Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state methylmercaptopurine ribonucleotide metabolite concentrations.
Dr Wong and colleagues from the Netherlands determined the predictive value of methylmercaptopurine ribonucleotide concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment.
The research team reported that the cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomized-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing.
Blood samples for metabolite assessment were collected at T1.
|The fecal immunochemical test is increasingly used relative to conventional fecal occult blood test|
|Alimentary Pharmacology & Therapeutics|
Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5.
The team noted that 17% of patients presented hepatotoxicity during the first 20 weeks of thiopurine treatment.
A T1 methylmercaptopurine ribonucleotide threshold of 3615 pmol/8 × 108 erythrocytes was defined.
Analysis of patients on stable thiopurine dose showed that those exceeding the methylmercaptopurine ribonucleotide threshold were at increased risk of hepatotoxicity.
The researchers observed that age, male gender and BMI were significant determinants.
The team developed a predictive algorithm based on these determinants, and the methylmercaptopurine ribonucleotide threshold to assess hepatotoxicity risk.
Methylmercaptopurine ribonucleotide concentrations above the threshold also correlated with gastrointestinal complaints, and general malaise.
Dr Wong's team concludes, "In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 methylmercaptopurine ribonucleotide concentrations, and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure."