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1
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Hu J, Wu Y, Zhang D, Wang X, Sheng Y, Liao H, Ou Y, Chen Z, Shu B, Gui R. Regulatory T cells-related gene in primary sclerosing cholangitis: evidence from Mendelian randomization and transcriptome data. Genes Immun 2024; 25:492-513. [PMID: 39496776 DOI: 10.1038/s41435-024-00304-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 10/14/2024] [Accepted: 10/22/2024] [Indexed: 11/06/2024]
Abstract
The present study utilized large-scale genome-wide association studies (GWAS) summary data (731 immune cell subtypes and three primary sclerosing cholangitis (PSC) GWAS datasets), meta-analysis, and two PSC transcriptome data to elucidate the pivotal role of Tregs proportion imbalance in the occurrence of PSC. Then, we employed weighted gene co-expression network analysis (WGCNA), differential analysis, and 107 combinations of 12 machine-learning algorithms to construct and validate an artificial intelligence-derived diagnostic model (Tregs classifier) according to the average area under curve (AUC) (0.959) in two cohorts. Quantitative real-time polymerase chain reaction (qRT-PCR) verified that compared to control, Akap10, Basp1, Dennd3, Plxnc1, and Tmco3 were significantly up-regulated in the PSC mice model yet the expression level of Klf13, and Scap was significantly lower. Furthermore, immune cell infiltration and functional enrichment analysis revealed significant associations of the hub Tregs-related gene with M2 macrophage, neutrophils, megakaryocyte-erythroid progenitor (MEP), natural killer T cell (NKT), and enrichment scores of the autophagic cell death, complement and coagulation cascades, metabolic disturbance, Fc gamma R-mediated phagocytosis, mitochondrial dysfunction, potentially mediating PSC onset. XGBoost algorithm and SHapley Additive exPlanations (SHAP) identified AKAP10 and KLF13 as optimal genes, which may be an important target for PSC.
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Affiliation(s)
- Jianlan Hu
- Department of Gastroenterology, The Central Hospital of Hengyang City, Hengyang, Hunan Province, PR China
| | - Youxing Wu
- Department of Gastroenterology, The Central Hospital of Hengyang City, Hengyang, Hunan Province, PR China
| | - Danxia Zhang
- Department of Gastroenterology, The Central Hospital of Hengyang City, Hengyang, Hunan Province, PR China
| | - Xiaoyang Wang
- Department of Gastroenterology, The Central Hospital of Hengyang City, Hengyang, Hunan Province, PR China
| | - Yaohui Sheng
- Department of Gastroenterology, The Central Hospital of Hengyang City, Hengyang, Hunan Province, PR China
| | - Hui Liao
- Department of Gastroenterology, The Central Hospital of Hengyang City, Hengyang, Hunan Province, PR China
| | - Yangpeng Ou
- Department of Oncology, Huizhou Third People's Hospital, Guangzhou Medical University, Huizhou, Guangdong Province, PR China.
| | - Zhen Chen
- Department of Intensive Care Unit, Shunde Hospital, Southern Medical University (the First people's hospital of Shunde), Foshan, Guangdong Province, PR China
| | - Baolian Shu
- Department of Gastroenterology, The Central Hospital of Hengyang City, Hengyang, Hunan Province, PR China.
| | - Ruohu Gui
- Department of Gastroenterology, The Central Hospital of Hengyang City, Hengyang, Hunan Province, PR China.
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Cançado GGL, Hirschfield GM. Management of primary sclerosing cholangitis: Current state-of-the-art. Hepatol Commun 2024; 8:e0590. [PMID: 39774274 PMCID: PMC11567710 DOI: 10.1097/hc9.0000000000000590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 10/08/2024] [Indexed: 01/11/2025] Open
Abstract
Primary sclerosing cholangitis is a chronic liver disease characterized by progressive inflammation and fibrosis of medium-large bile ducts, most commonly in association with inflammatory bowel disease. Most patients have a progressive disease course, alongside a heightened risk of hepatobiliary and colorectal cancer. Medical therapies are lacking, and this, in part, reflects a poor grasp of disease biology. As a result, current management is largely supportive, with liver transplantation an effective life-prolonging intervention when needed, but not one that cures disease. Emerging therapies targeting disease progression, as well as symptoms such as pruritus, continue to be explored. The trial design is increasingly cognizant of the application of thoughtful inclusion criteria, as well as better endpoints aimed at using surrogates of disease that can identify treatment benefits early. This is hoped to facilitate much-needed advances toward developing safe and effective interventions for patients.
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3
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Cornillet M, Geanon D, Bergquist A, Björkström NK. Immunobiology of primary sclerosing cholangitis. Hepatology 2024:01515467-990000000-01014. [PMID: 39226402 DOI: 10.1097/hep.0000000000001080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 08/21/2024] [Indexed: 09/05/2024]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, the presence of autoantibodies, the strong clinical link with inflammatory bowel disease, and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue residency and knowledge gained from novel technologies, including single-cell RNA sequencing and spatial transcriptomics. This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.
