Al-Hammada Y, Sharba S, Al-Dury S. Should the theory of methotrexate-induced liver toxicity be abandoned? World J Hepatol 2026; 18(2): 113743 [DOI: 10.4254/wjh.v18.i2.113743]
Corresponding Author of This Article
Samer Al-Dury, MD, PhD, School of Public Health and Community Medicine, University of Gothenburg, Universitetsplatsen 1, Gothenburg 40530, Sweden. samer.al-dury@gu.se
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Gastroenterology & Hepatology
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Minireviews
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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: http://creativecommons.org/licenses/by-nc/4.0/
Feb 27, 2026 (publication date) through Feb 12, 2026
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World Journal of Hepatology
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1948-5182
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Al-Hammada Y, Sharba S, Al-Dury S. Should the theory of methotrexate-induced liver toxicity be abandoned? World J Hepatol 2026; 18(2): 113743 [DOI: 10.4254/wjh.v18.i2.113743]
World J Hepatol. Feb 27, 2026; 18(2): 113743 Published online Feb 27, 2026. doi: 10.4254/wjh.v18.i2.113743
Should the theory of methotrexate-induced liver toxicity be abandoned?
Yahya Al-Hammada, Sinan Sharba, Samer Al-Dury
Yahya Al-Hammada, Sinan Sharba, Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Vastra Gotaland, Sweden
Samer Al-Dury, School of Public Health and Community Medicine, University of Gothenburg, Gothenburg 40530, Sweden
Samer Al-Dury, Department of Gastroenterology, Medical City Hospital for Military and Security Services, Muscat 111, Oman
Samer Al-Dury, Department of Gastroenterology and Hepatology, University Hospital Ghent, Gent 9000, Flanders, Belgium
Author contributions: Al-Hammada Y contributed to literature review and consolidation; Sharba S and Al-Dury S participated in the manuscript writing and revision; Al-Dury S contributed to study conceptualization and design. All authors have read and approved the final manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Samer Al-Dury, MD, PhD, School of Public Health and Community Medicine, University of Gothenburg, Universitetsplatsen 1, Gothenburg 40530, Sweden. samer.al-dury@gu.se
Received: September 10, 2025 Revised: October 21, 2025 Accepted: December 16, 2025 Published online: February 27, 2026 Processing time: 163 Days and 20.2 Hours
Abstract
Methotrexate (MTX) remains a cornerstone therapy for chronic inflammatory diseases (e.g., rheumatoid arthritis, psoriasis). However, long-standing concerns about MTX hepatotoxicity - especially liver fibrosis - have historically led to conservative monitoring and routine invasive liver biopsies at predefined cumulative dose thresholds. These practices often prompted early discontinuation of MTX therapy. These concerns originated from early liver biopsy studies in high-dose MTX patients that did not adequately account for metabolic risk factors. Emerging evidence indicates that advanced fibrosis is rare in MTX-treated patients and usually attributable to coexisting metabolic comorbidities (e.g., obesity, insulin resistance) rather than the cumulative MTX dose itself. Moreover, noninvasive fibrosis assessment modalities and recent large cohort studies demonstrate that MTX at standard doses with folate supplementation seldom drives fibrogenesis independently. This review reappraises MTX-related fibrosis risk in light of contemporary data and highlights a shift from dose-driven biopsy protocols to risk-based, noninvasive monitoring strategies. Recognizing that MTX is less hepatotoxic than historically assumed can prevent unnecessary drug discontinuation and refocus management on modifiable metabolic risk factors.
Core Tip: Methotrexate (MTX) has long been associated with a presumed risk of hepatotoxicity and progressive liver fibrosis, largely based on early biopsy-era studies. Contemporary evidence using non-invasive fibrosis assessment shows that significant fibrosis is uncommon in MTX-treated patients and more strongly linked to metabolic dysfunction-associated steatotic liver disease and related risk factors such as obesity, diabetes, and insulin resistance. This minireview challenges the traditional perception of intrinsic MTX hepatotoxicity and argues for risk-based rather than drug-based monitoring strategies.
