A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease

Eine systematische Studie zur Untersuchung der 6-Thioguanin-assoziierten Hepatotoxizität bei Patienten mit chronisch-entzündlichen Darmerkrankungen

Zusammenfassung

HINTERGRUND: Vor kurzem wurde von Leberveränderungen im Sinne einer nodulär regenerativen Hyperplasie (NRH) als Ausdruck einer 6-Thioguanin (6-TG) assoziierten Hepatotoxizität bei Patienten mit chronisch-entzündlichen Darmerkrankungen (CED) berichtet. Das Ziel dieser multi-zentrischen Internet-Studie war es, die Prävalenz der Hepatotoxizität von 6-TG in einer großen CED-Population zu untersuchen. METHODIK: Klinische Daten, Laborwerte, bildgebende Untersuchungen (Sonographie, CT, MRI) und histologische Ergebnisse von Leberbiopsien wurden bei Patienten mit CED unter Therapie mit 6-TG untersucht. Die Entscheidung zur Durchführung von bildgebenden Untersuchungen und Leberbiopsien lag ausschließlich bei den einzelnen Zentren. ERGEBNISSE: Bei 296 Patienten wurde die Anwendung von 6-TG über einen Zeitraum von 56 Wochen (Median, Spannweite < 1–207) dokumentiert. Laborveränderungen als Zeichen einer Hepatotoxizität wurden bei 43 Patienten (14,5%) beobachtet. Mittels bildgebender Verfahren wurden bei 68/176 Patienten (38,6%) pathologische Ergebnisse gefunden. An 60 Patienten erfolgte eine Leberbiopsie. Mit Durchführung einer Silber-Retikulin Färbung (n = 59) konnte bei 16 Patienten (27,1%) eine NRH gezeigt werden. Höheres Alter war der einzige unabhängige, aber schwache Risikofaktor dafür. SCHLUSSFOLGERUNG: Diese derzeit größte Studie bestätigt den starken Zusammenhang zwischen der Anwendung von 6-TG bei Patienten mit CED und dem signifikanten Risiko für die Entwicklung einer NRH. Die definitive Diagnose der NRH kann nur durch eine Leberbiopsie gestellt werden.

Summary

OBJECTIVE: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. METHODS: Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. RESULTS: 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1–207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. CONCLUSION: This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.

This is a preview of subscription content, log in to check access.

References

  1. Harms DO, Janka-Schaub GE (2000) Co-operative study group for childhood acute lymphoblastic leukemia (COALL): long-term follow-up of trials 82, 85, 89 and 92. Leukemia 14: 2234–2239

    PubMed  Article  CAS  Google Scholar 

  2. Ravindranath Y, Chang M, Steuber CP, Becton D, Dahl G, Civin C, et al (2005) Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000. Leukemia 19: 2101–2116

    PubMed  Article  CAS  Google Scholar 

  3. Mason C, Krueger GG (2001) Thioguanine for refractory psoriasis: a 4-year experience. J Am Acad Dermatol 44: 67–72

    PubMed  Article  CAS  Google Scholar 

  4. Dubinsky MC, Hassard PV, Seidman EG, Kam LY, Abreu MT, Targan SR, et al (2001) An open-label pilot study using thioguanine as a therapeutic alternative in Crohn's disease patients resistant to 6-mercaptopurine therapy. Inflamm Bowel Dis 7: 181–189

    PubMed  Article  CAS  Google Scholar 

  5. Herrlinger KR, Kreisel W, Schwab M, Schoelmerich J, Fleig WE, Ruhl A, et al (2003) 6-thioguanine – efficacy and safety in chronic active Crohn's disease. Aliment Pharmacol Ther 17: 503–508

    PubMed  Article  CAS  Google Scholar 

  6. Herrlinger KR, Deibert P, Schwab M, Kreisel W, Fischer C, Fellermann K, et al (2003) Remission maintenance by tioguanine in chronic active Crohn's disease. Aliment Pharmacol Ther 17: 1459–1464

    PubMed  Article  CAS  Google Scholar 

  7. Deibert P, Dilger K, Fischer C, Hofmann U, Nauck S, Stoelben S, et al (2003) High variation of tioguanine absorption in patients with chronic active Crohn's disease. Aliment Pharmacol Ther 18: 183–189

    PubMed  Article  CAS  Google Scholar 

  8. Bonaz B, Boitard J, Marteau P, Lemann M, Coffin B, Flourie B, et al (2003) Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine. Aliment Pharmacol Ther 18: 401–408

    PubMed  Article  CAS  Google Scholar 

  9. Derijks LJ, de Jong DJ, Gilissen LP, Engels LG, Hooymans PM, Jansen JB, et al (2003) 6-Thioguanine seems promising in azathioprine- or 6-mercaptopurine-intolerant inflammatory bowel disease patients: a short-term safety assessment. Eur J Gastroenterol Hepatol 15: 63–67

