Cell Injury, Adaptation & Death

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

Reversible cell injury: Cellular swelling (ballooning), fatty change (steatosis) — in liver, heart, kidney.

Irreversible cell injury: Membrane damage (blebbing, myelin figures), dense bodies (lysosomal residual bodies), nuclear changes → necrosis or apoptosis.

Necrosis types (NEET PG high-yield):

• Coagulative necrosis: Ischemia/infarction (most common); architecture preserved; denatured proteins
• Liquefactive necrosis: Brain abscess, bacterial infections; liquefaction by lysosomal enzymes
• Caseous necrosis: TB (cheese-like); no architecture preserved; granulomatous
• Gangrenous necrosis: Dry (coagulative) vs wet (liquefactive); depends on superinfection
• Fat necrosis: Pancreatic lipases digest fat; saponification (white chalky deposits); also traumatic fat necrosis
• Fibrinoid necrosis: Vasculitis, malignant hypertension; immune complex deposition

Apoptosis: Single cell death; cell shrinkage; chromatin condensation (pyknosis → karyorrhexis); apoptotic bodies; no inflammation.

⚡ Exam tip: “Cheese-like material in lung lesion” = caseous necrosis → TB. “Eosinophilic cytoplasm with no nucleus” = coagulative necrosis. “Apoptotic bodies with no inflammation” = apoptosis.

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Causes of Cell Injury

Hypoxia/ischemia (most common): Reduced oxygen delivery — atherosclerosis (arterial occlusion), anemia, cardiac failure. Reversible if <20 minutes; irreversible after prolonged ischemia.

Free radicals / Oxidative stress: Reactive oxygen species (ROS) — superoxide (O₂⁻), hydrogen peroxide (H₂O₂), hydroxyl (OH•); causes lipid peroxidation, protein denaturation, DNA damage. Antioxidants: Glutathione, superoxide dismutase, catalase, vitamin E.

Chemical/toxin injury: Cyanide (blocks cytochrome oxidase → blocks aerobic respiration → rapid death); carbon monoxide (binds Hb → cherry red skin); heavy metals (lead, mercury); drugs (acetaminophen depletes glutathione → hepatotoxicity)

Infectious agents: Viruses, bacteria, parasites — direct cytopathic effect or immune-mediated damage

Immunologic reactions: Autoimmune disease (SLE, Goodpasture), hypersensitivity reactions, transplant rejection

Nutritional deficiencies: Protein-energy malnutrition (kwashiorkor, marasmus), vitamin deficiencies (scurvy = Vit C, rickets = Vit D)

Physical agents: Trauma, burns, radiation (ionizing radiation → free radical formation), hypothermia, hyperthermia

Mechanisms of Cell Injury

1. ATP depletion → Na⁺/K⁺ ATPase failure → cellular swelling
2. Mitochondrial dysfunction → cytochrome c release → triggers apoptosis (intrinsic pathway)
3. Increased intracellular Ca²⁺ → activates proteases, endonucleases, ATPases → cell damage
4. Free radical accumulation → lipid peroxidation, protein oxidation, DNA damage
5. Loss of cell membrane integrity → irreversible injury

Reversible Cell Injury

• Cellular swelling: Blebbing, vacuolization (dilated ER); due to Na⁺/K⁺ pump failure
• Fatty change (steatosis): Accumulation of triglycerides in cytoplasm; liver (alcohol, toxins, metabolic syndrome), heart (obesity, alcoholism)
• Hydropic change: Intracellular water accumulation
• Nuclear changes: Chromatin clumping; myelin figures (membranous whorls from damaged ER/lysosomes)

Irreversible Cell Injury & Necrosis

Necrosis vs Apoptosis

Feature	Necrosis	Apoptosis
Nature	Accidental, pathologic	Programmed, physiologic
Extent	Affects groups of cells	Affects single cells
Cell size	Swells	Shrinks
Nucleus	Pyknosis → karyorrhexis → karyolysis	Chromatin condensation → internucleosomal cleavage
Cell membrane	Disrupted	Intact (until late)
Inflammation	Prominent	Absent
Example	Infarction, trauma	Embryologic development, hormone withdrawal

Types of Necrosis

Coagulative necrosis:

• Most common type; caused by ischemia/hypoxia in most organs EXCEPT brain
• Denaturation of structural proteins AND enzymes (blocks proteolysis temporarily)
• Architecture of dead cells preserved for days; eventually replaced by fibrosis/scar
• Gross: Pale, firm tissue with preserved outline
• Examples: Myocardial infarction (first 24–48 hrs before softening); renal infarction; splenic infarction

Liquefactive necrosis:

