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

Epidemiology of NAFLD/NASH

The incidence and prevalence of NAFLD are increasing dramatically in either Western or Eastern countries, reaching epidemic proportions.[8,9] The main reason for this dramatic increasing trend in NAFLD and NASH is the global increasing prevalence of obesity described by the World Health Organization.[10] In longitudinal studies, mostly performed in Asia, the incidence of NAFLD ranges from 19 to 44.5/1000 person-years and is higher in males compared to females.[11–21] The global prevalence of NAFLD has been recently updated,[1,8,9,22] the estimated prevalence of NASH in Europe is 23.71% (95% CI 16.12%-33.45%).[23] In Italy, the Dionysos Study comprising 6,917 persons from the general population in two Northern areas found a 25% prevalence of fatty liver and was higher in males compared to females (40% vs 23%).[24–26] Considering the different components of metabolic syndrome, prevalence NAFLD is dramatically high in obese patients, reaching 98%[27] and in T2DM patients, 55.5% of cases, with the highest prevalence in studies from Europe (68%), whereas the prevalence of NASH is 37.3%.[28]

Interestingly, children carry a high risk for NAFLD, having 8%-10% prevalence of NAFLD in the Italian population.[29] In a recent population-based study of young adults in UK, one in five young people had steatosis and one in 40 had fibrosis around the age of 24.[30] In the US, the prevalence of NAFLD in children and adolescents increased from 3.3 between 1988 and 1994 to 10.1% between 2005 and 2010. Similarly, the prevalence of NASH increased from 0.74% to 3.4% in the same period.[30,31]

The prevalence of NAFLD is higher in men than in women (Table 1, refs.[11,32–37]). In particular, the prevalence of men in NAFLD cohorts ranges between 4.3% and 42%, whereas the prevalence of women ranges between 1.6% and 24%. However, among each sex group, the wide difference in prevalence can be explained by the methods for definition of NAFLD, the gold standard being, among the non-invasive techniques, the magnetic resonance spectroscopy. The role of sex and reproductive status in the development and progression of NAFLD has been focused in a recent review by Ballestri et al.[38] One study from Japan[15] reported that the prevalence of NAFLD in pre-menopausal women was lower (6%) than in men (24%) and in post-menopausal women (15%). Moreover, NAFLD was more prevalent in women receiving HRT than in pre-menopausal women. In Shanghai population, the prevalence of NAFLD was higher in males than females under the age of 50, but was lower in males than females among people older than 50 years.[39] Analogously, a study from Japan reported a higher prevalence of NAFLD in males than females, and showed an increasing prevalence of NAFLD during adulthood from young to middle age, and a reduction of prevalence after the age of 50–60.[40] In general, women are at reduced risk of NAFLD compared to men in fertile age, whereas after menopause women lose their protective effect and have a comparable prevalence of NAFLD as men.[41] Post-menopausal women tend to increase body weight along with a shift in its distribution to an increase of visceral fat.[42] Moreover, post-menopausal women on hormone replacement therapy (HRT) have been found to have a lower prevalence of NAFLD compared to post-menopausal women not taking HRT.[43] A double-blind randomized trial with HRT or placebo in post-menopausal women with T2DM and presumed NAFLD showed a significantly decreased levels of aminotransferase in the group treated with HRT compared to placebo.[44] These figures contrast with a paper in which the prevalence of NAFLD was explored in 1170 community-based adolescents in the Western Australian Pregnancy cohort.[45] Females compared with males had a significantly higher prevalence of NAFLD (16.3% vs 10.1%, P =.004). In this study, the sex differences in NAFLD prevalence were associated with significant differences in adipose distribution and metabolic parameters, including adipocytokine levels. Finally, a recent review summarizes the current knowledge on sex differences in NAFLD, identifies gaps and discusses important considerations for future research.[3] Indeed, gender and sex hormones interact with numerous NAFLD factors including genetic variants, cytokines, stress, environmental factors and alter the risk profiles and phenotypes of NAFLD in individuals.[3]

