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Page 2 of 15 Benhammou et al. Hepatoma Res 2020;6:35 I http://dx.doi.org/10.20517/2394-5079.2020.16

Table 1. NAFLD-associated HCC epidemiology and burden
Country Incidence and prevalence Population Study period Ref.
United States 0.21 per 1000 person-years Veterans Affairs 2003-2011 Kanwal et al. [22]
14.1% of all cases SEER registries 2004-2009 Younossi et al. [136]
8% of all HCC cases Veterans Affairs 2005-2011 Mittal et al. [23]
1.56% of HCC cases Veterans Affairs 2012-2018 Ioannou et al. [24]
5.29 per 1000 person-years Meta-analysis 1989-2015 Younossi et al. [3]
13.5% of all liver transplants United Network Organ for Sharing 2000-2012 Wong et al. [26]
Spain, Italy, the Netherlands, United Kingdom 0.3 per 1000 person-years European primary care databases 2016 Alexander et al. [30]
United Kingdom 35% of all HCC referrals National Health Services 2010 Dyson et al. [137]
Japan 6% incidence Single hospital in Tokyo 1994-2007 Arase et al. [138]
South Korea 12.2% incidence South Korean hospital 2006-2010 Cho et al. [34]
NAFLD: nonalcoholic fatty liver disease; HCC: hepatocellular carcinoma; SEER: surveillance, epidemiology and end results

Non-alcoholic fatty liver disease (NAFLD), the liver manifestation of MetS, has increased in parallel and is
[2]
now the most common cause of liver disease in the United States . Although the true prevalence of NAFLD
remains unknown given the lack of validated and/or recommended screening practices, it is estimated
[3]
that the disease affects about a quarter of the world’s population, depending on geographical differences .
[3]
NAFLD can progress to nonalcoholic steatohepatitis (NASH) (characterized by ≥ 5% of hepatic steatosis
[4]
[5,6]
with lobular inflammation and hepatocyte ballooning ), cirrhosis and hepatocellular carcinoma (HCC) .
Given the estimated increase in NAFLD, NASH and NAFLD-associated HCC and the anticipated burden
[7]
on health care costs [8-10] , several studies have focused on understanding the clinical and biological drivers of
NAFLD-associated HCC and its potential treatment options.
Understanding this disease process is especially relevant since NAFLD-associated HCC can occur in a non-
cirrhotic background [11-13] . This poses a clinical dilemma given the lack of screening guidelines for this sub-
group of patients, thus prompting the need for further understanding of the natural history of NAFLD-
HCC and identifying at-risk populations who would benefit from screening. More recently, studies have also
identified the protective effects of statins and aspirin on fibrosis progression and HCC [14-17] , providing an
avenue for further research in this group of patients who are also at high risk for cardiovascular disease.

A full review and discussion of the pathophysiology of NAFLD and NASH is beyond the scope of this report
and has been summarized by Anstee et al. . In this review, we explore what is known about the genetic
[18]
(non-modifiable) and environmental (modifiable) risk factors of NAFLD-associated HCC, examine the role
of statins and aspirin and what microbiome research has to offer in the field of NAFLD-related HCC.

BURDEN OF NAFLD-ASSOCIATED HCC
HCC is a lethal cancer with a rising incidence over the last 30 years . Its incidence is increasing most
[19]
rapidly of any cancer, with an age-adjusted annual increase of 3.8% and 2.8% in men and women in the U.S.,
[20]
[21]
respectively . The rising HCC burden has largely been attributed to the rise in obesity and diabetes .
As follows, several epidemiological studies have specifically examined the incidence and risk of NAFLD-
associated HCC [Table 1]. The results have been varied however, due to differences between the studies in
patient population, time-period, and NAFLD and/or NASH ascertainment. For example, in a large Veterans
Affairs (VA) Health System study between 2003-2011, the incidence of HCC in a NAFLD cohort was
[22]
0.21 per 1000 person-years . A separate study within the VA further demonstrated that of the 1500 HCC
cases identified from 2005-2011, NAFLD was the underlying risk factor in 8% of all cases with an annual
[24]
[23]
proportion of NAFLD-related HCC ranging from 7.5%-12.0% . Ioannou et al. also reported that the
incidence of NAFLD-associated HCC was 1.56% within the VA from 2012-2018 over a 3.7 years follow up
period. In non-VA populations, the incidence rate for NAFLD-associated HCC and NASH-associated HCC
[3]
were 0.44 and 5.29 per 1000 person-years, respectively .
Changes in liver transplantation (LT) indications are also reflective of the increasing rates of NAFLD. For
[25]
instance, Younossi et al. demonstrated that of 158,347 LT candidates from 2002-2016, the prevalence of