OP10 End-stage methotrexate-associated chronic liver disease in the USA: interaction of drug, host and environmental factors

Abstract

Background and Aim: Methotrexate (MTX) is an effective and widely used immunosuppressant; however, long-term therapy has been been associated with steatosis, progressive hepatic fibrosis and cirrhosis. Given the similarity of the histologic features of methotrexate-associated chronic liver disease (MTXCLD), non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD), we hypothesized that these diseases may share a common pathogenesis. Patients and Methods: We analysed the diagnostic records of all individuals who have been listed for liver transplantation in the United States and reported to the Organ Procurement and Transplantation Network (OPTN) during the period 1st October 1987-22nd 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 MTXCLD, and these were compared with individuals listed for ALD (n=17,592) and NAFLD (n=3,259). 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. 27.2kg/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), had a lower median body mass index (28.2 vs. 32.1kg/m2, p<0.0001)but a similar age, gender, ethnicity and MELD distribution. The prevalence of a history of hypertension and vascular disease did not differ among the three groups, nor did their complications (ascites, encephalopathy, spontaneous bacterial peritonitis) profile. Conclusions: 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 that 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