Clinical Impact of Sexual Dimorphism in Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)

Patrizia Burra; Debora Bizzaro; Anna Gonta; Sarah Shalaby; Martina Gambato; Maria Cristina Morelli; Silvia Trapani; Annarosa Floreani; Fabio Marra; Maurizia Rossana Brunetto; Gloria Taliani; Erica Villa


Liver International. 2021;41(8):1713-173. 

In This Article


In Europe, NASH is an increasingly common aetiology for HCC.[94] The yearly cumulative incidence of HCC is 2.6% in patients with NASH-related cirrhosis.[95] Irrespective of its aetiology, HCC predominantly affects males with an incidence four times higher in males than females.[96] The reasons for this sex disparity are complex and may be associated with a protective role of oestrogen on HCC development,[97] until menopause. For this reason, the median age for women is higher than that of men at the time of HCC diagnosis. Most studies showed that men are more likely to have larger tumours with increased rates of macrovascular invasion and extrahepatic spread, and are more likely to undergo transplantation than women.[98,99] The pathogenesis of HCC in the context of NAFLD is not completely clear; importantly 20% of NAFLD-HCC are diagnosed in the setting of non-cirrhotic liver.[100–102] Grade-based recommendations for surveillance in patients with NASH did not justify a systematic surveillance in NAFLD patients without cirrhosis, as a result of low currently observed incidence of HCC in this setting.[103] Older age, diabetes, advanced fibrosis and obesity are the main risk factors associated with HCC development in NAFLD patients, with or without cirrhosis.[104–106] In a US multicentre retrospective study,[107] the authors showed that there was significantly more non-cirrhotic HCC in women than in men. This may reflect the large number of NAFLD-related HCC in women in the cohort. This is very important from a surveillance point of view. Finally, they found that women had less-advanced HCC and had a greater overall survival, leading to different treatment options. Even when HCC is diagnosed at a potentially curable stage, LT or resection is not always feasible because of obesity and comorbidities. However, there have been excellent long-term outcomes in patients undergoing liver resection,[108] loco-regional therapies such as radiofrequency ablation, selective internal radiotherapy and transarterial chemoembolization can also be proposed.[109–113] Sex has a role also in HCC treatment, related to different tumour morphology at diagnosis, as men present larger HCC than women. Moreover, some studies showed that oestrogen can reduce the activation of stellate cell, making slower the liver fibrinogenesis.[107] Thus, women are less likely to have complications such as portal vein thrombosis and renal dysfunction, which may prevent HCC curative treatments. For both reasons, curative treatments for HCC are more common in women than men.[114–116] Sobotka et al[115] confirmed that women are still more likely to undergo resection and also determined that women are more likely to undergo ablation because of more compensated liver disease, being NAFLD present similarly in the 2 groups.

In conclusions, women show frequently a more compensated liver disease compared to men, developing non-cirrhotic HCC-related NAFLD. Moreover, at diagnosis, women have smaller tumour than men, more amendable to curative HCC treatments.