23 - Hepatotoxicity

Question 1

What are the types of hepatotoxicity? Briefly describe each

Answer 1

1. Direct -> liver injury caused by the drug or its metabolites; usually dose related (so therapeutic doses shouldn’t cause hepatotoxicity); predictable
   - - Ex: acetaminophen
2. Idiosyncratic -> not predictable; not reproducible
3. Indirect -> drug or its metabolites aren’t directly causing hepatotoxicity, but are causing it in an indirect way (ex: chemotherapy decreases immune system, which can increase risk of viral hepatitis)

Question 2

What are the common phenotypes of drug-induced liver injury? What are characteristics of each?

Answer 2

1. Cholestatic -> alk phos will be high
2. Hepatocelluar -> AST/ALT significantly increased (10x ULN)
   - - When bilirubin is also high => acute liver injury

Question 3

Risk factors for drug-induced liver injury?

Answer 3

• Genotype, epigenetics
• Lifestyle, alcohol
• Co-medication
• Inflammatory episodes
• Disease
• Mitochondrial heteroplasmy

Question 4

High bilirubin commonly causes _____

Answer 4

Jaundice and itching

Question 5

When to d/c drug if suspected drug-induced liver injury?

Answer 5

• ALT/AST > 8x ULN
• ALT/AST > 5x ULN for > 2 weeks
• ALT/AST > 3x ULN and total bili > 2x ULN OR INR > 1.5
• ALT/AST > 3x ULN w/ symptoms

Question 6

When should the drug causing a drug-induced liver injury NOT be re-challenged?

Answer 6

• Px w/ significantly increased enzymes (> 5x ULN)

- Px w/ accompanying signs of an immunologic reaction

Question 7

What are other causes of liver injuries?

Answer 7

• Acute viral hepatitis
• Alcoholic and autoimmune hepatitis
• Biliary tract disorders
• CV causes
• Other uncommon causes

Question 8

Which patient groups are at high risk for acetaminophen toxicity?

Answer 8

• Glutathione depleted -> malnutrition, anorexia, alcoholic, AIDS
• CYP P450 (CYP2E1) induced -> increased production of NAPQI, ethanol, rifampicin, anticonvulsants (phenytoin, phenobarbital, carbamazepine)