Drug-Induced Liver Injury
Drug-induced liver injury (DILI) is a leading cause of acute liver failure. Understanding its mechanisms, risk factors, and early detection can prevent fatal outcomes.
Overview
Drug-induced liver injury (DILI) accounts for approximately 50% of acute liver failure cases in the United States. It ranges from asymptomatic transaminase elevation to fulminant hepatic failure requiring transplantation. Over 1,000 drugs and herbal products have been implicated.
Mechanisms of Hepatotoxicity
DILI occurs through two principal pathways. Intrinsic hepatotoxicity is dose-dependent and predictable, as seen with acetaminophen. Its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) depletes glutathione and causes centrilobular necrosis. Idiosyncratic hepatotoxicity is unpredictable, dose-independent, and may involve immune-mediated or metabolic mechanisms. Drugs like isoniazid and amoxicillin-clavulanate follow this pattern.
Additional mechanisms include mitochondrial dysfunction (valproic acid), bile duct injury (erythromycin estolate), and sinusoidal obstruction (oxaliplatin).
Common Offending Agents
- Acetaminophen: Most common cause of acute liver failure in Western countries. Toxicity threshold is generally above 150 mg/kg.
- Antibiotics: Amoxicillin-clavulanate is the most frequent cause of idiosyncratic DILI. Isoniazid, nitrofurantoin, and fluoroquinolones are also implicated.
- NSAIDs: Diclofenac carries higher hepatotoxicity risk than ibuprofen.
- Anticonvulsants: Valproic acid, phenytoin, and carbamazepine.
- Statins: Mild transaminase elevation is common but clinically significant injury is rare.
- Herbal supplements: Green tea extract, kava, and black cohosh.
Diagnosis and Hy's Law
Diagnosis requires excluding viral hepatitis, autoimmune hepatitis, biliary obstruction, and ischemic injury. The RUCAM (Roussel Uclaf Causality Assessment Method) score provides structured causality assessment.
Hy's Law predicts serious outcomes: if a drug causes hepatocellular injury (ALT >3x ULN) with jaundice (bilirubin >2x ULN) without biliary obstruction, the case fatality rate reaches 10-50%.
Risk Factors
Age over 55, female sex, chronic alcohol use, pre-existing liver disease, polypharmacy, and certain CYP450 polymorphisms increase susceptibility. Obesity raises acetaminophen toxicity risk through enhanced CYP2E1 activity.
Prevention
Baseline liver function testing before initiating known hepatotoxins is recommended. Patients on isoniazid, methotrexate, or anticonvulsants should undergo periodic monitoring. Acetaminophen intake should not exceed 3 g/day in healthy adults or 2 g/day in chronic alcohol users.
Key Takeaways
- DILI is the leading cause of acute liver failure and can be intrinsic or idiosyncratic
- Acetaminophen toxicity is dose-dependent; idiosyncratic reactions are unpredictable
- Hy's Law (ALT >3x ULN + bilirubin >2x ULN) signals high fatality risk
- Baseline and periodic liver monitoring is essential for known hepatotoxins
- Early drug withdrawal is the most important intervention