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8.2.7 Chronic HCV Infection and Steatosis
Hepatic steatosis (fatty liver) is characterized by the cytoplasmic accumulation of
lipid droplets (LDs). Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic
steatohepatitis (NASH) are associated with HCV with approximate prevalence of
55% and 4–10%, respectively. HCV genotype 3 preferentially induces “viral steato-
sis,” with a prevalence of about 86%, whereas genotypes 1 and 2 induce steatosis in
about 40 and 50% of infected patients, respectively. HCV-associated NAFLD has a
higher prevalence than in the general population and in HBV-infected population
[ 73 ]. Hepatic steatosis poses an additional risk for HCC in patients with hepatitis
C-related cirrhosis [ 63 ].
HCV infection perturbs host lipogenesis in a chimpanzee model [ 74 ]. Expressionof HCV proteins directly alters lipid metabolism in a transgenic mouse model
expressing a full length of viral polypeptide [ 75 , 76 ]. HCV chronically infected
patients has a unique composition of triglycerides enriched in carbon monounsatu-
rated (C18:1) fatty acids, suggesting that it may be induced via a virus-specific
mechanism [ 63 ]. HCV core protein may play an important role in hepatic steatosis.
Core protein accumulates on LD [ 77 ]. HCV core-transgenic mouse develops HCC
and shows hepatic steatosis early in life [ 64 ]. In a transgenic mouse model, hepatic
overexpression of core protein reduces microsomal triglyceride transfer protein
(MTP) activity and the particle size of nascent hepatic triglyceride-rich very low-
density lipoproteins (VLDL) [ 78 ]. In chronic hepatitis C, hypobetalipoproteinemia
that is characterized by a reduced plasma level of apolipoprotein B (apo B)-containing
lipoproteins (LDL, VLDL) is observed and associated with steatosis, especially in
patients infected with genotype 3 [ 79 ].
The mechanism of steatosis that contributes to fibrosis in hepatitis C may besimilar to that observed in NAFLD, in which steatosis acts as a “first hit” and
together with a “second hit” to progress to inflammation and fibrosis [ 80 ]. The oxi-
dative stress may act as a “second hit” and induces lipid peroxidation, generating
proinflammation and profibrotic products. A pilot study of antioxidant therapy with
d-α-tocopherol significantly decreases the oxidative stress and reduces stellate cell
activation and collagen α1 (I) expression, an important step in fibrogenesis [ 81 ].
8.2.8 The Cellular Origin of HCC
The origin to the cancer progenitor in HCV-associated HCC is poorly understood.
Both infected hepatocytes and uninfected hepatic progenitor cells are capable of
regeneration following liver injury to develop HCC founder cells [ 24 ]. Immune-
mediated liver damage prompts hepatocellular regeneration, which in turn results in
a “cancer field” with genetically altered hepatocyte. Whether HCV infects the
regenerated hepatocytes is unclear, given that robust interferon production is
detected within the HCV-infected hepatocytes from HCV-infected patients [ 82 ].
8 HCV-Associated Cancers