The Role of Thiopurine Metabolites in Thiopurine Related Toxicities in Pediatric Patients With IBD

Abstract

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic autoimmune condition affecting the gastrointestinal tract with 30% of diagnoses presenting by age 181. Thiopurines, 6-mercaptopurine and azathioprine, are popular treatment option for patients, but they have significant side effects, including myelosuppression and hepatotoxicity2,3. Monitoring of thiopurine metabolites, thioguanine nucleotide (6-TGN) and methyl mercaptopurine nucleotide (6-MMPN), can aid in dosing and identifying potential side effects4. The aim of this study is to identify the relationship between thiopurine metabolites, myelosuppression and hepatotoxicity in a racially diverse pediatric population with IBD. METHODS: We reviewed our established pediatric IBD database, composed of 384 patients diagnosed with Crohn's disease, ulcerative colitis, or IBD-indeterminate between Jan 2003 and Dec 2010, for usage of 6-mercaptopurine and/or azathioprine. Laboratory data were evaluated for thiopurine metabolites, evidence of leucopenia (WBC < 3,000/mm3), thrombocytopenia (platelet < 100,000/mm3) and transaminitis (ALT > 100 unit/L). We performed a retrospective chart review for patients with evidence of myelosuppression or hepatotoxicity to collect duration on thiopurines, dosing, thiopurine methyltransferase (TPMT) genetics and/or enzyme activity, other medical conditions, and demographic data. RESULTS: Of the 384 total patients, 244 (63.5%) took thiopurines. Thiopurine metabolites were obtained in 194 (79.5%) of these patients. Elevated TGN (>400 pmol/8 X108 RBC) was seen in 21 patients with 3 having evidence of myelosuppression. Twenty-three (9.4%) patients had evidence of myelosuppression while on thiopurines (Table 1), 18 of which had metabolites drawn at the time of myelosuppression. When other medical conditions likely to account for the myelosuppression were factored in, including 2 with lymphoma, 2 EBV infections, and 1 viral infection, there were only 18 patients (7.4%). Myelosuppression was transient (<1 month) in 16 patients. Dosing was decreased by 1/4 to 1/2 in 6 patients and stopped in 2 patients (1 due to poor response). Elevated 6-MMPN (>5700 pmole/ 8 X108 RBC) was seen in 23 patients with 2 having transaminitis. Eighteen patients (7.4%) overall had evidence of hepatotoxicity while on thiopurines (Table 1), 15 of which had metabolites drawn. When other medical conditions likely to account for transaminitis were evaluated, including 5 with primary sclerosing cholangitis, 2 EBV infections and 1 lymphoma, there were only 10 patients (4.1%). Increased levels were transient (<1 month) in 12 patients. Dosing was decreased by 1/4 to 1/3 in 3 patients and stopped in 1 (due to poor response). CONCLUSION(S): Thiopurine metabolites were obtained in most patients. Elevations were rare overall and unlikely to result in toxicity. Myelosuppression and hepatotoxicity were usually transient, responded to decreased dosing, and (Table Presented) resulted in cessation of therapy in only 1 patient. Both myelosuppression and hepatotoxicity were seen after 1 year of medication usage in preteen patients, and were unrelated to excessive dosing, sex or race. Crohn's disease was more prominent in both categories, although its implication is unclear. Patients with intermediate TMPT enzyme activity may be at increased risk for myelosuppression independent of dosing and metabolite levels. Monitoring for side effects of thiopurines in children with IBD should not rely only on metabolites.