Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two patients (a 48-year-old woman and a 62-year-old man) developed clinical and laboratory signs of hepatotoxicity due to troglitazone (Rezulin), a thiazolidinedione used in treatment of diabetes mellitus. There was no clear clinical evidence of drug allergy, although the woman experienced colitis before the onset of recognized hepatotoxicity. Liver biopsies showed bridging necrosis and fibrosis in the woman and hepatitis with granuloma formation in the man. The abnormalities in liver chemistries resolved promptly upon cessation of the drug. Cases involving 46 patients reported to the United States Food and Drug Administration are also reviewed. Troglitazone is a useful new oral antihyperglycemic agent, but in about 1.9% of patients hepatotoxicity has occurred, which may be severe and even fatal. Frequent monitoring of serum liver chemistries in patients taking the drug is essential.
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PMID:Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration. 1063 96

Troglitazone, a PPAR-gamma agonist, is a new drug for type 2 diabetes. The drug decreases blood glucose via enhancing insulin action. Recently Sankyo pharmaceutical company is warning severe hepatotoxicity by troglitazone. It recommends to examine liver function every month in diabetic patients treated with the drug in order early to find drug-induced hepatitis. In Japan 153 diabetic patients treated with the drug developed severe hepatitis and 8 of them died of drug-side effects. Quinone metabolite of troglitazone predominantly in the liver to a sulfate conjugate and activation of PPAR gamma and PXR(pregnane X receptor) by troglitazone are supposed to be factors of hepatotoxic mechanism.
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PMID:[Clinical effect and side effect of troglitazone]. 1070 61

A 68-year-old woman, with type 2 diabetes mellitus, hypercholesterolemia, and prior long-term simvastatin therapy, self-resumed troglitazone after running out of metformin. She developed an acute severe hepatitis with microvesicular steatosis and mysositis. There was subsequent resolution of the myositis but progression of the hepatitis to symptomatic cirrhosis over a period of 12 weeks. Both troglitazone and simvastatin are metabolized by cytochrome P-450 3A4. Troglitazone typically induces metabolism of drugs metabolized by this cytochrome so that simple simvastatin toxicity seems less likely to have been involved. The association with myositis, the severity of the hepatitis with progression to cirrhosis, and the presence of microvesicular steatosis suggests altered mitochondrial metabolism, which has been described with each agent, as the underlying pathogenic mechanism. Although troglitazone (Rezulin) has been withdrawn from the market, other similar agents are available for therapy of type 2 diabetes mellitus. Increased awareness of a potential interaction between these two classes of drugs is warranted.
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PMID:Myositis, microvesicular hepatitis, and progression to cirrhosis from troglitazone added to simvastatin. 1128 Nov 88

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 gamma-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.
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PMID:Severe cholestatic hepatitis caused by thiazolidinediones: risks associated with substituting rosiglitazone for troglitazone. 1214 28

Troglitazone is a thiazolidinedione antidiabetic agent with insulin-sensitizing activities that was withdrawn from the market in 2000 due to its association with idiosyncratic hepatotoxicity. To address the suspected autoantibody production associated with troglitazone, we investigated autoantibodies in sera from patients with type II diabetes mellitus with troglitazone-induced liver dysfunction. Two female patients (47- and 70-year-old) ceased taking troglitazone (400 mg/day) after 23.5 and 16 weeks, respectively, due to increased serum ALT. Using two-dimensional electrophoresis and amino acid sequence analyses, aldolase B was identified as an autoantigen that reacted with antibodies in sera from both patients. The titer of anti-aldolase B remained high for several weeks after stopping troglitazone administration. The mean reactivity of autoantibodies to aldolase B determined by ELISA with sera of patients with chronic hepatitis (n = 40) and liver cirrhosis (n = 40) was significantly higher (p < 0.05 and p < 0.001, respectively) than with sera of healthy subjects (n = 80). These findings suggest that liver injury may cause the appearance of autoantibodies to aldolase B which may then aggravate the hepatitis. In addition, the anti-aldolase B titer might indicate the severity of liver dysfunction.
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PMID:Detection of autoantibody to aldolase B in sera from patients with troglitazone-induced liver dysfunction. 1611 20

