Division of Internal Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana.
Am J Pathol. 2023 Oct;193(10):1355-1362. doi: 10.1016/j.ajpath.2023.06.010. Epub 2023 Jul 6.
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.
原发性胆汁性胆管炎（PBC）和原发性硬化性胆管炎（PSC）是两种胆汁淤积性肝病，具有显著的临床影响，会导致衰弱症状和死亡率。虽然 PBC 主要发生在绝经前和绝经后妇女中，但被诊断为 PBC 的男性的临床结局和全因死亡率更差。相比之下，60%至 70%的 PSC 患者为男性；数据表明，女性可能是 PSC 相关并发症的独立因素。这些发现表明这些差异存在性别依赖性的生物学基础。雌激素已被牵涉到妊娠肝内胆汁淤积症的发病机制中，可能通过多种相互作用引起胆汁淤积。然而，尚不清楚为什么尽管有诱导胆汁淤积的已知雌激素模型，但某些性别二态特征可能提供保护作用。本文提供了简要的背景介绍，并讨论了 PSC 和 PBC 临床表现中的性别二态性。它还探讨了雌激素信号在发病机制中的作用以及它与妊娠肝内胆汁淤积的关系。研究已经针对某些涉及雌激素信号的分子，本综述讨论了这些研究，确定了雌激素相关受体、雌激素受体-α、雌激素受体-β、法尼醇 X 受体和肥大细胞作为可能的靶点，此外还有长链非编码 RNA H19 诱导的胆汁淤积和性别二态性。它还探讨了这些相互作用及其在 PBC 和 PSC 发病机制中的作用。
