Methotrexate and histologic hepatic abnormalities: a meta-analysis

Am J Med. 1991 Jun;90(6):711-6.


Study objective: To determine the risk of liver toxicity from the long-term administration of methotrexate in patients with rheumatoid arthritis or psoriatic arthritis.

Design: A meta-analysis of 15 studies examining the relationship between long-term, low-dose methotrexate administration and biopsy evidence of liver fibrosis.

Patients: A total of 636 patients from 15 studies.

Results: The incidence of progression of liver disease (defined as worsening of at least one grade on the histologic classification of Roenigk) among 636 patients was 27.9% (95% confidence intervals 24.3 to 31.6). The rate of progression of liver disease in the 15 studies was associated with the cumulative dose of methotrexate (p = 0.01). Patients on average had a 6.7% (95% confidence intervals 2.1 to 11.4) chance of progressing at least one histologic grade on liver biopsy for each gram of methotrexate taken. The overall incidence of advanced pathologic changes on liver biopsy (grades IIIB or IV) among 636 patients was 5.0% (95% confidence intervals 3.5 to 7.0). The development of advanced histologic changes was not associated with the cumulative dose of methotrexate (p = 0.08). Patients who according to their history were heavy drinkers (at least 100 g of alcohol per week) were more likely to have advanced changes on liver biopsy (17.8% versus 4.5%, p = 0.0003) and to show histologic progression (73.3% versus 25.9%, p = 0.0002). Patients with psoriasis were more likely than patients with rheumatoid arthritis to have advanced changes (7.7% versus 2.7%, p = 0.003) and histologic progression (33.1% versus 24.3%, p = 0.02).

Conclusions: The risk of liver toxicity in patients undergoing long-term, low-dose methotrexate therapy is substantial, and that risk increases with the total cumulative dose and with heavy consumption of alcohol. Heavy users of alcohol should not receive long-term methotrexate therapy. For most patients who are not heavy users of alcohol, liver biopsies should be done periodically to monitor for the occurrence of liver toxicity.

Publication types

  • Meta-Analysis

MeSH terms

  • Alcohol Drinking / adverse effects
  • Arthritis, Psoriatic / drug therapy
  • Arthritis, Rheumatoid / drug therapy
  • Autoimmune Diseases / drug therapy
  • Biopsy
  • Female
  • Humans
  • Liver / drug effects
  • Liver / pathology
  • Liver Cirrhosis / chemically induced*
  • Liver Cirrhosis / pathology
  • Male
  • Meta-Analysis as Topic
  • Methotrexate / adverse effects*


  • Methotrexate