title: Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 × 108erythrocytes 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).
  
  
  
  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.
authors.affiliation: Sittard-Geleen, The Netherlands.
authors.forename: D R
authors.initials: DR
authors.lastname: Wong
authors.affiliation: Nijmegen, The Netherlands.
authors.forename: M J H
authors.initials: MJ
authors.lastname: Coenen
authors.affiliation: Veldhoven, The Netherlands.
authors.forename: L J J
authors.initials: LJ
authors.lastname: Derijks
authors.affiliation: Nijmegen, The Netherlands.
authors.forename: S H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: Nijmegen, The Netherlands.
authors.forename: C J
authors.initials: CJ
authors.lastname: van Marrewijk
authors.affiliation: Utrecht, The Netherlands.
authors.forename: O H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Scheffer
authors.affiliation: Nijmegen, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Franke
authors.affiliation: Leiden, The Netherlands.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Nijmegen, The Netherlands.
authors.forename: D J
authors.initials: DJ
authors.lastname: de Jong
authors.affiliation: Sittard-Geleen, The Netherlands.
authors.forename: L G J B
authors.initials: LG
authors.lastname: Engels
authors.affiliation: Nijmegen, The Netherlands.
authors.forename: A L M
authors.initials: AL
authors.lastname: Verbeek
authors.affiliation: Sittard-Geleen, The Netherlands.
authors.forename: P M
authors.initials: PM
authors.lastname: Hooymans
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001379:Azathioprine / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D042241:Early Diagnosis; D005260:Female; D005838:Genotype; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000031:analogs & derivatives; D008780:Methyltransferases / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D013868:Thioinosine / Q000031:analogs & derivatives / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D013873:Thionucleotides; D013868:Thioinosine; C010240:6-methylthiopurine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine