Methotrexate-Induced Hepatotoxicity in a Patient with a History of Alcohol Abuse: Case Report

Introduction

Methotrexate (MTX) is a widely prescribed immu- nosuppressive drug used to manage various condi- tions, including rheumatoid arthritis (RA) and pso- riasis [1]. Despite its therapeutic benefits, MTX carries a well-documented risk of hepatotoxicity, primarily through the accumulation of intracellular MTX-polyglutamate (MTX-PG) which induces oxidative stress, inflammation, steatosis, fibrosis, and apoptosis in hepatocytes [2]. This risk is par- ticularly pronounced in patients with existing liver Fatih Kaya (fatihonerkaya1@gmail.com) is with the Depart- ment of Internal Medicine, Maltepe University Hospital, Is- tanbul, Turkey; Mohammad Jamal Abunawas (moham- madabunawas9@gmail.com) is with the Maltepe University Hospital, Istanbul, Turkey; Manar Al-Suleh (manaral- suleh2@gmail.com); Ghayda Jarrar (ghaida@hotmail.ca); and Yare Sahin (yaresahin01@gmail.com) are with the Fac- ulty of Medicine, Maltepe University, Istanbul, Turkey. DOI: 10.52609/jmlph.v6i1.223

Case Presentation

above 21 units (≈ 168 g/week ≈ 24 g/day) increased the risk considerably [10]. Our patient’s history of chronic alcohol use, even if not quantified precisely, likely contributed to he- patic vulnerability. It is believed that alcohol and MTX exert synergistic toxicity, via shared path- ways, including mitochondrial dysfunction, in- creased oxidative stress, and disruption of folate metabolism [2]. A review by Ezhilarasan discusses how MTX induces hepatotoxicity through apopto- sis, oxidative stress, and cytokine-mediated inflam- mation, mechanisms which are also aggravated by alcohol [2]. Additionally, histologic abnormalities such as hepatic steatosis, fibrosis, and cirrhosis have been well documented in long-term MTX us- ers. A meta-analysis by Whiting-O’Keefe et al. found a significantly higher prevalence of hepatic fibrosis in patients on long-term MTX, particularly those with other risk factors such as alcohol use [9]. While the American College of Rheumatology has issued guidelines for liver function monitoring— initially every 2–4 weeks for a couple of months, then every 8–12 weeks—there is variability due to the lack of evidence-based methodology in creating those guidelines. This highlights the need for indi- vidualized patient monitoring based on risk factors such as alcohol use, pre-existing liver disease, or elevated baseline liver enzymes. Hepatotoxicity re- lated to MTX use can range from asymptomatic el- evation of liver enzymes to more severe manifesta- tions, including hepatic steatosis, fibrosis, and cir- rhosis. Alcohol intake adds to this risk by placing an additional metabolic burden on the liver, exac- erbating MTX-related hepatic damage [6]. What makes our case especially notable is the rapid onset and severity of hepatotoxicity, requiring not only drug cessation but also plasmapheresis [11]. Plasmapheresis may be beneficial in cases of se- vere drug-induced liver injury by removing circu- lating toxins or immune complexes. This therapeu- tic decision was based on the patient’s deteriorating condition and failure to improve with conventional supportive therapy. The American College of Rheumatology recommends routine liver function monitoring during MTX therapy, yet this may be insufficient in patients with additional risk factors such as alcohol use, especially if the extent of alco- hol consumption is underreported. Kremer et al. suggest more frequent liver enzyme monitoring or even liver biopsy in patients at high risk [6]. This case underscores the importance of thorough pre- treatment screening, including honest assessment

A 56-year-old male, with a significant history of al- cohol abuse, presented to the internal medicine out- patient clinic with complaints of abdominal pain, fatigue, and malaise. The patient reported jaundice, generalized muscle weakness, and right upper quadrant pain on palpation, with a positive Mur- phy’s sign noted during physical examination. The patient had been recently diagnosed with RA and had commenced MTX treatment one month prior at a dose of 10 mg weekly. He had been advised to abstain from alcohol during his treatment but ad- mitted to occasional drinking since starting MTX. On admission, the patient’s vital signs were stable, with a normal heart rate, blood pressure, and body temperature. The patient’s blood work is illustrated in Table 1. A hepatobiliary ultrasound revealed in- creased liver parenchymal echogenicity, consistent with grade 2 hepatic steatosis, and hepatospleno- megaly, measuring 19 cm and 17.3 cm, respec- tively. These findings were further confirmed by contrast-enhanced magnetic resonance imaging, demonstrating significant hepatic damage. Due to the severity of the condition, emergent plasmapher- esis was initiated to manage the patient’s acute liver injury.

