Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease

Aliment Pharmacol Ther. 2017 Feb;45(3):391-402. doi: 10.1111/apt.13879. Epub 2016 Dec 12.


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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Azathioprine / adverse effects*
  • Chemical and Drug Induced Liver Injury / diagnosis*
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Cohort Studies
  • Early Diagnosis
  • Female
  • Genotype
  • Humans
  • Inflammatory Bowel Diseases / diagnosis*
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / genetics
  • Inflammatory Bowel Diseases / metabolism
  • Male
  • Mercaptopurine / adverse effects*
  • Mercaptopurine / analogs & derivatives
  • Methyltransferases / metabolism
  • Middle Aged
  • Prognosis
  • Risk Factors
  • Thioinosine / analogs & derivatives
  • Thioinosine / metabolism
  • Thionucleotides / metabolism
  • Treatment Outcome
  • Young Adult


  • Thionucleotides
  • Thioinosine
  • 6-methylthiopurine
  • 6-methylthiopurine ribonucleoside-5'-phosphate
  • Mercaptopurine
  • Methyltransferases
  • thiopurine methyltransferase
  • Azathioprine

Associated data

  • GENBANK/NCT00521950
  • ClinicalTrials.gov/NCT00521950