Thiopurine Therapy in Patients With Inflammatory Bowel Disease: A Focus on Metabolism and Pharmacogenetics

  • Ji Young Chang
  • Jae Hee CheonEmail author
Mentored Reviews


Thiopurines have been widely used for the maintenance of remission or steroid sparing in patients with inflammatory bowel disease. However, potential drug-related adverse events frequently interfere with their use. Indeed, drug withdrawals associated with adverse reactions have been reported in approximately 25% of patients. To balance the efficacy, safety, and tolerability of thiopurines, regular monitoring of biomarkers (complete blood cell count, liver function test, and metabolic profiles), steady dose escalation, and pretreatment thiopurine S-methyltransferase (TPMT) genotype screening have been routinely recommended. However, the complex thiopurine metabolic pathway and individual differences attributed to pharmacogenetic diversity limit the effectiveness of these strategies in the optimization of thiopurine therapy. Recently, in an effort to facilitate more accurate and personalized prediction of thiopurine response or toxicity, novel genetic markers including NUDT15 and FTO genes were discovered. These discoveries are remarkable because TPMT screening has minimal efficacy for predicting myelosuppression especially in Asian populations, despite the fact that thee populations have a higher frequency of myelosuppression than Western populations. This review focuses on the current understanding of the metabolic pathway and the pharmacogenetics of thiopurines and suggests a personalized preventive strategy against potential adverse drug reactions to optimize their therapeutic application.


Inflammatory bowel disease Thionucleosides Drug-related side effects and adverse reactions Leucopenia Metabolism Pharmacogenetics 


Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Elion G. The purine path to chemotherapy. Science. 1989;244:41–47.Google Scholar
  2. 2.
    Goel RM, Blaker P, Mentzer A, Fong SCM, Marinaki AM, Sanderson JD. Optimizing the use of thiopurines in inflammatory bowel disease. Ther Adv Chronic Dis. 2015;6:138–146.Google Scholar
  3. 3.
    Timmer A, Patton PH, Chande N, McDonald JW, MacDonald JK. Azathioprine and 6-mercaptopurine for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2016. Scholar
  4. 4.
    Chande N, Patton PH, Tsoulis DJ, Thomas BS, MacDonald JK. Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2016. Scholar
  5. 5.
    Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American Gastroenterological Association Institute Technical Review on Corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterol. 2006;130:940–987.Google Scholar
  6. 6.
    Lee KM, Kim YS, Seo GS, Kim TO, Yang S-K. IBD study group of the Korean Association for the Study of Intestinsl Diseases use of thiopurines in inflammatory bowel disease: a consensus statement by the Korean Association for the Study of Intestinal Diseases (KASID). Intest Res. 2015;13:193–207.Google Scholar
  7. 7.
    Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for crohn’s disease. N Engl J Med. 2010;362:1383–1395.Google Scholar
  8. 8.
    Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis. Gastroenterol. 2014;146:392–400.Google Scholar
  9. 9.
    Chaparro M, Ordas I, Cabre E, et al. Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. Inflamm Bowel Dis. 2013;19:1404–1410.Google Scholar
  10. 10.
    Lim SZ, Chua EW. Revisiting the role of thiopurines in inflammatory bowel disease through pharmacogenomics and use of novel methods for therapeutic drug monitoring. Front Pharmacol. 2018;9:1107.Google Scholar
  11. 11.
    González-Lama Y, Gisbert JP. Monitoring thiopurine metabolites in inflammatory bowel disease. Frontline Ggastroenterol. 2016;7:301–307.Google Scholar
  12. 12.
    Watanabe A, Hobara N, Nagashima H. Demonstration of enzymatic activity converting azathioprine to 6-mercaptopurine. Acta Medica Okayama. 1978;32:173–179.Google Scholar
  13. 13.
    Derijks LJ, Gilissen LP, Engels LG, et al. Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease. Ther Drug Monit. 2006;28:45–50.Google Scholar
  14. 14.
    Amin J, Huang B, Yoon J, Shih DQ. Update 2014: advances to optimize 6-mercaptopurine and azathioprine to reduce toxicity and improve efficacy in the management of IBD. Inflamm Bowel Dis. 2015;21:445–452.Google Scholar
  15. 15.
