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Lonardo et al. Hepatoma Res 2020;6:83 I http://dx.doi.org/10.20517/2394-5079.2020.89 Page 7 of 12

Table 2. Sex differences relevant to the pathomechanisms of HCC in NAFLD
Sex differences
Authors Study characteristics
Risk factors Outcome Impact on HCC
Pre-hepatic factors increasing hepatic metabolic stress
Lemieux et al. [47] Total body fat and Visceral adiposity After adjusting for total body fat Higher FFA release in males
abdominal adipose tissue mass, men had significantly higher induces inflammation,
were evaluated in 89 men values of visceral adipose tissue insulin resistance, and
and 75 women using CT volume and areas, measured by lipotoxicity and fosters
CT, than women. An increase in a tumour-promoting
total fat mass was associated with environment in the liver
a significantly greater increase in and may contribute to an
visceral adipose tissue volume in increased recurrence of
men than in women HCC
Laughlin et al. [48] A cross-sectional study Visceral adipokines Serum adiponectin and leptin A higher adiponectine level
to measure serum leptin, levels were higher in women than may protect women from
adiponectin and sex in men. In both sexes, adiponectin developing HCC via the
hormone levels in 1510 concentrations were lower, and activation of AMPK and
community dwelling men leptin levels higher, with increasing p38α [49]
and postmenopausal BMI and waist girth
women aged 50-92 years
Lönnqvist et al. [50] BMI and age matched Visceral fat Catecholamine-induced rate of Higher FFA release in males
obese subjects (22 male lipolysis FFA mobilization from visceral induces inflammation,
and 23 female) undergoing fat to the portal venous system insulin resistance, and
elective surgery were is higher in obese men than in lipotoxicity and fosters
evaluated for visceral fat obese women, probably due to a a tumour-promoting
lypolysis larger fat-cell volume but also to environment in the liver
a decrease in the function of α 2 - and may contribute to an
adrenoceptors, an increase in the increase recurrence of HCC
function of β 3 -adrenoceptors, and
an increased ability of cyclic AMP
to activate hormone-sensitive
lipase
Oxidative stress/Senescence
Augustine et al. [51] Compared Nqo1 mRNA NAD(P)H: quinone ACI rats showed minimal Higher Nqo1 may lead to
and protein expression oxidoreducatase 1 differences in Nqo1. In SD rats, greater protection against
and activity in males and (Nqo1) Nqo1 mRNA, protein, and activity oxidative stress and thus
females before and after levels were significantly higher decreased susceptibility to
applying known inducers in females than in males. Female carcinogens
using SD and August SD rats showed greater induction
Copenhagen x Irish (ACI) than male
rat strains
Kratschmar et al. [52] The interaction among NFR-2 The study using the cell lines Higher activity of 11b-HSD1
corticosteroid, 11b-HSD1, demonstrated that glucocorticoids, and/or corticosteroid
and NFR-2 was evaluated activated by 11b-HSD1 and acting may lead to suppressed
using transfected HEK- through GR, suppress the Nrf2- antioxidant response, which
293 cells and hepatic dependent antioxidant response. may lead to higher oxidative
H4IIE cells. The hepatic This research also demonstrated DNA damage
expression levels of that the hepatic expression of
11b-HSD1 and NFR-2 target 11b-HSD1 was higher in male rats
genes were also compared vs. female rats while the Nrf-2
between male and female target genes (HMOX1, NQO1 and
Han Wistar rats ABCC3) were lower in male vs.
female rats, confirming the above-
demonstrated pathway
DNA damage/repair
Hofer et al. [53] DNA SSB and ALS were Oxidative DNA Males had higher levels of SSB + Men are associated with a
measured in blood damage ALS than females, although no higher risk of oxidative DNA
samples from 99 subjects difference was seen for oxidative damage
(age: 19-31 years) living lesions. There was no correlation
in Stockholm, Sweden. between FPG sites and 8-oxodG.
Oxidative DNA damage In females, there was a positive
was also analyzed using correlation between FPG levels
the DNA repair glycosylase and BMI and a negative correlation
FPG as well as HPLC-ECD between SSB + ALS and fruit
for specific analysis of intake
8-oxodG
Immune response