    PubMed  Article  CAS  Google Scholar 

  10. Dubinsky MC, Feldman EJ, Abreu MT, Targan SR, Vasiliauskas EA (2003) Thioguanine: a potential alternate thiopurine for IBD patients allergic to 6-mercaptopurine or azathioprine. Am J Gastroenterol 98: 1058–1063

    PubMed  Article  CAS  Google Scholar 

  11. Cheung TK, Florin TH (2003) 6-thioguanine: a new old drug to procure remission in inflammatory bowel disease. Intern Med J 33: 44–46

    Article  Google Scholar 

  12. Teml A, Schwab M, Harrer M, Miehsler W, Schaeffeler E, Dejaco C, et al (2005) A prospective, open-label trial of 6-thioguanine in patients with ulcerative or indeterminate colitis. Scand J Gastroenterol 40: 1205–1213

    PubMed  Article  CAS  Google Scholar 

  13. de Boer NK, Derijks LJ, Gilissen LP, Hommes DW, Engels LG, de-Boer SY, et al (2005) On tolerability and safety of a maintenance treatment with 6-thioguanine in azathioprine or 6-mercaptopurine intolerant IBD patients. World J Gastroenterol 11: 5540–5544

    PubMed  CAS  Google Scholar 

  14. Griner PF, Elbadawi A, Packman CH (1976) Veno-occlusive disease of the liver after chemotherapy of acute leukemia. Report of two cases. Ann Intern Med 85: 578–582

    PubMed  CAS  Google Scholar 

  15. Gill RA, Onstad GR, Cardamone JM, Maneval DC, Sumner HW (1982) Hepatic veno-occlusive disease caused by 6-thioguanine. Ann Intern Med 96: 58–60

    PubMed  CAS  Google Scholar 

  16. Krivoy N, Raz R, Carter A, Alroy G (1982) Reversible hepatic veno-occlusive disease and 6-thioguanine. Ann Intern Med 96: 788

    PubMed  CAS  Google Scholar 

  17. Stoneham S, Lennard L, Coen P, Lilleyman J, Saha V (2003) Veno-occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukaemia. Br J Haematol 123: 100–102

    PubMed  Article  Google Scholar 

  18. Key NS, Kelly PM, Emerson PM, Chapman RW, Allan NC, McGee JO (1987) Oesophageal varices associated with busulphan-thioguanine combination therapy for chronic myeloid leukaemia. Lancet 2: 1050–1052

    PubMed  Article  CAS  Google Scholar 

  19. Dubinsky MC, Vasiliauskas EA, Singh H, Abreu MT, Papadakis KA, Tran T, et al (2003) 6-thioguanine can cause serious liver injury in inflammatory bowel disease patients. Gastroenterology 125: 298–303

    PubMed  Article  CAS  Google Scholar 

  20. Seiderer J, Zech CJ, Reinisch W, Lukas M, Diebold J, Wrba F, et al (2005) A multicenter assessment of liver toxicity by MRI and biopsy in IBD patients on 6-thioguanine. J Hepatol 43: 303–309

    PubMed  Article  CAS  Google Scholar 

  21. Geller SA, Dubinsky MC, Poordad FF, Vasiliauskas EA, Cohen AH, Abreu MT, et al (2004) Early hepatic nodular hyperplasia and submicroscopic fibrosis associated with 6-thioguanine therapy in inflammatory bowel disease. Am J Surg Pathol 28: 1204–1211

    PubMed  Article  Google Scholar 

  22. Gilissen LP, Derijks LJ, Driessen A, Bos LP, Hooymans PM, Stockbrugger RW, et al (2007) Toxicity of 6-thioguanine: no hepatotoxicity in a series of IBD patients treated with long-term, low dose 6-thioguanine. Some evidence for dose or metabolite level dependent effects? Dig Liver Dis 39: 156–159

    PubMed  Article  CAS  Google Scholar 

  23. Piel B, Vaidya S, Lancaster D, Taj M, Pritchard-Jones K (2004) Chronic hepatotoxicity following 6-thioguanine therapy for childhood acute lymphoblastic leukaemia. Br J Haematol 125: 410–411

    PubMed  Article  Google Scholar 

  24. De Bruyne R, Portmann B, Samyn M, Bansal S, Knisely A, Mieli-Vergani G, et al (2006) Chronic liver disease related to 6-thioguanine in children with acute lymphoblastic leukaemia. J Hepatol 44: 407–410

    PubMed  Article  CAS  Google Scholar 

  25. de Boer NK, Reinisch W, Teml A, van Bodegraven AA, Schwab M, Lukas M, et al (2006) 6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party. Digestion 73: 25–31

