IgG4-related sclerosing cholangitis: all we need to know

Abstract

Our knowledge and experience of IgG4-related sclerosing cholangitis (ISC) have expanded in the last decade. ISC is one of the common organ manifestations of IgG4-related disease (IgG4-RD); approximately 60 % of patients with this systemic condition have ISC in the proximal and/or distal bile ducts. ISC needs to be discriminated from primary sclerosing cholangitis, cholangiocarcinoma, and other rare forms of lymphoplasmacytic cholangiopathy (e.g., follicular cholangitis and sclerosing cholangitis with granulocytic epithelial lesions). Its diagnosis requires a multidisciplinary approach, in which serology, histology, and imaging play crucial roles. Treatments with high-dose corticosteroids typically lead to the rapid and consistent induction of disease remission. Another promising therapeutic approach is B-cell depletion with rituximab. Although disease relapse is relatively common, provided that appropriate treatments are administered, ISC is considered a ''benign'' disease with a low risk of liver failure and biliary malignancy. Its molecular pathology is characterized by Th2-dominant immune reactions, regulatory T-cell activation, and CCL1-CCR8 interactions. Particular subsets of B cells such as plasmablasts and regulatory B cells also expand. A recent global proteomic study demonstrated that three significantly activated immunological cascades in ISC were all B-cell-or immunoglobulin-related (Fc-gamma receptormediated phagocytosis, B-cell receptor signaling pathway, and Fc-epsilon receptor I signaling pathway), suggesting the crucial roles of B cells in the underlying immune reactions. Despite the expansion of our knowledge of the pathophysiology of ISC, the exact role of IgG4 remains unclear. A better understanding of its immunopathology will offer some potential drug targets for this emerging biliary disease.

Pathogenesis and clinical spectrum of primary sclerosing cholangitis

“…ISC is seen in approximately 20%-88% of patients with IgG4-RD[77-79]. Individuals with ISC are commonly diagnosed with concomitant AIP[80]. Similar to PSC and unlike classic autoimmune disease, ISC is more commonly seen in males with a male-to-female ratio of 4:1[77].…”

IgG4-Related Disease

“…Major manifestations in these organ systems are type 1 autoimmune pancreatitis, sclerosing cholangitis, and an inflammatory pseudotumor of the liver (Zen et al 2016;Okazaki and Uchida 2015;. IgG4-RD at these anatomical sites produces prototypic histopathological features with no site-specific changes.…”

Recent advances in the diagnosis and treatment of primary biliary cholangitis

“…IgG4-SC is an immune-mediated peculiar sclerosing cholangitis of unknown etiopathogenesis that is frequently related to autoimmune pancreatitis (AIP)[151]. The diagnosis of IgG4-SC is performed on the basis of a combination of the following four standards: (1) distinctive cholangiography features; (2) elevated serum levels of IgG4; (3) concurrence of IgG4-associated illnesses, excluding those of the bile duct; and (4) typical histopathological characteristics[151,152].…”

“…The diagnosis of IgG4-SC is performed on the basis of a combination of the following four standards: (1) distinctive cholangiography features; (2) elevated serum levels of IgG4; (3) concurrence of IgG4-associated illnesses, excluding those of the bile duct; and (4) typical histopathological characteristics[151,152]. Moreover, the efficiency of corticosteroid treatment is a selectable additional diagnostic standard to affirm a precise diagnosis of IgG4-SC[151,152]. Typical characteristics of IgG4-SC may be divided into four types on the basis of the stenosis regions disclosed by endoscopic retrograde cholangiography and anti-diastole (Figure 5)[152].…”

“…Approximately 90% of IgG4-SC patients have AIP, so therefore the presence of AIP may contribute to the diagnosis of IgG4-SC[151,152]. Nevertheless, PBC/IgG4-SC overlap syndrome is an extremely rare condition that has been reported in very few published cases to date, with the diagnosis of PBC/IgG4-SC overlap syndromes without the coexistence of AIP being particularly difficult[164].…”