In our cohort study, the prevalence of MS and diabetes was significantly higher in patients with HCV-related chronic hepatitis than in patients with HBV-related chronic liver disease. This suggests that insulin resistance, which is the mechanism underlying MS, might at least in part be related to HCV infection. Insulin resistance is identified with the euglycemic clamp technique[27
] or with the homeostasis model assessment insulin resistance (HOMA-IR) test[28
]. Neither euglycemic clamp nor the HOMA-IR test was performed in our patients. However, we used the most practical worldwide accepted definition of MS according to the ATP-III NCEP clinical criteria[20
]. Moreover, unlike other authors[16,29–32
], we were able to measure, using these criteria, central obesity which is considered the fundamental condition for a clinical diagnosis of MS[33
]. The association of diabetes and severe chronic liver disease is widely recognized[4,16,32,34
], therefore the effect of severe liver disease on diabetes onset should be considered when comparing groups of patients affected by chronic liver disease. In our study, we were able to rule out that diabetes was related to the altered hepatic glycaemic homeostasis due to severe liver disease (i.e. cirrhosis). In fact, whereas the total prevalence of diabetes did not differ between HCV and HBV patients, the prevalence of diabetes among patients with mild chronic hepatitis was significantly higher in HCV subjects.
This finding confirms reports of a higher prevalence of diabetes in HCV patients[14,29,34
], and, vice versa
, a report of a higher prevalence of HCV in diabetic patients[30
]. Moreover, our data are in line with recent reports of a higher prevalence of diabetes in HCV patients compared with other liver diseases (e.g. HBV infection)[1
]. In particular, Jan et al[17
] reported a significantly higher prevalence of MS in HCV patients vs
HBV patients, and an inverse ratio between HBV infection and clinical expression of MS in a population-based study carried out in Taiwan.
The association between diabetes and HCV-related chronic hepatitis was reported to influence the clinical outcome of liver disease[35–37
]. Moreover, diabetes and/or obesity were found to be cofactors of liver disease in that they affect liver fibrosis progress and response to antiviral therapy[23,24,37–39
]. Here we report that, besides ALT, sex and age, also diabetes and BMI were independent risk factors for more severe liver fibrosis in HCV-positive patients, whereas they were not associated with the severity of liver fibrosis in HBV subjects. This finding supports the idea that obesity and diabetes might represent clinical epiphenomena of the pathogenesis of HCV infection. In line with this hypothesis, using an animal model, Shintani et al[40
] found that HCV directly affects serum glycaemic and insulinaemic levels, probably by acting via
TNF-α. Similarly, Kawaguchi et al[41
] reported that HCV directly affects intracellular insulin metabolic pathways via
genetic up-regulation. However, we cannot exclude the possibility that synergism between the two diseases (diabetes/non-alcoholic steatohepatitis and virus-related chronic hepatitis) affects the outcome of liver fibrosis[7,11
Steatosis has been associated with more severe liver fibrosis[23–26
] as well as with a worse response to antiviral therapy. Moreover, steatosis is defined “metabolic steatosis” in non-3-genotype-infected patients as opposed to the viral steatosis typical of genotype 3 patients[11
]. In our cohort of HCV patients, steatosis did not appear to be an independent risk factor for fibrosis stage. The discrepancy between our results and previous findings is apparent. Indeed, univariate and multivariate analyses vs
fibrosis showed that steatosis was associated with the severity of liver fibrosis in our HCV patients if they were also affected by diabetes and/or obesity. Moreover, at multivariate analysis vs
steatosis, BMI, diabetes and fibrosis were independent risk factors only for steatosis > 30%. This suggests that histological features of fibrosis, whether related to non-alcoholic steatohepatitis or to virus-associated steatohepatitis, will be found only in cases in which steatosis is > 30%.
This study provides clinical evidence that HCV directly affects insulin resistance in a large Italian retrospective, single-centre, consecutive population of HCV- and HBV-infected subjects. Biological, molecular and genetic studies are required to test this hypothesis.