Cell Injury, Death and Adaptation — Pathology Fundamentals
🟢 Lite — Quick Review (1h–1d)
Rapid summary for last-minute revision before your exam.
Cell injury and adaptation form the foundation of pathology. Understanding how cells respond to stress, the mechanisms of cell death, and the morphological consequences of injury is essential for diagnosing disease. Focus on the difference between reversible and irreversible injury, apoptosis vs necrosis, and the key morphological signs.
High-Yield Facts for INI CET:
- Reversible injury: Cell swelling, fatty change, plasma membrane blebbing; organelles (mitochondria, ER) show changes but cell can recover
- Irreversible injury: Membrane damage (especially mitochondrial), lysosome rupture, nuclear changes — pyknosis, karyorrhexis, karyolysis
- Apoptosis: Energy-dependent, caspase-mediated, cell shrinkage, membrane blebbing, phagocytosis (no inflammation)
- Necrosis: Energy-independent, membrane rupture, cell swelling, inflammation; types: coagulative, liquefactive, caseous, fat, fibrinoid
- Necrosis vs apoptosis: Apoptosis is regulated (programmed), necrosis is uncontrolled; apoptosis is physiological and pathological; necrosis always pathological
⚡ Exam tip: In exam questions, look for whether the process is “programmed” or “regulated” (apoptosis) vs. “accidental” or “membrane rupture” (necrosis). The presence of inflammation indicates necrosis, not apoptosis. When cells die from ischaemia without reperfusion, coagulative necrosis is typical.
🟡 Standard — Regular Study (2d–2mo)
Standard content for students with a few days to months.
Causes of Cell Injury:
Hypoxia
- Most common cause; oxygen delivery to cells is reduced
- Causes: Ischaemia (loss of blood supply), cardiac failure, respiratory failure, anaemia (reduced oxygen-carrying capacity), cyanotic heart disease
- Mechanism: ↓ aerobic respiration → ↓ ATP → failure of Na/K ATPase → cell swelling; shifts to anaerobic glycolysis → lactic acidosis; calcium influx
- Duration matters: Brief hypoxia → reversible injury; prolonged hypoxia → irreversible → necrosis
Ischaemia-Reperfusion Injury
- Re-oxygenation after ischaemia generates reactive oxygen species (ROS)
- ROS: Superoxide (O₂⁻), hydrogen peroxide (H₂O₂), hydroxyl radical (OH·); damage DNA, proteins, lipids
- ROS also activate neutrophils → inflammation
- Interventions: Ischaemic preconditioning (brief episodes protect against longer ischaemia); antioxidants
Physical Agents
- Mechanical trauma: Rupture, shear, crushing
- Thermal injury: Burns, hypothermia
- Radiation: Ionising (X-rays, gamma) causes DNA strand breaks → apoptosis; UV causes pyrimidine dimers → skin cancer
- Electrical injury: Burns at entry/exit points; cardiac arrhythmias
- Pressure changes: Decompression sickness (nitrogen bubbles in blood)
Chemical Injury
- Poisons: Cyanide blocks cytochrome oxidase; carbon monoxide binds haemoglobin
- Drugs: Chemotherapy agents (alkylating agents, antimetabolites); paracetamol (acetaminophen) → hepatotoxicity via N-acetyl-p-benzoquinone imine (NAPQI) depletes glutathione
- Alcohol: Acute intoxication → CNS depression; chronic → fatty liver → alcoholic hepatitis → cirrhosis
- Illicit drugs: Cocaine → vasoconstriction → ischaemia; methamphetamine → neurotoxicity
Infectious Agents
- Viruses: Hijack host machinery; cause cell death via direct cytopathic effect, immune-mediated damage, transformation
- Bacteria: Exotoxins (direct damage), endotoxins (systemic inflammation), intracellular infection (TB granulomas)
- Parasites: Direct tissue invasion (Entamoeba histolytica → amoebic liver abscess), immune-mediated (malaria → haemolysis)
Immunological Reactions
- Hypersensitivity reactions: Type I (anaphylaxis), Type II (antibody against cell surface), Type III (immune complex deposition), Type IV (delayed, cell-mediated)
- Autoimmune diseases: SLE (anti-dsDNA, anti-Smith antibodies → multi-organ damage), myasthenia gravis (anti-AChR antibodies)
Nutritional Imbalances
- Deficiencies: Protein-energy malnutrition (kwashiorkor, marasmus), vitamin deficiencies (B12, folate, iron, vitamin C, vitamin D)
- Excess: Obesity → metabolic syndrome → diabetes, atherosclerosis; hypervitaminosis A → hepatotoxicity; hypervitaminosis D → hypercalcaemia
🔴 Extended — Deep Study (3mo+)
Comprehensive coverage for students on a longer study timeline.
