Steatosis, fibrosis and hepatitis C virus infection

Hepatic steatosis is a common histological feature in chronic hepatitis C. Its prevalence varies between 40% and 85% (mean 55%), depending on the characteristics of the population studied in terms of alcohol intake, overweight, diabetes and other factors of steatosis [1], [2], [3]. If all known causes of fatty liver are excluded, the prevalence of steatosis in chronic hepatitis C remains elevated (about 40%), which is higher than that found in chronic hepatitis B (25–55%) and in the general population of Western countries (20–30%) [1], [2], [3]. Such observations suggest that the hepatitis C virus (HCV) itself may induce steatosis. In patients with chronic hepatitis C, steatosis is usually mild or moderate. Severe steatosis, involving more than 60% of hepatocytes, is observed in less than 10% of the patients [1]. Steatosis in chronic hepatitis C is predominantly macrovesicular and is located in the periportal area rather than in the centrilobular area. This is in contrast to what is observed in non-alcoholic fatty liver disease and alcoholic liver disease [1].

Two types of steatosis have been identified in chronic hepatitis C [1], [2], [3], [4]. The first type is host-related steatosis. This is caused by the association (to chronic hepatitis C) of factors responsible for steatosis, that is, excesses in alcohol consumption and metabolic factors (especially overweight). Such factors may be observed, whatever the HCV genotype. The second type is the virus-related steatosis. This results due to the induction of steatosis by the virus itself and is especially seen in patients with the HCV genotype-3 infection. The arguments for this cytopathic lesion induced by HCV genotype-3 are as follows [1], [2], [3], [4]:

The virus-induced steatosis is probably multifactorial and the HCV seems to interfere with lipid metabolism through three distinct and possibly non-mutually exclusive mechanisms [1], [2], [3], [4]:

A key question for clinicians is whether host-related or virus-related steatosis contributes to liver disease progression or is it simply an innocent bystander. Several studies have previously shown a link between the severity of steatosis and the stage of fibrosis in patients with chronic hepatitis C. These studies are critical: they are retrospective and generally based on a single biopsy examination. Besides, estimates of disease progression are highly cohort dependent, being influenced by specific risk factors of steatosis. In one of our studies conducted in patients with (1) moderate or marked metabolic or virus-related steatosis, and (2) no or mild steatosis, we could observe that the prevalence of fibrosis (F2–F4 according to the METAVIR score) was very high in patients with moderate or marked metabolic steatosis (65% of the patients). Interestingly, this prevalence was markedly lower (between 20% and 30%) and similar in patients with moderate or marked virus-induced steatosis and those with no or mild steatosis [10].

These observations suggest that steatosis itself may not be responsible for the progression of liver disease, but the metabolic factors associated with steatosis were the likely causes of disease progression. They are in accordance with the observation that in patients with non-alcoholic fatty liver disease, pure steatosis is rarely associated with disease progression by contrast to patients with non-alcoholic steatohepatitis.

This impact of steatosis on the response to antiviral treatment is also a key concern for clinicians. In some studies, the severity of steatosis and the low response to treatment were found to be related, but again, such observations do not permit a definite conclusion. Indeed, when patients with genotypes 1, 4, 5 or 6 were separated from patients with genotype-3, a marked reduction in the efficacy of the treatment was observed in patients with steatosis in the first group of patients (compared to patients with no steatosis), whereas no significant difference in response was found in genotype-3 patients, regardless of the presence or absence of steatosis [11]. In addition, when the number of metabolic factors in the patients were taken into consideration, the rate of response was inversely correlated to this number [11]. All these observations could lead to the proposal that, for disease progression, steatosis itself might not be responsible for the reduced efficacy of treatment, but causes such a reduction if associated with metabolic factors. In this regard, the impaired signalling pathway of interferon (through the up-regulation of SOCS3) was recently demonstrated in overweight patients [12]. All these findings suggest that the management of patients with chronic hepatitis C steatosis should include not only the cessation of alcohol abuse [13], [14], but also the correction of metabolic factors, mainly excess body weight, diabetes, hyperlipidemia and, more generally, insulin resistance, which both limit the risk of disease progression and reduce the efficacy of treatment. Studies are now being conducted to test the interest of PPARγ agonists as insulin sensitisers for improving therapy efficacy in chronic hepatitis C associated with the metabolic syndrome.