Introduction Methotrexate (MTX) is an effective and widely used immunosuppressant; however, long-term therapy has been associated with steatosis, progressive hepatic fibrosis and cirrhosis. Given the similarity of the histopathological features of methotrexate-associated chronic liver disease (MTX-CLD), non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), we hypothesised that these diseases may share a common pathogenesis.

Method We analysed the diagnostic records of all individuals who have been listed for liver transplantation in the USA and reported to the Organ Procurement and Transplantation Network (OPTN) during the period 1 October 1987 and 22 May 2009 to identify those whose liver disease was deemed to have been, wholly or partly, caused by methotrexate (MTX-CLD). We compared the demographic, clinical and laboratory characteristics of adult individuals with MTX-CLD with those listed for ALD and NAFLD.

Results Among 148 639 unique listings for liver transplantation, we identified 105 individuals with MTX-CLD, and these were compared with individuals listed for ALD (n=17 592) and NAFLD (n=3259). Concurrent liver disease among individuals with MTX-CLD included ALD in 4.8%, NAFLD in 7.7%, hepatocellular carcinoma in 2.9%, hepatitis C infection in 1% and other drug-induced liver disease in 1%. Compared to the ALD group, those with MTX-CLD were older (median age 57 vs 51 years, p<0.0001), more likely to be Caucasian (91.4% vs 80.9%, p<0.007), female (46.2% vs 19.2%, p<0.001) and diabetic (36.8% vs 18.3%, p<0.001), and had a higher body mass index (median 28.2 vs 27.2 kg/m², p<0.03), but a lower median MELD score (14.5 vs 16, p<0.007). In contrast, compared to individuals with NAFLD, those with MTX-CLD were less likely to be diabetic (36.8% vs 47.7%, p<0.05) and had a lower median body mass index (28.2 vs 32.1 kg/m², p<0.0001), but a similar age, gender, ethnicity and MELD distribution. The prevalence of hypertension and vascular disease did not differ among the three groups, nor did their complications (ascites, encephalopathy, spontaneous bacterial peritonitis) profile.

Conclusion This is the largest analysis of end-stage MTX-CLD reported to date, demonstrating that it is a rare form of cirrhosis that has a distinct risk factor profile from those of ALD and, to a lesser extent, NAFLD. The severity of MTX hepatotoxicity may be potentiated by host (ethnicity) and environmental (diabetes, obesity) factors, ultimately leading to decompensated disease. A common pathogenic process may underlie MTX-CLD, ALD and NAFLD.