IgG4-related Sclerosing Cholangitis Research Articles

IgG4 Sclerosing Cholangitis: Entity Rarely Described in Children

IgG4-related sclerosing cholangitis (IgG4-SC) is known in the adult patients as a steroid-responsive biliary disease, frequently associated with autoimmune pancreatitis; The diagnosis of IgG4-SC may be difficult to differentiate from primary sclerosing cholangitis (PSC) or cholangiocarcinoma; This entity is been described in the absence of pancreatic implication. It is defined by high level of serum IgG4 in contrast to primary sclerosing cholangitis. It’is morphologically characterized by dense lymphoplasmacellular infiltration, particularly IgG4+ plasma cells and CD4+ T cells and extensive fibrosis in bile duct. In patients with IgG4-related sclerosing cholangitis, response to steroid therapy is high; in patients with PSC corticosteroid therapy is unsuccessful. An Early recognition of IgG4-SC can save patients from potential harmful and unnecessary surgical interventions. In the literature, cholangiocarcinoma in patients with IgG4- related sclerosing cholangitis was not described, whereas cholangiocarcinoma develops in up to 10-30% of patients with PSC. We present the case of a 3 years old child with features of sclerosing IgG4 cholangitis with asymptomatic elevation in liver enzymes, bile duct strictures on imaging, characteristic pathology findings, elevated serum IgG4, without signs of pancreatic involvement, and excellent response to corticosteroids. Pediatric gastroenterologists and hepatologists, as well as pediatric hepatopathologists, need to be aware of IgG4-SC as a disease entity.

Endoscopic Retrograde Cholangiopancreatography-Related Procedures for the Differential Diagnosis of Isolated Immunoglobin G4-Related Sclerosing Cholangitis and Perihilar Cholangiocarcinoma.

Differential diagnosis of isolated immunoglobin (Ig)G4-related sclerosing cholangitis (IgG4-SC) and cholangiocarcinoma is challenging. We aimed to clarify the role of endoscopic retrograde cholangiography (ERCP)-related procedures in the differential diagnosis of isolated IgG4-SC and perihilar cholangiocarcinoma (PHCC). Seven patients with hilar-type isolated IgG4-SC diagnosed at Hiroshima University Hospital and sixty-five patients with surgically resected invasive PHCC were enrolled, and the diagnostic yields of intraductal ultrasonography (IDUS), peroral cholangioscopy (POCS), and pathological examinations were determined. In six of seven (86%) patients with isolated IgG4-SC, the stricture was in the perihilar bile duct. IDUS showed that symmetrical wall thickening (40% vs. 5%, p = 0.04), homogeneous internal echo (80% vs. 5%, p < 0.001), and smooth outer margins (80% vs. 6%, p < 0.001) were more frequent in isolated IgG4-SC than in PHCC. POCS showed a smooth mucosal surface more frequent in isolated IgG4-SC (75% vs. 7%, p = 0.006). Only one patient had two pathological findings characteristic of IgG4-SC. The sensitivity for diagnosing PHCC was 81% using two or more combined sampling methods. Pathological examinations have limitations in the differential diagnosis of isolated-IgG4-SC and PHCC, and a diagnostic strategy that combines multiple ERCP-related procedures, including IDUS and POCS, is recommended.

A Review of IgG4-related Sclerosing Cholangitis (IgG4-SC).

IgG4-related sclerosing cholangitis (IgG4-SC) is a unique, steroid-responsive, fibroinflammatory condition that is more commonly found in older men and is strongly associated with autoimmune pancreatitis (AIP). It may pose a diagnostic challenge at times due to closely mimicking hepatobiliary diseases such as primary sclerosing cholangitis (PSC), secondary sclerosing cholangitis (SSC), and cholangiocarcinoma. IgG4-SC has an excellent prognosis when promptly diagnosed and treated with steroids. Literature search strategy: The authors searched PubMed and Google Scholar, for articles with the search terms "autoimmune cholangiopathy" and "IgG4 cholangiopathy."

