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Women Have a Lower Risk of Nonalcoholic Fatty Liver Disease but a Higher Risk of Progression Vs Men: A Systematic Review and Meta-analysis
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July 2020
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In summary, we found that women have a lower risk of NAFLD than men; however, once NAFLD is established, a woman's risk of progressive disease (NASH and advanced fibrosis) is higher than in men. These finding have far-reaching implications for the future burden of liver disease, women's health, and gender disparities in liver disease.
prevalence of NAFLD was 19% higher among men than women.....Among patients with NAFLD, women had a 37% higher prevalence of advanced fibrosis than men........Central obesity, particularly visceral adiposity, is the main source of free fatty acids that drive NASH pathogenesis and progression.....Decreases in estrogen during the menopausal transition, typically occurring around the age of 50 years, leads to a shift in adipose tissue deposition to a visceral distribution....increases in the incidence of type 2 diabetes and atherogenic dyslipidemia beyond that expected by aging alone, are well documented among postmenopausal women.....Estrogen is believed to exert a direct antifibrotic effect in the liver and may play a protective role against steatohepatitis.... it is plausible that cirrhosis and its complications may occur with greater frequency among women than men.... it is possible that women with NAFLD, particularly those older than age 50 years, may require greater clinical vigilance to diagnose advanced fibrosis compared with men.....there were several unmeasured factors that may explain our findings. For example, polycystic ovarian syndrome, through high circulating androgens and insulin resistance, may account for the greater risk of NASH among women. The cumulative effects of hormonal therapies, pregnancies, and related complications over a woman's lifetime may contribute to NAFLD progression. Behavioral factors, which likely vary across cultural settings, may account for the increased risk of NAFLD severity among women.
Conclusions
In a systematic review and meta-analysis, we found women to have a lower risk of NAFLD than men. However, once NAFLD is established, women have a higher risk of advanced fibrosis than men, especially after age 50 years.
Association between gender and the prevalence of
nonalcoholic fatty liver disease
The NAFLD prevalence ranged from 8.6% to 52.0% across the included studies. The pooled overall NAFLD prevalence was 26.3% (95% CI, 21.4%-31.9%; I2 = 100%). Women had a 19% lower prevalence of NAFLD compared with men (pooled risk ratio [RR], 0.81; 95% CI, 0.68-0.97; I2 = 97.5%)
Association between sex and prevalence of advanced fibrosis
The prevalence of advanced fibrosis ranged from 9% to 74% across included studies. The pooled prevalence of advanced fibrosis was 22.9% (95% CI, 19.4-26.8; I2 = 95.2%). Women had a 37% higher pooled prevalence of advanced fibrosis than men in the 21 included studies (pooled RR, 1.37; 95% CI, 1.12-1.68; I2 = 74.0%)
Discussion
In our meta-analysis of 17 population-based studies, the prevalence of NAFLD was 19% higher among men than women. However, among individuals with established NAFLD, women were as likely as men to have NASH and more likely to have advanced fibrosis than men. Among patients with NAFLD, women had a 37% higher prevalence of advanced fibrosis than men. These findings have important implications not only for disease stratification and counseling patients about risk of NAFLD, but also indicate that the future burden of NAFLD complications are likely to affect men and women equally.
Age modified the gender effect in our analysis. Among populations of older individuals with biopsy-proven NAFLD, women had a substantially higher risk of NASH and advanced fibrosis compared with men. Our findings of an increased prevalence of severe phenotypes of NAFLD-NASH and advanced fibrosis-among older women fits well into the current understanding of disease pathogenesis. Central obesity, particularly visceral adiposity, is the main source of free fatty acids that drive NASH pathogenesis and progression.
Although men tend to accumulate adipose tissue centrally throughout their lifetime, adipose tissue distribution changes over the lifetime of women and is subject to estrogen exposure. Estrogen exposure during the premenopausal years promotes a gluteal femoral adipose pattern. Decreases in estrogen during the menopausal transition, typically occurring around the age of 50 years, leads to a shift in adipose tissue deposition to a visceral distribution. Several metabolic sequelae of this change in body fat distribution, including increases in the incidence of type 2 diabetes and atherogenic dyslipidemia beyond that expected by aging alone, are well documented among postmenopausal women.
