Hepatitis C Virus Diversity and Hepatic Steatosis

P. Roingeard


J Viral Hepat. 2013;20(2):77-84. 

In This Article

Abstract and Introduction


Hepatitis C virus (HCV) infection is closely associated with lipid metabolism defects throughout the viral lifecycle, with hepatic steatosis frequently observed in patients with chronic HCV infection. Hepatic steatosis is most common in patients infected with genotype 3 viruses, possibly due to direct effects of genotype 3 viral proteins. Hepatic steatosis in patients infected with other genotypes is thought to be mostly due to changes in host metabolism, involving insulin resistance in particular. Specific effects of the HCV genotype 3 core proteins have been observed in cellular models in vitro: mechanisms linked with a decrease in microsomal triglyceride transfer protein activity, decreases in the levels of peroxisome proliferator-activating receptors, increases in the levels of sterol regulatory element-binding proteins, and phosphatase and tensin homologue downregulation. Functional differences between the core proteins of genotype 3 viruses and viruses of other genotypes may reflect differences in amino acid sequences. However, bioclinical studies have failed to identify specific 'steatogenic' sequences in HCV isolates from patients with hepatic steatosis. It is therefore difficult to distinguish between viral and metabolic steatosis unambiguously, and host and viral factors are probably involved in both HCV genotype 3 and nongenotype 3 steatosis.


Hepatic steatosis, defined as excessive lipid accumulation in the cytoplasm of hepatocytes, is a frequent histological feature in patients chronically infected with hepatitis C virus (HCV) (Fig. 1). Before the identification and characterization of HCV in 1989, the presence of steatosis was used to discriminate between so-called non-A non-B hepatitis and other forms of chronic liver disease, such as hepatitis B or autoimmune hepatitis. This suggests a probable direct role for HCV in the development of excess fat accumulation in the liver. However, the mechanisms underlying hepatic steatosis in HCV-infected patients are difficult to unravel, due to the possible co-existence of several confounding factors, including metabolic syndrome, type 2 diabetes, obesity and a high body mass index (BMI), in patients. These cofactors may occur together in HCV-infected patients and may cause various degrees of hepatic steatosis through mechanisms similar to those of classical nonalcoholic fatty liver disease (NAFLD), mostly through insulin resistance.[1,2] Furthermore, hepatic steatosis may result from other challenges to the liver, particularly in cases of excessive alcohol consumption.

Figure 1.

Electron micrographs showing the accumulation of large lipid droplets (LD) in the cytoplasm of hepatocytes on liver biopsy specimens from four chronic HCV carriers. (nuc = nucleus). Scale bars: 5 μm in (a), 2 μm in (b), (c) and (d).

It has been suggested that there are two main types of steatosis in patients with hepatitis C. The first is a metabolic type of steatosis associated with a high BMI, hyperlipidaemia and insulin resistance. The second is a virally induced form of steatosis that develops in the absence of other 'steatogenic' cofactors and that seems to be directly triggered by the virus. The situation is further complicated by the possible role of HCV as a cofactor in the development of the metabolic type of steatosis; this virus has itself been shown to induce insulin resistance, potentially favouring the development of hepatic steatosis.[3,4] Nevertheless, virally induced steatosis is widely considered to be predominantly, and perhaps strictly, linked with HCV genotype 3 infection.[5] The HCV RNA genome displays considerable diversity, both within and between isolates, and three levels of classification have been adopted, grouping viral sequences into six genotypes, several dozen subtypes and intra-isolate variants. Hepatic steatosis is common in patients infected with genotype 3 viruses and seems to be directly related to intrahepatic viral load, suggesting a direct viral effect that is not observed with other genotypes.[6] Moreover, following successful HCV eradication by antiviral therapy, hepatic steatosis resolves in most individuals infected with genotype 3 viruses, but not in those infected with genotype 1 viruses.[7] Further evidence supporting this link has been provided by in vitro studies showing that the HCV core protein induces lipid droplet (LD) accumulation that is more pronounced with genotype 3 proteins than with proteins from viruses of other genotypes.[8–10] In this review, I discuss the basic and clinical aspects of this link between HCV diversity, including genotype classification, and steatosis development.