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Page 10 of 22 Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38

to an increase in the oxidation of fatty acids, as well as of lipogenesis, thus inducing the development of
[145]
steatosis . Ethanol is able to inhibit hepatocyte β-oxidation, increasing the synthesis and the uptake of
fatty acids as well as promoting liver steatosis and inflammation [146,147] . Acetaldehyde, in addition to being
toxic, is also highly oncogenic. The highest levels of ADH activity in tumor cells, when compared to ALDH,
[148]
indicate that they have a high oxidation capacity of ethanol but a low ability to remove acetaldehyde .
Chronic alcohol consumption acts as an activator of cytochrome CYP2E1, which in turn increases the
hepatic production of acetaldehyde. Its accumulation is responsible for the production of ROS that gives
rise to oxidative stress induced by alcohol. The latter is responsible for mitochondrial damage, which in
turn increases the production of ROS, thus creating a vicious circle that maximizes oxidative stress in the
[149]
[150]
hepatocytes . The accumulation of iron in the liver and the low oxygen tension of the tissue induced by
alcohol are also responsible for the production of ROS. Furthermore, accumulation of intracytoplasmic lipid
droplets in ethanol-induced steatosis (as well as in NAFLD) can make hepatocytes more susceptible to toxic
[151]
or other insults . It follows that the subsequent generation of ROS, in combination with the accumulation
of damaged proteins and the increased susceptibility acquired by hepatocytes to damage of other nature,
is able to induce lipid peroxidation, enzymatic inactivation and mutations of DNA, which can cause cell
[149]
damage and inhibit apoptosis . In particular, alterations in cellular DNA methylation processes (especially
at levels of the oncosuppressor genes such as RASSF1A and/or DOK1) represent one of the most frequent
[152]
genotoxic effects of chronic alcohol consumption . All this causes serious abnormalities in the proliferation
of hepatocytes, which may eventually lead to the development of HCC.

Alcohol induces alteration of the microbiota and may contribute to the development of liver injury and
HCC. Damage to the tight junctions of the intestinal epithelium following the chronic abuse of ethanol
increases the permeability of the intestinal barrier and promotes the migration of bacteria and endotoxins
[153]
from the intestine to the portal system, thus fuelling the previously caused liver inflammatory status .
Bacterial endotoxin interacts with the toll-like receptors (TLR) present at the Kupffer’s cells, stimulating
the production of pro-inflammatory cytokines that contribute to the progression of alcohol-induced
[153]
liver injury . The alteration of TLR4 following the translocation of intestinal bacteria is able to induce
carcinogenesis by interacting with cancer-initiating stem-like cells [154-156] . The TLR4/intestinal microbiota
interaction through processes of cellular proliferation stimulation and apoptosis inhibition play a role in the
[156]
progression of HCC but it is not required for the induction of HCC .

As for other etiologies, alteration in the length of the chromosomal telomere occurs also in the course of
ALD. It has been shown that the telomeres of individuals taking> 4 drinks/day are shorter than those of
[157]
subjects who take ≤ 4 drinks/day and that telomerase reactivation is closely related to the mechanisms of
induction of hepatocarcinogenesis through uncontrolled hepatocyte replication [148,158] .

A further mechanism of induction of HCC secondary to ALD is represented by the impact of alcohol on the
[159]
homeostasis of vitamin A, whose hepatic level decreases in chronic alcohol consumption . Alcohol acts
as a competitive inhibitor of vitamin A, inducer of its catabolism, through CYP2E1 and is a promoter of its
[160]
mobilization from the liver to peripheral tissues . Reduced levels of vitamin A in the liver can contribute
to the development of HCC by altering the mechanisms of cell proliferation and apoptosis [149,161] .

From the above it is clear that ethanol abuse plays an important role as a promoter rather than an inducer of
cancer development through a process in which oxidative stress is the basis of alcohol-induced cytotoxicity.

HCC and NAFLD
Clinical and epidemiological factors affecting development of NAFLD-related HCC
Due to the recent obesity and metabolic syndrome epidemic, NAFLD is currently the fastest growing
[5]
chronic liver disease worldwide. The overage prevalence of NAFLD is currently estimated at 25% . It is