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Page 2 of 8 Abbas et al. Hepatoma Res 2018;4:43 I http://dx.doi.org/10.20517/2394-5079.2018.26

as a significant risk factor for the disease . In the majority of cases, HCC in hepatitis C occurs following
[3]
persistent liver insult in the form of chronic hepatic inflammation, advanced fibrosis and cirrhosis .
[4,5]
Recently, studies have also shown a direct role for HCV in cancer promotion with various HCV proteins
demonstrating oncogenic properties . Overall, a combination of viral, genetic, host and environmental
[6]
factors likely influence HCC carcinogenesis . Factors that thus affect or modify the likelihood of HCC
[7]
development in patients with chronic hepatitis C, have been identified by clinical and epidemiologic studies.
This review seeks to identify and analyze these diverse factors.

AGE AND GENDER
Male sex and older age are independent risk factors for HCC in chronic hepatitis C patients [1,8-12] . In one study
investigating a Chinese cohort, age > 55, and male sex were associated with an increased risk of developing
HCC . Multivariate analyses of another study showed that older age, truncal obesity, and diabetes were
[13]
significant predictors of advanced disease and HCC [14,15] . Furthermore, a study on patients with transfusion-
acquired HCV infection concluded that age at transfusion > 36 affected the risk for hepatic decompensation
and was an independent risk factor for HCC development, alongside gender .
[16]

Interestingly, multiple pregnancies may also increase the risk of HCV-related HCC. This raises questions
about the role of estrogens and other pregnancy-related hormones in the modulation of HCV infection and
its progression to HCC in female patients .
[17]

ALCOHOL ABUSE
Patients with a history of alcohol abuse have a significantly higher prevalence of HCV infection than the
general population . Furthermore, alcohol consumption in patients with chronic hepatitis C accelerates
[18]
the process of fibrosis with an increased risk for progression to cirrhosis and HCC. Indeed, a study of 2235
patients with chronic hepatitis C, daily alcohol consumption of 50 g or greater was associated with a 34%
increase in the rate of fibrosis progression . A meta-analysis of 20 articles (published between 1995 and
[19]
2004), involving more than 15,000 HCV chronically infected persons, illustrated that the pooled relative risk
of cirrhosis associated with heavy alcohol intake (defined in the range of at least 210-560 gram per week) was
2.33 [95% confidence interval (CI), 1.67-3.26] .
[20]

Alcohol abuse has been shown to be a key independent predictor of progression to HCC [21,22] . The exact
amount of alcohol that increases the risk of HCC in patients with HCV is unknown but it appears that even
modest alcohol use can accelerate fibrosis and so the risk for HCC . Indeed, a case-control study to evaluate
[23]
the risk of HCC for HCV infection found that the odds ratio (OR) of HCC development in HCV RNA
positive patients was 26.1 (95% CI: 12.6-54.0) among subjects with alcohol intake of 0-40 g/day and increased
to 62.6 (23.3-168) and 126 (42.8-373) with an alcohol intake of 41-80 and greater than 80 g/day, respectively .
[24]
The progression to HCC may be the direct result of an increase in HCV replication and an attenuation of
the antiviral action of interferon due to alcohol . Impaired host cellular immunity (due to dendritic cell
[25]
dysfunction) and increased oxidative stress and mitochondrial injury due to alcohol consumption, all
[27]
[26]
contribute to the development of HCC.

DIABETES AND NON-ALCOHOLIC FATTY LIVER DISEASE
Hepatitis C patients with obesity, diabetes mellitus, and/or non-alcoholic fatty liver disease (NAFLD) have a
higher risk of developing HCC [28,29] . In fact, five of seven studies analyzing diabetes demonstrated significantly
increased HCC risk associated with concurrent diabetes with effect sizes ranging from HR 1.73 (95% CI:
1.30-2.30) to RR 3.52 (95% CI: 1.29-9.24). Additionally, insulin resistance, as measured by HOMA-IR, was