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Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38 Page 9 of 22

[119]
rate of 1.1%, 2.9% and 3.1% respectively . In this regard, however, the data in the literature seem to be con-
flicting.

The amount and duration of the alcohol consumption are directly related to the stage of the liver disease
[116]
and the risk of HCC . In particular, the cumulative lifetime amount of alcohol assumed acts as a major
[120]
determinant of oncologic risk . A ≥ 3 drink/day consumption is strongly associated with the incidence of
[121]
HCC and liver-related death . Furthermore, alcohol consumption is also closely related to the more rapid
[122]
increase in cancer growth once it has developed . This highlights the importance of the dose-response
relation between alcohol consumption and HCC.

The female gender has an approximately 5-fold higher risk of developing liver cirrhosis and/or HCC for
[121]
lower doses of alcohol than males . In addition, females appear to show a faster progression of the damage
[123]
towards cirrhosis in comparison with males .
[124]
A meta-analysis evaluated the occurrence of HCC after cessation of alcohol use. An annual reduction of
6%-7% of the risk of developing HCC after cessation of alcohol consumption was estimated and an average
period of 23 years because the risk is comparable to that of an ever ethylist.

Although the cumulative amount of alcohol during the lifetime is the main predictor of the risk of HCC, not
all alcohol users are destined to develop cirrhosis and/or HCC. Indeed, a number of both genetic and clinical
[125]
cofactors are also implicated in modulating the risk of ALD evolution to HCC . Several SNPs have been
reported to increase the risk of HCC, in particular those able to interfere with the metabolism of ethanol
and lipids (PNPLA3, TM6SF2), as well as hepatic iron accumulation [126-128] .

Different co-morbidities can modulate cancer risk. Obesity is an important co-factor in the development
of alcohol-induced HCC [129,130] . The risk of developing HCC is three times higher among alcohol users
2
with a BMI ≥ 30 kg/m compared to those not taking alcohol and with a lower BMI [131] . This synergy
is also recognized to exist between alcohol and other co-factors of liver injury [132] . The coexistence of
diabetes mellitus and chronic alcohol consumption leads to a significant increase in the risk of developing
HCC [129,133,134] .

A study of patients with alcoholic cirrhosis showed that the incidence of HCC among patients with and
without diabetes mellitus was 32.7% and 3.2% after 5 years, 32.7% and 20.2% at 10 years, 66.3% and 20.2% at
[135]
15 years, respectively . It has been reported that the risk of HCC among patients with diabetes mellitus
[136]
who consume more than 4 drinks/day has increased by 4.2 times .
The high consumption of alcohol in cirrhotic patients with concomitant HBV infection increases the risk of
HCC by about 10% per year, apart from the progression of its onset at an earlier age [132,137,138] . Similarly, data
are reported for OBI or previous HBV infection [139,140] . Several studies conducted on alcoholic subjects show
[143]
the synergistic effect with chronic HCV infection [141,142] or hemochromatosis on the incidence of HCC.
[129]
Simultaneous exposure to alcohol and tobacco also appears to increase the risk of HCC .

Pathogenic mechanisms of HCC secondary to alcohol abuse
The presence of cirrhosis is the major mechanism related to the development of HCC. However, alcohol is
able to directly induce carcinogenesis causing oxidative stress, inflammation and endotoxinemia.

Ethanol is first converted to acetaldehyde and then to acetate by alcohol-dehidrogenase (ADH) and
acetaldehyde-dehidrogenase (ALDH) respectively, within a process that increases the NADH/NAD +
[144]
ratio . This condition, in turn, causes a drastic change in the mitochondrial redox balance, which leads