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

Introduction

Methotrexate (MTX) is a widely prescribed immunosuppressive drug used to manage various conditions, including rheumatoid arthritis (RA) and psoriasis [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 particularly pronounced in patients with existing liver 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 hepatic vulnerability. It is believed that alcohol and MTX exert synergistic toxicity, via shared pathways, including mitochondrial dysfunction, increased oxidative stress, and disruption of folate metabolism [2]. A review by Ezhilarasan discusses how MTX induces hepatotoxicity through apoptosis, oxidative stress, and cytokine-mediated inflammation, 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 users. 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 individualized patient monitoring based on risk factors such as alcohol use, pre-existing liver disease, or elevated baseline liver enzymes. Hepatotoxicity related to MTX use can range from asymptomatic elevation of liver enzymes to more severe manifestations, including hepatic steatosis, fibrosis, and cirrhosis. Alcohol intake adds to this risk by placing an additional metabolic burden on the liver, exacerbating 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 severe drug-induced liver injury by removing circulating toxins or immune complexes. This therapeutic 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 alcohol 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

Case Presentation

A 56-year-old male, with a significant history of alcohol abuse, presented to the internal medicine outpatient 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 Murphy’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 admitted 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 increased liver parenchymal echogenicity, consistent with grade 2 hepatic steatosis, and hepatospleno-megaly, measuring 19 cm and 17.3 cm, respectively. These findings were further confirmed by contrast-enhanced magnetic resonance imaging, demonstrating significant hepatic damage. Due to the severity of the condition, emergent plasmapheresis 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 injury. While MTX is an important medication, hepatotoxicity 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 elevations 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 previously believed. A large prospective study by Humphreys et al. demonstrated that consuming less than 14 units of alcohol per week (≈ 112 g/week ≈ 16 g/day) was not significantly associated with elevated liver enzymes in MTX users, whereas intake of alcohol use, and individualized risk-benefit analysis when prescribing MTX. In ambiguous or borderline cases, alternatives such as biologic disease-modifying antirheumatic drugs (DMARDs) or non-hepatotoxic immunosuppressants may be considered. Guidance on alcohol use during MTX therapy is uniformly cautious, with jurisdiction-specific nuances 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 Rheumatology 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 alcohol ‐ related liver disease, metabolic comorbidities, viral hepatitis, or concomitant hepatotoxins—abstinence 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, particularly where any hepatic risk is present. Where alcohol is consumed, it should be kept within ≤14 units per week, liver function should be monitored regularly, and shared decision ‐ making should be embedded, tailored to local standards and individual risk profiles.

Ethical Approval

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