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Page 8 of 11 Wu et al. Hepatoma Res 2018;4:66 I http://dx.doi.org/10.20517/2394-5079.2018.87

that males in the cohort were more likely to be coinfected.

[21]
Behavioral risk factors such as smoking and alcohol are known independent risk factors for HCC . Alcohol
damages the liver through oxidative stress and inflammation that results in a spectrum of fatty changes from
reversible damage to cirrhosis. In the US, HCC attributed to alcohol usage is more common in males (27.8%)
[22]
than females (15.4%) . In our study, a larger proportion of males had significant alcohol usage compared to
females, although we did not exactly quantify the amount of alcohol used nor account for past vs. current
alcohol use. Smoking has been shown to increase both the incidence and mortality of HCC, and males in our
study were more likely to smoke. Smoking was also an independent predictor of mortality in males in our
study, while alcohol did not affect mortality in either gender. Despite the inability to determine dose effects of
alcohol and smoking, our data confirms that there are gender differences in behavioral risk factors for HCC.

Gender differences in metabolic risk factors for HCC are important as NAFLD is currently the most common
[23]
chronic liver disease in western industrialized countries . Differences in adipocyte metabolism may
[24]
contribute to the gender disparity in HCC . Visceral adiposity, more common in males, has been shown to
induce a pro-inflammatory state that could increase risk of fibrosis relative to females, who may be protected
[25]
by estrogen . This protection may be lost in postmenopausal women, where NAFLD rates have been shown
[26]
to increase with age relative to men . The relative increase in visceral adiposity in males may help explain
[27]
the gender disparity in HCC, as one study showed an association of BMI with HCC risk only in males .
Females in our study had higher rates of NAFLD/NASH than males, with older women having significantly
higher rates of NAFLD/NASH than younger women and older men. Our study showed that NASH associated
HCC disproportionately affected older women but a longitudinal study of a large population of NASH patients
would be necessary to validate this.

[27]
Surveillance has been shown to decrease mortality from HCC in multiple retrospective studies . However,
data on gender differences in HCC surveillance have been inconsistent [28-31] and gender disparities in
[32]
surveillance rates may impact prognosis . In this study, females with a screenable disease were more likely
to have HCC identified with surveillance, but this did not impact their survival. One possible explanation is
that females overall were less likely to have a known screenable disease and more likely to have a fat-related
liver disease, an HCC risk factor for which there are no established screening guidelines unless cirrhosis is
present. Furthermore, HCC attributed to NAFLD has been shown to frequently develop in non-cirrhotic
[33]
livers , decreasing the likelihood of early tumor detection. Despite a higher rate of HCC detection through
surveillance, a considerable proportion of females at risk for HCC may be overlooked with regards to
screening.

Gender disparities in transplantation are well described in the literature, with males tending to undergo
[33]
transplantation more than females . Gender disparity may result from the fact that males more commonly
present with the leading indications for transplant (alcohol and HCV induced cirrhosis) and are more likely
than females to have early-referral to a transplant center [34,35] while females may have lower MELD scores
due to relatively less muscle mass and creatinine [36,37] and finally, donor-recipient organ size mismatch [38,39] .
In our study, females trended towards meeting Milan criteria and males trended towards having more liver
transplants. If only those patients who met Milan criteria were considered as potential transplant candidates,
males were significantly more likely to undergo liver transplant. In the multivariate analysis, the significant
factors for receiving a liver transplant were age, the presence of NAFLD/NASH, and presence of screenable
disease. This may suggest that efforts to improve transplant rates should be directed towards better screening
for patients with NAFLD and NASH.

This study did not show a survival difference between the genders but contained a more detailed risk factor
[40]
analysis than previous studies which demonstrated that NAFLD/NASH was the only factor associated with