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Page 4 of 12 Balsano et al. Hepatoma Res 2018;4:38 I http://dx.doi.org/10.20517/2394-5079.2018.51

[20]
respectively . Accordingly, an increasing number of HCC has been reported in the setting of obesity and
[22]
diabetes [15,21] and it has been associated with an increased relative risk of dying for HCC .

Unfortunately, even if consistent epidemiological data concerning viral and alcoholic hepatitis have been
reported, there is a lack of strong epidemiological results regarding the incidence and prevalence of NAFLD-
related HCC. The problem is mainly due to the absence of a correct and clear definition of NAFL/NAFLD/
NASH. Thus, so far we cannot evaluate the real dimension of NAFLD-related HCC and how to lower and
prevent its appearance.

A few longitudinal outcome studies reveal that the cumulative mortality in NAFL/NASH, in a follow-up pe-
[23]
riod between 5.6 and 21 years, vary from 0% to 3% , but we have to take into account that there are 400,000
and 40,000-80,000 new cases/year of NAFL and NASH, respectively.

Finally, the unquestionable evidence showing the increased risk of HCC in patients with NAFLD, and
mainly its appearance in non-cirrhotic patients, is in close association with the alarming and more rapidly
[24]
increasing indication for liver transplantation in respect to any other liver disease .

PATHOGENESIS
The aberrant activation of immune response and inflammation signaling observed in NAFLD have a key
role in the pathogenesis and progression of this liver disease.

The accumulation of lipids in patients with NAFLD may induce an intracellular chronic status of oxidative
stress that, in turn, leads to the activation of low-grade inflammation. The enlargement of adipocytes may
lead over time to the rupture of these cells. As a consequence, macrophages are recruited in the site of in-
flammation and M1/M2 macrophage polarization is induced. The activation of macrophages stimulates the
production of adipose tissue related adipocytokines, that, once released in the systemic circulation, reach
different organs, including liver [25,26] . The inversion of M1/M2 ratio is due to the increase of M1 macrophages
[26]
and reduction of M2 macrophages . The higher number of M1 cells cause an over production of several
pro-inflammatory cytokines, such as IL-1b, IL-6, IL-8, IL-12, and TNF-a.

Consequently, the serum of NAFLD patients is characterized by the presence of high levels of TNF-a and
IL6, that in turn are correlated with a higher risk of progression to NASH [27-30] . Moreover, higher levels of
TNF-α induce insulin resistance [31-33] and contribute to exacerbate the liver damage through the activation
[34]
of nuclear factor-kappa-B (NFκB) inflammatory pathways . Furthermore, NFκB protein has been recently
found to be involved in the regulatory feedback of two important chemokine receptors: C-X-C chemokine
[35]
receptor type 4 and 7 (CXCR4/7) . The NFκB-CXCR4/7 axis mediates the signaling of toll-like receptors,
[36]
TLR3 and TLR4, promote, in this way, the progression of NASH towards HCC .
Thus, deeply understanding the role of chronic inflammation as underlying the cause of liver transformation
will improve the prevention and cure of this cancer.

An incorrect lifestyle is currently considered the main predisposing factor of NAFLD-related HCC. In fact,
the development of HCC in NAFLD includes low-grade chronic inflammatory response (NASH) associated
with genetic alterations, oxidative stress, obesity, insulin resistance and alteration of gut microbiota [Figure 1].
The pathogenic mechanisms involved in the progression of NAFL toward NASH are characterized by two
hits: excess accumulation of triglyceride (TG) in the hepatocyte and, in a second moment, induction of
[37]
oxidative stress and inflammation by several factors, such as free radicals . In line with these findings,
more and more researchers are recognizing the central role of low-grade inflammation in inducing all of the