USMLE Pathology Syllabus

What is the fatty-streak-to-plaque sequence in atherosclerosis, and what are the components of a mature plaque?

Endothelial injury → LDL entry and oxidation → macrophage uptake forming foam cells → fatty streak → smooth-muscle migration/proliferation and ECM deposition. A mature atheroma has a fibrous cap (smooth muscle + collagen) over a necrotic lipid core with cholesterol clefts and foam cells.

List the major modifiable and non-modifiable risk factors for atherosclerosis.

Non-modifiable: age, male sex, family history, genetics. Modifiable: hyperlipidemia (high LDL, low HDL), hypertension, diabetes mellitus, and smoking. Smoking and diabetes are especially strong. Homocysteinemia is an additional risk factor.

Give the timeline of gross and microscopic changes after a myocardial infarction from 0–24 h through weeks.

0–24 h: wavy fibers, coagulative necrosis begins, contraction bands. 1–3 days: neutrophil infiltrate (risk of fibrinous pericarditis). 3–7 days: macrophages remove debris (weakest wall — free-wall/septal rupture risk). 1–3 weeks: granulation tissue, neovascularization. >1 month: dense collagenous scar.

Which cardiac biomarkers are used to diagnose MI and what is the timing of troponin?

Cardiac troponins I and T are most sensitive/specific: rise at 2–4 h, peak ~24–48 h, stay elevated 7–10 days. CK-MB rises at 2–4 h, peaks ~24 h, normalizes in 48–72 h — useful for detecting reinfarction because it returns to baseline sooner.

Distinguish concentric from eccentric cardiac hypertrophy and their pressure/volume causes.

Concentric hypertrophy: pressure overload (hypertension, aortic stenosis) → sarcomeres added in parallel, thick wall, small cavity. Eccentric hypertrophy: volume overload (aortic/mitral regurgitation, dilated cardiomyopathy) → sarcomeres added in series, dilated chamber.

Compare the three main cardiomyopathies: dilated, hypertrophic, and restrictive.

Dilated: systolic dysfunction, 4-chamber dilation (alcohol, coxsackievirus, doxorubicin, peripartum, genetic). Hypertrophic: diastolic dysfunction, asymmetric septal hypertrophy (autosomal dominant $\beta$-myosin heavy chain mutation), risk of sudden death. Restrictive: diastolic dysfunction from stiff wall (amyloidosis, sarcoidosis, hemochromatosis, endomyocardial fibrosis).

What is the pathophysiology and V/Q consequence of pulmonary edema in left heart failure?

Increased pulmonary capillary hydrostatic pressure forces transudate into alveoli. Chronic congestion produces hemosiderin-laden macrophages ('heart failure cells'). Fluid-filled alveoli impair gas exchange, lowering V/Q and causing hypoxemia and dyspnea/orthopnea.

Contrast emphysema and chronic bronchitis in the COPD spectrum.

Emphysema: permanent alveolar destruction distal to terminal bronchioles, loss of elastic recoil, decreased $\ce{DLCO}$; 'pink puffer'; centriacinar (smoking) vs panacinar ($\alpha_1$-antitrypsin deficiency). Chronic bronchitis: productive cough $\geq 3$ months for $\geq 2$ years, mucus gland hyperplasia (Reid index >0.5); 'blue bloater' with hypoxemia.

Explain the pathophysiology of asthma and its characteristic airway findings.

Type I hypersensitivity: allergen → Th2 response, IgE-mediated mast-cell degranulation, bronchoconstriction and airway inflammation with eosinophils. Findings: Curschmann spirals (mucus casts), Charcot-Leyden crystals (eosinophil-derived), smooth-muscle hypertrophy, and reversible airflow obstruction ($\downarrow \text{FEV}_1/\text{FVC}$).

Give the diagnostic Berlin criteria concept and pathology of ARDS.

ARDS: acute-onset diffuse alveolar damage from injury (sepsis, aspiration, trauma) → increased alveolar-capillary permeability, protein-rich exudate, hyaline membranes. Bilateral infiltrates with $\frac{\text{PaO}_2}{\text{FiO}_2} \leq 300$ mmHg and no cardiogenic cause. Loss of surfactant causes collapse and refractory hypoxemia.

