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Wu et al. Hepatoma Res 2018;4:66 I http://dx.doi.org/10.20517/2394-5079.2018.87 Page 9 of 11

mortality in both genders. Receiving a liver transplant was associated with improved survival in males but not
females. While one would expect that liver transplant would improve survival in both genders, perhaps the
fewer numbers of females undergoing transplant in our cohort made the overall survival benefit in females less
apparent. Females were less likely to receive liver transplants despite being more likely to meet Milan criteria,
have NASH/NAFLD and have HCC found with surveillance. Clearly there are other reasons that contribute
to getting a liver transplant that could not be delineated in this study which may include insurance issues,
substance abuse, comorbidities and potentially cultural issues in a predominantly Asian population. Although
we cannot determine causation, our data suggests that NAFLD/NASH may lead to increased mortality due to
decreased surveillance in this population and less opportunity for curative therapies. Some of these patients
were likely diagnosed with NAFLD but were not followed closely and thus, were allowed to progress to HCC.

A limitation of this study was that it consisted of a single-center retrospective study in a relatively isolated
population. Some of the differences in risk factors and treatment by gender might have been affected by
ethnicity, as well as cultural and language barriers because more than a third of the patients were born outside
the US. It was also difficult to truly separate all of the risk factors to determine causality as many patients had
combinations of risk factors and dose/time/severity dependent factors such as alcohol usage, smoking, obesity
and diabetes. We also did not collect data on whether a patient was pre or post-menopausal and whether there
was any usage of hormone replacement therapy so it was difficult to make conclusions about the contribution
of sex steroids on the development of HCC. Finally, we may have underestimated the NAFLD/NASH group,
as there were patients with no viral risk factors or alcohol usage, but with metabolic risk factors and not
enough information on imaging or biopsy to categorize them as NAFLD/NASH. Despite these limitations, the
strengths of our study include a robust sample size, diverse study population, and detailed risk factor data that
may not be available in administrative or national cancer databases. Furthermore, because we are Hawaii’s
only dedicated liver center that sees nearly 70% of Hawaii’s HCC cases, we believe that this study gave an
accurate view of a state with a high burden of HCC.

We have shown that there are distinct gender differences in behavioral and metabolic risk factors as well as
access to liver transplantation that disproportionately affects certain subgroups with regards to HCC. Older
women with HCC appear to have higher rates of underlying NAFLD/NASH but this population may be
overlooked by current surveillance guidelines, thus losing a valuable opportunity for early tumor detection
and treatment. The epidemic of NAFLD/NASH may potentially increase HCC disproportionately in older
females but further studies will be needed to validate this. Future efforts should be directed towards better
identification of NAFLD/NASH in this population and how to effectively survey these patients for HCC.

DECLARATIONS
Authors’ contributions
Conception, data collection: Wong LL
Study design: Wong LL, Hernandez BY
Data analysis: Wong LL, Hernandez BY, Wu EM
Interpretation of results and manuscript writing: Jia W, Kwee SA, Wong LL, Wu EM
Manuscript review: Ji JF, Jia W, Kalathil S, Kwee SA

Availability of data and materials
The dataset used to support this study can only be shared in an IRB-approved collaborative study and with
permission from the authors.

Financial support and sponsorship
This work was supported by U.S. National Institutes of Health grant 3P30CA071789-12S6.