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Affiliation(s)
- Martin Cornillet
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Daniel Geanon
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Annika Bergquist
- Unit of Gastroenterology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K Björkström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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Zhou T, Fronhoffs F, Kristiansen G, Dold L, Kaczmarek DJ, Strassburg CP, Weismüller TJ. Primary sclerosing cholangitis with IgG4-positive plasma cells in bile duct biopsies - Frequency and characterization. J Dig Dis 2024. [PMID: 39010259 DOI: 10.1111/1751-2980.13295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 05/10/2024] [Accepted: 06/11/2024] [Indexed: 07/17/2024]
Abstract
OBJECTIVES Patients diagnosed with primary sclerosing cholangitis (PSC) but with characteristics of immunoglobulin G4 (IgG4)-associated cholangitis (IAC) have been described. IAC often presents with biliary IgG4-positive plasma cell (IgG4+ PC) infiltration and responds to corticosteroids. In PSC, the frequencies or implications of biliary IgG4+ PC are unknown. We aimed to characterize the phenomenon of biliary IgG4+ PC in patients with an established PSC diagnosis. METHODS Bile duct biopsies from 191 surveillance or therapeutic endoscopic retrograde cholangiography of 58 PSC patients were retrospectively analyzed for IgG4+ PC infiltration. Patients with ≥10 IgG4+ PC per high-power field (HPF) were identified and characterized by clinical parameters, including serum IgG4 and cholangiographic presentations. RESULTS Altogether 39.7% of the PSC patients showed ≥10 IgG4+ PC/HPF in bile duct biopsies. Patients with biliary IgG4+ PC infiltration were significantly younger at diagnosis of PSC (P = 0.023). There was no association between biliary IgG4+ PC infiltration and transplant-free survival (P = 0.618). Patients with IgG4+ PC infiltration in bile duct biopsies showed significantly higher baseline (P = 0.002) and maximum (P = 0.001) serum IgG4 compared to those without. Biliary IgG4+ PC infiltration was associated with high-grade bile duct strictures (P = 0.05). IgG4-positive plasma cell infiltrations were found multifocally in 72.7% of this subgroup of PSC patients. CONCLUSIONS IgG4+ PC ≥10/HPF can be found abundantly in bile duct biopsies in PSC. Histological findings correlated with serum IgG4, age, and high-grade bile duct strictures. IgG4+ PC was located multifocally, hinting at a systemic biliary phenotype.
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Affiliation(s)
- Taotao Zhou
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | | | - Leona Dold
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | | | - Tobias J Weismüller
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Department of Internal Medicine - Gastroenterology and Oncology, Vivantes Humboldt Hospital, Berlin, Germany
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5
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Malakar S, Mishra P, Paturu R, Verma R, Ghoshal UC. Primary sclerosing cholangitis with high immunoglobulin-G4. J Hepatol 2024; 80:e168-e170. [PMID: 37813240 DOI: 10.1016/j.jhep.2023.09.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 09/01/2023] [Indexed: 10/11/2023]
Affiliation(s)
- Sayan Malakar
- Department of Gastroenterology and Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Piyush Mishra
- Department of Gastroenterology and Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Radha Paturu
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Ritu Verma
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Uday C Ghoshal
- Department of Gastroenterology and Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
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Sohal A, Kowdley KV. Complete Biochemical Remission With Oral Vancomycin in a Patient With Primary Sclerosing Cholangitis and High Serum Immunoglobulin G4 Levels. ACG Case Rep J 2024; 11:e01256. [PMID: 38236497 PMCID: PMC10793982 DOI: 10.14309/crj.0000000000001256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 12/13/2023] [Indexed: 01/19/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease characterized by intrahepatic and extrahepatic bile duct strictures leading to cirrhosis. A subtype with elevated serum immunoglobulin (Ig) G4 levels has been recently identified. Elevated IgG4 titers can be present in 9%-15% of patients with PSC. Currently, liver transplantation is the only effective treatment of PSC, although multiple medical therapies are under evaluation. We report a case of a young adult with PSC and elevated IgG4 levels who had marked serum aminotransferase elevation; the patient had an incomplete response to steroids but achieved complete biochemical remission after initiation of oral vancomycin.
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Affiliation(s)
| | - Kris V. Kowdley
- Liver Institute Northwest, Seattle, WA
- Elson Floyd College of Medicine, Spokane, WA
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 141] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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8
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Recurrent IgG4 cholangitis after liver transplantation: Back to the future. Dig Liver Dis 2022; 54:1140-1142. [PMID: 35523701 DOI: 10.1016/j.dld.2022.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 04/13/2022] [Accepted: 04/14/2022] [Indexed: 12/12/2022]
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Peerani F, Du L, Lytvyak E, Bain VG, Mason AL, Bailey RJ, Montano-Loza AJ. Serum IgG4 cut-off of 70 mg/dL is associated with a shorter time to cirrhosis decompensation and liver transplantation in primary sclerosing cholangitis patients. CANADIAN LIVER JOURNAL 2022; 5:31-42. [PMID: 35990785 PMCID: PMC9231426 DOI: 10.3138/canlivj-2021-0023] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 09/05/2021] [Indexed: 10/11/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is an immune-mediated biliary disorder of unknown etiology with no effective treatment. The purpose of this study was to better prognosticate the development of cirrhosis, decompensation, and requirement for liver transplantation (LT) in PSC patients based on serum immunoglobulin G4 (IgG4) levels. METHODS A retrospective chart review was conducted on PSC patients seen at the University of Alberta Hospital between 2002 and 2017. PSC patients were categorized as high IgG4 group (≥70 mg/dL) or normal IgG4 group (<70 mg/dL). Laboratory parameters, clinical characteristics, and outcomes were compared between the groups. RESULTS One hundred and ten patients were followed over a mean period of 7.3 (SD 5) years. Seventy-two patients (66%) were male, the mean age at diagnosis of PSC was 35 (SD 15) years, and inflammatory bowel disease (IBD) was present in 80 patients (73%). High IgG4 levels were found in 37 patients (34%). PSC patients with high IgG4 had a shorter mean cholangitis-free survival time (5.3 versus 10.4 years, p = 0.02), cirrhosis-free survival time (8.7 versus 13.0 years, p = 0.02), and LT-free survival time (9.3 years versus 18.9 years, p <0.001). IgG4 ≥70 mg/dL was independently associated with liver decompensation and LT-free outcomes. A cut-off IgG4 value of ≥70 mg/dL performed better than a cut-off value of ≥140 mg/dL to predict time to LT (area under the curve [AUC] 0.68, p = 0.03, sensitivity 72%, specificity 78%). CONCLUSIONS Serum IgG4 ≥70 mg/dL in PSC predicts a shorter time to cirrhosis decompensation and LT.
