End‐stage methotrexate‐related liver disease is rare and associated with features of the metabolic syndrome

Abstract

SummaryBackgroundMethotrexate (MTX) is one of the most frequently prescribed drugs in contemporary medicine with a well‐recognised hepatotoxic potential, for which stringent laboratory and histological surveillance has long been advocated.AimTo estimate the population burden of end‐stage methotrexate‐related liver disease (MTX‐LD) in the United States and identify independent host risk factors for this disease entity.MethodsWe analysed the records of all individuals who had been listed for, and/or received, liver transplantation in the United States, as reported to the Organ Procurement and Transplantation Network between 1 October 1987 and 31 December 2011, and identified those whose liver disease was attributed, wholly or partly, to MTX therapy. We also compared the demographic and clinical characteristics of adult individuals with MTX‐LD with those listed and/or transplanted for alcoholic liver disease (ALD, n = 43 285), non‐alcoholic steatohepatitis (NASH, n = 7569) and primary sclerosing cholangitis (PSC, n = 8526) using the adjusted odds ratios (AORs) derived from multi‐variable logistic regression models.ResultsOf 158 904 adults who had been listed for, and/or received, liver transplantation during the study period, only 117 (0.07%) had MTX‐LD. Compared with individuals with ALD and PSC, those with MTX‐LD were more likely to be older (AORs per 5‐year increase: 1.27, P < 0.001 and 1.33, P < 0.001 respectively); female (AORs: 1.78, P = 0.003 and 3.87, P < 0.001); Caucasian (AORs: 3.03, P = 0.001 and 2.05, P = 0.04); and diabetic (AORs: 2.76, P < 0.001 and 4.12, P < 0.001). With the exception of Caucasian ethnicity (AOR: 1.94, P = 0.05), the odds of these characteristics did not differ from individuals with NASH. The odds of elevated body mass index among MTX‐LD individuals were higher than those with PSC (AOR per 5 kg/m2: 1.51, P < 0.001); similar to those with ALD (AOR per 5 kg/m2:1.15, P = 0.1); and lower than those with NASH (AOR per 5 kg/m2: 0.66, P < 0.001).ConclusionsThe United States population burden of end‐stage methotrexate‐related liver disease is likely to be exceedingly small, suggesting the need for reappraisal of current hepatotoxicity surveillance guidelines. The risk factor profile of methotrexate‐related liver disease supports the notion that it may share a common pathogenesis with NASH.

Methotrexate is not associated with increased liver cirrhosis in a population-based cohort of rheumatoid arthritis patients with chronic hepatitis C

“…In a study enrolling 24 patients on long-term MTX therapy for psoriasis, serial liver biopsies revealed that non-alcoholic steatohepatitis (NASH) is an important cause of liver injury in such patients, and a high cumulative dose of MTX alone can lead to a NASH-like liver injury pattern19. This observation was corroborated by a recent analysis of individuals who received or had been listed for liver transplantation in the US, which shows that the risk factor profile of end-stage MTX-related liver disease is similar to that of NASH20. In our recent study of RA patients with CHB4, we speculated that compared to MTX users, MTX non-users had less severe disease activity of RA, which was associated with higher body mass index2122.…”

Understanding the Cautions and Contraindications of Immunomodulator and Biologic Therapies for Use in Inflammatory Bowel Disease

“…MTX is associated with an increased incidence of negative liver events (RR, 2.19; 95% CI, 1.73–2.77) 97 through oxidative stress, 98 and thus hepatotoxic drugs and preexisting liver disease are contraindications to MTX use. This includes suspected or undiagnosed liver disease, as in patients who are heavy alcohol users and obese (body mass index >30 kg/m 2 ), diabetic and hyperlipidemic patients, of whom the latter three are at increased risk of nonalcoholic fatty liver disease.…”

“…This includes suspected or undiagnosed liver disease, as in patients who are heavy alcohol users and obese (body mass index >30 kg/m 2 ), diabetic and hyperlipidemic patients, of whom the latter three are at increased risk of nonalcoholic fatty liver disease. 94,98 Known chronic liver diseases, particularly chronic viral hepatitis B (HBV) and C (HCV) are also contraindications. Although rare and more often associated with anti-TNF-α agents, reactivation of resolved HBV infection in MTX-treated patients has been reported, 99 although a recent report claimed no reactivation in an HBV-infected population with rheumatological diseases in Thailand.…”

“…Moreover, Dawwas et al report that because MTX-induced hepatotoxicity is so rarely associated with need for liver transplant, in the absence of the abovementioned risk factors, the use of MTX should not be discouraged. 98 …”

Recomendaciones del Grupo Español de Trabajo de Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre el uso de metotrexato en la enfermedad inflamatoria intestinal

“…Sin embargo, en la AR se ha observado una tasa muy baja de hepatotoxicidad 55 , y directamente en las EII una dosis acumulada media de más de 2,5 gramos de MTX solo se asoció a un grado leve de fibrosis en uno de veinte pacientes estudiados por biopsia 60 . De hecho datos indirectos muy recientes sugieren que la hepatotoxicidad grave por MTX es realmente rara 61 . En las EII disponemos de un metaanálisis reciente, en el que si se medía la hepatotoxicidad por la hipertransaminasemia (> x2 el valor normal), su incidencia era de 0,9 pacientes/mes, con una tasa de retirada del tratamiento de 0,8 pacientes/mes 62 63 .…”