 |
 |
|
1 July 1998 | Volume 129 Issue 1 | Pages 38-41
Background: Troglitazone is a new drug for the treatment of type 2 diabetes. Although mild liver injury occurred in 1.9% of participants in controlled trials, the U.S. Food and Drug Administration has received reports of five postmarketing cases of severe liver disease that resulted in death or liver transplantation.
Objective: To report the clinical and histopathologic characteristics of a patient with troglitazone-associated severe liver injury leading to transplantation.
Design: Case report.
Setting: Two university hospitals.
Patient: A 55-year-old woman taking troglitazone, 400 mg/d, and insulin, 120 U/d.
Intervention: Discontinuation of troglitazone therapy, pretransplantation liver biopsy, and liver transplantation.
Results: Early nonspecific symptoms were attributed to other causes and were not evaluated. After the patient had used troglitazone for 3.5 months, massive loss of liver parenchyma and symptoms of liver failure developed, necessitating liver transplantation.
Conclusion: Troglitazone may cause subfulminant liver failure.
In clinical trials, troglitazone-induced hepatotoxicity (alanine aminotransferase level > three times the upper limit of normal) was identified in 1.9% of 2510 patients; these abnormalities resolved with discontinuation of therapy with the drug [5]. In contrast to this experience in clinical trials, postmarketing reports to the U.S. Food and Drug Administration since 15 December 1997 include liver transplantation and death caused by troglitazone hepatotoxicity in 3 of 500 000 patients treated in the United States and 2 deaths out of 150 000 patients treated in Japan [6]. Because of these reports, monthly monitoring of aminotransferase levels in all patients during the first 6 months of therapy and every 2 months for the remainder of the first year is now recommended [7].
The clinical characteristics and histologic correlates of severe troglitazone hepatotoxicity have not been described in detail or published, and physician awareness of troglitazone hepatotoxicity is primarily the result of mailings by the manufacturer. A recent summary of data from troglitazone clinical trials did not identify the possibility of troglitazone-induced hepatic failure [5]. Furthermore, it has been stated that troglitazone-induced changes in liver enzymes are largely mild and reversible [8]. We describe one of the patients reported to the Food and Drug Administration with liver failure apparently caused by troglitazone who ultimately required liver transplantation.
Troglitazone improved her glycemic control and diminished her insulin requirement. She noted the onset of nausea and vomiting within 2 weeks of starting troglitazone therapy and dark urine after 2 months but did not report these symptoms to her physicians. After 3 months, she presented with nausea, vomiting, malaise, and hematuria. Although trimethoprim-sulfamethoxazole was prescribed for presumed recurrent urinary tract infection and cisapride was prescribed for possible diabetic gastroparesis, neither medication was used for more than 2 days because of nausea and vomiting.
After receiving troglitazone for 3.5 months, the patient learned of potential troglitazone hepatotoxicity through the Internet and discontinued therapy with the drug. Over the following 2 weeks, she developed jaundice and was hospitalized. On presentation, she was noted to be icteric but showed no signs of hepatic encephalopathy. Laboratory tests revealed a prothrombin time of 16.5 seconds (international normalized ratio, 1.82), a bilirubin level of 148 µmol/L (8.7 mg/dL), an alkaline phosphatase level of 5.7 nkat/L (345 U/L), an aspartate aminotransferase level of 13.3 µkat/L (798 U/L), and an alanine aminotransferase level of 6.75 µkat/L (405 U/L). Results of tests for anti-hepatitis B core IgM, hepatitis B surface antigen, anti-hepatitis A virus IgM, anti-hepatitis C virus, hepatitis B virus DNA, and hepatitis C virus RNA (the latter by polymerase chain reaction) and results of serology for acute cytomegalovirus and Epstein-Barr virus infection were negative. Her anti-smooth-muscle antibody titer was 1:20, and tests for antinuclear and antimitochondrial antibodies had negative results. Levels of serum ceruloplasmin and
Transjugular liver biopsy showed severe parenchymal extinction and replacement of 80% of the tissue by loosely organized scar and collapsed parenchyma. Because her encephalopathy worsened from stage I to stage II and her prothrombin time increased to 24 seconds (international normalized ratio, 2.05), the patient underwent orthotopic liver transplantation 3 weeks after stopping troglitazone therapy. During the week before transplantation, her total bilirubin level increased to 279 µmol/L (16.3 mg/dL), her serum creatinine concentration increased from 124 µmol/L (1.4 mg/dL) to 256 µmol/L (2.9 mg/dL), her serum albumin level decreased from 27 g/L to 23 g/L, and her partial thromboplastin time increased from 36 seconds to 49 seconds (high normal, 31 seconds). Her venous ammonia concentration decreased from 77 µmol/L (134 µg/dL) to 38 µmol/L (64 µg/dL) with lactulose treatment despite progression of encephalopathy. Other precipitants of hepatic encephalopathy, such as infection or gastrointestinal hemorrhage, were not present.
