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Early prediction of thiopurine‐induced hepatotoxicity in inflammatory bowel disease
Author(s) -
Wong D. R.,
Coenen M. J. H.,
Derijks L. J. J.,
Vermeulen S. H.,
Marrewijk C. J.,
Klungel O. H.,
Scheffer H.,
Franke B.,
Guchelaar H.J.,
Jong D. J.,
Engels L. G. J. B.,
Verbeek A. L. M.,
Hooymans P. M.
Publication year - 2017
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.13879
Subject(s) - thiopurine methyltransferase , medicine , inflammatory bowel disease , inflammatory bowel diseases , gastroenterology , azathioprine , disease , immunology
Summary Background Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady‐state 6‐methylmercaptopurine ribonucleotide (6‐ MMPR ) metabolite concentrations. Aim To determine the predictive value of 6‐ MMPR concentrations 1 week after treatment initiation ( T1 ) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. Methods The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised‐controlled trial evaluating pre‐treatment thiopurine S‐methyltransferase genotype testing (ClinicalTrials.gov NCT 00521950). Blood samples for metabolite assessment were collected at T1 . Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5. Results Forty‐seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6‐ MMPR threshold of 3615 pmol/8 × 10 8 erythrocytes was defined. Analysis of patients on stable thiopurine dose ( n = 174) showed that those exceeding the 6‐ MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI : 1.8–8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6‐ MMPR threshold to assess hepatotoxicity risk [ AUC = 0.83 (95% CI : 0.75–0.91)]. 6‐ MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI : 1.4–4.3), and general malaise: OR = 2.0 (95% CI : 1.1–3.7). Conclusions In more than 80% of patients, thiopurine‐induced hepatotoxicity could be explained by elevated T1 6‐ MMPR concentrations and the independent risk factors age, gender and BMI , allowing personalised thiopurine treatment in IBD to prevent early failure.