Association of Thiopurine Methyltransferase Enzyme Level with Toxicity of 6-Mercaptopurine/Azathioprine in Pediatric Patients with Inflammatory Bowel Disease

36 BACKGROUND: 6-mercaptopurine (6-MP) and Azathioprine (AZA) are used to treat severe cases of IBD. Common medical side effects include infection & leukopenia (8-15%), hepatitis (5-10%), and pancreatitis (3%). 6-MP is S-methylated to its effective 6-methylmercaptopurine metabolites by the enzyme thiopurine methyltransferase (TPMT). A competitive pathway also converts 6-MP to its cytotoxic 6-thioguanine nucleotides (6-TGNs) that are associated with bone marrow suppression (leukopenia, neutropenia, thrombocytopenia). Patients with decreased TPMT activity have increased levels of 6-TGN. TPMT levels have also been associated with specific genotypes. 89% of the general population is homozygous for TPMTH and have a TPMT level of 13.8 - 25.1 U/ml RBC. Approximately 11% have the heterozygous allele, TPMTH/TPMTL, which correlates with a TPMT level of 5.0 - 13.7 U/ml RBC. 1/300 has the homozygous allele, TPML/TPMTL, which correlates with a TPMT level of < 5.0 U/ml RBC. AIM: To determine whether there is a relationship between the development of elevated aminotransferases, leukopenia, or pancreatitis and the TPMT level in patients with IBD. METHODS: The medical records between 7/94 and 6/98 of patients with IBD were retrospectively reviewed for TPMT levels. All erythrocyte TPMT levels were determined at the MAYO Medical Laboratories. Determination of leukopenia (WBC < 4,000), elevated aminotransferases, and pancreatitis was performed. RESULTS: 22 patients with IBD, mean age 13.7 years old, were treated with 6-MP or AZA and had TPMT levels obtained. 14 patients had Crohn's disease (CD) and 8 patients had ulcerative colitis (UC). AZA was used in 8 patients with CD and 2 with UC. 6-MP was used in 6 patients with CD and 6 with UC. The mean dose of 6-MP and AZA were 0.9 and 1.8 mg/kg/day, respectively. The TPMT levels ranged from 10.7 to 27.5 U/ml with a mean of 17.2 ± 3.2 U/ml. The mean TPMT level for patients who had transaminase elevations was 16.8 ± 1.4 U/ml and for leukopenia was 17.8 ± U/ml which were similar to the mean TPMT level of the study population. For these patients with side effects, their mean dose of 6-MP/AZA was identical to that of all study patients. 1 patient, who's TPMT level was 15.1 U/ml, developed pancreatitis. CONCLUSION: The TPMT level and dose of 6-MP/AZA were not predictive for the development of leukopenia, elevated transaminases or pancreatitis. Therefore close monitoring of the WBC, ALT & AST is indicated. Further studies of patients with IBD who have a low TPMT level, <5.0 U/ml, will be necessary to determine if this enzyme level is of clinical value. [Funded in part by GCRC grant MO1-RR00240]