Thiopurine S-Methyltransferase Phenotype and Genotype in Pediatric Patients with Inflammatory Bowel Disease; Implication for Azathioprine Treatment

Maciej Jankowski Piotr Landowski

doi:10.4172/2329-6887.1000113

Abstract

Inflammatory Bowel Disease (IBD) is more prevalent in children than adults, and the incidence is increasing. IBD is treated with thiopurines, metabolized by thiopurine S-methyltransferase (TPMT) and inter-individual variability in activity of TPMT affecting therapy efficiency and drug toxicity arises from genetic polymorphisms, mainly TPMT*2, *3A, and *3C. The aim was to investigate the frequency distribution of TPMT activity, determine the penetration rate of TPMT*2, *3A, and *3C alleles in children, and compare TPMT activity in children and adults with IBD. The study included 85 children, 45% with Crohn’s disease (CD) and 55% with ulcerative colitis (UC), and 31 adults with IBD. TPMT activity was measured with radiochemistry. TPMT*2, *3A, and *3C alleles were investigated with PCR and restriction fragment length polymorphism analyses. Children showed median TPMT activities of 13.12 and 13.19 U/ml RBC in CD and UC, respectively, with 4.8-fold variability (range, 4.74 - 22.56 U/ml RBC). TPMT activity was similar in children and adults; ranges: 5.56-21.34 vs. 9.61-17.84 U/ml RBC, respectively, in CD; and 4.74-22.56 vs. 5.19-21.98 U/ml RBC, respectively, in UC. Patients with CD and UC treated with azathioprine displayed similar TPMT activities, similar adverse event frequencies, and similar numbers of non-responders. One out of 85 patients (1.18%) was heterozygous with TPMT*1/TPMT*2 (TPMT activity: 5.19 ± 0.05 U/ml RBC). Individuals with low-intermediate TPMT activity (<8 U/ ml RBC) did not carry mutant alleles *3A or *3C. TPMT phenotypes were similar in children and adults with inflammatory bowel disease.

Highlights

Epidemiological studies from Europe have shown an increasing incidence of pediatric inflammatory bowel disease (IBD)
One hundred-sixteen patients (85 children and 31 adults) with IBD were included in the study; all were Caucasian
One of these pathways is regulated by thiopurine S-methyltransferase (TPMT)

Summary

Introduction

Epidemiological studies from Europe have shown an increasing incidence of pediatric inflammatory bowel disease (IBD). TPMT activity varies over a large range, but about 0.3% of Caucasians exhibit complete deficiency, and 11% exhibit intermediate TPMT activity These subjects are at elevated risk of life-threatening thiopurine-induced adverse drug reactions, and they should be considered for alternative forms of therapy, or they should receive low doses of thiopurines [7]. The variant alleles TPMT*2, *3A, and *3C account for over 95% of inherited TPMT deficiency cases in Caucasian subjects [8,9]. This has led to the general assumption that TPMT phenotype/ genotype should be determined in pediatric patients with IBD before treating with thiopurines [10]. Understanding how these variables occur in pediatric patients with IBD is critical for optimizing the management of IBD in children

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