Non-alcoholic steatohepatitis-like pattern in liver biopsy of rheumatoid arthritis patients with persistent transaminitis during low-dose methotrexate treatment

Abstract

ObjectiveThe mechanism of liver injury with low-dose methotrexate (MTX) is incompletely understood. This study was designed to evaluate the association between non-alcoholic fatty liver disease (NAFLD) and liver injury during MTX treatment for rheumatoid arthritis (RA).MethodsBetween October 2014 and May 2015, we enrolled all MTX users for RA and monitored participant serum hepatic transaminase levels for 1 year. All patients had normal transaminase levels before the first MTX prescription. Using diagnostic criteria for non-alcoholic steatohepatitis (NASH), we performed histological analyses for patients presenting persistent transaminitis, defined as elevations of hepatic transaminases in four of six determinations during the follow-up period. Possible risk factors for persistent transaminitis were also examined.ResultsWe followed 846 RA patients with a mean cumulative MTX dose of 2.48 g and identified 51 patients presenting persistent transaminitis. According to multivariate logistic regression analysis, obesity (odds ratio [OR] 3.23, p < 0.001), type 2 diabetes (OR 3.52, p = 0.001), hypercholesterolemia (OR 2.56, p = 0.004), and hyperuricemia (OR 3.52, p = 0.019), which are recognized as risk factors for NAFLD, were independently associated with a risk of persistent transaminitis. Among patients with persistent transaminitis, 42 showed fatty liver at ultrasonography. These patients had no evidence of alcoholic fatty liver, chronic viral hepatitis, autoimmune liver diseases, or hereditary liver diseases. Biopsy specimens were obtained from 32 patients, and we found that a NASH-like pattern was the most prevalent histological abnormality. There was no significant impact of MTX dose and duration on the histological severity.ConclusionRisk factors and histological findings are similar between NAFLD/NASH and liver injury during low-dose MTX treatment for RA, which suggests a strong association between both entities. NAFLD/NASH may be an underlying condition causing persistent transaminitis in MTX-treated RA patients. The results of this study illustrate the need for monitoring liver injury in RA patients with NAFLD risk factors during MTX treatment.

Fatty liver in Pakistani cohort with rheumatoid arthritis

“…5 Shunshuke Mori et al in their observational study of 846 RA found that 42 patients using methotrexate had persistent elevation of transaminases while ultrasound showed fatty liver disease and histological results revealed nonalcoholic steatoheapatitis as most prevalent pattern of liver injury, there was no significant impact of methotreaxte dose and duration on histological severity. 6 Systematic review by Salliot and van der Heijde identified increased levels of transaminases (ALT, AST) as the second most frequent adverse effects with methotrexate therapy (20.2%) after gastrointestinal probelms. 7 I t is found that fatty liver disease (NAFLD), diagnosed either by imaging or biopsy, has been associated with methotrexate therapy since long.…”

Is methotrexate hepatotoxicity associated with cumulative dose? A systematic review and meta‐analysis

“…Studies which show improvements in liver function tests when MTX is discontinued or interrupted, raise the possibility of MTX being an accelerating risk factor 69 . Interestingly, Mori et al found that a NASH‐like pattern was the most prevalent in biopsies of MTX‐treated RA patients with persistent transaminitis and abnormal ultrasound findings 10 . We therefore speculate whether MTX has the potential to ‘destabilise’ NAFLD into the more concerning subtype, NASH, in certain individuals.…”

“…10,68 Similarly, the histological findings of both conditions are quite indistinguishable and in studies with pre-MTX treatment liver biopsies, fibrotic change has been reported in 14% of patients. 10,24 Studies which show improvements in liver function tests when MTX is discontinued or interrupted, raise the possibility of MTX being an accelerating risk factor. 69 Interestingly, Mori et al found that a NASH-like pattern was the most prevalent in biopsies of MTX-treated RA patients with persistent transaminitis and abnormal ultrasound findings.…”

“…4,5,6 However, establishing an association with low-dose MTX has proven difficult, particularly as risk factors for non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are shared and highly prevalent amongst treated cohorts. [7][8][9][10] This has greatly hampered attempts to reach a decisive conclusion as to whether MTX-associated liver disease is a distinct entity, a subtype of NAFLD or if MTX is merely a risk factor that can accelerate NAFLD/NASH.…”

Incidence, predictive factors and severity of methotrexate-related liver injury in rheumatoid arthritis: a longitudinal cohort study

“…For RA patients, several studies identified obesity, type 2 diabetes and hypercholesterolaemia as risk factors for the increase in alanine and/or aspartate aminotransferase (ALT and/or AST) levels that is observed during MTX treatment [ 16–19 ]. A NASH-like pattern was reported to be a common histological abnormality in MTX-treated RA patients who had persistent transaminitis [ 19 ]. These findings suggest that use of MTX could favour aggravation of pre-existing NAFLD and progression to NASH.…”