Tumor Necrosis Factor Inhibitors and NAFLD

Nonalcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease reported in the United States. Some researchers have hypothesized that TNF-α, as a mediator of inflammation, might be a therapeutic target for NAFLD since inflammation seems to be a component of its etiology. However, case reports have identified a scattering of patients who have developed NAFLD during treatment with tumor necrosis factor inhibitors (TNFi). A study in the European Journal of Gastroenterology and Hepatology explores this paradox.

This study, a clinic case—control record review using records of veterans treat at VA hospitals located in Texas, identified The researchers examined 1 treatment and 3 control groups:

• TNFi-treated patients who developed aminotransferase elevations and who had liver biopsies indicating NAFLD
• Patients on TNFi treatment with normal aminotransferase levels
• Patients with biopsy-proven nonalcoholic steatohepatitis NASH(NASH) with no other inflammatory disease
• Healthy controls

All patients were tested for the PNPLA3 gene, which has been associated with a predisposition to develop NASH.

Eight TNFi-treated patients developed some form of NAFLD. Five developed steatohepatitis and 3 were diagnosed with steatosis. These patients’ aminotransferase levels became elevated an average of 12 months after staring TNFi. Treating clinicians discontinued TNFi therapy in 5 patients, with \aminotransferase levels subsequently returning to normal in 2 to 8 months. None of these patients had evidence of autoimmune hepatitis or drug-induced liver injury.

TNFi-treated patients who developed NALFD had more methotrexate exposure than inflammatory controls. The researchers note that methotrexate’s hepatic effects can mimic NAFLD and might have contributed to ALT elevations.

Three-quarters of NAFLD patients had PNPLA3 genotype mutations compared to 38% of inflammatory controls, 88% of NASH controls, and 63% of healthy controls.

These researchers indicate that potential risk factors for ALT elevation during TNFi therapy include concurrent methotrexate use, Hispanic race, and PNPLA3 genotype mutations, and urge further study.