IgG4-related sclerosing cholangitis (IgG4-SC) is a rare cholangiopathy that causes symptoms similar to those of primary sclerosing cholangitis. IgG4-SC can manifest with cholangitis and pancreatitis. Diagnosis requires an abnormal cholangiogram, elevated serum IgG4 levels, and histologic analysis. Treatment with glucocorticoids leads to dramatic and lasting remission.
(See also Overview of Biliary Function.)
IgG4-related sclerosing cholangitis (IgG4-SC) is a biliary stricturing disease caused by an IgG4-predominant subepithelial lymphoplasmacytic infiltration of intrahepatic and extrahepatic bile ducts.
IgG4-SC is clinically distinct from primary sclerosing cholangitis. It is the hepatobiliary manifestation of IgG4-related disease, a family of immune-mediated fibro-inflammatory conditions. IgG4-SC is rare, affecting predominantly men over 50 to 60 years of age (1). Seventy to 90% of patients with IgG4-SC also have autoimmune pancreatitis (AIP) (2). A form of IgG4-SC independent of AIP is less common.
General references
1. Beuers U, Trampert DC. IgG4-Related Cholangitis. Semin Liver Dis. Published online May 8, 2025. doi:10.1055/a-2588-3875
2. Umehara H, Okazaki K, Masaki Y, et al. A novel clinical entity, IgG4-related disease (IgG4RD): General concept and details. Mod Rheumatol. 2012;22(1):1-14. doi: 10.1007/s10165-011-0508-6
Symptoms and Signs of IgG4-SC
Presentation may be similar to that of primary sclerosing cholangitis or cholangiocarcinoma with symptoms that include jaundice, weight loss, and abdominal pain.
Diagnosis of IgG4-SC
Imaging
IgG4 levels
Histology
IgG4-SC should be considered particularly in patients with pancreatitis plus cholangiopathy.
Diagnosis is made based on HISORt (Histology, Imaging, Serology, Other organ system involvement, and Response to treatment) criteria originally developed for autoimmune pancreatitis and adapted for IgG4-SC (1, 2). On imaging, bile duct walls are thickened with long segment strictures (magnetic resonance cholangiopancreatography [MRCP], CT, or endoscopic ultrasound). On serology, IgG4 levels are elevated in most, but not all, patients; a level 4 times the upper limit of normal is considered pathognomic. Histology, obtained invasively by endoscopic retrograde cholangiopancreatography (ERCP) after initial imaging and serology, demonstrates a typical pattern of storiform fibrosis and IgG4-positive plasma cells. Other organ systems potentially involved in IgG-related disease are evaluated. Finally, the response to treatment is assessed and contributes to the diagnostic picture.
Accurate differentiation of IgG4-SC from other forms of sclerosing cholangitis is critical because IgG4-SC requires different treatment and confers favorable outcomes. In older patients, IgG4-SC can be misdiagnosed as hepatobiliary malignancy.
Diagnosis references
1. Chari ST, Smyrk TC, Levy MJ, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006;4(8):1010-934. doi:10.1016/j.cgh.2006.05.017
2. Ghazale A, Chari ST, Zhang L, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134(3):706-715. doi:10.1053/j.gastro.2007.12.009
Treatment of IgG4-SC
Glucocorticoids
Sometimes rituximab or inebilizumabSometimes rituximab or inebilizumab
Systemic glucocorticoids are the mainstay of treatment of IgG4-related sclerosing cholangitis (1). The goal is to induce complete remission. Treatment with high doses leads to rapid biochemical and symptomatic improvement with decreasing serum IgG4 levels, often preventing the need for biliary stenting. Complete remission can almost always be achieved with glucocorticoid monotherapy (prednisone or prednisolone). ). The goal is to induce complete remission. Treatment with high doses leads to rapid biochemical and symptomatic improvement with decreasing serum IgG4 levels, often preventing the need for biliary stenting. Complete remission can almost always be achieved with glucocorticoid monotherapy (prednisone or prednisolone).
If the response to glucocorticoid therapy is inadequate, B-cell depletion with rituximab (an anti-CD20 monoclonal antibody) or inebilizumab (an anti-CD19 monoclonal antibody) is also an effective treatment option (If the response to glucocorticoid therapy is inadequate, B-cell depletion with rituximab (an anti-CD20 monoclonal antibody) or inebilizumab (an anti-CD19 monoclonal antibody) is also an effective treatment option (2, 3). In addition, B-cell depletion is increasingly being used as a steroid-sparing agent as part of induction therapy. Because the rate of relapse approaches 50% (4), most patients require maintenance therapy with these B-cell depleting agents.
Treatment references
1. Beuers U, Trampert DC. IgG4-Related Cholangitis. Semin Liver Dis.Published online May 8, 2025. doi:10.1055/a-2588-3875
2. Stone JH, Khosroshahi A, Zhang W, et al. Inebilizumab for Treatment of IgG4-Related Disease. . Inebilizumab for Treatment of IgG4-Related Disease.N Engl J Med. 2025;392(12):1168-1177. doi:10.1056/NEJMoa2409712
3. Loganathan P, Siby N, Mohan BP, et al. Efficacy of Rituximab in Autoimmune-Mediated IgG4 Pancreaticobiliary Disease: A Systematic Review and Meta-Analysis. . Efficacy of Rituximab in Autoimmune-Mediated IgG4 Pancreaticobiliary Disease: A Systematic Review and Meta-Analysis.J Clin Gastroenterol. 2025;59(7):678-684. doi:10.1097/MCG.0000000000002078
4. Sandanayake NS, Church NI, Chapman MH, et al. Presentation and management of post-treatment relapse in autoimmune pancreatitis/immunoglobulin G4-associated cholangitis. Clin Gastroenterol Hepatol. 2009;7(10):1089-1096. doi: 10.1016/j.cgh.2009.03.021
Key Points
IgG-SC is a unique cholangiopathy, distinct from PSC.
Suspect IgG-SC particularly in patients with both pancreatitis and cholangiopathy.
Diagnosis requires abnormal imaging, elevated serum IgG4 levels, and histologic analysis, in addition to evaluation of other organ systems and response to treatment.
Treatment with glucocorticoids leads to complete remission and often requires maintenance therapy with B-cell depleting medications (eg rituximab, inebilizumab). Treatment with glucocorticoids leads to complete remission and often requires maintenance therapy with B-cell depleting medications (eg rituximab, inebilizumab).
Drugs Mentioned In This Article
