|
1
|
Beuers U, Trampert DC. IgG4-Related Cholangitis. Semin Liver Dis 2025. [PMID: 40342085 DOI: 10.1055/a-2588-3875] [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] [Indexed: 05/11/2025]
Abstract
IgG4-related cholangitis (IRC) is a rare fibroinflammatory disease of the biliary tree and liver and presents the major hepatobiliary manifestation of IgG4-related systemic disease (IgG4-RD). IRC also includes the IgG4-related inflammatory pseudotumor of the liver and IgG4-related cholecystitis. IRC mimics other cholangiopathies such as primary sclerosing cholangitis or cholangiocarcinoma. IRC may be found in 30 to 60% of cases with type 1 autoimmune pancreatitis, the most frequent manifestation of IgG4-RD. The pathogenesis of IRC (and IgG4-RD) is incompletely understood. Genetic predisposition, environmental factors, oligoclonal glucocorticosteroid-sensitive expansion of IgG4+ B cells/plasmablasts in blood and affected tissue and blocking autoantibody formation against protective IgG4-specific autoantigens such as annexin A11 and laminin 511-E8 with impaired protection of biliary epithelia against toxic bile acids have been described in IRC. Specific T cell subtypes are involved in the inflammatory process. The diagnosis of IRC is made according to HISORt criteria comprising histopathology, imaging, serology, other organ manifestations, and response to therapy. Treatment of IRC aiming to prevent organ failure and improve symptoms includes remission induction with highly effective glucocorticosteroids and long-term maintenance of remission with immunomodulators such as glucocorticosteroid sparing additives or B cell depleting approaches.
Collapse
Affiliation(s)
- Ulrich Beuers
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - David C Trampert
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Center, Amsterdam, The Netherlands
| |
Collapse
|
|
2
|
Herta T, Schröder M, Geisel D, Engelmann C, Tacke F. Management of IgG4-related cholangitis: diagnosis, therapy, and long-term surveillance. Gastroenterol Rep (Oxf) 2025; 13:goaf032. [PMID: 40191403 PMCID: PMC11972112 DOI: 10.1093/gastro/goaf032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 01/28/2025] [Accepted: 02/27/2025] [Indexed: 04/09/2025] Open
Abstract
IgG4-related cholangitis (IRC) is a chronic cholestatic liver disease that often occurs concomitantly with autoimmune pancreatitis type 1. Both conditions are manifestations of IgG4-related disease, a systemic autoimmune-mediated fibroinflammatory disorder. Patients often present with jaundice and weight loss, mimicking hepatobiliary malignancies, such as cholangiocarcinoma, primary sclerosing cholangitis, and pancreatic cancer. Accurate diagnosis is challenging due to the absence of pathognomonic findings but can be achieved using the HISORt criteria (histology, imaging, serology, other organ involvement, and response to immunosuppressive therapy). Early diagnosis is critical to avoid unnecessary surgery and prevent progression to liver fibrosis or cirrhosis. IRC responds well to corticosteroid therapy, though relapses are common, necessitating long-term immunosuppressive treatment in many cases. Steroid-sparing agents for remission induction and maintenance therapy comprise immunomodulators, such as azathioprine, as well as B-cell depletion therapies, such as rituximab. This review provides a structured clinical overview of the diagnosis, differential diagnosis, and therapy, including novel therapeutic options, such as inebilizumab, for this rare yet severe condition. A key focus is on long-term surveillance strategies, which include laboratory tests, imaging (contrast-enhanced magnetic resonance imaging/magnetic resonance cholangiopancreatography, ultrasound, endosonography), and, particularly in patients with fibrotic bile duct strictures, endoscopy (endoscopic retrograde cholangiopancreatography, cholangioscopy).
Collapse
Affiliation(s)
- Toni Herta
- Department of Hepatology and Gastroenterology, Charité–Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
- Berlin Institute of Health at Charité–Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin, Germany
| | - Maik Schröder
- Department of Hepatology and Gastroenterology, Charité–Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Dominik Geisel
- Department of Radiology, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité–Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité–Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| |
Collapse
|
|
3
|
Facciorusso A, Crinò SF, Gkolfakis P, Spadaccini M, Arvanitakis M, Beyna T, Bronswijk M, Dhar J, Ellrichmann M, Gincul R, Hritz I, Kylänpää L, Martinez-Moreno B, Pezzullo M, Rimbaş M, Samanta J, van Wanrooij RLJ, Webster G, Triantafyllou K. Diagnostic work-up of bile duct strictures: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2025; 57:166-185. [PMID: 39689874 DOI: 10.1055/a-2481-7048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2024]
Abstract
1: ESGE recommends the combination of endoscopic ultrasound-guided tissue acquisition (EUS-TA) and endoscopic retrograde cholangiopancreatography (ERCP)-based tissue acquisition as the preferred diagnostic approach for tissue acquisition in patients with jaundice and distal extrahepatic biliary stricture in the absence of a pancreatic mass. 2: ESGE suggests that brushing cytology should be completed along with fluoroscopy-guided biopsies, wherever technically feasible, in patients with perihilar biliary strictures. 3: ESGE suggests EUS-TA for perihilar strictures when ERCP-based modalities yield insufficient results, provided that curative resection is not feasible and/or when cross-sectional imaging has shown accessible extraluminal disease. 4: ESGE suggests using standard ERCP diagnostic modalities at index ERCP. In the case of indeterminate biliary strictures, ESGE suggests cholangioscopy-guided biopsies, in addition to standard ERCP diagnostic modalities. Additional intraductal biliary imaging modalities can be selectively used, based on clinical context, local expertise, and resource availability.
Collapse
Affiliation(s)
- Antonio Facciorusso
- Experimental Medicine, Università del Salento, Lecce, Italy
- Clinical Effectiveness Research Group, Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Paraskevas Gkolfakis
- Gastroenterology, "Konstantopoulio-Patision" General Hospital of Nea Ionia, Athens, Greece
| | | | - Marianna Arvanitakis
- Gastroenterology, Digestive Oncology and Hepatopancreatology, HUB Hôpital Erasme, Brussels, Belgium
| | - Torsten Beyna
- Internal Medicine, Evangelisches Krankenhaus Düsseldorf, Düsseldorf, Germany
| | - Michiel Bronswijk
- Gastroenterology and Hepatology, Imelda Hospital, Bonheiden, Belgium
- Gastroenterology and Hepatology, KU Leuven University Hospitals Leuven, Leuven, Belgium
| | | | - Mark Ellrichmann
- Interdisciplinary Endoscopy, Medical Department I, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Rodica Gincul
- Gastroenterology, Jean Mermoz Private Hospital, Lyon, France
| | - Istvan Hritz
- Centre for Therapeutic Endoscopy, Semmelweis University, Budapest, Hungary
| | - Leena Kylänpää
- Surgery, Helsinki Univeristy Central Hospital, Helsinki, Finland
| | | | | | - Mihai Rimbaş
- Gastroenterology, Colentina Clinical Hospital, Bucharest, Romania
- Internal Medicine Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | | | - Roy L J van Wanrooij
- Gastroenterology and Hepatology, Amsterdam UMC Locatie VUmc, Amsterdam, Netherlands
| | - George Webster
- Pancreatobiliary Medicine Unit, University College London, London, United Kingdom of Great Britain and Northern Ireland
| | - Konstantinos Triantafyllou
- Hepatogastroenterology Unit, 2nd Department of Internal Medicine, Propaedeutic, Medical School, National and Kapodistrian University of Athens, "Attikon" University General Hospital, Athens, Greece
| |
Collapse
|
|
4
|
Kersten R, Trampert DC, Hubers LM, Tolenaars D, Vos HR, van de Graaf SFJ, Beuers U. Galectin-3 and prohibitin 1 are autoantigens in IgG4-related cholangitis without clear-cut protective effects against toxic bile acids. Front Immunol 2024; 14:1251134. [PMID: 38332916 PMCID: PMC10851949 DOI: 10.3389/fimmu.2023.1251134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 12/15/2023] [Indexed: 02/10/2024] Open
Abstract
Background and aims IgG4-related cholangitis (IRC) is the hepatobiliary manifestation of IgG4-related disease, a systemic B cell-driven fibro-inflammatory disorder. Four autoantigens have recently been described in IgG4-RD: annexin A11, galectin-3, laminin 511-E8, and prohibitin 1. We have previously reported a protective role of annexin A11 and laminin 511-E8 in human cholangiocytes against toxic bile acids. Here, we explored the potentially protective role of the carbohydrate-binding lectin galectin-3 and the scaffold proteins prohibitins 1 and 2. Methods Anti-galectin-3, anti-prohibitin 1 and 2 autoantibody positivity in IRC and healthy and disease (primary sclerosing cholangitis (PSC)) control sera was assessed by ELISA/liquid chromatography-tandem mass spectrometry (LC-MS/MS). Human H69 cholangiocytes were subjected to short hairpin RNA (shRNA) knockdown targeting galectin-3 (LGALS3), prohibitin 1 (PHB1), and prohibitin 2 (PHB2). H69 cholangiocytes were also exposed to recombinant galectin-3, the inhibitor GB1107, recombinant prohibitin 1, and the pan-prohibitin inhibitor rocaglamide. Protection against bile acid toxicity was assessed by intracellular pH (pHi) measurements using BCECF-AM, 22,23-3H-glycochenodeoxycholic acid (3H-GCDC) influx, and GCDC-induced apoptosis using Caspase-3/7 assays. Results Anti-galectin-3 autoantibodies were detected in 13.5% of individuals with IRC but not in PSC. Knockdown of LGALS3 and galectin-3 inhibition with GB1107 did not affect pHi, whereas recombinant galectin-3 incubation lowered pHi. LGALS3 knockdown increased GCDC-influx but not GCDC-induced apoptosis. GB1107 reduced GCDC-influx and GCDC-induced apoptosis. Recombinant galectin-3 tended to decrease GCDC-influx and GCDC-induced apoptosis. Anti-prohibitin 1 autoantibodies were detected in 61.5% and 35.7% of individuals with IRC and PSC, respectively. Knockdown of PHB1, combined PHB1/2 KD, treatment with rocaglamide, and recombinant prohibitin 1 all lowered pHi. Knockdown of PHB1, PHB2, or combined PHB1/2 did not alter GCDC-influx, yet knockdown of PHB1 increased GCDC-induced apoptosis. Conversely, rocaglamide reduced GCDC-influx but did not attenuate GCDC-induced apoptosis. Recombinant prohibitin 1 did not affect GCDC-influx or GCDC-induced apoptosis. Finally, anti-galectin-3 and anti-prohibitin 1 autoantibody pretreatment did not lead to increased GCDC-influx. Conclusions A subset of individuals with IRC have autoantibodies against galectin-3 and prohibitin 1. Gene-specific knockdown, pharmacological inhibition, and recombinant protein substitution did not clearly disclose a protective role of these autoantigens in human cholangiocytes against toxic bile acids. The involvement of these autoantibodies in processes surpassing epithelial secretion remains to be elucidated.
