IgG4-related Sclerosing Cholangitis Patients Research Articles

IgG4-related sclerosing cholangitis may be a risk factor for cancer.

The relationship between autoimmune pancreatitis (AIP) and malignancy has been reported. However, the potential risk for cancer in patients with immunoglobulin 4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is unclear. The present study aimed to evaluate the incidence of cancer in IgG4-SC patients. We retrospectively collected clinical data for 121 patients diagnosed with IgG4-SC from 7 hospitals. We calculated the standardized incidence ratio (SIR) of cancer in IgG4-SC patients based on the national cancer rates. The SIR of the period after the diagnosis of IgG4-SC were calculated. The mean follow-up period was 6.4years, with 121 IgG4-SC patients. During the follow-up period, 26 patients had cancer, and 29 cancers were diagnosed. The SIR of cancer after the diagnosis of IgG4-SC was 1.90 (95% confidence interval [CI] 1.67-2.21). The SIR of pancreatic and bile duct cancer was 10.30 and 8.88, respectively. The SIR of cancer in <1year, 1-5years, and >5years after diagnosis of IgG4-SC were 2.58, 1.01, and 2.44, respectively. IgG4-SC patients have a high risk of cancer including pancreatic and bile duct cancer. The risk of cancer was high less <1year and >5years after diagnosis of IgG4-SC. Therefore, IgG4-SC patients may require careful long-term follow-up.

The significance of serum IgG4 and CA19-9, autoantibodies in diagnosis and differential diagnosis of IgG4-related sclerosing cholangitis

Objective: To investigate the value of serum levels of IgG4 and CA19-9, and autoantibodies in the diagnosis of IgG4-related sclerosing cholangitis (IgG4-SC).Methods: We detected the serum IgG4 and CA19-9 of 45 IgG4-SC patients, 173 non-IgG4-SC patients and 48 healthy controls by immunoassay and chemiluminescence, respectively, with antinuclear antibody (ANA), anti-neutrophil antibody (ANCA), anti-smooth muscle antibody (SMA) and anti-mitochondrial antibody (AMA) level detected by indirect immunofluorescence. Then analyze the detection results.Results: (1) The positive rates of ANA, ANCA, SMA and AMA in patients with IgG4-SC were 40%, 6.67%, 0 and 2.22%. Among them, the positive rate of ANA was significantly higher than that of the healthy control group (p < .01), and the positive rate of ANA, ANCA, SMA and AMA were significantly different from that of the non-IgG4-SC group (p < .05). (2) Serum levels of IgG4 and CA19-9 increased significantly in patients with IgG4-SC compared with the healthy controls (p < .01). The areas under the ROC curve (AUC) of IgG4 and CA19-9 were 0.9750 and 0.6498, respectively (p < .05).Conclusion: The high levels of serum IgG4 and CA19-9, and autoantibodies detections are of great important clinical value in diagnosis and differential diagnosis of IgG4-SC.

Comparing the clinical characteristics of IgG4-related sclerosing cholangitis with primary sclerosing cholangitis

Objective To analyze and compare the clinical characteristics of primary sclerosing cholangitis (PSC) with IgG4-related sclerosing cholangitis (IgG4-SC). Methods The clinical data of 32 PSC patients and 72 IgG4-SC patients who were hospitalized in Peking Union Medical College Hospital (PUMCH) from January 2004 to December 2014 were retrospectively analyzed. Results Of the 32 PSC patients, there were 16 male and 16 female. Of the 72 IgG4-SC patients, there were 61 male and 11 female, (ratio=5.5∶1). The average ages were 44.9 (11~77) and 59.8 (28~83) years, respectively (P<0.05). The most common symptoms of PSC and IgG4-SC were abdominal pain and jaundice, and the incidences of abdominal pain and jaundice were 50.0% and 68.1%, 78.1% and 81.9%, respectively. The serum IgG4 level of the IgG4-SC patients was significantly higher than the PSC patients (P<0.05). The total protein in serum of the IgG4-SC patients was higher than the PSC patients (P<0.05). The rate of bile duct wall thickening as detected on endoscopic ultrasonography (EUS) was higher than by abdominal ultrasound and abdominal CT, which were 91.2%, 11.5% and 33.3%, respectively (P<0.05). 12 PSC patients were followed up for over 2 years, including 2 patients who underwent liver transplantation after failure of conservative treatment, 5 patients who died from hepatic failure and infection, and 3 with stable condition. 43 IgG4-SC patients were followed up for over 2 years, including 16 patients with relapse. The recurrence rate was 37.2% (16/43). The more the extrabiliary organs or bile duct segments were involved, the higher was the recurrence rate. Conclusions Both PSC and IgG4-SC are cholestatic diseases, and they have many similarities in clinical and imaging manifestations. However, they still have unique features. IgG4-SC is sensitive to glucocorticoids therapy and has good prognosis. Thus, it is important to differentiate PSC from IgG4-SC. Key words: Primary sclerosing cholangitis; IgG4-related sclerosing cholangitis; Autoimmune disease; Cholestasis; Diagnosis; Therapy

