Page 148 - Read Online

Page 12 of 22 Nevola et al. Hepatoma Res 2018;4:55 I http://dx.doi.org/10.20517/2394-5079.2018.38

myocardial infarction and ischemic stroke, as well as a higher prevalence of obesity and diabetes mellitus.
NAFLD-HCC patients show lower mean ALT levels and a higher platelet count than HCV-related HCC pa-
tients [75,178] .

The onset of HCC in NAFLD is generally an early event in the natural history of liver disease [75,177] . In fact,
the incidence of HCC on metabolic cirrhosis in a Child-Pugh A score appears to be 1.8 times higher than
[75]
that observed in HCV-related cirrhosis . In a recent Italian study the diagnosis of HCC was placed at an
early stage (Child-Pugh A) in 82.3% of patients with NAFLD, compared to 68.1% of patients with chronic
[168]
HCV infection . The model for end-stage liver disease scoring (MELD) is also significantly lower for HCC
[177]
in NAFLD than in other etiologies .
Contrary to the stage of cirrhosis of the liver, the stage of the diagnosis of the neoplasia is generally
more advanced for the HCC related to the NAFLD than for other etiologies. Compared to patients with
HCV infection, HCC in patients with NAFLD often presents greater dimensions at diagnosis and more
frequently shows infiltration (21% in patients with NAFLD versus 4% in patients with HCV) or multifocal
lesions [168,170,178] .

The diagnosis in the advanced stage of neoplasia is not due only to the pathogenic mechanisms and
epidemiological factors mentioned above but is mainly due to the lower attention to follow-up and screening
of NAFLD [179,180] . The diagnosis of HCC in patients with NAFLD is often incidental, outside the surveillance
protocols and in any case late, as it is dependent on the appearance of symptoms [168,178] . Patients with NAFLD
seem to have the highest rate of cirrhosis undiagnosed before evidence of HCC compared to other etiologies,
resulting in a decrease in attention to ultrasound surveillance and subsequent delay in the diagnosis of HCC.
Furthermore, as another condition of difficulty in early diagnosis, it must be emphasized that the sensitivity
of ultrasound in detecting small cancer is low in patients with NAFLD [181,182] .

Along with a generally more advanced stage of cancer diagnosis, there are additional reasons why the
prognosis of patients with HCC related to NAFLD appears to be worse than patients with HCC of different
etiology [6,177] . In fact, the prognosis is negatively affected by a greater number of comorbidities, especially
cardiovascular, to which this subgroup of patients is exposed. The highest rate of co-morbidities such
as obesity, the highest mean age of patients with NAFLD and often delayed diagnosis lead to fewer liver
transplants for these patients [6,168,170,177] . Finally, the advanced stage of the disease is often a limitation for
the applicability of radical treatments (resection or ablation) in favour of purely palliative interventions
(chemoembolization or pharmacological therapy). In fact, liver resection and transplantation are only
[177]
practiced in 17.8% and 4.4% of cases, respectively . As a result, the death rate in HCC secondary to NAFLD
(61% of patients die within one year of diagnosis) is higher than in HCC secondary to viral hepatitis (50% of
[168]
[6]
deaths within one year of diagnosis), with a shorter average life expectancy of 5 months . Piscaglia et al.
observed an average survival of 25.5 months from diagnosis in patients with NAFLD-HCC, versus an average
33.7 months of patients with HCV-related HCC. However, when the patient is eligible for curative treatment,
[181]
survival does not appear to vary between HCC related to NAFLD and other etiologies .

The rs738409 polymorphism of phospholipase domain similar to the patatine containing 3 (PNPLA3) has been
[183]
reported to be an independent risk factor of HCC in patients with metabolic cirrhosis (odds ratio 1.40) . In
particular, homozygosity GG was associated with the onset of HCC at a younger age, in patients with
a shorter history of cirrhosis. Furthermore, it is associated with a worse prognosis [181] . The rs738409
polymorphism seems to alter the export of lipoproteins and lipogenic activity, thus causing the hepatic
accumulation of fatty acids with consequent increase of lipid β-oxidation, as well as the production of ROS,
[183]
increasing the risk of progression of fibrosis hepatic and HCC development .