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Affiliation(s)
- Farhad Peerani
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Lillian Du
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ellina Lytvyak
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Vincent G Bain
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Andrew L Mason
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Robert J Bailey
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Aldo J Montano-Loza
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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Drazilova S, Veseliny E, Lenartova PD, Drazilova D, Gazda J, Grgurevic I, Janicko M, Jarcuska P. IgG4-Related Sclerosing Cholangitis: Rarely Diagnosed, but not a Rare Disease. Can J Gastroenterol Hepatol 2021; 2021:1959832. [PMID: 34970512 PMCID: PMC8714375 DOI: 10.1155/2021/1959832] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 11/08/2021] [Accepted: 12/01/2021] [Indexed: 11/30/2022] Open
Abstract
IgG4-related sclerosing cholangitis, a biliary manifestation of an IgG4-related disease, belongs to the spectrum of sclerosing cholangiopathies which result in biliary stenosis. It presents with signs of cholestasis and during differential diagnosis it should be distinguished from cholangiocarcinoma or from other forms of sclerosing cholangitis (primary and secondary sclerosing cholangitis). Despite increasing information and recently established diagnostic criteria, IgG4-related sclerosing cholangitis remains underdiagnosed in routine clinical practice. The diagnosis is based on a combination of the clinical picture, laboratory parameters, histological findings, and a cholangiogram. Increased serum IgG4 levels are nonspecific but are indeed a part of the diagnostic criteria proposed by the Japan Biliary Association and the HISORt criteria for IgG4-SC. High serum IgG4 retains clinical utility depending on the magnitude of elevation. Approximately 90% of patients have concomitant autoimmune pancreatitis, while 10% present with isolated biliary involvement only. About 26% of patients have other organ involvement, such as IgG4-related dacryoadenitis/sialadenitis, IgG4-related retroperitoneal fibrosis, or IgG4-related renal lesions. A full-blown histological finding characterized by IgG4-enriched lymphoplasmacytic infiltrates, obliterative phlebitis, and storiform fibrosis is difficult to capture in practice because of its subepithelial localization. However, the histological yield is increased by immunohistochemistry, with evidence of IgG4-positive plasma cells. Based on a cholangiogram, IgG-4 related sclerosing cholangitis is classified into four subtypes according to the localization of stenoses. The first-line treatment is corticosteroids. The aim of the initial treatment is to induce clinical and laboratory remission and cholangiogram normalization. Even though 30% of patients have a recurrent course, in the literature data, there is no consensus on chronic immunosuppressive maintenance therapy. The disease has a good prognosis when diagnosed early.
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Affiliation(s)
- Sylvia Drazilova
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Eduard Veseliny
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Patricia Denisa Lenartova
- Department of Infectology and Travel Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Rastislavova 43, 040 01 Kosice, Slovakia
| | - Dagmar Drazilova
- 1 Faculty of Medicine, Charles University, Katerinska 1660/32, 121 08 Nove Mesto, Prague, Czech Republic
| | - Jakub Gazda
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University of Zagreb School of Medicine and University Hospital Dubrava, Avenija Gojka Suska 6, 10000 Zagreb, Croatia
| | - Martin Janicko
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
| | - Peter Jarcuska
- 2 Department of Internal Medicine, PJ Safarik University in Kosice and L. Pasteur University Hospital, Trieda SNP 1, 040 11 Kosice, Slovakia
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11
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Zhou T, Lenzen H, Dold L, Bündgens B, Wedemeyer H, Manns MP, Gonzalez-Carmona MA, Strassburg CP, Weismüller TJ. Primary sclerosing cholangitis with moderately elevated serum-IgG4 - characterization and outcome of a distinct variant phenotype. Liver Int 2021; 41:2924-2933. [PMID: 34328259 DOI: 10.1111/liv.15028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 07/24/2021] [Accepted: 07/26/2021] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIMS Immunoglobulin G4-associated cholangitis (IAC) is characterized by distinctly elevated immunoglobulin G4 in serum (sIgG4) and responds well to corticosteroid therapy. Primary Sclerosing Cholangitis (PSC) is a progressive liver disease without causal treatment options usually not responding to immunosuppression. Increased serum levels of sIgG4 in patients with PSC, that do not meet criteria of IAC, have been reported in 10%-25%. Therefore, we aimed to characterize this subgroup of patients in a retrospective, multicenter study. METHODS sIgG4 values of 289 patients with PSC from three German university hospitals were analysed. Patients with elevated sIgG4 levels were identified and further characterized by clinical and biochemical parameters and by cholangiographic presentation. Clinical endpoints, death and liver transplantation were compared between groups. Parameters associated with outcome were identified with Cox regression analysis. RESULTS 14.5% of patients with PSC showed increased sIgG4 levels (PSC-IgG4), presented with significantly higher (P < .02) albumin, aspartate-aminotransferase, bilirubin and alkaline phosphatase and had a significant lower prevalence of a concomitant autoimmune hepatitis (P = .025). Cholangiogram obtained via ERC showed extrahepatic dominant strictures more often in the PSC-IgG4 subgroup (P = .047). The disease severity models Amsterdam-Oxford-Score (P = .018) and Mayo-Risk-Score (P = .025) predicted lower survival rates for the PSC-IgG4 subgroup. Transplant-free survival after first diagnosis of PSC was shorter in patients with elevated sIgG4 (11.6 vs 15.1 years, P = .001). CONCLUSION Patients with PSC and elevated sIgG4 should be considered as a distinct subgroup, characterized by different clinical and cholangiographical features and are associated with an inferior outcome.
