Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease
Publication date
2017-02
Authors
Wong, D R
Coenen, M J H
Derijks, L J J
Vermeulen, S H
van Marrewijk, Corine J
Klungel, O H
Scheffer, H
Franke, B
Guchelaar, H-J
de Jong, Dirk J.
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Abstract
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 NCT00521950). 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.
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Citation
Wong, D R, Coenen, M J H, Derijks, L J J, Vermeulen, S H, van Marrewijk, C J, Klungel, O H, Scheffer, H, Franke, B, Guchelaar, H-J, de Jong, D J, Engels, L G J B, Verbeek, A L, Hooymans, P M & TOPIC Recruitment Team 2017, 'Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease', Alimentary Pharmacology and Therapeutics, vol. 45, no. 3, pp. 391-402. https://doi.org/10.1111/apt.13879