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Page 2 of 6 Bellentani. Hepatoma Res 2020;6:29 I http://dx.doi.org/10.20517/2394-5079.2020.10
[6,7]
[4,5]
period . There are significant geographic variations in the incidence of NASH and NASH-HCC .
HCC, in general, has the sixth highest cancer incidence, and is the fourth leading cause of cancer-related
[8]
death in the world . It is already known that the most prevalent cancer in obesity and T2DM is HCC,
and that the prevalence of NAFLD/NASH in obesity and T2DM is significantly higher than in the general
population, being 75%, 95% and 25%, respectively [9,10] . Obesity and high-fat diet are increasingly recognized
as major risk factors for HCC-NASH, but the exact molecular mechanisms integrating these events remain
[11]
unclear . Furthermore, the etiology and pathogenic link between obesity, T2DM and NASH-HCC is not
completely understood, at least in humans. It could be related to STAT-1/STAT-3 intracellular signaling
[12]
[11]
or, according to new pathogenetic interpretation, also to alteration of the gut microbiota . We also know
that a substantial proportion of patients with NAFLD/NASH will never develop HCC, and thus, it is very
important to understand the exact relationship between NASH-cirrhosis and NASH-HCC and metabolic
diseases to program good prevention and treatment measures for these patients.

We try to unravel these still less known diseases in the following section.

THE NATURAL HISTORY OF NASH
NAFLD is still interpreted as a negative definition used to describe a spectrum of metabolic liver
diseases due to excessive hepatic fat accumulation with associated insulin resistance, in the absence of
significant alcohol consumption or other causes [13,14] . While NAFLD can refer to simple steatosis, NASH is
characterized by inflammation and is associated with an increased risk of progression to fibrosis, advanced
fibrosis, cirrhosis, hepatic decompensation and HCC [13,14] . NASH can only be reliably differentiated from
NAFLD histologically, and the prevalence of NASH among biopsied NAFLD patients is estimated to
be 59.1% (95%CI: 47.55%-69.73%) from pooled NASH prevalence data . Fibrosis is an important bad
[15]
prognostic factor in NAFLD/NASH and in patients with NASH and advanced (F3) fibrosis or compensated
cirrhosis, and it has been shown that approximately 20% of them will progress to cirrhosis/HCC, or hepatic
[4,5]
[5]
decompensation over a 2-year period . As shown in Figure 1 and as reported by Goah and McCollough ,
the natural history of NASH and its passage to advanced fibrosis, and then to cirrhosis and to HCC,
depends on different risk factors such as sex, age, obesity, T2DM, genetic factors, and fibrosis stage. The
first steps are also driven by a genetic predisposition contributing by itself to the development of insulin
resistance and hepatic steatosis. Other co-factors could determine the lower or higher rate of progression
from NASH to advanced fibrosis and to cirrhosis or HCC [Figure 1].

It must also be considered that NAFLD and NASH prevalence and incidence are different according
to sex, usually higher in men than in premenopausal women (or age ≤ 50-60 years), while they tend to
become more common in women after menopause (or age ≥ 50-60 years) . This is probably due to sex
[16]
hormone levels that might influence hepatic lipid and carbohydrate metabolism; particularly, it seems that
estrogens may protect the liver from fibrosis in NAFLD/NASH. Estrogen seems to protect also from liver
tumorigenesis, and theoretically, prolonging estrogen depletion (i.e., premature menopause) may lead to
[16]
increased HCC risk in women with NASH .

OBESITY, GUT MICROBIOTA AND NASH-HCC
Mechanisms of obesity induced HCC
Obesity is a major driver of cancer, especially HCC.

The prevailing view is that NASH and fibrosis or cirrhosis are required for HCC in obesity. However,
[11]
they can also be dissociated in obesity. A recent work by Grohmann in mice showed a strict correlation
between STAT-1 signaling in inducing NASH and fibrosis and STAT-3 in promoting HCC formation. The
authors were able also to demonstrate that STAT-3 signaling can drive tumor development in a context