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Steatosis is a complication of hepatitis C virus (HCV) infection and the mechanisms of its development are complex, involving viral and host factors. Steatosis that is prevalently viral is associated with HCV genotype 3, and steatosis that is prevalently metabolic is associated with non-3 genotypes. Viral steatosis is correlated with the level of HCV replication, whereas metabolic steatosis is related to insulin resistance. The two types of steatosis have a different impact on HCV disease and may have an additive effect. HCV infection is a multifaceted disease with hepatic and extrahepatic manifestations. There is a body of evidence indicating that HCV-related steatosis plays a role in many HCV manifestations and, thus, the presence of steatosis is a predictive factor for the development of such events. The current data show that HCV-related steatosis predicts an advanced liver disease and a more rapid progression of fibrosis, as well as an increased risk of development of hepatocellular carcinoma. Moreover, the presence of steatosis in a HCV patient has a high predictive value that the subject may have or may develop insulin resistance, diabetes and metabolic syndrome. Recently, a strict association between HCV-related steatosis and development of atherosclerosis has been demonstrated. In addition, steatosis negatively impacts response rate to interferon-based treatment, even in HCV genotype-3 infection. Therapeutic strategies to improve steatosis and, consequently, response to standard antiviral therapy and outcome of disease are wanted. The authors summarize current knowledge of impact of steatosis on the above reported clinical conditions associated with HCV infection.

Summary Background Steatosis and insulin resistance (IR) have a pathogenic role in chronic hepatitis C (HCV). Adipocytokines balance modulates hepatic lipid content and IR. Aim To evaluate serum adipocytokines and relationship with virological, histological and metabolic parameters in chronic HCV. Methods Adiponectin and tumour necrosis factor-α (TNF-α) levels, HCV genotypes, HCV-RNA, IR (HOMA-IR), body mass index and liver steatosis and fibrosis were assessed in 161 non-diabetic chronic HCV patients. Results Chronic HCV patients with steatosis showed lower serum adiponectin levels and higher levels of TNF-α, HOMA, alanine aminotransferase, γ-glutamiltransferase and Histological Activity Index (HAI) and fibrosis scores. Low adiponectin levels were independently associated with grades of steatosis and HOMA-IR. Higher tumour necrosis factor-α levels were observed in patients with low adiponectin levels. The extension of steatosis was inversely correlated with adiponectin levels. A correlation between grade of steatosis with HOMA-IR and fibrosis was observed. HCV genotype 3-infected patients showed lower adiponectin levels than those with other genotypes. An independent predictor of low adiponectin levels in genotype 3 infection was the extension of steatosis. Liver fibrosis score was associated with steatosis, HAI and age. Conclusions Chronic HCV patients with steatosis showed a serum adiponectin/TNF-α imbalance that is associated with IR. Reduced adiponectin levels may be involved in the pathogenesis of steatosis, which in turn accelerates progression of fibrosis in chronic HCV.

The aim of this paper is to review and up to date the prevalence of hepatitis C virus (HCV)-associated non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and their significance in both accelerating progression of HCV-related liver disease and development of HCV-associated extrahepatic diseases. The reported mean prevalence of HCV-related NAFLD was 55%, whereas NASH was reported in 4%–10% of cases. HCV genotype 3 directly induces fatty liver deposition, namely “viral steatosis” and it is associated with the highest prevalence and degree of severity, whereas, HCV non-3 genotype infection showed lower prevalence of steatosis, which is associated with metabolic factors and insulin resistance. The host’s genetic background predisposes him or her to the development of steatosis. HCV’s impairment of lipid and glucose metabolism causes fatty liver accumulation; this seems to be a viral strategy to optimize its life cycle. Irrespective of insulin resistance, HCV-associated NAFLD, in a degree-dependent manner, contributes towards accelerating the liver fibrosis progression and development of hepatocellular carcinoma by inducing liver inflammation and oxidative stress. Furthermore, NAFLD is associated with the presence of metabolic syndrome, type 2 diabetes, and atherosclerosis. In addition, HCV-related “metabolic steatosis” impairs the response rate to interferon-based treatment, whereas it seems that “viral steatosis” may harm the response rate to new oral direct antiviral agents. In conclusion, a high prevalence of NAFLD occurs in HCV infections, which is, at least in part, induced by the virus, and that NAFLD significantly impacts progression of the liver disease, therapeutic response, and some extrahepatic diseases.

