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Page 8 of 12 Balsano et al. Hepatoma Res 2018;4:38 I http://dx.doi.org/10.20517/2394-5079.2018.51

[87]
blood promoting hepatic oxidative stress and liver inflammation . As demonstrated in obese patients, the
[83]
equilibrium can be restored in case of a fat restriction diet .

Target/biomarker discovery and “Omic” approaches will help in finding new pro-oncogenic and oncosup-
pressor to be used as novel biomarkers. The new knowledge on HCC pathogenesis will open new avenues in
the diagnosis and design of patient-tailored therapies.

HCC IN NAFLD CHRONIC HEPATITIS
NAFLD has a proportion of HCC, occurring in the absence of cirrhosis, higher than other chronic liver dis-
eases. HCC in NAFLD generally lacks encapsulation and is well differentiated and characterized by large di-
[88]
mensions . Multiple studies described a significant proportion of HCC (from 51% to 65%) that have stage 0-2
fibrosis [89-91] , highlighting a specific dangerous behavior of NAFLD chronic hepatitis. Given the high number
[15]
of patients with non cirrhotic NAFLD, screening for HCC in this population is not practicable . Interest-
ingly, the features of NAFLD-related HCC are similar to those of HCC of obese patients and of non-cirrhotic
HCC, independently of the etiology [92,93] . Accordingly, it has been reported that obese patients have a relative
[94]
risk of liver cancer of 189% relative to the 117% of overweight subjects . Thus, the pathogenic mechanisms
[95]
of hepatocarcinogenesis in steatosis might be different from the classic mechanisms involved in cirrhosis .
In fact, all the NAFLD-related HCC pathogenic mechanisms are independent from fibrosis and this might
explain the particular epidemiology of HCC in NASH, where non-cirrhotic HCC is quite frequent relative to
other etiological factors.

In the light of what has been reported above, pathophysiological studies are needed to better understand the
underlying mechanisms involved in NAFLD-related HCC development. In this context, it is important to
note that the EASL evidence based clinical practice guidelines should be improved because the up-to-date
version does not exhaustively represent this specific problem.

HCC IN NAFLD CIRRHOSIS
Cirrhosis in NAFLD modifies prognosis and management. Increasing age, obesity and diabetes are consid-
[96]
ered as risk factors for the progression of NAFLD to cirrhosis . Thus, it is well known that a subset of indi-
viduals with NAFLD may progress to liver cirrhosis, which in turn could be complicated by liver failure or
[97]
even HCC, requiring liver transplantation (LT), resection, or loco-regional therapies .

However, although NAFLD has begun the most common cause of chronic liver disease worldwide [3,98] , even
today, a significant amount of patients with NAFLD are already incidentally diagnosed with cirrhotic. Un-
fortunately, NAFLD patients are asymptomatic, thus, the diagnosis of cirrhosis often occurs incidentally (70%)
because it is done during clinical assessments for the investigation of different medical conditions unrelated
to liver disease or an unexpected surgical finding. Accordingly, about the 15% of NAFLD patients selected
for biopsy have cirrhosis, confirming that the prevalence of cirrhosis in patients with NAFLD is higher than
[99]
expected . In the presence of liver cirrhosis, the main problem is the occurrence of important complica-
tions, such as: liver decompensation, thrombocytopenia, splenomegaly or, sometimes, HCC related with a
poor survival [100,101] . Late diagnosis increases the risk to find a late stage HCC, no longer curable with the
available treatments, whereas the diagnosis of HCC, if done at the early stage, is associated with better re-
sults.

Cirrhosis has to be seen as a prognostic factor predicting negative outcomes in patients. Accordingly, in re-
cent studies, it has been reported in NAFLD cirrhotic patients an overall mortality of 80% and a liver-related
[99]
mortality of 55%, after 12 years .