• Complete enzymatic digestion of dead cells; tissue liquefies
• Brain (most common site): Ischemic stroke in brain → liquefactive necrosis (brain has high lipid content, low protein, abundant hydrolases); produces cystic cavity
• Bacterial infections (abscess): Neutrophils release lysosomal enzymes → liquefaction
• Gross: Yellow-white, soft, liquid/purulent material

Caseous necrosis:

• Combination of coagulative necrosis + fat necrosis
• Gross: White, cheesy, granular material (resembles cottage cheese)
• Microscopy: Granulomatous inflammation; epithelioid cells, Langhans giant cells, rim of lymphocytes; central acellular eosinophilic area with destroyed architecture
• Classic cause: Tuberculosis; also seen in some fungal infections (histoplasmosis), syphilis, and nodular vasculitis
• Distinguished from coagulative: No preserved architecture; appears amorphous with debris

Gangrenous necrosis:

• Not a true type but a clinical term; usually in limbs (legs) or hollow organs (gallbladder, bowel)
• Dry gangrene: Coagulative necrosis + superimposed ischemia; tissue becomes dry, black, shriveled; due to gradual arterial occlusion
• Wet gangrene: Liquefactive necrosis + superimposed bacterial infection; swollen, foul-smelling; due to both arterial and venous occlusion
• Gas gangrene: Clostridium perfringens infection of traumatic/surgical wounds; produces gas in tissues (crepitus); rapidly fatal

Fat necrosis:

• Enzymatic: Pancreatic lipases (released during acute pancreatitis) digest peripancreatic fat → saponification (fatty acids bind calcium → chalky white deposits); also seen in breast tissue trauma
• Non-enzymatic: Traumatic fat necrosis (breast, subcutaneous tissue after injury); release of intracellular fat

Fibrinoid necrosis:

• Immune complex deposition in walls of arterioles, capillaries, arterioles
• Microscopy: Bright pink (eosinophilic), amorphous material (fibrin + immune complexes + complement) within vessel wall; looks like fibrin
• Examples: Malignant hypertension (blood pressure >180/120 → arteriolar fibrinoid necrosis); vasculitis (PAN, SLE); rheumatic heart disease (Aschoff bodies at MV); hyperacute transplant rejection

Apoptosis

Pathways

Intrinsic (mitochondrial) pathway:

• Triggered by: DNA damage, growth factor withdrawal, free radicals, oncogenes, viral infections
• Cytochrome c release from mitochondria → Apoptosome (cytochrome c + Apaf-1 + procaspase-9) → Caspase-9 → Caspase-3
• Bcl-2 family: Pro-apoptotic (BAX, BAK, BAD); Anti-apoptotic (Bcl-2, Bcl-XL)
• Regulated by p53 (activates pro-apoptotic BAX)

Extrinsic (death receptor) pathway:

• Fas (CD95) + Fas ligand → Fas trimerization → FADD → Caspase-8 → Caspase-3
• TNF pathway: TNF-α binds TNFR1 → TRADD → FADD/Caspase-8 → Caspase-3
• Physiologic: Embryogenesis (web dissolution between digits), immune tolerance, hormone-dependent involution (endometrium, lactating breast)

Features of Apoptosis

• Cell shrinkage (not swelling)
• Chromatin condensation → nuclear fragmentation (karyorrhexis)
• Caspase-activated DNase (CAD) — cleaves DNA at internucleosomal sites → DNA laddering (180-bp multiples)
• Apoptotic bodies: Membrane-bound fragments containing nuclear/cytoplasmic debris; rapidly phagocytosed by neighboring cells/macrophages
• No inflammation — phosphatidylserine on outer membrane signals phagocytes (“eat me signal”)
• Blebbing: Membrane blebs detach → apoptotic bodies

Apoptosis vs Necrosis Morphology

	Apoptosis	Necrosis
Cell size	Shrinks	Swells
Nucleus	Condensed, fragmented	Liquefies
Cytoplasm	Dense, eosinophilic	Lethal enzyme release
Cell membrane	Intact (until end)	Ruptures
Inflammation	None	Prominent
Surrounding tissue	Normal	Inflammatory infiltrate

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🔴 Extended — Deep Study (3mo+)

Comprehensive coverage for students on a longer study timeline.