The explanted liver weighed 1950 g and had an irregular nodular surface with marked capsular wrinkling. Histologic examination of the explanted liver confirmed the initial biopsy findings (Figure 1). During 4 months of posttransplantation observation, the transplanted liver functioned well, and the patient regained full cognitive function. Difficulties with persistent hematuria necessitated percutaneous and transurethral removal of renal calculi. BRIEF COMMUNICATION
Troglitazone-Induced Hepatic Failure Leading to Liver Transplantation: A Case Report
Troglitazone (Rezulin, Parke-Davis, Morris Plains, New Jersey) is a new oral agent approved for treatment of patients with type 2 diabetes mellitus [1]. It inhibits hepatic gluconeogenesis and increases peripheral insulin sensitivity [2], possibly by binding to peroxisomal proliferator-activated receptors and altering insulin-dependent gene expression in the liver [3, 4]. Because troglitazone is the first available agent in a new class of drugs for treatment of a common disease, it has been widely prescribed since its approval by the U.S. Food and Drug Administration on 29 January 1997.
Case Report
Top
Case Report
Discussion
References
A 59-year-old obese woman had had type 2 diabetes mellitus for 9 years that was complicated by retinopathy, nephropathy and neuropathy. She was prescribed troglitazone, 400 mg/d, because of poor glycemic control despite use of insulin, 150 U/d. She had a history of medullary sponge kidney, surgical removal of kidney stones, and intermittent episodes of hematuria and pyuria Her baseline serum creatinine level was 133 µmol/L (1.5 mg/dL). She had no history of autoimmune diseases and had undergone hysterectomy and cholecystectomy. She was taking no other prescription or over-the-counter medications, denied using alcohol or intravenous drugs, and had not received recent blood transfusion. She reported allergy to penicillin and cephalosporins. 
1-antitrypsin and results of iron studies were normal. One year earlier, the patient had had minimal elevations of the alkaline phosphatase level (2.6 nkat/L [156.0 U/L]) and aspartate aminotransferase level (0.67 µkat/L [40.0 U/L]). The leukocyte count (4600 cells/mm3) and the peripheral eosinophil count (110 cells/mm3) were normal. Ultrasonography revealed a hyperechoic liver, and computed tomography revealed a mildly irregular liver contour. On the second hospital day, the patient developed stage 1 hepatic encephalopathy and was transferred to a liver transplantation center.
|
Discussion
|
|---|
|
TopCase ReportDiscussionReferences |
|---|
This patient had no other known exposure to hepatotoxins, and evaluation did not reveal any evidence of viral, metabolic, or autoimmune liver disease. Liver histologic findings were consistent with drug-induced liver injury. Although other causes of acute liver disease were not identified and biopsy results did not suggest chronic liver disease, the patient had risk factors for chronic liver disease. Nonalcoholic steatohepatitis causes slowly progressive fibrosis in some obese diabetic patients, but histologic examination of the liver did not show steatosis, inflammation, or sinusoidal fibrosis, characteristics that define this syndrome. Medullary sponge kidney is also associated with hepatic fibrosis in rare cases, but our patient did not have the characteristic ductal plate malformations and broad portal fibrosis.
