that both injure tissue and promote repair
• Angiogenesis, fibrosis occur simultaneously with ongoing injury

Types

1. Interstitial (diffuse) productive inflammation: Diffuse infiltration by macrophages, lymphocytes, plasma cells in stroma of parenchymal organs (liver, kidney); leads to diffuse fibrosis (e.g., chronic hepatitis, chronic pyelonephritis)
2. Granulomatous inflammation: (See topic 23)
3. Hypertrophic (vegetative) inflammation: Hyperplasia of epithelium and stroma forming polyps or condylomas (chronic irritation of mucosae); e.g., nasal polyps, cervical polyps
4. Productive inflammation around parasites and foreign bodies: (See topic 22)

• Mononuclear infiltrate: macrophages, lymphocytes, plasma cells (vs. neutrophils in acute)
• Tissue destruction
• Repair: angiogenesis (capillary sprouting), fibroblast proliferation, collagen deposition
• Vascular proliferation (granulation tissue)

• Fibrosis/sclerosis
• Atrophy of affected organ
• Chronic organ dysfunction
• Transformation to malignancy (e.g., H. pylori gastritis → gastric carcinoma)

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22. Productive Inflammation Around Foreign Bodies and Parasites

Around Foreign Bodies

• Mechanism: Large foreign bodies (suture material, talc, silica, prosthetic material) cannot be phagocytosed by single macrophages
• Morphology: Macrophages surround the material; fuse to form multinucleate foreign body giant cells (nuclei randomly distributed throughout cytoplasm - differs from Langhans giant cells where nuclei are peripheral)
• The foreign body can often be seen within the giant cells, particularly under polarized light
• No necrosis, no specific immune response; fibrous capsule forms around the reaction

Opisthorchiasis

• Infection by Opisthorchis felineus (liver fluke - raw freshwater fish), common in Siberia/SE Asia
• Parasites inhabit bile ducts
• Morphology: Productive periductal fibrosis; bile duct epithelial hyperplasia; granuloma-like reactions with eosinophils; chronic inflammation with lymphocytes, macrophages; ductal dilatation
• Outcomes: Cholangitis, cholestasis, cirrhosis, and importantly - cholangiocarcinoma (the most feared complication)

Echinococcosis (Hydatid Disease)

• Caused by Echinococcus granulosus (dog tapeworm)
• Cyst formation in liver (most common), lung, brain
• Cyst structure:
  1. Inner germinal (endocyst) layer (parasite-derived, produces brood capsules and protoscolices)
  2. Laminated (ectocyst) membrane (acellular, laminated, characteristic PAS-positive layer)
  3. Pericyst (host-derived): Fibrous capsule of compressed host tissue with:
     • Eosinophil infiltration (eosinophilia hallmark of helminth infections)
     • Giant cell reaction at parasite-host interface
     • Chronic granulomatous-like inflammation
     • Progressive fibrosis and calcification
• Outcomes: Compression of adjacent structures; rupture → anaphylaxis + dissemination; secondary bacterial infection; calcification

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23. Granulomatous Inflammation

• Infections: TB, leprosy, syphilis, fungal (histoplasmosis, coccidioidomycosis, blastomycosis), schistosomiasis
• Unknown/immune-mediated: Sarcoidosis, Crohn disease, primary biliary cirrhosis
• Inorganic particles: silicosis, berylliosis
• Foreign bodies (non-immunogenic): talc, sutures

Mechanisms of Development

• Persistent antigen that cannot be cleared → sustained T-cell activation
• Th1 cells produce IFN-γ → activates macrophages → epithelioid cells
• Activated macrophages fuse → Langhans giant cells (nuclei arranged in horseshoe/peripheral pattern)
• Some responses involve Th2 cells and eosinophils (schistosomiasis)

Morphological Characteristics

• Center: Epithelioid macrophages (pink granular cytoplasm, "footprint" nuclei, indistinct cell borders); may have central caseous necrosis (in TB)
• Giant cells: Langhans type (nuclei peripheral/horseshoe); foreign body type (nuclei scattered)
• Surrounding: Collar of lymphocytes (mainly CD4+ T cells)
• Older granulomas: Rim of fibroblasts and connective tissue; eventual fibrosis

• H&E for basic granuloma architecture
• ZN stain (Ziehl-Neelsen) / Auramine-rhodamine for acid-fast bacilli (TB)
• GMS (Grocott) / PAS for fungi
• Culture and PCR for infectious agents
• ACE level, chest CT (sarcoidosis)
• Polarized light (birefringent foreign material)

• Fibrosis (most common fate of granulomas)
• Calcification (dystrophic)
• Resolution (if antigen cleared)
• Liquefaction of caseous material → cavity formation (TB)

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24. Granulomatous Diseases - Classification and Features

Classification by Etiology

• Sarcoidosis: Multi-system non-caseating granulomas; primarily lung, skin, lymph nodes, eyes; hypercalcemia; elevated serum ACE; Löfgren syndrome (acute: erythema nodosum + hilar adenopathy + polyarthritis); treat with corticosteroids
• Silicosis: Progressive massive fibrosis; upper lobe nodular shadows; increased susceptibility to TB; no treatment except supportive

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25. Tuberculous Granuloma - Structure and Histogenesis

Granuloma Structure in Tuberculosis

Histogenesis of Cells

• M. tuberculosis phagocytosed but not killed by macrophages (blocks phagolysosome fusion via ESAT-6, other virulence factors)
• Mycobacterial antigens presented on MHC II → CD4+ Th1 activation
• Th1 release IFN-γ → classical macrophage activation → reactive oxygen/nitrogen species → partial killing, but also tissue injury
• TNF-α essential for granuloma maintenance (anti-TNF therapy → granuloma breakdown → TB reactivation)
• Hypersensitivity (type IV/DTH) contributes to caseous necrosis

Outcomes of Tuberculous Granuloma

1. Healing with fibrosis: Granuloma encapsulates, fibroses, calcifies (Ghon focus in primary TB)
2. Progressive caseous necrosis: Central necrosis expands; giant cells destroyed
3. Liquefaction of caseous material: Cavity formation (post-primary pulmonary TB - the basis of infectivity)
4. Calcification: Dystrophic calcification of caseous material (Ghon complex = calcified primary focus + lymph node)
5. Reactivation: Years later if immunity declines (immunosuppression, HIV, anti-TNF therapy) → reactivation TB with cavity formation

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