DOP58 Human Leukocyte Antigen drives methylation signatures in primary sclerosing cholangitis but not in IgG4-related sclerosing cholangitis

Abstract Background Primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IgG4-SC) are fibro-inflammatory hepatobiliary conditions, with genetic, environmental, and immunologic risk factors, in which epigenetic alterations may provide insights into pathophysiology and novel biomarkers. Methods Whole blood DNA methylation profiling and genotyping was performed in 70 PSC (57 with PSC and ulcerative colitis (PSC-UC)), 56 IgG4-SC, 66 UC, and 88 healthy controls (HC), with MethylationEPIC and Global Screening arrays (Illumina). UC patients were selected to match the clinical characteristics of UC in the PSC-UC cohort. Methylation data was processed with Minfi and limma, genotyping analysed with Plink, and meQTLs with linear models. Results There were 31, 13 and 8 Holm-significant methylation differences between PSC and controls, IgG4-SC and controls, and UC and controls respectively (8 probes shared). Inflammatory genes (including CEP97, IFNAR1, TXK, and SMAD2) and methylation loci associated with mitochondrial DNA copy number (C5orf36, PYY, and MTRNR2L1) were predominant. Sub-analyses of PSC-UC and PSC without IBD detected 25 and 4 differences with HC respectively (p&amp;lt;0.05). DNA methylation age acceleration was observed in IgG4-SC, but not on PSC, PSC-IBD or UC. MeQTL analyses to identify genetic determinants of methylation revealed a strong HLA signal in PSC but not IgG4-SC, with 19/40 significant findings in 5 clusters (HLA-DRB1, HLA-DPB1, BTNL2, CSNK2B, and SFTA2). There was no overlap with the 36 meQTLs found in IgG4-SC. Using multivariate adaptive shrinkage for meQTLs in PSC, IgG4-SC, and UC yielded 5505 meQTLs with local false discovery rate &amp;lt;0.05 in at least one condition, with 1230 unique to PSC, and 1043 to IgG4-SC. Conclusion We identify characteristic epigenetic alterations in PSC and IgG4-related disease, providing insights into disease pathogenesis; and highlight the potential interaction with germ-line variation.

IgG4 Cholangitis Simulating Cholangiocarcinoma: A Diagnostic Trap

IgG4‐related sclerosing cholangitis (IgG4‐SC) is the biliary manifestation of IgG4‐related disease, systemic fibroinflammatory condition that is characterized by lesions with classical histopathological findings in involved organs. We presented a case of isolated IgG4‐SC with the normal serum IgG4 which was hard to differentiate with cholangiocarcinoma.

Inflammasome and pyroptosis in autoimmune liver diseases.

Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and IgG4-related sclerosing cholangitis (IgG4-SC) are the four main forms of autoimmune liver diseases (AILDs), which are all defined by an aberrant immune system attack on the liver. Most previous studies have shown that apoptosis and necrosis are the two major modes of hepatocyte death in AILDs. Recent studies have reported that inflammasome-mediated pyroptosis is critical for the inflammatory response and severity of liver injury in AILDs. This review summarizes our present understanding of inflammasome activation and function, as well as the connections among inflammasomes, pyroptosis, and AILDs, thus highlighting the shared features across the four disease models and gaps in our knowledge. In addition, we summarize the correlation among NLRP3 inflammasome activation in the liver-gut axis, liver injury, and intestinal barrier disruption in PBC and PSC. We summarize the differences in microbial and metabolic characteristics between PSC and IgG4-SC, and highlight the uniqueness of IgG4-SC. We explore the different roles of NLRP3 in acute and chronic cholestatic liver injury, as well as the complex and controversial crosstalk between various types of cell death in AILDs. We also discuss the most up-to-date developments in inflammasome- and pyroptosis-targeted medicines for autoimmune liver disorders.

Inflammatory Conditions of the Pancreatobiliary Tree.

