Autopsy and Case Reports
Autopsy and Case Reports
Article / Clinical Case Report

Histological remission of autoimmune hepatitis after the addition of allopurinol and azathioprine dose reduction

Ana Luiza Vilar Guedes; Adriana Ribas Andrade; Vinicius Santos Nunes; Fabiana Roberto Lima; Evandro Sobroza de Mello; Suzane Kioko Ono; Débora Raquel Benedita Terrabuio; Eduardo Luiz Rachid Cançado

Downloads: 0
Views: 1238


The standard therapy for some autoimmune diseases consists of a combination of corticosteroids and thiopurines. In non-responders to thiopurine drugs, the measurement of the metabolites of azathioprine, 6-thioguanine, and 6-methylmercaptopurine, can be a useful tool. The measurement has been used during the treatment of inflammatory bowel diseases and, less commonly, in autoimmune hepatitis. Many patients preferentially metabolize thiopurines to 6-methylmercaptopurine (6-MMP), which is potentially hepatotoxic, instead of 6-thioguanine, the active immunosuppressive metabolite. The addition of allopurinol shifts the metabolism of thiopurine towards 6-thioguanine, improving the immunosuppressive effect. We present the case of a 51-year-old female with autoimmune hepatitis who had a biochemical response after azathioprine and prednisone treatment without histological remission, and who preferentially shunted to 6-MMP. After the addition of allopurinol, the patient’s 6-thioguanine levels increased, and she reached histological remission with a reduction of 67% of the original dose of azathioprine. The patient did not develop clinical manifestations as a consequence of her increased immunosuppressive state. We also review the relevant literature related to this issue. In conclusion, the addition of allopurinol to thiopurine seems to be an option for those patients who do not reach histological remission and who have a skewed thiopurine metabolite profile.


Hepatitis, Autoimmune; Azathioprine; Allopurinol; Azathioprine Metabolism


1. Soloway RD, Summerskill WH, Baggenstoss AH, et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology. 1972;63(5):820-33. PMid:4538724.

2. Czaja AJ, Freese DK. Diagnosis and management of autoimmune hepatitis. Hepatology. 2002;36(2):479-97. PMid:12143059.

3. MacFarlane IG. The relationship between autoimmune markers and different clinical syndromes in autoimmune hepatitis. Gut. 1998;42(5):509-602. PMid:9659147.

4. Yeoman AD, Longhi MS, Heneghan MA. Review article: the modern management of autoimmune hepatitis. Aliment Pharmacol Ther. 2010;31(8):771-87. PMid:20096018.

5. Al-Shamma S, Eross B, Mclaughlin S. Use of xanthine oxidase inhibitor in autoimmune hepatitis. Hepatology. 2013;57(3):1281-2. PMid:23238820.

6. Wolf A, Burnat P, Garcia-Hejl C, Ceppa F. Étude pharmacologique et pharmacogénétique de deux immunodulateurs: l’azathioprine et la 6-mercaptopurine. Stratégies de prévention des complications. Gastroenterol Clin Biol. 2009;33(3):176-84. PMid:19243907.

7. Czaja AJ, Carpenter HA. Thiopurine methyltransferase deficiency and azathioprine intolerance in autoimmune hepatitis. Dig Dis Sci. 2006;51(5):968-75. PMid:16773433.

8. Osterman MT, Kundu R, Lichtenstein GR, Lewis JD. Association of 6-thioguanine nucleotide levels and inflammatory bowel disease activity: a meta-analysis. Gastroenterology. 2006;130(4):1047-53. PMid:16618398.

9. Neto MP, Alves ANL, Fortini AS, et al. Monitoração terapêutica da azatioprina: uma revisão. J Bras Patol Med Lab. 2008;44(3):161-7.

10. Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118(4):705-13. PMid:10734022.

11. Alvarez F, Berg PA, Bianchi FB, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31(5):929-38. PMid:10580593.

12. Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48(1):169-76. PMid:18537184.

13. Gleeson D, Heneghan MA. British Society of Gastroenterology (BSG) guidelines for management of autoimmune hepatitis. Gut. 2011;60(12):1611-29. PMid:21757447.

14. Gayotto LCC, Alves VA, Cerski CT. Visão Histórica e consenso nacional sobre a classificação das hepatites crônicas. GED. 2000;19:137-40.

15. Rumbo C, Emerick KM, Emre S, Shneider BL. Azathioprine metabolite measurements in the treatment of autoimmune hepatitis in pediatric patients: a preliminary report. J Pediatr Gastroenterol Nutr. 2002;35(3):391-8. PMid:12352536.

16. Nguyen TM, Daubard M, Le Gall C, Larger M, Lachaux A, Boulieu R. Monitoring of azathioprine metabolites in pediatric patients with autoimmune hepatitis. Ther Drug Monit. 2010;32(4):433-7. PMid:20479703.

17. Dhaliwal HA, Anderson R, Thornhill EL, et al. Clinical significance of azathioprine metabolites for the maintenance of remission in autoimmune hepatitis. Hepatology. 2012;56(4):1401-8. PMid:22488741.

18. Jonsson CA, Carlsten H. Inosine monophosphate dehydrogenase (IMPDH) inhibition in vitro suppresses lymphocyte proliferation and the production of immunoglobulins, autoantibodies and cytokines in splenocytes from MRLlpr/lpr mice. Clin Exp Immunol. 2001;124(3):486-91. PMid:11472413.

19. Weyer N, Kroplin T, Fricke L, Iven H. Human thiopurine S methyltransferase activity in uremia and after renal transplantation. Eur J Clin Pharmacol. 2001;57(2):129-36. PMid:11417444.

20. Roberts RL, Gearry RB, Barclay ML. Allopurinol-thiopurine combination therapy in inflammatory bowel disease: are there genetic clues to this puzzle? Pharmacogenomics. 2010;11(11):1505-8. PMid:21121769.

21. Duley JA, Chocair PR, Florin TH. Observations on the use of allopurinol in combination with azathioprine or mercaptopurine. Aliment Pharmacol Ther. 2005;22(11-12):1161-2. PMid:16305731.

22. Chocair P, Ianhez L, Arap S, et al. Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen. Lancet. 1993;342(8863):83-4. PMid:8100914.

23. Sparrow MP, Hande SA, Friedman S, et al. Allopurinol safely and effectively optimizes tioguanine metabolites in inflammatory bowel disease patients not responding to azathioprine and mercaptopurine. Aliment Pharmacol Ther. 2005;22(5):441-6. PMid:16128682.

24. Dunkin D, Kerkar N, Arnon R, Suchy F, Miloh T. Allopurinol salvage therapy in pediatric overlap autoimmune hepatitis-primary sclerosing cholangitis with 6-MMP toxicity. J Pediatr Gastroenterol Nutr. 2010;51(4):524-6. PMid:20531025.

25. de Boer YS, Van Gerven NMF, Boer NKH, et al. Allopurinol safely and effectively optimizes thiopurine metabolites in patients with autoimmune hepatitis. Aliment Pharmacol Ther. 2013;37(6):640-6. PMid:23347359.

Publication date:

595507ae0e8825974f24dc1e autopsy Articles
Links & Downloads

Autops Case Rep

Share this page
Page Sections