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Page 2 of 22 Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38

INTRODUCTION
Liver cancer is the fourth leading cause of cancer-related death in the world, with about 810,000 deaths
[1]
annually . It has a high incidence rate and is the fifth most commonly diagnosed cancer in males and
[2]
the ninth in females . In addition, unlike other more common neoplasms that have a downward trend in
[3]
incidence, the rate of incidence of liver cancer appears to be increasing . Hepatocellular carcinoma (HCC) is
[4]
the most common liver cancer histotype, accounting for 80% of the liver cancers .
At present the main causes of HCC are viral infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV)
and alcohol abuse, but the obesity and the metabolic syndrome epidemic that is occurring in Western countries
[1,5]
is leading to a significant increase in HCC secondary to non-alcoholic fatty liver disease (NAFLD) . Chronic
HBV infection is associated with about 33% of total deaths observed for HCC, while 30% is associated with
alcohol abuse, 21% with chronic HCV infection and 16% with the remaining etiologies, including the ever-
[1]
increasing metabolic etiology . In fact, widespread lifestyle changes and the pandemic of the metabolic
syndrome are causing a significant increase of about 9% per year in the incidence rates of NAFLD-associated
HCC. Looking to the future, particularly in industrialized countries, this last condition could become the
[6]
main factor of HCC causing an important epoch-making change between metabolic and viral forms .

The pathogenic mechanisms underlying the development of HCC, as well as the epidemiology, the clinics
and the underlying diseases from each etiology are extremely dissimilar and explain the heterogeneous
clinical impact of HCC. The different clinical behavior of HCC often makes diagnosis difficult at an early
stage that is necessary for an effective therapeutic approach. Increasing evidence is emerging, emphasizing
how the development of HCC is a complex and multifactorial process. The comprehension of the molecular
mechanisms involved is important for the understanding of the basic factors of the development of
hepatocarcinogenesis and of possible therapeutic approaches.

This review aims to define an updated clinical picture of HCC, its epidemiological changes and, above all, to
highlight the differences in the pathogenic mechanisms related to each single etiology associated with HCC.
Table 1 summarizes the main characteristics of HCC in relation to the different etiological association.

The common denominator in the pathogenesis of HCC
Regardless of etiology, any chronic hepatitis can alter the balance of the immune system causing a low-grade
chronic inflammation that leads to the creation of reactive oxygen species (ROS), as well as the induction
of cell proliferation and the onset and progression of liver fibrosis. A high turnover of hepatocytes exposes
the patient to a higher rate of genetic alteration, such as point mutations, chromosomal abnormalities or
epigenetic alterations, whose accumulation represents the first phase of hepatocarginogenesis. In addition,
there are specific risk factors of the host such as diabetes mellitus and the male sex, and factors related to the
etiological agent that increase the oncogenic potential of the inflammatory liver disease, thus causing the
[7]
development of HCC, either in the presence or absence of significant hepatic fibrosis .
Irrespective of etiology, cirrhosis of the liver is an already pre-malignant condition that promotes the
development of genetic aberrations and cellular transformations. In fact, the chronic hepatic inflammatory
state and the accelerate hepatocyte turnover observed in cirrhosis promote the accumulation of genic
mutations. The subsequent uncontrolled proliferation and the high rate of genetic errors will lead to the
development of HCC.

HCC and HBV chronic infection
Clinical and epidemiological factors affecting development of HBV-related HCC
Currently, chronic HBV infection is responsible for about half of all observed HCC cases [8-11] . It has been
estimated that HCC occurs 10-25 times more frequently in patients with positivity for HBV than uninfected