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[2]
disease in the Western industrialized countries . NAFLD has a wide geographic distribution to take on epi-
demic proportions: prevalence of NAFLD has been reported to be 25% worldwide. The highest prevalence is
reported from South America (31%) and Middle East (32%), followed by Asia (27%) and USA (24%), while the
prevalence is lowest in Africa (14%). In Europe the median prevalence is 23%-26% with variations in different
[3]
European populations .

NAFLD is caused by an insulin resistance and, as reported above, often occurs with the presence of diabetes,
obesity, and metabolic syndrome; therefore, liver can be considered the alarm bell of all of these patholo-
[4]
gies . The progressive form of NAFLD is non-alcoholic steatohepatitis (NASH) that can lead to advanced
fibrosis, cirrhosis and HCC. It is worrying that NAFLD related HCC has been at present recognized as a
growing burden worldwide, and its impact is expected to further grow together with the increasing inci-
[4]
dence of obesity and diabetes .
Of particular interest is the emergence of HCC during chronic liver disease in absence of liver cirrhosis, that
[5,6]
is known as the major risk factor for HCC development .

HCC development requires decades and is characterized by a gradual transition through a dysplastic to
[7]
transformed liver tissue . Liver transformation is the result of uncontrolled cell growth that results in the
accumulation of genomic alterations occurring during cell division thus becoming the driving force for tu-
morigenesis. Five mechanisms are involved in maintaining genomic stability during cell division: (1) high-
fidelity of DNA replication in S-phase; (2) precise distribution of chromosomes in daughter cells during
mitosis; (3) DNA repair throughout the cell cycle; (4) cell cycle checkpoints; and (5) induction of apoptosis
[8]
or senescence in case of genomic instability . On the other hand, there are multiple oncogenic mechanisms
that participate in genomic instability: alterations in the DNA-damage-response pathways, telomere erosion,
[9]
chromosome segregation defects .
Even if several pathogenic mechanisms, such as obesity-mediated chronic inflammation and diabetes, have
been described to be involved in NAFLD related HCC till now, as extensively reported below, we do not have
clear ideas on the pathogenic mechanisms driving transformation of the cell during NAFLD [10,11] . In this
context, low grading chronic inflammation has indubitably a crucial role in NAFLD disease progression to-
[12]
ward HCC . During low grade inflammation, the overproduction of reactive oxygen species (ROS) induces
the output of advanced glycation end-products (AGEs), advanced lipoxidation end-products (ALEs) and pro-
tein oxidation products (PrOPs) in tissues [13,14] , inducing pro-inflammatory cascades and increasing the risk
of liver tissue transformation. Thus, to better understand the pathogenic mechanisms underlying NAFLD
related HCC, first of all, we should better know all the biological factors involved in promoting inflamma-
tion that consequently participate in hepatocarcinogenesis.

Further studies should be performed to highlight new insights in the pathogenesis of HCC during NAFLD.
However, scientific consensus exists a on the concept that the progression of NAFLD toward HCC is surely
linked not only to environmental but also genetic factors. Accordingly, genome-wide association studies
highlighted several single nucleotide polymorphisms (SNPs) associated with the pathology of NAFLD [Table 1].
Furthermore, induction of epigenetic alterations due to unhealthy diet and/or other environmental factors
are surely involved in NAFLD related HCC.

Perspective studies are needed to implement screening strategies and preventive approaches for NAFLD-
related HCC development, particularly in the non-cirrhotic population. The notions reported in this review,
describing several NAFLD-related molecular target pathways, will be useful to clinicians to outline diagnos-
tic and prognostic profiles of these complex and heterogeneous patients.