    PubMed  Article  CAS  Google Scholar 

  26. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47: 207–214

    PubMed  Article  CAS  Google Scholar 

  27. Reshamwala PA, Kleiner DE, Heller T (2006) Nodular regenerative hyperplasia: Not all nodules are created equal. Hepatology 44: 7–14

    PubMed  Article  Google Scholar 

  28. Kuchenbecker J, Dick HB, Schmitz K, Behrens-Baumann W (2001) Use of internet technologies for data acquisition in large clinical trials. Telemed J E Health 7: 73–76

    PubMed  Article  CAS  Google Scholar 

  29. Lindh JD, Kublickas M, Westgren M, Rane A (2004) Internet based clinical trial protocols – as applied to a study of warfarin pharmacogenetics. Br J Clin Pharmacol 58: 482–487

    PubMed  Article  Google Scholar 

  30. de Boer NK, Gilissen LP, Derijks LJ, den Hartog G, Westerveld BD, Engels LG, et al (2006) Hepatotoxicity of long-term and low-dose 6-thioguanine in IBD patients. Gastroenterology 130: A-202–203

    Google Scholar 

  31. Derijks LJ, Gilissen LP, de Boer NK, Mulder CJ (2006) 6-Thioguanine-related hepatotoxicity in patients with inflammatory bowel disease: dose or level dependent? J Hepatol 44: 821–822

    PubMed  Article  Google Scholar 

  32. de Boer NK, de GP, Wilhelm AJ, Mulder CJ, van Bodegraven AA (2005) On the limitation of 6-tioguaninenucleotide monitoring during tioguanine treatment. Aliment Pharmacol Ther 22: 447–451

    PubMed  Article  CAS  Google Scholar 

  33. Derijks LJ, Gilissen LP, Engels LG, Bos LP, Bus PJ, Lohman JJ, et al (2006) Pharmacokinetics of 6-thioguanine in patients with inflammatory bowel disease. Ther Drug Monit 28: 45–50

    PubMed  Article  CAS  Google Scholar 

  34. Lancaster DL, Lennard L, Rowland K, Vora AJ, Lilleyman JS (1998) Thioguanine versus mercaptopurine for therapy of childhood lymphoblastic leukaemia: a comparison of haematological toxicity and drug metabolite concentrations. Br J Haematol 102: 439–443

    PubMed  Article  CAS  Google Scholar 

  35. Herrlinger KR, Fellermann K, Fischer C, Kreisel W, Deibert P, Schoelmerich J, et al (2004) Thioguanine-nucleotides do not predict efficacy of tioguanine in Crohn's disease. Aliment Pharmacol Ther 19: 1269–1276

    PubMed  Article  CAS  Google Scholar 

  36. Duley JA, Florin TH (2005) Thiopurine therapies: problems, complexities, and progress with monitoring thioguanine nucleotides. Ther Drug Monit 27: 647–654

    PubMed  Article  CAS  Google Scholar 

  37. Khalil PN, Erb N, Khalil MN, Escherich G, Janka-Schaub GE (2006) Validation and application of a high-performance liquid chromatographic-based assay for determination of the inosine 5′-monophosphate dehydrogenase activity in erythrocytes. J Chromatogr B Analyt Technol Biomed Life Sci 842: 1–7

    PubMed  Article  CAS  Google Scholar 

  38. Daniel F, Cadranel JF, Seksik P, Cazier A, Duong Van Huyen JP, Ziol M, et al (2005) Azathioprine induced nodular regenerative hyperplasia in IBD patients. Gastroenterol Clin Biol 29: 600–603

    PubMed  Article  Google Scholar 

  39. Chatelain D, Van Damme H, Brazier F, Geslin G, Bartoli E, Khac EN, et al (2005) High 6-thioguanine nucleotide (6-TGN) levels after azathioprine treatment are not associated with increased risk for serious hepatic damage. Gastroenterology 128: A-305–306

    Google Scholar 

  40. Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D, et al (2007) Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. Gut: May 15 (epub ahead of print)

  41. Wanless IR (1990) Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 11: 787–797

    PubMed  Article  CAS  Google Scholar 

  42. Zech CJ, Seiderer J, Reinisch W, Ochsenkuhn T, Schima W, Diebold J, et al (2007) Thioguanin-induced nodular regenerative hyperplasia of the liver-ROC analysis of different MR techniques. Eur Radiol 17: 1898–1905

    PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Walter Reinisch.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Teml, A., Schwab, M., Hommes, D. et al. A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease. Wien Klin Wochenschr 119, 519–526 (2007). https://doi.org/10.1007/s00508-007-0841-0

Download citation

Keywords

  • 6-thioguanine
  • Drug-induced liver injury
  • Inflammatory bowel disease
  • Nodular regenerative hyperplasia
  • Thiopurines