Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps

Abstract

Despite tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex differences in NAFLD remains insufficient. This review summarizes the current knowledge on sex differences in NAFLD, identifies gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women, suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate the sex differences observed in patients, with more severe steatosis and steatohepatitis, more proinflammatory/profibrotic cytokines, and a higher incidence of hepatic tumors in male than female subjects. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex-specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause), and synthetic hormone use. Conclusion: Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD, suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines; adequate consideration of sex differences, sex hormones/menopausal status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD.

Figure. 1.. Number of annual publications on sex differences in NAFLD and related fields.

Data were obtained from PubMed using the keyword ‘sex difference’ combined with ‘inflammation’, ‘immunology’, ‘cell death or apoptosis’, ‘diabetes mellitus’, or ‘ischemic heart disease’. Research on sex differences in NAFLD has apparently lagged behind other areas.

Figure. 2.. Overview of NAFLD pathogenesis and sex differences.

TG: triglycerides. Women and men store surplus calories differently: gluteo-femoral subcutaneous in women vs. visceral adiposity in men. Enlarged, dysfunctional adipose tissue, especially visceral adiposity, leads to systemic inflammation and insulin resistance, which facilitates energy influx to the liver and increases metabolic stress in hepatocytes. Sarcopenia exacerbates these changes, by generating a vicious cycle. When hepatocytes fail to adapt, the increased metabolic stress triggers oxidative stress or direct toxic effect of free FA on hepatocytes, and induces lipoapoptosis, which, in turn, leads to sterile inflammation. Chronic inflammation promotes fibrosis, cirrhosis, and tumorigenesis. Intestinal microbiota and BA play pivotal roles in regulating NAFLD pathogenesis in a multi-phasic manner while interacting with key players. Known sex differences and hormonal effects are depicted in a mechanism-specific way for further discussion in this review. Sex differences in TG synthesis, FA oxidation, and oxidative stress are not covered in this review. Sex difference in oxidative stress is well accepted. * see reference (85)

Figure. 3.. Sex difference considerations in NAFLD research.

Risk factor A- A factor whose effect is significantly modified by sex or innate sex-related attributes (i.e., chromosomes) so that the outcome will significantly differ between women and men. Risk factor B- A factor whose effect is modified by neither sex nor sex hormones, resulting in an outcome which is invariably consistent among premenopausal women, postmenopausal women and men. Risk factor C- A factor whose effect is significantly modified by female sex hormones. In this case, the association between risk factor C and the outcome will significantly differ among premenopausal, postmenopausal women, and men. In the analysis of risk factors A and C, the lack of proper cohort classification (i.e., subgroup analysis) would either result in a spurious conclusion or mask important sex-specific effects. Both sex and sex hormones interact with numerous NAFLD risk factors and alter the risk profiles and phenotypes of NAFLD in individuals.