Hepatotoxicity after long-term methotrexate therapy

To reassess the need for repeat liver biopsies in patients receiving long-term methotrexate therapy, we reviewed the results of 15 biopsies in 14 such patients seen from 1979 to 1984 at the Medical University of South Carolina. Significant changes in liver histology were found in seven patients. These findings did not correlate with biochemical abnormalities, presence of anemia or obesity, or age when methotrexate therapy was initiated. Four of the 15 biopsies (27%) showed grade III or IV histologic changes (fibrosis or cirrhosis), which led to discontinuance of treatment. The single most significant factor predisposing to toxicity appeared to be the duration of therapy, though the cumulative dose of methotrexate may also be important. Despite a wide range of cumulative doses, no patient with grade III or IV histology had been treated for less than five years. Thus, surveillance liver biopsies at suitable intervals are advisable once the patient has been treated for five years or more. Conversely, liver biopsies within the first five years of treatment with methotrexate appear not to be necessary, though these results should be confirmed in a larger patient group.