Worldwide, viral hepatitis is the leading cause of acute liver failure, whereas acetaminophen hepatotoxicity is the most commonly identified cause in Western countries. Restricting the quantity of acetaminophen tablets dispensed has been shown to reduce morbidity and mortality in countries with a high incidence of acetaminophen overdose. Troglitazone and bromfenac are two recently approved medications that were withdrawn from the market due to an unacceptably high incidence of severe hepatotoxicity. In addition, trovafloxacin, nefazodone, and ritonavir were reported to be associated with severe hepatitis and acute liver failure. Moderate hypothermia is a simple and potentially effective means of reducing intracranial pressure in patients with acute liver failure and cerebral edema. However, controlled clinical trials are needed to determine proper patient selection and optimize treatment. Extracorporeal bioartificial liver support devices remain an exciting but as yet unproven means of supporting acute liver failure patients with advanced encephalopathy. Living donor liver transplantation has recently been reported for adults and children with acute liver failure. However, ethical concerns regarding donor safety and the ability to obtain informed consent without coercion have been raised. Lastly, advances in the identification and isolation of pluripotent liver stem cells in human bone marrow provides hope for a simple and effective means of enhancing native liver regeneration.
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PMID:Acute liver failure. 1703 Nov 71

Troglitazone induced an idiosyncratic, hepatocellular injury-type hepatotoxicity in humans. Statistically, double null genotype of glutathione S-transferase isoforms, GSTT1 and GSTM1, was a risk factor, indicating a low activity of the susceptible patients in scavenging chemically reactive metabolites. CYP3A4 and CYP2C8 were involved in the metabolic activation and CYP3A4 was inducible by repeated administrations of troglitazone. The genotype analysis, however, indicated that the metabolic idiosyncrasy resides in the degradation of but not in the production of the toxic metabolites of troglitazone. Antibody against hepatic aldolase B was detected in the case patients, suggesting involvement of immune reaction in the toxic mechanism. Troglitazone induced apoptotic cell death in human hepatocytes at a high concentration, and this property may have served as the immunological danger signal, which is thought to play an important role in activating immune reactions. Hypothesis is proposed in analogy to the virus-induced hepatitis. After the troglitazone-case, pharmaceutical companies implemented screening systems for chemically reactive metabolites at early stage of drug development, taking both the amount of covalent binding to the proteins in vitro and the assumed clinical dose level into consideration. At the post-marketing stage, gene analyses of the case patients, if any, to find pharmacogenetic biomarkers could be a powerful tool for contraindicating to the risky patients.
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PMID:Drug-induced idiosyncratic hepatotoxicity: prevention strategy developed after the troglitazone case. 2117

This report is the story of the long journey to identify the mechanism of fulminant hepatitis by the antigout drug, Benzbromarone. As soon as the 8th gout patient prescribed Benzbromarone (Benz) died of fulminant hepatitis in 20 years, the letter was sent to doctors identifying it as the causative agent in February 2000. At that time, Benz had been prescribed to 350,000 patients/year for 20 years. Is Benz the real cause of fulminant hepatitis? 1. Benz is a PPARa agonist like fenofibrate, and not a PPARgamma like troglitazone. 2. Troglitazone and Allopurinol have shown apoptosis in a human primary hepatocyte culture with the DNA laddering method, but Benz has not. 3. It was reported in 1979 that benzarone is a metabolite dissociated from two Br bases of Benz, but Walter et al. reported in 1987 that the Br base was not dissociated. Benzarone was not produced by an in vitro study with human S-9 and by an in vivo clinical study of Japanese volunteers. 4. The main metabolite of Benz in humans is 6-OH Benz, which has URAT-1 activity, like Benz. 5. It has been newly discovered that CYP2C9 is only one hepatic metabolism enzyme of Benz. 6. The rate of poor metabolizers of CYP2C9*3 (homozygous) in Japan is 1/2500, meanwhile, the rate of fulminant hepatitis at this time is 8 patients in 20 years, with 350,000 patients/year; therefore, it is difficult to view poor metabolizers as the cause. 7. Hepatic injury by Benz is an idiosyncrasy, the same as with many other drugs.
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PMID:[Drug-induced hepatic injury, the challenge for cause investigation]. 2233 14