Reproductive Status Is Associated with the Severity of Fibrosis in Women with Hepatitis C

Abstract

IntroductionChronic hepatitis C is the main cause of death in patients with end-stage liver disease. Prognosis depends on the increase of fibrosis, whose progression is twice as rapid in men as in women. Aim of the study was to evaluate the effects of reproductive stage on fibrosis severity in women and to compare these findings with age-matched men.Materials and Methods A retrospective study of 710 consecutive patients with biopsy-proven chronic hepatitis C was conducted, using data from a clinical database of two tertiary Italian care centers. Four age-matched groups of men served as controls. Data about demographics, biochemistry, liver biopsy and ultrasonography were analyzed. Contributing factors were assessed by multivariate logistic regression analysis.ResultsLiver fibrosis was more advanced in the early menopausal than in the fully reproductive (P<0.0001) or premenopausal (P = 0.042) group. Late menopausal women had higher liver fibrosis compared with the other groups (fully reproductive, P<0.0001; premenopausal, P = <0.0001; early menopausal, P = 0.052). Multivariate analyses showed that male sex was independently associated with more severe fibrosis in the groups corresponding to premenopausal (P = 0.048) and early menopausal (P = 0.004) but not late menopausal pairs. In women, estradiol/testosterone ratio decreased markedly in early (vs. reproductive age: P = 0.002 and vs. premenopausal: P<0.0001) and late menopause (vs. reproductive age: P = 0.001; vs. premenopausal: P<0.0001). In men age-matched with menopausal women, estradiol/testosterone ratio instead increased (reproductive age group vs. early: P = 0.002 and vs. late M: P = 0.001).ConclusionsThe severity of fibrosis in women worsens in parallel with increasing estrogen deprivation and estradiol/testosterone ratio decrease. Our data provide evidence why fibrosis progression is discontinuous in women and more linear and severe in men, in whom aging-associated estradiol/testosterone ratio increase occurs too late to noticeably influence the inflammatory process leading to fibrosis.

The effects of alcohol on spontaneous clearance of acute hepatitis C virus infection in females versus males

“…One hypothesis is that there may be sex-hormone-specific receptors for many of the immune pathways responsible for HCV natural history. Animal studies have demonstrated estrogen effects hepatic stellate cells that contribute to fibrosis (Shimizu et al, 1999), and human studies have also documented lower rates of fibrosis associated with higher estrogen states (Di Martino et al, 2004; Villa et al, 2012). However, it is also possible that the gender-related differences in spontaneous clearance that we observed could be related to unmeasured differences in the patterns of drinking and/or alcohol exposure among women compared to men.…”

Influence of Age and Gender Before and After Liver Transplantation

“…A possible explanation for the protective role of estrogens in women with chronic liver disease resides in their role in keeping inflammation under control. With menopause, the fall of estrogen levels is accompanied by a rapid increase in the levels of proinflammatory and anti‐inflammatory cytokines . This leads to differential speeds of fibrosis development during fertile and menopausal ages, with women catching up with men in fibrosis progression after menopause .…”

Gender Mainstreaming and Transplant Surgery

“…In conclusion, the outcome for both sexes after transplantation is equal for all indications except hepatitis C-induced cirrhosis [4,15,28,36,37,38,39,40,41,42,43]. Women undergoing transplantation because of a hepatitis C-induced cirrhosis have a higher risk for graft loss and rejection and a worse outcome in the case of a recurrent hepatitis C infection [8,15,44,45,46]. The donor's gender does not affect survival or outcome after liver transplantation [4,47].…”