Severe Neutropenia Related with Azathioprine Treatment in Autoimmune Hepatitis: The Impact of Homozygous Inactive Allele Mutation of Thiopurine S-Methyltransferase (TPMT) Gene

Introduction: Azathioprine is considered part of the standard-of-care treatment strategy in autoimmune hepatitis. Despite the fact that several practice guidelines recommend Thiopurine Methyltransferase (TPMT) genotyping, phenotyping and/or measurement of metabolites activity, hepatology guidelines do not consider TPMT testing mandatory, due to scarce available information referring to its controversial utility. We report the case of a 56 year-old woman with recent autoimmune hepatitis diagnosis, who received two months of combined immunosuppressive treatment (decreasing doses of prednisone and azathioprine 50 mg during one month, with later increase to 100 mg per day). She was admitted in the Emergency Room due to severe febrile neutropenia. Azathioprine treatment was discontinued and TPMT genotyping was performed. A genetic homozygous variant (rs1800462) corresponding to homozygous TPMT*2 polymorphism was detected. The patient's treatment was modified to prednisone combined with mycophenolate with normalization of liver enzymes and resolution of the adverse event. Discussion: TPMT is a polymorphic enzyme involved in the metabolism and inactivation of thiopurine substances (such as azathioprine) administered as immune suppressants in the treatment of malignancies and autoimmune diseases. Mutations in the gene that encodes this enzyme may augment the risk of adverse events. Three genetic variants in the TPMT gene (rs12201199, rs1142345, and rs1800460) account for more than 90% of inactivating alleles. There are four nonfunctional alleles responsible of 80% to 95% of low enzyme activity: *2, *3A,*3B, *3C. Performing genetic testing to determine the TPMT polymorphism prior to treatment initiation with azathioprine has proven to be a valuable tool to prevent severe adverse events. Conclusion: Routine screening of TPMT polymorphisms in autoimmune hepatitis may prevent severe adverse events in patient with null enzyme activity. Grech IM1, Dirchwolf M2* and Ruf AE2,3 1Hospital Medicine, Private Hospital of Rosario, Argentina 2Liver Unit, Private Hospital of Rosario, Argentina 3Foundation for Teaching and Research of Liver Diseases, Argentina Dirchwolf M, et al., Annals of Clinical Case Reports Immunology Remedy Publications LLC. , | http://anncaserep.com/ 2018 | Volume 3 | Article 1562 2 the presence of different types of TPMT polymorphisms has been linked to the occurrence of severe side effects, or to the lack of proper immunosuppressive activity in patients receiving standard azathioprine doses [4]. Despite the fact that TPMT testing is currently a standard practice for internal medicine and gastroenterology guidelines [7], it has not been proposed as a mandatory test in the treatment of autoimmune hepatitis, due to scarce data regarding its clinical utility [9]; thus it is seldomly solicited prior to treatment initiation in daily practice. We will describe the case of a patient with autoimmune hepatitis treated with a combination of steroids and azathioprine at standard doses that develops severe febrile neutropenia associated with a homozygous TPMT polymorphism with null activity.