Insulin resistance, metabolic and adipokine profiles in chronic hepatitis C patients: Case-control study and mechanistic exploration
Date Issued
2010
Date
2010
Author(s)
Hsu, Ching-Sheng
Abstract
Hepatitis C virus (HCV) is a major causative agent of chronic hepatitis, liver cirrhosis, end-stage liver disease and hepatocellular carcinoma worldwide. About 55% to 85% HCV infected people will become chronic hepatitis, 5% to 20% of them will turn to liver cirrhosis after duration of 20 to 25 years, 30 % of these cirrhotic patients will become end stage liver disease in 10 years, and once cirrhosis is established, the risk of hepatocellular carcinoma is approximately 1% to 5 % per year. In Taiwan, about 2–4% Taiwanese people are chronic carriers of HCV; hence, effective tackling this virus is an important issue in Taiwan.
The goal of treating chronic hepatitis C (CHC) patients is to eradicate the virus or, in a clinical term, to attain a sustained virological response (SVR, defined as undetectable serum HCV RNA level 24 weeks after treatment cessation). However, currently approved pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy has many unpleasant side effects and is only effective in a certain proportion of patients with HCV genotype 1 (GT1) infection, especially in Western countries. Therefore, identifying baseline and on-treatment factors predictive of SVR in CHC patients is important in terms of increasing efficacy, avoiding unnecessary side effects and saving medical costs.
Several factors have been linked to the therapeutic response of CHC patients, including viral factors, host factors, metabolic factors, histological factors, the type of regimens, and the duration of infection. Among these factors, early viral kinetics following therapy has become increasingly recognized and widely used in both clinical trials and daily practice. On the other hand, there is increasing interest in the impact of chronic HCV infection on metabolic abnormalities, including glucose, lipid, cytokines, insulin resistance and adipokines. Insulin resistance and type 2 diabetes have inceased incidence in CHC patients than in other disease or chronic hepatitis B patients, and serum lipid profiles as well as hepatic steatosis are associated with HCV infection and may afftect the therapeutic response of CHC patients. Howevr, the interacions between HCV infection and host metabolism as well as the underlying mechanisms remained not fully clarified.
To examine the influence of hepatitis C virus infection on adipokines, glucose and lipid metabolism, we examine the underlying mechanisms by which HCV affects host adipokines, glucose and lipid metabolism, and vice versa, from both clinical and molecular points of views. We found CHC patients had higher alanine aminotransferase (ALT) and high-density lipoprotein-cholesterol levels, but lower total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol levels than controls. By using multiple linear regression analyses for subjects with available adiponectin data, presence of HCV infection was independently associated with higher serum adiponectin. In addition, we found body mass index and genotype were related to viral load decline at day 2, and baseline viral load and HDL level were correlated with viral load decline between day 2 and day 28 in multivariate analysis. Genotype 2, lower baseline viral load and more substantial viral load decline at day 28 predicted a higher SVR.
Recently, several groups have found that the genetic polymorphism near IL28B gene may predict the therapeutic response of CHC GT 1 infected patients receiving Peg-IFN plus RBV. Thus, it is important and will be informative to evaluate the association of genetic polymorphism near IL28B gene, SVR and metabolic profiles in CHC GT 1 infected patients. We found Taiwanese CHC patients with rs8099917 TT genotype have a better SVR and lower baseline serum TG level than subjects with GT gentype.
In the in vitro studies, we found that cells expressing HCV core proteins had lower cellular triglyceride and total cholesterol levels than controls (P<0.05, ANOVA; P<0.05, Nonparametric test for trend). HCV GT1 core proteins might down-regulate mRNA expressions of 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) synthase, HMG-CoA reductase and microsomal triglyceride transfer protein, but up-regulate mRNA expressions of farnesyl-diphosphate farnesyltransferase 1and ATP citrate lyase. Although mRNA expression of SREBP1c was up-regulated under lower levels of HCV core proteins, its expression was down-regulated with increasing HCV core protein levels. The mRNA expression of SREBP2 was up-regulated by HCV core proteins, but down-regulated with the increasing HCV core protein levels.
CONCLUSIONS: HCV is a curable disease, and the evaluation of HCV genotype, viral kinetic parameters as well as host gene SNPs before treatment has let individualized therapies for CHC patients become possible approaches. However, the interactions and underlying mechanisms of host factors and HCV infection, especially glucose and lipid metabolsim as well as their impacts on therapeutic resposes, remain not fully understood. Further experimental and clinical studies based on these lines of evidence are needed to clearly clarify underlying mechanisms and provide clinicians useful information to opitimize the mangement of chronic HCV infection.
Subjects
hepatitis C virus
chronic hepatitis C
insuin resistance
lipid metabolism
adipokines
sustained virologic response
single nucleotide polymorphism
SDGs
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