The thiazolidinediones (TZDs) are an important class of antidiabetic drugs that improve glycemic control by improving sensitivity to insulin(1). The first agent in this class was troglitazone, which has been associated with idiosyncratic hepatotoxicity that included cases of liver failure, liver transplantation,and death(2,3). Troglitazone was voluntarily withdrawn from the market in the U.S. in March 2000. Two additional second-generation agents in this class remain on the market: rosiglitazone maleate (Avandia; SmithKline Beecham Pharmaceuticals)and pioglitazone (Actos; Takeda Pharmaceuticals America/Eli Lilly and Co.). Post-marketing surveillance by the manufacturers of the second-generation TZDs have shown no confirmed hepatotoxicity with either agent. Two isolated cases of drug-induced liver disease with rosiglitazone have been reported(4,5),although some debate over the strength of this association has been raised(6). We present a case of a patient with extreme insulin resistance who developed classic troglitazone-induced liver disease but showed no signs of this while on rosiglitazone.

A 36-year-old woman presented with crampy abdominal pain and evidence of jaundice. She had a 4-year history of uncomplicated type 2 diabetes, initially treated with glyburide and acarbose. Insulin was required, and she was eventually treated with 35 U of U-500 insulin twice a day. Troglitazone 400 mg/day was added in March 1997 and was increased to 800 mg/day in April 1997. Biochemical measurements of liver function were normal before initiation of troglitazone and 2 months after its start. Four months after starting troglitazone, she developed clinical evidence of jaundice, malaise, and crampy abdominal pain.

Her past medical history included an episode of gallstone-induced pancreatitis treated with endoscopic retrograde cholangiopancreatography. Her liver function tests were normal during this episode. She also had a history of modest hyperc-holesterolemia, obesity, and oligoamenorrhea. She was taking no other medications, including over the counter preparations. She denied any alcohol use.

When she developed clinical evidence of jaundice, troglitazone was stopped and an outpatient evaluation was undertaken. Her total and direct bilirubin levels were elevated to 127 and 100.8 μmol/l (7.5 and 5.9 mg/dl). The alanine aminotransferase (ALT) level was 2,040 mg/dl. The serum and leukocyte alkaline phosphatase levels were both normal, as were electrolytes and the blood count, including platelets. The prothrombin time and the international normalized ratio were also normal. Antibody studies were ordered. Antinuclear and anti-mitochondrial antibodies were negative. The α1 antitrypsin level was normal. The ceruloplasmin level was mildly elevated at 61.0 mg/dl(range 20-55). A panel for hepatitis A, B, and C was nonreactive. Iron and transferrin saturation levels were normal. Her HbA1c level was 7.0%(4.3-6.1).

Within several months of stopping troglitazone, her symptoms had disappeared and her liver tests had normalized. Her insulin requirements increased with cessation of troglitazone and at one point, she was taking 80 U of U-500 insulin twice a day. Metformin (1 mg) twice a day was added, which decreased the insulin requirement. She requested that an additional TZD be attempted. Rosiglitazone 4 mg twice a day was initiated, with prescriptions being rewritten every 2 weeks depending on liver function tests being obtained. All liver function tests were normal up to 10 months after beginning rosiglitazone treatment.

In this patient, the time course of hepatic dysfunction and the subsequent improvement after the use and withdrawal of troglitazone were completely consistent with drug-induced hepatotoxicity. No other viral or autoimmune causes for her hepatic dysfunction were identified. We believe that the patient experienced troglitazone-induced hepatotoxicity. At the patient's insistence, and with a fair amount of hesitancy, a second TZD was added, which to date has been very well tolerated. This suggests that there may be significant differences between the first and second generation TZDs.

There are similarities between the first and second generation TZDs. All of the agents are selective agonists of peroxisome proliferator-activated receptor (PPAR)-γ, and they all improve sensitivity to insulin,especially at the skeletal muscle level(1). Some side effects, such as fluid retention, weight gain, and changes in lipoproteins, appear to occur in all of the TZDs (9).

Differences also exist. All three available agents have different side chains, with troglitazone having a lipophilic α-tocopherol side chain. Other differences include the binding affinity, with rosiglitazone having a greater binding avidity for the PPAR-γ receptor than troglitazone(7). This allows the drug to be administered at an 80- to 100-fold lower dose than troglitazone. Rosiglitazone is predominantly metabolized by cytochrome P4502C8 and does not seem to induce this system, whereas troglitazone induces and is metabolized by cytochrome P4503A4. Although troglitazone is extensively metabolized (3% excreted in the urine), 64% of rosiglitazone is excreted in the urine(7). Troglitazone is metabolized into a quinone derivative, whereas rosiglitazone is not(8).

In clinical trials, troglitazone-induced hepatotoxicity, defined as having an ALT level greater than three times the upper limit of normal, was identified in 1.9% of 2,510 patients. Of the 4,598 patients that were included in rosiglitazone clinical trials, 0.2% of patients had an increase in ALT to three times the normal limit. An identical 0.2% of patients receiving placebo also had elevations in ALT, and the elevations in the rosiglitazone group were not clearly causally related. Two recent reports have suggested that rosiglitazone may be associated with hepatotoxicity(4,5),although one of these patients may have had an element of ischemic liver dysfunction (6), and the other patient was taking acetaminophen and zafirlukast, both of which can cause hepatitis and liver dysfunction(10).

The current recommendations for second generation TZDs include monitoring of liver function tests at baseline and every 2 months for the first year, and then periodically. While idiosyncratic responses to any drug may include adverse effects on the liver, there is currently very little evidence to suggest that hepatic dysfunction is a class effect for the second generation TZDs. Nevertheless, until the clinical experience with the second generation TZDs can match that of troglitazone, liver enzymes should be monitored regularly.

M.J.L. has been a member of a speaker's panel for both SmithKline Beecham and Parke-Davis pharmaceuticals. In addition, M.J.L. has received research support as a primary investigator and sub-investigator from SmithKline Beecham and Parke-Davis.

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