Review
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2020; 26(23): 3126-3144
Published online Jun 21, 2020. doi: 10.3748/wjg.v26.i23.3126
Review of primary sclerosing cholangitis with increased IgG4 levels
Charis D Manganis, Roger W Chapman, Emma L Culver
Charis D Manganis, Roger W Chapman, Emma L Culver, Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
Author contributions: Manganis CD and Culver EL performed the literature review and drafted the original manuscript; Chapman RW and Culver EL were responsible for conception and design of the study, critical revision and editing of the manuscript; all authors approved the final manuscript.
Supported by the National Institute of Health Research Biomedical Research Centre, based at Oxford University Hospitals Trust; Oxfordshire Health Service Research Committee as part of Oxford Hospitals Charity, Oxford.
Conflict-of-interest statement: There are no commercial or financial conflicts of interest related to 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: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Emma L Culver, BSc, MBChB, DPhil, MRCP Gastro, Consultant Hepatologist and Senior Lecturer, Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, United Kingdom. emma.culver@nhs.net
Received: December 23, 2019
Peer-review started: December 23, 2019
First decision: March 23, 2020
Revised: April 7, 2020
Accepted: June 5, 2020
Article in press: June 5, 2020
Published online: June 21, 2020
Processing time: 180 Days and 23.2 Hours
Abstract

Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease. Sub-types of PSC have been described, most recently PSC with elevated serum and/or tissue IgG4 subclass. We aim to summarise the clinical phenotype, disease associations, differential diagnosis, response to therapy and pathogenic mechanisms underlying PSC-high IgG4 subtype. We reviewed PubMed, MEDLINE and Embase with the search terms “primary sclerosing cholangitis”, “IgG4”, and “IgG4-related sclerosing cholangitis (IgG4-SC)”. Elevated serum IgG4 are found in up-to one-quarter, and abundant IgG4-plasma cell infiltrates in the liver and bile ducts are found in up-to one-fifth of PSC patients. This group have a distinct clinical phenotype, with some studies reporting a more aggressive course of liver and associated inflammatory bowel disease, compared to PSC-normal IgG4 and the disease mimic IgG4-SC. Distinguishing PSC-high IgG4 from IgG4-SC remains challenging, requiring careful assessment of clinical features, organ involvement and tissue morphology. Calculation of serum IgG4:IgG1 ratios and use of a novel IgG4:IgG RNA ratio have been reported to have excellent specificity to distinguish IgG4-SC and PSC-high IgG4 but require validation in larger cohorts. A role for corticosteroid therapy in PSC-high IgG4 remains unanswered, with concerns of increased toxicity and lack of outcome data. The immunological drivers underlying prominent IgG4 antibodies in PSC are incompletely defined. An association with PSC-high IgG4 and HLA class-II haplotypes (B*07, DRB1*15), T-helper2 and T-regulatory cytokines (IL4, IL10, IL13) and chemokines (CCL1, CCR8) have been described. PSC-high IgG4 have a distinct clinical phenotype and need careful discrimination from IgG4-SC, although response to immunosuppressive treatments and long-term outcome remains unresolved. The presence of IgG4 likely represents chronic activation to persistent antigenic exposure in genetically predisposed individuals.

Keywords: Primary sclerosing cholangitis; IgG4; IgG4-related disease; IgG4-related sclerosing cholangitis

Core tip: Elevated serum IgG4 titres and/or abundant IgG4-positive plasma cell infiltrates in the liver and bile ducts are present in up-to one-quarter of patients with primary sclerosing cholangitis (PSC). It should be distinguished from IgG4-related sclerosing cholangitis. PSC with high IgG4 have a different clinical phenotype to those with normal IgG4, with higher bilirubin and alkaline phosphatase, higher PSC Mayo Risk Score, more advanced liver disease, shorter time to liver transplantation, more aggressive colitis and shorter time to colectomy. Corticosteroids may provide biochemical improvement but rarely results in cholangiographic resolution. Concerns include steroid toxicity, infection and disease progression in those with advanced cirrhosis.