    Dubinsky MC. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol. 2004;2:731–743.Google Scholar
  16. 16.
    Haglund S, Vikingsson S, Soderman J, et al. The role of inosine-5′-monophosphate dehydrogenase in thiopurine metabolism in patients with inflammatory bowel disease. Ther Drug Monit. 2011;33:200–208.Google Scholar
  17. 17.
    Aarbakke J, Janka-Schaub G, Elion GB. Thiopurine biology and pharmacology. Trends Pharmacol Sci. 1997;18:3–7.Google Scholar
  18. 18.
    Thomas CW, Myhre GM, Tschumper R, et al. Selective inhibition of inflammatory gene expression in activated T lymphocytes: a mechanism of immune suppression by thiopurines. J Pharmacol Exp Ther. 2005;312:537–545.Google Scholar
  19. 19.
    Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4 + T lymphocytes. J Clin Invest. 2003;111:1133–1145.Google Scholar
  20. 20.
    Wildenberg ME, Koelink PJ, Diederen K, et al. The ATG16L1 risk allele associated with Crohn’s disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines. Mucosal Immunol. 2016;10:352.Google Scholar
  21. 21.
    Warner B, Johnston E, Arenas-Hernandez M, Marinaki A, Irving P, Sanderson J. A practical guide to thiopurine prescribing and monitoring in IBD. Frontline Gastroenterol. 2018;9:10–15.Google Scholar
  22. 22.
    Axelrad JE, Roy A, Lawlor G, Korelitz B, Lichtiger S. Thiopurines and inflammatory bowel disease: current evidence and a historical perspective. World J Gastroenterol. 2016;22:10103–10117.Google Scholar
  23. 23.
    Panes J, Lopez-Sanroman A, Bermejo F, et al. Early azathioprine therapy is no more effective than placebo for newly diagnosed Crohn’s disease. Gastroenterol. 2013;145(766–774):e1.Google Scholar
  24. 24.
    Park JJ, Yang S-K, Ye BD, et al. Second Korean guidelines for the management of Crohn’s disease. Intest Res. 2017;15:38–67.Google Scholar
  25. 25.
    Onali S, Calabrese E, Petruzziello C, et al. Post-operative recurrence of Crohn’s disease: a prospective study at 5 years. Dig Liver Dis. 2016;48:489–494.Google Scholar
  26. 26.
    Doherty G, Bennett G, Patil S, Cheifetz A, Moss AC. Interventions for prevention of post-operative recurrence of Crohn’s disease. Cochrane Database Syst. 2009. Scholar
  27. 27.
    Papay P, Reinisch W, Ho E, et al. The impact of thiopurines on the risk of surgical recurrence in patients with Crohn’s disease after first intestinal surgery. Am J Gastroenterol. 2010;105:1158–1164.Google Scholar
  28. 28.
    Pearson DC, May GR, Fick GH, Sutherland LR. Azathioprine and 6-mercaptopurine in Crohn disease. A meta-analysis. Ann Intern Med. 1995;123:132–142.Google Scholar
  29. 29.
    Vande Casteele N, Gils A, Singh S, et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am J Gastroenterol. 2013;108:962–971.Google Scholar
  30. 30.
    Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease. Gut. 2015;64:1539–1545.Google Scholar
  31. 31.
    Yarur AJ, Kubiliun MJ, Czul F, et al. Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy. Clin Gastroenterol Hepatol. 2015;13:1118–1124.Google Scholar
  32. 32.
    Broekman M, Coenen MJH, van Marrewijk CJ, et al. More dose-dependent side effects with mercaptopurine over azathioprine in IBD treatment due to relatively higher dosing. Inflamm Bowel Dis. 2017;23:1873–1881.Google Scholar
  33. 33.
    Konidari A, Matary WE. Use of thiopurines in inflammatory bowel disease: safety issues. World J Gastrointest Pharmacol Ther. 2014;5:63–76.Google Scholar
  34. 34.
    Benmassaoud A, Xie X, AlYafi M, et al. Thiopurines in the management of Crohn’s disease: safety and efficacy profile in patients with normal TPMT activity-A retrospective study. Can J Gastroenterol Hepatol. 2016;2016:1034834.Google Scholar
  35. 35.
