Is methotrexate hepatotoxicity associated with cumulative dose? A systematic review and meta-analysis

Background/objective: Methotrexate (MTX) is widely used in various medical specialties. However, hepatotoxicity is an ongoing concern and this is thought to be directly associated with cumulative dose. We sought to synthesise the published literature to evaluate the association between methotrexate hepatotoxicity and cumulative dose. Methods: A systematic review of Medline (PubMed) EMBASE, CINAHL and The Cochrane Library was performed. Full texts of articles were examined, and excluded articles were recorded with reasons for exclusion. A meta-analysis of correlation coefficients was performed using Fisher's z-transformation and a random effects model. Cochran's Q-test and the I-2 statistic were calculated to assess heterogeneity. Results: A total of 35 studies met inclusion criteria. Measures of hepatotoxicity were highly varied and included liver biopsy, elastography, FibroTest, biochemical tests and scoring systems (Fib-4, APRI, AST:ALT). Some studies analysed for the association with MTX cumulative dose using more than one modality. Overall, 38 analyses found no significant association between MTX cumulative dose and hepatoxicity vs eight that identified a significant association. The pooled correlation coefficient from five studies which utilised elastography was 0.18 (95% CI, -0.09 to 0.42), with significant heterogeneity between studies (P < 0.0001), I-2 = 92%). Conclusions: Our synthesis of a large volume of studies in this review found no significant association between MTX cumulative dose and hepatotoxicity, both in terms of vote counting and with regard to the meta-analysis of correlation coefficients from studies that utilised elastography. This challenges the long-held belief that liver injury is a direct result of drug accumulation.