Collapse
Affiliation(s)
- Remco Kersten
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - David C. Trampert
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Lowiek M. Hubers
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Dagmar Tolenaars
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Harmjan R. Vos
- Oncode Institute and Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, Netherlands
| | - Stan F. J. van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Ulrich Beuers
- Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, Netherlands
| |
Collapse
|
|
5
|
Gialanella JP, Steidl T, Korpela K, Grandhi MS, Langan RC, Alexander HR, Hudacko RM, Ecker BL. Hepatic pseudotumor associated with Strongyloides infection: A case report. World J Hepatol 2023; 15:1338-1343. [PMID: 38223414 PMCID: PMC10784808 DOI: 10.4254/wjh.v15.i12.1338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/21/2023] [Accepted: 11/29/2023] [Indexed: 12/25/2023] Open
Abstract
BACKGROUND Strongyloides sterocoralis is a parasitic infection caused by a roundworm that is transmitted through soil contaminated with larvae. It can infrequently cause hepatic abscesses in immunocompromised patients and is rarely reported to form hepatic lesions in immunocompetent hosts. CASE SUMMARY We present a case study of a 45-year-old female who presented with right upper quadrant abdominal pain and constitutional symptoms for several weeks. Cross-sectional imaging identified several malignant-appearing liver masses. Further investigation, including serological testing and histopathologic examination, revealed the presence of serum Strongyloides antibodies and hepatic granulomas with extensive necrosis. Following treatment with ivermectin for 2 wk, there was complete resolution of the liver lesions and associated symptoms. CONCLUSION This case highlights the importance of considering parasitic infections, such as Strongyloides, in the differential diagnosis of hepatic masses. Early recognition and appropriate treatment can lead to a favorable outcome and prevent unnecessary invasive procedures. Increased awareness among clinicians is crucial to ensure the timely diagnosis and management of such cases.
Collapse
Affiliation(s)
- Jessica P Gialanella
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, United States
| | - Tyler Steidl
- Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Kokkola Korpela
- Department of Infectious Disease, Cooperman Barnabas Medical Center, Livingston, NJ 07039, United States
| | - Miral S Grandhi
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, United States
| | - Russell C Langan
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, United States
| | - H Richard Alexander
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, United States
| | - Rachel M Hudacko
- Department of Pathology and Labratory Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States
| | - Brett L Ecker
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, United States.
| |
Collapse
|
|
6
|
Kersten R, Trampert DC, Herta T, Hubers LM, Maillette de Buy Wenniger LJ, Verheij J, van de Graaf SFJ, Beuers U. IgG4-related cholangitis - a mimicker of fibrosing and malignant cholangiopathies. J Hepatol 2023; 79:1502-1523. [PMID: 37598939 DOI: 10.1016/j.jhep.2023.08.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 07/24/2023] [Accepted: 08/14/2023] [Indexed: 08/22/2023]
Abstract
IgG4-related cholangitis (IRC) is the major hepatobiliary manifestation of IgG4-related disease (IgG4-RD), a systemic fibroinflammatory disorder. The pathogenesis of IgG4-RD and IRC is currently viewed as multifactorial, as there is evidence of a genetic predisposition while environmental factors, such as blue-collar work, are major risk factors. Various autoantigens have been described in IgG4-RD, including annexin A11 and laminin 511-E8, proteins which may exert a partially protective function in cholangiocytes by enhancing secretion and barrier function, respectively. For the other recently described autoantigens, galectin-3 and prohibitin 1, a distinct role in cholangiocytes appears less apparent. In relation to these autoantigens, oligoclonal expansions of IgG4+ plasmablasts are present in patients with IRC and disappear upon successful treatment. More recently, specific T-cell subtypes including regulatory T cells, follicular T helper 2 cells, peripheral T helper cells and cytotoxic CD8+ and CD4+ SLAMF7+ T cells have been implicated in the pathogenesis of IgG4-RD. The clinical presentation of IRC often mimics other biliary diseases such as primary sclerosing cholangitis or cholangiocarcinoma, which may lead to inappropriate medical and potentially invalidating surgical interventions. As specific biomarkers are lacking, diagnosis is made according to the HISORt criteria comprising histopathology, imaging, serology, other organ manifestations and response to therapy. Treatment of IRC aims to prevent or alleviate organ damage and to improve symptoms and consists of (i) remission induction, (ii) remission maintenance and (iii) long-term management. Glucocorticosteroids are highly effective for remission induction, after which immunomodulators can be introduced for maintenance of remission as glucocorticosteroid-sparing alternatives. Increased insight into the pathogenesis of IRC will lead to improved diagnosis and novel therapeutic strategies in the future.
Collapse
Affiliation(s)
- Remco Kersten
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - David C Trampert
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Toni Herta
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands; Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Lowiek M Hubers
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | | | - Joanne Verheij
- Department of Pathology, Amsterdam University Medical Centers, the Netherlands
| | - Stan F J van de Graaf
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, Tytgat Institute for Liver and Intestinal Research, AGEM, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
| |
Collapse
|
|
7
|
Wu S, Wang H. IgG4-related digestive diseases: diagnosis and treatment. Front Immunol 2023; 14:1278332. [PMID: 37868965 PMCID: PMC10585276 DOI: 10.3389/fimmu.2023.1278332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 09/22/2023] [Indexed: 10/24/2023] Open
Abstract
IgG4-related digestive diseases encompass a group of chronic inflammatory disorders characterized by autoimmune reactions and fibrosis affecting multiple digestive organs. These diseases are identified by elevated serum levels of IgG4 and the presence of IgG4-positive plasma cell infiltration in the affected sites, along with storiform fibrosis, obliterative phlebitis, and eosinophilic infiltration. Although extensive research has been conducted, a comprehensive understanding of these conditions remains elusive. Current clinical diagnosis often relies on the application of integrated diagnostic criteria for IgG4-related diseases, combined with specific organ involvement criteria. Distinguishing them from malignancies poses considerable challenges. Moreover, further investigations are required to elucidate the underlying pathogenic mechanisms and explore potential therapeutic interventions. This review provides a systematic classification of IgG4-related digestive diseases while discussing their diagnostic strategies, clinical presentations, and treatment modalities. The comprehensive insights shared herein aim to guide clinicians in their practice and contribute to the advancement of knowledge in this field.
Collapse
Affiliation(s)
- Siyu Wu
- Graduate School, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Haiqiang Wang
- Department of Internal Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| |
Collapse
|
|
8
|
Abstract
Hepatic inflammatory pseudotumor (IPT) describes a mass lesion composed of fibroblasts or myofibroblasts with a dense inflammatory infiltrate comprising lymphocyte, plasma cells, and histiocytes. These lesions are presumed to be an exuberant response to an infectious organism, although in most cases the causative agent is unknown. In specific circumstances, pathologists should consider ancillary techniques to exclude specific infections, such as mycobacteria, Candida, or syphilis. IgG4-related disease may cause a plasma-cell rich IPT. Finally, true neoplasms can mimic IPTs and must be excluded with appropriate ancillary studies, including inflammatory myofibroblastic tumor, follicular dendritic cell tumor, inflammatory angiomyolipoma, Hodgkin lymphoma, and inflammatory hepatocellular carcinoma.
Collapse
Affiliation(s)
- Donghai Wang
- Department of Pathology, New York University Grossman School of Medicine, NYU Langone Health, 560 First Avenue TH-483, New York, NY 10016, USA
| | - Joseph Misdraji
- Department of Pathology, Yale School of Medicine, Yale New Haven Hospital, 20 York Street EP2-611, New Haven, CT 06510, USA.
| |
Collapse
|
|
9
|
Cho SH, Song TJ, Park JS, Yoon JH, Yang MJ, Yoon SB, Lee JM, Lee YN, Kim SH, Choi EK, Park SW, Oh D, Park DH, Lee SS, Seo DW, Lee SK, Kim MH. Comparison of the long-term outcomes between proximal and distal IgG4-related sclerosing cholangitis: A multicenter cohort study. J Gastroenterol Hepatol 2023; 38:648-655. [PMID: 36710432 DOI: 10.1111/jgh.16136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 01/11/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND AIMS Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is considered a biliary manifestation of IgG4-related diseases. However, there has been a controversy on the clinical outcomes according to the location of the involved bile duct. We therefore compared the clinical outcomes and long-term prognosis of IgG4-SC with proximal bile duct involvement (proximal IgG4-SC) and IgG4-SC with distal bile duct involvement (distal IgG4-SC). METHODS We reviewed the data of patients with IgG4-SC that were prospectively collected at 10 tertiary centers between March 2002 and October 2020. Clinical manifestations, outcomes, association with autoimmune pancreatitis (AIP), steroid-responsiveness, and relapse of IgG4-SC were evaluated. RESULTS A total of 148 patients (proximal IgG4-SC, n = 59; distal IgG4-SC, n = 89) were analyzed. The median age was 65 years (IQR, 56.25-71), and 86% were male. The two groups were similar in terms of jaundice at initial presentation (51% vs 65%; P = 0.082) and presence of elevated serum IgG4 (66% vs 70%; P = 0.649). The two groups showed significant differences in terms of steroid-responsiveness (91% vs 100%; P = 0.008), association with AIP (75% vs 99%; P = 0.001), and occurrence of liver cirrhosis (9% vs 1%; P = 0.034). During a median follow-up of 64 months (IQR, 21.9-84.7), the cumulative relapse-free survival was significantly different between the two groups (67% vs 79% at 5 years; P = 0.035). CONCLUSIONS Relapse of IgG4-SC frequently occurred during follow-up. Proximal IgG4-SC and distal IgG4-SC had different long-term outcomes in terms of steroid-responsiveness, occurrence of liver cirrhosis, and recurrence. It may be advantageous to determine the therapeutic and follow-up strategies according to the location of bile duct involvement.
Collapse
Affiliation(s)
- Sung Hyun Cho
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Tae Jun Song
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Jin-Seok Park
- Division of Gastroenterology, Department of Internal Medicine, Inha University School of Medicine, Incheon, South Korea
| | - Jai Hoon Yoon
- Division of Gastroenterology, Department of Internal medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, South Korea
| | - Min Jae Yang
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, South Korea
| | - Seung Bae Yoon
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jae Min Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Yun Nah Lee
- Department of Gastroenterology, Soonchunhyang University School of Medicine, Bucheon, South Korea
| | - Seong-Hun Kim
- Division of Gastroenterology, Department of Internal Medicine, Jeonbuk National University Medical School, Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju, South Korea
| | - Eun Kwang Choi
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, South Korea
| | - Se Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Gyeonggi-do, South Korea
| | - Dongwook Oh
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Do Hyun Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Sang Soo Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Dong-Wan Seo
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Sung Koo Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Myung-Hwan Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| |
Collapse
|
|
10
|
Möller K, Braden B, Culver EL, Jenssen C, Zadeh ES, Alhyari A, Görg C, Ignee A, Hocke M, Dong Y, Sun S, Faiss S, Dietrich CF. Secondary sclerosing cholangitis and IgG4-sclerosing cholangitis - A review of cholangiographic and ultrasound imaging. Endosc Ultrasound 2023; 12:181-199. [PMID: 36588352 PMCID: PMC10237613 DOI: 10.4103/eus-d-22-00208] [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: 11/20/2022] [Accepted: 12/08/2022] [Indexed: 01/01/2023] Open
Abstract
Sclerosing cholangitis (SC) represents a spectrum of chronic progressive cholestatic diseases of the intrahepatic and/or extrahepatic biliary system characterized by patchy inflammation, fibrosis, and stricturing. Primary and secondary SC must be distinguished given the different treatment modalities, risks of malignancy, and progression to portal hypertension, cirrhosis, and hepatic failure. This review focuses on secondary SC and the pathogenic mechanisms, risk factors, clinical presentation, and novel imaging modalities that help to distinguish between these conditions. We explore the detailed use of cholangiography and ultrasound imaging techniques.
