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Raza et al. Hepatoma Res 2019;5:42 I http://dx.doi.org/10.20517/2394-5079.2019.014 Page 7 of 11

[119]
the progression of NAFLD in both rodents and humans . Several new studies provide evidence for a
potential role of androgen and the androgen receptor pathway in the development of NASH-related HCC
[121]
[120]
and in the treatment of HCC . Gender disparity exists in the incidence of NAFLD associated HCC .
Intriguingly, although males are more likely to develop both NAFLD and HCC than females, after the age
of 60 this trend is reversed [122-124] . This has been attributed to the loss of the protective effects of oestrogen
[125]
in females . Besides hormonal stimuli, deregulation of hepatic circadian clock genes also significantly
[126]
contributes towards the progression of NAFLD to HCC .
FUTURE DIRECTIONS AND CONCLUSIONS
Studies from clinical and basic research have provided a better understanding of the aetiology of NASH-
associated HCC. Data from various studies reveal that the co-ordinated actions of genetic instability,
impaired lipid metabolism, increased oxidative stress altered lipid metabolism, hepatocyte apoptosis,
inflammation, fibrosis and altered hormone signalling contribute to the development of HCC. These
pathways likely act simultaneously and in combination to activate genetic and epigenetic mechanisms
that cause progression of NAFLD and promote the development of NAFLD/NASH-associated HCC. At
the clinical level, currently, it is not possible to determine which patients with NASH are most prone to
develop HCC. Further studies are required to identify the patients who are at a risk of developing HCC.
The identification of specific biomarkers is essential for predicting the transition from NASH to HCC.
Currently, there are no pharmacological therapies for the prevention or treatment of NASH and NASH-
associated HCC, thus understanding the mechanisms for the pathogenesis of these conditions may lead to
the development of novel therapies. Anti-fibrotic, anti-diabetic, anti-inflammatory, antibiotics/probiotics
and lipid-lowering drugs either alone or in combination could hold promise for the treatment for NAFLD/
NASH-associated HCC.

DECLARATIONS
Acknowledgments
We wish to acknowledge Dr. Paul M. Yen, Duke-NUS Medical School, Singapore for his advice and
suggestion while writing the review.

Authors’ contributions
Study concept and design: Raza S, Sinha RA
Literature search: Raza S, Rajak S, Anjum B, Sinha RA
Drafting of the manuscript: Raza S, Sinha RA
Critical revision of the manuscript for important intellectual content: Raza S, Sinha RA

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by the ICMR (59/05/2019/ONLINE/BMS/TRM) and Wellcome Trust/DBT India
Alliance Fellowship (IA/I/16/2/502691) awarded to Sinha RA.

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

Ethical approval and consent to participate
Not applicable.