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Page 8 of 22 Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38

insulin signalling and induce insulin-resistance, which in turn is responsible for the activation of hepatic
stellate cells and subsequent fibrosis [104,105] . The presence of insulin resistance or diabetes mellitus represent
independent risk factors for the progression of the liver disease and the development of HCC in patients
[106]
with chronic HCV infection . Some evidence suggests that somatic mutations of the leptin receptor (LEPR)
[107]
gene may increase the susceptibility to hepatocyte cancer transformation .
Finally, virus-induced immune alterations can also help create an ideal environment for HCC development.
The HCV, in fact, is able to inhibit the production of interferon type 1 and to alter the immune response of
both T cells CD8+ and natural killer [105,108] . In combination with the aforementioned cytokine alterations
and oxidative stress, these immune alterations contribute to the persistence of chronic inflammatory hepatic
disease, which provides fertile soil for malignant degeneration.

Effect of treatment on development of HCV-related HCC
The recent introduction of direct-action antivirals (DAAs) for the treatment of HCV infection that causes
a sustained virologic response (SVR) in more than 95% of cases appears to induce a significant decrease
in HCC cases associated with this infection. As already demonstrated for interferon-based therapeutic
regimens [109,110] , several studies seem to demonstrate that achieving SVR using DAAs reduces the risk of
[111]
HCC . The incidence rate of HCC in cirrhotic patients with SVR may decrease up to 1% per year, although
a lower rate of reduction is observed in patients with concomitant metabolic syndrome. However, because
the risk of HCC in patients with cirrhosis persists even after HCV elimination, a reasonable time frame will
[109]
be required before significant epidemiological changes can be observed . Although it is quite clear that the
achievement of SVR reduces the long-term risk of HCC, the possible role of DAAs in increasing the risk of
[112]
HCC de novo and recurrence of HCC successfully treated is still a matter of debate . In a meta-analysis
[113]
of 26 studies including 11,523 patients it was found that there were no significant differences in incidence
[114]
rates of de novo HCC between treatment regimens based on DAAs and IFN. Ioannou et al. identified a
71% HCC risk reduction after achieving SVR through DAAs on a cohort of approximately 62,000 patients
and confirming that there are no substantial differences in the HCC rate between patients treated with
[115]
DAA and those treated with IFN. Kanwal et al. show that achieving SVR in patients treated with DAA is
associated with a 76% reduction in the risk of HCC.

For what concerns the impact of DAAs on the recurrence of HCC previously treated with curative intent,
the data available are still controversial and further studies may be necessary for a correct evaluation of the
impact of DAAs therapeutic regimens on HCC recurrence risk.

HCC and alcohol abuse
Clinical and epidemiological factors affecting development of HCC secondary to alcohol abuse
Consumption of alcohol is the second leading cause of HCC worldwide, as it is responsible for around a third
[1]
of cases . Europe and Latin America are the areas with the highest incidence rates of HCC secondary to
alcohol abuse, accounting for about half of the total. It has been estimated that chronic alcohol consumption
is associated with an approximately 2-fold increase in the odds ratio for the development of HCC, but this
risk increases up to 5-7 times if consumption exceeds 80 g/day for a time period of more than 10 years, thus
underlining the close dose/risk correlation [116,117] . Although there is no absolute “threshold” dose that can be
applied as a parameter to all people, as the risk of alcohol-related damage is individual, an average chronic
consumption of ≥ 2 drink/day in females and ≥ 3 drink/day in males for longer than a 10-year time span is
associated to the onset of alcoholic liver disease (ALD), which encompasses a wide spectrum of clinical pic-
tures ranging from steatosis to steatohepatitis to the development of liver cirrhosis. From the time when cir-
rhosis is established, the risk of occurrence of HCC is 1%-2.5% per year [118,119] . Compared to other etiologies,
the risk of neoplastic transformation appears to be lower among ALD patients. In fact, a recent observational
study showed that the cumulative incidence rates of HCC after 10 years of observation were lower in ALD
cases (8.4%) than in cases of chronic HCV infection (22%) and NAFLD (23,7%), with an annual incidence