Collapse
Affiliation(s)
- Kathleen Möller
- Medical Department I/Gastroenterology, Sana Hospital Lichtenberg, Berlin, Germany
| | - Barbara Braden
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| | - Emma L. Culver
- Translational Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
| | - Christian Jenssen
- Department of Internal Medicine, Krankenhaus Märkisch Oderland GmbH, Strausberg, Wriezen, Germany
- Brandenburg Institute of Clinical Medicine at Medical University Brandenburg, Neuruppin, Germany
| | - Ehsan Safai Zadeh
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - Amjad Alhyari
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - Christian Görg
- Interdisciplinary Center of Ultrasound Diagnostics, University Hospital Giessen and Marburg, Philipps University Marburg, Marburg, Germany
| | - André Ignee
- Department of Internal Medicine – Gastroenterology and Rheumatology; Klinikum Wuerzburg Mitte, Wuerzburg, Germany
| | - Michael Hocke
- Medical Department II, Helios Klinikum Meiningen, Meiningen, Germany
| | - Yi Dong
- Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Siyu Sun
- Department of Endoscopy Center, Shengjing Hospital of China Medical University, Liaoning Province, China
| | - Siegbert Faiss
- Medical Department I/Gastroenterology, Sana Hospital Lichtenberg, Berlin, Germany
| | - Christoph F. Dietrich
- Department of Internal Medicine (DAIM), Hirslanden Private Hospital, Beau Site, Salem und Permanence, Bern, Switzerland
| |
Collapse
|
|
11
|
Diagnosis of Cholangiocarcinoma. Diagnostics (Basel) 2023; 13:diagnostics13020233. [PMID: 36673043 PMCID: PMC9858255 DOI: 10.3390/diagnostics13020233] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Cholangiocarcinoma (CCA), a tumor of the bile duct epithelium, is increasing in incidence. CCA remains a highly fatal malignancy because early diagnosis is difficult. Based on its anatomical location, CCA can be categorized into the following three groups: perihilar, intrahepatic, and extrahepatic. Patients with CCA complain of asymptomatic jaundice, weight loss, and right upper quadrant abdominal discomfort. Imaging modalities, including transabdominal ultrasound, computed tomography, and magnetic resonance imaging, play an important role in detecting tumors as well as guiding biopsy procedures and staging workups in CCA. Characteristically, extrahepatic CCA shows abrupt changes in ductal diameter with upstream ductal dilation. Endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) are recommended as the next step in the evaluation of extrahepatic CCA. Tissue is obtained through EUS-FNA or ERCP (biopsy, brush cytology), and therapeutic intervention (such as stent insertion) is performed with ERCP. Moreover, several serum tumor markers (carbohydrate antigen 19-9 and carcinoembryonic antigen) can be useful in diagnosing CCA in some patients.
Collapse
|
|
12
|
Vergoossen DLE, Ruiter AM, Keene KR, Niks EH, Tannemaat MR, Strijbos E, Lipka AF, van der Zijde ECJ, van Tol MJD, Bakker JA, Wevers BA, Westerberg E, Borges LS, Tong OC, Richman DP, Illa I, Punga AR, Evoli A, van der Maarel SM, Verschuuren JJ, Huijbers MG. Enrichment of serum IgG4 in MuSK myasthenia gravis patients. J Neuroimmunol 2022; 373:577978. [PMID: 36240543 DOI: 10.1016/j.jneuroim.2022.577978] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/26/2022] [Accepted: 10/05/2022] [Indexed: 11/05/2022]
Abstract
Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.
Collapse
Affiliation(s)
- Dana L E Vergoossen
- Department of Human Genetics, Leiden University Medical Centre LUMC, Einthovenweg 20, 2300 RC Leiden, the Netherlands
| | - Annabel M Ruiter
- Department of Neurology, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Kevin R Keene
- Department of Neurology, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Erik H Niks
- Department of Neurology, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Martijn R Tannemaat
- Department of Neurology, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Ellen Strijbos
- Department of Neurology, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Alexander F Lipka
- Department of Neurology, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Els C Jol van der Zijde
- Willem-Alexander Children's Hospital, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Maarten J D van Tol
- Willem-Alexander Children's Hospital, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Jaap A Bakker
- Department of Clinical Chemistry, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Brigitte A Wevers
- Department of Clinical Chemistry, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Elisabet Westerberg
- Clinical Neurophysiology, Department of Medical Sciences, Uppsala University, Akademiska sjukhuset, Ingång 85, 3rd floor, 751 85 Uppsala, Sweden
| | - Lúcia S Borges
- Department of Neurology, University of California Davis, 1515 Newton Court, Davis, CA 95618, USA
| | - Olivia C Tong
- Department of Neurology, University of California Davis, 1515 Newton Court, Davis, CA 95618, USA
| | - David P Richman
- Department of Neurology, University of California Davis, 1515 Newton Court, Davis, CA 95618, USA
| | - Isabel Illa
- Neuromuscular diseases Neurology department, Hospital Sant Pau UAB, Avenida Pare Claret N° 167, Barcelona 08025, Spain
| | - Anna Rostedt Punga
- Clinical Neurophysiology, Department of Medical Sciences, Uppsala University, Akademiska sjukhuset, Ingång 85, 3rd floor, 751 85 Uppsala, Sweden
| | - Amelia Evoli
- Department of Neurology, Università Cattolica del Sacro Cuore, Largo A. Gemelli 1, 00168 Rome, Italy
| | - Silvère M van der Maarel
- Department of Human Genetics, Leiden University Medical Centre LUMC, Einthovenweg 20, 2300 RC Leiden, the Netherlands
| | - Jan J Verschuuren
- Department of Neurology, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands
| | - Maartje G Huijbers
- Department of Human Genetics, Leiden University Medical Centre LUMC, Einthovenweg 20, 2300 RC Leiden, the Netherlands; Department of Neurology, Leiden University Medical Centre LUMC, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
| |
Collapse
|
|
13
|
Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
Collapse
|
|
14
|
Chen Z, Lu H, Xu J, Ma L. A case of hilar biliary cystadenoma with elevated IgG4 levels. Intractable Rare Dis Res 2022; 11:158-160. [PMID: 36200029 PMCID: PMC9438001 DOI: 10.5582/irdr.2022.01076] [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: 07/18/2022] [Revised: 08/16/2022] [Accepted: 08/21/2022] [Indexed: 11/05/2022] Open
Abstract
Cholangiocytic adenoma in the hilar bile duct is rare, and elevated IgG4 at the same time is extremely rare. This situation has not been reported in the literature. Nonetheless, the current case involved hilar biliary cystadenoma with elevated IgG4 levels. A 66-year-old man presented at this hospital with dark tea-colored urine. Preoperative imaging studies suggested hilar cholangiocarcinoma. This case demonstrates the difficulty of preoperative diagnosis of benign hilar lesions and the rarity of two combined benign lesions. A point of contention is whether this case should be treated with surgery or hormone therapy.
Collapse
Affiliation(s)
| | | | | | - Liang Ma
- Address correspondence to:Liang Ma, Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Nanning, Guangxi, 530021, China. E-mail:
| |
Collapse
|
|
15
|
Park JK, Kim D, Lee JM, Lee KH, Lee KT, Park JK, Lee JK. 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). J Pers Med 2022; 12:855. [PMID: 35743640 PMCID: PMC9225113 DOI: 10.3390/jpm12060855] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/10/2022] [Accepted: 05/21/2022] [Indexed: 11/16/2022] Open
Abstract
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.
Collapse
Affiliation(s)
- Jae Keun Park
- Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07441, Korea;
| | - Dongwuk Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (D.K.); (J.M.L.); (K.H.L.); (K.T.L.); (J.K.P.)
| | - Jeong Min Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (D.K.); (J.M.L.); (K.H.L.); (K.T.L.); (J.K.P.)
| | - Kwang Hyuck Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (D.K.); (J.M.L.); (K.H.L.); (K.T.L.); (J.K.P.)
- Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul 16419, Korea
| | - Kyu Taek Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (D.K.); (J.M.L.); (K.H.L.); (K.T.L.); (J.K.P.)
| | - Joo Kyung Park
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (D.K.); (J.M.L.); (K.H.L.); (K.T.L.); (J.K.P.)
| | - Jong Kyun Lee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (D.K.); (J.M.L.); (K.H.L.); (K.T.L.); (J.K.P.)
| |
Collapse
|
|
16
|
Löhr JM, Vujasinovic M, Rosendahl J, Stone JH, Beuers U. IgG4-related diseases of the digestive tract. Nat Rev Gastroenterol Hepatol 2022; 19:185-197. [PMID: 34750548 DOI: 10.1038/s41575-021-00529-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/22/2021] [Indexed: 12/15/2022]
Abstract
IgG4-related conditions affecting the digestive tract are part of a multi-organ fibro-inflammatory disorder termed IgG4-related disease (IgG4-RD), with autoimmune pancreatitis and IgG4-related cholangitis being the most prominent manifestations. Gastrointestinal symptoms include jaundice, weight loss, abdominal pain, biliary strictures, and pancreatic and hepatic masses that mimic malignant diseases. IgG4-RD manifestations occur less frequently elsewhere in the digestive tract, namely in the oesophagus, retroperitoneum or intestine. Evidence-based European guidelines frame the current state-of-the-art in the diagnosis and management of IgG4-related digestive tract disease. Diagnosis is based on histology (if available), imaging, serology, other organ involvement and response to therapy (HISORt criteria). Few biomarkers beyond serum IgG4 concentrations are reliable. The first-line therapy (glucocorticoids) is swiftly effective but disease flares are common at low doses or after tapering. Second-line therapy might consist of other immunosuppressive drugs such as thiopurines or rituximab. Further trials, for example, of anti-CD19 drugs, are ongoing. Although an association between IgG4-RD and the development of malignancies has been postulated, the true nature of this relationship remains uncertain at this time.
Collapse
Affiliation(s)
- J-Matthias Löhr
- Department for Upper Digestive Diseases, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
| | - Miroslav Vujasinovic
- Department for Upper Digestive Diseases, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Jonas Rosendahl
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - John H Stone
- Division of Rheumatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, Location AMC, Amsterdam, Netherlands
| |
Collapse
|
|
17
|
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.
