What medications should be avoided in patients with hepatic steatosis?

Medications to Avoid in Hepatic Steatosis

Patients with hepatic steatosis should avoid or discontinue medications known to cause or worsen steatosis, particularly amiodarone, tamoxifen, methotrexate, valproate, glucocorticoids, and certain antiretrovirals, with methotrexate requiring special attention in overweight or diabetic patients due to increased risk of fibrosis progression. 1

High-Priority Medications to Avoid or Discontinue

Antiarrhythmics

• Amiodarone is a well-established cause of drug-induced hepatic steatosis and should be avoided when alternative antiarrhythmic options exist 1, 2, 3

Antimetabolites

• Methotrexate is particularly problematic as it not only contributes to hepatic fat accumulation but also accelerates disease progression to advanced fibrosis/cirrhosis, especially in patients who are overweight or diabetic 1
• Document cumulative dose and duration of methotrexate exposure, as these factors correlate with risk of persistent transaminitis and fibrosis 1
• 5-Fluorouracil can precipitate steatosis and should be used cautiously 1

Hormone Modulators

• Tamoxifen (estrogen receptor modulator) causes hepatic fat accumulation and should be reconsidered in consultation with oncology when steatosis is present 1, 2, 3

Anticonvulsants

• Valproate (sodium valproate) induces steatosis and should be avoided when alternative anticonvulsants are suitable 1, 3
• Carbamazepine is also implicated in drug-induced steatosis 1

Corticosteroids

• Glucocorticoids contribute to hepatic steatosis through metabolic effects and should be minimized or discontinued when clinically feasible 1, 3

Antiretrovirals

• Efavirenz can cause steatosis and alternative antiretroviral regimens should be considered 1

Analgesics

• NSAIDs are associated with drug-induced steatosis and should be used sparingly 1

Specialized Lipid-Lowering Agents with Hepatotoxicity Risk

Contraindicated in Hepatic Steatosis

• Lomitapide carries a black box warning for causing hepatic steatosis with or without transaminase elevations, which may progress to steatohepatitis and cirrhosis 1

• This medication is contraindicated in patients with moderate/severe hepatic impairment or active liver disease 1

• Available only through REMS program due to hepatotoxicity risk 1

• Mipomersen increases hepatic fat (hepatic steatosis) with or without concomitant transaminase increases and may be a risk factor for progressive liver disease including steatohepatitis and cirrhosis 1

• Also requires REMS program enrollment 1

Clinical Implementation Strategy

Medication Review Process

• Conduct a comprehensive medication review including prescription drugs, over-the-counter medications, and alternative/complementary medicines in all patients with hepatic steatosis 1
• Approximately 2% of NAFLD cases are attributable to prescribed medications, making drug history essential 1

Risk-Benefit Assessment

• Consider discontinuation of hepatotoxic medications after risk assessment, involving relevant specialists (e.g., cardiology for amiodarone, oncology for tamoxifen, rheumatology for methotrexate) as necessary 1
• Polypharmacy is common in patients with hepatic steatosis due to metabolic comorbidities, requiring systematic rationalization 1

Special Considerations for Methotrexate

• The evidence regarding methotrexate is somewhat conflicting, but capturing duration of exposure and cumulative dose is particularly relevant 1
• Methotrexate poses increased risk in patients who are overweight or diabetic—the exact population most likely to have hepatic steatosis 1

Common Pitfalls to Avoid

• Do not overlook medication as a cofactor for steatosis progression even when metabolic risk factors are present—drugs may synergistically worsen outcomes 1
• Do not assume all patients accurately report their medication use—discrepancies between patient-reported and medical record documented medications exist in more than 50% of patients with liver disease, particularly those taking more than five medications 1
• Do not forget to document alcohol use (using tools like AUDIT-C), illicit drug use, and smoking history, as these are additional cofactors that interact with drug-induced steatosis 1