Which dermatologic medications can cause or worsen non‑alcoholic fatty liver disease (NAFLD)?

Dermatologic Medications That Can Cause or Worsen NAFLD

Methotrexate is the primary dermatologic medication that causes or worsens NAFLD, particularly in patients with pre-existing risk factors such as obesity, diabetes, and metabolic syndrome. 1

Key Hepatotoxic Dermatologic Medications

Methotrexate (Highest Risk)

Methotrexate carries significant hepatotoxicity risk and is more likely to cause liver damage in psoriasis patients compared to rheumatoid arthritis patients, even at equivalent doses. 1

• Patients with obesity (BMI ≥40 kg/m²), diabetes, and hyperlipidemia are at substantially increased risk for methotrexate-induced hepatotoxicity because these conditions predispose to nonalcoholic fatty liver disease. 1

• Nonalcoholic steatohepatitis is a common comorbidity in psoriasis that can be directly aggravated by methotrexate treatment. 1

• The incidence of hepatic fibrosis in psoriasis patients receiving methotrexate is twice that of rheumatoid arthritis patients, adjusted for dosage. 1

• High cumulative doses of methotrexate are associated with increased risk of liver damage. 1

Acitretin (Oral Retinoids)

Acitretin causes significant metabolic disturbances that can contribute to or worsen fatty liver disease. 1

• Up to 16% of acitretin-treated patients develop elevations in serum transaminase levels. 1

• Between 25% and 50% of patients develop elevations in serum triglycerides during acitretin therapy. 1

• These lipid abnormalities are dose-dependent and represent additional risk factors for NAFLD development. 1

• Acitretin is particularly problematic in patients with pre-existing obesity and metabolic syndrome features. 1

Isotretinoin

Isotretinoin can cause hepatotoxicity and is associated with elevated liver enzymes, particularly in patients with pre-existing risk factors. 1

• Routine monitoring of liver function tests at baseline and until response to treatment is established is recommended. 1

• The drug should be used with extreme caution in patients with obesity and steatohepatitis. 1

TNF Inhibitors (Biologics) - Emerging Concern

TNF inhibitors may paradoxically cause NAFLD development despite their anti-inflammatory properties. 2

• Case reports demonstrate that patients can develop aminotransferase elevations 1-63 months into TNF inhibitor therapy (average 12 months), with liver biopsies showing NAFLD. 2

• When TNF inhibitor therapy was stopped in affected patients, aminotransferase levels normalized within 2-8 months. 2

• Methotrexate co-exposure may increase this risk (50% vs 12.5% in controls). 2

Clinical Monitoring Algorithm for Patients on Hepatotoxic Dermatologic Medications

Before Starting Methotrexate:

• Perform noninvasive baseline liver fibrosis assessment using FIB-4 Index (https://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis). 1

• Baseline liver biopsy is NOT recommended regardless of risk factors. 1

• Screen for NAFLD risk factors: obesity (BMI ≥40), diabetes, hyperlipidemia, metabolic syndrome, alcohol use, and family history of inheritable liver disease. 1

During Treatment:

• Perform laboratory monitoring (CBC and liver function tests) every 3-6 months in stable patients. 1

• For patients WITH risk factors: obtain annual GI/hepatology referral or vibration-controlled transient elastography. 1

• For patients WITHOUT risk factors: continue routine monitoring unless abnormalities develop. 1

For Acitretin/Isotretinoin:

• Monitor liver function tests and lipid panels at baseline and regularly during treatment. 1

• Manage elevated triglycerides with fibrates (alone or combined with statins) and elevated cholesterol with statins, exercising caution regarding rhabdomyolysis risk when combining these agents. 1

Critical Clinical Pitfalls

The relationship between NAFLD and drug-induced liver injury is bidirectional: drugs can cause NAFLD, and pre-existing NAFLD increases susceptibility to drug-induced liver injury. 3

• Psoriasis patients have a 65.6% prevalence of NAFLD compared to 35% in matched controls, making this population particularly vulnerable. 1

• Polypharmacy in obese patients treating multiple comorbidities potentiates the association between obesity and drug-induced liver injury. 3

• Patients with psoriasis and known NAFLD have 11% prevalence of significant liver fibrosis, with higher rates in those with diabetes, elevated AST, and increased waist circumference. 1

Do not assume normal aminotransferase levels exclude NAFLD—liver biochemistries can be within normal ranges in patients with NAFLD and NASH. 1