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Lonardo et al. Hepatoma Res 2020;6:83 I http://dx.doi.org/10.20517/2394-5079.2020.89 Page 9 of 12

analyses is warranted in future trials to better understand whether and how these factors may modify
treatment response to specific therapeutic targets and influence clinical outcomes.

CONCLUSIONS AND RESEARCH AGENDA
A robust line of research has shown multifaceted sexual dimorphisms in the NAFLD domain [10-12] . It is
important to note that the observed sex differences in NAFLD are not linear throughout the course of
the disease but rather mechanism-specific. Further studies will eventually contribute to more effectively
reducing the NAFLD-HCC incidence by delineating sex differences in individual pathways and therefore
allowing the development of a personalized approach in preventing NAFLD progression. Similarly, sex
differences in HCC epidemiology have not been fully characterized with proper consideration of women’s
reproductive status/history. Therefore, we recommend that sex/gender and reproductive history should
be considered in future clinical and epidemiological HCC studies. Further mechanistic understanding,
together with the epidemiological characterization of sex differences and the impact of reproductive history
will predictably help clinicians by allowing more accurate risk stratification and personalized therapeutic
approaches in the future. A scoring system combining genetic and non-genetic HCC risk factors while
considering biological disparities by sex and reproductive status may improve our future care, although
sufficient data to develop such a scoring system is pending future research.

DECLARATIONS
Acknowledgments
We are indebted to Ms. Jacqueline Mole for her careful editing of English.

Authors’ contributions
Made substantial contributions to conception and design of the study and performed data analysis and
interpretation: Lonardo A, Suzuki A
Wrote the section on the epidemiology: Ballestri S, Lonardo A
Contributed to the section on pathobiology: Chow PKH, Suzuki A
Edited the final draft: Lonardo A, Ballestri S, Chow PKH, Suzuki A
Prepared the revised version of the manuscript based on Reviewers’ suggestions and comments: Lonardo A,
Suzuki A

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2020.