The Pancreatobiliary Pathology Society (PBPS) would like to thank Alain C. Borczuk, MD, and the Archives of Pathology & Laboratory Medicine for again highlighting our society by publishing 3 review articles based on the presentations at the PBPS companion society symposium, which was held at the 2021 United States and Canadian Academy of Pathology (USCAP) meeting. As always, PBPS's mission remains the education of surgical pathologists and cytopathologists about the importance of recent advances in this complex field, which will hopefully transform the way we practice pancreatobiliary pathology. The PBPS fosters excellence and international collaboration in education, research, and the global practice of pancreatobiliary pathology. PBPS became an official society in 2016 and a USCAP companion society in 2018. However, the sharing of knowledge, enthusiasm, and ideas in pancreatobiliary pathology actually began more than 20 years ago as an annual “Pancreas Club” luncheon, held during the annual USCAP meeting, which grew over the years and eventually became the PBPS. The first advisory council members of the Pancreas Club were Volkan Adsay, MD; Ralph Hruban, MD; David Klimstra, MD; Günter Klöppel, MD; and Giuseppe Zamboni, MD. Thanks to their continued dedication to pancreatobiliary pathology and contagious enthusiasm, many other pathologists interested in the field were attracted to join and motivated its transformation into the official 501c3 society that it is today (PBPath.org).Because of the COVID-19 pandemic, the 2021 annual USCAP meeting (and by extension the PBPS companion society meeting) was held virtually. The theme of the 2021 PBPS Companion Society Symposium was “Inflammatory Conditions of the Pancreatobiliary Tree.” It featured 1.5 hours of on-demand educational content provided by 4 invited speakers, as well as a live 30-minute question-and-answer session with the speakers and moderators, Michelle Reid, MD, MS, and Rondell Graham, MBBS. The theme of the 2021 meeting was updates on acute and chronic inflammatory conditions of the pancreatobiliary tree, and it featured 4 outstanding presentations by experts in the field (Barbara Centeno, MD, Vikram Deshpande, MD, Dr Klöppel, and Dr Zamboni) entitled (1) “Cytopathology of Inflammatory Lesions of the Pancreatobiliary Tree” (Centeno), (2) “IgG4-Related (Autoimmune) Pancreatitis” (Deshpande), (3) “Acute and Alcoholic Pancreatitis” (Klöppel), and (4) “Paraduodenal Pancreatitis” (Zamboni).All 4 presentations from the 2021 companion meeting have been converted into review articles and are featured in this issue of Archives of Pathology & Laboratory Medicine. In the first article, “Cytopathology of Inflammatory Lesions of the Pancreatobiliary Tree,” Dr Centeno reviews the cytopathology of inflammatory lesions of the pancreas and bile duct, including the different types of pancreatitis. The cytologic criteria useful for differentiating reactive ductal atypia from adenocarcinoma and other malignant mimics are also discussed, and the application of ancillary techniques for this differential diagnosis is emphasized. In addition, Dr Centeno reviews pertinent and best pathology practices in the application of ancillary immunohistochemical and molecular studies for the differential diagnosis of benign from malignant processes in the bile duct. The second article is entitled “Navigating the Challenges Associated With a Diagnosis of Autoimmune Pancreatitis and IgG4-Related Sclerosing Cholangitis” and is written by Dr Deshpande, along with his colleagues Osman Yilmaz, MD, and Karen Pinto, MBBS, DNB, FRCPath. In this article Drs Yilmaz, Pinto, and Deshpande examine the clinicopathologic features of type 1 and 2 autoimmune pancreatitis and immunoglobulin G4–related sclerosing cholangitis. They emphasize the use of a multimodal approach (clinical, radiographic, serologic, histopathologic, and immunohistochemical correlation) and highlight the distinctive overlapping qualities that can aid in diagnosing these entities and distinguishing them from other fibroinflammatory and/or neoplastic mimics. The authors also discuss diagnostic pitfalls and differential diagnoses and offer an approach to the interpretation of needle biopsies, including ampullary biopsies. The third article is entitled “Acute and Chronic Alcoholic Pancreatitis, Including Paraduodenal Pancreatitis.” It combines the talks of our third and fourth speakers, Dr Klöppel and Dr Zamboni. In this combined article, Drs Klöppel and Zamboni present the current state of pathology and pathogenesis of alcohol-associated pancreatitis, including paraduodenal pancreatitis. In the context of the most important epidemiologic, clinical, and radiologic features, the role of alcohol overconsumption and related macroscopic changes and histopathologic characteristics are addressed. Pathologic findings that distinguish mild from severe pancreatitis, as well as a histologic staging system for chronic pancreatitis, are emphasized. The morphologic features of paraduodenal pancreatitis as well as the anatomic peculiarities associated with it are also described.We are extremely proud of our society and the continued contributions of its members to the field of pancreatobiliary pathology. We hope that you will enjoy these review articles highlighting the experts' perspectives on inflammatory conditions of the pancreatobiliary tree.

Reducing relapse through maintenance steroid treatment can decrease the cancer risk in patients with IgG4-sclerosing cholangitis: Based on a Japanese nationwide study.

IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk. We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated. Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89-8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients. Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer.

S1840 The Importance of Cholangioscopic Biopsies: An IgG4-Related Sclerosing Cholangitis Story

Introduction: IgG4 related sclerosing cholangitis (IgG4-SC) has generally been associated with autoimmune pancreatitis, retroperitoneal fibrosis, and sialadenitis. However, there are rare cases involving only the biliary tree. In addition, IgG4-SC can be easily confused with cholangiocarcinoma and primary sclerosing cholangitis (PSC). IgG4 serum levels more than 135 suggest IgG4-SC, but lower levels do not rule out the disease. Here, we present an atypical case of IgG4-SC. Case Description/Methods: 68-year-old male with past medical history of alcohol misuse disorder presented for pruritis, scleral icterus, and 40 pounds of weight loss in three weeks. On admission, notable labs were AST 158, ALT 81, ALP 713, total bilirubin 5.8, and direct bilirubin 4.9. IgG was 3203 and IgG4 was 113. Remainder of the work up was negative. Magnetic resonance cholangiopancreatography showed isolated left intrahepatic biliary dilation. Endoscopic retrograde cholangiopancreatography (ERCP) showed segmental strictures at the common hepatic duct and left intrahepatic duct. Cholangioscopy showed a fibrotic intraluminal growth in the upper third of the common bile duct, which was unable to be traversed. Biliary brushings showed only acute inflammation (Figure). A plastic biliary stent was placed for decompression and a percutaneous internal-external biliary drain was performed to facilitate subsequent rendez-vous ERCP. Repeat cholangioscopy showed scarring and fibrosis of the entire biliary tree and segmental stricturing at the hilum and left intrahepatic duct. Cholangioscopy-guided forceps biopsies showed more than ten IgG4 cells per high powered field indicating IgG4-SC. Patient was started on high dose corticosteroids with improvement of his symptoms and lab abnormalities. Discussion: Awareness of IgG4-SC is important as it can mimic cholangiocarcinoma and PSC. Our patient presented with obstructive jaundice and isolated dilatation of the biliary tree with a normal serum IgG4 suggestive of underlying malignancy. However, he also had elevation of total serum IgG, which was suspicious for an underlying autoimmune disorder. Biliary brushings can exclude malignancy but have a poor sensitivity for the diagnosis of IgG4-SC (36%). The most useful modality of diagnosis is cholangioscopy-guided forceps biopsy as this is positive in about 88% of specimens. Thus, IgG4-SC should be considered in patients with an atypical presentation of obstructive jaundice with incongruent lab and imaging findings, as this condition is treatable.Figure 1.: Left picture shows common hepatic duct stricturing and mass on cholangioscopy. Right picture shows left intrahepatic duct stone in light of stricturing on cholangioscopy.

S1891 A Diagnostic Dilemma: Primary Sclerosing Cholangitis With High IgG4 vs IgG4-Related Sclerosing Cholangitis

Introduction: Two etiologies of sclerosing cholangitis with overlapping features are Type 2 IgG4-Related Sclerosing Cholangitis (IgG4-SC) and Primary Sclerosing Cholangitis with high IgG4 (PSC). Here, we present a complex case of a young patient with features of both diseases. Case Description/Methods: A 25-year-old Caucasian female with a medical history of diabetes and no previous pancreatic disease was incidentally found to have an AST and ALT in the low 200s, total bilirubin 2.6, and alkaline phosphatase of 1130 concerning for cholestatic obstruction. She was asymptomatic and not jaundiced at the time. Subsequent MRCP revealed a dilated common bile duct. The patient underwent ERCP/EUS demonstrating a common bile duct stricture. A plastic stent was placed, and cells for cytology/FISH analysis were unyielding for malignancy. Repeat ERCP/EUS was performed a few months later for stent exchange. Biopsies to evaluate the indeterminate stricture yielded IgG4+ plasma cells up to 14/HPF. Based on the findings suspicious for IgG4-SC, she started prednisone therapy for one month. Subsequent labs demonstrated mild improvement in alkaline phosphatase to 450, total bilirubin 0.2, and a normal IgG4 level but with persistent elevation of total IgG 1.5 times the upper limit of normal. Repeat ERCP demonstrated resolution of the distal biliary stricture. She never developed abdominal pain, jaundice, weight changes or loss of appetite. Six months later, LFTs began to uptrend and a third ERCP/EUS demonstrated new distal biliary stricture. Biliary biopsies showed dense lymphoplasmacytic infiltrates and fibrosis with an average of 10 IgG4 positive plasma cells/HPF. Liver biopsies showed periductal fibrosis and a fibro-obliterative duct lesion. Given the concern for PSC, colonoscopy was performed with biopsies showing mild crypt distortion, mild eosinophilia, and rare neutrophils in the lamina propria. The patient remained asymptomatic throughout the disease course but had persistent biochemical hepatitis despite being on steroid therapy. A shared provider-patient decision was made to withhold immunosuppressive or biologic therapy. Discussion: In this case, the patient’s epidemiologic, clinical, and histological factors were more consistent with PSC. Conversely, the mild biochemical and stricture steroid-responsiveness were initially more suggestive of IgG4-SC. It is imperative to delineate between the two, as prognosis, treatment-responsiveness, and anticipated comorbidities differ.

