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Marahrens L, Thomas R, Malley T. Hyperviscosity Syndrome in Immunoglobulin G4 (IgG4)-Related Disease and the Use of Therapeutic Plasma Exchange: A Case Report. Cureus 2024; 16:e70972. [PMID: 39507158 PMCID: PMC11540124 DOI: 10.7759/cureus.70972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2024] [Indexed: 11/08/2024] Open
Abstract
Immunoglobulin G4 (IgG4)-related disease is a rare multi-system immune-mediated inflammatory condition. Pathologically, it is associated with an increase in plasma IgG4 levels and tissue infiltration of IgG4-secreting plasma cells of any organ. Clinical features vary, but it usually presents with the diffuse enlargement and dysfunction of the affected organ. IgG4-related disease leading to hyperviscosity syndrome from polyclonal hypergammaglobulinaemia has only been described in two case reports, and no consensus regarding the treatment of this organ- and life-threatening complication exists. We report the case of a 50-year-old man who was admitted with symptoms of hyperviscosity and an extremely elevated IgG4 level. A presumptive diagnosis of IgG4-related disease causing hyperviscosity syndrome was made. He underwent a therapeutic plasma exchange with a resolution of his symptoms. In view of the likely diagnosis of IgG4-related disease and only refractory improvements in IgG4 levels, immunosuppression with steroids and rituximab was commenced. This led to a sustained fall in IgG4 levels and remission. Hyperviscosity syndrome should be recognised as a complication of IgG4-related disease, and therapeutic plasma exchange can be employed in the emergency treatment of this life-threatening condition.
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Affiliation(s)
| | - Rhys Thomas
- Rheumatology, Royal Free London NHS Foundation Trust, London, GBR
| | - Tamir Malley
- Rheumatology, Royal Free London NHS Foundation Trust, London, GBR
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Cornillet M, Geanon D, Bergquist A, Björkström NK. Immunobiology of primary sclerosing cholangitis. Hepatology 2024:01515467-990000000-01014. [PMID: 39226402 DOI: 10.1097/hep.0000000000001080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 08/21/2024] [Indexed: 09/05/2024]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory progressive cholestatic liver disease. Genetic risk factors, the presence of autoantibodies, the strong clinical link with inflammatory bowel disease, and associations with other autoimmune disorders all suggest a pivotal role for the immune system in PSC pathogenesis. In this review, we provide a comprehensive overview of recent immunobiology insights in PSC. A particular emphasis is given to immunological concepts such as tissue residency and knowledge gained from novel technologies, including single-cell RNA sequencing and spatial transcriptomics. This review of the immunobiological landscape of PSC covers major immune cell types known to be enriched in PSC-diseased livers as well as recently described cell types whose biliary localization and contribution to PSC immunopathogenesis remain incompletely described. Finally, we emphasize the importance of time and space in relation to PSC heterogeneity as a key consideration for future studies interrogating the role of the immune system in PSC.