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Affiliation(s)
- Taotao Zhou
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Henrike Lenzen
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Leona Dold
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Bennet Bündgens
- Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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12
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Patel AM, Liu YS, Davies SP, Brown RM, Kelly DA, Scheel-Toellner D, Reynolds GM, Stamataki Z. The Role of B Cells in Adult and Paediatric Liver Injury. Front Immunol 2021; 12:729143. [PMID: 34630404 PMCID: PMC8495195 DOI: 10.3389/fimmu.2021.729143] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022] Open
Abstract
B lymphocytes are multitasking cells that direct the immune response by producing pro- or anti-inflammatory cytokines, by presenting processed antigen for T cell activation and co-stimulation, and by turning into antibody-secreting cells. These functions are important to control infection in the liver but can also exacerbate tissue damage and fibrosis as part of persistent inflammation that can lead to end stage disease requiring a transplant. In transplantation, immunosuppression increases the incidence of lymphoma and often this is of B cell origin. In this review we bring together information on liver B cell biology from different liver diseases, including alcohol-related and metabolic fatty liver disease, autoimmune hepatitis, primary biliary and primary sclerosing cholangitis, viral hepatitis and, in infants, biliary atresia. We also discuss the impact of B cell depletion therapy in the liver setting. Taken together, our analysis shows that B cells are important in the pathogenesis of liver diseases and that further research is necessary to fully characterise the human liver B cell compartment.
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Affiliation(s)
- Arzoo M. Patel
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Yuxin S. Liu
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Scott P. Davies
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Rachel M. Brown
- Department of Histopathology, Queen Elizabeth Hospital, Birmingham Women’s and Children’s National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
| | - Deirdre A. Kelly
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Dagmar Scheel-Toellner
- Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
| | - Gary M. Reynolds
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- The Liver Unit, Birmingham Women’s and Children’s Hospital and the University of Birmingham, Birmingham, United Kingdom
| | - Zania Stamataki
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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13
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Nasser R, Gilshtein H, Mansour S, Yasin K, Borzellino G, Khuri S. Isolated Type Immunoglobulin G4 Sclerosing Cholangitis: The Misdiagnosed Cholangiocarcinoma. J Clin Med Res 2021; 13:75-81. [PMID: 33747321 PMCID: PMC7935625 DOI: 10.14740/jocmr4428] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Accepted: 01/21/2021] [Indexed: 12/13/2022] Open
Abstract
Immunoglobulin G4 sclerosing cholangitis (IgG4-SC), firstly described in 2004, is the biliary manifestation of a recently described multisystem immune-mediated disease known as IgG4-related disease. IgG4-SC is a unique and rare type of cholangitis of unknown etiology and its precise prevalence rate is still unclear. It is characterized by bile duct wall thickening and high levels of systemic serum IgG4 plasma cells. Differential diagnoses for IgG4-SC include benign (primary sclerosing cholangitis) as well as malignant (extra-hepatic cholangiocarcinoma) diseases. Discrimination between these entities is very important, due to the fact that they have different biological behaviors and different therapeutic strategies. The rare IgG4-SC subgroup with its puzzling manifestations carries a hefty diagnostic challenge for the treating physicians, and inaccurate diagnosis can lead to unnecessary morbid surgical procedures. With the paucity and relative weakness of available data in the current literature, one needs to carefully review all available parameters. A low threshold of suspicion is required to try and prevent missing IgG4-SC. IgG4-SC is highly responsive to steroid treatment, especially during the early inflammatory phase, while delay in management could lead to fibrosis and organ dysfunction. On the other hand, cholangiocarcinoma is treated by means of surgery and/or chemotherapeutic agents.
