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

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

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

Toxic Hepatocellular Injury COMMON MEDS – ACETAMINOPHEN – NSAIDS – STATINS – ANTIBIOTICS (especially Amox/Clav)

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

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 glucoronyl transferases (UGT1, UGT2) Products excreted via transport on canalicular or sinusoidal membranes (Phase III) – Transport into bile

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

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

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

Sooo…. Our Patient Markedly Elevated AST/ALT, mild Alk Phos, nl bili, 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