Collapse
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
| |
Collapse
|
|
18
|
Nikolic S, Ghorbani P, Pozzi Mucelli R, Ghazi S, Baldaque-Silva F, Del Chiaro M, Sparrelid E, Verbeke CS, Löhr JM, Vujasinovic M. Surgery in Autoimmune Pancreatitis. Dig Surg 2021; 39:32-41. [PMID: 34915509 PMCID: PMC8985041 DOI: 10.1159/000521490] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/28/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Autoimmune pancreatitis (AIP) is a disease that may mimic malignant pancreatic lesions both in terms of symptomatology and imaging appearance. The aim of the present study is to analyze experiences of surgery in patients with AIP in one of the largest European cohorts. PATIENTS AND METHODS We performed a single-center retrospective study of patients diagnosed with AIP at the Department of Abdominal Diseases at Karolinska University Hospital in Stockholm, Sweden, between January 2001 and October 2020. RESULTS There were 159 patients diagnosed with AIP, and among them, 35 (22.0%) patients had surgery: 20 (57.1%) males and 15 (42.9%) females; median age at surgery was 59 years (range 37-81). Median follow-up period after surgery was 50 months (range 1-235). AIP type 1 was diagnosed in 28 (80%) patients and AIP type 2 in 7 (20%) patients. Malignant and premalignant lesions were diagnosed in 8 (22.9%) patients for whom AIP was not the primary differential diagnosis, but in all cases, it was described as a simultaneous finding and recorded in retrospective analysis in histological reports of surgical specimens. CONCLUSIONS Diagnosis of AIP is not always straightforward, and in some cases, it is not easy to differentiate it from the malignancy. Surgery is generally not indicated for AIP but might be considered in patients when suspicion of malignant/premalignant lesions cannot be excluded after complete diagnostic workup.
Collapse
Affiliation(s)
- Sara Nikolic
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Gastroenterology, Clinic for Internal Medicine, University Medical Centre Maribor, Maribor, Slovenia
| | - Poya Ghorbani
- Department of Clinical Science, Intervention, and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Raffaella Pozzi Mucelli
- Department of Clinical Science, Intervention, and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
- Department of Abdominal Radiology, Karolinska University Hospital, Stockholm, Sweden
| | - Sam Ghazi
- Department of Pathology, Karolinska University Hospital, Stockholm, Sweden
| | - Francisco Baldaque-Silva
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Marco Del Chiaro
- Department of Clinical Science, Intervention, and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Aurora, Colorado, USA
| | - Ernesto Sparrelid
- Department of Clinical Science, Intervention, and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Caroline S. Verbeke
- Department of Pathology, Karolinska University Hospital, Stockholm, Sweden
- Department of Pathology, Oslo University Hospital, Oslo, and University of Oslo, Oslo, Norway
| | - J.-Matthias Löhr
- Department of Clinical Science, Intervention, and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Miroslav Vujasinovic
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
19
|
Yuzawa M, Ohta H, Nomura M, Minegishi K, Oshiro H, Yamaguchi Y. A case of prominent immunoglobulin G4-positive lymphadenopathy in response to microscopic lung cancer. Respirol Case Rep 2021; 9:e0854. [PMID: 34631102 PMCID: PMC8488362 DOI: 10.1002/rcr2.854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/30/2021] [Accepted: 09/12/2021] [Indexed: 11/06/2022] Open
Abstract
Immunoglobulin G4 (IgG4)-related disease is established as a new clinical entity, characterized by high levels of plasma IgG4 and IgG4-positive plasma cell infiltration. However, the elevation of plasma IgG4 and infiltration of IgG4-positive cells have been observed in other diseases, including malignancy. We experienced a case of prominent IgG4-positive lymphadenopathy, which was diagnosed as a reactive lesion in response to lung cancer. The cancerous lesion was so small in size that it was difficult to reveal the coexisting lung cancer. Surgical lymph node biopsy and endobronchial ultrasound-guided transbronchial needle aspiration did not reveal lymph node metastasis of cancer. Mediastinal lymph node dissection finally revealed it. After the right upper lobectomy, the patient underwent postoperative chemotherapy and remains cancer-free after 1 year. Our case suggests that close examination and careful follow-up are necessary when IgG4-positive lymphadenopathy is observed.
Collapse
Affiliation(s)
- Motoi Yuzawa
- Department of Respiratory Medicine, Saitama Medical CenterJichi Medical UniversitySaitamaJapan
| | - Hiromitsu Ohta
- Department of Respiratory Medicine, Saitama Medical CenterJichi Medical UniversitySaitamaJapan
| | - Motoko Nomura
- Department of Respiratory Medicine, Saitama Medical CenterJichi Medical UniversitySaitamaJapan
| | - Kentaro Minegishi
- Department of Thoracic Surgery, Saitama Medical CenterJichi Medical UniversitySaitamaJapan
| | - Hisashi Oshiro
- Department of Pathology, Saitama Medical CenterJichi Medical UniversitySaitamaJapan
| | - Yasuhiro Yamaguchi
- Department of Respiratory Medicine, Saitama Medical CenterJichi Medical UniversitySaitamaJapan
| |
Collapse
|
|
20
|
Song S, Jo S. Isolated mass-forming IgG4-related sclerosing cholangitis masquerading as extrahepatic cholangiocarcinoma: A case report. World J Clin Cases 2021; 9:8773-8781. [PMID: 34734055 PMCID: PMC8546832 DOI: 10.12998/wjcc.v9.i29.8773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/20/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND IgG4-related sclerosing cholangitis (IgG4-RSC) is an uncommon benign disease, and its rarer, isolated and mass-forming subtype poses a significant challenge to differential diagnosis from cholangiocarcinoma of the extrahepatic bile duct. We herein report a case of isolated IgG4-RSC with an obstructing bile duct mass, for which extrahepatic bile duct resection was performed under the impression of proximal common bile duct (CBD) cancer.
CASE SUMMARY A 79-year-old male was admitted for jaundice that had developed 1 mo prior. There was no family history for autoimmune diseases or biliary cancer. Computed tomography (CT) and magnetic resonance cholangiopancreaticography revealed a short segmental concentric wall thickening of the proximal CBD with diffuse dilatation of the bile duct to the periphery. The endoscopic biopsy specimen showed no malignant cells. Positron emission tomography-CT showed a focal hypermetabolic lesion (SUVmax 4.2) in and around the proximal CBD area. With the impression of proximal CBD cancer, we performed segmental resection of the extrahepatic bile duct. Histopathology demonstrated marked sclerosis with diffuse lymphoplasmacytic infiltration and some eosinophils. Immunohistochemical staining for IgG4 showed increased positivity in some areas (up to 30/high-power field) and IgG4+/IgG+ cell ratio as 30%-50%. Pathologists’ impression was IgG4-related sclerosing disease. Follow-up serum IgG4 levels were continuously elevated; however, no evidence of relapse or other organ involvement related to IgG4-RSC presented.
CONCLUSION Isolated and mass-forming IgG4-RSC displays striking similarity with cholangiocarcinoma. To avoid unnecessary major surgery, high index of suspicion is needed.
Collapse
Affiliation(s)
- Sanghyun Song
- Department of Surgery, Dankook University Hospital, Cheonan 31116, Chungnam Province, South Korea
| | - Sungho Jo
- Department of Surgery, Dankook University Hospital, Cheonan 31116, Chungnam Province, South Korea
| |
Collapse
|
|
21
|
Naitoh I, Nakazawa T. Classification and Diagnostic Criteria for IgG4-Related Sclerosing Cholangitis. Gut Liver 2021; 16:28-36. [PMID: 34380781 PMCID: PMC8761932 DOI: 10.5009/gnl210116] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/06/2021] [Accepted: 06/14/2021] [Indexed: 11/20/2022] Open
Abstract
IgG4-related sclerosing cholangitis (IgG4-SC) can be classified into four types based on cholangiographic findings and regions of biliary stricture. This cholangiographic classification is useful to differentiate IgG4-SC from mimickers including cholangiocarcinoma, primary sclerosing cholangitis, and pancreatic cancer. Autoimmune pancreatitis (AIP) is a valuable clue for the diagnosis of IgG4-SC because the two are frequently found in association with each other. Two sets of diagnostic criteria for IgG4-SC have been proposed. In Japan, the clinical diagnostic criteria 2020 were recently developed. These clinical diagnostic criteria include narrowing of the intrahepatic and/or extrahepatic bile duct, thickening of the bile duct wall, serological findings, pathological findings, other organ involvement, and effectiveness of steroid therapy. When these criteria are applied, IgG4-SC is initially classified as associated or not associated with AIP, and cholangiographic classification is used for differential diagnosis. In most instances, IgG4-SC can be diagnosed on the basis of clinical diagnostic criteria. However, it is challenging to diagnose isolated IgG4-SC or IgG4-SC not associated with AIP. Here, we review the classification and diagnostic criteria for IgG4-SC, specifically focusing on the clinical diagnostic criteria 2020 and a large IgG4-SC case series from a nationwide survey in Japan.
Collapse
Affiliation(s)
- Itaru Naitoh
- Department of Gastroenterology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takahiro Nakazawa
- Department of Gastroenterology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| |
Collapse
|
|
22
|
Fibrohistiocytic Variant of Hepatic Pseudotumor: An Antibiotic Responsive Tumefactive Lesion. Am J Surg Pathol 2021; 45:1314-1323. [PMID: 34334689 DOI: 10.1097/pas.0000000000001767] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory pseudotumor is a term used to designate inflammation-rich tumefactive lesions. Following the exclusion of specific entities such as IgG4-related disease and other neoplastic entities previously included in this entity, the majority of hepatic pseudotumors show a prominent fibrohistiocytic inflammatory reaction and have been previously categorized as fibrohistiocytic variant of hepatic pseudotumor (FHVHPT). The goal of this study was to examine the clinical, radiologic, histologic, and etiologic aspects of this entity. After excluding neoplastic diseases, we identified 30 patients with FHVHPT from 3 institutions between 2009 and 2019. We extracted demographic and clinical data, liver function tests as well as culture results and radiologic information. Hematoxylin and eosin-stained slides were reviewed for pattern of inflammation as well as its cellular composition. Immunohistochemistry for IgG4 and IgG was performed in all cases. The mean age of the 30 lesions characterized as FHVHPT was 56 years (range: 23 to 79 y). Nineteen patients showed solitary lesions; 11 were multiple. The mean size of the lesion was 3.8 cm (range: 1 to 7.5 cm). On imaging, a neoplastic process or metastasis was the leading diagnostic consideration (n=15, 50%). The most common symptom was abdominal pain (n=14/30); 8 patients presented with symptoms compatible with an infectious process, including fever. The inflammatory infiltrate was dominated by lymphocytes and plasma cells, and in most cases, a prominent histiocytic infiltrate (22/30). Neutrophils were identified in 12 cases, with microabscess noted in 8. Storiform pattern of fibrosis was seen in 14/30 cases; obliterative phlebitis was not identified. Culture identified a microorganism in 4 of 9 cases evaluated. The mean IgG4 count was 9.3 per HPF (range: 0 to 51) with 9 of the 26 (35%) biopsies showing >10 IgG4 positive plasma cells per HPF. The mean IgG4 to IgG ratio was 8% (range: 8% to 46%). A hepatectomy was performed in 4 cases. On broad spectrum antibiotics (n=14) the lesions either resolved or decreased in size. Eight patients did not receive specific therapy, nevertheless, the lesion(s) resolved spontaneously in 6 cases, remained stable or decreased in size in 2 cases. Notably, none of these patients showed evidence of a hepatic recurrence. FHVHPT, a tumefactive lesion that mimics hepatic neoplasia, is histologically characterized by a fibrohistiocytic infiltrate. In the majority of patients FHVHPT represents the organizing phase of hepatic abscess and can be successfully managed with antibiotic therapy.
