Methotrexate Hepatotoxicity

Abstract

Methotrexate (MTX) is an antimetabolite and is a structural analogue of folinic acid. There is also significant interest in low-dose methotrexate as a therapy for a variety autoimmune, inflammatory, and rheumatologic conditions. Adverse reactions with low-dose weekly methotrexate have been frequently reported in clinical trials. The most common adverse event with methotrexate is gastrointestinal toxicity, including anorexia, nausea, vomiting, diarrhea, weight loss, and hepatotoxicity. In the 1950's, it became apperent that previous methotrexate treatment of leukemia caused severe hepatic fibrosis and cirrhosis. In the late 1960's, case reports first appeared describing liver toxicity in psoriasis patients being treated with methotrexate. The pathogenesis of chronic MTX hepatotoxicity is poorly understood. Dose, alchol intake, and pre-existing liver disease are the most significant factors in the pathogeesis. There are not correlation between liver-associated enzymes and hepatic fibrosis and cirrhosis. Cases of severe hepatic fibrosis are often associated with lack of progression after discontinuation of MTX. Many investigators advocate folic acid or folinic acid supplementation during MTX therapy. Pretreatment liver biopsies were recommended for patients with a history of excessive alchol use, abnormal baseline AST levels, and chronic hepatitis B or C infection.