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Affiliation(s)
- Roni Nasser
- Gastroenterology and Hepatology Department, Rambam Health Care Campus, Haifa, Israel
| | - Hayim Gilshtein
- Colorectal Surgery Unit, General Surgery Department, Rambam Health Care Campus, Haifa, Israel
| | - Subhi Mansour
- HPB and Surgical Oncology Unit, General Surgery Department, Rambam Health Care Campus, Haifa, Israel
| | - Kamel Yasin
- Gastroenterology and Hepatology Department, Rambam Health Care Campus, Haifa, Israel
| | | | - Safi Khuri
- HPB and Surgical Oncology Unit, General Surgery Department, Rambam Health Care Campus, Haifa, Israel
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Floreani A, Okazaki K, Uchida K, Gershwin ME. IgG4-related disease: Changing epidemiology and new thoughts on a multisystem disease. J Transl Autoimmun 2020; 4:100074. [PMID: 33490938 PMCID: PMC7806798 DOI: 10.1016/j.jtauto.2020.100074] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 11/19/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
IgG4-related disease (IgG4-RD) represents an immune-mediated fibroinflammatory condition with peculiar histopathologic changes that can affect various organs. In 2012 its unified nomenclature was published, which allows to abandon other synonymous names. Up to now, only little is known about its epidemiology around the world. However, although it is generally considered a rare condition, the number of patients with IgG4-RD is increasing enormously. Likewise, the annual number of publications on this subject has increased progressively. The spectrum of clinical manifestations in IgG4-RD is highly variable, depending on the severity of the disease as well as the presence of organ(s) involvement. This review gives an overview on changing epidemiology of IgG4-RD focusing the attention on the large cohorts of patients published in the literature.
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Affiliation(s)
- Annarosa Floreani
- Scientific Consultant IRCCS Negrar, Verona, Italy
- Senior Scholar, University of Padova, Italy
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - Kazushige Uchida
- Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan
| | - M. Eric Gershwin
- Division of Rheumatology Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
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Manganis CD, Chapman RW, Culver EL. Review of primary sclerosing cholangitis with increased IgG4 levels. World J Gastroenterol 2020; 26:3126-3144. [PMID: 32684731 PMCID: PMC7336326 DOI: 10.3748/wjg.v26.i23.3126] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 04/07/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease. Sub-types of PSC have been described, most recently PSC with elevated serum and/or tissue IgG4 subclass. We aim to summarise the clinical phenotype, disease associations, differential diagnosis, response to therapy and pathogenic mechanisms underlying PSC-high IgG4 subtype. We reviewed PubMed, MEDLINE and Embase with the search terms "primary sclerosing cholangitis", "IgG4", and "IgG4-related sclerosing cholangitis (IgG4-SC)". Elevated serum IgG4 are found in up-to one-quarter, and abundant IgG4-plasma cell infiltrates in the liver and bile ducts are found in up-to one-fifth of PSC patients. This group have a distinct clinical phenotype, with some studies reporting a more aggressive course of liver and associated inflammatory bowel disease, compared to PSC-normal IgG4 and the disease mimic IgG4-SC. Distinguishing PSC-high IgG4 from IgG4-SC remains challenging, requiring careful assessment of clinical features, organ involvement and tissue morphology. Calculation of serum IgG4:IgG1 ratios and use of a novel IgG4:IgG RNA ratio have been reported to have excellent specificity to distinguish IgG4-SC and PSC-high IgG4 but require validation in larger cohorts. A role for corticosteroid therapy in PSC-high IgG4 remains unanswered, with concerns of increased toxicity and lack of outcome data. The immunological drivers underlying prominent IgG4 antibodies in PSC are incompletely defined. An association with PSC-high IgG4 and HLA class-II haplotypes (B*07, DRB1*15), T-helper2 and T-regulatory cytokines (IL4, IL10, IL13) and chemokines (CCL1, CCR8) have been described. PSC-high IgG4 have a distinct clinical phenotype and need careful discrimination from IgG4-SC, although response to immunosuppressive treatments and long-term outcome remains unresolved. The presence of IgG4 likely represents chronic activation to persistent antigenic exposure in genetically predisposed individuals.
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Affiliation(s)
- Charis D Manganis
- Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Roger W Chapman
- Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Emma L Culver
- Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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Chapman MH, Thorburn D, Hirschfield GM, Webster GGJ, Rushbrook SM, Alexander G, Collier J, Dyson JK, Jones DE, Patanwala I, Thain C, Walmsley M, Pereira SP. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut 2019; 68:1356-1378. [PMID: 31154395 PMCID: PMC6691863 DOI: 10.1136/gutjnl-2018-317993] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/21/2019] [Accepted: 03/24/2019] [Indexed: 12/11/2022]
Abstract
These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
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Affiliation(s)
- Michael Huw Chapman
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Liver Unit, Royal Free London NHS Foundation Trust, London, UK
| | | | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | | | - Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | | | | | - Jessica K Dyson
- Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - David Ej Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Imran Patanwala
- Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | | | | | - Stephen P Pereira
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Institute for Liver & Digestive Health, University College London, London, UK
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Kamisawa T, Nakazawa T, Tazuma S, Zen Y, Tanaka A, Ohara H, Muraki T, Inui K, Inoue D, Nishino T, Naitoh I, Itoi T, Notohara K, Kanno A, Kubota K, Hirano K, Isayama H, Shimizu K, Tsuyuguchi T, Shimosegawa T, Kawa S, Chiba T, Okazaki K, Takikawa H, Kimura W, Unno M, Yoshida M. Clinical practice guidelines for IgG4-related sclerosing cholangitis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2019; 26:9-42. [PMID: 30575336 PMCID: PMC6590186 DOI: 10.1002/jhbp.596] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
IgG4‐related sclerosing cholangitis (IgG4‐SC) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4‐related disease. Although clinical diagnostic criteria of IgG4‐SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4‐SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions (CQs) with clinical statements were developed regarding diagnosis (14 CQs) and treatment (4 CQs). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4‐SC.
