Pathology I — Cellular Injury, Adaptation & Death — USMLE Step 1 Notes
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Why this chapter is worth the most
Cell injury, inflammation and neoplasia are the general principles the rest of pathology is built on. Test-takers report several questions drawn straight from them, and their logic recurs in every organ system.
Cellular adaptations (reversible, purposeful)
| Adaptation | Meaning | Example |
|---|---|---|
| Hypertrophy | Bigger cells | Cardiac muscle in hypertension |
| Hyperplasia | More cells | Endometrium, prostate (BPH) |
| Atrophy | Smaller / fewer cells | Disuse, denervation, ischaemia |
| Metaplasia | One mature type → another | Barrett oesophagus |
| Dysplasia | Disordered, pre-malignant | Cervical CIN |
Reversible vs irreversible injury
- Reversible: cellular swelling (failed Na/K ATPase), ribosomal detachment, fatty change
- Irreversible marker: membrane damage with calcium influx; mitochondrial vacuolisation; the point of no return
- Ischaemia depletes ATP → the earliest lesion is cellular swelling
Necrosis — six patterns to recognise
- Coagulative — ischaemia in solid organs; preserved outlines, lost nuclei
- Liquefactive — brain infarct, and abscesses (neutrophil enzymes)
- Caseous — TB and fungi; granuloma with central 'cheese'
- Fat — pancreatitis (saponification) and breast trauma
- Fibrinoid — vessel walls in vasculitis and malignant hypertension
- Gangrenous — dry (coagulative) or wet (superimposed infection)
Apoptosis vs necrosis
| Apoptosis | Necrosis | |
|---|---|---|
| Trigger | Programmed signal | Injury |
| Cell | Shrinks | Swells |
| Membrane | Intact | Ruptures |
| Inflammation | None | Yes |
| Enzymes | Caspases | — |
Intrinsic pathway: BCL-2 family, mitochondrial cytochrome c. Extrinsic: Fas/FasL and TNF death receptors.
Free radicals and pigments
- Reactive oxygen species cause reperfusion injury, CCl4 toxicity, ageing; scavenged by SOD, catalase, glutathione
- Lipofuscin ('wear and tear'), haemosiderin (iron overload), and amyloid (Congo red, apple-green birefringence)
Fatty change (steatosis) — how fat accumulates
Reversible accumulation of triglyceride in the cytoplasm, classically hepatocytes. It arises whenever the balance of fat entering, made, exported or oxidised is tipped:
- More free fatty acids entering the liver
- More fatty-acid synthesis by the liver
- Less oxidation of fatty acids to ketones (so more is esterified to triglyceride)
- Rising α-glycerophosphate, which also drives esterification to triglyceride
- Less apoprotein (lipid-acceptor protein), so triglyceride cannot be packaged into lipoprotein
- Blocked export of lipoprotein from the hepatocyte into plasma
Gross: enlarged liver, glistening capsule, greasy to the touch. Histology: lipid vacuoles in hepatocyte cytoplasm, ranging from fine microvesicular droplets to large macrovesicular vacuoles that push the nucleus to the edge.
Serum enzymes — what leaks tells you what died
When membranes fail, intracellular enzymes spill into serum. The pattern localises the injured tissue — foundational for Step 1 mechanism and Step 2 diagnosis alike.
| Marker | Points to |
|---|---|
| AST (SGOT) | Viral & alcoholic hepatitis; also myocardial infarction (non-specific) |
| ALT (SGPT) | Viral hepatitis — more liver-specific than AST |
| CK-MB | MI, myocarditis, skeletal-muscle injury; early re-infarction marker |
| Troponin (cTn) | Myocardial infarction — the specific cardiac marker |
| Lipase | Acute pancreatitis — more specific than amylase |
| Amylase | Acute pancreatitis and sialadenitis |
| LDH | MI, myocarditis, skeletal-muscle injury, haemolysis (broad) |
The cell cycle and its checkpoints
Progression is driven by cyclins activating cyclin-dependent kinases (CDKs); CDK inhibitors hold the brakes. The two guard-points — G1/S and G2/M — are where damaged cells are stopped or sent to apoptosis.