    Frei P, Biedermann L, Nielsen OH, Rogler G. Use of thiopurines in inflammatory bowel disease. World J Gastroenterol. 2013;19:1040–1048.Google Scholar
  36. 36.
    Bodelier A, Masclee AAM, Bakker J, Hameeteman WH, Pierik M. Azathioprine induced pneumonitis in a patient with ulcerative colitis. J Crohns Colitis. 2009;3:309–312.Google Scholar
  37. 37.
    Teich N, Mohl W, Bokemeyer B, et al. Azathioprine-induced acute pancreatitis in patients with inflammatory bowel diseases–a prospective study on incidence and severity. J Crohns Colitis. 2016;10:61–68.Google Scholar
  38. 38.
    Gisbert JP, Gonzalez-Lama Y, Mate J. Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol. 2007;102:1518–1527.Google Scholar
  39. 39.
    Gisbert JP, Gomollon F. Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review. Am J Gastroenterol. 2008;103:1783–1800.Google Scholar
  40. 40.
    Kim HS, Cheon JH, Jung ES, et al. A coding variant in FTO confers susceptibility to thiopurine-induced leukopenia in East Asian patients with IBD. Gut. 2017;66:1926–1935.Google Scholar
  41. 41.
    Lee HJ, Yang S-K, et al. The safety and efficacy of azathioprine and 6-mercaptopurine in the treatment of Korean patients with Crohn’s disease. Intest Res. 2009;7:22–31.Google Scholar
  42. 42.
    Kim JH, Cheon JH, Hong SS, 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:e242–e248.Google Scholar
  43. 43.
    Qiu Y, Mao R, Zhang SH, et al. Safety profile of thiopurines in crohn disease: analysis of 893 patient-years follow-up in a Southern China Cohort. Medicine. 2015;94:e1513.Google Scholar
  44. 44.
    Odahara S, Uchiyama K, Kubota T, et al. A prospective study evaluating metabolic capacity of thiopurine and associated adverse reactions in Japanese patients with inflammatory bowel disease (IBD). PLoS ONE. 2015;10:e0137798.Google Scholar
  45. 45.
    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;34:1081–1085.Google Scholar
  46. 46.
    Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med. 1989;111:641–649.Google Scholar
  47. 47.
    Fraser AG, Orchard TR, Jewell DP. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut. 2002;50:485–489.Google Scholar
  48. 48.
    Lopez A, Mounier M, Bouvier AM, et al. Increased risk of acute myeloid leukemias and myelodysplastic syndromes in patients who received thiopurine treatment for inflammatory bowel disease. Clin Gastroenterol Hepatol. 2014;12:1324–1329.Google Scholar
  49. 49.
    Ochenrider MG, Patterson DJ, Aboulafia DM. Hepatosplenic T-cell lymphoma in a young man with Crohn’s disease: case report and literature review. Clin Lymphoma Myeloma Leuk. 2010;10:144–148.Google Scholar
  50. 50.
    Hagen JW, Pugliano-Mauro MA. Nonmelanoma skin cancer risk in patients with inflammatory bowel disease undergoing thiopurine therapy: a systematic review of the literature. Dermatol Surg. 2018;44:469–480.Google Scholar
  51. 51.
    Zhu Z, Mei Z, Guo Y, et al. Reduced risk of inflammatory bowel disease-associated colorectal neoplasia with use of thiopurines: a systematic review and meta-analysis. J Crohns Colitis. 2018;12:546–558.Google Scholar
  52. 52.
    Rahier JF, Magro F, Abreu C, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8:443–468.Google Scholar
  53. 53.
    Beaugerie L, Brousse N, Bouvier AM, et al. Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study. Lancet. 2009;374:1617–1625.Google Scholar
  54. 54.
    Vos AC, Bakkal N, Minnee RC, et al. Risk of malignant lymphoma in patients with inflammatory bowel diseases: a Dutch nationwide study. Inflamm Bowel Dis. 2011;17:1837–1845.Google Scholar
  55. 55.
    Magro F, Peyrin-Biroulet L, Sokol H, et al. Extra-intestinal malignancies in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (III). J Crohns Colitis. 2014;8:31–44.Google Scholar
  56. 56.