How are the obstructive and restrictive lung disease patterns distinguished on PFTs?

Obstructive: $\frac{\text{FEV}_1}{\text{FVC}} < 0.7$ (both fall but $\text{FEV}_1$ more), increased TLC/RV (air trapping). Restrictive: $\frac{\text{FEV}_1}{\text{FVC}}$ normal or increased, with decreased TLC, FVC, and $\text{FEV}_1$.

What is the classic triad and mechanism of a pulmonary thromboembolism?

Most emboli arise from deep leg veins (Virchow triad: stasis, endothelial injury, hypercoagulability). Presentation: acute dyspnea, pleuritic chest pain, and hemoptysis (with a wedge-shaped hemorrhagic infarct). Large saddle emboli cause sudden death from acute right heart strain.

Distinguish nephrotic from nephritic syndrome.

Nephrotic: massive proteinuria ($>3.5$ g/day), hypoalbuminemia, edema, hyperlipidemia/lipiduria; podocyte/basement-membrane damage. Nephritic: hematuria with RBC casts, hypertension, oliguria, azotemia, and mild-to-moderate proteinuria; glomerular inflammation.

Match each nephrotic disease to its hallmark finding: minimal change, FSGS, membranous, diabetic nephropathy.

Minimal change: effaced foot processes on EM, normal LM (kids, steroid-responsive). FSGS: segmental sclerosis (HIV, heroin). Membranous: diffuse GBM thickening, subepithelial 'spike and dome' deposits (anti-PLA2R). Diabetic: Kimmelstiel-Wilson nodules and GBM thickening.

Match each nephritic disease to its key feature: PSGN, IgA nephropathy, RPGN, Alport, anti-GBM.

PSGN: subepithelial 'humps', granular IF, post-streptococcal. IgA (Berger): mesangial IgA deposits, post-mucosal infection. RPGN: crescents on biopsy. Alport: split GBM (type IV collagen mutation), deafness. Anti-GBM (Goodpasture): linear IF, lung + kidney.

What are the causes and morphology of acute tubular necrosis, and its clinical phases?

ATN causes: ischemia (shock) or nephrotoxins (aminoglycosides, contrast, myoglobin, cisplatin). Morphology: necrotic tubular epithelium, muddy-brown granular casts. Phases: initiation, maintenance (oliguria, hyperkalemia, uremia — riskiest), and recovery (polyuria). Most common cause of intrinsic acute kidney injury.

Give the standard formulas for GFR estimation, filtration fraction, and renal clearance.

Clearance: $C_x = \frac{U_x \cdot V}{P_x}$. GFR is estimated by inulin or creatinine clearance. Filtration fraction: $FF = \frac{GFR}{RPF}$ (normal ~0.20). Effective renal plasma flow is estimated with PAH clearance.

How do prerenal, intrinsic (ATN), and postrenal azotemia differ by BUN/Cr ratio and FENa?

Prerenal: $\frac{\text{BUN}}{\text{Cr}} > 20$, $FE_{Na} < 1\%$, urine osmolality $>500$ (kidney conserves). Intrinsic/ATN: $\frac{\text{BUN}}{\text{Cr}} < 15$, $FE_{Na} > 2\%$, urine osmolality $<350$ (tubules can't concentrate). Postrenal: variable, becomes intrinsic-like if prolonged.

Contrast an ischemic (thrombotic/embolic) stroke with a hemorrhagic stroke, including the most common vessel and region.

Ischemic (~85%): thrombotic (atherosclerosis, often MCA) or embolic (cardiac, e.g., AF) → liquefactive (colliquative) necrosis, pale then possibly hemorrhagic. Hemorrhagic (~15%): intracerebral (hypertension, Charcot-Bouchard microaneurysms of lenticulostriate arteries at basal ganglia) or subarachnoid (ruptured berry aneurysm).

Give the timeline of histologic changes in the brain after ischemic stroke.

12–24 h: red neurons (eosinophilic, shrunken). 24–72 h: neutrophils. 3–5 days: macrophages/microglia (foamy). 1–2 weeks: reactive gliosis and vascular proliferation. >2 weeks: cystic, fluid-filled cavity surrounded by dense glial scar (astrocytes).