Autoimmune Pancreatitis and Immunoglobulin G4-related Sclerosing Cholangitis: Past, Present, and Future.

The emergence of glucocorticoid-responsive autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC), a new disease entity, has attracted considerable interest within the international gastroenterology community. The typical manifestations of AIP/IgG4-SC are obstructive jaundice and pancreatic enlargement in the elderly, which may mimic the presentations of pancreatobiliary malignancies. The timely diagnosis of AIP/IgG4-SC can lead to adequate glucocorticoid treatment, whereas a misdiagnosis can result in unnecessary major surgery. The diagnostic criteria used to diagnose AIP include several cardinal features of AIP that can be detected via pancreatic parenchymal imaging, ductal imaging, serum IgG4 levels, histopathology, other organ involvement, and response to glucocorticoid therapy. The differential diagnosis of AIP/IgG4-SC may include pancreatobiliary malignancies and primary sclerosing cholangitis. Although most patients with AIP/IgG4-SC respond well to glucocorticoid therapy, there is a frequent relapse of the disease in the long term. This review describes the evolution of the concept of AIP and IgG4-related disease, including the development of diagnostic criteria, discusses the current practice for diagnosis and treatment, and suggests prospects for research.

Navigating the Challenges Associated With a Diagnosis of Autoimmune Pancreatitis and IgG4-Related Sclerosing Cholangitis.

The pancreatobiliary tract exhibits a spectrum of heterogeneous fibroinflammatory conditions that may be the result of a primary immune-mediated mechanism, or a reaction to neoplasm. This often results in significant overlap regarding clinical presentation, symptoms, radiographic findings, serology, and histopathology between inflammatory and neoplastic lesions of the pancreas, which can lead to inadvertent surgical intervention. Among the multitude of primary fibroinflammatory pancreatic diseases, autoimmune pancreatitis, including type 1 and type 2 autoimmune pancreatitis, and immunoglobulin G4-related sclerosing cholangitis (IgG4-RSC) are particularly challenging and require a multidisciplinary perspective to reliably make a diagnosis. This is of particular significance because these diseases typically have a favorable prognosis and readily respond to steroid therapy. To present a multimodal approach to highlight distinctive and overlapping qualities that will aid in the diagnosis of these entities. The review and analysis of literature describing autoimmune pancreatitis types 1 and 2 and IgG4-RSC. Diagnosis of autoimmune pancreatitis types 1 and 2 and IgG4-RSC requires a multimodal approach that relies on clinical, radiographic, serologic, histopathologic, and immunohistochemical correlation.

Request for biliary drainage for IgG4-SC could be waived before steroid administration?

In IgG4-related sclerosing cholangitis (IgG4-SC), the necessity of biliary drainage (BD) is unclear. In this study, we aimed to retrospectively investigate the improvement of liver damage and jaundice in cases of IgG4-SC with and without BD, before starting steroids. A total of 52 patients with IgG4-SC were investigated in the study. The study endpoints were the normalization rate of alkaline phosphatase (ALP)/total bilirubin (T-Bil) after 8 weeks of steroids, with and without BD. Propensity score matching was performed based on ALP and T-Bil, and 28 patients were included. There were 14 patients each in the BD and non-BD groups. Before initiation of steroids, the mean ALP in the BD group and the non-BD group was 378/461 (P=.541); the mean T-Bil was 2.5/1.8 (P=.401). Eight weeks after initiation of steroids, ALP improvement rate in the BD group/non-BD group was 69.2%/61.5% (P=1.000), and T-Bil improvement rate was 100%/100% (P=Ns). Steroids for IgG4-SC could prove effective in improving liver damage and jaundice, regardless of the presence or absence of BD. BD for IgG4-SC aimed to improve jaundice may not be necessary.

