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Page 2 of 13 Farrell et al. Hepatoma Res 2020;6:18 I http://dx.doi.org/10.20517/2394-5079.2019.019
[2]
coincided with the onset of the obesity and type 2 diabetes mellitus (T2DM) epidemics . Previously, due
to the strong association between NAFLD and the metabolic syndrome, NAFLD was considered a disease
of affluent nations; however, with the epidemiological transition and increasing urbanisation in low and
middle income countries, prevalence of the metabolic syndrome and NAFLD is now increasing rapidly
[3-5]
across the globe . This high prevalence and subsequent burden of progressive liver disease has resulted
in NAFLD becoming an increasingly important cause of hepatocellular carcinoma (HCC) . This review
[6-8]
outlines the epidemiology of NAFLD-related HCC, with a focus on Western countries.

METHODS
We conducted a search of the Medline, PubMed and Cochrane databases to identify English language,
original research articles conducted in adults over the age of 18, and published between 1 January 1990
and 1 September 2019 using the Medical Subject Headings “Nonalcoholic Fatty Liver Disease” and
“Hepatocellular carcinoma”. Duplicate results were removed using Endnote X9, before screening by title
and abstract was performed to find research relating to HCC in patients with NAFLD (single reviewer -
AF). Original research articles were eligible for selection, including meta-analyses, controlled trials, cohort
studies and case-series, which clearly described their study population including their diagnostic criteria
for NAFLD, and described the incidence or prevalence of NAFLD-related HCC.

NAFLD, nonalcoholic steatohepatitis and the natural history of disease
NAFLD is a broad term used to describe a spectrum of liver diseases characterised by excessive hepatic fat
accumulation with associated insulin resistance, in the absence of a secondary cause or significant alcohol
consumption [9,10] . More precisely, NAFLD is defined as the presence of steatosis in > 5% of hepatocytes
histologically or by proton density fat fraction on magnetic resonance imaging (MRI-PDFF), and it can
be subclassified into nonalcoholic fatty liver (NAFL) or nonalcoholic steatohepatitis (NASH) [9,10] . While
NAFL refers to simple steatosis, NASH is characterised by hepatic lobular inflammation and is associated
[9]
with an increased risk of progression to fibrosis, cirrhosis and hepatic decompensation . NASH can only
reliably be differentiated from NAFL histologically, and the prevalence of NASH in liver biopsies from
[1]
NAFLD patients is estimated to be 59.10% (95%CI: 47.55%-69.73%) from pooled NASH prevalence data .
This estimate is higher than previous estimates, suggesting NASH occurred in approximately one third of
NAFLD patients; however, retrospective biopsy studies are inherently affected by selection bias of patients
in whom there is high clinical suspicion for steatohepatitis [11,12] .

Fibrosis is an important prognostic factor in NAFLD. Fibrosis stage is independently associated with
mortality, liver transplantation and liver-related events, with fibrosis occurring at twice the rate in patients
with NASH compared with NAFL [13,14] . Furthermore, liver-related mortality increases significantly with
[15]
increasing fibrosis stage . In a meta-analysis of 411 patients from 11 cohort studies with biopsy proven
NAFLD (2145.5 person-years of follow-up), the annual fibrosis progression rate in patients with NAFL
and stage 0 fibrosis at baseline was 0.07 stages per year (95%CI: 0.02-0.11 stages/year), and 0.14 stages
[16]
per year in NASH (95%CI: 0.07-0.21 stages per year) . This is the equivalent of one stage of progression
over 14.3 years (95%CI: 9.1-50 years) in NAFL vs. 7.1 years (95%CI: 4.8-14.3 years) for NASH. In patients
with NASH, approximately 20% of those with advanced (F3) fibrosis will progress to cirrhosis, and 20% of
compensated NASH cirrhotics will develop hepatic decompensation over a two-year period [17,18] .

Current global trends in HCC
Liver cancer, of which HCC is the main subtype, has the sixth highest cancer incidence, and is the fourth
leading cause of cancer-related death worldwide . There are significant geographic variations in the
[19]
[20]
incidence of HCC, reflecting the differences in aetiology of liver diseases in each region . In Asian
countries where the highest incidence rates of HCC are reported (20 per 100,000 in men and 6.9 in