Assessment in steroid trial for IgG4-related sclerosing cholangitis

PurposeResponse to steroids is included in the diagnostic criteria for IgG4-related sclerosing cholangitis (IgG4-SC). To assess how to appropriately conduct steroid trials for IgG4-related SC, we examined the clinical pictures of steroid responsiveness in IgG4-SC patients. Material and methodsA total of 29 patients with IgG4-SC (lower bile duct involvement, n=29; hilar/intrahepatic bile duct involvement, n=6) initially treated with steroids were enrolled in this study. Blood biochemistry was examined at about 5, 10 and 15 days after commencing steroid therapy. Endoscopic retrograde cholangiography (ERC) and magnetic resonance cholangiopancreatography (MRCP) were performed after steroid administration in 18 and 25 patients, respectively. ResultsIn 19 patients without biliary drainage, elevated serum levels of total bilirubin, alanine aminotransferase, and alkaline phosphatase were halved in 50%, 25%, and 44% of patients at about 5 days after starting steroids, and in 17%, 38%, and 44% at about 10 days. Responsiveness to steroids could be evaluated at 1–2 weeks on ERC or MRCP, but response was lower in the hilar/intrahepatic bile duct than in the lower bile duct. ConclusionsSteroid responsiveness of IgG4-SC is recommended to be assessed by blood biochemistry at 5 and 10 days and on MRCP and/or ERC at 1–2 weeks after starting steroid.

Nationwide survey for primary sclerosing cholangitis and IgG4‐related sclerosing cholangitis in Japan

We previously conducted nationwide surveys for primary sclerosing cholangitis (PSC) in Japan, and demonstrated several characteristic features of Japanese PSC patients, yet patients with IgG4-related sclerosing cholangitis (IgG4-SC) might be misdiagnosed as PSC. Since the clinical diagnostic criteria of IgG4-SC were established in 2012, we again conducted a nationwide survey to investigate the characteristics of PSC and IgG4-SC lacking pancreatic involvement. The design was a questionnaire-based, multi-center retrospective study. The enrolled subjects were patients with PSC and IgG4-SC without pancreatic involvement diagnosed after 2005. We enrolled 197 PSC and 43 IgG4-SC patients without pancreatic lesions. The male dominance was significantly evident in IgG4-SC (P = 0.006). In patients with PSC, two peaks in age distribution were clearly observed. IgG4-SC was not detected in any patient younger than 45 years of age. At presentation, serum albumin and IgM were significantly higher in PSC, while serum IgG and IgG4 were significantly elevated in IgG4-SC. Inflammatory bowel disease (IBD) was detected in only 68/197 PSC patients (34%). The prognosis of IgG4-SC was considerably better than that of PSC. We confirmed several interesting clinical details of PSC in Japanese patients: two peaks in the age distribution and lower prevalence of IBD.

Establishment of a serum IgG4 cut‐off value for the differential diagnosis of IgG4‐related sclerosing cholangitis: A Japanese cohort

IgG4-related sclerosing cholangitis (IgG4-SC) must be precisely distinguished from primary sclerosing cholangitis and cholangiocarcinoma (CC) because the treatments are completely different. However, the pathological diagnosis of IgG4-SC is difficult. Therefore, highly specific non-invasive criteria such as serum IgG4 should be established. This study established a cut-off for serum IgG4 to differentiate IgG4-SC from respective controls using serum IgG4 levels measured in Japanese centers. A total of 344 IgG4-SC patients were enrolled in this study. As controls, 245, 110, and 149 patients with pancreatic cancer, primary sclerosing cholangitis, and CC, respectively, were enrolled. IgG4-SC patients were classified into three groups: type 1 (stenosis only in the lower part of the common bile duct), type 2 (stenosis diffusely distributed throughout the intrahepatic and extrahepatic bile ducts), and types 3 and 4 (stenosis in the hilar hepatic region) with 246, 56, and 42 patients, respectively. Serum IgG4 levels were compared, and the cut-offs were established. The cut-off obtained from receiver operator characteristic curves showed similar sensitivity and specificity to that of 135 mg/dL when all IgG4-SC and controls were compared. However, a new cut-off value was established when subgroups of IgG4-SC and controls were compared. A cut-off of 182 mg/dL can increase the specificity to 96.6% (4.7% increase) for distinguishing types 3 and 4 IgG4-SC from CC. A cut-off of 207 mg/dL might be useful for completely distinguishing types 3 and 4 IgG4-SC from all CC. Serum IgG4 is useful for the differential diagnosis of IgG4-SC and controls.

