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Farrell et al. Hepatoma Res 2020;6:18 I http://dx.doi.org/10.20517/2394-5079.2019.019 Page 9 of 13

Obesity and type 2 diabetes and HCC risk
Obesity and T2DM are metabolic comorbidities closely associated with NAFLD, which have also been
independently linked to the development of HCC [53,54] . T2DM has been found to be associated with
increased HCC risk, particularly in patients with non-viral liver disease. A 2012 meta-analysis including
17 case-control studies and 32 cohort studies showed a statistically significant increased risk of HCC
[53]
prevalence among diabetic individuals (RR: 2.31, 95%CI: 1.87-2.84) . The pooled risk estimate from 17
case-control studies (OR: 2.40, 95%CI: 1.85-3.11) was slightly higher than that from the 25 cohort studies
included (RR: 2.23, 95%CI: 1.68-2.96). This analysis was limited by lower patient numbers, which prevented
adequate subgroup analysis, and, while there was some adjustment for the presence of viral hepatitis and
cirrhosis, the possible presence of underlying NAFLD was not accounted for. In a study from the Mayo
Clinic, the hazard ratio of HCC in cirrhotic patients without HCV infection was found to be two times
[55]
higher in patients with T2DM compared to those without [Hazard Ratio (HR): 2.1, 95%CI: 1.1-4.1] .
Additionally, T2DM has also been found to be an independent risk factor for HCC in patients with
cryptogenic cirrhosis; however, these patients also demonstrated features of NAFLD based on markers of
[56]
insulin resistance and lipid profiles . Overall, while T2DM does appear to be associated with an increased
risk of HCC in those with or without known liver disease, current studies are limited by confounding and
the difficulty of excluding underlying NAFLD as a contributing factor.

Obesity is associated with an increased risk of many types of malignancy, and several epidemiological
studies suggest a modest increase in the relative risk of HCC in obese populations . A 2012 meta-analysis
[57]
of 26 prospective cohort studies, including 25,337 individuals, found excess body weight [body mass
index (BMI) ≥ 25 kg/m ] and obesity (BMI ≥ 30 kg/m ) to be associated with an increased risk of primary
2
2
liver cancer [Summary Relative Risks (SRR) 1.48, 95%CI: 1.31-1.67; and SRR 1.83, 95%CI: 1.59-2.11,
[54]
respectively] . While this evidence is somewhat limited by heterogeneity, on subgroup analysis, there was
an increased risk in males, those with HCV and cirrhosis from any aetiology compared with the general
population, suggesting that obesity may be an important cofactor in the development of HCC.

Genetic markers in NAFLD-related HCC
Several host genetic polymorphisms have been linked to the presence of NAFLD, risk of fibrosis
[58]
progression and the development of NAFLD-related HCC . These are particularly relevant as they may
present novel biomarkers to help triage those at most risk of HCC and therefore in need of screening,
particularly among those with NAFLD and no cirrhosis. The most studied of these is a single-nucleotide
polymorphism (SNP) in PNPLA3. The association between PNPLA3 (rs738409) and hepatic steatosis was
first identified in the genome-wide survey performed on the > 2000 participants of the Dallas Heart Study
[59]
who underwent Magnetic Resonance Spectroscopy of the liver for quantification of liver fat . The presence
of this SNP has since been found to be associated with an increased risk of advanced fibrosis in all patients
with liver disease, and a 2014 meta-analysis confirmed that it was also associated with an increased risk of
HCC in patients with NASH and alcohol-related cirrhosis (OR: 1.67, 95%CI: 1.27-2.21), but not in other
[60]
aetiologies (OR: 1.33, 95%CI: 0.96-1.82) . Moreover, in a large well-characterised Northern European
cohort of patients with histologically proven NAFLD patients, 100 of whom had NAFLD-related HCC, it
was shown that PNPLA3 rs738409, especially the C > G polymorphism, was associated with an increased
risk of HCC independent of other traditional risk factors including age, gender, BMI, presence of T2DM
[61]
or the presence of advanced fibrosis or cirrhosis . Despite this evidence, the potential use of this SNP as
a predictive biomarker to identify high-risk individuals for HCC screening has not yet been validated in
larger cohorts, and it is not widely used.

Other potential genetic risk modifiers of interest include a variant in the MBOAT7 gene, which was
associated with an increased risk of NAFLD-related HCC in an Italian cohort of NAFLD patients (OR:
1.65, 95%CI: 1.08-2.55; n = 765), particularly in those without advanced fibrosis (P < 0.001), and TERT