IgG4-related Sclerosing Cholangitis Research Articles

Diagnostic procedures for IgG4-related sclerosing cholangitis

IgG4-related sclerosing cholangitis (IgG4-SC) is one of several diseases associated with autoimmune pancreatitis (AIP). However, diffuse cholangraphic abnormalities seen in association with AIP may resemble those seen in primary sclerosing cholangitis (PSC), and the presence of segmental stenosis suggests cholangiocarcinoma. IgG4-SC responds well to steroid therapy, whereas in contrast, liver transplantation is the only effective therapy for PSC, and surgical intervention is also needed for cholangiocarcinoma. The aim of this review was to establish the diagnostic procedures for IgG4-SC. A literature search was conducted, covering English-language articles dealing with IgG4-SC published between 1991 and March 2010. As clinical data on IgG4-SC are limited, the author also took into consideration his own clinical experience with the treatment of IgG4-SC over a period of more than 19 years. When intrapancreatic stenosis is detected, pancreatic cancer should be ruled out. If multiple intrahepatic stenosis is evident, PSC should be discriminated on the basis of cholangiographic findings and liver biopsy with IgG4 immunostaining. An association with inflammatory bowel disease (IBD) is suggestive of PSC. If stenosis is demonstrated in the hepatic hilar region, cholangiocarcinoma should be discriminated by US, EUS, IDUS, and bile duct biopsy. For diagnosis of IgG4-SC, coexistence of AIP is the most useful finding. However, the most important consideration for clinicians is to be aware of IgG4-SC when encountering patients with obstructive jaundice.

IgG4‐related sclerosing cholangitis and autoimmune pancreatitis: Histological assessment of biopsies from Vater's ampulla and the bile duct

Autoimmune pancreatitis is commonly associated with immunoglobulin (Ig) G4-related sclerosing cholangitis (IgG4-SC). The discrimination between IgG4-SC and pancreatobiliary malignancies or primary sclerosing cholangitis (PSC) is now an important issue. The present study was carried out to examine the usefulness of endoscopic biopsies from Vater's ampulla and the bile duct to diagnose IgG4-SC. The present study included 29 IgG4-SC patients (26 with both pancreatitis and cholangitis, and 3 with cholangitis only), 6 PSC patients, and 27 pancreatobiliary carcinoma patients. All patients underwent endoscopic biopsies from Vater's ampulla and the common bile duct. Biopsied specimens were histologically examined using immunostaining for IgG4. For the ampullary and bile duct biopsies, the IgG4-SC samples had a significantly greater number of IgG4-positive plasma cells than the PSC or pancreatobiliary carcinoma specimens. In addition, bile duct biopsies from five patients (17%) with IgG4-SC showed diffuse inflammatory cell infiltration with irregular fibrosis corresponding to the histological features of lymphoplasmacytic sclerosing pancreatocholangitis. Based on the threshold of 10 IgG4-positive plasma cells per high power field, the diagnostic rates of the ampullar and bile duct biopsies were both 52% (15/29 cases). Twenty-one patients (72%) had more than 10 IgG4-positive plasma cells in at least one biopsy. The bile duct biopsy was significantly valuable for IgG4-SC patients with swelling of the pancreatic head. The present study suggested that ampullar and bile duct biopsies are useful for diagnosing IgG4-SC.

Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases

Patients with autoimmune pancreatitis (AIP) characteristically show elevated serum levels of immunoglobulin G4 (IgG4) and abundant infiltration of IgG4-positive plasmacytes in the involved organs. The most common involved organ showing extrapancreatic lesions is the bile duct, which exhibits sclerosing cholangitis (SC). However, the role of IgG4 in the development of IgG4-related SC (IgG4-SC) remains unclear. To clarify the role of IgG4 in IgG4-SC, we have performed an immunohistochemical analysis of the bile duct. Laboratory and immunohistochemical findings of liver biopsy specimens obtained from patients with IgG4-SC, primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and primary biliary cirrhosis (PBC) were compared. The biopsy specimens were first stained with anti-IgG1, anti-IgG4, and anti-Foxp3 (forkhead box P3) antibodies, and the ratio of IgG4-, IgG1-, and Foxp3-positive cells, respectively, to infiltrated mononuclear cells (IgG4/Mono, IgG1/Mono, Foxp3/Mono) was assessed. The ratio of IgG4/IgG1-positive plasma cells was significantly higher in specimens obtained from patients with IgG4-SC than in those from patients with PSC, AIH, and PBC. The Foxp3/Mono ratio in patients with PBC was significantly higher than that in patients with IgG4-SC and PSC. In patients with IgG4-SC, the number of Foxp3-positive cells was significantly correlated with the number of IgG4-positive cells; in the other patient groups, there was no correlation. The IgG4/IgG1 ratio in the liver may be a useful marker for differential diagnosis of IgG4-SC and PSC. In IgG4-SC, abundant infiltration of regulatory T cells (Tregs) may affect the switching of B cells to IgG4-producing plasmacytes, and there is a possibility that the function of Tregs is different in IgG4-SC and other liver diseases (PSC, AIH, and PBC).

Endoscopic transpapillary intraductal ultrasonography and biopsy in the diagnosis of IgG4-related sclerosing cholangitis

IgG4-related sclerosing cholangitis (IgG4-SC) is one of the diseases associated with autoimmune pancreatitis. Several cases of IgG4-SC showed no pancreas abnormalities and it was difficult to distinguish cholangiocarcinoma. We aimed to clarify the findings of transpapillary intraductal ultrasonography (IDUS) and bile duct biopsy in the patients with IgG4-SC. We retrospectively evaluated the findings of transpapillary IDUS and biopsy in 23 consecutive patients with IgG4-SC at Nagoya City University Hospital between 2004 and 2008. Eleven patients with cholangiocarcinoma were enrolled as a control group. IDUS findings of circular-symmetric wall thickness, a smooth outer margin, a smooth inner margin and a homogeneous internal echo in the stricture were significantly higher in IgG4-SC than in cholangiocarcinoma (p < 0.01). The wall thickness in IgG4-SC in regions of non-stricture on the cholangiogram was significantly greater than that in cholangiocarcinoma (p < 0.0001). A bile duct wall thickness exceeding 0.8 mm in regions of non-stricture on the cholangiogram was highly suggestive of IgG4-SC (sensitivity 95.0%, specificity 90.9%, accuracy 93.5%). In transpapillary biopsy, lymphoplasmacytic infiltration was observed in 100% (17/17), fibrosis in 82% (14/17), and obliterative phlebitis in 0%. The abundant IgG4-positive plasma cells were observed in 18% (3/17). The IDUS findings were useful for distinction of IgG4-SC from cholangiocarcinoma. Transpapillary biopsy was not useful for direct diagnosis of IgG4-SC even after IgG4 immunostaining, but it did allow distinction of IgG4-SC from cholangiocarcinoma in some cases. IDUS and transpapillary biopsy after endoscopic retrograde cholangiopancreatography can provide further information for precise diagnosis of IgG4-SC.

Pathology and immunopathology of immunoglobulin G4‐related sclerosing cholangitis: The latest addition to the sclerosing cholangitis family

Sclerosing cholangitis is heterogeneous in its etiopathogenesis. Recently, sclerosing cholangitis showing abundant immunoglobulin (Ig)G4+ plasma cell infiltration was added to the sclerosing cholangitis group. This form was frequently associated with sclerosing pancreatitis (autoimmune pancreatitis) and also occasionally with other diseases such as chronic sclerosing sialadenitis, all of which falls within IgG4-related sclerosing disease. Herein, this new member, called IgG4-related sclerosing cholangitis (IgG4-SC), is reviewed. IgG4-SC shows grossly medullary and fleshy lesions along the biliary tree, and histologically marked lymphoplasmacytic infiltration with extensive fibrosis, and obliterative phlebitis, sharing histopathological features with sclerosing pancreatitis. Peribiliary glands are also severely affected. Interestingly, hepatic inflammatory pseudotumor (HIP) is not infrequently associated with IgG4-SC, and is thought as a local exaggeration of IgG4-SC. Immunohistochemically, many IgG4+ plasma cells and CD4+/CD25+ regulatory T cells are found around the affected bile ducts and portal tracts. Incontrast, these cells are scarce in the affected bile ducts of primary sclerosing cholangitis (PSC), a prototype of sclerosing cholangitis. Biliary lining epithelia are relatively spared in IgG4-SC in comparison with those of PSC showing degeneration and ulceration. In some cases of IgG4-SC, IgG4+ plasma cells are also found considerably in small portal tracts, so needle liver biopsy is useful for the diagnosis of IgG4-SC. Therapeutically, IgG4-SC responds well to steroid therapy, while such character is not reported in PSC. Taken together, IgG4-SC may be etiologically different from PSC, and immunopathological processes relating to IgG4 and regulatory T cells may be involved in the pathogenesis of IgG4-SC. Further studies are needed to clarify the etiopathogenesis of IgG4-SC and its related disorders.

Immunoglobulin G4 associated cholangitis: Description of an emerging clinical entity based on review of the literature

During the last decade, patients with steroid responsive sclerosing cholangitis have been described in a number of case reports and a few cases series. These patients meet diagnostic criteria for primary sclerosing cholangitis (PSC) but seem to have a better prognosis and are often, but not always, associated with autoimmune pancreatitis (AIP). Unlike biliary strictures in PSC, most PSC-like biliary strictures seen in association with AIP respond well to steroids and some have been shown to resolve after immunosuppressive treatment during prolonged follow-up. In addition, steroid-responsive dominant bile duct lesions, sometimes mimicking infiltrating hilar cholangiocarcinoma, without pancreatic abnormalities have also been reported. Here we review the literature on this emerging clinical entity and suggest that this condition of steroid responsive biliary strictures be named Immunoglobulin G4 (IgG4) Associated Cholangitis (IAC). We performed an electronic database search of MEDLINE for case reports and case series of sclerosing cholangitis with pancreatitis and/or pancreatic mass (1960–July 2006). Articles were limited to English and these case reports and cases series were reviewed and all references on the combination of sclerosing cholangitis and pancreatitis as well as IgG4 positive cholangitis without pancreatic involvement not identified by our original search were obtained. Terminology and Definition