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
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