Of note, the patient became aware of possible troglitazone-induced hepatotoxicity through information available on the Internet. Patients increasingly obtain information of varying accuracy from the Internet. In this case, the patient identified relevant drug information before her physicians had received new monitoring recommendations from the manufacturer. Unfortunately, it was still too late to affect her outcome.
The cause of troglitazone hepatotoxicity remains unknown. Troglitazone is primarily metabolized to sulfate and glucuronide conjugates in the liver. It also induces cytochrome P450 3A4 activity, and a small fraction undergoes cytochrome P450 oxidation to a quinone derivative. The molecular structure of the drug is similar to that of vitamin E; thus, it may be subject to oxidation-reduction reactions. It is thought to have protective properties against oxidant stress [9, 10], but its ability to undergo single-electron reduction could also confer injurious prooxidant reactivity. Examples of toxic quinones include the reactive metabolite of acetaminophen, doxorubicin, and various compounds from tobacco smoke.
In this patient, the use of troglitazone seems to have been associated with the development of hepatic failure. The basis for this idiosyncratic reaction is unknown and is therefore unpredictable. Patients treated with troglitazone should have their serum aminotransferase and bilirubin levels monitored in accordance with the manufacturer's recommendations: at the start of therapy, monthly during the first 6 months of treatment, every 2 months for the remainder of the first year, and periodically thereafter or if symptoms develop. Therapy with the drug should be discontinued if clinically significant abnormalities are found.
From St. Louis University School of Medicine, St. Louis, Missouri; and University of Missouri-Kansas City, Kansas City, Missouri.
Drs. Phillips and Brunt: Department of Pathology, St. Louis University School of Medicine, 3635 Vista Avenue, St. Louis, MO 63110.
Drs. Quiason, Oki, and Isley: University of Missouri-Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64108.
References
|
|---|
|
TopCase ReportDiscussionReferences |
|---|
1. 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.
2. Spencer CM, Markham A. Troglitazone. Drugs. 1997; 54:89-101.
3. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kllewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor 
(PPAR ). J Biol Chem. 1995; 270:12953-6.
4. Henry RR. Thiazolidinediones. Endocrin Metab Clin North Am. 1997; 26:553-73.
5. Watkins PB, Whitcomb RW. Hepatic dysfunction associated with troglitazone [Letter]. N Engl J Med. 1998; 338:916-7.
6. Misbin RI. Review of liver toxicity of troglitazone. Meeting of the Food and Drug Administration Cardiorenal Advisory Committee, 21 January 1998. Bethesda, MD.
7. Prescribing information for Rezulin. Parke-Davis, Morris Plains, NJ. December 1997.
8. Imura H. A novel antidiabetic drug, troglitazone-reason for hope and concern [Editorial]. N Engl J Med. 1998; 338:908-9.
9. Cominacini L, Garbin U, Pastorino AM, Campagnola M, Fratta Pasini A, Davoli A, et al. Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells. Diabetologia. 1997; 40:165-72.
10. Inoue I, Katayama S, Takahashi K, Negishi K, Miyazaki T, Sonoda M, et al. Troglitazone has a scavenging effect on reactive oxygen species. Biochem Biophys Res Comm. 1997; 235:113-6.
