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Page 6 of 14 Moriguchi et al. Hepatoma Res 2019;5:43 I http://dx.doi.org/10.20517/2394-5079.2019.20
[21]
PYs) . However, US-born Hispanic patients had higher HCC incidence rates than Hispanic patients born
[68]
outside of the US , which suggests the importance of other risk factors such as the environment, lifestyle
habits, and MetS, in addition to polymorphism of the patatin-like phospholipase domain-containing
protein 3 (PNPLA3) gene.

PNPLA3 rs738409 single-nucleotide polymorphism, which is a risk factor of steatosis, NASH, and
[69]
[70]
fibrosis , is also a risk factor of HCC (odds ratio: 1.40) . Furthermore, the risk allele “G” is observed in
[71]
40% of the European population, and it reportedly increases the risk of HCC by approximately 12 times .
In HCC patients, GG homozygosity is related to early onset (at young age), background liver disease with
[71]
short cirrhotic history or less fibrosis, diffuse-type HCC, and poor prognosis .
In addition, it has been reported that the H63D gene, which is a common polymorphism of human
[72]
hereditary hemochromatosis, is related to the risk of non-cirrhotic HCC incidence in Africans , whereas
the membrane-bound O-acyltransferase (MBOAT7) rs641738 variant is reportedly related to NAFLD-
[73]
related HCC with non-advanced fibrosis .

Others
Previous alcohol intake and iron level in hepatocytes have been reported as risk factors of HCC in NASH
[76]
patients [74,75] , with the increase in hepatocellular iron levels being related to advanced fibrosis in NAFLD .
A study in Italy compared 51 NASH cirrhosis-related HCC patients against 102 patients without HCC and
found that hepatocytes staining positive to iron were in significantly greater quantity in the HCC cohort
than in the non-HCC cohort .
[75]
HCC in NAFLD with cirrhosis
As mentioned above, a study that examined 296,707 NAFLD patients showed that 490 patients developed
HCC (0.21 per 1000 PYs), and the incidence rate of HCC was significantly higher than that of the control
group (0.02 per 1000 PYs, HR: 7.62, 95%CI: 5.76-10.09). Among the NAFLD patients, those with cirrhosis
had the highest annual incidence rate of HCC (10.6 per 1000 PYs), and 1.6-23.7 people per 1000 PYs were at
[21]
risk . In another report, the incidence of NAFLD patients with cirrhosis who developed HCC was from
2.4% at seven years to 12.8% over three years , which was marginally lower than the 4% annual incidence
[77]
of cancer observed in cases of cirrhosis caused by HCV [22,77] .

With respect to the relationship between the indicators of fibrosis and development of cancer from
NAFLD, patients with a cirrhosis diagnosis and a high Fibrosis-4 (FIB-4) score had the greatest risk of
HCC (13.5 per 1000 PYs), whereas patients without a cirrhosis diagnosis and a low FIB-4 score had a low risk
[21]
of HCC development (0.04 per 1000 PYs) . A separate study showed that a high NAFLD fibrosis score and a
[78]
high FIB-4 score were strongly related to the incidence of HCC . Furthermore, sex (male), age (≥ 70 years),
T2DM, and high blood pressure have been reported as risk factors of HCC in NAFLD patients with
[30]
cirrhosis .
Relationship between cryptogenic cirrhosis and NAFLD
Liver cirrhosis is the most common cause of HCC, and 80%-90% of HCC patients have had cirrhosis .
[79]
Although viruses are common origins of liver cirrhosis, it has been reported that, in 6.9%-50% of HCC
[82]
cases, the etiology of liver disease could not be determined [80-82] . A prospective US study showed that
cryptogenic cirrhosis (CC) is responsible for up to 29% of the etiology of HCC. Half of these patients had
histological and clinical features of NAFLD, and another retrospective study showed that HCC patients
with CC had a greater prevalence of T2DM and obesity than those who developed the condition from a
[83]
virus or alcoholic cirrhosis . Given its similarity to NASH cirrhosis, a strong correlation between CC