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Benhammou et al. Hepatoma Res 2020;6:35 I http://dx.doi.org/10.20517/2394-5079.2020.16 Page 3 of 15

NAFLD-associated HCC increased by 11.8 fold, which was higher than hepatitis B, hepatitis C and alcoholic
liver disease. Other studies have also corroborated that NAFLD and NAFLD-associated HCC are the most
rapidly growing indications for LT [26,27] .

Other countries in Europe and Asia have made similar observations to these U.S.-based studies [28,29] . In a
European Electronic Health Record study of patients seen in primary care in Spain, Italy, the Netherlands
and the United Kingdom, the incidence of NAFLD-associated HCC diagnosis was 0.3 per 1000 person-years
[30]
over a median follow up of 3.3 years . A study of the European Liver Transplant Registry database from
2002-2016 also showed that among the 68,950 transplant patients, 8.4% were for NASH in 2016 (compared
[31]
to 1.3% in 2002), 39% of whom had HCC . In Asian countries, where hepatitis B has been the main driver
of liver disease and HCC, the prevalence of NAFLD is also about 25% depending on the country studied,
ranging from 6.2% in South China to 51% in Indonesia [3,32,33] . NAFLD-associated HCC has also increased in
[34]
countries such as South Korea where its prevalence rose from 3.8% (2001-2005) to 12.2% (2006-2010) .
Although a rise in sedentary life styles leading to increase in MetS and diabetes are thought to be the culprits
in NAFLD-associated HCC, Asian patients are more likely to have “lean” or “non-obese” NAFLD, potentially
representing a pathophysiolocally different group of patients from those seen in Western countries. Few
studies have addressed this although a recent European study assessing the outcomes of biopsy-proven
2
lean NAFLD (BMI < 25 kg/cm ; n = 123) patients compared to healthy controls, overweight NAFLD
2
(BMI 25-30 kg/cm ; n = 335) and obese NAFLD patients (BMI > 30 kg/cm ; n = 188) demonstrated
2
that lean NAFLD patients had a tendency towards more liver-related complications including cirrhosis,
[35]
decompensated cirrhosis and HCC over a follow-up period of 19.9 years .
In summary, the burden of NAFLD-HCC is on the rise with the prevalence of NAFLD, depending on
geographical and ethnic differences, affecting about a quarter of the world’s population. Although NASH is
thought to be a more severe form of NAFLD that more commonly progresses to chronic liver disease and
HCC, the true prevalence of NAFLD (6.2%-51%) and NASH (10%-20%), based on large epidemiological
data, remains unclear given that no specific biomarkers exist to differentiate the two other than a liver biopsy,
which is scarcely performed, yet the gold standard for diagnosis.

GENETIC RISK FACTORS FOR NAFLD-HCC
There is a large body of literature linking genetic polymorphisms to the development of NAFLD and NASH
but few have addressed the genetic contributions to NAFLD-associated HCC [Table 2]. Early studies
in the field of NAFLD identified ethnic differences in disease prevalence whereby Hispanics were the
most commonly affected group followed by Caucasians and African Americans [36-38] , suggesting a genetic
predisposition to NAFLD. Consistent with these findings, twin studies and phenotypic clustering of fatty liver
were also more commonly seen in patients in the same family, suggesting heritability of the disease, which
has been reported to range from 38%-50%, depending on the modality used for phenotyping of NAFLD
(biopsy, MRI or abdominal ultrasound) [39,40] . In recent years, large genome-wide studies have followed and
revolutionized what is known about NAFLD and NASH, and possibly the risk for HCC development.

[41]
Romeo et al. conducted the first genome-wide association study in the Dallas Heart Study using proton
magnetic resonance spectroscopy to quantitate hepatic steatosis as the phenotype. Patatin-like phospholipase
domain 3, PNPLA3 (rs738409), was the single variant strongly associated with hepatic steatosis. Although
the mechanism by which PNPLA3 leads to hepatic steatosis accumulation remains unknown, it was shown
to play a role in hepatocellular lipid droplet remodeling and very low-density lipoprotein secretion [42,43] .
Interestingly, subsequent association studies of PNPLA3 also demonstrated that the variant was associated
with histological severity of the disease, thus suggesting that it may influence HCC development, where GG
[44]
[45]
sequence carriers had more necroinflammation and fibrosis compared to CC carriers . Indeed, Liu et al. ,