Mechanisms of Cell Injury:
ATP Depletion
- Na/K ATPase failure → Na influx, K efflux → cell swelling
- Ca ATPase failure → increased cytosolic Ca²⁺ → activates phospholipases → membrane damage
- Loss of cellular membrane integrity → lysosomal enzymes released → autolysis
Mitochondrial Dysfunction
- Mitochondria are the ” Achilles heel” of cell injury
- MPTP (mitochondrial permeability transition pore) opens → loss of membrane potential → cessation of ATP production
- Cytochrome c release → activates caspases → apoptosis
- Irreversible injury: If mitochondrial membrane potential cannot be restored
Reactive Oxygen Species (ROS)
- Normally: Antioxidant systems (superoxide dismutase, catalase, glutathione peroxidase) neutralise ROS
- Oxidative stress: Excess ROS production or inadequate antioxidants
- Effects: Lipid peroxidation → membrane damage; protein oxidation → enzyme inactivation; DNA damage → mutations, apoptosis
- Diseases with ROS component: Atherosclerosis (oxidised LDL → foam cells), neurodegeneration (Parkinson’s, Alzheimer’s), cancer (DNA damage), IRI (ischaemia-reperfusion)
Disruption of Calcium Homeostasis
- Normal: Cytosolic Ca²⁺ ~100nM; ER stores ~500x higher; mitochondria store more
- Injury: ↑ cytosolic Ca²⁺ → activates phospholipases (membrane damage), proteases (cytoskeletal damage), endonucleases (DNA fragmentation)
- Calcium is the “final common pathway” of cell death
Damage to DNA and Proteins
- DNA damage: Alkylation, oxidation, radiation → single and double strand breaks; p53-mediated arrest → DNA repair or apoptosis
- Protein misfolding: Accumulation → ER stress → unfolded protein response; prolonged → apoptosis
- Examples: Alcohol adducts → fatty liver; smoking → COPD (alpha-1 antitrypsin deficiency → unopposed neutrophil elastase → emphysema)
Cellular Adaptations:
Hypertrophy
- Increase in cell size; no new cells; occurs in cells that cannot divide (neurons, cardiac myocytes, skeletal muscle)
- Mechanism: Increased synthesis of structural proteins; replication of organelles (mitochondria, ribosomes)
- Causes: Increased workload (chronic hypertension → LVH), hormonal stimulation (uterus in pregnancy → oestrogen)
- Pathology: Cell and organ enlargement; increased protein/DNA ratio
Hyperplasia
- Increase in cell number; occurs in cells capable of division (epithelial, liver, fibroblast)
- Mechanism: Growth factor-mediated stimulation of cell proliferation
- Causes: Hormonal (oestrogen → endometrial proliferation), compensatory (liver regeneration after partial hepatectomy), pathological (viral warts — HPV causes epidermal hyperplasia)
- Can be physiological (wound healing) or pathological (BPH — dihydrotestosterone)
Atrophy
- Decrease in cell size; occurs when workload decreases or hormonal stimulation is reduced
- Mechanism: Increased protein degradation via ubiquitin-proteasome pathway; decreased protein synthesis
- Causes: Disuse (immobilisation → muscle atrophy), denervation (nerve damage → muscle atrophy), loss of trophic stimulation (menopause → uterine atrophy), decreased blood supply (ischaemia), lack of hormonal stimulation (post-puberty → thymus)
- Pathology: Smaller cells, less cytoplasm, more lipofuscin (wear and tear pigment) accumulation
Metaplasia
- Replacement of one differentiated cell type with another; usually reversible
- Mechanism: Change in stem cell differentiation program (reprogramming)
