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When cure becomes a threat: A case series on methotrexate-induced liver injury in a tertiary care setting
*Corresponding author: Gowri P. Pillai, Department of Clinical Pharmacy, Nazareth College of Pharmacy, Thiruvalla, Kerala, India. gowripillai17@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Pillai GP, Parvathy PR, Harikrishnan S, Jesuran SJ. When cure becomes a threat: A case series on methotrexate-induced liver injury in a tertiary care setting. Indian J Physiol Pharmacol. doi: 10.25259/ IJPP_298_2025
Abstract
Methotrexate, a cornerstone of modern therapeutics, is widely used as an immunosuppressant and anticancer agent. The occurrence of methotrexate-associated hepatotoxicity has been well documented. This case series highlights the spectrum of methotrexate-induced liver injury and emphasises the need for regular liver function monitoring to facilitate early detection and prevention of hepatotoxicity in patients receiving methotrexate therapy. This case series details have been collected from the outpatient department between the years 2019 and 2023 at a tertiary care teaching hospital. Causality assessment was performed using the World Health Organisation-Uppsala Monitoring Centre criteria. Methotrexate was prescribed for a duration ranging from 3 weeks to 4 years on a dose ranging from 2.5 mg to 25 mg once weekly. Among them, five were female and two were male, aged 19 years–70 years. Three patients already had renal involvement, and two more had diabetes. This case series reaffirms the principle that prevention is better than cure. It majorly emphasises the importance of routine liver monitoring in methotrexate patients to early detection and prevention of hepatotoxic effects.
Keywords
Drug-induced liver injury
Hepatotoxicity
Immunosuppressant
Methotrexate
Pharmacovigilance programme of India
INTRODUCTION
Methotrexate is frequently used as an immunosuppressant and anticancer drug.[1] It is a folate antagonist that primarily penetrates cells through the reduced folate carrier. Inside the cell, methotrexate undergoes polyglutamation, a process catalysed by folylpolyglutamate synthetase, which enhances its intracellular retention and inhibitory potential. Methotrexate polyglutamates inhibit several key enzymes involved in purine and pyrimidine nucleotide synthesis. One of the primary targets is dihydrofolate reductase, which blocks the conversion of dihydrofolate into tetrahydrofolate, thereby disrupting the synthesis of thymidylate and purines. Thymidylate synthase facilitates the synthesis of thymidine monophosphate, essential for DNA replication. Inhibiting aminoimidazole carboxamide ribonucleotide transformylase (AICART) causes aminoimidazole carboxamide ribonucleotide accumulation, leading to elevated adenosine levels, thereby exerting anti-inflammatory effects. Overall, methotrexate hampers cellular replication by interfering with the synthesis of DNA, RNA and proteins through enzyme inhibition.[2,3]
Methotrexate treats cancers such as leukaemia and lymphoma, as well as rheumatoid arthritis (RA) and psoriasis. The adverse effects include bone marrow suppression, nausea, abdominal pain, diarrhoea, hepatotoxicity, stomatitis, exanthems and mouth ulcers. According to the World Health Organisation (WHO) VigiBase pharmacovigilance data, approximately 3% of global adverse drug reaction (ADR) reports linked to methotrexate are related to liver toxicity. The pathophysiology in the induction of hepatotoxicity with methotrexate involves several mechanisms such as oxidative stress, mitochondrial dysfunction, folate depletion and inflammatory cytokine release and induction of hepatic stellate cell activation and fibrogenesis through adenosine accumulation.[4]
Aim
The aim of this study was to facilitate the early detection of methotrexate-induced hepatotoxicity through regular monitoring and to improve patient safety and better outcomes.
