Abdelmalek, Manal

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.

Postmenopausal women with nonalcoholic steatohepatitis are at an increased risk of hepatic fibrosis compared with premenopausal women. Whether duration of estrogen deficiency in postmenopausal state dictates an individual's fibrosis risk remains uninvestigated. We assessed the associations of age at menopause and time from menopause with fibrosis severity in postmenopausal women with nonalcoholic fatty liver disease. Data from 488 postmenopausal women with (1) histologic diagnosis of nonalcoholic fatty liver disease and (2) self‐reported information on age at menopause were analyzed. The associations of premature menopause (age at menopause of <40 years) and time from menopause (age at study enrollment ‐ age at menopause, years) with fibrosis severity (stage 0‐4) were assessed using multiple ordinal logistic regression models with and without adjusting for clinical confounders. Among the participants (age at menopause 43.7 ± 8.6 years), women with premature menopause (29.3%) were younger at enrollment ( P < 0.001) and used hormone replacement therapy more often ( P < 0.003). After adjusting for age at enrollment, race, waist circumference standardized by body mass index, current smoking, current alcohol use, hypertension, diabetes/impaired fasting glucose, homeostatic model assessment of insulin resistance, and hormone replacement therapy, premature menopause was associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio = 1.9, 95% confidence interval 1.3‐2.7, P = 0.001), while time from menopause was directly associated with an increased likelihood of having more severe fibrosis (adjusted cumulative odds ratio for 5‐year unit = 1.2, 95% confidence interval 1.1‐1.3, P = 0.002). Conclusion : Duration of estrogen deficiency in postmenopausal state confers fibrosis risk among postmenopausal women with nonalcoholic fatty liver disease. (H epatology 2016;64:85–91)