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Lonardo et al. Hepatoma Res 2020;6:83 I http://dx.doi.org/10.20517/2394-5079.2020.89 Page 5 of 12

CLINICAL SEX DIFFERENCES IN HCC
Recent large epidemiological studies conducted in the USA have shown that, compared to men, women
with HCC presented with older age, higher frequency of NAFLD, non-cirrhotic HCC, less-advanced
tumour stage (by size, local/vascular invasion, metastasis) and lower frequency of alcoholic liver
disease [32-34] .

Studies regarding sex differences in survival rates have yielded conflicting results so far. Two recent large
multi-centre US studies enrolling 5,327 patients with HCC (22.6% women) and 1,110 (23.5% women),
respectively, reported higher overall survival rates among women after adjusting for confounding
factors [33,34] . Consistently, one of these found that female sex was independently associated with early
[33]
tumour detection [odds ratio (OR) 1.46] and response to first HCC treatment (OR 1.72) . Conversely,
other US studies found no sex-related difference in HCC prognosis [32,35] , while Asian studies did [36-39] .
Another US study showed age, sex, and ethnicity intersection in survival rates; women had higher survival
rates from HCC than men before age 55, while after 65 years or among Hispanics, there was no such a
[38]
survival difference between sexes . Another US study also suggested a similar interplay of age and sex in
[16]
HCC survival and further possible age-, sex-, and race/ethnicity-interaction in HCC survival . Table 1
provides a synthetic overview of sex differences in risk factors, presentation, and outcome of HCC owing
to NAFLD and non-NAFLD aetiologies. Future studies with proper consideration of these interactions are
warranted to reconcile some inconsistency in the literature.

SEX DISPARITY IN HCC PATHOBIOLOGY
Chronic persistent injury induces wound-healing responses through the release of pro-inflammatory
[40]
cytokines (e.g., IL-6, TNF-alpha) and increased oxidative stress in the liver . The wound-healing process,
together with persistent liver damage, promotes fibrogenesis and tissue DNA damages and facilitates
hepatic carcinogenesis . The liver tissue concentration of 8-OHdG, a marker of oxidative DNA damage,
[41]
has been associated with epigenetic inactivation of tumour suppressor genes (i.e., methylated tumour
suppressor genes) [42,43] . An increased number of methylated tumour suppressor genes was, in its turn,
[44]
associated with a shorter time-to-HCC development in patients with chronic hepatitis C , demonstrating
a mechanistic link of oxidative DNA damage, epigenetic alteration of tumour suppressor genes, and
development of HCC. In NAFLD patients, chronic metabolic stress to hepatocytes aggravates oxidative
stress, induces cellular protein/DNA damage, and promotes premature senescence of hepatocytes,
contributing to an increased risk of HCC among obese individuals [12,45] , even in the absence of cirrhosis.

[46]
Sex differences are well documented in cancer mechanisms . Several well studied mechanisms accounting
for sex differences are summarized in Table 2 [47-56] . Compared to females, males are more susceptible to
oxidative stress due to a higher NADPH oxidase activity, a lower NFR-2, and lower anti-oxidants [51,52,57] ,
and have a higher induction of IL-6 by hepatic Kupffer cells under liver injury . In contrast, higher
[54]
physiological oestrogens protect females from HCC development via the anti-oxidative effects of
estrogenic [51,57] , anti-fibrotic effects , and inhibitory effects on IL-6 production by hepatic Kupffer
[12]
[54]
cells . The protective effects of oestrogen are lost after menopause, which may explain the fact that the
[58]
male predominance observed in HCC incidence decreases with advancing age . Gut microbiota also
exhibits sex differences [56,59-61] . In an experimental mouse model, higher hepatic hydrophobic bile acids
were observed in males, which was causally associated with a decreased expression of tumour-suppressive
[61]
microRNA in the liver and increased incidence of HCC . Importantly, similar sex differences in bile
[56]
acid profile exist in humans , suggesting that sex-differences in gut microbiota and bile acid profile may
contribute to male dominance in the development of HCC in man.

Despite the fact that evidence supports oestrogen exerting protective effects on the development of HCC,
whether oestrogens have protective effects on the progression of HCC and patients’ survival remains