Review
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World J Gastroenterol. Oct 7, 2023; 29(37): 5292-5304
Published online Oct 7, 2023. doi: 10.3748/wjg.v29.i37.5292
New insights into the pathogenesis of primary biliary cholangitis asymptomatic stage
Vasiliy Ivanovich Reshetnyak, Igor Veniaminovich Maev
Vasiliy Ivanovich Reshetnyak, Igor Veniaminovich Maev, Department of Propaedeutics of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow 127473, Russia
Author contributions: Reshetnyak VI and Maev IV have equally contributed to the study conception and design, literature review and analysis, drafting, critical revision and editing, and approval of the final version.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Vasiliy Ivanovich Reshetnyak, DSc, MD, PhD, Full Professor, Department of Propaedeutics of Internal Diseases and Gastroenterology, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, No. 20 Delegatskaya St, Moscow 127473, Russia. vasiliy.reshetnyak@yandex.ru
Received: July 19, 2023
Peer-review started: July 19, 2023
First decision: August 5, 2023
Revised: August 10, 2023
Accepted: September 14, 2023
Article in press: September 14, 2023
Published online: October 7, 2023
Processing time: 67 Days and 14.3 Hours
Abstract

Primary biliary cholangitis (PBC) is a chronic cholestatic progressive liver disease and one of the most important progressive cholangiopathies in adults. Damage to cholangiocytes triggers the development of intrahepatic cholestasis, which progresses to cirrhosis in the terminal stage of the disease. Accumulating data indicate that damage to biliary epithelial cells [(BECs), cholangiocytes] is most likely associated with the intracellular accumulation of bile acids, which have potent detergent properties and damaging effects on cell membranes. The mechanisms underlying uncontrolled bile acid intake into BECs in PBC are associated with pH change in the bile duct lumen, which is controlled by the bicarbonate (HCO3-) buffer system “biliary HCO3- umbrella”. The impaired production and entry of HCO3- from BECs into the bile duct lumen is due to epigenetic changes in expression of the X-linked microRNA 506. Based on the growing body of knowledge on the molecular mechanisms of cholangiocyte damage in patients with PBC, we propose a hypothesis explaining the pathogenesis of the first morphologic (ductulopenia), immunologic (antimitochondrial autoantibodies) and clinical (weakness, malaise, rapid fatigue) signs of the disease in the asymptomatic stage. This review focuses on the consideration of these mechanisms.

Keywords: Primary biliary cholangitis; Antimitochondrial autoantibodies; MicroRNA 506; Inositol-1,4,5-trisphosphate receptor type 3; Chloride/bicarbonate anion exchanger 2; Biliary bicarbonate umbrella; Dihydrolipoyl transacetylase (E2 subunit); Pyruvate dehydrogenase complex

Core Tip: This review considers the mechanisms contributing to the damage of the E2 subunit of the pyruvate dehydrogenase complex, formation of antimitochondrial autoantibodies (AMAs), and the development of ductulopenia in primary biliary cholangitis asymptomatic stage. A hypothesis explaining the pathogenesis of the initial morphological (ductulopenia), immunologic (AMAs), and clinical (weakness, malaise, rapid fatigue) signs of the disease in the asymptomatic stage is proposed.