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Review of existing evidence demonstrates that methotrexate does not cause liver fibrosis
  1. Hira Imad Cheema1,
  2. Dirk Haselow1,
  3. Jonathan Ankin Dranoff2,3
  1. 1 Baptist Health, Little Rock, Arkansas, USA
  2. 2 VA Connecticut Healthcare System–West Haven Campus, West Haven, Connecticut, USA
  3. 3 Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
  1. Correspondence to Dr Jonathan Ankin Dranoff, VA Connecticut Healthcare System–West Haven Campus, West Haven, CT 06516, USA; Jonathan.dranoff{at}


It has long been believed that methotrexate in therapeutic doses causes progressive liver injury resulting in advanced fibrosis and cirrhosis. Historically, this was a common indication for serial liver biopsy. However, new evidence suggests that methotrexate may not be a direct cause of liver injury; rather the injury and fibrosis attributed to methotrexate may be mediated by other mechanisms, specifically non-alcoholic fatty liver disease. The recent widespread use of non-invasive assessment of liver fibrosis has provided new evidence supporting this hypothesis. Thus, we conducted a meta-analysis and systematic review to determine whether methotrexate is indeed a direct cause of liver injury. For the meta-analysis portion, a comprehensive literature search was performed to identify manuscripts relevant to the topic. Of the 138 studies examined, 20 met our inclusion criteria. However, only 3 studies had sufficient homogeneity to allow aggregation. Thus, the remainder of the study was dedicated to a critical review of all studies relevant to the topic with particular attention to populations examined, risk factors, and assessment of injury and/or fibrosis. Meta-analysis did not show a statistically significant association between methotrexate dose and liver fibrosis. Individual studies reported fibrosis related to confounding factors such as diabetes, obesity, pre-existing chronic liver disease but not methotrexate exposure. In conclusion, existing evidence demonstrates that advanced liver fibrosis and cirrhosis previously attributed to methotrexate are in fact caused by metabolic liver disease or other chronic liver diseases, but not by methotrexate itself. This observation should direct the care of patients treated with long-term methotrexate.

  • liver diseases
  • fatty liver
  • liver cirrhosis

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  • Contributors HIC wrote the first draft and contributed to editing. DH provided support for statistical analysis. JAD oversaw the entire project and wrote the final draft.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.