Collapse
|
|
23
|
Hori Y, Chari ST, Tsuji Y, Takahashi N, Inoue D, Hart PA, Uehara T, Horibe M, Yamamoto S, Satou A, Zhang L, Notohara K, Naitoh I, Nakazawa T. Diagnosing Biliary Strictures: Distinguishing IgG4-Related Sclerosing Cholangitis From Cholangiocarcinoma and Primary Sclerosing Cholangitis. Mayo Clin Proc Innov Qual Outcomes 2021; 5:535-541. [PMID: 34195545 PMCID: PMC8240333 DOI: 10.1016/j.mayocpiqo.2021.03.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023] Open
Abstract
Biliary strictures caused by inflammation or fibrosis lead to jaundice and cholangitis which often make it difficult to distinguish malignant strictures. In cases when malignancy cannot be excluded, surgery is often performed. The concept of immunoglobulin G4 (IgG4)-related sclerosing cholangitis (SC) as a benign biliary stricture was recently proposed. The high prevalence of the disease in Asian countries has resulted in multiple diagnostic and treatment guidelines; however, there is need to formulate a standardized diagnostic strategy among various countries considering the utility, invasiveness, and cost-effectiveness. We evaluated accuracies of various diagnostic modalities for biliary strictures comparing pathology in the Delphi meetings which were held in Rochester, MN. The diagnostic utility for each modality was graded according to the experts, including gastroenterologists, endoscopists, radiologists, and pathologists from the United States and Japan. Diagnostic utility of 10 modalities, including serum IgG4 level, noninvasive imaging, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography-related diagnostic procedures were advocated and the reasons were specified. Serum IgG4 level, noninvasive imaging, diagnostic endoscopic ultrasound and intraductal ultrasonography under endoscopic retrograde cholangiopancreatography were recognized as useful modalities for the diagnosis. The information in this article will aid in the diagnosis of biliary strictures particularly for distinguishing IgG4-SC from cholangiocarcinoma and/or primary SC.
Collapse
Key Words
- AIP, autoimmune pancreatitis
- CT, computed tomography
- ERC, endoscopic retrograde cholangiography
- ERCP, endoscopic retrograde cholangiopancreatography
- EUS, endoscopic ultrasound
- FNA, fine-needle aspiration
- IDUS, intraductal ultrasonography
- IgG4, immunoglobulin G4
- IgG4-RD, IgG4-related disease
- IgG4-SC, IgG4-related sclerosing cholangitis
- MRCP, magnetic resonance cholangiopancreatography
- MRI, magnetic resonance imaging
- PSC, primary sclerosing cholangitis
Collapse
Affiliation(s)
- Yasuki Hori
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Suresh T. Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Yoshihisa Tsuji
- Department of General Medicine, Sapporo Medical University, Sapporo, Japan
| | | | - Dai Inoue
- Department of Radiology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University, Matsumoto, Japan
| | - Masayasu Horibe
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Satoshi Yamamoto
- Department of Gastroenterology, Bantane Hospital, Fujita Health University, Nagoya, Japan
| | - Akira Satou
- Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan
| | - Lizhi Zhang
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Kenji Notohara
- Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takahiro Nakazawa
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| |
Collapse
|
|
24
|
Björnsson ES, Kalaitzakis E. Recent advances in the treatment of primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol 2021; 15:413-425. [PMID: 33283566 DOI: 10.1080/17474124.2021.1860751] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: PSC is a rare liver disease that leads frequently to cirrhosis and need for liver transplantation. No medical treatment is of proven value. Liver transplantation is the only curative therapy available. There is a big medical need to find medical therapy that can alter the natural history of the disease.Areas covered: The authors highlight advances in PSC, based on recent literature retrieved from PubMed until September 2020 regarding both medical and endoscopic biliary therapy.Future possibilities for treatment of PSC are discussed.Expert opinion: Biliary endoscopy is the cornerstone in the treatment of dominant strictures. Single-user peroral cholangioscopy is an emerging modality. Balloon dilatation therapy is the treatment of choice of dominant strictures. The most promising medical therapies showing efficacy in phase II trials are nor-Ursodeoxycholic acid, obethicolic acid, the non-steroidal FXR agonist Cilofexor and Aldafermin, a synthetic analogue of FGF-19. Antibiotics, particularly vancomycin have shown potential benefits, particularly in children but phase III studies are lacking. In observational studies of effects of biological therapy in patients with IBD/PSC adalimumab was associated with reduction in ALP. Results of liver transplantation are favorable but recurrence can be of clinical relevance particularly in patients transplanted before the age of 40.
Collapse
Affiliation(s)
- Einar S Björnsson
- Department of Internal Medicine, Faculty of Medicine, University of Iceland, Division of Gastroenterology and Hepatology, Landspitali University Hospital of Iceland
| | - Evangelos Kalaitzakis
- Department of Internal Medicine, University Hospital Heraklion, Faculty of Medicine, University of Crete, Rethymno, Greece
| |
Collapse
|
|
25
|
Zhu K, Yang J, Chen YZ, Zhang XR, Yu XH, Wang J, Zhang R, Liu C. Differences in Clinical Features and Diagnostic Strategies Between IgG4-Related Autoimmune Cholangitis and Cholangiocarcinoma. Front Oncol 2021; 11:540904. [PMID: 33816216 PMCID: PMC8012807 DOI: 10.3389/fonc.2021.540904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 01/18/2021] [Indexed: 11/13/2022] Open
Abstract
IgG4-related autoimmune cholangitis (IgG4-AIC) is often difficult to distinguish from cholangiocarcinoma (CCA). This study aimed to determine a practical clinical strategy for distinguishing between IgG4-AIC and CCA to avoid unnecessary surgical resection. We retrospectively collected and compared the clinicopathological data between IgG4-AIC and CCA patients, including the clinical, serological, and radiological characteristics, to follow up on these patients to investigate the prognosis. Among the 377 patients who received surgical resection for suspecting CCA at the Sun Yat-Sen Memorial Hospital between June 2004 and June 2014, 14 patients were diagnosed as IgG4-AIC through histochemistry after surgery. Immunohistochemistry revealed that IgG4 was up-regulated in the plasma cells of IgG4-AIC tissues in 13 out of 14 patients. The serum CA19-9 level was significantly lower than in the CCA group. Patients with IgG4-AIC can only see slight or no enhancement under the contrast enhancement CT scan, while there are no signs of ring-like or delayed enhancement that is unique to CCA. Thirteen patients were followed up, and the time was 12 to 92 months. Three of them were regularly treated with prednisone after surgery, and original symptoms disappeared. Our study demonstrated that the combination of imaging with serum CA19-9 could improve the preoperative diagnostic value and reduce the rate of unnecessary resection.
Collapse
Affiliation(s)
- Ke Zhu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jin Yang
- Department of Hepatobiliary Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Ying-Zhen Chen
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xue-Rong Zhang
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xian-Huan Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jie Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Rui Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Chao Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation and Department of Biliary-Pancreatic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
26
|
Akahoshi M, Arinobu Y, Kashiwado Y, Omoto A, Ayano M, Mitoma H, Kimoto Y, Ono N, Horiuchi T, Niiro H. IgG4-related disease presenting as a paraneoplastic syndrome: report of two cases and literature review. Mod Rheumatol Case Rep 2021; 5:371-376. [PMID: 33719923 DOI: 10.1080/24725625.2021.1896096] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
An association between immunoglobulin G4-related disease (IgG4-RD) and malignancy has been suggested. We report two cases of IgG4-RD with suspected paraneoplastic syndrome. In both patients, malignancy was observed immediately after diagnosis of IgG4-RD, and surgical resection resulted in spontaneous regression of IgG4-RD. We review the reports on IgG4-RD associated with malignancy, including these two cases, and discuss their relevance.
Collapse
Affiliation(s)
- Mitsuteru Akahoshi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yojiro Arinobu
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yusuke Kashiwado
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Aya Omoto
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Masahiro Ayano
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Hiroki Mitoma
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yasutaka Kimoto
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Oita, Japan
| | - Nobuyuki Ono
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takahiko Horiuchi
- Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Oita, Japan
| | - Hiroaki Niiro
- Department of Medical Education, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| |
Collapse
|
|
27
|
Tanisaka Y, Mizuide M, Fujita A, Ogawa T, Suzuki M, Katsuda H, Saito Y, Miyaguchi K, Tashima T, Mashimo Y, Ryozawa S. Diagnostic Process Using Endoscopy for Biliary Strictures: A Narrative Review. J Clin Med 2021; 10:jcm10051048. [PMID: 33802525 PMCID: PMC7961606 DOI: 10.3390/jcm10051048] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/17/2021] [Accepted: 02/27/2021] [Indexed: 12/13/2022] Open
Abstract
The diagnostic process for biliary strictures remains challenging in some cases. A broad differential diagnosis exists for indeterminate biliary strictures, including benign or malignant lesions. The diagnosis of indeterminate biliary strictures requires a combination of physical examination, laboratory testing, imaging modalities, and endoscopic procedures. Despite the progress of less invasive imaging modalities such as transabdominal ultrasonography, computed tomography, and magnetic resonance imaging, endoscopy plays an essential role in the accurate diagnosis, including the histological diagnosis. Imaging findings and brush cytology and/or forceps biopsy under fluoroscopic guidance with endoscopic retrograde cholangiopancreatography (ERCP) are widely used as the gold standard for the diagnosis of biliary strictures. However, ERCP cannot provide an intraluminal view of the biliary lesion, and its outcomes are not satisfactory. Recently, peroral cholangioscopy, confocal laser endomicroscopy, endoscopic ultrasound (EUS), and EUS-guided fine-needle aspiration have been reported as useful for indeterminate biliary strictures. Appropriate endoscopic modalities need to be selected according to the patient's condition, the lesion, and the expertise of the endoscopist. The aim of this review article is to discuss the diagnostic process for indeterminate biliary strictures using endoscopy.
Collapse
|
|
28
|
Feng L, You Z, Ma D, Yan L, Cheng H, Gou J, Chen L. Immunoglobulin (Ig) G4-related sclerosing cholangitis in patients resected for presumed perihilar cholangiocarcinoma: a 10-year experience. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:415. [PMID: 33842636 PMCID: PMC8033389 DOI: 10.21037/atm-21-140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background This study aimed to investigate the incidence of immunoglobulin (Ig) G4-related sclerosing cholangitis (IgG4-SC) in patients resected for perihilar cholangiocarcinoma (PHC) in a designated hospital from 2010 to 2019. We also aimed to evaluate the diagnostic dilemma of IgG4-SC clinically. Methods Between January 2010 and December 2019, all patients who underwent radical resection due to presumed PHC were included. Independent pathologists scored bile duct samples based on the International Consensus Pathology Criteria for IgG4-related Disease (ICPD). Results Of the 289 patients who underwent radical resection of primary liver cancer, 26 (9%) were diagnosed as benign, without histological evidence of malignancy, among them, 23 had sclerosing inflammation, 1 had cystadenoma, and 2 had xanthogranulomatous cholangitis. Additionally, 18 had a definitive diagnosis of IgG4-SC. The misdiagnosis rate was 19% (54/289), of which, 26 patients had benign disease, and 28 patients had malignancies. Conclusions It is difficult to distinguish IgG-SC from PHC. The misdiagnosis has resulted in a large number of ineffective hepatectomies. Improving the detection rate of serum IgG4 (sIgG4) may therefore avoid misdiagnosis, surgery, and life-threatening complications.