Intracellular Accumulations

Fatty Change (Steatosis)

• Triglycerides accumulate in liver, heart, kidney (due to increased uptake, synthesis, or decreased oxidation/export)
• Causes: Alcohol (most common in developed countries), obesity, diabetes mellitus, protein-calorie malnutrition, toxins (CCl₄, aflatoxin), Reye syndrome, Wilson disease
• Gross: Enlarged, yellow, greasy liver
• Microscopy: Microvesicular (small droplets displacing nucleus) or macrovesicular (one large droplet displacing nucleus) — both seen in different conditions
• Alcoholic fatty liver: Macrovesicular; reversible with abstinence
• Microvesicular steatosis: Seen in acute fatty liver of pregnancy, Reye syndrome, valproic acid toxicity (impaired beta-oxidation of fatty acids)

Amyloid

• Misfolded proteins forming β-pleated sheet structure; deposits in extracellular space
• Congo red stain: Apple-green birefringence under polarized light (pathognomonic)
• Types: AL (primary, light chain), AA (secondary, reactive), ATTR (transthyretin = familial amyloid, senile systemic)
• Sites: Kidney (nephrotic syndrome), liver (hepatomegaly), heart (restrictive cardiomyopathy), spleen, peripheral nerves

Cholesterol & Cholesterol Esters

• Atherosclerosis: Lipid-laden macrophages (foam cells) in intima of arteries
• Xanthomas: Tendon xanthomas (Achilles, extensor tendons of hands) in familial hypercholesterolemia; eruptive xanthomas in diabetics

Glycogen

• Glycogen storage diseases (GSD): Type I (von Gierke — glucose-6-phosphatase deficiency → hepatomegaly, hypoglycemia); Type II (Pompe — lysosomal acid maltase deficiency → cardiomegaly, muscle weakness)
• Diabetes mellitus: Glycogen in proximal tubule cells (Armanni-Ebstein lesion — clear cells with glycogen)

Bilirubin

• Jaundice: Unconjugated hyperbilirubinemia (hemolysis, Gilbert syndrome, Crigler-Najjar) vs conjugated (hepatocellular, cholestatic)
• Hemosiderin (iron storage): Blue granules; Prussian blue stain

Calcification

Dystrophic calcification:

• Calcium deposits in dead/necrotic tissue; serum calcium is NORMAL
• Examples: Atherosclerotic plaques, damaged/necrotic heart valves (post-MI), tuberculous lesions (caseous necrosis), fat necrosis (saponification)

Metastatic calcification:

• Calcium deposits in normal tissues due to HYPERCALCEMIA
• Causes: Hyperparathyroidism (primary > secondary > tertiary), vitamin D intoxication, milk-alkali syndrome, chronic renal failure (renal osteodystrophy → secondary hyperparathyroidism), bone destruction (malignancy, Paget disease)
• Sites: Gastric mucosa, kidney (nephrocalcinosis), lungs (interstitial), blood vessels (medial calcification), cornea (band keratopathy)
• Metastatic = calcium goes TO tissues; Dystrophic = calcium deposits IN dead tissue

Cellular Aging

• Telomere shortening: Somatic cells lose ~50-200 bp of telomeric DNA per cell division; when critically short → senescence
• Oxidative damage: Free radical accumulation over time
• Advanced glycation end-products (AGEs): Non-enzymatic glycation of proteins (associated with diabetes complications)
• DNA damage accumulation: Mutations, mitochondrial DNA deletions
• Lipofuscin (“wear and tear” pigment): Brown, granular pigment = lipid peroxidation products + protein aggregates; accumulates in long-lived cells (neurons, cardiac myocytes, hepatocytes); no known functional significance

Autophagy

• Self-eating; cells degrade their own components for survival during nutrient deprivation
• Steps: Isolation membrane → autophagosome (double membrane) → fusion with lysosome → autolysosome
• Regulated by: mTOR (inhibits) and AMPK (activates); Beclin-1 gene
• Types: Macroautophagy (most common), microautophagy, chaperone-mediated autophagy
• Role: Adapt to starvation, remove damaged organelles (mitochondria = mitophagy), quality control, tumor suppression (defective autophagy → cancer)
• Defects: Neurodegeneration (Huntington, Parkinson), myopathy, cancer predisposition

Key NEET PG Pearls

1. Reversible injury: Cellular swelling, fatty change — return to normal if insult removed
2. Coagulative necrosis: Architecture preserved (ischemia in all organs EXCEPT brain); most common type
3. Liquefactive necrosis: Brain + bacterial infections; complete digestion by enzymes
4. Caseous necrosis: Granulomatous; “cheese-like”; TB is the classic cause
5. Fibrinoid necrosis: Immune complex in vessel wall; malignant hypertension, vasculitis, rheumatic heart disease
6. Fat necrosis: Pancreatic lipases → saponification (chalky white calcium soaps)
7. Apoptosis: Single cell death, no inflammation; DNA laddering (180-bp internucleosomal fragments)
8. Caspase-3 = executioner caspase (common to both intrinsic and extrinsic apoptosis pathways)
9. Dystrophic calcification = calcium in dead tissue (NORMAL calcium levels); Metastatic calcification = calcium in normal tissue (HIGH calcium levels)
10. Lipofuscin: “Wear and tear” brown pigment; accumulates in aging hearts, livers, neurons; harmless

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