Sex-Dependent Differences in Cholestasis: Why Estrogen Signaling May Be a Key Pathophysiological Driver.

Abstract

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are cholestatic liver diseases that have significant clinical impact with debilitating symptoms and mortality. While PBC is predominantly seen in perimenopausal and postmenopausal women, men who are diagnosed with PBC have worse clinical outcomes and all-cause mortality. In contrast, 60% to 70% of patients with PSC are men; the data indicate that female sex may be an independent factor against PSC-related complications. These findings suggest a sex-dependent biological basis for these differences. Estrogen has been implicated in the pathogenesis of intrahepatic cholestasis of pregnancy and may induce cholestasis through a variety of interactions. However, it is unclear why some sexual dimorphic features may provide a protective effect despite known estrogen models that induce cholestasis. This article provides a brief introductory background and discusses the sexual dimorphism in clinical presentation in PSC and PBC. It also explores the role of estrogen signaling in pathogenesis and how it relates to intrahepatic cholestasis of pregnancy. Studies have already targeted certain molecules involved in estrogen signaling, and this review discusses these studies that identify estrogen-related receptor, estrogen receptor-α, estrogen receptor-β, farnesoid X receptor, and mast cells as possible targets, in addition to long noncoding RNA H19-induced cholestasis and sexual dimorphism. It also explores these interactions and their role in the pathogenesis of PBC and PSC.

• Authors: AbdiGhani Ismail, Lindsey Kennedy, Heather Francis
• Journal: The American journal of pathology (Am J Pathol) Vol. 193 Issue 10 Pg. 1355-1362 (10 2023) ISSN: 1525-2191 [Electronic] United States
• PMID: 37422150 (Publication Type: Journal Article, Review, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 American Society for Investigative Pathology. All rights reserved.

Chemical References

• Estrogens

Topics

• Male
• Humans
• Female
• Liver Cirrhosis, Biliary
• Sex Characteristics
• Cholangitis, Sclerosing (genetics)
• Cholestasis (pathology)
• Estrogens