Collapse
Affiliation(s)
- Lei Feng
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zhen You
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Dongyang Ma
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Lvjun Yan
- Department of Oncology, Second Affiliated Hospital of Army Medical University, Chongqing, China
| | - Hua Cheng
- Department of Intensive Care Unit, West China Hospital, Sichuan University, Chengdu, China
| | - Junhe Gou
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Liping Chen
- Department of Biliary Surgery, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
29
|
Velegraki M, Vardas E, Dervenis C, Fragaki M, Nikolaou P, Mpitouli A, Kazamias G, Sepsa A, Giannikaki E, Paspatis GA. IgG4-related sclerosing cholangitis: not always an obvious entity. Ann Gastroenterol 2021; 34:594-596. [PMID: 34276201 PMCID: PMC8276355 DOI: 10.20524/aog.2021.0610] [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: 11/23/2020] [Accepted: 12/11/2020] [Indexed: 12/04/2022] Open
Abstract
Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is a distinct type of cholangitis, currently recognized as a biliary manifestation of IgG4-related disease. We present a case of type 3 IgG4-SC in a patient with normal IgG4 serum levels, surgically treated for suspicion of cholangiocarcinoma. This case highlights that differentiating between isolated IgG4-SC and cholangiocarcinoma can present a challenging diagnostic dilemma.
Collapse
Affiliation(s)
- Magdalini Velegraki
- Department of Gastroenterology, Venizeleion General Hospital, Heraklion (Magdalini Velegraki, Emmanouil Vardas, Maria Fragaki, Pinelopi Nikolaou, Afroditi Mpitouli, Gregorios A. Paspatis)
| | - Emmanouil Vardas
- Department of Gastroenterology, Venizeleion General Hospital, Heraklion (Magdalini Velegraki, Emmanouil Vardas, Maria Fragaki, Pinelopi Nikolaou, Afroditi Mpitouli, Gregorios A. Paspatis)
| | - Christos Dervenis
- Hepatobiliary and Pancreatic Surgery Clinic, Metropolitan Hospital, Athens (Christos Dervenis)
| | - Maria Fragaki
- Department of Gastroenterology, Venizeleion General Hospital, Heraklion (Magdalini Velegraki, Emmanouil Vardas, Maria Fragaki, Pinelopi Nikolaou, Afroditi Mpitouli, Gregorios A. Paspatis)
| | - Pinelopi Nikolaou
- Department of Gastroenterology, Venizeleion General Hospital, Heraklion (Magdalini Velegraki, Emmanouil Vardas, Maria Fragaki, Pinelopi Nikolaou, Afroditi Mpitouli, Gregorios A. Paspatis)
| | - Afroditi Mpitouli
- Department of Gastroenterology, Venizeleion General Hospital, Heraklion (Magdalini Velegraki, Emmanouil Vardas, Maria Fragaki, Pinelopi Nikolaou, Afroditi Mpitouli, Gregorios A. Paspatis)
| | - George Kazamias
- Department of Histopathology, Venizeleion General Hospital, Heraklion (George Kazamias, Elpida Giannikaki)
| | - Athanasia Sepsa
- Department of Histopathology, Metropolitan Hospital, Athens (Athanasia Sepsa), Greece
| | - Elpida Giannikaki
- Department of Histopathology, Venizeleion General Hospital, Heraklion (George Kazamias, Elpida Giannikaki)
| | - Gregorios A Paspatis
- Department of Gastroenterology, Venizeleion General Hospital, Heraklion (Magdalini Velegraki, Emmanouil Vardas, Maria Fragaki, Pinelopi Nikolaou, Afroditi Mpitouli, Gregorios A. Paspatis)
| |
Collapse
|
|
30
|
Mantripragada S, Chawla A. Cholangiocarcinoma - Part 2, Tumoral and Nontumoral Mimics and Imaging Features Helpful in Differentiation. Curr Probl Diagn Radiol 2021; 51:362-374. [PMID: 33627221 DOI: 10.1067/j.cpradiol.2021.02.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/01/2021] [Indexed: 12/13/2022]
Abstract
Each of the 3 morphological subtypes of cholangiocarcinoma has a different set of imaging differentials. Emulators of mass-forming cholangiocarcinoma include other primary and secondary hepatic malignancies, benign tumors and tumor-like mimics such as abscess, hemangioma and confluent hepatic fibrosis. Benign inflammatory biliary strictures constitute the major differential of periductal-infiltrative type and intraductal calculi are the main consideration for intraductal-growth type. CT and MRI are the standard imaging tools for characterization of cholangiocarcinoma and differentiating it from close mimics. Here we will describe the various tumoral and non-tumoral mimics of cholangiocarcinoma and discuss specific imaging features useful in differentiation.
Collapse
Affiliation(s)
- Sravanthi Mantripragada
- Department of Diagnostic Radiology, Khoo Teck Puat Hospital, Singapore, Republic of Singapore.
| | - Ashish Chawla
- Department of Diagnostic Radiology, Khoo Teck Puat Hospital, Singapore, Republic of Singapore.
| |
Collapse
|
|
31
|
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.
Collapse
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
| |
Collapse
|
|
32
|
Kingham TP, Aveson VG, Wei AC, Castellanos JA, Allen PJ, Nussbaum DP, Hu Y, D'Angelica MI. Surgical management of biliary malignancy. Curr Probl Surg 2021; 58:100854. [PMID: 33531120 PMCID: PMC8022290 DOI: 10.1016/j.cpsurg.2020.100854] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Accepted: 06/12/2020] [Indexed: 02/07/2023]
Affiliation(s)
| | - Victoria G Aveson
- New York Presbyterian Hospital-Weill Cornel Medical Center, New York, NY
| | - Alice C Wei
- Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Peter J Allen
- Duke Cancer Center, Chief, Division of Surgical Oncology, Duke University School of Medicine, Durham, NC
| | | | - Yinin Hu
- Division of Surgical Oncology, University of Maryland, Baltimore, MD
| | - Michael I D'Angelica
- Memorial Sloan Kettering Cancer Center, Professor of Surgery, Weill Medical College of Cornell University, New York, NY..
| |
Collapse
|
|
33
|
Özden İ, Poyanlı A, Sanlı Y, Kaymakoğlu S. Steroid-induced reconstitution of the biliary tree ravaged by IgG4-related disease. Clin Case Rep 2020; 8:3553-3554. [PMID: 33363974 PMCID: PMC7752589 DOI: 10.1002/ccr3.3109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 06/05/2020] [Accepted: 06/24/2020] [Indexed: 11/19/2022] Open
Abstract
The steroid-induced, rapid healing of the biliary tree ravaged by IgG4-related disease shows that the point of irreversibility remains to be defined.
Collapse
Affiliation(s)
- İlgin Özden
- General Surgery (Hepatopancreatobiliary Surgery Unit)Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey
| | - Arzu Poyanlı
- RadiologyIstanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey
| | - Yasemin Sanlı
- Nuclear MedicineIstanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey
| | - Sabahattin Kaymakoğlu
- Internal Medicine (Gastroenterology Unit)Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey
| |
Collapse
|
|
34
|
Martinez NS, Trindade AJ, Sejpal DV. Determining the Indeterminate Biliary Stricture: Cholangioscopy and Beyond. Curr Gastroenterol Rep 2020; 22:58. [PMID: 33141356 DOI: 10.1007/s11894-020-00797-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Indeterminate biliary strictures (IDBS) continue to be an area of frustration for clinicians. Standard endoscopic retrograde cholangiopancreatography (ERCP) with conventional brush cytology and/or forceps biopsy has a low sensitivity for distinguishing benign from malignant biliary strictures. A delay in diagnosis of malignancy has consequences for subsequent therapy or surgery. In this article, we review current and emerging technologies that may aid in this diagnostic dilemma. RECENT FINDINGS Several technologies have been utilized in IDBS to establish a diagnosis which include peroral cholangioscopy, confocal laser endomicroscopy, endoscopic ultrasound with fine needle aspiration, intraductal ultrasound, optical coherence tomography, fluorescence in situ hybridization, next generation sequencing, integrated molecular pathology, and DNA-image cytometry. While cholangioscopy and confocal laser endomicroscopy have become standards of care in expert centers for the evaluation of patients with IDBS, there are several endoscopic and molecular modalities that may also aid in establishing a diagnosis. Further head-to-head prospective diagnostic studies as well as cost-efficacy studies are needed.
Collapse
Affiliation(s)
- Nichol S Martinez
- Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 300 Community Drive, Manhasset, NY, 11030, USA
| | - Arvind J Trindade
- Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 300 Community Drive, Manhasset, NY, 11030, USA
| | - Divyesh V Sejpal
- Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 300 Community Drive, Manhasset, NY, 11030, USA.
| |
Collapse
|
|
35
|
Ali AH, Bi Y, Machicado JD, Garg S, Lennon RJ, Zhang L, Takahashi N, Carey EJ, Lindor KD, Buness JG, Tabibian JH, Chari ST. The long-term outcomes of patients with immunoglobulin G4-related sclerosing cholangitis: the Mayo Clinic experience. J Gastroenterol 2020; 55:1087-1097. [PMID: 32770464 DOI: 10.1007/s00535-020-01714-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 07/27/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known. METHODS The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age- and gender-matched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC). RESULTS We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.7 years. Seventy-eight patients received prednisone for induction of remission, and 53 received at least one other immunosuppressive agent for maintenance of remission. Of the IgG4-SC group, 10 died (median time from diagnosis until death was 6.5 years): 2 due to cirrhosis, 3 due to cholangiocarcinoma (CCA), and 5 due to non-hepatobiliary causes. Eleven patients in the PSC group underwent liver transplantation, while none did in the IgG4-SC group. The incidence of a hepatobiliary adverse event (cirrhosis or CCA) was 3.4 times greater in the PSC compared to the IgG4-SC group (events per 1000 person-years: 52.6; 95% CI 38-73; vs. 15.6; 95% CI 7-32). The probability of development of a hepatobiliary adverse event within 10 years was 11% in the IgG4-SC compared to 45% in the PSC group (P = 0.0001). The overall survival tended to be higher in the IgG4-SC compared to the PSC group (10-year: 79% vs. 68%, respectively; P = 0.11). CONCLUSIONS In a cohort of IgG4-SC patients, 88% of whom were treated with immunosuppressive drugs, the risk of cirrhosis and CCA was significantly lower compared to an age- and gender-matched group with PSC.
