Z Ailing1, Y Jing1, L Jingli1, X Yun2, Z Xiaojian1. 1. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 2. Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract
WHAT IS KNOWN AND OBJECTIVE: Thiopurine methyltransferase (TPMT) enzyme is an important component in the metabolism of azathioprine (AZA). Its mutation may lead to AZA-induced toxicity. The dysfunctional genetic variant TPMT *3C is of low frequency among Asians. Moreover, AZA-induced toxicity still occurs in some patients with normal TPMT activity. This suggests that additional factors, including other genetic variants, may contribute to such toxicity. Recent studies described a strong association between a variant of the NUDT15, a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives, and thiopurine-related myelosuppression in Asians. We report the first case of a Chinese patient with AZA-induced severe toxicity with no clinically significant TPMT variant but with the NUDT15 c.415C>T allele. CASE SUMMARY: A 40-year-old Chinese patient with PBC-AIH overlap syndrome had been receiving for one month, azathioprine (50 mg/day) and methylprednisolone (24 mg/day) based on his TPMT*3C wild-type genotype. The patient developed serious myelosuppression and hair loss. AZA was stopped, and the patient was given liver-protective drugs and supportive treatment. TPMT and NUDT15 gene sequencing suggests that NUDT15 c.415C>T mutation was the likely cause of the adverse reaction. WHAT IS NEW AND CONCLUSION: NUDT15 c.415C>T may be another predictor of AZA-induced leukocytopenia. If further well-controlled studies validate this association with sufficient predictive power, NUDT15 and TPMT genotyping before starting AZA treatment may become appropriate.
WHAT IS KNOWN AND OBJECTIVE:Thiopurine methyltransferase (TPMT) enzyme is an important component in the metabolism of azathioprine (AZA). Its mutation may lead to AZA-induced toxicity. The dysfunctional genetic variant TPMT *3C is of low frequency among Asians. Moreover, AZA-induced toxicity still occurs in some patients with normal TPMT activity. This suggests that additional factors, including other genetic variants, may contribute to such toxicity. Recent studies described a strong association between a variant of the NUDT15, a gene that mediates the hydrolysis of some nucleoside diphosphate derivatives, and thiopurine-related myelosuppression in Asians. We report the first case of a Chinese patient with AZA-induced severe toxicity with no clinically significant TPMT variant but with the NUDT15 c.415C>T allele. CASE SUMMARY: A 40-year-old Chinese patient with PBC-AIH overlap syndrome had been receiving for one month, azathioprine (50 mg/day) and methylprednisolone (24 mg/day) based on his TPMT*3C wild-type genotype. The patient developed serious myelosuppression and hair loss. AZA was stopped, and the patient was given liver-protective drugs and supportive treatment. TPMT and NUDT15 gene sequencing suggests that NUDT15 c.415C>T mutation was the likely cause of the adverse reaction. WHAT IS NEW AND CONCLUSION:NUDT15 c.415C>T may be another predictor of AZA-induced leukocytopenia. If further well-controlled studies validate this association with sufficient predictive power, NUDT15 and TPMT genotyping before starting AZA treatment may become appropriate.
Authors: Mary V Relling; Matthias Schwab; Michelle Whirl-Carrillo; Guilherme Suarez-Kurtz; Ching-Hon Pui; Charles M Stein; Ann M Moyer; William E Evans; Teri E Klein; Federico Guillermo Antillon-Klussmann; Kelly E Caudle; Motohiro Kato; Allen E J Yeoh; Kjeld Schmiegelow; Jun J Yang Journal: Clin Pharmacol Ther Date: 2019-01-20 Impact factor: 6.875