What medications can cause elevated liver enzymes in an adult with no pre-existing liver conditions?

Medication Causes of Elevated Liver Enzymes

Numerous medications can cause elevated liver enzymes in adults without pre-existing liver disease, with the most common culprits being statins, antibiotics (particularly macrolides, sulfonamides, and nitrofurantoin), anticonvulsants (carbamazepine), antifungals (terbinafine), methotrexate, and antiretroviral drugs. 1

High-Risk Medication Classes

Statins

• Statins cause transient ALT elevations in 2.6-5.0% of patients, typically <3× upper limit of normal (ULN), which are dose-related and often reversible with continued therapy 2, 3, 4
• Elevations are most common in the first 4 weeks after initiation and almost always remain <2× ULN 5
• Acute liver failure is extremely rare (approximately 1 per 1.14 million patient-treatment years), roughly equal to the background rate of idiopathic acute liver failure 4
• Statins should be continued if ALT <3× ULN; consider dose reduction or temporary discontinuation only if ALT ≥3× ULN on repeat testing 5, 2, 3

Antibiotics

• Macrolide antibiotics, sulfonamides, and nitrofurantoin are commonly implicated in drug-induced liver injury 1
• Trimethoprim-sulfamethoxazole (TMP-SMX) causes allergic reactions with liver involvement in up to 60% of HIV-positive patients versus 5% of HIV-negative patients 1
• Medication-induced liver injury accounts for 8-11% of cases with mildly elevated liver enzymes 5

Anticonvulsants

• Carbamazepine is frequently associated with hepatotoxicity and requires monitoring 1
• Liver enzyme elevations typically occur within the first few months of therapy 1

Antifungals

• Terbinafine causes hepatotoxicity requiring monitoring during treatment 1

Immunosuppressants and DMARDs

• Methotrexate causes dose-dependent liver fibrosis and requires special monitoring with non-invasive markers of fibrosis 1
• Elevated ALT/AST occurs in 48.9% of patients above ULN and 16.8% above 2× ULN after mean 3.3 years of methotrexate therapy 1
• Methotrexate should be stopped if ALT/AST increases >3× ULN on confirmation, but may be reinstituted at lower dose following normalization 1
• If ALT/AST persistently elevated up to 3× ULN, dose adjustment is required; diagnostic procedures should be considered if elevation >3× ULN persists after discontinuation 1

Antiretroviral Drugs

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):

• Nevirapine causes hepatotoxicity in 0.3-1% of patients 1
• Efavirenz causes Grade 2-3 hepatotoxicity in 4% of patients 1
• Etravirine causes mild liver enzyme elevation (grade 1-2) 1
• Rilpivirine causes mild liver enzyme elevation and hepatitis 1

Protease Inhibitors:

• Tipranavir causes grade 3 ALT elevations in 6.3% of patients 1
• Atazanavir, lopinavir, fosamprenavir, and darunavir all cause rash and abnormal liver function tests in varying percentages 1

CCR5 Inhibitors:

• Maraviroc causes increased liver enzymes, though no significant differences in grade 3-4 abnormalities 1

Integrase Inhibitors:

• Raltegravir has few reported hypersensitivity reactions, suggesting this class may be safer 1

Leukotriene Modifiers

• Zafirlukast has postmarketing reports of reversible hepatitis and rarely irreversible hepatic failure resulting in death and liver transplantation 1
• Zileuton causes elevation of liver enzymes with limited case reports of reversible hepatitis and hyperbilirubinemia 1
• Montelukast has rare cases of Churg-Strauss syndrome, though the association is unclear 1

COVID-19 Therapies

• Lopinavir-ritonavir, interferon, tocilizumab, and remdesivir can cause elevation in ALT or AST concentrations 1
• Off-label COVID-19 treatment should be withheld in moderate-to-severe (category 2-3) liver injury 1
• Patients with abnormal liver function should be closely monitored when using these agents, preferably in clinical trial settings 1

Critical Management Principles

Monitoring Thresholds

• For ALT 2-3× ULN: repeat testing within 2-5 days and intensify evaluation 5
• For ALT >3× ULN or bilirubin >2× ULN: urgent follow-up within 2-3 days is warranted 5
• If ALT increases to >5× ULN, referral to hepatology is recommended 5

Medication Discontinuation Criteria

• Discontinue suspected hepatotoxic medications if ALT/AST >3× ULN confirmed on repeat testing 5
• Immediate discontinuation required if ALT/AST >3× ULN plus bilirubin >2× ULN (Hy's Law criteria), suggesting potential for acute liver failure 5
• Expected normalization occurs within 2-8 weeks after drug discontinuation if medication-induced 5

Special Populations

• Patients on potentially hepatotoxic medications require monitoring twice weekly 1
• Patients on immune checkpoint inhibitors or immunomodulatory therapy require more frequent monitoring (every 1-2 weeks) 5

Common Pitfalls to Avoid

• Do not assume mild ALT elevations on statins require discontinuation—most are transient and reversible, and cardiovascular benefits typically outweigh risks 5, 4
• Do not overlook over-the-counter medications and herbal supplements—these account for a significant proportion of drug-induced liver injury 1, 5
• Do not attribute ALT elevation ≥5× ULN to NAFLD alone—this level warrants investigation for viral hepatitis, autoimmune hepatitis, or drug-induced liver injury 5
• Check all medications against the LiverTox® database for hepatotoxic potential, as medication-induced liver injury is often preventable 5
• Alcohol consumption, even moderate amounts, can significantly exacerbate medication-induced liver enzyme elevations 1, 5