Toxic Hepatocellular Injury

Mike Contarino, MDInternal 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