Complemental Diagnosis of IgG4-Related Pancreaticobiliary Diseases by Multiple Hypoechoic Lesions in the Submandibular Glands.

The diagnosis of autoimmune pancreatitis (AIP) and immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) may require a somewhat invasive pathological examination and steroid responsiveness. This retrospective study assessed the complemental diagnosis of AIP and IgG4-SC using submandibular gland (SG) ultrasonography (US) in 69 patients, including 54 patients with AIP, 2 patients with IgG4-SC, and 13 patients with both AIP and IgG4-SC. The data from the physical examination and US of SGs to diagnose AIP (n = 67) and IgG4-SC (n = 15) were analyzed. The steroid therapy efficacy in resolving hypoechoic lesions in SGs was evaluated in 36 cases. The presence of IgG4-related pancreaticobiliary disease with multiple hypoechoic lesions in SGs was reduced from 31 to 11 cases after steroid therapy, suggesting that multiple hypoechoic lesions in SGs are strongly associated with IgG4-positive cell infiltrations. Multiple hypoechoic lesions in SGs were observed in 53 cases, whereas submandibular swelling on palpation was observed in 21 cases of IgG4-related pancreaticobiliary diseases. A complemental diagnosis of IgG4-related pancreaticobiliary diseases without a histological diagnosis and steroid therapy was achieved in 57 and 68 cases without and with multiple hypoechoic lesions in SGs, respectively. In conclusion, multiple hypoechoic lesions in SGs are useful for the complemental diagnosis of IgG4-related pancreaticobiliary diseases.

Hypereosinophilia with IgG4 Associated Cholangiopathy

IgG4-related sclerosing cholangitis (IgG4-SC) belongs to the spectrum of IgG4-related disease which encompasses many medical conditions. We report a case of a 59-year-old man who presented with clinical and radiologic features of primary sclerosing cholangitis but where hypereosinophilia along with an extremely high blood level of IgG4, liver infiltration with IgG4-positive plasma cell and a spectacular response to corticoids treatment, confirmed the diagnosis of IgG4-SC.

Clinical Utility of Personalized Serum IgG Subclass Ratios for the Differentiation of IgG4-Related Sclerosing Cholangitis (IgG4-SC) from Primary Sclerosing Cholangitis (PSC) and Cholangiocarcinoma (CCA).

Background: The differential diagnosis of immunoglobulin G4-sclerosing cholangitis (IgG4-SC) from primary sclerosing cholangitis (PSC) or cholangiocarcinoma (CCA) is important. In this study, we aimed to find the best combinations of serum IgG subclasses and IgG4 levels for differentiating IgG4-SC from PSC or CCA. Methods: In total, 31 patients with IgG4-SC, 27 patients with PSC, and 40 patients with CCA were enrolled from 2003 to 2017 at a single tertiary referral center. We retrospectively assessed the IgG4, IgG4/IgG1, IgG4/(IgG1+IgG3), and (IgG4+IgG2)/(IgG1+IgG3) in each of the patients. ROC curves were established to obtain the optimal cutoff value for each parameter. McNemar’s test was used to compare the sensitivities, specificities, and accuracies of diagnostic algorithms. Results: In differentiating IgG4-SC from PSC, the accuracies of IgG4/IgG1 ≥ 0.087 and of IgG4/(IgG1+IgG3) ≥ 0.081 were significantly higher than that of IgG4 ≥ 135 mg/dL alone (78% vs. 66%, p = 0.025). Serum IgG4 ≥ 52 mg/dL showed the best accuracy for differentiation of IgG4-SC from CCA, with a sensitivity and specificity of 80% and 82%, respectively, but this was statistically not significant (p = 0.405). Conclusions: The serum IgG4/IgG1 or IgG4/(IgG1+IgG3) level may help to differentiate IgG4-SC from PSC. IgG4 alone is the most accurate serologic marker for the differentiation of IgG4-SC from CCA.

