P44 Liver injury in children on long-term low dose methotrexate
Authors: Kelgeri Chayarani , HR Somashekhar , Brown Rachel , Al-Abadi Eslam , Gupte Girish 
Published: October 2019

Abstract

Background
Liver injury is known in patients on methotrexate (MTX). We retrospectively reviewed records of patients who had liver biopsy for suspected MTX induced liver injury and identify risk factors if any.

Methods
Children (≤ 16 years) referred to us from 2002 to 2015 with suspected MTX induced liver injury were identified and data related to their underlying diagnosis, biochemical parameters, Body Mass Index (BMI), dose and duration of MTX at the time of liver biopsy, use of concomitant drugs, duration and other causes for elevated transaminases, liver histology including clinical decisions to continue or stop MTX were extracted from the data base. All the liver biopsies were re-analysed for this study and scored using the Roenigk classification by a single histopathologist blinded to patient characteristics.

Results
Seventeen liver biopsies were performed in 14 children (3 had repeat biopsies) who were referred for frequent/persistent transaminitis (> 2 times upper limit normal).
The base line bilirubin, transaminases and synthetic liver function were normal in all prior to MTX therapy. All were on MTX at the time of biopsy except two who had been off the drug for 3 and 8 months following frequent transaminitis. They had liver biopsy to guide reintroduction of MTX in their treatment regime. None of the patients had renal impairment, diabetes or underlying liver disease.
Thirteen biopsies (82 %) had none (n = 6) to mild liver injury (n = 7) and were advised to continue MTX. Four biopsies (18%) showed significant liver injury (grade 3b and 4). Of these 3 patients were advised to stop MTX while one was advised to continue and repeat liver biopsy in 6 months. He however, stopped MTX soon thereafter. All biopsies of children (n = 3) with BMI ≥ 91st centile had liver damage. Two of thirteen biopsies with BMI < 91 centile had moderate-severe damage. No correlation was seen between the histologic findings or their severity with dose or duration of MTX, concomitant use of other drugs, severity/highest transaminase peak, total duration of transaminase abnormality, longest single episode of transaminase abnormality or frequency/number of peaks of abnormal transaminases. Of the 3 with repeat biopsies, fibrosis had progressed in 2, necessitating discontinuation of MTX in 1.

Conclusion
The finding of significant liver injury in our cohort is not entirely in keeping with previous paediatric studies which report non-significant fibrosis or cirrhosis. We could not identify any risk factors though children with BMI ≥ 91st centile seemed more likely to have liver injury. This finding is similar to adult studies implicating obesity as risk factor though it is difficult to draw definitive conclusions given the small size of our cohort. Other limitations include the retrospective nature of the study, bias as MTX dose modifications and referral were at the discretion of the rheumatologist and no information on alcohol intake in the teenagers.
This study emphasises the need for careful monitoring to prevent severe fibrosis and cirrhosis.

Conflicts of Interest
The authors declare no conflicts of interest.