Where do berry (saccular) aneurysms typically form and what condition classically presents with them?

Berry aneurysms form at branch points of the anterior circle of Willis, most commonly the anterior communicating artery. Rupture causes subarachnoid hemorrhage ('worst headache of my life'). Associations: autosomal dominant polycystic kidney disease, Ehlers-Danlos, and Marfan syndrome.

Distinguish epidural, subdural, and subarachnoid hemorrhage by vessel and CT appearance.

Epidural: middle meningeal artery (temporal bone fracture), biconvex/lens shape, lucid interval, does not cross sutures. Subdural: bridging veins (elderly, alcoholics, shaken infants), crescent shape, crosses sutures. Subarachnoid: berry aneurysm rupture, blood in sulci/cisterns, xanthochromic CSF.

What are lacunar infarcts, their vessels, and associated risk factor?

Lacunar infarcts are small (<15 mm) cavitary infarcts from occlusion of deep penetrating arteries (lenticulostriate). They are caused by chronic hypertension and diabetes producing hyaline arteriolosclerosis/lipohyalinosis. Common sites: basal ganglia, internal capsule, thalamus, pons — cause pure motor or pure sensory syndromes.

What is multiple sclerosis, its target, and the classic CSF and MRI findings?

MS is an autoimmune, T-cell–mediated demyelination of CNS white matter (oligodendrocytes destroyed), disseminated in space and time. CSF: oligoclonal IgG bands and increased IgG index. MRI: periventricular plaques (Dawson fingers). Classic signs: internuclear ophthalmoplegia (MLF lesion), optic neuritis, and scanning speech.

Compare the demyelination target and mechanism of Guillain-Barré syndrome versus multiple sclerosis.

Guillain-Barré: acute inflammatory demyelination of the peripheral nervous system (Schwann cells), often post-infectious (Campylobacter jejuni, molecular mimicry), causing ascending symmetric paralysis and albuminocytologic dissociation in CSF. MS targets CNS myelin (oligodendrocytes).

What is central pontine myelinolysis and its classic precipitating cause?

Central pontine myelinolysis (osmotic demyelination syndrome) is destruction of myelin in the pons caused by rapid correction of hyponatremia ('low to high, your pons will die'). It produces acute paralysis, dysarthria, dysphagia, and can cause 'locked-in' syndrome.

What are the characteristic gross and microscopic findings of Alzheimer disease?

Gross: diffuse cortical atrophy (widened sulci, narrowed gyri), especially hippocampus, with dilated ventricles (hydrocephalus ex vacuo). Micro: extracellular amyloid-$\beta$ (A$\beta$) senile plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau. Associations: ApoE4 (risk), APP on chromosome 21 (Down syndrome).

Match each neurodegenerative disease to its pathology: Parkinson, Huntington, ALS, Pick disease.

Parkinson: loss of dopaminergic neurons in substantia nigra pars compacta with Lewy bodies ($\alpha$-synuclein). Huntington: caudate atrophy from CAG trinucleotide repeat (chromosome 4), decreased GABA/ACh. ALS: motor neuron loss (anterior horn + corticospinal), SOD1 mutation. Pick disease: frontotemporal atrophy with tau Pick bodies.

Explain the neurochemical basis and inheritance of Parkinson disease and Huntington disease.

Parkinson: degeneration of dopaminergic nigrostriatal neurons → dopamine deficiency → resting tremor, rigidity, bradykinesia, postural instability. Huntington: autosomal dominant CAG repeat expansion in the huntingtin gene showing anticipation → loss of GABAergic and cholinergic neurons in the caudate → chorea and dementia.

What distinguishes a transient ischemic attack from a stroke, and what defines a watershed infarct?

A TIA is a transient focal neurologic deficit from ischemia that resolves (classically <24 h, usually <1 h) with no infarction on imaging; a stroke causes permanent tissue infarction. Watershed infarcts occur at border zones between major arterial territories (e.g., ACA-MCA) during severe hypotension, causing proximal limb weakness ('man in a barrel').