| Phase | Cyclin | CDK | Inhibitors |
|---|---|---|---|
| G1 | E | CDK2 | p16, p15, p18 (INK4) |
| G1/S checkpoint | D / E | CDK4, CDK6, CDK2 | p21, p27, p57 (CIP/KIP) |
| S | A | CDK2, CDK1 | p21, p27, p57 |
| G2/M checkpoint | B | CDK1 | p21, p27, p57 |
| M | B | CDK1 | CIP/KIP family |
p16 (INK4) blocks CDK4/6; the CIP/KIP family (p21, p27, p57) is broad-acting. p21 is a key effector of p53 — the link between DNA damage and cell-cycle arrest.
Growth factors that drive repair and proliferation
| Factor | Made by | Role & high-yield hook |
|---|---|---|
| EGF / TGF-α | Macrophages, epithelium | Epithelial proliferation & repair via EGFR (a tyrosine-kinase receptor). Note: the related receptor ERBB2 (HER2/neu) — distinct from EGFR — is amplified in ~20% of breast cancers |
| TGF-β | Platelets, leucocytes, endothelium | Anti-inflammatory; blocks G1; stimulates collagen & fibrosis; signals through SMADs. Chemotactic for leucocytes |
| PDGF | Platelets, macrophages, endothelium, smooth muscle | Mesenchymal-cell proliferation, vessel growth, extracellular-matrix synthesis; TK receptor |
| VEGF | Mesenchymal cells | Angiogenesis; VEGF-C/D drive lymphangiogenesis; TK receptor (anti-VEGF is a cancer-therapy target) |
| HGF (scatter factor) | Mesenchymal cells | Hepatocyte & endothelial proliferation, cell migration; receptor is the c-Met oncogene |
| FGF | Macrophages, endothelium | Granulation-tissue formation, angiogenesis, ECM synthesis; TK receptor |
Hyperplasia vs metaplasia — don't confuse them
| Hyperplasia | Metaplasia | |
|---|---|---|
| What changes | More cells of the same type | One mature cell type replaced by another |
| Which cells | Only dividing cells | Reprogrammed precursor / stem cells |
| Driver | Growth factors on surface receptors → signal transduction | Chronic stress reprogramming the stem cell (e.g. reflux → Barrett) |
Ischaemic / hypoxic injury — the cascade
Read this as a sequence; the earliest lesion is swelling, and calcium influx marks the point of no return.
- 1. Ischaemia / hypoxia
- 2. Oxidative phosphorylation fails → ATP falls; HIF-1 drives a shift to anaerobic glycolysis
- 3. Na⁺/K⁺-ATPase fails → cellular swelling (reversible); lactate accumulates, pH drops, ribosomes detach
- 4. Cytosolic calcium rises → activates phospholipases (membrane breakdown) and proteases (cytoskeletal injury)
- 5. Membrane damage + free-radical / reperfusion injury → irreversible
- 6. Intracellular enzymes leak; myelin figures appear
- 7. Nuclear death: pyknosis → karyorrhexis → karyolysis; serum AST / LDH / CK-MB / troponin rise
Apoptosis — the molecular sequence
- 1. Trigger: survival signals withdrawn (hormones, growth factors, cytokines) or injury (heat, hypoxia, toxins, radiation)
- 2. Rebalance: pro-apoptotic BCL proteins rise (BAX, BAK, BAD, BID, BIM, PUMA, NOXA); anti-apoptotic fall (BCL-2, BCL-XL, MCL1)
- 3. Initiator caspases: intrinsic — mitochondrial cytochrome c binds APAF-1 → apoptosome → caspase-9; extrinsic — Fas/CD95 & TNFR1 → caspase-8/10
- 4. Executioner caspases: caspase-3 and -6 → chromatin clumping, cytoskeletal & organelle breakdown, membrane blebbing
- 5. Clearance: the dying cell flips phosphatidylserine outward and is coated with thrombospondin and complement C1q → recognised and eaten by macrophages, with no inflammation
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