Related articles in Annals:
This article has been cited by other articles:
|
|
 |
|
  M. Collino, N. S.A. Patel, and C. Thiemermann Review: PPARs as new therapeutic targets for the treatment of cerebral ischemia/reperfusion injury Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 179 - 197. [Abstract] [PDF]
|
|
|
|
 |
|
 M. A. Peraza, A. D. Burdick, H. E. Marin, F. J. Gonzalez, and J. M. Peters The Toxicology of Ligands for Peroxisome Proliferator-Activated Receptors (PPAR) Toxicol. Sci., April 1, 2006; 90(2): 269 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. I. Misbin Evaluating the Safety of Diabetes Drugs: Perspective of a Food and Drug Administration insider Diabetes Care, October 1, 2005; 28(10): 2573 - 2576. [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Baughman, R. A. Graham, K. Wells-Knecht, I. S. Silver, L. O. Tyler, M. Wells-Knecht, and Z. Zhao METABOLIC ACTIVATION OF PIOGLITAZONE IDENTIFIED FROM RAT AND HUMAN LIVER MICROSOMES AND FRESHLY ISOLATED HEPATOCYTES Drug Metab. Dispos., June 1, 2005; 33(6): 733 - 738. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Maniratanachote, K. Minami, M. Katoh, M. Nakajima, and T. Yokoi Chaperone Proteins Involved in Troglitazone-Induced Toxicity in Human Hepatoma Cell Lines Toxicol. Sci., February 1, 2005; 83(2): 293 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Lee and J. R. Senior Recognizing Drug-Induced Liver Injury: Current Problems, Possible Solutions Toxicol Pathol, January 1, 2005; 33(1): 155 - 164. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Brettenthaler, C. De Geyter, P. R. Huber, and U. Keller Effect of the Insulin Sensitizer Pioglitazone on Insulin Resistance, Hyperandrogenism, and Ovulatory Dysfunction in Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 3835 - 3840. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Sawant, A. V. Dnyanmote, K. Shankar, P. B. Limaye, J. R. Latendresse, and H. M. Mehendale Potentiation of Carbon Tetrachloride Hepatotoxicity and Lethality in Type 2 Diabetic Rats J. Pharmacol. Exp. Ther., February 1, 2004; 308(2): 694 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Lee Drug-Induced Hepatotoxicity N. Engl. J. Med., July 31, 2003; 349(5): 474 - 485. [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Chan, A. Truman, J. H. Gurwitz, J. S. Hurley, B. Martinson, R. Platt, J. E. Everhart, R. H. Moseley, N. Terrault, L. Ackerson, et al. A Cohort Study of the Incidence of Serious Acute Liver Injury in Diabetic Patients Treated With Hypoglycemic Agents Arch Intern Med, March 24, 2003; 163(6): 728 - 734. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Lebovitz, M. Kreider, and M. I. Freed Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials: Evidence that rosiglitazone does not cause hepatic dysfunction Diabetes Care, May 1, 2002; 25(5): 815 - 821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Buchweitz, P. E. Ganey, S. J. Bursian, and R. A. Roth Underlying Endotoxemia Augments Toxic Responses to Chlorpromazine: Is There a Relationship to Drug Idiosyncrasy? J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 460 - 467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Graham, C. R. Drinkard, D. Shatin, Y. Tsong, and M. J. Burgess Liver Enzyme Monitoring in Patients Treated With Troglitazone JAMA, August 15, 2001; 286(7): 831 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Azziz, D. Ehrmann, R. S. Legro, R. W. Whitcomb, R. Hanley, A. G. Fereshetian, M. O’Keefe, and M. N. Ghazzi Troglitazone Improves Ovulation and Hirsutism in the Polycystic Ovary Syndrome: A Multicenter, Double Blind, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1626 - 1632. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. Funk, C. Ponelle, G. Scheuermann, and M. Pantze Cholestatic Potential of Troglitazone as a Possible Factor Contributing to Troglitazone-Induced Hepatotoxicity: In Vivo and in Vitro Interaction at the Canalicular Bile Salt Export Pump (Bsep) in the Rat Mol. Pharmacol., March 1, 2001; 59(3): 627 - 635. [Abstract] [Full Text]
