Distinct immune surveillance in primary biliary cholangitis and primary sclerosing cholangitis is linked with discrete cholangiocarcinoma risk

Sep 24, 2026

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are major liver autoimmune diseases with distinct epidemiology and target bile-duct cells. PBC mainly affects intrahepatic small bile ducts in women and rarely progresses to cholangiocarcinoma (CCA), whereas PSC predominates in men, targets medium-to-large intrahepatic and extrahepatic ducts, and carries a higher CCA risk. Increasing CCA incidence and limited early diagnosis and effective therapies make immune-surveillance differences clinically critical. This review summarizes mechanisms that may explain why PBC is more resistant and PSC more susceptible.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages7

Reading Time18 min

AccessFree to download

Abstract

Introduction

DOI: 10.1097/HC9.0000000000000218 SPECIAL A RTICLE Distinct immune surveillance in primary biliary cholangitisand primary sclerosing cholangitis is linked with discrete cholangiocarcinoma risk Roopa H. Nanjundappa1 | Urs Christen2 | Channakeshava S. Umeshappa 1,3 1Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada 2Department of General Pharmacology and Toxicology, Pharmazentrum Frankfurt, Goethe University Frankfurt, Frankfurt am Main, Germany 3Department of Pediatrics, IWK Health Center, Halifax, Nova Scotia, Canada Correspondence Channakeshava S. Umeshappa, Department of Microbiology and Immunology, Dalhousie University, 5850 University Ave. Halifax, NS, Canada B3K 6R8 Email: [csumesha@dal.ca](csumesha@dal.ca) | | Abstract | | | --- | --- | --- | | | Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are 2 major liver autoimmune diseases. PBC is common in women and primarily affects intrahepatic small bile duct epithelial cells, known as cholangiocytes. In contrast, PSC is dominant in men and primarily affects medium and big intrahepatic and extrahepatic bile duct epithelial cells. Cholangiocarcinoma (CCA) is a malignancy arising from cholangiocytes, and its incidence is increasing worldwide in both men and women. Numerous retrospective and clinical studies have suggested that PBC patients rarely develop CCA compared to PSC patients. CCA is accountable for the higher deaths in PSC patients due to ineffective therapies and our inability to diagnose the disease at an early stage. Therefore, it is paramount to understand the differences in immune surveillance mechanisms that render PBC patients more resistant while PSC patients are susceptible to CCA development. Here, we review several potential mechanisms contributing to differences in the susceptibility to CCA in PBC versus PSC patients. | | | | | | INTRODUCTION Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are debilitating progressive diseases of the hepatobiliary system. The development of these diseases is multifactorial, where genetic, immunological, and environmental factors play an important role.[1–3] PBC is the most common autoimmune liver disease, predominantly seen in women (9:1 woman: man ratio), and ~53% of patients have at least 1 concomitant autoimmune condition. It primarily affects epithelial cells of the small/intrahepatic bile ducts, known as cholangiocytes. Antimitochondrial antibodies and high levels of IgM are considered serological markers of PBC.[4] Importantly, autoreactivity to the E2-component of the mitochondrial pyruvate dehydrogenase complex has been suggested in PBC. [3,5] Unlike PBC, PSC is prevalent in men (1:2 woman: man ratio) and primarily affects medium and large-sized intrahepatic and extrahepatic bile duct epithelial cells. There is no curative drug for PBC and PSC, and patients invariably develop cirrhosis and die if the liver is not transplanted. At Abbreviations: CCA, cholangiocarcinoma; CTL, cytotoxic T lymphocyte; IBD, inflammatory bowel disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; UC, ulcerative colitis. -- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- ----- - This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2023 The Author(s) . Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases. present, the FDA-approved ursodeoxycholic acid is being used as a main treatment for PBC; however, it is effective in about 60% of the patients with PBC, who will show

FAQs

How do PBC and PSC differ in who they affect and which bile-duct cells they target?

PBC is more common in women and primarily affects intrahepatic small bile-duct epithelial cells (cholangiocytes). PSC predominates in men and primarily affects medium and large intrahepatic and extrahepatic bile-duct epithelial cells.

Why is cholangiocarcinoma risk higher in PSC than in PBC?

The document states that CCA develops far more often in PSC patients than in PBC patients, contributing to higher PSC-related deaths. It attributes this to differences in immune-surveillance mechanisms that render PBC more resistant and PSC more susceptible.

What does the article propose about mechanisms underlying the different CCA susceptibilities?

It proposes several potential mechanisms, including differences in autoimmunity and helper T cell responses, the presence of concomitant inflammatory bowel disease in PSC, sex differences between PBC and PSC, and ductopenia.

Sep 24, 2026

Uploaded by Quinn Holloway