Gender and Menopause Impact Severity of Fibrosis among Patients with Nonalcoholic Steatohepatitis

Abstract

BACKGROUND/AIM: Estrogens inhibit stellate cell activation and fibrogenesis. Thus, gender/menopause may influence the degree of fibrosis in patients with nonalcoholic steatohepatitis (NASH). We assessed whether gender/menopause is associated with severity of fibrosis (FIB) in adult patients with NASH after taking account of degrees of hepatocyte ballooning (BAL) and portal inflammation (PORT), two significant histologic features well correlated with FIB. METHODS: We analyzed 550 adult patients enrolled at two clinical sites [referral liver clinic (N=344) and bariatric surgery center (N=206)] who had histologic diagnosis of NASH with no co-existing liver conditions or excess alcohol use. Menopausal state was classified based on self-reported reproductive information, history of oophorectomy, and age relative to the average US age at menopause (50 years old). Liver histology was scored for BAL, PORT, and FIB according to the NASH CRN scoring system. Two different modeling approaches, classification and regression tree model (CART) and multiple ordinal logistic regression model (MOLR), were used to assess the association between the gender/menopause and FIB, taking into consideration age, race, BMI, diabetes mellitus (DM) and hypertension (HTN). RESULTS: Overall, men, pre-menopausal and post-menopausal women composed 35.1%, 28.4%, and 36.5% of the population, respectively. Mean (SD) age and BMI were 48±11 years and 40±10 kg/m2, 51% had DM/pre-DM, 71% had HTN, and 22% had advanced fibrosis. There was no significant siteinteraction between FIB and the gender/menopause categories; thus the association was assessed in the total population adjusting for the sites. The non-parametric CART model identified pre-menopausal women as one of the important factors in the classification of FIB severity, which was associated with lower stages of FIB vs. others. In the MOLR model adjusting for BAL, PORT, and the sites, men and post-menopausal women had a higher likelihood of greater FIB severity vs. premenopausal women: adjusted cumulative odds ratio (ACOR) and 95% confident interval (CI) = 1.6[1.0, 2.4], p<0.04 for post-menopausal women and 1.7[1.1, 2.6], p<0.02 for men. After adjusting for other confounders, ACOR and 95% CI was 1.4[0.9, 2.1], p=0.17 for post-menopausal women and 1.5 [1.0, 2.4], p<0.06 for men. CONCLUSION: Before menopause, men are at a higher risk of having more advanced fibrosis vs. women, at any given grade of hepatocyte ballooning and portal inflammation, while post-menopausal women have a similar risk for fibrosis as men. These findings may be explained by the protective effects of estrogen on fibrogenesis.