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General Pathology - High-Yield Exam Notes

Based on Robbins Basic Pathology & Robbins & Cotran Pathologic Basis of Disease

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PART 1: CELL INJURY, CELL DEATH & ADAPTATIONS

Key Definitions

• Etiology - the cause/origin of a disease (the "why")
• Pathogenesis - the steps/mechanisms by which disease develops (the "how")
• Morphology - the structural changes in cells/tissues that characterize a disease

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Cellular Responses to Stress (in order of severity)

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Causes of Cell Injury (HIGH YIELD)

1. Hypoxia & Ischemia - most common; deprive cells of oxygen (ATP depletion is the key event)
2. Physical agents - trauma, extreme temperature, radiation, electric shock
3. Chemical agents & drugs - poisons, pollutants, therapeutic drugs
4. Infectious agents - viruses, bacteria, fungi, parasites
5. Immunologic reactions - autoimmune disease, hypersensitivity
6. Genetic defects - mutations causing protein dysfunction
7. Nutritional imbalances - deficiencies or excess

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Reversible vs Irreversible Injury

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Mechanisms of Cell Injury - The "Big 5"

1. Mitochondrial dysfunction - ATP depletion → Na⁺/K⁺ pump fails → cell swelling
2. Oxidative stress (ROS) - damage to DNA, lipids, proteins; generated by reperfusion, drugs, radiation
3. Membrane damage - lysosomal leakage, mitochondrial permeability, plasma membrane damage
4. Calcium influx - activates destructive enzymes (phospholipases, proteases, endonucleases, ATPases)
5. DNA damage / ER stress - misfolded proteins trigger cell death pathways

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Necrosis vs Apoptosis (VERY HIGH YIELD)

• Coagulative - most organs (heart, kidney); structure preserved, cells ghost-like (ischemia)
• Liquefactive - brain infarct; bacterial abscesses (enzymes dissolve tissue)
• Caseous - TB; soft, cheese-like; surrounded by granuloma
• Fat - breast, pancreas; saponification, chalky deposits
• Fibrinoid - vessel walls in malignant hypertension, vasculitis
• Gangrenous - limb ischemia; dry (coagulative) or wet (liquefactive with infection)

• Intrinsic (mitochondrial) pathway - DNA damage, growth factor withdrawal → Bcl-2 family → cytochrome c release → caspase-9 → caspase-3
• Extrinsic (death receptor) pathway - FasL/TNF binds receptor → DISC → caspase-8 → caspase-3
• Bcl-2 is anti-apoptotic (overexpressed in follicular lymphoma)
• p53 triggers apoptosis via DNA damage

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Cellular Adaptations to Stress

• Atrophy = ↓ protein synthesis + ↑ protein degradation (ubiquitin-proteasome pathway + autophagy)
• Metaplasia is reversible but predisposes to dysplasia/cancer

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Intracellular Depositions

• Fatty change (steatosis) - liver, heart; in alcoholism, obesity, diabetes
• Cholesterol deposits - atherosclerosis, xanthomas
• Protein - Mallory bodies (alcoholic liver), Russell bodies (plasma cells)
• Glycogen - diabetes, glycogen storage diseases
• Pigments:
  • Lipofuscin ("wear-and-tear" pigment) - brown, in aging cells
  • Hemosiderin - iron pigment from hemoglobin degradation; hemosiderosis vs hemochromatosis
  • Melanin - normal, increased in Addison disease
  • Carbon - anthracosis (coal miners' lung)

• Dystrophic calcification - in dead/necrotic tissue; serum Ca²⁺ NORMAL; seen in TB, atherosclerosis, dead parasites
• Metastatic calcification - in normal tissue; serum Ca²⁺ HIGH (hypercalcemia); seen in hyperparathyroidism, sarcoidosis

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PART 2: INFLAMMATION & REPAIR

What is Inflammation?

