Digestive Diseases and Sciences

, Volume 47, Issue 7, pp 1632–1637 | Cite as

Severe Cholestatic Hepatitis Caused by Thiazolidinediones: Risks Associated with Substituting Rosiglitazone for Troglitazone

  • Herbert L. Bonkovsky
  • Riad Azar
  • Steven Bird
  • Gyongyi Szabo
  • Barbara Banner


Troglitazone maleate (Rezulin) has been associated with severe hepatotoxicity, which led to its withdrawal from the U.S. market in March 2000. Rosiglitazone maleate (Avandia) is being marketed as a safe alternative in the treatment of type 2 diabetes mellitus. We report a case of severe thiazolidinedione-induced cholestatic hepatitis in a 56-year-old female patient at a university hospital who was given rosiglitazone, 8 mg/day, after she developed milder hepatotoxicity while taking troglitazone. Rosiglitazone was discontinued, and the patient was treated with prednisone, azathioprine, and ursodiol. Clinical evaluation and liver biopsy were performed and liver function tests were monitored. After being switched from troglitazone to rosiglitazone the patient developed a severe cholestatic hepatitis with marked jaundice and moderate increases in serum alkaline phosphatase and γ-glutamyltranspeptidase but only mild increases in serum aminotransferases. Discontinuation of rosiglitazone and treatment with prednisone, azathioprine, and ursodiol led to improvement, albeit with residual injury, dropout of intrahepatic bile ducts, and persisting elevations of serum alkaline phosphatase. Rosiglitazone is not always a safe alternative in patients who have had hepatotoxicity to troglitazone. It is important to monitor the serum alkaline phosphatase in addition to the serum aminotransferases in patients taking thiazolidinediones.

severe cholestatic hepatitis thiazolidinediones rosiglitazone troglitazone 


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  1. 1.
    Kahn CR, Chen L, Cohen SE: Unraveling the mechanism of action of thiazolidinediones. J Clin Invest 106:1305–1307, 2000Google Scholar
  2. 2.
    Gale EAM: Lessons from the glitazones: A story of drug development. Lancet 357:1870–1875, 2001Google Scholar
  3. 3.
    Gitlin N, Neil LJ, Spurr CL, Lim KN, Juarbe HM: Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med 129:36–38, 1998Google Scholar
  4. 4.
    Neuschwander-Tetri BA, Isley WL, Oki JC, Ramrakhiani S, Quiason SG, Phillips NJ, Brunt EM: Troglitazone-induced hepatic failure leading to liver transplantation: A case report. Ann Intern Med 129:38–41, 1998Google Scholar
  5. 5.
    Watkins P, Whitcomb R: Hepatic dysfunction associated with troglitazone [Letter]. N Engl J Med 338:916–917, 1998Google Scholar
  6. 6.
    Herrine SK, Choudhary C: Severe hepatotoxicity associated with troglitazone. Ann Intern Med 130:163–164, 1999Google Scholar
  7. 7.
    Kohlroser JO, Mathai J, Reichheld JH, Banner, BF, Bonkovsky HL: Hepatotoxicity due to troglitazone: Report of two cases and review of adverse events reported to the United States Food and Drug Administration. Am J Gastroenterol 95:272–276, 2000Google Scholar
  8. 8.
    Lumpkin MM: Presentation to FDA Advisory Committee, May 19, 2000Google Scholar
  9. 9.
    Forman LM, Simmons DA, Diamond RH: Hepatic failure in a patient taking rosiglitazone. Ann Intern Med 132:118–121, 2000Google Scholar
  10. 10.
    Al-Salman J, Arjomand H, Kemp D, Mittal M: Hepatocellularinjury in a patient receiving rosiglitazone: A case report. Ann Intern Med 132:121–124, 2000Google Scholar
  11. 11.
    Yamazaki H, Shibata A, Suzuki M, Nakajima M, Shimada N, Guengerich FP, Yokoi T: Oxidation of troglitazone to a quinone-type metabolite catalyzed by cytochrome P-450 2C8 and P-450 3A4 in human liver microsomes. Drug Metab Dispos 27:1260–1266, 1999Google Scholar
  12. 12.
    Kostrubsky VE, Sinclair JF, Ramachandran V, Venkataramanan R, Wen YH, Kindt E, Galchev V, Rose K, Sinz M, Strom SC: The role of conjugation in hepatotoxicity of troglitazone in human and porcine hepatocyte cultures. Drug Metab Dispos 28:1192–1197, 2000Google Scholar
  13. 13.
    Menon KV, Angulo P, Lindor KD: Severe cholestatic hepatitis from troglitazone in a patient with nonalcoholic steatohepatitis and diabetes mellitus. Am J Gastroenterol 96:1631–1634, 2001Google Scholar
  14. 14.
    Zimmerman HJ. Drug-induced liver disease. In Schiff's Diseases of the Liver, 8th ed. Schiff ER, Sorrel MF, Maddrey WC (eds). Philadelphia: Lippincott- Raven, 1999, pp 973–1064Google Scholar
  15. 15.
    Pendergrass KA, Berg CL, Wisniewski R: Troglitazone-associated hepatotoxicity treated successfully with steroids. Ann Intern Med 133:751, 2000Google Scholar
  16. 16.
    Prescribing information for rosiglitazone maleate (Avandia). Philadelphia: SmithKline Beecham Pharmaceuticals, May 1999Google Scholar
  17. 17.
    Salzman A, Patel J: Rosiglitazone therapy is not associated with hepatotoxicity [abstract]. Diabetes 48:A95, 1999Google Scholar
  18. 18.
    Freid J, Everitt D, Boscia J: Rosiglitazone and hepatic failure [Letters]. Ann Intern Med 132:164, 2000Google Scholar
  19. 19.
    Aithal PG, Day CP: The natural history of histologically proved drug induced liver disease. Gut 44:731–735, 1999Google Scholar
  20. 20.
    James OF, Day CP: Non-alcoholic steatohepatitis (NASH): A disorder of emerging identity and importance. J Hepatol 29:495–501, 1998Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Herbert L. Bonkovsky
    • 1
  • Riad Azar
    • 1
  • Steven Bird
    • 1
  • Gyongyi Szabo
    • 1
  • Barbara Banner
    • 1
  1. 1.University of Massachusetts Medical SchoolWorcesterUSA

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