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BRIEF COMMUNICATION

Two Cases of Severe Clinical and Histologic Hepatotoxicity Associated with Troglitazone

Norman Gitlin, MD; Neil L. Julie, MD; Charles L. Spurr, MD; Kie N. Lim, MD; and Herbert M. Juarbe, MD

1 July 1998 | Volume 129 Issue 1 | Pages 36-38

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Several oral antihyperglycemic agents are available for management of type 2 diabetes. These agents generally fall into the chemical or function groups sulfonylureas, biguanides, or -glucosidase inhibitors. Recently, the U.S. Food and Drug Administration approved troglitazone (Rezulin, Parke-Davis, Morris Plains, New Jersey), a thiazolidinedione agent that is unrelated to the aforementioned categories, as a novel oral antihyperglycemic agent. It decreases hepatic glucose output and increases insulin-dependent glucose metabolism in skeletal muscle [1, 2]. It is not an insulin secretagogue. We report two patients who had severe hepatotoxicity associated with troglitazone administration.

Patient 1

A 44-year-old woman with a history of type 1 diabetes mellitus since 1978 presented with nausea, low-grade fever, and progressive jaundice. She had required insulin for diabetes control for 10 years. Comorbid conditions included essential hypertension, hypothyroidism, and obesity. The patient had started taking troglitazone 20 weeks before presentation. Initially, she received 200 mg daily for 4 weeks, then received 400 mg daily thereafter. Before starting therapy, the patient's hepatic biochemical markers were normal. Other medications included lisinopril, 20 mg/d; levothyroxine sodium, 88 µg/d; and insulin. The patient reported no history of exposure to hepatotoxins or alcohol ingestion. On examination, the patient was icteric, and her liver was tender and enlarged to 14 cm; she was hospitalized for evaluation. Results of serology for hepatitis A, B, and C and studies for cytomegalovirus and Epstein-Barr virus were negative. Immunoglobulin levels were normal, and the ratio of antinuclear antibodies was positive (1:80). Troglitazone therapy was discontinued, and other therapies were maintained. Table 1 summarizes the patient characteristics.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

 

The patient had a protracted hospital course with prolonged cholestasis, a decrease in albumin level to 18 g/L, a prothrombin time of 14.8 seconds, and development of ascites. Because of concern that the patient was developing subacute hepatic necrosis, a liver biopsy was performed (Figure 1). Biopsy results showed diffuse necrosis of hepatocytes with bridging necrosis, regenerating hepatocytes, intracanalicular cholestasis, no substantial steatosis, and no cellular infiltrate. Early fibrosis was evident. The patient gradually improved over the subsequent 3 months: Her bilirubin level decreased to 171 µmol/L, her albumin level increased to 27 g/L, and her prothrombin time returned to normal.

View larger version (129K): [in this window] [in a new window]   Figure 1. Low-power view of portal tract showing interface hepatitis, mild inflammatory infiltrate, bile duct reduplication, and necrotic hepatocytes (hematoxylin-eosin stain; original magnification, x96).

 

Patient 2

A 65-year-old woman presented with a 3-week history of nausea, anorexia, pruritus, and jaundice. She had had type 2 diabetes for 4 years. Comorbid conditions included obesity, essential hypertension, mild osteoarthritis, and a solitary renal calculus. She had started therapy with troglitazone, 400 mg/d, 6 weeks before presentation. Other medications included insulin; atenolol, 50 mg/d; and furosemide, 40 mg/d, for the past 2 years. The patient had no history of alcohol ingestion, liver disease, blood transfusion, or known exposure to hepatotoxins or potentially hepatotoxic chemicals. No information from the physical examination was available. Laboratory values at presentation were as follows: bilirubin level, 342 µmol/L; alanine aminotransferase level, 19.42 µkat/L; cholesterol, 12.9 µmol/L; and prothrombin time, 12.6 seconds. Serum protein levels were normal (Table 1). Results of serology were negative for hepatitis A, B, and C and infectious mononucleosis. Results of an antinuclear antibody test and endoscopic retrograde cholangiopancreatography were negative. Treatment with troglitazone was discontinued, and other therapies were maintained. Eight weeks after presentation, she underwent liver biopsy. Histology revealed hepatocyte necrosis with bridging necrosis and fibrosis, a portal inflammatory infiltrate (mostly plasma cells and eosinophils) and minimal cholestasis. Three months after discontinuation of troglitazone therapy, the patient's bilirubin level was 78.66 µmol/L and her alanine aminotransferase level was 5.48 µkat/L.