MATERIALS AND METHODS
This case series details have been collected from the outpatient department (OPD) between the years 2019 and 2024 at a tertiary care teaching hospital. Causality assessment was performed using the WHO-UMC criteria, which were based on data from the Believers Church Medical Colleges ADR monitoring centre. Only instances with appropriate and credible evidence of methotrexate-induced hepatotoxicity were considered for the final analysis. Therefore, seven cases met the inclusion requirements and were chosen for this case series. All participating patients provided written informed consent in a language that they understood, assuring both ethical compliance and patient understanding.
CASE SERIES
Case 1: Methotrexate-induced transaminitis
A 70-year-old female with seropositive RA, type 2 diabetes mellitus with diabetic nephropathy, systemic hypertension, dyslipidaemia and lumbar spondylosis was admitted on 24th May 2024 for her 10th dose of IV infliximab (200 mg). She had been on methotrexate 10 mg once weekly since March 2023, along with hydroxychloroquine (HCQ), glimepiride, dapagliflozin, folic acid, vildagliptin, losartan and rosuvastatin with ezetimibe. During admission, routine investigations revealed elevated liver enzymes, alanine aminotransferase range 81 U/L and aspartate aminotransferase 49 U/L, indicating transaminitis. Based on rheumatology and general medicine consultations, methotrexate was discontinued. At 1-month follow-up, liver function tests (LFTs) had normalised, suggesting methotrexate-induced hepatotoxicity. Further clinical details are summarised in Table 1.
| Case no. | Case no.1 | Case no.2 | Case no.3 | Case no.4 | Case no.5 | Case no.6 | Case no.7 |
|---|---|---|---|---|---|---|---|
| Age | 70-year | 49-year | 19-year | 56-year | 64-year | 57-year | 58-year |
| Gender | Female | Female | Female | Male | Male | Female | Female |
| Underlying disease | Rheumatoid arthritis | Psoriatic arthritis | Psoriasis | Psoriasis | Rheumatoid arthritis | Rheumatoid arthritis +CKD | Rheumatoid arthritis |
| Methotrexate Start date and Stop date | March 2023 and 24 May 2024 |
2022 and 21 June 2024 |
03-May-23 and 24 May 2023 |
2019 and 8 September 2023 |
2019 and 22 September 22 |
2018 and 1 March 2023 |
12 March 20 and 14 December 2022 |
| Dosage | 10 mg weekly | 5 mg weekly | 5 mg weekly | 15 mg weekly | 10 mg weekly | 2.5 mg weekly | 25 mg weekly |
| Hepatic ADR | Transaminitis | Fatty liver and transaminitis | Hyperbilirubinemia | Transaminitis | Hepatic injury | Early CLD | Hepatic injury |
| Co-medications | Hydroxychloroquine, glimepiride, dapagliflozin, folic acid, vildagliptin, losartan and rosuvastatin with ezetimibe | Tofacitinib, rosuvastatin | Apremilast, topical steroids | None reported | HCQ, anti-diabetics | Statins, Erythropoietin, nebivolol, cilnidipine |
HCQ, statins, dapagliflozin, metformin |
| WHO-UMC scale | Probable | Probable | Probable | Probable | Probable | Probable | Probable |
| Action taken | Withdrawn | Withdrawn | Withdrawn | Withdrawn | Withdrawn | Withdrawn | Withdrawn |
| Outcome | Recovered | Recovered | Recovered | Recovered | Recovered | Recovered | Recovered |
| Test | Before dose withheld | After dose withheld | Normal range | ||||
| SGOT | 49 U/L | 32 U/L | 10–40 U/L | ||||
| SGPT | 81 U/L | 35 U/L | 10–40 U/L | ||||
| SGOT | 68 U/L | 23 U/L | 10–40 U/L | ||||
| SGPT | 91 U/L | 35 U/L | 10–40 U/L | ||||
| Total bilirubin | 1.45 mg/dL | 1.04 mg/dL | 0.20–1.00 mg/dL | ||||
