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The level of HCV replication within the tumor remains controversial. There are
reports showing no differences in the levels of viral RNA between the tumor and
nontumorous liver tissues [ 83 , 84 ], whereas other reports show low levels of viral
RNA in the tumor tissue [ 85 , 86 ], which is probably due to the loss of miR-122, a
host factor required for HCV replication [ 87 , 88 ]. Harouaka et al. reported that HCV
infection is dramatically reduced in HCC tissues compared with non-tumor tissue.
And the diminished viral replication is not associated with the abundance of miR-
122 [ 89 ]. Previous studies demonstrate HCV replication is compartmental in the
liver and the percentage of infected hepatocytes is low, ranging from 5 to 20% [ 82 ,
90 – 93 ], which may reflect the cell-to-cell transmission of HCV in vivo [ 94 ]. A
recent study shows limited intrahepatic compartmentalization in end stage of liver
disease [ 95 ]. In agreement with this finding, Harouaka et al. found no compartmen-
talization of HCV replication between non-tumor cells and serum, indicating effi-
cient HCV replication in nontumorous liver tissue [ 89 ].
8.2.9 HCV Genotypes and HCC
There are seven main HCV genotypes with distinct geographical distributions [ 8 ].
Several studies suggest certain HCV genotypes as an increased risk factor for
HCC. HCV genotype 3 may increase the risk of HCC compared to genotype 1 [ 96 ],
which might be due to its association with steatosis as discussed above. HCV geno-
type 1b shows a higher risk than genotype 2 to develop HCC [ 97 ]. Some mutations
in HCV core region of genotype 1a and 1b are associated with high risk of develop-
ing HCC [ 98 , 99 ].
8.3 Association of HCV Infection and Lymphoma
8.3.1 HCV Infection and Mixed Cryoglobulinemia (MC)
Chronic HCV infection is commonly associated with extrahepatic manifestation
[ 12 ]. Type II mixed cryoglobulinemia (MC) is the most common extrahepatic mani-
festation in HCV-infected patients, ranging from 10 to 70%. MC is characterized by
the presence of cryoglobulins in the circulation. Cryoglobulins are cold-insoluble
immune complexes, which precipitate at temperature below 37 °C. Type II MC is
characterized by a mixture of polyclonal immunoglobulin (IgG) and monoclonal
IgM with rheumatoid factor activity usually against IgG. Cryoglobulins contain
rheumatoid factor, polyclonal IgG, and HCV particles and can form intravascular
deposition [ 100 ].
Z. Yi and Z. Yuan