A novel serum metabolomic panel distinguishes IgG4-related sclerosing cholangitis from primary sclerosing cholangitis.

Background & AimsPrimary sclerosing cholangitis (PSC) and IgG4‐related sclerosing cholangitis (IgG4‐SC) are chronic fibro‐inflammatory immune‐mediated hepatobiliary conditions that are challenging to distinguish in a clinical setting. Accurate non‐invasive biomarkers for discriminating PSC and IgG4‐SC are important to ensure a correct diagnosis, prompt therapy and adequate cancer surveillance.MethodsWe performed nuclear magnetic resonance (NMR)‐based metabolomic profiling using serum samples collected prospectively from patients with PSC (n = 100), IgG4‐SC (n = 23) and healthy controls (HC; n = 16).ResultsMultivariate analysis of the serum metabolome discriminated PSC from IgG4‐SC with greater accuracy (AUC 0.95 [95%CI 0.90–0.98]) than IgG4 titre (AUC 0.87 [95%CI 0.79–0.94]). When inflammatory bowel disease (IBD) was excluded as a comorbid condition (IgG4‐SC n = 20, PSC n = 22), the diagnostic AUC increased to 1.0, suggesting that the metabolome differences identified are not a result of the increased prevalence of IBD in PSC relative to IgG4‐SC patients. Serum lactate (p < .0001), glucose (p < .01) and glutamine (p < .01) metabolites were increased in IgG4‐related disease (IgG4‐RD) and IgG4‐SC individuals compared to PSC, whereas mobile choline (p < .05), 3‐hydroxybutyric acid (p < .01) and ‐CH3 lipoprotein resonances (p < .01) were decreased.ConclusionsTaken together, serum metabolomic profiling has the potential to be incorporated as a diagnostic criterion, independent of IgG4 titre, to improve the diagnosis of IgG4‐RD and help distinguish IgG4‐SC from PSC.

S1506 IgG4-Related Sclerosing Cholangitis: An Important Diagnostic Consideration for Painless Jaundice

Introduction: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of IgG4-related disease, an immune-mediated fibroinflammatory condition affecting multiple organs. Histopathology reveals lymphoplasmacytic infiltrate with dense IgG4-positive plasma cells and varying degrees of fibrosis. IgG4-SC is characterized by mass lesions and/or biliary strictures and often occurs concurrently with type 1 autoimmune pancreatitis. The differential diagnosis between primary sclerosing cholangitis (PSC), and IgG4-SC is challenging due to similar clinical and imaging characteristics, leading to treatment delay, and irreversible end organ damage. Case Description/Methods: A 62-year-old man presented with 10 days of painless jaundice, light colored stools, pruritus, and 10 kg weight loss over six months. The patient had diabetes and 20 pack-year smoking history. Exam showed jaundice and scleral icterus. The abdomen was soft with no hepatosplenomegaly. Laboratory studies were significant for ALT 449 U/L, AST 302 U/L, total bilirubin 20.4 mg/dL, ALP 989 U/L, CA-19-9 2,302 U/mL, and normal pancreatic enzymes. CT abdomen and MRCP revealed dilated intrahepatic bile ducts with no masses, and cystic changes of the pancreas with chronic calcifications. ERCP revealed hilar stricture and downstream dilatation of intrahepatic ducts. Biliary brushings showed no tumor cells. Subsequent ERCPs showed diffuse beading and structuring in the bile ducts. Liver transplant evaluation was considered for presumed PSC with concerns for cholangiocarcinoma. Further workup showed an elevated total IgG level of 2,701 mg/dL and IgG-4 level of 1,160 mg/dL. The diagnosis of IgG4-SC was established. Treatment was initiated with high dose steroids, gradually tapered down, and azathioprine to prevent disease recurrence. Patient had excellent biochemical response with normalization of liver enzymes and Ca 19-9 and biliary stricture resolution on follow up ERCP. Discussion: IgG4-SC poses a diagnostic challenge for clinicians. Total IgG and IgG4 should be obtained after ruling out common causes of obstructive jaundice. Although the presentation of IgG4-SC and PSC is similar, treatment response and outcomes differ significantly, and it is essential to establish an accurate diagnosis. Elevated IgG4 exceeding 135 mg/dL is the generally accepted cutoff. Prompt recognition of IgG4-SC is crucial as the condition is responsive to steroids with excellent outcomes.Figure 1.: ERCP showing diffuse proximal intrahepatic bile duct dilation with sparing of imaging at the hilum due to IgG4 related tactile stricturing.