| Direct bilirubin | 0.3 mg/dL | 0.19 mg/dL | 0.00–0.2 mg/dL | ||||
| Indirect bilirubin | 1.15mg/dL | 0.85 mg/dL | 0.20–1.00 mg/dL | ||||
| Total bilirubin | 1.53 mg/dL | 0.98 mg/dL | 0.20–1.00mg/dL | ||||
| Direct bilirubin | 0.23 mg/dL | 0.19 mg/dL | 0.00–0.2mg/dL | ||||
| Indirect bilirubin | 1.30 mg/dL | 0.79 mg/dL | 0.20–1.00 mg/dL | ||||
| SGOT | 45 U/L | 33 U/L | 10–40 U/L | ||||
| SGPT | 52 U/L | 37 U/L | 10–40 U/L | ||||
| SGOT | 102 U/L | 37 U/L | 10–40 U/L | ||||
| SGPT | 96 U/L | 37 U/L | 10–40 U/L | ||||
| USG Abdomen+pelvis showed chronic parenchymal liver disease, bilateral increased renal cortical echogenicity and liver enzymes found to be normal | |||||||
| SGOT | 133 U/L | 19 U/L | 10–40 U/L | ||||
| SGPT | 200 U/L | 26 U/L | 10–40 U/L | ||||
WHO: World health organization, CKD: Chronic kidney disease, CLD: Chronic liver disease, HCQ: Hydroxychloroquine, ADR: Adverse drug reaction, USG: Ultrasound, SGOT: Serum glutamic-oxaloacetic transaminase, SGPT: Serum glutamic-pyruvic transaminase, WHO-UMC: World health organization-Uppsala monitoring centre scale
Case 2: Methotrexate-induced fatty liver and transaminitis
A 49-year-old female with psoriatic arthritis (diagnosed in 2022) and a history of uveitis presented on 21st June 2024 with joint pain and stiffness. She had been on methotrexate 5 mg once weekly, tofacitinib and rosuvastatin. Routine laboratories revealed elevated liver enzymes (serum glutamicoxaloacetic transaminase [SGOT]: 68 U/L, serum glutamicpyruvic transaminase [SGPT]: 91 U/L), and ultrasound (USG) showed Grade I fatty liver changes. Methotrexate was discontinued due to suspected hepatotoxicity, and she was started on apremilast 20 mg and udiliv 300 mg twice daily. On follow-up after 2 weeks, liver enzymes had normalised, indicating methotrexate-induced liver injury. Further clinical details are summarised in Table 1.
Case 3: Methotrexate-induced hyperbilirubinemia
A 19-year-old female patient came for review in the dermatology department with complaints of new lesions over the forearms on 24 May 2023. She had a previous history of childhood nephrotic syndrome and psoriasis from the age of 10. On general examination, there are numerous well-defined erythematous plaques with silvery white scales covering the scalp, trunk and upper and lower limbs. She had been started on methotrexate 5 mg once weekly on 3 May 2023. After 4 weeks, the direct bilirubin was recorded at 0.3 mg/dL, indirect at 1.2 mg/dL, resulting in a total bilirubin of about 1.5 mg/dL, prompting discontinuation of methotrexate. On follow-up after 4 weeks, bilirubin levels improved to 1.04 mg/ dL, suggesting methotrexate-induced liver dysfunction. Further clinical details are summarised in Table 1.
Case 4: Methotrexate-induced transaminitis
A 56-year-old male patient with psoriasis came for a follow-up visit with scaly lesions on the trunk and limbs. On general examination, it was noted with scaly plaques in the trunk, presence of limb follicular papules and onycholysis. The patient was prescribed to take T. Methotrexate 15 mg P/O once weekly for psoriasis from 2019. On routine, mild abnormalities were noted in the LFT: Total bilirubin was 1.53 mg/dL, indirect bilirubin 1.30 mg/dL, with SGOT and SGPT measured at 60 U/L and 52 U/L, respectively. Methotrexate was discontinued on 8 September 2023 due to transaminitis. Follow-up after 2 weeks showed normalisation of liver function, indicating methotrexate-induced liver dysfunction. Further clinical details are summarised in Table 1.