Collapse
Affiliation(s)
- Ahmad Hassan Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st St SW, Rochester, MN, 55905, USA
| | - Yan Bi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Jorge D Machicado
- Division of Gastroenterology and Hepatology, Mayo Clinic Health System, Eau Claire, WI, USA
| | - Sushil Garg
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st St SW, Rochester, MN, 55905, USA
| | - Ryan J Lennon
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Lizhi Zhang
- Department of Pathology, Mayo Clinic, Rochester, MN, USA
| | | | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
- Arizona State University, Tempe, AZ, USA
| | - J Gage Buness
- Arizona College of Osteopathic Medicine, Midwestern University, Glendale, AZ, USA
| | - James H Tabibian
- Division of Gastroenterology, Olive View-UCLA Medical Center, Sylmar, CA, USA
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 1st St SW, Rochester, MN, 55905, USA.
| |
Collapse
|
|
36
|
Abstract
Cholangiocarcinoma is a highly lethal biliary epithelial tumor that is rare in the general population but has increased rates in patients with primary sclerosing cholangitis (PSC). It is heterogenous, and management varies by location. No effective prevention exists, and screening is likely only feasible in PSC. Patients often present in an advanced state with jaundice, weight loss, and cholestatic liver enzymes. Diagnosis requires imaging with magnetic resonance cholangiopancreatography, laboratory testing, and endoscopic retrograde cholangiopancreatography. Potentially curative options include resection and liver transplant with neoadjuvant or adjuvant chemoradiation. Chemotherapy, radiation, and locoregional therapy provide some survival benefit in unresectable disease.
Collapse
Affiliation(s)
- Adam P Buckholz
- Division of Gastroenterology and Hepatology, NewYork-Presbyterian/Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, NewYork-Presbyterian/Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA.
| |
Collapse
|
|
37
|
Dondossola D, Ghidini M, Grossi F, Rossi G, Foschi D. Practical review for diagnosis and clinical management of perihilar cholangiocarcinoma. World J Gastroenterol 2020; 26:3542-3561. [PMID: 32742125 PMCID: PMC7366054 DOI: 10.3748/wjg.v26.i25.3542] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 06/05/2020] [Accepted: 06/18/2020] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinoma (CCC) is the most aggressive malignant tumor of the biliary tract. Perihilar CCC (pCCC) is the most common CCC and is burdened by a complicated diagnostic iter and its anatomical location makes surgical approach burden by poor results. Besides its clinical presentation, a multimodal diagnostic approach should be carried on by a tertiary specialized center to avoid miss-diagnosis. Preoperative staging must consider the extent of liver resection to avoid post-surgical hepatic failure. During staging iter, magnetic resonance can obtain satisfactory cholangiographic images, while invasive techniques should be used if bile duct samples are needed. Consistently, to improve diagnostic potential, bile duct drainage is not necessary in jaundice, while it is indicated in refractory cholangitis or when liver hypertrophy is needed. Once resecability criteria are identified, the extent of liver resection is secondary to the longitudinal spread of CCC. While in the past type IV pCCC was not considered resectable, some authors reported good results after their treatment. Conversely, in selected unresectable cases, liver transplantation could be a valuable option. Adjuvant chemotherapy is the standard of care for resected patients, while neoadjuvant approach has growing evidences. If curative resection is not achieved, radiotherapy can be added to chemotherapy. This multistep curative iter must be carried on in specialized centers. Hence, the aim of this review is to highlight the main steps and pitfalls of the diagnostic and therapeutic approach to pCCC with a peculiar attention to type IV pCCC.
Collapse
Affiliation(s)
- Daniele Dondossola
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi of Milan, Milan 20122, Italy
| | - Michele Ghidini
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
| | - Francesco Grossi
- Medical Oncology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy
| | - Giorgio Rossi
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan 20122, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi of Milan, Milan 20122, Italy
| | - Diego Foschi
- Department of Biomedical and Clinical Sciences "Luigi Sacco", L. Sacco Hospital, Università degli Studi of Milan, Milan 20157, Italy
| |
Collapse
|
|
38
|
Löhr JM, Beuers U, Vujasinovic M, Alvaro D, Frøkjær JB, Buttgereit F, Capurso G, Culver EL, de-Madaria E, Della-Torre E, Detlefsen S, Dominguez-Muñoz E, Czubkowski P, Ewald N, Frulloni L, Gubergrits N, Duman DG, Hackert T, Iglesias-Garcia J, Kartalis N, Laghi A, Lammert F, Lindgren F, Okhlobystin A, Oracz G, Parniczky A, Mucelli RMP, Rebours V, Rosendahl J, Schleinitz N, Schneider A, van Bommel EFH, Verbeke CS, Vullierme MP, Witt H, the UEG guideline working group. European Guideline on IgG4-related digestive disease - UEG and SGF evidence-based recommendations. United European Gastroenterol J 2020; 8:637-666. [PMID: 32552502 PMCID: PMC7437085 DOI: 10.1177/2050640620934911] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 05/04/2020] [Indexed: 12/12/2022] Open
Abstract
The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6-0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2-4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added.
Collapse
Affiliation(s)
- J-Matthias Löhr
- Department of Upper Gastrointestinal Diseases, Karolinska University Hospital, Stockholm, Sweden and Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Miroslav Vujasinovic
- Department of Upper Gastrointestinal Diseases, Karolinska University Hospital, Stockholm, Sweden and Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Frank Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Berlin, Germany
| | - Gabriele Capurso
- PancreatoBiliary Endoscopy and EUS Division Pancreas Translational and Clinical Research Center IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Emma L Culver
- Translational Gastroenterology Unit, John Radcliffe Hospital and Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Enrique de-Madaria
- Gastroenterology Department, Alicante University General Hospital, ISABIAL, Alicante, Spain
| | - Emanuel Della-Torre
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy; Unit of Immunology, Rheumatology, Allergy and Rare Disease (UnIRAR), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sönke Detlefsen
- Department of Pathology, Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
| | - Enrique Dominguez-Muñoz
- Department of Gastroenterology and Hepatology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Piotr Czubkowski
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Nils Ewald
- Institute of Endocrinology, Diabetology and Metabolism, Johannes Wesling University hospital, Minden, Germany and Justus Liebig University Giessen, Giessen, Germany
| | - Luca Frulloni
- Department of Medicine, Pancreas Institute, University of Verona, Verona, Italy
| | - Natalya Gubergrits
- Department of Internal Medicine, Donetsk National Medical University, Lyman, Ukraine
| | - Deniz Guney Duman
- Department of Gastroenterology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Julio Iglesias-Garcia
- Department of Gastroenterology and Hepatology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Nikolaos Kartalis
- Department of Abdominal Radiology, Karolinska University Hospital, Stockholm, Sweden
| | - Andrea Laghi
- Department of Surgical and Medical Sciences and Translational Medicine, Sapienza University of Rome, Sant’Andrea Hospital, Rome, Italy
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Fredrik Lindgren
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Karolinska University Hospital, Stockholm, Sweden
| | | | - Grzegorz Oracz
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Andrea Parniczky
- Institute for Translational Medicine, Szentágothai Research Centre, Medical School, University of Pécs, Pécs, Hungary; Heim Pál National Insitute of Pediatrics, Budapest, Hungary
| | | | - Vinciane Rebours
- Pancreatology Department, Beaujon Hospital, Clichy, Université de Paris, France
| | - Jonas Rosendahl
- Department of Internal Medicine I, Martin Luther University, Halle, Germany
| | - Nicolas Schleinitz
- Département de Médicine Interne Timone, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille Université, Marseille, France
| | - Alexander Schneider
- Department of Gastroenterology and Hepatology, Klinikum Bad Hersfeld, Bad Hersfeld, Germany
| | - Eric FH van Bommel
- Department of Internal Medicine, Dutch National Center of Expertise Retroperitoneal Fibrosis, Albert Schweitzer hospital, Dordrecht, the Netherlands
| | | | | | - Heiko Witt
- Else Kröner-Fresenius-Zentrum für Ernährungsmedizin, Paediatric Nutritional Medicine, Technische Universität München, Freising, Germany
| | | |
Collapse
|
|
39
|
de Vries E, Tielbeke F, Hubers L, Helder J, Mostafavi N, Verheij J, van Hooft J, Besselink M, Fockens P, de Vries N, Beuers U. IgG4/IgG RNA ratio does not accurately discriminate IgG4-related disease from pancreatobiliary cancer. JHEP Rep 2020; 2:100116. [PMID: 32642635 PMCID: PMC7332528 DOI: 10.1016/j.jhepr.2020.100116] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 04/01/2020] [Accepted: 04/01/2020] [Indexed: 01/13/2023] Open
Abstract
Background & Aims IgG4-related disease (IgG4-RD) of the biliary tract and pancreas is often difficult to distinguish from pancreatobiliary cancer. The blood IgG4/IgG RNA ratio has been reported to discriminate IgG4-RD from primary sclerosing cholangitis/pancreatobiliary cancer with high accuracy. This study aimed to prospectively assess the diagnostic accuracy of the blood IgG4/IgG RNA ratio for distinguishing IgG4-RD from cancer in patients with a suspected pancreatobiliary malignancy. Methods In this prospective, single center, observational study, patients presenting at a specialized multidisciplinary, hepato-pancreato-biliary clinic with suspicion of pancreatobiliary malignancy were included. The IgG4/IgG RNA ratio (threshold 5.0%) was determined by quantitative PCR in addition to standard diagnostic procedures. Clinical, biochemical, radiological, and histo-/cytopathological findings were analyzed. For the diagnosis of IgG4-RD, the HISORt criteria were used as a reference standard. Malignancy was defined by the presence of neoplastic tissue at histo-/cytopathological examination. Results Overall, 213 consecutive patients (mean age 68 years) with a suspected pancreatobiliary malignancy were analyzed, of whom 3 patients were diagnosed with IgG4-RD and 178 patients were diagnosed with malignancy (165 patients with primary pancreatobiliary malignancy). The IgG4/IgG RNA ratio was true positive in 3 patients and false positive in 87 (40.8%) patients. In 123 (57.7%) patients the test was true negative. The sensitivity of blood IgG4/IgG RNA ratio was 100%, the specificity 58.6%, the positive predictive value 3.3%. Conclusion In the setting of a high a priori risk of malignancy, an elevated IgG4/IgG RNA ratio did not accurately discriminate pancreatobiliary cancer from IgG4-RD as illustrated by low specificity and concordant low positive predictive value. We advise against the use of this test to discriminate IgG4-RD from pancreatobiliary malignancies. Lay summary IgG4-related disease is a benign inflammatory multiorgan disease which predominantly affects the pancreas and biliary tree. Clinical symptoms, laboratory and imaging finding are often difficult to distinguish from pancreatic or biliary tract cancer. This prospective trial indicates that the recently proposed blood IgG4/IgG RNA ratio does not accurately distinguish benign IgG4-RD from malignant pancreatobiliary disease.
IgG4-related disease and malignancy of bile ducts/pancreas can be indistinguishable. Blood IgG4/IgG RNA ratio was prospectively tested as an IgG4-RD marker when malignancy was suspected. IgG4/IgG RNA ratio >5% did not accurately discriminate IgG4-RD from pancreatobiliary cancer.
