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

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-ß, 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.

Bile Acids in Autoimmune Liver Disease: Unveiling the Nexus of Inflammation, Inflammatory Cells, and Treatment Strategies.

As bile acids not solely play an essential role in nutrition absorption, but also in regulating metabolic functions as well as immune response, bile acids and their signaling pathways are increasingly acknowledged as potential therapeutic targets in the context of chronic liver diseases. Bile acid receptors such as G protein bile acid-activated receptor 1 and farnesoid X receptor are expressed in different immune cells engaged in innate immunity. Recently, a series of studies have revealed distinct functions of bile acids and bile acid receptors within the adaptive immune system. In addition, a variety of molecules targeting bile acid receptors and transporters are currently in advanced stages of clinical development. Autoimmune liver diseases including conditions like primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis can lead to chronic inflammation, fibrosis, and even cirrhosis and liver failure. In this review, we focus on the role of bile acids in the inflammatory aspects of autoimmune liver diseases.

A Rare Anatomic Variant of Double Replaced Hepatic Arteries: A Case Report and Brief Review of the Anomalous Hepatic Vasculature Literature.

BACKGROUND The liver is a frequent site of surgical resection for both benign and malignant lesions. Advanced knowledge of the hepatic arterial system and its variants is crucial to avoid incidental injuries during a resection procedure. Many variants have been previously described in the literature, yet extremely rare cases continue to be encountered in clinical practice. Documentation of these variants can thus allow for proper preoperative procedural planning when considering interventions involving the liver. Our aim is to present one such unique and extremely rare anomaly. CASE REPORT During routine cadaveric dissection of a 78-year-old man who had died of acute myeloid leukemia, a rare anatomic variant of the hepatic vasculature was revealed: a replaced right hepatic artery (rRHA) coming directly from the celiac trunk, a middle hepatic artery (MHA) continuing from the common hepatic artery (CHA), and a replaced left hepatic artery (rLHA) branching from the left gastric artery (LGA). To the best of our knowledge, this anomaly has only been described once before in the literature. CONCLUSIONS We report a rare anatomical variant of the hepatic vasculature. The significance of this variant must be considered during preoperative planning and the intra-arterial infusion of targeted drugs. This case further emphasizes the importance of proper medical imaging and documentation to ensure the best course of treatment for each patient. Given that this variant has only so far been identified in 2 post-mortem subjects, further work should include attempts at characterizing its physiologic effects in a living patient.