Our findings indicate that once NAFLD is established, the risk of progressive disease (ie, NASH and advanced fibrosis) is not different and may be slightly higher among women than men. Estrogen is believed to exert a direct antifibrotic effect in the liver and may play a protective role against steatohepatitis. In studies of patients with chronic viral hepatitis, the slower progression of fibrosis as well as the later onset of cirrhosis observed in women has been attributed largely to the protective role of estrogen.
In contrast to the case of viral hepatitis, we found that among younger populations with NAFLD, women possess an equal risk of advanced fibrosis as men NAFLD; furthermore, our findings suggest that the loss of estrogen may in fact accelerate disease progression among postmenopausal women.
There were geographic variations in the association between sex and NAFLD severity. Although the effect of sex on risk of NAFLD did not vary across geographic locations, a significantly higher prevalence of the severe histologic subtypes of NAFLD was observed among women compared with men among studies out of East Asia (for NASH and advanced fibrosis) and Europe (advanced fibrosis), but not North America. Age partially may explain the NASH and advanced fibrosis trends, because most of the large East Asian studies that examined NASH or advanced fibrosis included older patients, but not completely, because the majority of European studies (4 of 5) comprised younger study populations. These geographic differences may reflect cultural differences in gender behaviors (ie, dietary habits) that influence NAFLD pathogenesis and risk of NASH and fibrotic progression. Alternatively, they also may be related to a differential prevalence of PNPLA3 genetic variants that interact with gender to drive NAFLD progression.
Our findings have implications for chronic liver disease epidemiology as well as women's health. The presence of severe fibrosis (METAVIR stages F2-F4 on liver biopsy) independently predicts an increased liver-related mortality in NAFLD.
Given the higher risk of advanced fibrosis observed among women compared with men with NAFLD in our meta-analysis, it is plausible that cirrhosis and its complications may occur with greater frequency among women than men. Thus, women with NAFLD should be evaluated for NASH and fibrosis as vigorously as men. Furthermore, it is possible that women with NAFLD, particularly those older than age 50 years, may require greater clinical vigilance to diagnose advanced fibrosis compared with men. Moreover, consideration of undiagnosed cirrhosis may be warranted among younger women with NAFLD risk factors who are considering pregnancy because cirrhosis can be a serious health problem in a woman's reproductive life. In addition, there are potential downstream effects of advanced maternal liver disease on fetal development and neonatal health. However, these hypotheses will need to be evaluated in future studies before firm recommendations can be made. Younger women with NASH also may be less likely to receive pharmacologic therapies given that nearly all existing and pipeline options are contraindicated during pregnancy or have unstudied fetal effects. Thus, more focused and intensified efforts may be warranted to target lifestyle modifications and weight loss among young women with NAFLD, particularly in the presence of NASH and/or advanced fibrosis.
Our study had limitations. First, there was significant heterogeneity among the included studies, as observed in previously published meta-analyses addressing NAFLD prevalence and severity.
It is unlikely that the mode of NAFLD detection was a significant source of heterogeneity given that ultrasound was used among 13 of 17 studies included in the NAFLD prevalence analysis. A large proportion of studies that were included in the NASH (15 of 22 studies) and advanced fibrosis (17 of 21 studies) analyses used data among patients with biopsy-proven NAFLD. It is plausible that the included study cohorts had undergone biopsies because more severe disease was suspected, however, it is unlikely that gender influenced the likelihood of receiving a liver biopsy among the included patients. Thus, inclusion of these study cohorts may have accounted for some of the observed heterogeneity, but were unlikely to have introduced bias into the analyses. Sex, age, and body weight may interact to influence the risk of advanced fibrosis among patients with NAFLD. However, none of the studies included in our analysis were designed specifically to address gender differences in NAFLD and granular data regarding metabolic comorbidities or body weight classification were not available by gender. Therefore, we could not explore potential interactions between body weight and sex in the current analysis. Finally, there were several unmeasured factors that may explain our findings. For example, polycystic ovarian syndrome, through high circulating androgens and insulin resistance, may account for the greater risk of NASH among women. The cumulative effects of hormonal therapies, pregnancies, and related complications over a woman's lifetime may contribute to NAFLD progression. Behavioral factors, which likely vary across cultural settings, may account for the increased risk of NAFLD severity among women.
In summary, we found that women have a lower risk of NAFLD than men; however, once NAFLD is established, a woman's risk of progressive disease (NASH and advanced fibrosis) is higher than in men. These finding have far-reaching implications for the future burden of liver disease, women's health, and gender disparities in liver disease.
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