- Causes: Chronic irritation (smoke → bronchial ciliated columnar → squamous); chronic acid reflux → Barrett’s oesophagus (squamous → columnar with goblet cells); vitamin A deficiency → squamous metaplasia of respiratory epithelium
- Significance: Adaptive but may predispose to dysplasia and cancer (squamous epithelium in bronchus lacks protective mucus; Barrett’s increases oesophageal adenocarcinoma risk)
- Types: Squamous (most common), intestinal (Barrett’s), osseous (bone in soft tissue), myxoid (cartilage in lungs)
Dysplasia
- Abnormal cell growth with loss of uniformity and orientation; considered a pre-neoplastic condition
- Features: Nuclear pleomorphism, hyperchromasia, increased nuclear/cytoplasmic ratio, loss of polarity, increased mitoses (may be abnormal)
- Mild dysplasia: May be reversible; severe dysplasia/carcinoma in situ → carcinoma if barrier is breached
- Found in: Cervical intraepithelial neoplasia (CIN), bronchial dysplasia, Barrett’s with dysplasia
Cell Death — Apoptosis:
Morphology of Apoptosis
- Cell shrinkage (contrast to necrosis — cell swelling)
- Chromatin condensation (pyknosis) and fragmentation (karyorrhexis)
- Membrane blebbing (formation of apoptotic bodies — membrane-enclosed fragments)
- Phagocytosis by adjacent cells or macrophages (no inflammation)
- No release of intracellular contents
Mechanisms of Apoptosis
- Mitochondrial (intrinsic) pathway: Stress signals → BAX/BAK (pro-apoptotic) → mitochondrial outer membrane permeabilisation → cytochrome c release → apoptosome (Apaf-1 + caspase-9) → effector caspases (3, 6, 7); regulated by BCL-2 family (BCL-2, BCL-XL are anti-apoptotic; BIM, BAD, BAX are pro-apoptotic)
- Death receptor (extrinsic) pathway: Fas (CD95) + FasL → DISC (death-inducing signalling complex) → caspase-8 → effector caspases; TNF + TNFR1 → TRADD → RIP + caspase-8 → caspases
- Granzyme pathway: CTLs release perforin (creates pores) + granzymes (enter via pores → activate caspase-10 or directly activate caspases)
Physiological apoptosis: Normal development (embryogenesis — digit formation, neural tube closure), tissue homeostasis (turnover of intestinal epithelium every 3-5 days), immune regulation (elimination of autoreactive T and B cells — central and peripheral tolerance)
Pathological apoptosis: DNA damage (p53 → BAX → apoptosis); growth factor withdrawal (neurons without NGF → apoptosis — relevant in Alzheimer’s); viral infections (infected cells are eliminated); endocrine atrophy (removal of hormonal stimulation); neurodegenerative diseases (excessive neuronal apoptosis in Alzheimer’s, Parkinson’s)
BCL-2 family key members:
- Anti-apoptotic: BCL-2, BCL-XL, MCL-1
- Pro-apoptotic: BAX, BAK (directly form pores), BIM, BAD, PUMA, NOXA
Inhibitors of apoptosis: BCL-2 (overexpressed in follicular lymphoma — t(14;18) translocation); IAPs (survivin, XIAP) — block caspases
Necrosis:
Types of Necrosis
Coagulative necrosis:
- Most common type; occurs in ischaemic injury (MI, stroke) except brain
- Mechanism: Denaturation of structural proteins AND enzymes (so architecture is preserved initially)
- Pathology: Tissue firmness; cell outlines preserved; nuclei lost; tissue eosinophilic; inflammatory infiltrate at margins
- Seen in: MI (heart becomes pale and firm → then yellow and soft as neutrophils digest tissue)
Liquefactive necrosis:
- Enzymatic digestion → liquefied tissue mass
- Most common in brain (infarcted brain tissue is liquefied by microglia — not ischaemic necrosis of other organs)
- Mechanism: Lysosomal enzyme release (from neutrophils and macrophages)