Case 5: Methotrexate-induced hepatic injury
A 64-year-old male with type 2 diabetes mellitus and RA, on methotrexate 10 mg once weekly since 2019, presented with joint stiffness and nocturnal paresthesia and was on T. Methotrexate 10 mg once a week from 2019, T. Ziten, T. Glyciphage SR, T. Remogliflozin and T. Diamicron, HCQ.
The patient was advised to do LFT and USG, then review back in the OPD. Initial LFT on 15th February 2022 showed mildly elevated SGPT/SGOT (46/41 U/L), which worsened to 96/102 U/L by 22nd September 2022. USG revealed Grade 1 fatty liver with subtle surface nodularity. Consequently, the T. Methotrexate was discontinued on 22 September 2022 as there were noticeable hepatic changes. Follow-up after 2 months showed normalised liver function. Further clinical details are summarised in Table 1.
Case 6: Methotrexate-induced early chronic liver disease
A 57-year-old female with chronic kidney disease (CKD) stage IV, hypertension, sero-positive RA and secondary Sjogren’s syndrome had been on Methotrexate 2.5 mg once a week from 2018, T. Ferrisome, T. Folic acid, C. Calcitriol, T. Nebivolol, T. Cilnidipine, T. Neurobion forte and T. Rosuvastatin. The USG Abdomen + Pelvis done on 1 March 2023 showed Chronic parenchymal liver disease, bilateral increased renal cortical echogenicity and liver enzyme SGOT/PT was found to be normal (31 and 35 U/L). Methotrexate was discontinued on 1 March 2023 based on imaging findings. Further clinical details are summarised in Table 1.
Case 7: Methotrexate-induced hepatic injury
A 58-year-old female came for review in the rheumatology OPD with a history of seropositive RA, type 2 diabetes mellitus and dyslipidaemia. The patient was on the following medications such as HCQ 200 mg 1-0-1, T. Methotrexate 25 mg weekly since March 2020, T. Glyciphage SR 500 mg 1-0-1, T. Dapagliflozin 10 mg 1-0-0 and T. Atorvastatin 10 mg 0-0-1. On 14 December 2022, liver enzymes were markedly elevated (SGPT 200 U/L, SGOT 130 U/L). To prevent further hepatic complications, T. Methotrexate 25 mg once weekly was ceased on 14 December 2022. On follow-up after 1 month, LFT normalised. Further clinical details are summarised in Table 1.
DISCUSSION
Our findings are supported by previous studies. Sotoudehmanesh et al. reported transaminitis in 23.7% of RA patients on methotrexate doses ≥7.5 mg/week.[5] Tilling et al. reported methotrexate-induced hepatotoxicity in 12% of patients overall, underscoring its potential to cause liver injury irrespective of the underlying autoimmune condition.[6] Conway and Carey demonstrated a 2.63-fold increase in the risk of transaminase elevation with methotrexate.[7] Zhi directly implicated methotrexate as a causative agent of hepatotoxicity, particularly in patients with metabolic dysfunction-associated fatty liver disease and type 2 diabetes, both common in our cohort.[8] Similarly, Bilal et al. identified increasing age as a key risk factor for methotrexate-induced liver injury, with no significant difference between genders.[9] Despite the presence of comorbidities such as diabetes and CKD, hepatotoxicity resolved in all cases after stopping methotrexate, confirming its central role.[10]
CONCLUSION
Methotrexate, a commonly used drug for immunosuppression and cancer therapy, demands cautious administration and vigilant monitoring. Routine LFT is crucial for early identification of liver complications, allowing prompt management and recovery, as demonstrated in all seven cases in this series. Implementing preventive measures, especially regular biochemical surveillance, is vital, particularly in patients with underlying kidney disease or diabetes reduce the risk of serious hepatic damage.
Ethical approval:
Institutional Review Board approval is not required.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
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