Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease
D R Wong, M J H Coenen, L J J Derijks, S H Vermeulen, C J van Marrewijk, O H Klungel, H Scheffer, B Franke, H-J Guchelaar, D J de Jong, L G J B Engels, A L M Verbeek, P M Hooymans, TOPIC Recruitment Team, Aam Masclee, M Pierik, W Mares, W Hameeteman, P J Wahab, H Seinen, McM Rijk, I M Harkema, M de Bièvre, L Oostenbrug, C M Bakker, M Aquarius, C van Deursen, A B van Nunen, J G Goedhard, M Hamacher, Iam Gisbertz, B J Brenninkmeijer, Acitl Tan, M N Aparicio-Pagés, E M Witteman, Sac van Tuyl, R Breumelhof, A Stronkhorst, Lpl Gilissen, E J Schoon, Jwm Tjhie-Wensing, A Temmerman, J J Nicolaï, J D van Bergeijk, D J Bac, Bjm Witteman, N Mahmmod, J J Uil, H Akol, RJTh Ouwendijk, I P van Munster, M Pennings, Amp De Schryver, ThJM van Ditzhuijsen, Rch Scheffer, Teh Römkens, D L Schipper, P J Bus, Jwa Straathof, M L Verhulst, P J Boekema, JTh Kamphuis, H J van Wijk, Jmjl Salemans, J R Vermeijden, Sdj van der Werf, R J Verburg, P Spoelstra, Jml de Vree, K van der Linde, Hja Jebbink, M Jansen, H Holwerda, N van Bentem, J J Kolkman, Mgvm Russel, G H van Olffen, M J Kerbert-Dreteler, M Bargeman, J M Götz, R Schröder, J M Jansen, L P Bos, Lgjb Engels, Mjl Romberg-Camps, Etp Keulen, Aaj van Esch, Jph Drenth, McA van Kouwen, Gja Wanten, T J Bisseling, Teh Römkens, Mwj van Vugt, P C van de Meeberg, S J van den Hazel, Wnhm Stuifbergen, Mjal Grubben, U de Wit, Gah Dodemont, R F Eichhorn, Jmh van den Brande, Ahj Naber, E J van Soest, P J Kingma, N C Talstra, K F Bruin, Fhj Wolfhagen, D W Hommes, Ppj van der Veek, Jca Hardwick, R J Stuyt, H H Fidder, B Oldenburg, T G Tan, D R Wong, M J H Coenen, L J J Derijks, S H Vermeulen, C J van Marrewijk, O H Klungel, H Scheffer, B Franke, H-J Guchelaar, D J de Jong, L G J B Engels, A L M Verbeek, P M Hooymans, TOPIC Recruitment Team, Aam Masclee, M Pierik, W Mares, W Hameeteman, P J Wahab, H Seinen, McM Rijk, I M Harkema, M de Bièvre, L Oostenbrug, C M Bakker, M Aquarius, C van Deursen, A B van Nunen, J G Goedhard, M Hamacher, Iam Gisbertz, B J Brenninkmeijer, Acitl Tan, M N Aparicio-Pagés, E M Witteman, Sac van Tuyl, R Breumelhof, A Stronkhorst, Lpl Gilissen, E J Schoon, Jwm Tjhie-Wensing, A Temmerman, J J Nicolaï, J D van Bergeijk, D J Bac, Bjm Witteman, N Mahmmod, J J Uil, H Akol, RJTh Ouwendijk, I P van Munster, M Pennings, Amp De Schryver, ThJM van Ditzhuijsen, Rch Scheffer, Teh Römkens, D L Schipper, P J Bus, Jwa Straathof, M L Verhulst, P J Boekema, JTh Kamphuis, H J van Wijk, Jmjl Salemans, J R Vermeijden, Sdj van der Werf, R J Verburg, P Spoelstra, Jml de Vree, K van der Linde, Hja Jebbink, M Jansen, H Holwerda, N van Bentem, J J Kolkman, Mgvm Russel, G H van Olffen, M J Kerbert-Dreteler, M Bargeman, J M Götz, R Schröder, J M Jansen, L P Bos, Lgjb Engels, Mjl Romberg-Camps, Etp Keulen, Aaj van Esch, Jph Drenth, McA van Kouwen, Gja Wanten, T J Bisseling, Teh Römkens, Mwj van Vugt, P C van de Meeberg, S J van den Hazel, Wnhm Stuifbergen, Mjal Grubben, U de Wit, Gah Dodemont, R F Eichhorn, Jmh van den Brande, Ahj Naber, E J van Soest, P J Kingma, N C Talstra, K F Bruin, Fhj Wolfhagen, D W Hommes, Ppj van der Veek, Jca Hardwick, R J Stuyt, H H Fidder, B Oldenburg, T G Tan
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 × 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.
© 2016 John Wiley & Sons Ltd.
Source: PubMed