🧬 Pathophysiology

  • Hepatic failure – acute necrosis, chronic disease, or metabolic failure
    • Acute: massive necrosis (drugs, viruses, ischemia)
    • Chronic: progressive fibrosis → cirrhosis
  • Portal hypertension – increased resistance or flow
    • Prehepatic: portal vein thrombosis
    • Intrahepatic: cirrhosis, schistosomiasis
    • Posthepatic: Budd-Chiari, heart failure
  • Cholestasis – impaired bile formation or obstruction
    • Hepatocellular: drug-induced, sepsis
    • Obstructive: stones, stricture, malignancy
  • Cirrhosis – end-stage fibrosis + regenerative nodules
    • Micronodular (<3 mm) – alcohol, hemochromatosis
    • Macronodular (>3 mm) – viral, Wilson
    • Mixed pattern in advanced disease
  • Jaundice mechanism – bilirubin overload or defective handling
    • Unconjugated (indirect): hemolysis, Gilbert, Crigler-Najjar
    • Conjugated (direct): obstruction, Dubin-Johnson, Rotor
    • hepatocyte injury→inflammation→fibrosis→nodular regeneration→cirrhosis

🫁 Anatomy & physiology

  • Functional unit – hepatic lobule (portal triad + central vein)
    • Hepatocytes: metabolic, synthetic, excretory
    • Sinusoids: fenestrated endothelium, Kupffer cells
    • Space of Disse: stellate cells (vitamin A storage)
  • Bile flow – canaliculi → bile ducts → gallbladder / intestine
  • Blood supply – hepatic artery (25%) + portal vein (75%)
  • Major synthetic products
    • Albumin, coagulation factors (II, VII, IX, X)
    • Complement, acute-phase proteins
  • Detoxification – phase I (CYP450), phase II (conjugation)

⚗️ Metabolic & hereditary

  • Wilson disease – ATP7B mutation (copper excretion defect)
    • Liver: fatty change, chronic hepatitis, micronodular cirrhosis
    • Cornea: Kayser-Fleischer rings (copper in Descemet membrane)
    • Brain: movement disorder, psychiatric symptoms
    • Diagnosis: low ceruloplasmin, elevated urinary Cu, liver Cu
    • Treatment: D-penicillamine, liver transplant (curative)
  • Hemochromatosis – HFE (C282Y) → increased iron absorption
    • Cirrhosis, HCC (200x risk), diabetes, bronze skin, cardiomyopathy
    • Diagnosis: ferritin >1000, transferrin sat >45%, liver biopsy (Prussian blue)
    • Treatment: phlebotomy (goal ferritin 50–100)
  • α1-antitrypsin deficiency – SERPINA1, PiZZ severe deficiency
    • Liver: PAS+ globules, cirrhosis, HCC
    • Lung: panacinar emphysema (unopposed neutrophil elastase)
    • Treatment: smoking cessation, liver transplant
  • Reye syndrome – aspirin + viral illness (varicella, flu)
    • Microvesicular steatosis, cerebral edema, mitochondrial injury
  • NAFLD / NASH – obesity, insulin resistance, type 2 DM
    • Steatosis → steatohepatitis → cirrhosis (diagnosis of exclusion)

• α1-AT deficiency: low serum α1-AT, PAS+ diastase-resistant globules in hepatocytes.

💊 Treatment & pharmacology

  • Wilson disease – D-penicillamine (chelation), zinc (blocks absorption)
  • Hemochromatosis – therapeutic phlebotomy (1 unit/week) until ferritin normal
  • PBC – ursodeoxycholic acid (slows progression)
  • Hepatitis B / C – antivirals (nucleos(t)ide analogs, DAAs), interferon (less used)
  • Alcoholic hepatitis – supportive, corticosteroids (severe cases)
  • Cirrhosis complications
    • Ascites: diuretics (spironolactone), paracentesis, TIPS
    • Encephalopathy: lactulose, rifaximin, protein restriction
    • Varices: β-blockers, EVL, TIPS
  • HCC – resection, ablation, TACE, sorafenib/lenvatinib, transplant (Milan criteria)

• Prothrombin time (not PTT) is the key coagulopathy marker in liver disease.

🔬 Diagnosis & labs

PatternLab findingsExamples
HepatocellularALT/AST ↑↑ (ALT > AST)viral, alcoholic, NAFLD
CholestaticALP, GGT, 5′-NT ↑↑, bilirubin ↑PBC, PSC, obstruction
MixedALT + ALP ↑drugs, sepsis
Synthetic failure↓ albumin, ↑ INR/PTcirrhosis, acute failure
  • Serology – viral hepatitis
    • HAV: anti-HAV IgM (acute), IgG (past/immune)
    • HBV: HBsAg, anti-HBc IgM, HBeAg (high infectivity)
    • HCV: anti-HCV, HCV RNA (active)
    • HDV: anti-HDV (requires HBV co-infection)
  • Autoimmune markers – AMA (PBC), ANA, SMA, anti-LKM
  • Iron/copper – ferritin, transferrin sat, ceruloplasmin, 24h urinary Cu
  • Imaging – ultrasound (first-line), CT, MRI, elastography (fibrosis)
  • Biopsy – histology, special stains (Prussian blue, PAS, rhodanine)

🩺 Clinical pearls & high-yield

  • Kernicterus – unconjugated bilirubin crosses BBB → basal ganglia deposition (newborns)
  • PBC vs PSC
    • PBC: middle-aged women, AMA+, granulomatous duct destruction
    • PSC: young males, associated with UC, cholangiocarcinoma risk, “beaded” cholangiogram
  • Hepatitis B serology window – HBsAg negative, anti-HBc IgM positive, HBsAb negative
  • HCC tumor marker – α-fetoprotein (AFP) elevated in 60–70%
  • Fibrolamellar HCC – younger patients, fibrous bands, better prognosis
  • Amebic abscess – Entamoeba histolytica, RUQ pain, “anchovy paste” aspirate, serology +
  • Budd-Chiari – hepatic vein thrombosis, polycythemia/OCP/PNH, US Doppler

• HBeAg positive = high viral replication and infectivity.

⚠️ Risk factors & etiology

  • Cirrhosis causes – alcohol, HBV/HCV, NAFLD, hemochromatosis, Wilson, α1-AT, PBC/PSC
  • HCC risk – cirrhosis (any etiology), HBV/HCV, aflatoxin B1, alcohol, hemochromatosis
  • Hepatocellular adenoma – oral contraceptive use (young women), regression after stopping
  • Angiosarcoma – vinyl chloride exposure (rare, fatal)
  • Metastatic liver tumors – most common malignancy in liver; primaries: colon, breast, lung
  • Alcoholic liver disease – steatosis (reversible) → hepatitis (20% mortality) → cirrhosis (15%)

🔪 Surgical & interventions

  • Liver transplantation – curative for Wilson, α1-AT, acute failure, HCC (Milan)
  • Resection – hepatocellular adenoma (risk of bleeding/malignancy), hepatoblastoma
  • TIPS – transjugular intrahepatic portosystemic shunt (for refractory ascites/varices)
  • Endoscopic variceal ligation (EVL) – for acute variceal bleeding
  • Paracentesis – for tense ascites (diagnostic + therapeutic)
  • Phlebotomy – mainstay for hereditary hemochromatosis
  • Liver biopsy – percutaneous (risk bleeding), transjugular (if coagulopathy)

• Biopsy of suspected hemangioma is contraindicated (bleeding risk).