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Page 4 of 12 Lonardo et al. Hepatoma Res 2020;6:83 I http://dx.doi.org/10.20517/2394-5079.2020.89

Family history
HCC commonly exhibits familial clustering, and family history of disease is a risk factor for the
development of HCC. Interestingly, family history of HCC was identified as a favourable prognostic factor
for improved survival particularly in those individuals whose tumours can be radically cured, even in
[19]
the stage-stratified analysis . In the study, female sex and younger age, non-diabetics, and lifetime non-
drinkers were more common among individuals with first-degree family histories of HCC than among
[19]
those without such histories . The exact mechanisms underlying the above associations remain uncertain.
Genetic risk determinants of NAFLD and inherited metabolic liver diseases
Genetic variants associated with an increased risk of NAFLD, advanced NAFLD, and NAFLD-HCC
appear to contribute to the risk of HCC in the general population. A recent study conducted using Danish
and UK databases demonstrated that a genetic risk score using three genetic variants [i.e., patatin-like
phospholipase domain-containing protein 3 (PNPLA3) p.I148M, transmembrane 6, superfamily member 2
(TM6SF2) p.E167K, and hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) rs72613567], is associated
with an up to 12-fold higher risk of cirrhosis and up to a 29-fold higher risk of HCC in individuals from
[20]
the general population from these countries .
Certain inheritable metabolic disorders such as hemochromatosis, α-1 antitrypsin deficiency, tyrosinemia,
glycogen storage diseases and several porphyrias also increase HCC risk, although they account for a
negligible HCC risk globally [21,22] .

Other risk factors of HCC
[1]
Smoking and co-infection with HIV also contribute to the development of HCC . Certain environmental
factors or occupational factors, such as vinyl chloride, polycyclic aromatic hydrocarbons, aflatoxins, and
aristolochic acid, a common ingredient of traditional herbal medicine, have been suggested to play a role
in the development of HCC [23,24] . How these factors and underlying mechanisms intersect with sex and sex
hormones in the development of HCC has not been fully elucidated.

Interaction between sex/gender and metabolic risk factors
Sexual dimorphisms in metabolism are well-known (recently reviewed elsewhere [9,10,12] ) and likely account
for sex differences in HCC risk. A few other risk factors have been suggested for sex/gender-interaction,
which are also discussed in this section.

Obesity has been associated with a higher risk of HCC incidence in men than women, especially in non-
[25]
Asians . A recent study conducted in an Asian population found a different relationship between BMI and
[26]
HCC risk according to sex, following a U-shaped and a linear curve in men and women, respectively .
Studies reported a stronger risk association between pre-diabetes/diabetes and HCC in men than
women [26-28] .

NAFLD has a definite sexual dimorphism; men are more prone than women to the risk of uncomplicated
steatosis, NASH fibrosis, and HCC. However, aging and menopause are associated with the disappearance
of protection in women [12,29,30] .

Prospective studies indicate that regular alcohol intake, although within safe thresholds, is a risk factor for
[31]
the progression to HCC among individuals with NAFLD . Moreover, among those with HCC, alcohol use
is more frequent in men than in women [26,32] .

Additionally, men are more prone to acquire HBV and HCV infection, develop chronic hepatitis, cirrhosis
[14]
and HCC than women .