Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease

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Title:	Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease
Author(s):	Wong, D.R.; Coenen, M.J.H. ; Derijks, L.J.; Vermeulen, S.H. ; Marrewijk, C.J. van ; Klungel, O.H.; Scheffer, H. ; Franke, B. ; Guchelaar (LUMC), H.J.; Jong, D.J. de ; Engels, L.G.; Verbeek, A.L.M. ; Hooymans, P.M.
Publication year:	2017
Source:	Alimentary Pharmacology & Therapeutics, vol. 45, iss. 3, (2017), pp. 391-402
ISSN:	0269-2813
DOI:	https://doi.org/10.1111/apt.13879
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : http://hdl.handle.net/2066/169966
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Subject:	Radboudumc 0: Other Research RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences Radboudumc 17: Women's cancers RIHS: Radboud Institute for Health Sciences Radboudumc 2: Cancer development and immune defence RIMLS: Radboud Institute for Molecular Life Sciences Radboudumc 3: Disorders of movement DCMN: Donders Center for Medical Neuroscience Radboudumc 5: Inflammatory diseases RIHS: Radboud Institute for Health Sciences Radboudumc 7: Neurodevelopmental disorders DCMN: Donders Center for Medical Neuroscience
Organization:	Radboudumc Extern Human Genetics Health Evidence Haematology Psychiatry Gastroenterology
Journal title:	Alimentary Pharmacology & Therapeutics
Volume:	vol. 45
Issue:	iss. 3
Page start:	p. 391
Page end:	p. 402
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 x 108 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.