The role of peroral video cholangioscopy in patients with IgG4-related sclerosing cholangitis

The cholangioscopic features of IgG4-related sclerosing cholangitis (IgG4-SC) remain undefined. The aim of this study was to clarify these endoscopic features using peroral video cholangioscopy (PVCS) in IgG4-SC patients. PVCS was performed in 33 patients: IgG4-SC (n=13); primary sclerosing cholangitis (PSC; n=5); and cholangiocarcinoma (n=15), which included hilar cholangiocarcinoma (HCCA; n=5) and distal cholangiocarcinoma (DCCA; n=10). The most frequent findings on PVCS in the IgG4-SC patients were dilated (62%) and tortuous (69%) vessels, and absence of partially enlarged vessels. The incidence of dilated and tortuous vessels was significantly higher in IgG4-SC patients than in PSC patients (p=0.015). Scarring and pseudodiverticula were found significantly more often in PSC patients than in IgG4-SC patients (p=0.001 and p=0.0007, respectively). The incidence of partially enlarged vessels was significantly higher in DCCA patients than in IgG4-SC patients (p=0.004). In contrast, the incidence of dilated vessels was significantly higher in IgG4-SC patients than in HCCA patients (p=0.015). PVCS performed after corticosteroid therapy showed resolution of bile duct stenosis and dilated, tortuous, or partially enlarged vessels, as well as resolution of friability in all patients with IgG4-SC. Cholangioscopy was useful in differentiating IgG4-SC from PSC. In addition, monitoring the patterns of proliferative vessels on PVCS may be useful to differentiate IgG4-SC from cholangiocarcinoma.

Diagnostic criteria for IgG4-related sclerosing cholangitis based on cholangiographic classification

IgG4-related sclerosing cholangitis (IgG4-SC) needs to be differentiated from pancreatic cancer (PCa), primary sclerosing cholangitis (PSC), and cholangiocarcinoma (CC). We attempted to establish diagnostic criteria for IgG4-SC based on cholangiographic classification by comparison with several diagnostic modalities. We classified 62 IgG4-SC patients into three groups on the basis of cholangiographic findings to allow differentiation from PCa, PSC, and CC: Group A IgG4-SC showed features similar to PCa (Type 1, n=32), Group B showed similarity to PSC (Type 2, n=15), and Group C showed similarity to CC (Type 3, 4, n=15). Thirty-five patients with PCa, 40 with PSC, and 32 CC were enrolled as controls. We retrospectively compared the clinical, imaging, serological, and histopathological features and involvement of other organs between Group A and PCa, Group B and PSC, and Group C and CC. Association with autoimmune pancreatitis (AIP) (P<0.001) and involvements with other organs (specificity 100%) were common useful diagnostic parameters in all three IgG4-SC groups. A high serum IgG4 level was a useful parameter in Groups A and B (P<0.001). Discriminant analysis of cholangiograms (P<0.001), liver biopsy (specificity 100%), and exclusion of inflammatory bowel disease (specificity 100%) were useful parameters in Group B. Intraductal ultrasonography findings (P<0.001) and exclusion of malignancy by bile duct biopsy (specificity 100%) were useful parameters in Group C. We established diagnostic criteria for IgG4-SC (sensitivity 100%, specificity 96.3%) by incorporating parameters that showed P<0.001 or 100% specificity. Diagnostic criteria for IgG4-SC based on cholangiographic classification are useful for distinguishing it from PCa, PSC, and CC.

Small bile duct involvement in IgG4-related sclerosing cholangitis: liver biopsy and cholangiography correlation

IgG4-related sclerosing cholangitis (IgG4-SC) needs to be differentiated from primary sclerosing cholangitis (PSC). In this study, we performed a retrospective study to reveal cases in which liver needle biopsy was useful for differential diagnosis. Nineteen patients with IgG4-SC and 22 patients with PSC were studied. All patients underwent endoscopic retrograde cholangiography and liver needle biopsy. We defined small bile duct involvement of IgG4-SC histologically as damage to the small bile duct associated with infiltration of ≥10 IgG4+ plasma cells per high power field (HPF). Clinicopathological characteristics were compared between IgG4-SC patients with and without small bile duct involvement. Small bile duct involvement was observed in 5 (26%) of the patients with IgG4-SC. Patients with small bile duct involvement showed a higher incidence of intrahepatic biliary strictures on cholangiography (80 vs. 21%, p = 0.038). Conversely, 4 of 7 (57%) patients with intrahepatic biliary strictures on cholangiography had histologically evident small duct involvement. The number of IgG4+ plasma cells was significantly correlated with the site of the most proximal stricture on cholangiograms (p = 0.021). The number of IgG4+ plasma cells per HPF was significantly higher in IgG4-SC patients with intrahepatic biliary strictures than in those with PSC (13.4 vs. 0.4 cells/HPF, p < 0.001). Involvement of small bile ducts is more frequent in patients with intrahepatic biliary strictures on cholangiography, and liver needle biopsy is especially useful for these patients.

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.