Severe cholestatic hepatitis caused by thiazolidinediones: risks associated with substituting rosiglitazone for troglitazone

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 -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.     

Vascular endothelial growth factor increases heme oxygenase-1 protein expression in the chick embryo chorioallantoic membrane

(1) Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. It has been recently suggested that the inducible heme oxygenase (HO-1) isoform may play a role in angiogenesis. (2) The aims of this study were to determine, in chicken embryo chorioallantoic membranes (CAM), whether VEGF increases HO-1 protein expression, and, if so, by which molecular mechanism, and whether HO-1 activity is required for VEGF-induced angiogenesis. (3) Treatment of CAMs with VEGF for 48 h caused a significant increase in HO-1 protein expression, simultaneously with angiogenesis. (4) VEGF-stimulated angiogenesis in CAMs was markedly attenuated by the HO inhibitor zinc mesoporphyrin (ZnMP). This inhibitory effect of ZnMP was not observed with copper mesoporphyrin (CuMP), a metalloporphyrin that has a similar structure to ZnMP but does not inhibit HO enzymatic activity. (5) Overexpression of HO-1 protein elicited by VEGF in CAMs was significantly attenuated by the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). The effects of BAPTA-AM were, in turn, compensated by the calcium ionophore A-23187. (6) In addition, the protein kinase C inhibitor staurosporine significantly attenuated, in a dose-dependent manner, the VEGF-stimulated HO-1 induction observed in CAMs. (7) These results demonstrate, for the first time, that VEGF upregulates HO-1 protein expression in vivo in CAMs by a mechanism dependent on an increase in cytosolic calcium levels and activation of protein kinase C. Our findings also suggest that HO-1 activity is necessary for VEGF-induced angiogenesis in CAMs.     

Hepatitis C: a review and update

The hepatitis C virus is an RNA virus that is a major cause of acute and chronic hepatitis. It is contracted chiefly through parenteral exposure to infected material such as blood transfusions or injections with dirty needles. Those at highest risk for development of hepatitis C are injection-drug users, people who snort cocaine with shared straws, and health care workers who are at risk for needle-stick and other exposures. Although the incidence of acute hepatitis C infection has fallen dramatically in the United States during the past decade, the prevalence of infection remains high (approximately 2.7 million Americans) because chronic hepatitis C develops in about 75% of those infected. Both acute and chronic hepatitis C are asymptomatic in most patients. However, chronic hepatitis C is a slowly progressive disease and results in severe morbidity in 20% to 30% of infected persons. Chronic hepatitis C is associated with a host of extrahepatic manifestations, many of which may be seen by dermatologists. The most frequent of these are mixed cryoglobulinemia with leukocytoclastic vasculitis and porphyria cutanea tarda. (J Am Acad Dermatol 2001;44:159-79.) Learning objective: At the conclusion of this learning activity, participants should be familiar with the essentials of the virology of the hepatitis C virus and the major features of the human diseases caused by hepatitis C viral infection; the extrahepatic manifestations of hepatitis C viral infection, with particular emphasis upon dermatologic manifestations, including leukocytoclastic vasculitis, porphyria cutanea tarda, and lichen planus; and the current methods of management of hepatitis C and its extrahepatic manifestations.     

Role of HFE gene mutations in liver diseases other than hereditary hemochromatosis

Heavy iron overload, as occurs in primary and secondary hemochromatosis, may cause fibrosis of parenchymal organs, including the heart, liver, and pancreas, and it is a risk factor for the development of hepatocellular carcinoma. Recent evidence indicates that lesser degrees of hepatic iron deposition are also risk factors for nonhemochromatotic liver disease. For example, several recent studies showed extraordinarily high prevalences (about 60% to 75%) of HFE mutations in patients with porphyria cutanea tarda and significantly increased prevalences of these mutations in patients with nonalcoholic steatohepatitis from Australia and the United States. It is less well established that the prevalence of the HFE mutations is increased in alcoholic liver disease and in chronic viral hepatitis, but in both conditions, patients harboring one of these mutations, especially C282Y, are more likely to have advanced hepatic fibrosis or cirrhosis. Thus, these mutations both incite and exacerbate nonhemochromatotic liver disease. In this review, we summarize current knowledge of these associations and emphasize important unresolved questions that require further study     

Antiviral Response of HCV Genotype 1 to Consensus Interferon and Ribavirin Versus Pegylated Interferon and Ribavirin

Achieving an antiviral response at a reasonable cost is a challenge in the treatment of patients with chronic hepatitis C. A previous study indicated that consensus interferon with ribavirin had promising activity against hepatitis C virus (HCV) genotype 1. The objective of this study was to determine the virologic response with consensus interferon or pegylated interferon α-2b plus weight-ribavirin in patients chronically infected with HCV genotype 1. Intention-to-treat analysis showed response in 37% and 41% of subjects treated with consensus interferon/ribavirin or pegylated interferon/ribavirin, respectively, with response rates of 42% and 44% observed in analysis of the per-protocol population, not a significant difference. Tolerability of the two treatment regimens was similar. In conclusion, both treatment regimens were safe and gave a similar antiviral response. It is possible that if consensus interferon is administered daily rather than three times weekly, eradication of HCV could be achieved in a larger proportion of patients infected with HCV genotype 1.     

The Role of Iron in Hepatitis C Infection

Iron overload of varying degrees is common among patients with chronic hepatitis C. The clinical significance of this iron overload is uncertain. Studies that have evaluated the effect of hepatic iron stores on the response to anti-viral treatment or on the natural history of chronic hepatitis C have found variable results depending on the technique used to measure hepatic iron stores and the degree of iron overload present among the study population. We have tried to comprehensively analyze the literature regarding the clinical interaction between iron overload and the natural history of chronic hepatitis C. The one clear relationship that emerges is that pre treatment serum ferritin inversely correlates with the odds of achieving sustained virological(SVR) response after combination interferon ribavirin treatment. We have also reviewed the limited literature that reports the effect of therapeutic phlebotomy to reverse iron overload among patients with chronic hepatitis C. A small meta-analysis of 6 prospective randomized trials and a subsequent seventh trial do suggest that phlebotomy to induce iron depletion enhances the likelihood of achieving (SVR) after anti-viral therapy. However, these studies are primarily in patients receiving interferon monotherapy, which is of course now obsolete. Finally, a few small studies suggest that therapeutic phlebotomy to induce iron depletion reduces liver transaminase levels and may improve histology, and perhaps even reduce the risk of hepato-cellular carcinoma. Prospective randomized controlled trials of phlebotomy among patients with advanced hepatitis C and iron overload are needed.