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Affiliation(s)
- Terumi Kamisawa
- Department of Internal Medicine, Tokyo Metropolitan, Komagome Hospital, Tokyo, Japan
| | - Takahiro Nakazawa
- Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
| | - Susumu Tazuma
- Department of General Internal Medicine, Hiroshima University Graduate School of Biomedical & Health Science, Hiroshima, Japan
| | - Yoh Zen
- Department of Diagnostic Pathology, Kobe University, Kobe, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Hirotaka Ohara
- Department of Community-Based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takashi Muraki
- Department of Medicine, Gastroenterology, Shinshu University, Matsumoto, Nagano, Japan
| | - Kazuo Inui
- Department of Gastroenterology, Second Teaching Hospital, Fujita Health University, Nagoya, Japan
| | - Dai Inoue
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Takayoshi Nishino
- Department of Gastroenterology, Tokyo Womens' Medical University Yachiyo Medical Center, Yachiyo, Japan
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takao Itoi
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Kenji Notohara
- Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Atsushi Kanno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kensuke Kubota
- Department of Endoscopy, Yokohama City University Hospital, Yokohama, Japan
| | - Kenji Hirano
- Department of Gastroenterology, Tokyo Takanawa Hospital, Tokyo, Japan
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Kyoko Shimizu
- Department of Gastroenterology, Tokyo Womens' Medical University, Tokyo, Japan
| | | | - Tooru Shimosegawa
- Division of Gastroenterology, South-Miyagi Medical Center, Ohgawara, Japan
| | - Shigeyuki Kawa
- Department of Internal Medicine, Matsumoto Dental University, Matsumoto, Japan
| | | | - Kazuichi Okazaki
- The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Japan
| | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Wataru Kimura
- Faculty of Medicine, Departments of Gastroenterology and Gastroenterological, General, Breast, and Thyroid Surgery, Yamagata University, Yamagata, Japan
| | - Michiaki Unno
- Division of Hepato-Biliary Pancreatic Surgery, Tohoku University Graduate School, of Medicine, Sendai, Japan
| | - Masahiro Yoshida
- Department of Hepato-Biliary-Pancreatic and Gastrointestinal Surgery, School of Medicine, International University of Health and Welfare, Ichikawa, Japan
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IgG4 Status in Explanted Livers Does Not Affect the Outcome of Primary Sclerosing Cholangitis (PSC) After Liver Transplant. HEPATITIS MONTHLY 2018. [DOI: 10.5812/hepatmon.66037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Roos E, Hubers LM, Coelen RJS, Doorenspleet ME, de Vries N, Verheij J, Beuers U, van Gulik TM. IgG4-Associated Cholangitis in Patients Resected for Presumed Perihilar Cholangiocarcinoma: a 30-Year Tertiary Care Experience. Am J Gastroenterol 2018; 113:765-772. [PMID: 29549357 DOI: 10.1038/s41395-018-0036-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 01/18/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Distinguishing perihilar cholangiocarcinoma (PHC) from benign forms of sclerosing cholangitis affecting the hilar bile ducts is challenging, since histological confirmation of PHC is difficult to obtain and accurate non-invasive diagnostic tests are not available. IgG4-associated cholangitis (IAC), an imitator of PHC, may present with clinical and radiographical signs of PHC. IAC can be accurately diagnosed with a novel qPCR test. The aim of this study was to investigate the incidence and long-term activity of IAC in patients resected for PHC in a single tertiary center over a period of 30 years. METHODS All patients with benign disease who underwent surgery for presumed PHC in our institute between 1984 and 2015 were identified. Benign liver and bile duct specimens were re-evaluated by a pathologist and scored according to international consensus pathology criteria for IgG4-related disease (IgG4-RD). Patients with benign disease still alive were followed-up and a clinical diagnosis of IAC was made using a combination of the HISORt group C (response to steroids) criteria and elevated serum IgG4 levels and/or the novel IgG4/IgG RNA ratio. Also, recurrent symptomatic disease at any time after surgery requiring immunosuppression was assessed. RESULTS Out of 323 patients who underwent surgery for presumed PHC, 50 patients (15%) had benign disease. In 42% (n = 21/50) of these patients a histological (n = 17) or clinical (n = 4) diagnosis of IAC was established. The remaining patients were diagnosed with unclassified sclerosing inflammation, cystadenoma, or sclerosing hemangioma. Nine out of 12 IAC patients who were followed-up showed episodes of recurrent disease requiring immunosuppressive treatment. CONCLUSIONS Liver and bile duct resections for PHC during three decades disclosed in 15% benign biliary disorders mimicking PHC of which 42% were definitely diagnosed as IAC. IgG4-RD remains active in the majority of patients with IAC years after surgery. Novel diagnostic tests for IAC might reduce misdiagnosis, unnecessary surgery, and life-threatening complications.