HCV genotypes 2- or 3-infected patients with a rapid virological response (RVR) to therapy with pegylated interferon and ribavirins who have a low viral load, noncirrhotic and nonobese may be considered for a shorter course of treatment. However, no studies have assessed host-viral factors associated with relapse in genotype 2 and 3 separately. Accordingly, we assessed whether 12 weeks of pegylated interferon and ribavirin was an optimized regimen for treatment of HCV genotype 2 and 3 with positive predictors of response. Power and sample size were a priori calculated and 96 consecutive chronic hepatitis C patients (53, genotype 2 and 43, genotype 3) without cirrhosis who were not obese and who achieved a RVR to therapy with peg-IFN-α-2a and ribavirin were enrolled. Fibrosis, steatosis, homeostatic model assessment-insulin resistance and HCV RNA were predefined variables to be evaluated in relapse. An intention-to-treat analysis was performed. SVR rates were 98% and 84% for genotype 2 and 3, respectively. Analysis of genotype 3 patients who had relapse showed a negative correlation with steatosis (P0.0001) and HCV RNA (P0.015). Multivariate analysis showed that steatosis was the independent predictor of relapse (OR, 0.988; 95% CI, 0.981-0.993; P0.001). Genotype 3 patients with steatosis had a relapse rate of 36.4% and 15.8% in those with high and low viral load, respectively, whereas there was no relapse in those without steatosis. In conclusion, a 12-week course of therapy is sufficient for patients without cirrhosis, not obese and infected with HCV genotype 2 achieve a RVR. This is not the case for genotype 3. Steatosis is the independent predictor of relapse. New therapeutic strategies are necessary for this subgroup of HCV genotype 3.

Chronic hepatitis C (HCV) infection is considered a metabolic disease. It is associated with a specific metabolic syndrome, HCV-associated dysmetabolic syndrome (HCADS), consisting of steatosis, hypocholesterolemia and insulin resistance/diabetes. These metabolic derangements contribute to a decrease in sustained virological response (SVR) to pegylated-interferon-α-ribavirin as standard of care (SOC), and are associated with progression of liver fibrosis.The review, highlighting the impact of HCADS and metabolic syndrome components of HCV disease progression and SOC, discusses current knowledge and perspectives on metabolic therapeutic strategies aimed at improving SVR rate of SOC for chronic hepatitis C.HCV, features of HCADS and of metabolic syndrome may coexist in the same patient, thus all components of the metabolic syndrome must be assessed to individualize treatment. The results of therapeutic trials evaluating metabolic strategies combined with current SOC indicate that weight loss is a critical part of treatment which will improve both disease outcome and therapeutic response to SOC. Similarly, statins seem to improve response rate to SOC representing, once confirmed to be safe, an important therapeutic tool for HCV-infected patients. Findings from studies using insulin sensitizers combined with SOC are not conclusive and do not justify the use of this class of drugs in clinical practice.

Treatments for chronic hepatitis C (CHC) patients intolerant to pegylated interferons (peg-IFNs) are lacking. Thus, such patients remain at high risk of developing an advanced and decompensated liver disease. Leukocyte IFN-alpha (Le-IFN-alpha) seems to possess a safer profile than other natural and recombinant alpha-interferons, but no information is available for peg-IFN intolerant patients. Accordingly, we evaluated the safety and efficacy of Le-IFN-alpha in patients intolerant to peg-IFNs. Twenty-five consecutive CHC patients intolerant to peg-IFNs were prospectively enrolled. HCV genotype 1 was present in 80% and cirrhosis in 68% of cases. Thirteen patients (52%) had thrombocytopenia. Le-IFN-alpha (3 MU three times a week) was administered for 48 weeks plus ribavirin 800 or 1,000 mg/day for HCV genotype 2/3 and 1, respectively. The follow-up was at 24 weeks. Compliance with treatment was satisfactory if the patient received 80% of the therapeutic regimen. An intention-to-treat analysis was done. Eighty-eight percent of CHC patients completed the prescribed treatment course with Le-IFN-alpha. In these patients the side effects, when observed, were mild to moderate, and did not require Le-IFN-alpha dose adjustment. Le-IFN-alpha showed significantly less hematological toxicity than peg-IFN (4 vs 48%; P < 0.02). The overall sustained virologic response was 32%, i.e., 24% for cirrhotics and 50% for CHC, and 25% for genotype 1 and 60% for genotypes 2/3. The data indicate that Le-IFN-alpha plus ribavirin is a useful and effective treatment for CHC patients who are intolerant to peg-IFNs.

BACKGROUND/AIMS: The contribution of oxidative stress to the pathogenesis of chronic hepatitis C (CHC) is still poorly elucidated. This study investigated the relationship between oxidative stress, insulin resistance, steatosis and fibrosis in CHC. METHODS: IgG against malondialdehyde-albumin adducts and HOMA-IR were measured as markers of oxidative stress and insulin resistance, respectively, in 107 consecutive CHC patients. RESULTS: Oxidative stress was present in 61% of the patients, irrespective of age, gender, viral load, BMI, aminotransferase level, histology activity index (HAI) and HCV genotype. Insulin resistance and steatosis were evident in 80% and 70% of the patients, respectively. In the patients infected by HCV genotype non-3, but not in those with genotype 3 infection HOMA-IR (p