Page 147 - Read Online

Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38 Page 11 of 22

characterized by the intrahepatic accumulation of triglycerides and includes a spectrum of diseases ranging
from simple steatosis to steatohepatitis (NASH) and to cirrhosis of the liver. The annual incidence of HCC in
patients with NAFLD is reported to be 0.44 in 1000 patients, while the annual incidence in patients who have
[5]
already developed NASH is 5.29 cases in 1,000 patients . It has been estimated that NAFLD is responsible
[6]
for about 14% of HCC cases in the United States, with an annual rate of increase of 9% .
A recent meta-analysis of cases of liver cancer diagnosed in the United States between 2004 and 2009 showed
[6]
that the prevalence of HCC secondary to NAFLD is about 14% . The estimated annual cumulative incidence of
HCC in cirrhosis by NAFLD is 2.6% [5,73,160] . A recent study of our group found an annual rate of incidence of 3.5%
of HCC in patients with cirrhosis from NAFLD, this incidence is slightly lower than that observed in cirrhosis
[162]
[75]
secondary to HCV (4.5%) . Similar annual incidence rates of HCC were also observed by Ascha et al. (2.6%
and 4.0% in patients with metabolic cirrhosis and HCV-related cirrhosis, respectively).
However, as already mentioned, increasing evidence suggests that NAFLD may cause the development of
HCC even in non-cirrhotic patients with mild or absent fibrosis [133,163-168] . There are conflicting data on the
[169]
true prevalence of HCC on non-cirrhotic steatotic liver . A recent review of data on 61 studies published
between 1992 and 2011 shows that the risk of HCC in non-cirrhotic patients with NAFLD appears to
be extremely low [166] . On the other hand, there are several studies that support the opposite hypothes
[164]
is [163,164,167,168,170] . In a group of 31 patients with NAFLD and HCC, Paradis et al. observed that, 65% of cases
were in a F0-F2 fibrosis stage, whereas in the control group with liver disease of another etiology, only 26%
[167]
of HCC were in the F0-F2 fibrosis stage. Mittal et al. , in a cohort of 107 patients with HCC and NAFLD,
[168]
34.6% of liver cancer cases occurred in the absence of cirrhosis. Piscaglia et al. have recently observed
a high incidence rate (70%) of HCC in non-cirrhotic patients with NAFLD, although histology was only
available for one third of patients.

The evaluation of further co-factors appears to be fundamental for the individual assessment of the risk of
HCC. Obesity and diabetes mellitus in particular are by now well-known independent risk factors for HCC.
[78]
Calle et al. have shown, in a large cohort of patients, how obesity increases the risk of HCC by 2-4 times.
[171]
In comparison with individuals with normal weight, Larsson et al. estimated the risk of HCC in normal
weight and obese subjects by establishing a relative risk of 1.17 and 1.89, respectively.

It has been shown that the presence of diabetes mellitus increases the risk of HCC in patients with
NAFLD [19,172,173] . A recent study of 480 patients with NAFLD or ALD showed that the prevalence of
HCC among diabetic patients was statistically higher compared to normoglycemic patients (8% and 3%,
respectively) and the incidence rate of HCC during 3 years follow-up was almost three times higher (27%
[172]
[173]
and 10% respectively) . Davila et al. confirm that the risk of HCC is three times greater in the presence
of diabetes mellitus. Furthermore, diabetes mellitus and obesity can act in synergy. An Italian study has
observed that the presence of one of the two factors leads to 3.5 odds ratio (OR) of HCC, while the OR
[174]
increases to 11.8 in the presence of both, compared to normal weight and normo-glycemic subjects .
Therefore, an obese and diabetic patient with NAFLD is the most classic patient phenotype that shows a high
probability of developing HCC, particularly when co-factors are associated with an existing hepatic damage.
In fact, when obesity is accompanied by chronic alcohol consumption or by HCV or HBV infection, the
risk of developing HCC shows a tendency to increase exponentially, thus observing the synergistic action of
these co-factors of hepatic injury [130,175,176] .

The general clinical picture of HCC occurring in NAFLD shows peculiar characteristics. In this regard,
[6]
Younossi et al. showed how the development of HCC on NAFLD involves an older average popula-
[177]
tion with a higher prevalence of cardiovascular disease. Weinmann et al. confirm a high average age
(67.6 years) of patients with HCC in NAFLD, a higher prevalence among males, a higher incidence of