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Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38 Page 13 of 22

An alteration of the intestinal microbiota is often associated with NAFLD and this condition contributes to
[184]
exacerbating the inflammatory liver . In particular, there is the appearance of endotoxinemia that interacts
with TLR receptors on Kupffer cells and hepatic stellate cells triggering a cascade of inflammatory signaling
[185]
causing the production of TNF-a, IL-1β, IL-6 and ROS . This condition contributes to the progression of
liver injury and to carcinogenesis as reported above for ALF.

Pathogenic mechanisms of NAFLD-related HCC
Most of the HCC secondary to NAFLD occurs in the cirrhotic liver following the mechanism shown above
for other etiologies. However, the literature shows a consistent set of evidence on how the development of
HCC may also occur in patients without evidence of significant hepatic fibrosis [133,168] . As shown in mouse
[186]
models , hepatic steatosis secondary to the metabolic syndrome is a pre-malignant condition, long before
cirrhosis. In this regard, obesity and type 2 diabetes mellitus can be considered as independent risk factors
for the onset of HCC [78,172,187] .

The pathogenic mechanisms involved in the carcinogenesis of liver cancer in NASH, with or without
significant fibrosis, could be related to chronic low-grade inflammation induced by obesity and the metabolic
syndrome and mediated by the crucial role of insulin resistance. The development of oxidative stress, lipid
peroxidation and mitochondrial damage also play a fundamental pathogenic role. Moreover, it has been
shown that alterations of the intestinal microbiota, the presence of gene polymorphism and IR induced
hyperinsulinemia can be significant co-factors for the development of NASH and HCC. These data support
the concept of “multiple hits hypothesis” in which several factors cooperate in the pathogenesis of NAFLD
and HCC [188-190] .

The IR, the cornerstone of the metabolic syndrome, is able to induce the onset of HCC by increasing the
release of free fatty acids from the adipose tissue and subsequent accumulation in the hepatocytes on one
hand and inducing the formation of ROS and subsequent oxidative stress with mitochondrial damage
and endoplasmic reticulum dysfunction on the other hand [167] . Moreover, IR is able to alter the balance
between pro-inflammatory cytokine production (IL-6, TNF-a, leptin, resistin) and those anti-inflammatory
[191]
(adiponectin) with a significant increase in pro-inflammatory cytokine , leading to a chronic hepatic and
systemic inflammatory state. The IR-induced TNF-a stimulation leads to the activation of the nuclear factor
Kappa B (NF-κB) and of the N-terminal kinase c-Jun (JNK) on one side, as well as to the overexpression
of tumor growth promotion genes [192] on the other side. The increase in free fatty acids and TNF-a and
ROS production are all powerful activators of JNK, overexpressed in more than half of the cases of HCC,
which in turn causes the phosphorylation of the substrate-1 of the insulin receptor (IRS-1). The signalling
mediated by IRS1 can therefore act as a stimulus for cell survival, promoting the proliferation of hepatocytes
[193]
through the mitogenated protein kinase and PI3K and inhibiting cell apoptosis by blocking the TGF-β1 .
IR-induced hyperinsulinemia is also able to stimulate the production of growth factors such as IGF-1. All
the previously mentioned pathways are able to cause liver inflammation and aberrant stimulation of several
genes that are crucial in regulating cell growth and inhibition of apoptosis [175,194] .

The cytokinetic imbalance associated with the release of unsaturated fatty acids also contributes to
[195]
inhibition of tumor suppression factors (for example, phosphatase and homologue of the tensin, PTEN)
[175]
and inhibition of apoptotic cell abilities . In this regard, IR-induced oxidative stress can increase lipid
peroxidation, thus leading to the production of trans-4-hydroxy-2-nonenal, which in turn can interact with
DNA and cause mutations in the oncosuppressor gene p53, thus favouring hepatocarcinogenesis and the
[196]
progression of HCC .

[197]
The IR-induced increase in TNF-a and IL-6 also stimulates leptin production . The latter acts as a growth
factor activating the Janus-activated kinase (JAK), which in turn stimulates signal transducers and activators