- Pathology: Liquid, creamy appearance; cavitation common
- Seen in: Brain infarcts, abscesses (bacterial infection → neutrophil influx → enzymatic digestion)
Caseous necrosis:
- Cheese-like; specific to TB infection
- Mechanism: Combination of coagulative and liquefactive necrosis; mycobacterial cell wall lipids resist digestion
- Pathology: Central caseous material (cheese-like); granulomatous rim (Langhans giant cells, epithelioid macrophages, lymphocytes); surrounded by fibrous capsule
- Not truly coagulative or liquefactive — has both features; best described as “granulomatous inflammation with central caseation”
Fat necrosis:
- Enzymatic: Acute pancreatitis → lipase released → digests fat → saponification (fat + calcium = white chalky deposits); peripancreatic fat necrosis
- Traumatic: Rupture of fat cells (breast tissue, subcutaneous fat) → fat released → inflammatory reaction
- Pathology: Chalky white areas of saponification
Fibrinoid necrosis:
- Deposition of fibrin-like material + immune complex deposition in vessel walls
- Mechanism: Immune complex deposition (Type III hypersensitivity) or direct vascular injury
- Pathology: Bright eosinophilic (pink) deposits in vessel wall; looks like fibrin; “fibrinoid” refers to the appearance
- Seen in: Malignant hypertension ( arterioles), rheumatic heart disease (valve leaflets), polyarteritis nodosa (medium vessels), Goodpasture’s (anti-GBM antibodies → alveoli and glomeruli)
Gangrene:
- Not a type of necrosis per se — refers to tissue death with putrefaction
- Dry gangrene: Coagulative necrosis + desiccation (evaporation); seen in peripheral vascular disease, diabetes; tissue becomes black, dry, mummified
- Wet gangrene: Liquefactive necrosis + bacterial infection + foul odour; seen in poorly perfused tissues; spreads rapidly; requires urgent debridement
- Gas gangrene: Clostridium perfringens infection; gas bubbles in tissue; crepitus on palpation; rapidly fatal
Apoptosis vs Necrosis — Summary:
| Feature | Apoptosis | Necrosis |
|---|---|---|
| Stimulus | Physiological/pathological | Pathological only |
| Cell fate | Individual cells die | Often groups of cells |
| Cell size | Shrinks | Swells |
| Nucleus | Pyknosis → karyorrhexis | Karyolysis, pyknosis |
| Cell membrane | Intact, blebbing | Ruptures |
| Inflammation | None | Prominent |
| Energy required | Yes (caspases) | No (passive) |
| Mechanism | Regulated (gene-directed) | Uncontrolled |
Calcification:
Dystrophic calcification:
- Deposition of calcium in damaged/necrotic tissue
- Normal serum calcium levels; normal phosphate
- Causes: Necrotic tissue, atherosclerotic plaques, damaged heart valves, old TB granulomas
- Mechanism: Membrane-bound vesicles (from dead cells) accumulate calcium and phosphate
Metastatic calcification:
- Deposition of calcium in normal tissues due to hypercalcaemia
- Elevated serum calcium; elevated phosphate
- Causes: Hyperparathyroidism (primary — tumour; secondary — chronic kidney disease), vitamin D intoxication, milk-alkali syndrome, bone destruction (malignancy, Paget’s disease), sarcoidosis
- Tissues affected: Stomach, kidney (interstitial, tubular), lungs, systemic arteries; occurs in alkaline tissues (where bicarbonate precipitates with Ca)
Nuclear Changes in Cell Death:
- Pyknosis: Nuclear shrinkage and condensation ( chromatin becomes dense)
- Karyorrhexis: Nuclear fragmentation (breaks into scattered pieces)
- Karyolysis: Nuclear dissolution (fade away — loss of chromatin basophilia)