Page 970 - Read Online

Lonardo et al. Hepatoma Res 2020;6:83 I http://dx.doi.org/10.20517/2394-5079.2020.89 Page 3 of 12

Multi-ethnic populations display a clear ethnic gradient. For example, in the United States, Asians/Pacific
Islanders have been reported to have the highest incidence rate per 100,000 (11.7), followed by Hispanics
[13]
(9.5), Blacks (7.5), while Whites had the lowest (4.2) .
Sex
With few exceptions, the male to female (M:F) ratio of the incidence of HCC ranges between 2 to 3 in the
most of the countries, irrespective of whether they are high-rate areas or not, and are maximal in middle
European countries (M:F ratio up to 5) [13,14] . In contrast, in Costa Rica, Colombia, Ecuador and Uganda, the
M:F ratio of the incidence of HCC is smaller, ranging from 1.3 to 1.6 [13,14] .

The biological grounds underlying this sex disparity in the prevalence of HCC are incompletely defined
and probably related to multiple behavioural, hormone-metabolic risk factors, and cancer biology. Sex
differences in HCC pathogenesis are discussed below under sex disparity in HCC pathobiology.

The difference in the M:F ratio of the incidence of HCC among different countries is intriguing, suggesting
potential race/ethnicity-sex interplay in HCC. At this point, sufficient data do not exist to delineate whether
the difference is explained by a biological interplay and/or an interplay of gender attributes and culture/
ethnicity.

Age
The overall incidence of HCC consistently peaks at 70 years in various countries worldwide, such as
France, Italy, Japan, and USA (whites) and this is approximately 5-15 years before the peak occurrence
[15]
of cholangiocarcinoma, the second most common PLC after HCC . However, other authors report that
the mean ages of diagnosis with HCC are 55-59 years in China and 63-65 years in Europe and North
[14]
America . In Qidong, China, where the HCC burden is among the world’s highest, the age-specific
incidence rates increase up to the age of 45 among men and then plateau; while increasing to the age of 60
[14]
and then plateauing among women . A surveillance, epidemiology, and end results (SEER) Analysis (from
1988 to 2010) including 39,345 patients with HCC (Men 76%, women 34%) showed that men are diagnosed
[16]
4-7 years earlier than women across the race/ethnic groups . These findings suggest that sex and age
interact in the occurrence of HCC, implying that consideration of this interaction (as opposed to treating
age and sex as independent variables) will be essential in future research.

Severity of liver histology
While cirrhosis is an almost essential pre-requisite for the development of HCC in those with HCV
[1]
infection, infection with HBV exerts a more direct carcinogenic effect on the liver . Similar to HBV
infection and to alcoholic liver disease, NAFLD-HCC may occur in non-cirrhotic livers [14,15] . A Japanese
descriptive study reported that men with nonalcoholic steatohepatitis (NASH) developed HCC at earlier
[17]
liver fibrosis stages than women . The study was too small to confirm the sex difference but provides an
intriguing hypothesis pertaining to carcinogenesis. Further larger studies are warranted to investigate this.

Viral hepatitis
With the exceptions of Japan and Egypt (where HCV infection is the chief risk factor of HCC), in most
high-risk countries, chronic HBV infection and aflatoxin B1 are the major risk factors for the development
of HCC, whereas HCV infection, excessive alcohol consumption, and common metabolic disorders
[15]
(diabetes, obesity and metabolic syndrome) prevail in low-rate areas . Chronic drinking of alcohol >
80 g/day for over 10 years increases the risk of HCC by a factor of 5; and alcohol consumption enhances
the risk of HCC in those with either chronic hepatitis C or NAFLD [10,18] . However, given that these data
often combine both sexes, research needs to be conducted urgently to clarify the sex-specific thresholds of
alcohol consumption that are associated with a raised HCC risk.