Diagnosing Drug-Induced Liver Injury (DILI)
The diagnosis of drug-induced liver injury requires a comprehensive evaluation including detailed medication history, characteristic pattern recognition, exclusion of alternative causes, and application of causality assessment tools.
Initial Assessment and Pattern Recognition
Biochemical Pattern Identification
- Calculate R value to determine injury pattern 1:
- R = (ALT/ALT ULN)/(ALP/ALP ULN)
- Hepatocellular pattern: R ≥ 5
- Mixed pattern: R > 2 but < 5
- Cholestatic pattern: R ≤ 2
Temporal Relationship Assessment
- Document precise timing of:
- Drug initiation
- Onset of liver test abnormalities
- Latency period (typically within first 6 months of exposure) 1
- Improvement after drug discontinuation (dechallenge)
Diagnostic Workup
Essential Laboratory Tests
- Complete liver biochemistry panel:
- ALT, AST, ALP, GGT, total and direct bilirubin 2
- Coagulation studies (INR/PT)
- Complete blood count with differential (look for eosinophilia)
Exclusion of Alternative Causes
- Viral hepatitis serologies:
- Hepatitis A, B, C, E
- EBV, CMV, HSV, VZV 1
- Autoimmune markers:
- ANA, ASMA, AMA, LKM-1 antibodies
- Imaging studies:
- Ultrasound, CT, or MRI to exclude biliary obstruction
- MRCP if cholestatic pattern present 1
- Alcohol and toxin screening when appropriate
Liver Biopsy Considerations
- Not mandatory but helpful when 1:
- Diagnosis remains uncertain after initial evaluation
- Suspicion of autoimmune-like DILI
- Prolonged or severe cholestasis
- Concern for vanishing bile duct syndrome
Causality Assessment
Standardized Tools
- RUCAM (Roussel Uclaf Causality Assessment Method) scoring system 3
- Drug's known "signature" pattern of injury 3
- LiverTox website (http://livertox.nih.gov/) for drug-specific information
Key Clinical Indicators
- Improvement after drug discontinuation (positive dechallenge)
- Presence of hypersensitivity features (rash, fever, eosinophilia)
- Previous reports of hepatotoxicity with the suspected drug
- Exclusion of competing etiologies
Monitoring and Management
Initial Management
- Immediate discontinuation of suspected drug 2
- Close monitoring with repeat liver tests:
- Within 2-5 days for hepatocellular DILI
- Within 7-10 days for cholestatic DILI 2
Criteria for Specialist Referral
- ALT ≥ 5× baseline or ≥ 500 U/L
- ALT ≥ 3× ULN with total bilirubin ≥ 2× ULN (Hy's Law criteria)
- Any signs of hepatic decompensation 2
Special Considerations
- For patients with elevated baseline ALT:
- Consider drug discontinuation when ALT reaches 5× baseline or 500 U/L
- Or if ALT ≥ 2× baseline with total bilirubin ≥ 2× ULN 2
Pitfalls and Challenges
- Polypharmacy complicates identification of culprit drug
- Delayed recognition may lead to continued exposure and worsening injury
- Rechallenge is generally contraindicated in severe cases 2
- Some drugs can cause chronic injury or vanishing bile duct syndrome 4
- Herbal and dietary supplements are often overlooked as potential causes
Prevention Strategies
- Regular monitoring of liver enzymes for high-risk medications
- Patient education about signs and symptoms of liver injury
- Avoidance of alcohol and other hepatotoxic substances while taking potentially hepatotoxic medications 2
- Dose adjustment in patients with pre-existing liver disease
Remember that DILI remains largely a diagnosis of exclusion, and the key to accurate diagnosis is diligent exclusion of alternative causes while identifying characteristic drug-related patterns of injury.