    Andrisani G, Armuzzi A, Marzo M, et al. What is the best way to manage screening for infections and vaccination of inflammatory bowel disease patients? World J Gastrointest Pharmacol Ther. 2016;7:387–396.Google Scholar
  57. 57.
    Beaugerie L. Lymphoma: the bete noire of the long-term use of thiopurines in adult and elderly patients with inflammatory bowel disease. Gastroenterol. 2013;145:927–930.Google Scholar
  58. 58.
    Sokol H, Beaugerie L. Inflammatory bowel disease and lymphoproliferative disorders: the dust is starting to settle. Gut. 2009;58:1427–1436.Google Scholar
  59. 59.
    Setshedi M, Epstein D, Winter TA, Myer L, Watermeyer G, Hift R. Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study. J Gastroenterol Hepatol. 2012;27:385–389.Google Scholar
  60. 60.
    Cuffari C, Hunt S, Bayless TM. Enhanced bioavailability of azathioprine compared to 6-mercaptopurine therapy in inflammatory bowel disease: correlation with treatment efficacy. Aliment Pharmacol Ther. 2000;14:1009–1014.Google Scholar
  61. 61.
    Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterol. 2000;118:705–713.Google Scholar
  62. 62.
    Smith M, Blaker P, Patel C, et al. The impact of introducing thioguanine nucleotide monitoring into an inflammatory bowel disease clinic. Int J Clin Pract. 2013;67:161–169.Google Scholar
  63. 63.
    Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterol. 2006;130:1047–1053.Google Scholar
  64. 64.
    Gisbert JP, Gonzalez-Lama Y, Mate J. Monitoring of thiopurine methyltransferase and thiopurine metabolites to optimize azathioprine therapy in inflammatory bowel disease. Gastroenterologia y hepatologia. 2006;29:568–583.Google Scholar
  65. 65.
    Sanderson JD, Smith MA, Blaker P, Irving PM, Anderson SH, Marinaki AM. Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. J Crohns Colitis. 2012;6:905–912.Google Scholar
  66. 66.
    Kreijne JE, Seinen ML, Wilhelm AJ, et al. Routinely established skewed thiopurine metabolism leads to a strikingly high rate of early therapeutic failure in patients with inflammatory bowel disease. Ther Drug Monit. 2015;37:797–804.Google Scholar
  67. 67.
    Deshpande AR, Abreu MT. Optimizing therapy with 6-mercaptopurine and azathioprine: to measure or not to measure? Ther Adv Gastroenterol. 2010;3:275–279.Google Scholar
  68. 68.
    Moon W, Loftus EV Jr. Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease. Aliment Pharmacol Ther. 2016;43:863–883.Google Scholar
  69. 69.
    Dassopoulos T, Dubinsky MC, Bentsen JL, et al. Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn’s disease. Aliment Pharmacol Ther. 2014;39:163–175.Google Scholar
  70. 70.
    Teml A, Schaeffeler E, Herrlinger KR, Klotz U, Schwab M. Thiopurine treatment in inflammatory bowel disease: clinical pharmacology and implication of pharmacogenetically guided dosing. Clin Pharmacokinet. 2007;46:187–208.Google Scholar
  71. 71.
    Ansari A, Arenas M, Greenfield SM, et al. Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease. Aliment Pharmacol Ther. 2008;28:973–983.Google Scholar
  72. 72.
    Roblin X, Oussalah A, Chevaux JB, Sparrow M, Peyrin-Biroulet L. Use of thiopurine testing in the management of inflammatory bowel diseases in clinical practice: a worldwide survey of experts. Inflamm Bowel Dis. 2011;17:2480–2487.Google Scholar
  73. 73.
    Shih DQ, Nguyen M, Zheng L, et al. Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism. Aliment Pharmacol Ther. 2012;36:449–458.Google Scholar
  74. 74.
    Lees CW, Maan AK, Hansoti B, Satsangi J, Arnott IDR. Tolerability and safety of mercaptopurine in azathioprine-intolerant patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2008;27:220–227.Google Scholar
  75. 75.
    Kennedy NA, Rhatigan E, Arnott IDR, et al. A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis. Aliment Pharmacol Ther. 2013;38:1255–1266.Google Scholar
  76. 76.
