Peribiliary and colonic crypt glands in primary sclerosing cholangitis and inflammatory bowel disease pathogenesis: New research perspectives

Abstract

Primary sclerosing cholangitis (PSC) is a chronic, continuously progressive cholestatic liver disease of unknown etiology. It is characterized by inflammation, local foci of obliterating fibrosis with proximal segmental dilatation of the bile ducts, which is caused by the formation of multifocal biliary concentric strictures. The classic form of PSC affects mainly men and occurs with damage to the extrahepatic and large intrahepatic (segmental and lobar) bile ducts. The disease naturally progresses to secondary biliary cirrhosis of the liver, portal hypertension, liver failure with the possible development of cholangiocellular carcinoma. In 60%-80% of cases, it is associated with inflammatory bowel disease (IBD). In recent years, a rarer form of PSC with involvement of small (septal) intrahepatic bile ducts has been highlighted separately. However, in any form of PSC, the small intralobular and interlobular bile ducts remain intact. The mechanism of PSC development remains unclear, as well as why the pathological process develops mainly in the extrahepatic and large intrahepatic bile ducts. The question of the mechanism of formation of multiple local irregularly distributed concentric strictures alternating with proximal dilatation of the bile ducts also remains unanswered. Furthermore, the strong association between PSC and IBD remains unexplained. In the proposed review, the authors try for the first time to answer these questions based on the assumption that in the bile ducts and colon the presence of a common morpho-functional structure, and damage to or dysfunction of these structures may provoke the development of a pathological process in PSC. Such a unifying structure is the glands that produce a protective secretion containing mucin for the bile ducts and colon. In the bile ducts, these are the peribiliary glands (PBGs), and in the large intestine, these are the glands that form the crypts. It is known that PBGs are absent in small intralobular and interlobular bile ducts. PBGs and the glands that form the crypts of the colon mucosa have a similar structure and consist of two types of cells: Secretory cells, which produce secretions, and stem cells, which play an important role in the processes of repair and regeneration. Structural damage and/or functional disorders to cells of the PBGs and glands of the colon crypts are most likely trigger factor in the development of the pathological process in bile duct and colon in PSC with often concomitant IBD.

Keywords: Primary sclerosing cholangitis; Inflammatory bowel disease; Peribiliary glands; Glands of colon crypts; Mucins of the bile ducts; Mucins of the colon mucosa; Fucosyltransferase 2

Core Tip: This review presents a novel hypothesis explaining the pathogenesis of primary sclerosing cholangitis (PSC), focusing on the key role of peribiliary glands (PBGs) and colonic crypt glands as a common morphofunctional structure linking pathology of bile ducts and colon. The hypothesis proposes that simultaneous structural and functional impairment of these mucin-producing glands may trigger PSC development. The unifying mechanism, which links PSC and inflammatory bowel disease (IBD) through dysfunction PBGs and colonic crypt glands, probably closely related to mutations in the FUT2 gene affecting fucosylation of protective mucins in bile ducts and colonic mucosa. This hypothesis explains key clinical features of PSC: (1) Selective involvement of extrahepatic and large intrahepatic bile ducts; (2) Formation of characteristic concentric strictures; (3) Strong association between PSC in IBD; (4) Sparing of small intralobular and interlobular bile ducts; and (5) Increased risk of cholangiocellular carcinoma and colorectal cancer. The proposed mechanism provides a comprehensive framework for understanding PSC pathogenesis and identifies potential therapeutic targets.