Page 35 - Read Online

Moriguchi et al. Hepatoma Res 2019;5:43 I http://dx.doi.org/10.20517/2394-5079.2019.20 Page 3 of 14

Table 2. Summary of clinical features of patients with NAFLD hepatocellular carcinoma
Incidence rate NAFLD Ref.[5,20-23]
NAFLD with cirrhosis Ref.[20,77]
NAFLD without cirrhosis Ref.[23,77]
NASH Ref.[22,77]
Age and sex Higher incidence rate in older and male patients (compared with HCV-derived HCC)
Complications Obesity, type 2 diabetes mellitus, insulin resistance, cardiovascular disease, dyslipidemia, metabolic
syndrome, etc.
Race Highest incidence rate in Hispanic patients, followed by Caucasian and African American patients
Genetic elements PNPLA3 rs738409 SNP, H63D polymorphism, and MBOAT7 rs641738 variant, etc.
Other risks Past history of drinking, iron, etc.
Clinical features Detection Detected more often in the advanced stage and with symptoms outside of
surveillance (compared with HCV-related HCC)
Morphology Larger tumor size, absence of encapsulation, and a more infiltrative
characteristic (compared with HCV-related HCC)
Tumor marker Less frequently elevated AFP levels (compared with HCV-related HCC) and
often elevated PIVKA-II levels
Liver function Relatively well preserved (compared with other etiologies)
Background Less advanced fibrosis (compared with HCV-related HCC)
Prognosis Controversial
Prevention and treatment Metformin, exercise
One promising approach; prevention of the development of fibrosis: GLP-1 receptor antagonist

NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; HCV: hepatitis C virus; HCC: hepatocellular carcinoma;
PIVKA-II: prothrombin induced by vitamin K absence-II; GLP-1: glucagon like peptide-1; SNP: single-nucleotide polymorphism; AFP: alpha-
fetoprotein

Although complete elimination of HBV is difficult, it has been possible to prevent the onset of cancer
to some degree by suppressing the viral replication and calming the inflammation using nucleotide and
[18]
nucleoside analogs , while the emergence of direct-acting antiviral agents has made it possible to eliminate
[19]
HCV in almost all cases, thereby reducing the risk of cancer . Based on these clinical advancements, the
incidence of viral-related HCC, especially HCV-related HCC, is likely to continue to decrease, while the
[4]
incidence of NAFLD-related HCC is likely to increase due to the lifestyle changes mentioned above .
This paper aims to provide a review of the literature regarding the epidemiology of NAFLD-related HCC
and elucidate the problems and challenges in cases of NAFLD-related HCC that have been on the rise.

Table 2 shows a summary of the features of NAFLD HCC.

INCIDENCE OF HCC IN PATIENTS WITH NAFLD
In recent years, there have been many reports suggesting that NAFLD is an important etiology of HCC.
In the US, the Surveillance, Epidemiology, and End Results reported that, between 2004 and 2009, there
[5]
was a 9% annual increase in NAFLD-related HCC cases . The Global HCC BRIDGE Study showed that
10%-12% of cases in North America/Europe and 1%-6% of cases in Asia diagnosed as HCC were caused by
[20]
NAFLD . Moreover, in Japan, the percentage of HCC patients with a nonviral etiology has increased from
10.0% in 1991 to 24.1% in 2010, which consolidates the observation that there is an increase in the number
[4]
of NAFLD-related HCC cases .

The 130-facility cohort of the US Veterans Health Administration showed that the risk of HCC onset in
NAFLD cases was 0%-38% over 5-10 years of observation, and showed that, when adjusted for the patients’
race and MetS characteristics, NAFLD patients had greater annual risk of developing HCC than the
controls [0.21/1000 vs. 0.02/1000 person-years (PYs); hazard ratio (HR): 7.62; 95% confidence interval (CI):
[21]
5.76-10.1] . Furthermore, the estimated annual incidence rate of HCC derived from NASH, which is an