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Recognition of Injury - Pattern Recognition Receptors (PRRs)

• Toll-like receptors (TLRs) - on surface and in endosomes; recognize PAMPs (microbial) and DAMPs (damaged self)
• NOD-like receptors (NLRs) - cytosolic; form the inflammasome → activates IL-1β
• PAMPs = pathogen-associated molecular patterns (e.g., LPS)
• DAMPs = damage-associated molecular patterns (e.g., leaked DNA, ATP)

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Acute Inflammation - The Three Key Components

1. Vasodilation (↑ blood flow → redness + heat)
2. ↑ Vascular permeability (fluid leaks into tissue → swelling)
3. Leukocyte emigration (mainly neutrophils)

• Vasodilation → stasis → margination → rolling → adhesion → transmigration → chemotaxis → phagocytosis

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Phagocytosis

1. Recognition/Attachment - opsonins (IgG, C3b) bind to Fc receptors and CR3
2. Engulfment - pseudopods form phagosome
3. Killing - oxidative (myeloperoxidase-H₂O₂-halide system → HOCl) and non-oxidative (defensins, lysozyme, lactoferrin)

• Chediak-Higashi syndrome - defective lysosomal fusion
• Chronic Granulomatous Disease (CGD) - defective NADPH oxidase; catalase-positive organisms survive
• LAD (Leukocyte Adhesion Deficiency) - defective CD18 (integrin); delayed umbilical cord separation

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Chemical Mediators of Inflammation (HIGH YIELD)

Key drug targets: Aspirin/NSAIDs block COX → ↓ PGs; Glucocorticoids block phospholipase A2 → ↓ all AA metabolites; Montelukast blocks LT receptors

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Morphologic Patterns of Acute Inflammation

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Outcomes of Acute Inflammation

1. Resolution - complete restoration (most viral infections)
2. Abscess formation - walling off of pus
3. Fibrosis/Scarring - if tissue cannot regenerate
4. Progression to chronic inflammation

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Chronic Inflammation

• Duration: weeks-months; mononuclear cells predominate (lymphocytes, plasma cells, macrophages)
• Causes: persistent infection (TB, syphilis), autoimmune, prolonged exposure to toxic agents
• Key cells: Macrophages (most important), Lymphocytes (T and B), Plasma cells, Eosinophils (parasites, allergy), Mast cells

• Activated by IFN-γ (from T cells) → produce TNF, IL-12, ROS, lysosomal enzymes
• Form the backbone of granulomas

• Special form of chronic inflammation
• Core: Epithelioid macrophages + Langhans giant cells (horseshoe-shaped nuclei) + CD4⁺ T cells
• Causes:
  • Infectious: TB (caseous necrosis, AFB positive), leprosy, syphilis, cat-scratch disease
  • Non-infectious: Sarcoidosis (non-caseating!), Crohn disease, berylliosis, foreign body reaction

Tip: "Naked granulomas" = sarcoidosis (no caseation). "Caseating granulomas" = TB.

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Systemic Effects of Inflammation - Acute Phase Response

• Fever - IL-1, TNF, IL-6 → COX in hypothalamus → ↑ PGE2 → set point rises
• Acute-phase proteins (from liver, induced by IL-6): CRP, fibrinogen, serum amyloid A, haptoglobin (↑); albumin and transferrin (↓)
• Leukocytosis:
  • Bacterial infections → neutrophilia
  • Viral infections → lymphocytosis
  • Parasites/allergy → eosinophilia
• Septic shock - systemic TNF/IL-1 overproduction → ↓ BP, DIC, multi-organ failure

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Tissue Repair

• Labile cells (always dividing) - GI epithelium, skin, bone marrow → best regeneration
• Stable cells (quiescent; can re-enter cycle) - liver, kidney, fibroblasts → good regeneration
• Permanent cells (cannot divide) - neurons, cardiac muscle, skeletal muscle → replaced by scar

1. Granulation tissue forms (fibroblasts + new capillaries)
2. Angiogenesis (VEGF, FGF)
3. Fibroblast activation → collagen deposition (TGF-β is the key cytokine)
4. Remodeling (MMPs degrade collagen; balance of synthesis vs degradation)

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PART 3: NEOPLASIA

Definitions

• Neoplasia - abnormal, uncontrolled, purposeless proliferation of cells; persists after stimulus removed
• Tumor - a mass formed by neoplastic cells (also means swelling)
• Benign - grows locally, does NOT invade or metastasize; well-differentiated
• Malignant - can invade locally AND metastasize; varying differentiation

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Nomenclature (HIGH YIELD)

