What drugs can raise transaminases (liver enzymes)?

Drugs That Raise Transaminases

Many medications can elevate liver enzymes (transaminases), with statins, tyrosine kinase inhibitors (TKIs), and certain antibiotics being among the most common culprits. These elevations can range from mild, asymptomatic increases to severe hepatotoxicity requiring medication discontinuation.

Common Drug Classes That Elevate Transaminases

Statins

• Frequency and severity: Approximately 0.5-2% of patients experience elevated transaminases >3 times the upper limit of normal (ULN) 1, 2, 3
• Mechanism: Idiosyncratic drug-induced liver injury
• Specific agents:
  • Atorvastatin: Persistent increases >3x ULN occur in approximately 0.7% of patients 3
  • Simvastatin: Persistent increases >3x ULN occur in approximately 1% of patients 2
• Timing: Usually within first 12 weeks of therapy; often transient and resolve with continued therapy 3

Tyrosine Kinase Inhibitors (TKIs)

• Frequency: Varies by agent; 20-62% experience some degree of transaminase elevation 4
• Specific agents with incidence rates 4:
  • Imatinib: 6-12%
  • Dasatinib: 50%
  • Nilotinib: 35-62%
  • Bosutinib: 20%
  • Ponatinib: 56%
• Timing: Variable; imatinib typically causes elevations within 12-77 days of initiation 4

Other Common Medications

• NSAIDs: Both oral and topical formulations can cause transaminase elevations 5
• Antibiotics:
  • Clarithromycin (also a CYP3A inhibitor that can increase statin levels) 4
• Antifungals:
  • Itraconazole, ketoconazole, fluconazole (also CYP3A inhibitors) 4
• Antiarrhythmics:
  • Amiodarone 4
• Anticonvulsants
• Antituberculosis drugs
• Tolvaptan: Approximately 5% of patients with ADPKD develop transaminase elevations >3x ULN 4

Monitoring and Management

Monitoring Recommendations

• Statins: Baseline liver function tests (LFTs) before starting therapy, follow-up at approximately 12 weeks after initiation, and then annually or more frequently if indicated 1
• TKIs: Regular monitoring throughout treatment; frequency varies by agent 4
• Tolvaptan: Monthly monitoring for first 18 months, then every 3 months until drug discontinuation 4

Management of Transaminase Elevations

1. Mild elevations (<2x ULN): Generally continue monitoring without dose adjustment
2. Moderate elevations (2-3x ULN):
   • Repeat LFTs within 48-72 hours
   • Assess for other etiologies (other diseases, drugs, exposures)
   • Consider dose reduction or temporary discontinuation based on clinical context 4, 1
3. Significant elevations (>3x ULN):
   • Temporarily discontinue medication
   • Evaluate for other causes of liver injury
   • Consider permanent discontinuation if no other explanation is found 4, 2, 3

Special Considerations

Drug-Drug Interactions Increasing Risk

• CYP3A4 inhibitors can increase levels of statins and TKIs, potentially increasing hepatotoxicity risk 4:
  • Strong inhibitors: itraconazole, ketoconazole, clarithromycin, protease inhibitors
  • Moderate inhibitors: fluconazole, erythromycin, diltiazem, verapamil, amiodarone

Risk Factors for Hepatotoxicity

• High daily dose (>100 mg) 4
• Being a substrate of CYP450 enzymes 4
• Concomitant hepatotoxic medications
• Pre-existing liver disease
• Alcohol consumption
• Advanced age

Important Caveats

• Transaminase elevations are not always indicative of clinically significant liver injury 6
• Some elevations may be pharmacology-related rather than true hepatotoxicity 6
• AST is less liver-specific than ALT as it's also present in cardiac and skeletal muscle 1
• Fatal hepatic failure from medications is rare but has been reported with statins and some TKIs 2, 3

Remember that monitoring practices should be tailored to the specific medication, with more intensive monitoring for drugs with higher hepatotoxicity risk profiles.