Indian Journal of Critical Care Medicine

Register      Login



Volume / Issue

Online First

Related articles

VOLUME 25 , ISSUE 2 ( February, 2021 ) > List of Articles


Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report

Prasanta Debnath, Sujit Nair, Shubham Jain, Suhas Udgirkar, Qais Contractor, Pravin Rathi

Citation Information : Debnath P, Nair S, Jain S, Udgirkar S, Contractor Q, Rathi P. Thiopurine-induced Myelosuppression with Severe Sepsis in a Patient with Crohn's Disease: A Case Report. Indian J Crit Care Med 2021; 25 (2):228-230.

DOI: 10.5005/jp-journals-10071-23738

License: CC BY-NC 4.0

Published Online: 01-02-2021

Copyright Statement:  Copyright © 2021; The Author(s).


Thiopurines by their glucocorticoid-sparing property help in maintaining remission for patients with inflammatory bowel disease (IBD), when glucocorticoids are reduced and withdrawn. However, due to bone marrow suppression, it cannot be used in various conditions where it is indicated. A 17-year-old patient presented with pancytopenia with neutropenic sepsis and alopecia after 3 weeks of starting azathioprine for her underlying Crohn's disease. Thiopurine S-methyltransferase (TPMT;*2, *3A, *3C) analysis resulted in a wild-type genotype, whereas homozygous Nudix hydrolase 15 (NUDT 15 C415T) variant was positive. Azathioprine was stopped immediately, and she was started on broad-spectrum antibiotics that led to some clinical improvements initially, but later on, the patient developed intestinal obstruction along with postoperative complications leading to death. In this report, we highlight a case of serious hematological toxicity associated with azathioprine use in a patient with Crohn's disease with homozygous NUDT 15 variant, thus favoring the implementation of a pharmacogenomic approach before starting azathioprine, particularly in the Asian population.

  1. Gearry RB, Barclay RL. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J Gastroenterol Hepatol 2005;20(8):1149–1157. DOI: 10.1111/j.1440-1746.2005.03832.x.
  2. Yarur AJ, Abreu MT, Deshpande AR, Kerman DH, Sussman DA. Therapeutic drug monitoring in patients with inflammatory bowel disease. World J Gastroenterol 2014;20(13):3475–3484. DOI: 10.3748/wjg.v20.i13.3475.
  3. Moriyama T, Nishii R, Perez-Andreu V, Yang W, Klussmann FA, Zhao X, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet 2016;48(4):367–373. DOI: 10.1038/ng.3508.
  4. Bessman MJ, Frick DN, O'Handley SF. The MutT proteins or ‘Nudix’ hydrolases, a family of versatile, widely distributed, ‘housecleaning’ enzymes. J Biol Chem 1996;271(41):25059–25062. DOI: 10.1074/jbc.271.41.25059.
  5. Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993;34(8):1081–1085. DOI: 10.1136/gut.34.8.1081.
  6. Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics 1999;9(1):37–42. DOI: 10.1097/00008571-199902000-00006.
  7. Kumagai K, Hiyama K, Ishioka S, Sato H, Yamanishi Y, McLeod HL, et al. Allelotype frequency of the thiopurine methyltransferase (TPMT) gene in Japanese. Pharmacogenetics 2001;11(3):275–278. DOI: 10.1097/00008571-200104000-00012.
  8. Cao Q, Zhu Q, Shang Y, Gao M, Si J. Thiopurine methyltransferase gene polymorphisms in Chinese patients with inflammatory bowel disease. Digestion 2009;79(1):58–63. DOI: 10.1159/000205268.
  9. Kim JH, Cheon JH, Hong SS, Eun CS, Byeon JS, Hong SY, et al. Influences of thiopurine methyltransferase genotype and activity on thiopurine induced leukopenia in Korean patients with inflammatory bowel disease: a retrospective cohort study. J Clin Gastroenterol 2010;44(1):e242–e248. DOI: 10.1097/MCG.0b013e3181d6baf5.
  10. Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T, et al. Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol 2009;24(7):1258–1264. DOI: 10.1111/j.1440-1746.2009.05917.x.
  11. Davavala SK, Desai DC, Abraham P, Ashavaid T, Joshi A, Gupta T. Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance. Indian J Gastroenterol 2014;33(1):41–45. DOI: 10.1007/s12664-013-0374-6.
  12. Yang SK, Hong M, Baek J, Choi H, Zhao W, Jung Y, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 2014;46(9):1017–1020. DOI: 10.1038/ng.3060.
  13. Shah SA, Paradkar MU, Desai DC, Ashavaid TF. Preemptive NUDT15 genotyping: redefining the management of patients with thiopurine-induced toxicity. Drug Metab Pers Ther 2018;33(1):57–60. DOI: 10.1515/dmpt-2017-0038.
  14. Schaeffeler E, Jaeger SU, Klumpp V, Yang JJ, Igel S, Hinze L, et al. Impact of NUDT15 genetics on severe thiopurine-related hematotoxicity in patients with European ancestry. Genet Med 2019;21(9):2145–2150. DOI: 10.1038/s41436-019-0448-7.
  15. Walker GJ, Harrison JW, Heap GA, Voskuil MD, Andersen V, Anderson CA, et al. Association of genetic variants in NUDT15 with thiopurine-induced myelosuppression in patients with inflammatory bowel disease. JAMA 2019;321(8):773–785. DOI: 10.1001/jama.2019. 0709.
  16. Asada A, Nishida A, Shioya M, Imaeda H, Inatomi O, Bamba S, et al. NUDT15 R139C-related thiopurine leukocytopenia is mediated by 6-thioguanine nucleotide-independent mechanism in Japanese patients with inflammatory bowel disease. J Gastroenterol 2016;51:22–29. DOI: 10.1007/s00535-015-1142-4.
  17. Zhu X, Wang XD, Chao K, Zhi M, Zheng H, Ruan HL, et al. NUDT15 polymorphisms are better than thiopurine S-methyltransferase as predictor of risk for thiopurine-induced leukopenia in Chinese patients with Crohn's disease. Aliment Pharmacol Ther 2016;44(9):967–975. DOI: 10.1111/apt.13796.
  18. Fei X, Shu Q, Hua BZ, Wang SY, Chen ZY, Ge WH, et al. NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects: Case report and literature review. Medicine (Baltimore) 2018;97(17):e0301. DOI: 10.1097/MD.0000000000010301.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.