What medications can cause elevated Liver Function Tests (LFTs)?

Medications That Cause Elevated Liver Function Tests

Numerous medication classes can cause elevated LFTs through direct hepatotoxicity, idiosyncratic reactions, or cholestatic injury, with antifungals, antibiotics, anticonvulsants, and cardiovascular drugs being among the most common culprits.

High-Risk Hepatotoxic Medications by Class

Antifungal Agents

• Terbinafine is associated with cholestatic liver injury and requires baseline liver function tests and complete blood count in adult patients with a history of hepatotoxicity or hematological abnormalities 1, 2
• Itraconazole carries hepatotoxicity risk, with monitoring of hepatic function tests recommended in patients with pre-existing deranged results, those receiving continuous therapy for more than a month, and with concomitant use of hepatotoxic drugs 1
• Fluconazole requires baseline liver function tests and full blood count, with monitoring during high-dose or prolonged therapy and in those at risk due to concomitant hepatotoxic drug use 1

Antibiotic Agents

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

Anticonvulsants

• Carbamazepine requires baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, and should be discontinued based on clinical judgment if indicated by newly occurring or worsening clinical or laboratory evidence of liver dysfunction 3, 4
• The most severe hepatic reaction with carbamazepine occurs as part of DRESS syndrome (drug reaction, eosinophilia and systemic symptoms), which can progress to fulminant hepatic failure 4

Cardiovascular Medications

• Amiodarone carries the highest risk of clinically significant hepatotoxicity and should be discontinued when liver enzymes exceed 3 times the upper limit of normal, with liver toxicity occurring at a rate of 0.6% annually in patients on long-term therapy 2
• Methyldopa can cause both acute and chronic liver injury 2
• Statins (atorvastatin, rosuvastatin) cause dose-dependent borderline elevations of liver function tests over time, with elevations almost always <2× ULN, though greater elevations are seen with atorvastatin 40 mg/day 5, 6

Psychiatric Medications

• Chlorpromazine is associated with cholestatic liver injury 2

Immunosuppressive Agents

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

Antimicrobial Combinations

• Multiple antimicrobial agents significantly increase the risk of drug-induced liver injury through various mechanisms including direct hepatotoxicity, idiosyncratic reactions, and immune-mediated injury 7
• Colistin and teicoplanin are among the most hepatotoxic antimicrobials and should be considered for discontinuation first when managing elevated LFTs in patients on multiple antimicrobials 7

Additional Medications with Hepatotoxic Potential

Other Notable Agents

• Colchicine can cause elevated liver function tests, particularly in children during viral infections when combined with NSAIDs and antibiotics 1
• NSAIDs contribute to hepatotoxicity risk, especially when combined with other hepatotoxic agents 1
• Obeticholic acid (for primary biliary cholangitis) has been associated with hepatic decompensation and failure in patients with decompensated cirrhosis or Child Pugh class B or C who were incorrectly dosed 1

Risk Factors That Compound Medication-Induced Hepatotoxicity

Patient-Specific Factors

• Polypharmacy (use of multiple potentially hepatotoxic medications) compounds the risk of drug-induced liver injury 2, 7
• Pre-existing liver dysfunction reduces drug metabolism capacity and increases vulnerability to further injury 2, 7
• Age can be a risk factor, with elderly patients potentially having increased susceptibility 2
• Alcohol use can potentiate hepatotoxicity of many medications 2

Drug Interaction Considerations

• CYP3A4 inhibitors (including macrolides, azole antifungals, grapefruit juice) can increase levels of hepatotoxic drugs metabolized through this pathway 3
• Concomitant use of isoniazid with carbamazepine has been reported to increase isoniazid-induced hepatotoxicity 3

Monitoring Recommendations

Baseline Assessment

• Baseline liver function tests should be obtained before starting potentially hepatotoxic medications 2
• Comprehensive testing should include ALT, AST, alkaline phosphatase, GGT, bilirubin (total and direct), and INR 7

Ongoing Monitoring

• Regular monitoring of liver tests (ALT, AST, ALP, total bilirubin) is recommended for high-risk medications 2
• For patients on NSAIDs, CBC, LFTs, and renal function tests should be monitored every 6-12 months 2
• For methotrexate, monitoring should occur within the first 1-2 months and every 3-4 months thereafter 2

Important Clinical Caveats

When to Discontinue Medications

• For ALT/AST ≥3× ULN, hold the medication and repeat LFTs within 48-72 hours 2
• For severe elevations (ALT/AST >5× ULN) or any elevation with symptoms, discontinue all potentially hepatotoxic medications if clinically feasible 2, 7
• Moderate elevations may require dose reduction or temporary discontinuation of the most hepatotoxic agent 2

Special Considerations

• Idiosyncratic drug reactions are equally common in patients with normal or abnormal liver function 8
• Drug-induced liver injury can progress despite discontinuation of the offending drugs, requiring continued vigilance 7
• Rechallenge with suspected hepatotoxic agents should be avoided unless absolutely necessary for life-threatening conditions with no alternatives 7