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