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Affiliation(s)
- Eva Roos
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Department of Gastroenterology & Hepatology and Tytgat institute for Liver and intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Department of Clinical immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, & Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. These authors contributed equally: Eva Roos, Lowiek M. Hubers
| | - Lowiek M Hubers
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Department of Gastroenterology & Hepatology and Tytgat institute for Liver and intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Department of Clinical immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, & Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. These authors contributed equally: Eva Roos, Lowiek M. Hubers
| | - Robert J S Coelen
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Department of Gastroenterology & Hepatology and Tytgat institute for Liver and intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Department of Clinical immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, & Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. These authors contributed equally: Eva Roos, Lowiek M. Hubers
| | - Marieke E Doorenspleet
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Department of Gastroenterology & Hepatology and Tytgat institute for Liver and intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Department of Clinical immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, & Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. These authors contributed equally: Eva Roos, Lowiek M. Hubers
| | - Niek de Vries
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Department of Gastroenterology & Hepatology and Tytgat institute for Liver and intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Department of Clinical immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, & Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. These authors contributed equally: Eva Roos, Lowiek M. Hubers
| | - Joanne Verheij
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Department of Gastroenterology & Hepatology and Tytgat institute for Liver and intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Department of Clinical immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, & Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. These authors contributed equally: Eva Roos, Lowiek M. Hubers
| | - Ulrich Beuers
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Department of Gastroenterology & Hepatology and Tytgat institute for Liver and intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Department of Clinical immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, & Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. These authors contributed equally: Eva Roos, Lowiek M. Hubers
| | - Thomas M van Gulik
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands. Department of Gastroenterology & Hepatology and Tytgat institute for Liver and intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. Department of Clinical immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, & Laboratory of Experimental Medicine, Academic Medical Center, Amsterdam, The Netherlands. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. These authors contributed equally: Eva Roos, Lowiek M. Hubers
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de Nanassy J, El Demellawy D. Review of Current Applications of Immunohistochemistry in Pediatric Nonneoplastic Gastrointestinal, Hepatobiliary, and Pancreatic Lesions. ANALYTICAL CHEMISTRY INSIGHTS 2017; 12:1177390117690140. [PMID: 28469406 PMCID: PMC5400017 DOI: 10.1177/1177390117690140] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 01/02/2017] [Indexed: 12/13/2022]
Abstract
Immunohistochemical (IHC) stains are widely used by pathologists for a variety of considerations in the diagnostic workup of pediatric nonneoplastic lesions in gastrointestinal (GI), hepatic, biliary, and pancreatic lesions. The pathologic changes cover a wide range and types of presentations, including inflammatory (bacterial and viral), metaplastic, posttransplant lymphoproliferative, autoimmune, metabolic, degenerative, developmental, and genetic conditions, among others. The everyday practical value of IHC stains covers primary identification, confirmation, differential, and/or exclusionary roles in the hands and eyes and minds of the practitioners. This article is intended to review and discuss the currently available IHC stains for a variety of pediatric GI, hepatobiliary, and pancreatic lesions as encountered in the day-to-day practice of pathologists and clinicians. It reflects the most recent methods and types of IHC stains with the stated aim of helping to provide a quick reference for diagnostic considerations and thereby facilitate the workup of a broad range of GI and related conditions in a pediatric population. The tables provide a handy reference on a wide range of IHC stains for commonly encountered lesions covering a variety of pediatric GI, hepatobiliary, and pancreatic conditions that are amenable to light microscopic diagnostic interpretation.
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Affiliation(s)
- Joseph de Nanassy
- Department of Anatomical Pathology, Children's Hospital of Eastern Ontario (CHEO), Ottawa, ON, Canada.,Department of Pathology, University of Ottawa, Ottawa, ON, Canada
| | - Dina El Demellawy
- Department of Anatomical Pathology, Children's Hospital of Eastern Ontario (CHEO), Ottawa, ON, Canada.,Department of Pathology, University of Ottawa, Ottawa, ON, Canada
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Doorenspleet ME, Hubers LM, Culver EL, Maillette de Buy Wenniger LJ, Klarenbeek PL, Chapman RW, Baas F, van de Graaf SF, Verheij J, van Gulik TM, Barnes E, Beuers U, de Vries N. Immunoglobulin G4(+) B-cell receptor clones distinguish immunoglobulin G 4-related disease from primary sclerosing cholangitis and biliary/pancreatic malignancies. Hepatology 2016; 64:501-7. [PMID: 27015613 PMCID: PMC5017301 DOI: 10.1002/hep.28568] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2015] [Revised: 02/20/2016] [Accepted: 03/24/2016] [Indexed: 12/24/2022]
Abstract
UNLABELLED Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) of the biliary tree and pancreas is difficult to distinguish from sclerosing cholangitis and biliary/pancreatic malignancies (CA). An accurate noninvasive test for diagnosis and monitoring of disease activity is lacking. We demonstrate that dominant IgG4(+) B-cell receptor (BCR) clones determined by next-generation sequencing accurately distinguish patients with IgG4-associated cholangitis/autoimmune pancreatitis (n = 34) from those with primary sclerosing cholangitis (n = 17) and CA (n = 17). A novel, more affordable, and widely applicable quantitative polymerase chain reaction (qPCR) protocol analyzing the IgG4/IgG RNA ratio in blood also achieves excellent diagnostic accuracy (n = 125). Moreover, this qPCR test performed better than serum IgG4 levels in sensitivity (94% vs. 86%) and specificity (99% vs. 73%) and correlates with treatment response (n = 20). CONCLUSIONS IgG4(+) BCR clones and IgG4/IgG RNA ratio markedly improve delineation, early diagnosis, and monitoring of IgG4-RD of the biliary tree and pancreas. (Hepatology 2016;64:501-507).