    Appell ML, Wagner A, Hindorf U. A skewed thiopurine metabolism is a common clinical phenomenon that can be successfully managed with a combination of low-dose azathioprine and allopurinol. J Crohns Colitis. 2013;7:510–513.Google Scholar
  77. 77.
    Blaker PA, Arenas-Hernandez M, Smith MA, et al. Mechanism of allopurinol induced TPMT inhibition. Biochem Pharmacol. 2013;86:539–547.Google Scholar
  78. 78.
    Seinen ML, van Asseldonk DP, de Boer NK, et al. The effect of allopurinol and low-dose thiopurine combination therapy on the activity of three pivotal thiopurine metabolizing enzymes: results from a prospective pharmacological study. J Crohns Colitis. 2013;7:812–819.Google Scholar
  79. 79.
    Hoentjen F, Seinen ML, Hanauer SB, et al. Safety and effectiveness of long-term allopurinol-thiopurine maintenance treatment in inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:363–369.Google Scholar
  80. 80.
    Lang PG Jr. Severe hypersensitivity reactions to allopurinol. South Med J. 1979;72:1361–1368.Google Scholar
  81. 81.
    Ansari A, Hassan C, Duley J, et al. Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. Aliment Pharmacol Ther. 2002;16:1743–1750.Google Scholar
  82. 82.
    Dong X-W, Zheng Q, Zhu M-M, Tong J-L, Ran Z-H. Thiopurine S-methyltransferase polymorphisms and thiopurine toxicity in treatment of inflammatory bowel disease. World J Gastroenterol. 2010;16:3187–3195.Google Scholar
  83. 83.
    Collie-Duguid ES, Pritchard SC, Powrie RH, et al. The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. Pharmacogenetics. 1999;9:37–42.Google Scholar
  84. 84.
    Katsanos KK, Tsianos EV. Azathioprine/6-mercaptopurine toxicity: the role of the TPMT gene. Ann Gastroenterol. 2007;20:251–264.Google Scholar
  85. 85.
    Yang SK, Hong M, Baek J, et al. A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014;46:1017–1020.Google Scholar
  86. 86.
    Kham SKY, Soh CK, Liu TC, et al. Thiopurine S-methyltransferase activity in three major Asian populations: a population-based study in Singapore. Eur J Clin Pharmacol. 2008;64:373–379.Google Scholar
  87. 87.
    Dewit O, Moreels T, Baert F, et al. Limitations of extensive TPMT genotyping in the management of azathioprine-induced myelosuppression in IBD patients. Clin Biochem. 2011;44:1062–1066.Google Scholar
  88. 88.
    Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48:367–373.Google Scholar
  89. 89.
    Chao K, Wang X, Cao Q, et al. Combined detection of NUDT15 variants could highly predict thiopurine-induced leukopenia in Chinese patients with inflammatory bowel disease: a multicenter analysis. Inflamm Bowel Dis. 2017;23:1592–1599.Google Scholar
  90. 90.
    Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol. 2015;33:1235–1242.Google Scholar
  91. 91.
    Kakuta Y, Naito T, Onodera M, et al. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J. 2016;16:280–285.Google Scholar
  92. 92.
    Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008;8:24–36.Google Scholar
  93. 93.
    Fedeles BI, Singh V, Delaney JC, Li D, Essigmann JM. The AlkB family of Fe(II)/α-Ketoglutarate-dependent dioxygenases: repairing nucleic acid alkylation damage and beyond. J Biol Chem. 2015;290:20734–20742.Google Scholar
  94. 94.
    Costantino G, Furfaro F, Belvedere A, Alibrandi A, Fries W. Thiopurine treatment in inflammatory bowel disease: response predictors, safety, and withdrawal in follow-up. J Crohns Colitis. 2012;6:588–596.Google Scholar
  95. 95.
    Moran GW, Dubeau MF, Kaplan GG, et al. Clinical predictors of thiopurine-related adverse events in Crohn’s disease. World J Gastroenterol. 2015;21:7795–7804.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Internal Medicine, Institute of GastroenterologyYonsei University College of MedicineSeoulRepublic of Korea
  2. 2.Department of Health Promotion CenterEwha Womans University School of MedicineSeoulKorea

Personalised recommendations