Hepatitis C virus and glucose and lipid metabolismVirus de l’hépatite C et métabolisme du glucose et des lipides
Introduction
The hepatitis C virus (HCV) is a major cause of chronic liver disease, affecting an estimated 170 million people worldwide. The spectrum of severity of the liver disease associated with HCV—from minimal liver damage to full-blown hepatitis, both acute and chronic—varies widely as does its rate of progression towards cirrhosis. This rate seems to depend on many host-related cofactors such as age, gender, alcohol consumption, overweight and co-infections [1], [2]. The objective of this review is to discuss two such cofactors-steatosis and insulin resistance. Although both may occur independently of HCV, a direct role of HCV infection is now accepted in their pathogenesis. Steatosis and insulin resistance may not only modify the course of chronic hepatitis C, but may also influence the response to interferon alpha-based therapy.
Section snippets
HCV and steatosis
Liver steatosis is the accumulation of triglycerides in hepatocytes, and is a common finding in any chronic liver disease. Liver steatosis and steatohepatitis, once thought to arise only as a result of alcohol consumption, are now most often seen in association with the metabolic syndrome. The concomitance of increased fatty acid synthesis and the free fatty acid overflow to hepatocytes that accompanies the metabolic syndrome are the major pathogenic mechanisms leading to fatty liver in these
Clinical impact of HCV-induced steatosis
Steatosis has been reported to contribute to disease progression in chronic hepatitis C [2], [3], [9]. Steatosis on the initial biopsy has been associated with a more rapid development of fibrosis [40], [41], [42], [43], [44], [45], higher risk of hepatocellular carcinoma (HCC) [46] and decreased response to antiviral therapy [43]. In view of the discordant data reported in the literature, especially concerning the relative contribution of the different genotypes to liver fibrosis [41], [42],
HCV and insulin resistance
Insulin resistance is defined as a condition in which higherthan-normal insulin concentrations are needed to achieve normal metabolic responses or, alternatively, normal insulin concentrations are unable to achieve normal metabolic responses [51]. Even before we started measuring the level of insulin resistance in chronic hepatitis C patients, most often by measuring the homeostasis assessment score of insulin resistance, known as HOMA score, several reports suggested an association between HCV
HCV interference with insulin signaling
Experimental data suggest a direct interference of HCV with the insulin cascade. This was first shown by a study where liver specimens obtained from 42 non-obese and non-diabetic HCV-infected subjects and 10 non-HCV-infected subjects matched for age and BMI were exposed ex vivo to insulin, and examined for the contents and phosphorylation/activation status of insulin-signaling molecules [72]. Insulin-stimulated IRS-1 tyrosine phosphorylation was decreased twofold in HCV-infected patients
Clinical consequences of insulin resistance in hepatitis C
There are two major clinical consequences of the insulinresistant state associated with hepatitis C, independent of its pathogenesis: the accelerated progression of liver fibrosis; and the reduced response to therapy. We have already mentioned the role of non-virus-induced steatosis as an independent predictor of fibrosis [47]. The mechanisms by which non-viral steatosis can promote liver fibrosis range from oxidative stress to proinflammatory cytokines, insulin resistance and increased
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