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Affiliation(s)
- Martin Cornillet
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Daniel Geanon
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Annika Bergquist
- Unit of Gastroenterology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K Björkström
- Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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3
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Zhou T, Fronhoffs F, Kristiansen G, Dold L, Kaczmarek DJ, Strassburg CP, Weismüller TJ. Primary sclerosing cholangitis with IgG4-positive plasma cells in bile duct biopsies - Frequency and characterization. J Dig Dis 2024. [PMID: 39010259 DOI: 10.1111/1751-2980.13295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 05/10/2024] [Accepted: 06/11/2024] [Indexed: 07/17/2024]
Abstract
OBJECTIVES Patients diagnosed with primary sclerosing cholangitis (PSC) but with characteristics of immunoglobulin G4 (IgG4)-associated cholangitis (IAC) have been described. IAC often presents with biliary IgG4-positive plasma cell (IgG4+ PC) infiltration and responds to corticosteroids. In PSC, the frequencies or implications of biliary IgG4+ PC are unknown. We aimed to characterize the phenomenon of biliary IgG4+ PC in patients with an established PSC diagnosis. METHODS Bile duct biopsies from 191 surveillance or therapeutic endoscopic retrograde cholangiography of 58 PSC patients were retrospectively analyzed for IgG4+ PC infiltration. Patients with ≥10 IgG4+ PC per high-power field (HPF) were identified and characterized by clinical parameters, including serum IgG4 and cholangiographic presentations. RESULTS Altogether 39.7% of the PSC patients showed ≥10 IgG4+ PC/HPF in bile duct biopsies. Patients with biliary IgG4+ PC infiltration were significantly younger at diagnosis of PSC (P = 0.023). There was no association between biliary IgG4+ PC infiltration and transplant-free survival (P = 0.618). Patients with IgG4+ PC infiltration in bile duct biopsies showed significantly higher baseline (P = 0.002) and maximum (P = 0.001) serum IgG4 compared to those without. Biliary IgG4+ PC infiltration was associated with high-grade bile duct strictures (P = 0.05). IgG4-positive plasma cell infiltrations were found multifocally in 72.7% of this subgroup of PSC patients. CONCLUSIONS IgG4+ PC ≥10/HPF can be found abundantly in bile duct biopsies in PSC. Histological findings correlated with serum IgG4, age, and high-grade bile duct strictures. IgG4+ PC was located multifocally, hinting at a systemic biliary phenotype.
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Affiliation(s)
- Taotao Zhou
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | | | - Leona Dold
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | | | | | - Tobias J Weismüller
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
- Department of Internal Medicine - Gastroenterology and Oncology, Vivantes Humboldt Hospital, Berlin, Germany
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Sohal A, Kowdley KV. Novel preclinical developments of the primary sclerosing cholangitis treatment landscape. Expert Opin Investig Drugs 2024; 33:335-345. [PMID: 38480008 DOI: 10.1080/13543784.2024.2330738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 03/11/2024] [Indexed: 03/19/2024]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease associated with inflammation, fibrosis, and destruction of intra- and extrahepatic bile ducts. Despite substantial recent advances in our understanding of PSC, the only proven treatment of PSC is liver transplantation. There is an urgent unmet need to find medical therapies for this disorder. AREAS COVERED Multiple drugs are currently under evaluation as therapeutic options for this disease. This article summarizes the literature on the various novel therapeutic options that have been investigated and are currently under development for the treatment of PSC. EXPERT OPINION In the next decade, more than one drug will likely be approved for the treatment of the disease, and we will be looking at combination therapies for the optimal management of the disease.
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Affiliation(s)
- Aalam Sohal
- Department of Hepatology, Liver Institute Northwest, Seattle, USA
| | - Kris V Kowdley
- Department of Hepatology, Liver Institute Northwest, Seattle, USA
- Elson S. Floyd College of Medicine, Washington State University, Spokane, USA
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Elfert K, Abosheaishaa H, Aboursheid T, Beran A, Ahmed M, Musallam R, Al-Taee A. Primary sclerosing cholangitis hospitalizations in the United States: characteristics and predictors of clinical outcomes. Proc AMIA Symp 2023; 36:700-704. [PMID: 37829220 PMCID: PMC10566382 DOI: 10.1080/08998280.2023.2254196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/29/2023] [Indexed: 10/14/2023] Open
Abstract
Background Primary sclerosing cholangitis (PSC) is a chronic progressive disease that primarily affects the medium and large biliary ducts. Methods This study investigated the baseline characteristics and predictors of clinical outcomes among hospitalized patients with PSC in the US. Using the National Inpatient Sample database from 2018 to 2020, we included adults with a principal diagnosis of PSC. Results Our study included 2585 adult hospitalizations. The prevalence of cirrhosis, ulcerative colitis (UC), Crohn's disease (CD), and cholangiocarcinoma among hospitalized PSC patients was 44.5%, 32.3%, 13.15%, and 5.2%, respectively. Over a third of patients (38.1%) underwent endoscopic retrograde cholangiopancreatography (ERCP). UC, CD, cholangiocarcinoma, and autoimmune hepatitis had no impact on mortality, length of stay, or ERCP utilization. Interestingly, individuals of Asian/Pacific Islander ethnicity had higher odds of undergoing ERCP compared to White ethnicity (odds ratio 4.67, 95% confidence interval 1.25-17.4). Conversely, patients with cirrhosis and liver transplant recipients were less likely to undergo ERCP. Conclusion This is the first nationwide study to assess the clinical characteristics and outcomes of hospitalized patients with PSC. It highlights various factors associated with increased utilization of ERCP, longer length of stay, and increased inpatient mortality. Further research is warranted to explore these associations.
