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Toxic Hepatocellular Injury
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  1. Toxic Hepatocellular Injury Mike Contarino, MD Internal Medicine and Pediatrics 1/22/10

  2. Liver Injury Patterns • Hepatocellular • Elevated aminotransferases +/- alk phos, bili • Cholestasis • Elevated alk phos, bili +/- aminotransferases • Isolated Hyperbilirubinemia • Jaundice if bili >2.5 • Infiltrative • Elevated Alk Phos; Bili/ALT/AST nl

  3. Hepatocellular Pattern • Viral Hepatitis: A, B, C, (ED), CMV, EBV, HSV, VZV • Autoimmune hepatitis • Drugs and Toxins: EtOH, Acetaminophen, Meds • NAFLD: Obese, DM, Hyperlipidemia • Vascular/Ischemic: Hypotension, CHF, Budd Chiari • Hereditary: Often systemic - Hemochromatosis, Alpha 1 antitrypsin def, Wilson’s Dx, Celiac

  4. Toxic Hepatocellular Injury • COMMON MEDS • ACETAMINOPHEN • NSAIDS • STATINS • ANTIBIOTICS (especially Amox/Clav)

  5. SOME SPECIFICS • ALT- more specific for liver than AST • >1000 indicative of ischemia, tylenol, severe viral hepatitis. • ALT> AST viral or fatty, AST:ALT >2:1 EtOH • Elevated LDH: ischemic or toxic

  6. Mechanism for drug excretion • Phase I and phase II reactions metabolize drugs • Phase I- Cytochrome P450 (oxidases, CYP3A4) • make polar for water solubility • Phase II- UDP glucoronyltransferases (UGT1, UGT2) • Products excreted via transport on canalicularor sinusoidal membranes (Phase III) • Transport into bile

  7. DILI- Drug Induced Liver Injury • Requires high index of suspicion • CLASSIFICATION: • Clinical: Hepatocellular, cholestatic, or mixed • Mechanism: Direct vs Idiosyncratic (immune/ metabolic) • Histology: Necrosis/apoptosis, Steatosis, Fibrosis, SOS (sinusoidal obstruction syndrome), Granulomatous

  8. Mechanism of DILI • Intrinsic hepatotoxins- dose dependent hepatocellular necrosis • Idiosyncratic reactions- most common • 0.01 to 1 percent of people taking drug • Allergic- hypersensitivity reaction • Metabolic- aberrant metabolism in susceptible pts

  9. VARIABLES • EtOH- CYP induction, GSH depletion • Diet- • CYP induction- Brussel sprouts, cabbage, broccoli, high protein diet • CYP inhibition- grapefruit juice, malnutrition • Other drugs- VAST!! • Alcohol and drugs do not mix! • Age- Decrease in CYP activity • Genetics, Underlying liver disease

  10. Sooo…. Our Patient • Markedly Elevated AST/ALT, mild AlkPhos, nlbili, Increased LDH • Toxic vs Ischemic • Not AST:ALT >2, No tylenol • ? In setting of early fatty liver, EtOH, and hx of paroxysmal atrial tachycardia • Biopsy: Stage 1 fibrosis of portal tracts, no steatosis or cholestasis, rare inflammatory cells. Resolving toxic-metabolic injury. • Ischemic 2/2 shock liver thought most likely • ? Holter monitor