• Hamartoma - disorganized mass of native tissue (e.g., pulmonary hamartoma)
• Choristoma - normal tissue in wrong location (e.g., gastric mucosa in Meckel's diverticulum)
• Teratoma - all 3 germ layers; mature (benign) vs immature (malignant)

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Benign vs Malignant Tumors

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Carcinogenesis: A Multistep Process

• Cancer is clonal in origin (from a single mutated cell)
• Accumulation of multiple somatic mutations over time
• Key steps: Initiation → Promotion → Progression → Malignant transformation

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Hallmarks of Cancer (Hanahan & Weinberg - MUST KNOW)

1. Self-sufficiency in growth signals - oncogenes mimic growth factor signaling (RAS, MYC)
2. Insensitivity to growth-inhibitory signals - loss of tumor suppressors (RB, TP53)
3. Evasion of apoptosis - overexpression of Bcl-2; loss of p53
4. Limitless replicative potential (immortality) - telomerase activation
5. Sustained angiogenesis - VEGF, FGF; "angiogenic switch"
6. Invasion and metastasis - ↓ E-cadherin; ↑ metalloproteinases (MMPs); epithelial-mesenchymal transition (EMT)
7. Evasion of immune surveillance - PD-L1 expression, loss of MHC-I
8. Altered cellular metabolism (Warburg effect) - aerobic glycolysis even in presence of O₂
9. Tumor-promoting inflammation
10. Genome instability and mutation

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Key Cancer Genes

Knudson "Two-Hit" Hypothesis: Both alleles of a TSG must be inactivated - one inherited mutation + one somatic mutation.

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Tumor Invasion and Metastasis

1. Local invasion (loss of E-cadherin, ↑ MMPs, EMT)
2. Intravasation into blood/lymphatics
3. Survival in circulation (immune evasion)
4. Extravasation
5. Colonization of new site (organ-specific "seed and soil" hypothesis - Paget)

• Hematogenous - sarcomas; liver and lung most common sites
• Lymphatic - carcinomas; regional nodes first
• Seeding of body cavities - colon/ovary → peritoneum (Krukenberg tumor: gastric ca → bilateral ovaries)

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Carcinogenic Agents

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Tumor Immunology

• Tumor antigens:
  • Neoantigens (mutated proteins) - most immunogenic
  • Overexpressed normal proteins (HER2, CEA)
  • Cancer-testis antigens (MAGE, NY-ESO-1)
  • Viral antigens (EBV, HPV)
• Immune surveillance: CD8⁺ CTLs are primary killers; NK cells also important
• Immune evasion: ↓ MHC-I expression, PD-L1/PD-1 axis, CTLA-4, TGF-β
• Checkpoint inhibitors (anti-PD-1, anti-CTLA-4) harness this for cancer therapy

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Tumor Effects on Host

• Local effects - compression, obstruction (e.g., bowel obstruction, hydronephrosis)
• Cachexia - wasting; TNF (cachectin), IL-1, IFN-γ reduce appetite and increase catabolism
• Paraneoplastic syndromes (tumor products that act at distant sites):

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RAPID REVIEW TABLE - Key Buzzwords

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• More MCQ-style practice questions
• Specific mechanisms in more detail (e.g., apoptosis pathways, complement cascade)
• Systemic pathology topics (CVS, respiratory, GI, hematology, etc.)
• Any specific area you're uncertain about

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• Cover page with a clean dark-blue title block and table of contents
• Running header and footer on every page (title + page number)
• Part 1 - Cell Injury, Cell Death & Adaptations - causes of injury, reversible vs irreversible, mechanisms (Big 5), necrosis types, apoptosis pathways, cellular adaptations, intracellular accumulations, calcification
• Part 2 - Inflammation & Repair - cardinal signs, PRRs, acute inflammation steps, leukocyte defects, all mediators with drug targets, morphologic patterns, chronic inflammation, granuloma causes, acute-phase response, tissue repair
• Part 3 - Neoplasia - nomenclature, benign vs malignant, Hallmarks of Cancer, oncogenes, tumour suppressors, metastasis steps, carcinogens, paraneoplastic syndromes
• Rapid Review buzzword table at the end - 23 high-yield exam facts in gold-highlighted format