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Affiliation(s)
- Khaled Elfert
- Department of Internal Medicine, SBH Health System, New York, New York, USA
| | - Hazem Abosheaishaa
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens, New York, USA
| | - Tarek Aboursheid
- Department of Internal Medicine, Ascension Saint Francis Hospital, Evanston, Illinois, USA
| | - Azizullah Beran
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA
| | - Mohamed Ahmed
- Department of Internal Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA
| | - Rami Musallam
- Department of Internal Medicine, Case Western Reserve University, Cleveland, Ohio, USA
| | - Ahmad Al-Taee
- Department of Gastroenterology, Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois, USA
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6
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Wentworth BJ, Khot R, Caldwell SH. The Many Faces of Primary Sclerosing Cholangitis: Controversy Abounds. Dig Dis Sci 2023; 68:3514-3526. [PMID: 37358638 DOI: 10.1007/s10620-023-08003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/10/2023] [Indexed: 06/27/2023]
Abstract
Primary sclerosing cholangitis (PSC) is notoriously challenging to manage given its heterogeneity with regard to diagnosis, management, and progression. The lack of disease-modifying therapy and variable rate of onset of cirrhosis, portal hypertension-related decompensating events, jaundice, pruritus, biliary complications, and need for liver transplantation is deeply unsettling to clinicians and patients alike. Recent updated practice guidance by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver endeavored to highlight some of these challenges. However, these references only briefly address clinical dilemmas that providers face on a daily basis. This review aims to further discuss these controversial topics, including providing insight into the utility of ursodeoxycolic acid, the significance of alkaline phosphatase normalization, when to consider PSC variants and mimickers, and the implications of continuous hepatobiliary malignancy screening. In particular, there has been a growing body of literature raising concern about repeat exposure to gadolinium-containing contrast. Patients with PSC are potentially at risk for large lifetime exposure to gadolinium related to frequent magnetic resonance imaging scans and whether this carries any negative long-term adverse effects remains unknown.
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Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology and Hepatology, School of Medicine, University of Virginia, PO Box 800708, Charlottesville, VA, 22908, USA.