|
|
|
|
 |
|
 A. A. Parulkar, M. L. Pendergrass, R. Granda-Ayala, T. R. Lee, and V. A. Fonseca Nonhypoglycemic Effects of Thiazolidinediones Ann Intern Med, January 2, 2001; 134(1): 61 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Lebovitz, J. F. Dole, R. Patwardhan, E. B. Rappaport, and M. I. Freed Rosiglitazone Monotherapy Is Effective in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 280 - 288. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Lenhard and W. B. Funk Failure to Develop Hepatic Injury From Rosiglitazone in a Patient With a History of Troglitazone-Induced Hepatitis Diabetes Care, January 1, 2001; 24(1): 168 - 169. [Full Text]
|
|
|
|
 |
|
 S. Matthaei, M. Stumvoll, M. Kellerer, and H.-U. Häring Pathophysiology and Pharmacological Treatment of Insulin Resistance Endocr. Rev., December 1, 2000; 21(6): 585 - 618. [Abstract] [Full Text]
|
|
|
|
|
|
K. A. Prendergast, C. L. Berg, and R. Wisniewski Troglitazone-Associated Hepatotoxicity Treated Successfully with Steroids Ann Intern Med, November 7, 2000; 133(9): 751 - 751. [Full Text] [PDF]
|
|
|
|
|
|
V. E. Kostrubsky, J. F. Sinclair, V. Ramachandran, R. Venkataramanan, Y. H. Wen, E. Kindt, V. Galchev, K. Rose, M. Sinz, and S. C. Strom The Role of Conjugation in Hepatotoxicity of Troglitazone in Human and Porcine Hepatocyte Cultures Drug Metab. Dispos., October 1, 2000; 28(10): 1192 - 1197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. L. Isley and J. C. Oki Rosiglitazone and Liver Failure Ann Intern Med, September 5, 2000; 133(5): 393 - 393. [Full Text] [PDF]
|
|
|
|
|
|
S. Jagannath and R. Rai Rapid-Onset Subfulminant Liver Failure Associated with Troglitazone Ann Intern Med, April 18, 2000; 132(8): 677 - 677. [Full Text] [PDF]
|
|
|
|
|
|
E. R. Schiff Update in Hepatology Ann Intern Med, March 21, 2000; 132(6): 460 - 466. [Full Text] [PDF]
|
|
|
|
|
|
L. M. Forman, D. A. Simmons, and R. H. Diamond Hepatic Failure in a Patient Taking Rosiglitazone Ann Intern Med, January 18, 2000; 132(2): 118 - 121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Al-Salman, H. Arjomand, D. G. Kemp, and M. Mittal Hepatocellular Injury in a Patient Receiving Rosiglitazone: A Case Report Ann Intern Med, January 18, 2000; 132(2): 121 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Ramachandran, V. E. Kostrubsky, B. J. Komoroski, S. Zhang, K. Dorko, J. E. Esplen, S. C. Strom, and R. Venkataramanan Troglitazone Increases Cytochrome P-450 3A Protein and Activity in Primary Cultures of Human Hepatocytes Drug Metab. Dispos., October 1, 1999; 27(10): 1194 - 1199. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. M. Grundy, I. J. Benjamin, G. L. Burke, A. Chait, R. H. Eckel, B. V. Howard, W. Mitch, S. C. Smith Jr, and J. R. Sowers Diabetes and Cardiovascular Disease : A Statement for Healthcare Professionals From the American Heart Association Circulation, September 7, 1999; 100(10): 1134 - 1146. [Full Text] [PDF]
|
|
|
|
|
|
D. Altkorn, K. Roach, S. Stern, and W. Levinson Update in General Internal Medicine Ann Intern Med, August 3, 1999; 131(3): 199 - 206. [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Demetri, C. D. M. Fletcher, E. Mueller, P. Sarraf, R. Naujoks, N. Campbell, B. M. Spiegelman, and S. Singer Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma PNAS, March 30, 1999; 96(7): 3951 - 3956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. I. Misbin Troglitazone-Associated Hepatic Failure Ann Intern Med, February 16, 1999; 130(4_Part_1): 330 - 330. [Full Text] [PDF]
|
|
|
|
|
|
S. K. Herrine and C. Choudhary Severe Hepatotoxicity Associated with Troglitazone Ann Intern Med, January 19, 1999; 130(2): 163 - 164. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Article
