PRE-SCREENING TPMT STATUS OF LIVER TRANSPLANT PATIENTS FOR AZATHIOPRINE THERAPY–A SINGLE CENTRE EXPERIENCE FROM SOUTH INDIA
DOI:
https://doi.org/10.22159/ijpps.2017v9i2.15630Keywords:
Azathioprine, Immunosuppressive regimens, Liver transplantation, Myelosuppression, Thiopurine methyltransferase, TPMT genotype testingAbstract
Objective: To assess azathioprine-induced bone marrow toxicity and its correlation with thiopurine methyltransferase (TPMT) mutation in liver transplant patients who develop myelosuppression while on azathioprine therapy.
Methods: A prospective observational study was conducted from 1st September 2014 to 30thJune 2015 on 60 liver transplant patients who were tested for TPMT allele activity prior to receiving azathioprine. Haemoglobin levels, platelet counts and white blood cell counts of the patients were monitored for the occurrence of myelotoxicity. Patients who underwent liver transplant during the retrospective period from 1st September 2011 to 31st August 2014 and who developed myelosuppression while on azathioprine therapy were also tested for TPMT genotype.
Results: A total of 76 liver transplant patients were tested for TPMT mutation. Prevalence of TPMT mutation in the study patients was 3.95%. The heterozygous TPMT*1/*3C genotype was traced in 2.63% of the patients while 1.32% of patients were homozygous for TPMT*3C allele. Interestingly 43.4% of patients with wild allele also showed azathioprine-induced myelosuppression. Azathioprine dose of 100 mg showed a higher degree of myelotoxicity than lower doses. Haematological indices of 42.1% of patients normalised on cessation of azathioprine therapy.
Conclusion: Myelosuppression following the introduction of azathioprine was observed in patients with both ‘mutant' and ‘wild-type' alleles. Therefore a cautious approach has to be taken in pre-screening liver transplant recipients for TPMT allele determination in our population. The absence of TPMT mutation does not ensure freedom from myelosuppression. Hence regular monitoring of haematological indices of such patients receiving thiopurine therapy should be continued.
Downloads
References
Germani G, Plaguezuelo M, Villamil F, Vaghjiani S, Tsochatzis E, Andreana L, et al. Azathioprine in liver transplantation: a reevaluation of its use and a comparison with mycophenolate mofetil. Am J Transplant 2009;9:1725-31.
Tai HL, Krynetski EY, Yates CR, Loennechen T, Fessing MY, Krynetskaia NF, et al. Thiopurine S-methyltransferase deficiency: two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in caucasians. Am J Hum Genet 1996;58:694–702.
Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW, et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89:387–91.
6-mercaptopurine (6-MP) metabolite monitoring and TPMT testing in the treatment of inflammatory bowel disease with 6-MP or azathioprine. Available from: http://www.uptodate.com/ contents/6-mercaptopurine-6-mp-metabolite-monitoring-and-tpmt-testing. [Last accessed on 01 Jul 2015]
Katsanos K, EV Tsianos. Non-TPMT determinants of azathioprine toxicity in inflammatory bowel disease. Ann Gastroenterol 2010;23:95-101.
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;46:1017-20.
Kapoor G, Sinha R, Naithani R, Chandgothia M. Thiopurine S-methyltransferase gene polymorphism and 6-mercaptopurine dose intensity in Indian children with acute lymphoblastic leukaemia. Leuk Res 2010;34:1023-6.
Murugesan R, Vahab SA, Patra S, Rao R, Rao J, Rai P, et al. Thiopurine S-methyltransferase alleles, TPMT *2, *3B and *3C, and genotype frequencies in an Indian population. Exp Ther Med 2010;1:121-7.
Desire S, Balasubramanian P, Bajel A, George B, Viswabandya A, Mathews V, et al. Frequency of TPMT alleles in Indian patients with acute lymphatic leukaemia and effect on the dose of 6-mercaptopurine. Med Oncol 2010;27:1046-9.
Umamaheswaran G, Krishnakumar D, Kayathiri D, Rajan S, Shewade DG, Dkhar SA, et al. Inter and intra-ethnic differences in the distribution of the molecular variants of TPMT, UGT1A1 and MDR1 genes in the South Indian population. Mol Biol Rep 2012;39:6343-51.
Dorababu P, Naushad SM, Linga VG, Gundeti S, Nagesh N, Kutala VK, et al. Genetic variants of thiopurine and folate metabolic pathways determine 6-MP mediated haematological toxicity in childhood ALL. Pharmacogenomics 2012;13:1001-8.
Iyer SN, Tilak AV, Mukherjee MS, Singhal RS. Genotype frequencies of drug-metabolizing enzymes responsible for purine and pyrimidine antagonists in a healthy Asian-Indian population. Biochem Genet 2012;50:684-93.
Digumarti R, Gundeti S, Kalpathi KI, Linga VG, Patchva DB, Pillai A. Thiopurine methyltransferase polymorphisms in children with acute lymphoblastic leukemia. Indian J Med Paediatr Oncol 2014;35:276-80.
Davavala SK, Desai DC, Abraham P, Ashavaid T, Joshi A, Tarun Gupta, et al. Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance. Indian J Gastroenterol 2014;33:41-5.
Anstey A, Lennard L, Mayou SC, Kirby JD. Pancytopenia related to azathioprine-an enzyme deficiency caused by a common genetic polymorphism: a review. J R Soc Med 1992;85:752-6.
Appell ML, Berg J, Duley J, Evans WE, Kennedy MA, Lennard L, et al. Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics 2013;23: 242–8.
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;9:37-42.
Derijks LJ, Wong DR. Pharmacogenetics of thiopurines in inflammatory bowel disease. Curr Pharm Des 2010;16:145-54.
Gisbert JP, Gomollón F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol 2008;103:1783-800.
Wiesner R, Rabkin J, Klintmalm G, McDiarmid S, Langnas A, Punch J, et al. A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients. Liver Transpl 2001;7:442-50.
Breen PD, Marinaky AM, Areenas M, Hayes PC. Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation. Liver Transpl 2005;11:826-33.
Liu YP, Xu HQ, Li M, Yang X, Yu S, Fu WL, et al. Association between thiopurine S-methyltransferase polymorphisms and azathioprine-induced adverse drug reactions in patients with autoimmune diseases: a meta-analysis. PLoS One 2015;10:e0144234. Doi:10.1371/journal.pone.0144234
Stolk JN, Boerbooms AM, de Abreu RA, de Koning DG, van Beusekom HJ. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum 1998;41:1858-66.
Gazouli M, Pachoula L, Panayotou L, Chouliaras G, Anagnou NP, Chroussos G. Thiopurine methyltransferase genotype and thiopurine S-methyltransferase activity in Greek children with inflammatory bowel disease. Ann Gastroenterol 2012;25:249-53.
Lee YJ, Hwang EH, Park JH, Shin JH, Kang B, Kim SY. NUDT15 variant is the most common variant associated with thiopurine-induced early leukopenia and alopecia in Korean paediatric patients with Crohn's disease. Eur J Gastroenterol Hepatol 2016;28:475-8.
Liang DC, Yang CP, Liu HC, Jaing TH, Chen SH, Hung IJ, et al. NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukaemia. Pharmacogenomics J 2015;15:441-51.
Yang S, Hong M, Baek J, Choi H, Zhao W. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nature Genetics 2014;46:1017–20.
Yang JJ, Landier W, Yang W, Liu C, Hageman L, Cheng C, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukaemia. J Clin Oncol 2015;33:1235–42.
Published
How to Cite
Issue
Section