| | - Rachita Khot
- Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, VA, USA
| | - Stephen H Caldwell
- Division of Gastroenterology and Hepatology, School of Medicine, University of Virginia, PO Box 800708, Charlottesville, VA, 22908, USA
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 139] [Impact Index Per Article: 69.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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8
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Fuchs Y, Valentino PL. Natural history and prognosis of pediatric PSC with updates on management. Clin Liver Dis (Hoboken) 2023; 21:47-51. [PMID: 36950306 PMCID: PMC10022853 DOI: 10.1097/cld.0000000000000006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 11/13/2022] [Indexed: 03/24/2023] Open
Affiliation(s)
- Yonathan Fuchs
- Section of Gastroenterology and Hepatology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Pamela L. Valentino
- Section of Gastroenterology and Hepatology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
- Section of Gastroenterology and Hepatology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, Washington, USA
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9
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Ionescu VA, Gheorghe G, Varlas VN, Stanescu AMA, Diaconu CC. Hepatobiliary Impairments in Patients with Inflammatory Bowel Diseases: The Current Approach. GASTROENTEROLOGY INSIGHTS 2022; 14:13-26. [DOI: 10.3390/gastroent14010002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Inflammatory bowel disease (IBD) refers to chronic conditions with a low mortality but high disability. The multisystemic nature of these diseases can explain the appearance of some extraintestinal manifestations, including liver damage. Abnormal liver biochemical tests can be identified in approximately one third of patients with IBD and chronic liver disease in 5% of them. Among the liver diseases associated with IBD are primary sclerosing cholangitis, cholelithiasis, fatty liver disease, hepatic amyloidosis, granulomatous hepatitis, drug-induced liver injury, venous thromboembolism, primary biliary cholangitis, IgG4-related cholangiopathy, autoimmune hepatitis, liver abscesses or the reactivation of viral hepatitis. The most common disease is primary sclerosing cholangitis, a condition diagnosed especially in patients with ulcerative colitis. The progress registered in recent years in the therapeutic management of IBD has not eliminated the risk of drug-induced liver disease. Additionally, the immunosuppression encountered in these patients increases the risk of opportunistic infections, including the reactivation of viral hepatitis. Currently, one of the concerns consists of establishing an efficiency and safety profile of the use of direct-acting antiviral agents (DAA) among patients with hepatitis C and IBD. Early diagnosis and optimal treatment of liver complications can improve the prognoses of these patients.
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Affiliation(s)
- Vlad Alexandru Ionescu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Gastroenterology Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Gina Gheorghe
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Gastroenterology Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Valentin Nicolae Varlas
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
| | | | - Camelia Cristina Diaconu
- Faculty of Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania
- Internal Medicine Department, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
- Medical Sciences Section, Academy of Romanian Scientists, 050085 Bucharest, Romania
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10
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Efficacy and safety of immune-modulating therapy for primary sclerosing cholangitis: A systematic review and meta-analysis. Pharmacol Ther 2022; 237:108163. [DOI: 10.1016/j.pharmthera.2022.108163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 11/17/2022]
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11
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New agents for immunosuppression. Best Pract Res Clin Gastroenterol 2021; 54-55:101763. [PMID: 34874846 DOI: 10.1016/j.bpg.2021.101763] [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: 07/19/2021] [Revised: 08/16/2021] [Accepted: 08/30/2021] [Indexed: 01/31/2023]
Abstract
The human abdomen harbors organs that the host's immune system can attack easily. This immunological storm front leads to diseases like Crohn's Disease, Ulcerative Colitis or Autoimmune Hepatitis. Serious symptoms like pain, diarrhea, fatigue, or malnutrition accompany these diseases. Moreover, many patients have an increased risk for developing special kind of malignancies and some autoimmune disease can show a high mortality. The key to treat them consists of a deep understanding of their pathophysiology. In vitro and especially in vivo basic research laid the foundation for our increasing knowledge about it during the past years. This enabled the development of new therapeutic approaches that interact directly with cytokines or immune cells instead of building the treatment on a total immunosuppression. Different kind of antibodies, kinase inhibitors, and regulatory T cells build the base for these approaches. This review shows new therapeutical approaches in gastrointestinal autoimmune diseases in context to their pathophysiological basis.