Discussion

Top Discussion Author & Article Info References

Drug hepatotoxicity is usually attributable to an intrinsic or an idiosyncratic hepatotoxin [3, 4]. The former is a dose-dependent, reproducible mechanism that is common, well understood, and preventable. The latter mechanism is not dose-dependent, is rare, is not reproducible, and usually reflects host hypersensitivity to an intermediate metabolite of the parent molecule.

Troglitazone is rapidly absorbed after oral administration, reaching maximal plasma concentration within 2 to 3 hours. Concurrent administration with food accelerates the rate of absorption. Troglitazone is highly bound to albumin and is metabolized in the liver, mostly to a sulfate conjugate. It induces cytochrome P4503A4 and does not seem to inhibit cytochrome P450 enzymes. The induction of cytochrome P4503A4 may result in accelerated metabolism of other medications that make use of this enzyme. No other suspected drug interactions were clinically evident in the two patients discussed here. In studies of troglitazone in patients with chronic liver disease (Child-Pugh grade B or C), elevated levels of sulphate conjugates were noted without any adverse increase or change in hepatic biochemistry^[5]. In clinical studies in North America, a total of 2510 patients received troglitazone; 20 (2.2%) of these patients had increases in the alanine aminotransferase level that were greater than threefold above normal, and 2 of these patients developed reversible jaundice (Parke-Davis, Morris Plains, New Jersey. Data on file).

We describe two patients with severe hepatotoxicity caused by troglitazone therapy after 138 days and 35 days of exposure to standard dosages of this medication. Neither patient had preexisting hepatic or renal disease. Patient 1 was also receiving lisinopril, which can cause cholestatic hepatitis; however, the patient had been receiving this agent for more than 1 year. Histologic and biochemical findings in both patients showed a predominant acute hepatocellular necrosis with bridging necrosis and fibrosis with some evidence of cholestasis. Hepatotoxicity in this case may reflect an idiosyncratic mechanism caused by a hypersensitivity to a troglitazone metabolite. It is anticipated that further evidence with the use of troglitazone will reveal the extent and frequency of this hepatotoxicity. Until such information is available, physicians and patients must be aware of this potential adverse association. We recommend close monitoring of biochemical markers in persons receiving troglitazone.

The manufacturer of troglitazone and the U.S. Food and Drug Administration were notified of these cases. Distribution of the medication by a licensee was halted in the United Kingdom in November 1997 on the basis of reports of hepatic dysfunction. The manufacturer of troglitazone altered its prescribing information on 3 November 1997 to specify a need for monitoring liver function in patients taking this drug.

Dr. Julie: 15225 Shady Grove Road, #207, Rockville, MD 20852.

Dr. Spurr: 820 St. Sebastian Way, #5B, Augusta, GA 30901.

Dr. Juarbe: 19241 Montgomery Village Avenue, Suite E23, Montgomery Village, MD 20886.

Author and Article Information

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From Emory University School of Medicine and Shady Grove Adventist Hospital, Atlanta, Georgia.
Requests for Reprints: Norman Gitlin, MD, Emory University School of Medicine, Division of Digestive Diseases, WMB 2101, Pierce Drive, Atlanta, GA 30322.
Current Author Addresses: Drs. Gitlin and Lin: Emory University School of Medicine, Division of Digestive Diseases, WMB 2101, Pierce Drive, Atlanta, GA 30322.

References

Top Discussion Author & Article Info References

1. Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 1994; 331:1188-93.

2. Kumar S, Boulton AJ, Beck-Nielsen H, Berthezene F, Muggeo M, Persson B, et al. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group. Diabetologia. 1996; 39:701-9.

3. Lee WM. Review article: drug-induced hepatotoxicity. Aliment Pharmacol Ther. 1993; 7:477-85.

4. Farrell GC. Drug-induced Liver Disease. London: Churchill Livingstone; 1994:247-300.

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