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Affiliation(s)
- Marieke E. Doorenspleet
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical CenterAmsterdamThe Netherlands
- Department of Genome AnalysisAcademic Medical CenterAmsterdamThe Netherlands
| | - Lowiek M. Hubers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CenterAmsterdamThe Netherlands
| | - Emma L. Culver
- Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
- NDM Oxford University, Oxford Martin School, Oxford UniversityOxfordUnited Kingdom
| | - Lucas J. Maillette de Buy Wenniger
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CenterAmsterdamThe Netherlands
- Present address: Department of OphthalmologyVU Medical CenterAmsterdamThe Netherlands
| | - Paul L. Klarenbeek
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical CenterAmsterdamThe Netherlands
- Department of Genome AnalysisAcademic Medical CenterAmsterdamThe Netherlands
| | - Roger W. Chapman
- Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
- NDM Oxford University, Oxford Martin School, Oxford UniversityOxfordUnited Kingdom
| | - Frank Baas
- Department of Genome AnalysisAcademic Medical CenterAmsterdamThe Netherlands
| | - Stan F. van de Graaf
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CenterAmsterdamThe Netherlands
| | - Joanne Verheij
- Department of PathologyAcademic Medical CenterAmsterdamThe Netherlands
| | | | - Eleanor Barnes
- Translational Gastroenterology UnitJohn Radcliffe HospitalOxfordUnited Kingdom
- NDM Oxford University, Oxford Martin School, Oxford UniversityOxfordUnited Kingdom
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal ResearchAcademic Medical CenterAmsterdamThe Netherlands
| | - Niek de Vries
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical CenterAmsterdamThe Netherlands
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Adult bile duct strictures: differentiating benign biliary stenosis from cholangiocarcinoma. Med Mol Morphol 2016; 49:189-202. [PMID: 27350291 DOI: 10.1007/s00795-016-0143-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2016] [Accepted: 06/04/2016] [Indexed: 12/17/2022]
Abstract
Biliary epithelial cells preferentially respond to various insults under chronic pathological conditions leading to reactively atypical changes, hyperplasia, or the development of biliary neoplasms (such as biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, and cholangiocarcinoma). Moreover, benign biliary strictures can be caused by a variety of disorders (such as IgG4-related sclerosing cholangitis, eosinophilic cholangitis, and follicular cholangitis) and often mimic malignancies, despite their benign nature. In addition, primary sclerosing cholangitis is a well-characterized precursor lesion of cholangiocarcinoma and many other chronic inflammatory disorders increase the risk of malignancies. Because of these factors and the changes in biliary epithelial cells, biliary strictures frequently pose a diagnostic challenge. Although the ability to differentiate neoplastic from non-neoplastic biliary strictures has markedly progressed with the advance in radiological modalities, brush cytology and bile duct biopsy examination remains effective. However, no single modality is adequate to diagnose benign biliary strictures because of the low sensitivity. Therefore, understanding the underlying causes by compiling the entire clinical, laboratory, and imaging data; considering the under-recognized causes; and collaborating between experts in various fields including cytopathologists with multiple approaches is necessary to achieve an accurate diagnosis.
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Abstract
Primary sclerosing cholangitis (PSC) is a heterogeneous, idiopathic, inflammatory disorder frequently associated with inflammatory bowel diseases. PSC patients may be classified into several subphenotypes. Investigations of pediatric, nonwhite, and female PSC patients have revealed distinguishing features. The natural history of PSC is variable in progression with numerous possible clinical outcomes. PSC patients may suffer bacterial cholangitis, cholangiocarcinoma, or colorectal adenocarcinoma. Treatments focusing on bile acid therapy and immunosuppression have not proven beneficial. Interest in PSC and international collaboration has led to improved understanding of the heterogeneity and the genetic structure and introduced possible effective therapeutics.
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Affiliation(s)
- Souvik Sarkar
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA. Phone: 1 916 734 3751, Fax: 1 916 734 7908
| | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, 4150 V Street, PSSB 3500, Sacramento, CA 95817, USA. Phone: 1 916 734 3751, Fax: 1 916 734 7908
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Abstract
PURPOSE OF REVIEW There are two distinct steroid responsive chronic fibro-inflammatory diseases of the pancreas, called type 1 and type 2 autoimmune pancreatitis (AIP). We review recent progress in this field. RECENT FINDINGS It has recently been suggested that the term AIP be used to describe type 1 AIP and the term idiopathic duct-centric chronic pancreatitis (IDCP) be used for type 2 AIP. Clinical features and long-term outcomes of AIP and IDCP are well characterized and prognosis of both diseases is excellent. Diagnostic strategies tailored to regional practice patterns have emerged with the application of International Consensus Diagnostic Criteria for AIP. Although corticosteroids remain the mainstay of treatment, management of relapses and strategies for preventing multiple relapses are better understood, including the role of maintenance therapy and B-cell depletion therapy with rituximab. Association studies with malignancies have yielded conflicting results regarding risk of cancer in AIP. SUMMARY The treatment, follow-up guidelines and associations continue to evolve with our increasing experience with both AIP and IDCP. In AIP, rituximab can be used for both induction and maintenance of remission. IDCP responds to steroids without need for maintenance therapy. Both AIP and IDCP have excellent prognosis.
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Recent publications by ochsner authors. Ochsner J 2014; 14:724-30. [PMID: 25598740 PMCID: PMC4294413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023] Open
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