NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk

Abstract

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals’ ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.

Prevalence of prediabetes and type 2 diabetes in children with obesity and increased transaminases in European German‐speaking countries. Analysis of the APV initiative

“…On the contrary, postmenopausal women are known to carry a greater risk of NAFLD than men, suggesting a protective role of oestrogens. Further, the role of NAFLD as a sexual dimorphic disease is also supported by animal models that demonstrate a disposition of male individuals to more advanced fatty liver disease compared to females that is linked to a state of subclinical inflammation and increased hepatic morbidity . A study applying a computational model concluded that due to sex‐specific metabolic demands, female and male livers are metabolically diverse and therefore differently regulated .…”

“…A study applying a computational model concluded that due to sex‐specific metabolic demands, female and male livers are metabolically diverse and therefore differently regulated . In addition, a recent review stated that most published clinical and epidemiological studies fail to examine sex differences appropriately' and suggested to consider sex differences, sex hormones, age and other reproductive information in clinical investigation and gene association studies of NAFLD 'in order to fill current gaps and implement precision medicine for patients with NAFLD' …”

No effect of resveratrol on VLDL‐TG kinetics and insulin sensitivity in obese men with nonalcoholic fatty liver disease

“…8 Our results extend these findings to include also basal EGP and EGP during insulin suppression. Moreover, as numerous studies have shown clear differences between sexes in lipid and FFA metabolism, and we studied only men, 14 the results cannot be extended to women. The difference, however, is probably explained by the "regression to the mean" phenomenon, as the baseline difference was abated after the intervention period.…”

Prevalence of Nonalcoholic Fatty Liver Disease in the Female Population

“…In this context, NAFLD is considered the hepatic manifestation of the metabolic syndrome (MS), which is a multisystem disruption of energy homeostasis primarily driven by insulin resistance (IR) . In addition, some studies have demonstrated that the prevalence of NAFLD is higher among the male population, increases with age, and varies among different ethnicities . Moreover, it has been clearly demonstrated that NAFLD is associated with an increased risk of cardiovascular disease (CVD), independent of other risk factors of CVD, such as obesity and diabetes, and CVD is the most frequent cause of death among patients with NAFLD …”

“…Although the spectrum of NAFLD is reported to be more common in men, NASH was initially described as a liver disease of elderly women . It is known that after menopause, the prevalence of NAFLD increases compared to the premenopausal state, with rates similar to the prevalence of NAFLD in men as well as a comparable risk of progression of liver disease . Given that most of these data come from tertiary care centers or review articles, there is a paucity of data using a population‐based data set about the burden and outcomes of NAFLD in the adult female population.…”