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

Grech IM, Dirchwolf M and Ruf AE

Hospital Medicine, Private Hospital of Rosario, Argentina
Liver Unit, Private Hospital of Rosario, Argentina
Foundation for Teaching and Research of Liver Diseases, Argentina

^*Correspondance to: Dirchwolf M 

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Abstract:

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.

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Cite the Article:

Grech IM, Dirchwolf M, Ruf AE. Severe Neutropenia Related with Azathioprine Treatment in Autoimmune Hepatitis: The Impact of Homozygous Inactive Allele Mutation of Thiopurine S-Methyltransferase (TPMT) Gene. Ann Clin Case Rep. 2018; 3: 1562.