Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Sep 18, 2017; 9(26): 1092-1100
Published online Sep 18, 2017. doi: 10.4254/wjh.v9.i26.1092
Risk of liver disease in methotrexate treated patients
Richard Conway, John J Carey
Richard Conway, Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Dublin 4, Ireland
Richard Conway, CARD Newman Research Fellow, University College Dublin, Belfield, Dublin 4, Ireland
John J Carey, Department of Rheumatology, Galway University Hospitals, Merlin Park, Galway H91 YR71, Ireland
John J Carey, Clinical Sciences Institute, National University of Ireland Galway, Galway H91 TK33, Ireland
Author contributions: Conway R and Carey JJ wrote the paper.
Conflict-of-interest statement: We report no conflicts of interest for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Dr. Richard Conway, Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland.
Telephone: +353-876097345 Fax: +353-12214170
Received: February 20, 2017
Peer-review started: February 20, 2017
First decision: April 1, 2017
Revised: April 20, 2017
Accepted: July 7, 2017
Article in press: July 10, 2017
Published online: September 18, 2017

Methotrexate is the first line drug treatment for a number of rheumatic and non-rheumatic diseases. It is effective in controlling disease activity and preventing disease-related damage, and significantly cheaper than many alternatives. Use in rheumatoid arthritis infers a significant morbidity and mortality benefit. Methotrexate is generally well tolerated but can cause symptomatic adverse events. Multiple serious adverse events have been attributed to methotrexate, based largely on older reports using high or daily doses, and subsequent case reports and circumstantial evidence. The risk with modern dosing regimens: Lower doses, weekly schedules, and concomitant folic acid is less clear. Clarification and dissemination of the actual risk is crucial so appropriate judgements can be made for patients who may benefit from this treatment. Methotrexate has been associated with a range of liver related adverse events ranging from asymptomatic transaminase elevations to fibrosis and fatal hepatic necrosis. Concern over potential liver toxicity has resulted in treatment avoidance, cessation, or recommendations for investigations which may be costly, invasive and unwarranted. Modern laboratory monitoring of liver blood tests may also influence the risk of more serious complications. The majority of present day studies report an approximate doubling of the relative risk of elevated transaminases in methotrexate treated patients but no increased risk of symptomatic or severe liver related adverse events. In this article we will review the evidence around methotrexate and liver related adverse events.

Keywords: Liver disease, Transaminases, Fibrosis, Cirrhosis, Methotrexate, Hepatic

Core tip: Methotrexate is a highly effective treatment for many diseases. In rheumatoid arthritis it controls symptoms, prevents damage, and reduces mortality. The risks of methotrexate use are often over-estimated. Methotrexate may result in asymptomatic transaminase elevations. Historically methotrexate has been infrequently associated with more severe liver adverse events. With modern monitoring and management of liver blood tests serious liver related adverse events related to methotrexate use appear to be avoidable.