What medications can worsen fatty liver disease, particularly in patients with non-alcoholic fatty liver disease (NAFLD) who are overweight or obese?

Medications That Worsen Fatty Liver Disease

Medications to Avoid or Use with Extreme Caution

Several commonly prescribed medications can precipitate or worsen hepatic steatosis and should be identified and discontinued when possible in patients with NAFLD, particularly those who are overweight or obese. 1

High-Risk Medications That Directly Cause or Worsen Steatosis

The following drug classes are implicated in approximately 2% of NAFLD cases and can either precipitate steatosis or accelerate disease progression: 1

• Methotrexate: This is the most clinically significant medication to avoid or carefully monitor in NAFLD patients. Methotrexate causes both acute hepatotoxicity (elevated transaminases) and chronic hepatotoxicity (fibrosis and cirrhosis), particularly after cumulative doses exceeding 1.5 grams. 2 The drug should be used with extreme caution in patients with preexisting liver damage, and those who are overweight or diabetic face increased risk of advanced fibrosis. 1 Liver biopsy is recommended at cumulative doses of 1.5 grams and after each additional 1-1.5 grams, with moderate fibrosis or any cirrhosis requiring discontinuation. 2

• Amiodarone: This antiarrhythmic agent is a well-established cause of drug-induced steatosis and should be avoided when alternative antiarrhythmics are available. 1

• Tamoxifen: This estrogen receptor modulator can precipitate or worsen hepatic steatosis and should be reconsidered in patients with established NAFLD. 1

• Glucocorticoids: Systemic corticosteroids promote hepatic fat accumulation and worsen insulin resistance, making them particularly problematic in overweight/obese NAFLD patients. 1

• Anticonvulsants: Both carbamazepine and sodium valproate are associated with hepatic steatosis and should be avoided when alternative seizure medications are suitable. 1

• Antiretrovirals: Efavirenz and other antiretroviral agents can cause or worsen steatosis, requiring careful monitoring in HIV-positive patients with NAFLD. 1

• NSAIDs: Non-steroidal anti-inflammatory drugs are implicated in drug-induced steatosis and should be used cautiously, particularly in patients already taking other hepatotoxic medications. 1

• 5-Fluorouracil: This anti-metabolite chemotherapy agent can cause hepatic steatosis. 1

Medications That May Accelerate Fibrosis Progression

Beyond causing steatosis, certain medications specifically accelerate the progression from simple steatosis to advanced fibrosis:

• Methotrexate stands out as particularly dangerous for fibrosis progression, with duration of exposure and cumulative dose being critical risk factors. 1, 2 In patients with preexisting NAFLD who are overweight or diabetic, methotrexate significantly increases the risk of developing advanced fibrosis or cirrhosis. 1

Diabetes Medications With Concerning Effects

While managing diabetes is crucial in NAFLD patients, certain diabetes medications may paradoxically worsen outcomes:

• Sulfonylureas: These agents increased the incidence of hepatocellular carcinoma by 1.6-fold in a large cohort study, though their direct effect on steatosis is less clear. 1

• Insulin: Although insulin treatment increases body fat, it does not appear to promote or worsen NAFLD in diabetes when used chronically, as it improves adipose tissue insulin resistance and reduces hepatic fat content. 1 However, sulfonylureas and insulin increased HCC incidence by 1.6 and 2.6 times respectively. 1

Critical Clinical Approach

A comprehensive medication review must be performed at initial assessment and regularly thereafter in all NAFLD patients, with particular attention to cumulative methotrexate exposure, duration of potentially hepatotoxic medications, and polypharmacy. 1

Specific Actions to Take

• Document all prescribed medications, over-the-counter medications, and complementary/alternative medicines, as discrepancies exist in more than 50% of patients with liver disease taking more than five medications. 1

• Calculate cumulative methotrexate dose in any patient with current or past exposure, as doses exceeding 1.5 grams significantly increase fibrosis risk. 2

• Discontinue hepatotoxic medications after risk assessment, involving other relevant specialists as necessary (e.g., rheumatology for methotrexate, cardiology for amiodarone). 1

• Avoid combining multiple hepatotoxic agents (e.g., methotrexate with azathioprine, retinoids, or sulfasalazine), as the potential for increased hepatotoxicity has been reported. 2

Common Pitfall to Avoid

Do not withhold statins due to concerns about hepatotoxicity—statins are safe and strongly recommended for managing dyslipidemia in NAFLD patients and should not be discontinued based on liver disease concerns. 3 The outdated belief that statins worsen liver disease persists among some clinicians (34.1% of general practitioners in one survey stated statins should be avoided), but this is contradicted by current evidence showing statins reduce HCC risk by 37%. 1

Monitoring Requirements

• Perform liver function tests at baseline and every 4-8 weeks in patients receiving known hepatotoxic medications like methotrexate. 2

• Consider liver biopsy in patients with persistent liver function test abnormalities while on methotrexate or other high-risk medications, particularly if cumulative doses are high or if the patient has risk factors (obesity, diabetes, alcohol use). 2

• Reassess medication necessity every 3-6 months, as rationalizing medications that may accelerate disease progression is a key management strategy. 1