Alcohol- and drug-induced liver diseases

1. Toxic Liver Damage (overview)

• Any liver disease (tumor, hepatitis, fulminant) can result from toxic injury.
• Predictable (dose-dependent): same effect in anyone reaching threshold dose.
• Unpredictable (idiosyncratic): individual variation in cytochrome P450 metabolism of xenobiotics.
• Reye syndrome (special form):
  • Acute liver failure WITHOUT necrosis + microvesicular fatty change.
  • Children <10 yr; triggered by viral infection + aspirin (acetylsalicylic acid).

2. Alcoholic Liver Disease — 3 Forms

1. Hepatic steatosis (fatty liver)
2. Alcoholic hepatitis
3. Cirrhosis

Pathogenesis

• Women more susceptible (↓ gastric alcohol dehydrogenase + body composition).
• Alcohol induces CYP P450 → ↑ conversion of drugs to toxic metabolites.
• Steatosis:
  • Excess NADH (from alcohol/acetaldehyde dehydrogenase) → shunts substrate toward lipid biosynthesis.
  • Impaired lipoprotein assembly/secretion.
  • ↑ Peripheral fat catabolism.
• Alcoholic hepatitis:
  • Acetaldehyde → lipid peroxidation, protein adducts → disrupts cytoskeleton/membranes.
  • Mitochondrial dysfunction, ROS, altered membrane fluidity.
  • TNF = main cytokine effector.
• Cirrhosis: only a small fraction of chronic alcoholics progress.

Morphology

Form	Macroscopic	Microscopic
Steatosis	Large, soft, yellow, greasy liver	Lipid droplets in hepatocytes; central-vein fibrosis with time
Alcoholic hepatitis	Mottled red, bile-stained	Hepatocyte swelling + necrosis, Mallory(-Denk) bodies (eosinophilic cytoplasmic inclusions), neutrophil infiltrate, fibrosis
Cirrhosis	Shrunken, nodular	Final, irreversible stage; micronodular pattern typical

Clinical features

• Steatosis: hepatomegaly, mildly ↑ bilirubin & ALP.
• Alcoholic hepatitis: develops after 15–20 yr of heavy drinking; acute fever, malaise, weight loss; ↑ bilirubin, ↑ ALP, neutrophilic leukocytosis; cirrhosis in ~1/3 after repeated bouts.
• Cirrhosis: portal hypertension, variceal hemorrhage, encephalopathy, jaundice; abstinence is the key Tx.
• Causes of death in end-stage alcoholics: hepatic failure, GI hemorrhage, hepatorenal syndrome, HCC.

3. Drug-Induced Liver Disease

Predictable hepatotoxins

• Acetaminophen — #1 cause of acute liver failure (centrilobular necrosis via NAPQI).
• Tetracycline (microvesicular steatosis).
• Amanita phalloides toxin.
• Alcohol.

Unpredictable (idiosyncratic) hepatotoxins

• Chlorpromazine, sulfonamides, halothane.

Notes

• Drug-induced chronic hepatitis is clinically + histologically indistinguishable from chronic viral hepatitis → serology is critical.
• Injury patterns may include: hepatocellular necrosis, cholestasis, steatosis, steatohepatitis, fibrosis, vascular lesions, acute liver failure.

Morphology / course

• Massive loss → shrunken, red liver with wrinkled capsule.
• Histology: hepatocyte destruction with collapsed reticulin framework; inflammatory infiltrate after several days.
• Survival >1 wk → hepatocyte regeneration; prolonged course → macronodular cirrhosis.

💡 High-yield: Alcohol → steatosis → alcoholic hepatitis (Mallory bodies + neutrophils) → micronodular cirrhosis; TNF main mediator. Acetaminophen = #1 acute liver failure (centrilobular). Reye = aspirin + viral in child → microvesicular steatosis + acute liver failure (no necrosis). Drug-induced → macronodular cirrhosis; pattern indistinguishable from viral — serology critical.