S1694 IgG4-Related Sclerosing Cholangitis - An EUS Diagnosis

Introduction: Sclerosing cholangitis is a heterogenous disease associated with choledocholithiasis, biliary tumor or infection. The participation of IgG4 subclass in the pathology of sclerosing cholangitis is typically associated with autoimmune pancreatitis (60%), sialadenitis (34%), tubulo-interstitial nephritis (23%) and peri-aortitis (20%). Isolated lower duct IgG4 related sclerosing cholangitis (IgG4-Sc) is extremely uncommon and we present one such rare case. Case Description/Methods: A 73-year-old former smoker presents with complaints of yellowish discoloration of the skin and decreased appetite for a month. He has lost 44 lbs and endorses diarrhea. His family history is remarkable for lung cancer and kidney disease. Laboratory data shows cholestatic jaundice- total bilirubin of 14.2 mg/dL, AST 61 U/L, ALT 60 U/L and Alkaline phosphatase 328 U/L. CT Abdomen and Pelvis shows intra and extra-hepatic biliary ductal dilatation with common bile duct distension up to 1.4 cm. Subsequent MRCP notable for focal wall thickening involving the mid and lower portion of the common bile duct causing severe stenosis, concerning for CBD malignancy. ERCP shows proximal dilatation of the CBD with stricture of the distal end of bile duct. Biopsies obtained from the stricture were negative and tumor markers showed CEA 2.4 and CA 19-9 212. ANA screen was positive with high DsDNA antibody and elevated IgG4 at 761 mg/dL. Serum lipase was normal, anti-smooth muscle antibody and anti-mitochondrial antibody were negative. He subsequently underwent EUS/ERCP, and the CBD stricture and peri-portal lymph nodes were biopsied. Pathology from CBD stricture showed fibrosis and chronic inflammation with increased IgG4 positive plasma cells by immunohistochemistry. Hence, the patient was diagnosed with IgG4-related sclerosing cholangitis and initiated on 40 mg of Prednisone. Discussion: IgG4 related disease is a multiorgan fibro-inflammatory disease that involves infiltration of IgG4 positive plasma cells into multiple organs. IgG4-Sc is observed in elderly men who present with obstructive jaundice. HISORt criteria is used to make the diagnosis and was initially designed for diagnosis of autoimmune pancreatitis. Radiographically, Type 1 IgG4-Sc involves stenosis of only the lower bile duct and may resemble cholangiocarcinoma. Additionally, IgG4 levels may be normal further confounding the diagnostic picture. A high degree of clinical suspicion and biopsy (via EUS guidance or cholangioscopy) is imperative in making a diagnosis.Figure 1.: Endoscopic ultrasound revealing pancreatic body pseudocyst measuring 11x10 cm in diameter.

Differentiating Primary Sclerosing Cholangitis from Similar Diseases of Autoimmune Origin.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease. Differential diagnostics can confuse it with immunoglobulin (Ig) G4-related sclerosing cholangitis (SC), an IgG4-related disease with clearly proven autoimmune origin. Differential diagnosis is made even more challenging because PSC with increased IgG4 levels (PSC-increased IgG4) also occurs. In order to facilitate their differential diagnosis, we reviewed recent literature regarding the etiologies, identifying characteristics, the most useful diagnostics, treatment, and the progression of these partially similar diseases. It is clear that PSC's pathogenesis differs from that of IgG4-related SC. In any differential diagnosis between PSC and PSC-increased IgG4, high IgG1 and low or normal IgG2 levels are characteristic for patients with PSC. Histological examination of the biliary tree wall in patients with IgG4-related SC typically reveals such changes as storiform fibrosis, obliterative phlebitis, and venulitis. These are absent in PSC-increased IgG4, which is characterized by a typical circular thickness in different parts of the biliary ducts. Finally, PSC is associated with inflammatory bowel disease, which is rare in IgG4-related SC, and more frequently is associated with cholangiocarcinomas and colon cancers. As distinct from IgG4-related SC, PSC is not a primary autoimmune disease.