An Autopsy Case of Troglitazone-Induced Fulminant Hepatitis

Shibuya, Akitaka; Watanabe, Masaaki; Fujita, Yoshikuni; Saigenji, Katsunori; Kuwao, Sadahito; Takahashi, Hirotaka; Takeuchi, Haruo

doi:10.2337/diacare.21.12.2140

Cited by 102 publications

(49 citation statements)

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“…The discovery of the selective peroxisomal proliferator-activated receptor-␥ (PPAR-␥) agonist thiazolidinediones and the introduction of the first approved thiazolidinedione, troglitazone, were significant advances in the search for effective insulinsensitizing agents (6,8 -10). However, postmarketing reports of serious hepatic reactions to troglitazone, including fatal fulminant hepatitis (11)(12)(13)(14)(15)(16), raised concerns about the safety of troglitazone and other members of this class. In the U.K., troglitazone was voluntarily withdrawn from the market, and in the U.S., the Food and Drug Administration (FDA) requested removal of the drug after prescribing information had been revised several times to include stronger warnings and guidelines for extensive monitoring of hepatic function in patients taking troglitazone (6,17,18).…”

Section: Diabetes Care 25:815-821 2002mentioning

confidence: 99%

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

2002

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OBJECTIVE -Troglitazone treatment has been associated with idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. This raises questions regarding whether all thiazolidinediones or peroxisomal proliferator-activated receptor-␥ (PPAR-␥) agonists are hepatotoxic and whether data from clinical trials are adequate to detect a signal of potentially serious drug-related hepatotoxicity. The purpose of this study was to assess whether the idiosyncratic liver toxicity reported with troglitazone is molecule-specific or a thiazolidinedione class effect, based on liver enzyme data collected prospectively during phase 2/3 clinical trials with rosiglitazone, a new, potent, and specific member of the thiazolidinedione class. RESEARCH DESIGN AND METHODS-This is an analysis of liver function in type 2 diabetic patients at baseline and serially in 13 double-blind, 2 open-label active-controlled, and 7 open-label extension studies of rosiglitazone treatment conducted in outpatient centers throughout North America and Europe. The study comprised Ͼ6,000 patients aged 30 -80 years with type 2 diabetes. Patients underwent baseline liver function studies and were excluded from clinical trials if they had an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase value 2.5 times greater than the upper limit of the reference range. The main outcome measures were liver enzyme levels, which were assessed at screening, at baseline, and every 4 weeks for the first 3 months of treatment and at 6-to 12-week intervals thereafter. Patients with at least one on-therapy ALT value Ͼ3 times the upper limit of the reference range were identified, and their case records examined in detail.RESULTS -At baseline, 5.6% of the patients with type 2 diabetes (mean HbA 1c 8.5-9.0%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range. On antidiabetic therapy, most of those patients (ϳ83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value Ͼ3 times the upper limit of the reference range during double-blind and open-label treatment were as follows: rosiglitazone-treated 0.32%, placebo-treated 0.17%, and sulfonylurea-, metformin-, or insulintreated 0.40%. The respective rates of ALT values Ͼ3 times the upper limit of the reference range per 100 person-years of exposure were 0.29, 0.59, and 0.64.CONCLUSIONS -No evidence of hepatotoxic effects was observed in studies that involved 5,006 patients taking rosiglitazone as monotherapy or combination therapy for 5,508 personyears. This is in keeping with hepatic data from clinical trials of another member of the class, pioglitazone, and in contrast to the clear evidence of hepatotoxic effects observed during the troglitazone clinical trial program. These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-␥ agonist class effect. Poorly controlled patients with type 2 diabetes may ...

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Section: Diabetes Care 25:815-821 2002mentioning

confidence: 99%

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

2002

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“…Two patients were confirmed to have suffered serious hepatocellular injury from an idiosyncratic drug reaction (Watkins and Whitcomb 1998). Meanwhile, troglitazone was concomitantly reported to be associated with idiosyncratic hepatotoxicity with some patients showing severe or fatal liver damage (Gitlin et al 1998;Neuschwander-Tetri et al 1998;Shibuya et al 1998). Consequently, it was withdrawn from the market in the US and Japan in March 2000.…”

Section: Introductionmentioning

confidence: 99%

Troglitazone

Yokoi

2009

Handbook of Experimental Pharmacology

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Troglitazone was the first thiazolidinedione antidiabetic agent approved for clinical use in 1997, but it was withdrawn from the market in 2000 due to serious idiosyncratic hepatotoxicity. Troglitazone contains the structure of a unique chroman ring of vitamin E, and this structure has the potential to undergo metabolic biotransformation to form quinone metabolites, phenoxy radical intermediate, and epoxide species. Although troglitazone has been shown to induce apoptosis in various hepatic and nonhepatic cells, the involvement of reactive metabolites in the troglitazone cytotoxicity is controversial. Numerous toxicological tests, both in vivo and in vitro, have been used to try to predict the toxicity, but no direct mechanism has been demonstrated that can explain the hepatotoxicity that occurred in some individuals. This chapter summarizes the proposed mechanisms of troglitazone hepatotoxicity based in vivo and in vitro studies. Many factors have been proposed to contribute to the mechanism underlying this idiosyncratic toxicity.

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“…1 Although only 49 of these liver failure cases were considered to be possibly or probably related to TGZ, 9 the numbers may be higher because of incompleteness of reporting. 1 TGZ treatment was associated with a characteristic hepatocellular injury, 18,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] with rare instances of either a mixed hepatocellular/cholestatic injury or a predominant cholestatic reaction. [36][37][38] The liver injury associated with TGZ is idiosyncratic 39 ; it is unpredictable, neither timenor dose-dependent, 40 and cannot be reproduced in animals.…”

Section: In the Unitedmentioning

confidence: 99%