Hepatic Estrogen Receptor Expression Prevents Liver Fibrosis through Decreasing the Risk of Early Activation of Hepatic Stellate Cells

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IntroductionHepatic stellate cells (HSCs), in response to various inflammatory stimuli, undergo phenotypic changes from non-proliferating to proliferating cells that express alpha-smooth-muscle actin (α-SMA). Previous studies suggest that the estrogen presents an antifibrogenic action through inhibiting the myofibroblastic transformation of HSCs. The aim of this study is twofold: first, to understand the impact of early HSC activation on the fibrotic evolution of liver allografts; second, to find out the effect of estrogen and gender on this process.Materials and MethodsLiver allograft biopsies of 71 (M/F: 49/22) cases that taken during first 4 months included in the study. All biopsies scored for liver fibrosis(LF) and immunostained with the estrogen receptor (ER), α-SMA, and TGF-β. Activated HSCs determined by the expression of α-SMA. Only 50 patients had follow-up biopsies taken within 18 months, and all 50 biopsies were scored for LF.ResultsEvaluation of initial first biopsy showed that only 35 of 71 patients had LF and almost all had fibrosis score (FS) lower than 2. Among 50 patients who had follow-up biopsies, 33 had developed variable scores of LF after initial biopsy. Of 71 patients 15 (M/F: 13/2) had no ER expression while 56 (M/F: 36/20) showed ER expression. Women showed higher degrees of ER expression compared to men (p<.001). The degree of LF both in initial and follow-up biopsies found to increase with decreasing ER expression (p<.01) and increasing degree of α-SMA and TGF-β expression (p<.001).ER expression in liver showed a significant negative correlation with α-SMA and TGF-β expression (p=.001).Also, the degree of the α-SMA and TGF-β expression found higher in males compared to females (p<.05). During 18 months the development of LF found higher in males and patients with low ER expression (p<.05). Patients with high expression of ER and women tend to develop a lower incidence of cirrhosis (p=.001), while men and patients with high expression of α-SMA and TGF-β developed a high frequency of cirrhosis(p<.01).Overall 5- and 10-year survival was 58% and 42% for negative and low ER expression while it was 82,5% and 80% for high ER expression (p=0.001). In multivariate logistic regression analyses, ER expression continued to be an independent predicting factor of liver fibrosis in patients (OR: 0.05; 95% CI: 0.01-0.248; P<.001).ConclusionEarly activation of HSCs is a critical sign of the progressive fibrosis, and an increased number of HSCs represent an unfavorable event related to cirrhotic evolution. We suggested that lower progression of fibrosis in women may be due to the antifibrogenic action of estrogen which was confirmed by our results that ER expression in the liver has a negative correlation with HSCs and TGF-β expression. Consequently female and patients with high levels of estrogen have a better prognosis because of the antifibrotic action of estrogen.

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