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Review
. 2020 Jun 21;26(23):3126-3144.
doi: 10.3748/wjg.v26.i23.3126.

Review of primary sclerosing cholangitis with increased IgG4 levels

Charis D Manganis  1 , Roger W Chapman  1 , Emma L Culver  2
Affiliations
Review

Review of primary sclerosing cholangitis with increased IgG4 levels

Charis D Manganis et al. World J Gastroenterol. .

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

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Conflict of interest statement

Conflict-of-interest statement: There are no commercial or financial conflicts of interest related to this article.

Figures

Figure 1
Figure 1
Decision tree for literature research strategy. PSC: Primary sclerosing cholangitis.
Figure 2
Figure 2
IgG4-related sclerosing cholangitis type 2 (primary sclerosing cholangitis-like). A 58-year old female with cholestatic liver biochemistry, elevated serum IgG4 and IgE, and peripheral blood eosinophilia. A: Magnetic resonance cholangiopancreatography (MRCP) demonstrates common bile duct stricture (CBD) (arrow), intrahepatic duct irregularity and strictures (arrows) and beading (arrows). The liver biochemistry, serum IgG4 level, common bile duct and intrahepatic duct strictures improved after 12 wk of corticosteroid therapy. Endoscopic retrograde cholangiopancreatography and brushings of the CBD stricture were negative for dysplasia. B: MRCP demonstrates new right intra-hepatic duct stricture (arrow) and improvement of CBD stricture (arrow) one year later. Azathioprine (1.5 mg/kg) started to reduce further risk of disease relapse. CBD: Common bile duct.
Figure 3
Figure 3
Pathogenic factors driving the phenotype of primary sclerosing cholangitis with an increased IgG4 level. HLA: Human leukocyte antigen; PSC: Primary sclerosing cholangitis.
See this image and copyright information in PMC

References

    1. Singh S, Talwalkar JA. Primary sclerosing cholangitis: diagnosis, prognosis, and management. Clin Gastroenterol Hepatol. 2013;11:898–907. - PMC - PubMed
    1. Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T, Lie BA, Bergquist A, Schramm C, Weismüller TJ, Gotthardt D, Rust C, Philipp EE, Fritz T, Henckaerts L, Weersma RK, Stokkers P, Ponsioen CY, Wijmenga C, Sterneck M, Nothnagel M, Hampe J, Teufel A, Runz H, Rosenstiel P, Stiehl A, Vermeire S, Beuers U, Manns MP, Schrumpf E, Boberg KM, Schreiber S. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology. 2010;138:1102–1111. - PubMed
    1. Boonstra K, de Vries EM, van Geloven N, van Erpecum KJ, Spanier M, Poen AC, van Nieuwkerk CM, Witteman BJ, Tuynman HA, Naber AH, Kingma PJ, Beuers U, Ponsioen CY Epi PSC PBC Study Group. Risk factors for primary sclerosing cholangitis. Liver Int. 2016;36:84–91. - PubMed
    1. Boonstra K, van Erpecum KJ, van Nieuwkerk KM, Drenth JP, Poen AC, Witteman BJ, Tuynman HA, Beuers U, Ponsioen CY. Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease. Inflamm Bowel Dis. 2012;18:2270–2276. - PubMed
    1. Floreani A, Rizzotto ER, Ferrara F, Carderi I, Caroli D, Blasone L, Baldo V. Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome. Am J Gastroenterol. 2005;100:1516–1522. - PubMed

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