Nutritional Factors and NAFLD

The dietary pattern has been investigated in several studies including NAFLD patients from different countries.[46–51] All studies utilized standardized food questionnaires. In one study from US including morbid obese patients undergoing bariatric surgery, carbohydrate intake was positively correlated with NAFLD.[46] Soft drink and meat intake were shown to be correlated with fatty liver in Israel,[47] whereas a positive correlation with high-fat diet or high-energy intake was related with NAFLD in Portugal,[48] Canada[49] and Germany.[50] Finally, a study from Korea showed a positive correlation between NAFLD and low vitamin C, K, folate, omega-3, nuts and seeds.[51]

An interesting review focused on the role of sex-specific nutrition patterns in the pathogenesis of NAFLD and including eight nutrition trials indicates that there are "typical" female patterns.[52] Women of all age groups are healthier than men with regard to their food behaviour. In particular, a higher proportion of men reported eating meat and certain types of poultry than women, whereas a high proportion of women ate fruits and vegetables. Moreover, a study supported by the European Union's FAIR (agriculture, fisheries and agro-industrial sectors) program showed that overall consumption of fruit and vegetables is likely to be higher among those Europeans with high compared to low socioeconomic status.[53]

Interestingly, an epidemiological study examining dietary factors in NAFLD by cirrhosis status was conducted within a multi-ethnic cohort in US.[54] This survey was performed prospectively in 215,000 participants in Hawaii and California. Overall, 2,974 cases of NAFLD were identified (518 with cirrhosis, 2,456 without cirrhosis); 29,474 matched controls were also analysed. Red meat, processed red meat, poultry and cholesterol intake were significantly associated with NAFLD. Conversely, fibre intake was inversely associated with the risk of NAFLD (P = .003). NAFLD was generally similar across racial/ethnic groups, except for poultry consumption (heterogeneity P = .004). The same risk factors (red meat, cholesterol) showed a strongest association in subjects with cirrhosis compared to non-cirrhotics (heterogeneity P = .004). It has been also been demonstrated that consumption of high-fructose diet beginning in adolescents lead to adult pathology that is modified by sex.[55] Choline is a nutrient obtained through both dietary intake and endogenous synthesis. Indeed, choline disturbances have a role in the pathogenesis of NAFLD, due to the gut microbiota in determining its availability and other factors including oestrogens status and genetic polymorphism.[56] Moreover, in a cross-sectional analysis of 664 subjects enrolled in the multicentre, prospective NASH Clinical Research Network focusing on diet consumption, it had been found that post-menopausal women with deficient choline intake had significantly worse fibrosis.[57] Pure choline deficiency may only become apparent in post-menopausal women who carry a genetic variant in the choline synthesis pathway that have oestrogen-response elements in their promoters.[58]

As far as alcohol consumption is concerned, in general, this parameter is not clearly defined in the population series. Indeed, the current criteria allow alcohol intake <30 g/day for men and <20 g/day for women, but the rate of abstinent subjects remains generally unknown. A population survey including 6,462 NAFLD subjects with a 70,401 person-years of follow-up was performed to analyse risk factors of advanced liver disease.[59] In the multivariate analysis, drinking habit (additional alcohol/drink/day) was an independent predictor of incident advanced liver disease.[59] These results suggest that considering patients with NAFLD only two drinks per day do not protect the liver from damage but, on the contrary, promote the progression to a more severe liver disease. The relationship between average alcohol use and incidental liver disease was adjusted for age and sex separately. In fact, women are more likely than men to develop alcoholic liver disease, because of several factors including differences in body structure, volume distribution, enzymatic activity and hormones.[60]

It has also been demonstrated that consuming a greater percentage of the daily calories in the morning decreased the odds of steatosis by 14% and 21%. Conversely, the odds of steatosis were 20% greater when morning and midday meals were skipped or when meals were consumed late in the night (73%). Late eating also increased the probability of developing significant fibrosis (61%).[61]