Collapse
Affiliation(s)
- Elsemieke de Vries
- Department of Gastroenterology & Hepatology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| | - Floor Tielbeke
- Department of Gastroenterology & Hepatology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| | - Lowiek Hubers
- Department of Gastroenterology & Hepatology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| | - Jeltje Helder
- Department of Gastroenterology & Hepatology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| | - Nahid Mostafavi
- Department of Gastroenterology & Hepatology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| | - Joanne Verheij
- Department of Pathology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| | - Jeanin van Hooft
- Department of Gastroenterology & Hepatology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| | - Marc Besselink
- Department of Surgery, Cancer Center Amsterdam, The Netherlands
| | - Paul Fockens
- Department of Gastroenterology & Hepatology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| | - Niek de Vries
- Department of Rheumatology & Clinical Immunology, all at Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, The Amsterdam Gastroenterology & Metabolism (AG&M) Research Institute, The Netherlands
| |
Collapse
|
|
40
|
Abstract
OBJECTIVE. The purpose of this article is to present the pathologic and clinical features of IgG4-related sclerosing cholangitis (ISC), illustrate the associated imaging findings, and discuss treatment of the disorder. CONCLUSION. ISC is an inflammatory disorder involving the biliary system and resulting in strictures. Although often associated with autoimmune pancreatitis, it may be an isolated disease. Differentiation of ISC from other forms of cholangitis and cholangiocarcinoma is difficult but necessary for management. Imaging is important in diagnosing and assessing the extent of disease and planning a management strategy.
Collapse
|
|
41
|
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.
Collapse
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
| |
Collapse
|
|
42
|
[Immune-mediated cholangiopathies : Diagnostic and therapeutic challenges]. Radiologe 2019; 59:348-356. [PMID: 30874827 DOI: 10.1007/s00117-019-0513-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND Immune-mediated cholangiopathies comprise primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and IgG4-associated cholangitis (IAC). A common feature is the progressive destruction of bile ducts leading to cholestasis with fibrosis and cirrhosis of the liver over time. The diseases are mostly identified during routine laboratory testing. Clinical signs and symptoms such as pruritus, fatigue or jaundice are infrequent in the early stage. DIAGNOSIS The diagnostic work-up involves the patient's history, physical examination, serological tests, abdominal ultrasonography, magnetic resonance cholangiopancreatography (MRCP) and, where necessary, liver biopsy and genetic testing. THERAPY Ursodeoxycholic acid (UDCA) is an effective treatment of PBC. Second-line therapies in addition to UDCA for incomplete UDCA responders are obeticholic acid (OCA) and bezafibrate, whereby only OCA has received approval for this indication from American (Federal Drug Administration) and European (European Medicines Agency) authorities. In PSC, UDCA improves prognostic markers; dominant bile duct strictures are treated with endoscopic balloon dilatation. Despite therapy, liver transplantation is frequently necessary for PSC. The risk of developing cholangiocarcinoma, colon cancer, and gallbladder cancer is increased for patients with PSC. In contrast to PBC and PSC, IAC responds well to corticosteroids. Disease relapse, however, is common, making long-term treatment with low-dose prednisolone or azathioprine necessary.
Collapse
|
|
43
|
Kamisawa T, Zen Y, Nakazawa T, Okazaki K. Advances in IgG4-related pancreatobiliary diseases. Lancet Gastroenterol Hepatol 2019; 3:575-585. [PMID: 30047448 DOI: 10.1016/s2468-1253(18)30121-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 03/30/2018] [Accepted: 04/04/2018] [Indexed: 02/07/2023]
Abstract
Autoimmune pancreatitis is an unusual form of pancreatitis that is histologically characterised by a massive infiltration of lymphocytes and IgG4-positive plasma cells and storiform fibrosis. The disease is recognised as a pancreatic manifestation of IgG4-related disease. IgG4-related sclerosing cholangitis is a biliary counterpart that is typically associated with autoimmune pancreatitis. Two parallel immunological responses are thought to underlie the pathophysiology of these diseases: a pro-inflammatory, tissue-destructive process and an anti-inflammatory feedback response, which probably relates to IgG4 production. These diseases should be differentiated from conditions with a similar presentation (eg, pancreatobiliary malignancy, primary sclerosing cholangitis) by comparison of serum IgG4 concentration, imaging features, other organ involvement, histology, and steroid responsiveness. Corticosteroids are first-line drugs, although rituximab has been shown to effectively deplete B cells in IgG4-related disease. Although the risk of relapse is high, no standardised treatment protocol exists for relapsed cases.
Collapse
Affiliation(s)
- Terumi Kamisawa
- Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, Bunkyo-ku, Tokyo, Japan.
| | - Yoh Zen
- Department of Diagnostic Pathology, Kobe University, Chuo-ku, Kobe, Japan
| | - Takahiro Nakazawa
- Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Showa-ku, Nagoya, Japan
| | - Kazuichi Okazaki
- Department of Gastroenterology and Hepatology, Kansai Medical University, Hirakata, Osaka, Japan
| |
Collapse
|
|
44
|
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.
Collapse
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
| |
Collapse
|
|
45
|
IgG4-Related Sclerosing Cholangitis Involving the Intrahepatic Bile Ducts Diagnosed with Liver Biopsy. Case Rep Pathol 2018; 2018:2309293. [PMID: 30305974 PMCID: PMC6165622 DOI: 10.1155/2018/2309293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 07/15/2018] [Accepted: 08/14/2018] [Indexed: 11/18/2022] Open
Abstract
IgG4-related disease is characterized by lymphoplasmacytic inflammation and fibrosis, often leading to mass-forming lesions in different organs. When IgG4-related disease affects the bile ducts, it is called IgG4-related sclerosing cholangitis. A 74-year-old male complained of dysphagia and abdominal pain. Endoscopic retrograde cholangiography and magnetic resonance cholangiography revealed bile duct changes suspicious of a bile duct carcinoma or cholangitis. Liver biopsy showed storiform fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, and a portal-based inflammatory nodule with expansion of a portal tract. Hot spots revealed 339 IgG4-positive cells per high power field (HPF) and an IgG4/IgG ratio of 72%. Eight months earlier, an inguinal lymph node had been removed, showing expanded interfollicular zones and increased plasma cells. Hot spots revealed 593 IgG4-positive cells and an IgG4/IgG ratio of 92%. The serum IgG4 of the patient was elevated nearly 10 times upper limit of normal. The diagnosis of IgG4-related sclerosing cholangitis associated with IgG4-related lymphadenopathy was made. There was good response to treatment with prednisolone and azathioprine. The differentiation of IgG4-related sclerosing cholangitis from primary sclerosing cholangitis and bile duct carcinoma is often difficult. Liver biopsy only rarely contributes to this setting, but we describe and report in detail a case where liver biopsy showed a portal-based inflammatory nodule with the characteristic features of this disease.
Collapse
|
|
46
|
Miyabe K, Zen Y, Cornell LD, Rajagopalan G, Chowdhary VR, Roberts LR, Chari ST. Gastrointestinal and Extra-Intestinal Manifestations of IgG4-Related Disease. Gastroenterology 2018; 155:990-1003.e1. [PMID: 30012334 DOI: 10.1053/j.gastro.2018.06.082] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 06/06/2018] [Accepted: 06/12/2018] [Indexed: 12/13/2022]
Abstract
IgG4-related disease (IgG4-RD) is a chronic relapsing multi-organ fibro-inflammatory syndrome of presumed autoimmune etiology. It is characterized by increased serum levels of IgG4 and tissue infiltration by IgG4+ cells. Increased titers of autoantibodies against a spectrum of self-antigens and response to steroids have led to its characterization as an autoimmune disease. However, the pathognomonic antigens probably differ among manifestations, and different antigens or autoantibodies produce similar immune reactions in different organs. Little is known about the pathogenic effects, if any, of serum IgG4 or IgG4+ plasma cells in tissues. Despite several animal models of the disease, none truly recapitulates human IgG4-RD. Histologic analyses of tissues from patients with IgG4-RD reveal a dense lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, although these features vary among organs. Typical presentation and imaging findings include mass-forming synchronous or metachronous lesions in almost any organ, but most commonly in the pancreas, bile duct, retroperitoneum, kidneys, lungs, salivary and lacrimal glands, orbit, and lymph nodes. In all organs, inflammation can be reduced by corticosteroids and drugs that deplete B cells, such as rituximab. Patients with IgG4-RD have relapses that respond to primary therapy. Intense fibrosis accompanies the inflammatory response, leading to permanent organ damage and insufficiency. Death from IgG4-RD is rare. IgG4-RD is a multi-organ disease with predominant pancreatico-biliary involvement. Despite its relapsing-remitting course, patients have an excellent prognosis.
Collapse
Affiliation(s)
- Katsuyuki Miyabe
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Yoh Zen
- Department of Laboratory Medicine and Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Lynn D Cornell
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | | | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| |
Collapse
|
|
47
|
Goodchild G, Pereira SP, Webster G. Immunoglobulin G4-related sclerosing cholangitis. Korean J Intern Med 2018; 33:841-850. [PMID: 30045615 PMCID: PMC6129623 DOI: 10.3904/kjim.2018.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 02/06/2018] [Indexed: 12/22/2022] Open
Abstract
Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory condition of which IgG4-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation. In this review, we provide an overview of IgG4-RD, with a focus on the biliary manifestations. In particular, we describe the important differential diagnoses of IgG4-SC, namely, primary sclerosing cholangitis and cholangiocarcinoma, outline diagnostic criteria for IgG4-SC, provide insight into possible pathophysiological mechanisms underlying the disease and discuss short and long-term management options of this recently described disease.
Collapse
Affiliation(s)
- George Goodchild
- Department of Gastroenterology, University College Hospital, London, UK
| | | | - George Webster
- Department of Gastroenterology, University College Hospital, London, UK
- Correspondence to George Webster, M.D. Department of Gastroenterology, University College Hospital, 250 Euston Rd, London NW1 2PG, UK Tel: +44-2034567890 Fax: +44-2034479218 E-mail:
| |
Collapse
|
|
48
|
Abstract
Immunoglobulin G4-related disease is a fibroinflammatory systemic disease that is characterized by focal or diffuse organ infiltration by immunoglobulin G4-bearing plasma cells. Immunoglobulin G4-related disease may affect any organ, and a high index of suspicion is necessary for early detection to avoid irreversible fibrosis, organ dysfunction, and death. Tumor-forming lesions are common radiological features of immunoglobulin G4-related disease that need to be differentiated from malignancies. The diagnostic approach requires the integration of clinical, biochemical, and radiographic manifestations with classic histopathologic features, which remain crucial to diagnosis. The histology of immunoglobulin G4-related disease is determined by a dense lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis in the presence of increased immunoglobulin G4-positve plasma cells. Although immunoglobulin G4-related disease forms a distinct, clinically independent disease category, many questions and problems remain unanswered, especially on its pathogenesis and the role of immunoglobulin G4. Advances in the understanding of immunoglobulin G4-related disease are likely to change the diagnostic approach in the future and create potential targets for therapeutic purposes. Here we describe the concept of immunoglobulin G4-related disease and the most recent knowledge in the clinico-pathological characteristics on this emerging disease. This study can guide clinicians in early diagnosis and prevent unnecessary surgical resections.
Collapse
Affiliation(s)
| | | | - Metin Özdemirli
- Department of Pathology, Medstar Georgetown University Hospital, Washington, USA
| |
Collapse
|
|
49
|
Herta T, Verheij J, Beuers U. IgG4-assoziierte Cholangitis – klinische Präsentation eines lange übersehenen Krankheitsbildes. Internist (Berl) 2018; 59:560-566. [DOI: 10.1007/s00108-018-0431-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
|
|
50
|
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.
Collapse
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
| |
Collapse
|