Annual Meeting of the North American Society for Pediatric Gastroenterology and Nutrition; Orlando, October 22-24, 1998
MOLECULAR DIAGNOSIS OF THIOPURINE S-METHYLTRANSFERASE DEFICIENCY AS A GUIDE TO 6-MERCAPTOPURINE THERAPY IN CHILDHOOD IBD
Thiopurine S-methyltransferase (TPMT) is the major enzyme controlling metabolism of 6-mercaptopurine (6-MP). Low TPMT activity results in enhanced production of 6-TG and dose-dependent toxicity. High TPMT activity results in reduced therapeutic efficacy with 6-MP therapy. Eleven percent of the population has intermediate TPMT activity and 1:300 are TPMT deficient. The most common allelic variants of the TPMT gene responsible for reduced TPMT activity have been identified. We have previously reported preliminary data showing a low incidence of TPMT deficiency in IBD. We have now genotyped a large group of pediatric IBD patients and controls to determine the incidence of TPMT deficiency and have correlated TPMT genotyping with 6-MP toxicity and with RBC TPMT enzyme activity. TPMT genotyping was performed by restriction enzyme digestion of PCR-amplified DNA extracted from buccal brushings. Two of 50 IBD patients (4%) and five of 44 controls (11%) were found to carry low activity TPMT alleles. Twenty-eight of the 50 IBD patients had been treated with 6-MP or AZA. Five had experienced pancreatitis, hepatitis, or both associated with 6-MP therapy, none of which were found to have TPMT-deficient alleles. In preliminary studies in a control group, genotyping was 100% sensitive and specific for the determination of normal or low RBC TPMT activity. RBC TPMT activity was normal in 1 IBD patient with normal genotyping who had experienced pancreatitis and was above the normal range for 1 IBD patient with normal genotyping who had not been treated with 6-MP. These data suggest that TPMT deficiency may be less frequent in the IBD population than in the general population. Genotyping is predictive of low TPMT enzyme activity, but does not distinguish between the high and low ends of the normal TPMT activity range. Pancreatitis with 6-MP therapy does not appear to relate to TPMT activity. The combination of TPMT genotyping and enzyme assay may be useful for identifying patients at risk for dose-dependent toxicity and those who may need increases in dosage for therapeutic efficacy. (Supported by a grant from the Nemours Foundation)
PLENARY SESSION II© 1998 Lippincott Williams & Wilkins, Inc.