What are common drugs that can elevate liver function tests (LFTs)?

Common Drugs That Elevate Liver Function Tests

The most common drugs associated with liver function test elevations include carbamazepine, methyldopa, minocycline, macrolide antibiotics, nitrofurantoin, statins, sulfonamides, terbinafine, chlorpromazine, and methotrexate. 1

Patterns of Drug-Induced Liver Injury

• Drug-induced liver injury can present in different patterns:
  • Hepatocellular pattern: Predominantly elevated ALT/AST 2
  • Cholestatic pattern: Predominantly elevated alkaline phosphatase and GGT 2
  • Mixed pattern: Features of both hepatocellular and cholestatic injury 2

Specific Hepatotoxic Medications

Antimicrobials

• Macrolide antibiotics (erythromycin, clarithromycin): Cause direct hepatotoxicity and increase levels of other hepatotoxic drugs by inhibiting CYP3A4 2
• Sulfonamides: Associated with idiosyncratic liver injury 2
• Nitrofurantoin: Linked to both acute and chronic liver injury 3
• Minocycline: Can cause autoimmune-like hepatitis 2

Neuropsychiatric Medications

• Carbamazepine: Requires baseline and periodic evaluations of liver function, particularly in patients with history of liver disease 4
• Chlorpromazine: Associated with cholestatic liver injury 2
• Methyldopa: Can cause both acute and chronic liver injury 2

Immunosuppressants and Antirheumatic Drugs

• Methotrexate: Requires special monitoring to prevent dose-dependent liver fibrosis 1
  • CBC, LFTs, and renal function should be monitored within the first 1-2 months of usage and every 3-4 months thereafter 1
  • Dose should be decreased or held if clinically relevant elevation in LFTs occurs 1

Other Common Hepatotoxic Medications

• Terbinafine: Associated with cholestatic liver injury 2
• Statins: Associated with elevations in aminotransferases in up to 3% of treated patients, but rarely lead to serious drug-induced liver injury 5
  • Elevations are usually mild (<2x upper limit of normal) and often clinically insignificant 6

Monitoring Recommendations

General Monitoring Principles

• Baseline liver function tests should be obtained before starting potentially hepatotoxic medications 2
• The pattern of liver blood tests, timing of medication use relative to liver abnormality development, and clinical setting should influence decisions about discontinuing medication 1

Medication-Specific Monitoring

• NSAIDs: CBC, LFTs, and renal function tests should be monitored every 6-12 months 1
• Methotrexate: CBC, LFTs, and renal function should be monitored within 1-2 months of starting and every 3-4 months thereafter 1
• Sulfasalazine: CBC, LFTs, and renal function should be monitored within 1-2 months of starting and every 3-4 months thereafter 1
• Leflunomide: CBC and LFTs should be monitored within 1-2 months of starting and every 3-4 months thereafter 1
• Hydroxychloroquine: CBC and LFTs should be monitored annually 1
• TNF inhibitors: CBC and LFTs should be monitored annually 1
• Tolvaptan: Monthly monitoring of LFTs for the first 18 months, then every 3 months until drug discontinuation 1

Management of Drug-Induced LFT Elevations

Assessment of Severity

• Mild elevations (<3x upper limit of normal): May continue therapy with increased monitoring 2
• Moderate elevations (3-5x upper limit of normal): Consider dose reduction or temporary discontinuation 2
• Severe elevations (>5x upper limit of normal or >3x with symptoms): Discontinue hepatotoxic medications 1

Decision Algorithm for Managing Elevated LFTs

1. Determine the pattern of liver enzyme elevation (hepatocellular, cholestatic, or mixed) 2
2. Consider the timing of medication use relative to the liver test abnormality 1
3. Rule out other causes of liver dysfunction (viral hepatitis, autoimmune liver disease, etc.) 2
4. For clinically relevant elevations in LFTs:
   • Hold the medication if ALT/AST ≥3x upper limit of normal 1
   • Repeat LFTs within 48-72 hours 1
   • Assess for other etiologies (other diseases, drugs, exposures) 1
   • Consider rechallenge only after LFTs return to normal and if benefits outweigh risks 1

Risk Factors for Drug-Induced Liver Injury

• Polypharmacy: Use of multiple potentially hepatotoxic medications compounds risk 2
• Pre-existing liver dysfunction: Reduces drug metabolism capacity and increases vulnerability 2
• Age: Elderly patients may have increased susceptibility 1
• Alcohol use: Can potentiate hepatotoxicity of many medications 1

Common Pitfalls and Caveats

• Liver enzymes are a poor guide to the development of progressive liver fibrosis in alcohol-related liver disease 1
• Statins are often unnecessarily discontinued due to mild LFT elevations, despite evidence that they rarely cause clinically significant liver injury 5
• Drug-induced liver injury can be difficult to distinguish from underlying liver disease; clinical judgment is needed to determine the major contributor 1
• Context matters: A patient receiving statin therapy with an ALT of 80 U/L who is well requires different management than a patient with end-stage liver disease with an ALT of 30 U/L 1