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Hepatotoxicity Caused by Methotrexate Therapy in Children with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis

Valentino, Pamela L. MD, CM1; Church, Peter C. MD1; Shah, Prakeshkumar S. MD2; Beyene, Joseph PhD3; Griffiths, Anne M. MD1; Feldman, Brian M. MD, MSc4; Kamath, Binita M. MBBChir1

doi: 10.1097/01.MIB.0000436953.88522.3e
Original Clinical Articles

Background: Methotrexate (MTX) is an immunomodulator used in pediatric inflammatory bowel disease (IBD) maintenance regimens. However, MTX use is associated with liver toxicity. We aimed to systematically review and meta-analyze the incidence of hepatotoxicity with MTX use among children with IBD.

Methods: We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases from 1946 to April 2013 for cohort studies and collected information about the study design, IBD treatment results, and hepatotoxicity. Pooled proportions of toxicity with 95% confidence interval (CI) were estimated using a random-effects model.

Results: Twelve high-quality studies were included in this review. Fifty-seven of 457 patients treated with MTX developed varied degrees of abnormal liver biochemistry. The pooled proportion of patients with abnormal liver biochemistry was 10.2% (95% CI 5.4%–18.5%) across all studies included in the meta-analysis. Due to hepatotoxicity, dose reductions were required in 6.4% (95% CI 4.3%–9.5%), whereas 4.5% (95% CI 2.8%–7.2%) of patients required discontinuation.

Conclusions: Hepatotoxicity after the use of MTX among IBD patients was a relatively common event. Monitoring for hepatotoxicity is strongly recommended, as discontinuation of MTX may be necessary in a significant proportion of children.

Article first published online 25 November 2013

1Division of Gastroenterology, Hepatology, and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada;

2Neonatal Intensive Care Unit, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada;

3Department of Clinical Epidemiology and Biostatistics, McMaster University, Toronto, ON, Canada; and

4Division of Rheumatology, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Reprints: Binita M. Kamath, MBBChir, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8 (e-mail:

The authors have no conflicts of interest to disclose.

Received October 02, 2013

Accepted October 02, 2013

© Crohn's & Colitis Foundation of America, Inc.
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