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Farrell et al. Hepatoma Res 2020;6:18 I http://dx.doi.org/10.20517/2394-5079.2019.019 Page 3 of 13

women), viral hepatitis, particularly hepatitis B, accounts for the majority of cases with the population
attributable fraction due to hepatitis B approximately 51%-57% [21,22] . Comparatively, in high income regions
of the world such as Western Europe, North America and Australasia, where the predominant aetiologies
[8]
are hepatitis C and alcohol, HCC incidence rates are much lower . In Europe, the age-standardised
incidence rate is estimated at 6.8 per 100,000 population in men and 2.2 in women, while, in the US, the
overall incidence is 11.6 per 100,000 population in men and 4.3 per 100,000 in women [21,23] . This is on the
background of an almost three-fold increase in HCC cases in the United States over the past two decades [24,25] .
Australia and New Zealand have also demonstrated a significant increase in HCC with a 7.5-fold increase
[26]
between 1982 and 2014 . In 2015, the Australian incidence of HCC was 7.6 per 100,000 persons,
again with higher rates in men (12 per 100,000) than women (3.9 per 100,000), which is expected to
[27]
have increased to 8.6 cases per 100,000 persons in 2019 . This increase is likely due in part to an aging
population, with a high prevalence of hepatitis C; however, the rise of the obesity epidemic, and an
associated increase in the prevalence of NAFLD-related HCC, may also be contributing [28,29] . Furthermore,
within these Western countries, particularly in the US, NAFLD, fibrosis and HCC are more prevalent in
some ethnic sub-populations. This has been seen in Hispanic, Pacific Islander and subcontinental Indian
groups, whereas other sub-populations, such as African Americans, appear to have lower rates despite
similar risk factors [30-32] . Whether this difference is due to disparities in socioeconomic status or diet
remains to be seen; however, there may also be inherent biological differences with a higher prevalence of
[33]
the PNPLA3 genetic polymorphism noted in the Hispanic population .
Prevalence of NAFLD-related HCC
NAFLD has become the most rapidly increasing cause of HCC in Western countries, with the proportion of
HCC attributable to NAFLD increasing significantly over the past two decades [34,35] . This shift has mirrored
the rise of obesity and the metabolic syndrome, while also coinciding with the development of effective
[6]
treatments for viral hepatitis and greater coverage of hepatitis B vaccination programmes . This increase
in NAFLD-related HCC is most pronounced in Western nations: in the BRIDGE study, a multiregional,
large-scale longitudinal cohort study of consecutive newly diagnosed HCC cases, NAFLD accounted for
10%-12% of HCC cases in North America and Europe, but only 1%-6% in Asian countries . In North
[7]
America, NAFLD is a common cause of HCC. In a large early cohort study of HCC patients identified from
a healthcare claims database in the USA, NAFLD was found to be the most common aetiology, accounting
[36]
for 59% of their 4406 cases . However, subsequent similar US-based longitudinal cohort studies have
reported a much lower proportion of NAFLD-related HCC. The Surveillance, Epidemiology, and End
Results (SEER) cancer registry database found that NAFLD was the predominant aetiology in 14.1% of
their 4929 HCC cases; this was even lower in the Veteran Affairs (VA) Hospitals cohort, where 8% of 1500
HCCs were attributable to NAFLD [8,37] . This may reflect differences in the diversity of the groups studied
here, with the VA group enriched with older males with hepatitis C. NAFLD is now the second leading
cause of liver transplantation for HCC in the United States after Hepatitis C virus (HCV), and is the most
rapidly growing indication for HCC-related liver transplantation, having increased from 8.3% in 2002 to
[38]
13.5% in 2012 . Moreover, the number of people with NAFLD-related HCC on liver transplant waiting
lists in the United States has also risen from 2.1% in 2002 to 17.9% in 2017 [38,39] .

European and Australasian studies have also described an increase in the prevalence of NAFLD-related
HCC. In the UK, between 2000 and 2010 there was a 10-fold increase in NAFLD-related HCC, with
histologically or radiologically proven NAFLD accounting for 34.8% of all HCC cases in 2010 in one cohort
[34]
of 633 patients . Data from the European Transplant Registry also show an increase in transplantation for
[40]
NAFLD-related HCC from 0.2% in 2007 to 1.2% in 2017 . In Australia and New Zealand, NAFLD is the
third leading cause of HCC in those who underwent transplantation, and an Australian cohort of 272 HCC
patients found NAFLD to be the underlying aetiology with 14% of cases [41,42] . A summary of these cohorts
is outlined in Table 1.