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Page 2 of 12 Lonardo et al. Hepatoma Res 2020;6:83 I http://dx.doi.org/10.20517/2394-5079.2020.89

Keywords: Liver cancer, pathobiology, personalized medicine, sex differences

BACKGROUND
Hepatocellular carcinoma (HCC), the most common primary liver cancer (PLC), carries an ominous
[1,2]
prognosis, and is the fourth most common cause of mortality owing to cancer . The chief modifiers
[2]
of HCC risk include geographic variability, demographics and severity of liver disease . Cirrhosis,
[1]
irrespective of aetiology, increases the risk of HCC . On a global basis, the proportion of HCCs attributed
to nonalcoholic fatty liver disease (NAFLD) is increasing owing to trajectories of declining HCV infection
and escalating NAFLD [1,3,4] . Additional risk factors for the development of HCC are infection with HBV,
[5]
alcoholic liver disease, aflatoxin, and genetic haemochromatosis .
Spanning a wide range of liver histology changes, NAFLD faithfully recapitulates the whole spectrum
[6]
of alcoholic liver disease though it is observed in the nonalcoholic patient and in the absence of other
[7]
competing causes of (steatogenic) liver disease . Similar to HCC, NAFLD accounts for a substantial
[8]
clinical burden and exacts a heavy toll of healthcare-related expenses .
Sex disparities in various human diseases, from initial manifestations to disease outcome, are often
encountered in clinical practice. In fact, sex and gender act as powerful modifiers of the top ten causes
of mortality and morbidity, including heart disease, cancer, chronic lung disease, Alzheimer’s disease,
influenza and pneumonia, chronic kidney and chronic liver diseases . Clear sex disparity exists in
[9]
[1]
HCC, which is twice as common in men as in women . NAFLD also exhibits multifaceted sexual
dimorphism [10,11] . It occurs more often in men than in women of fertile age and is heavily affected by
[12]
reproductive status . Understanding these sex differences is the key to deciphering the pathophysiology of
[12]
the disease as well as in guiding personalized care .
On this background of evidence, we aimed at illustrating our current knowledge of sex differences in HCC
and clarifying gaps to be filled in future research, while placing special focus on NAFLD-related HCC.

METHODS
The PubMed database was extensively searched for articles published as of the 31st of July 2020. The
keywords used in our search include, but are not limited to: HCC, liver cancer, sex differences, gender
differences, epidemiology, natural course, pathogenesis, risk factors, immune response, genetics, and sex
hormones. Additional terms were used to search for articles reporting sex differences and/or the effect of
sex hormones in specific mechanisms pertaining to carcinogenesis. Among the retrieved publications, only
those that were deemed to be relevant based on consensus among the authors were retained.

EPIDEMIOLOGICAL MODIFIERS OF HCC RISK
Irrespective of its aetiology, HCC affects men more commonly than women owing to complex and multi-
factorial reasons. This section reviews risk factors of HCC in general and discusses interactions between
sex and risk factors.

Geographic area and ethnicity
Eastern Asia, Southeast Asia, and sub-Saharan Africa exhibit a high incidence and prevalence of HCC;
[1]
Mongolia, China, Japan, Papua New Guinea, and Egypt are top-ranked countries . By contrast, countries
with a low incidence and prevalence include India, Russia, northern countries of South America,
Argentina, European countries (except for southern countries), USA, and Australia with the rest of the
[1]
world exhibiting intermediate rates of incidence and prevalence .