Discussion

The interaction between methotrexate (MTX) and alcohol represents a significant clinical concern due to their synergistic potential to cause liver in- jury. While MTX is an important medication, hepa- totoxicity remains one of its most serious adverse effects, especially when risk factors such as alcohol consumption are present. This case highlights a rare and severe manifestation of MTX-induced hepatotoxicity in a patient with a history of alcohol abuse, necessitating plasmapheresis and supportive measures. Chronic low-dose MTX therapy has been associated with a spectrum of hepatic adverse effects ranging from transient transaminase eleva- tions to fibrosis and, in rare cases, hepatic failure [7-9]. Alcohol use is a well-established risk factor that may potentiate the hepatotoxic effects of MTX. While older guidelines often discouraged any alcohol use, a study in 2017 suggested that low-to-moderate intake may be safer than previ- ously believed. A large prospective study by Hum- phreys et al. demonstrated that consuming less than 14 units of alcohol per week (≈ 112 g/week ≈ 16 g/day) was not significantly associated with ele- vated liver enzymes in MTX users, whereas intake

of alcohol use, and individualized risk-benefit anal- ysis when prescribing MTX. In ambiguous or bor- derline cases, alternatives such as biologic disease- modifying antirheumatic drugs (DMARDs) or non- hepatotoxic immunosuppressants may be consid- ered. Guidance on alcohol use during MTX therapy is uniformly cautious, with jurisdiction-specific nu- ances that shape practice. The Turkish Society of Rheumatology recommends complete abstinence [12], aligning with European Medicines Agency (EMA) requirements for product information , which list alcohol misuse as a contraindication and advises against concurrent intake [13]. In contrast, UK guidance from the British Society for Rheuma- tology and the NHS permits consumption within national limits—up to 14 units per week, ideally spread across several days—provided there are no additional hepatic risk factors and liver function is monitored regularly [14]. Synthesizing these positions highlights the need for a pragmatic, risk ‐ stratified approach. For high ‐ risk patients—such as those with a history of alco- hol ‐ related liver disease, metabolic comorbidities, viral hepatitis, or concomitant hepatotoxins—ab- stinence should be compelled. For selected low ‐ risk patients with robust monitoring, limited intake within UK thresholds (≤14 units per week) may be reasonable, provided counselling is explicit and limits are documented. Intakes exceeding 21 units per week, or sustained heavy drinking, should be avoided given the substantial increase in risk of liver enzyme derangement and fibrosis. In conclusion, alcohol exposure increases the risk of MTX ‐ related hepatotoxicity in a dose ‐ dependent manner. The safest course is abstinence, particu- larly where any hepatic risk is present. Where alco- hol is consumed, it should be kept within ≤14 units per week, liver function should be monitored regu- larly, and shared decision ‐ making should be em- bedded, tailored to local standards and individual risk profiles.

2006;58(4):473–92. Available from:https://citeseerx.ist.psu.edu/docu- ment?repid=rep1&type=pdf&doi=b82a3bd b4ae6882aae2ba 39127273ce3d6c34c8d 2. Ezhilarasan D. Hepatotoxic potentials of methotrexate: understanding the possible toxicological molecular mechanisms. Toxi- cology . 2021;463:152980. doi:10.1016/j.tox.2021.152980 3. Rosenberg P, Urwitz H, Johannesson A, Ros AM, Lindholm J, Kinnman N, et al. Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol. 2007; 46:1111-8. 4. Aithal GP, Haugk B, Das S, Card T, Burt Ad, Record CO: Monitoring methotrexate- induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified? Aliment Pharmacol Ther 2004;19:391-9. 5. Malatjalian DA, Ross JB, Williams CN, Colwell SJ, Eastwood BJ. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long-term follow- up. Can J Gastroenterol. 1996;10:369-75 6. Kremer JM, Alarcón GS, Weinblatt ME, Kaymakcian MV, Macaluso M, Thompson A. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. Arthritis Rheum. 1994 Mar;37(3):316–28. doi:10.1002/art.1780370306 7. National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: Clinical and research information on drug-induced liver injury. Methotrexate [Internet]. Be- thesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases. 2020 Feb 19 [cited 2025 Jun 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK 548219/ 8. Visser K, van der Heijde DMFM. Risk and management of liver toxicity during meth- otrexate treatment in rheumatoid and psori- atic arthritis: a systematic review of the lit- erature. Clin Exp Rheumatol . 2009 Nov- Dec;27(6):1017–25. 9. Whiting-O'Keefe QE, Fye KH, Sack KD. Methotrexate and histologic hepatic abnor- malities: a meta-analysis. Am J Med . 1991

Ethical Approval

The patient was informed about the study and con- sented to its publication. The study was conducted in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.