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12
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Ponsioen CY, Assis DN, Boberg KM, Bowlus CL, Deneau M, Thorburn D, Aabakken L, Färkkilä M, Petersen B, Rupp C, Hübscher SG. Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process. Gastroenterology 2021; 161:1764-1775.e5. [PMID: 34384749 DOI: 10.1053/j.gastro.2021.07.046] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 07/29/2021] [Indexed: 12/24/2022]
Affiliation(s)
- Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands
| | - David N Assis
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Kirsten M Boberg
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; ERN RARE Liver, Hamburg, Germany
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California
| | - Mark Deneau
- University of Utah and Intermountain Primary Children's Hospital, Salt Lake City, Utah
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free Hospital and Institute for Liver and Digestive Health, University College London, London, United Kingdom; ERN RARE Liver, Hamburg, Germany
| | - Lars Aabakken
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; ERN RARE Liver, Hamburg, Germany
| | - Martti Färkkilä
- Abdominal Center, Helsinki University Hospital, Helsinki, Finland; ERN RARE Liver, Hamburg, Germany
| | - Bret Petersen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Christian Rupp
- Department of Internal Medicine IV, Gastroenterology, and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan G Hübscher
- Institute of Immunology and Immunotherapy, University of Birmingham and, Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom
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13
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Saffioti F, Hall A, de Krijger M, Verheij J, Hübscher SG, Maurice J, Luong TV, Pinzani M, Ponsioen CY, Thorburn D. Collagen proportionate area correlates with histological stage and predicts clinical events in primary sclerosing cholangitis. Liver Int 2021; 41:2681-2692. [PMID: 34051052 DOI: 10.1111/liv.14979] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 04/25/2021] [Accepted: 05/25/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease in need of accurate biomarkers for stratification and as surrogates for clinical endpoints in trials. Quantitative liver fibrosis assessment by collagen proportionate area (CPA) measurement has been demonstrated to correlate with clinical outcomes in chronic hepatitis C, alcohol-related and non-alcoholic fatty liver disease. We aimed to investigate the ability of CPA to quantify liver fibrosis and predict clinical events in PSC. METHODS Biopsies from 101 PSC patients from two European centres were retrospectively assessed by two expert pathologists in tandem, using grading (Ishak and Nakanuma) and staging (Ishak, Nakanuma, Ludwig) systems recently validated to predict clinical events in PSC. CPA was determined by image analysis of picro-Sirius red-stained sections following a standard protocol. We assessed the correlations between CPA, staging and grading and their associations with three outcomes: (1) time to PSC-related death, liver transplant or primary liver cancer; (2) liver transplant-free survival; (3) occurrence of cirrhosis-related clinical manifestations. RESULTS CPA correlated strongly with histological stage determined by each scoring system (P < .001) and was significantly associated with the three endpoints. Median time to endpoint-1, endpoint-2 and endpoint-3 was shorter in patients with higher CPA, on Kaplan-Meier analyses (P = .011, P = .034 and P = .001, respectively). CONCLUSION Quantitative fibrosis assessment by CPA has utility in PSC. It correlates with established histological staging systems and predicts clinical events. CPA may be a useful tool for staging fibrosis and for risk stratification in PSC and should be evaluated further within prospective clinical trials.
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Affiliation(s)
- Francesca Saffioti
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK.,Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Andrew Hall
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK.,Department of Cellular Pathology, Royal Free Hospital, London, UK
| | - Manon de Krijger
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Joanne Verheij
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Stefan G Hübscher
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, UK
| | - James Maurice
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free Hospital, London, UK
| | - Massimo Pinzani
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK
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14
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Abstract
Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.
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15
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Manganis CD, Chapman RW, Culver EL. Review of primary sclerosing cholangitis with increased IgG4 levels. World J Gastroenterol 2020; 26:3126-3144. [PMID: 32684731 PMCID: PMC7336326 DOI: 10.3748/wjg.v26.i23.3126] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 04/07/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease. Sub-types of PSC have been described, most recently PSC with elevated serum and/or tissue IgG4 subclass. We aim to summarise the clinical phenotype, disease associations, differential diagnosis, response to therapy and pathogenic mechanisms underlying PSC-high IgG4 subtype. We reviewed PubMed, MEDLINE and Embase with the search terms "primary sclerosing cholangitis", "IgG4", and "IgG4-related sclerosing cholangitis (IgG4-SC)". Elevated serum IgG4 are found in up-to one-quarter, and abundant IgG4-plasma cell infiltrates in the liver and bile ducts are found in up-to one-fifth of PSC patients. This group have a distinct clinical phenotype, with some studies reporting a more aggressive course of liver and associated inflammatory bowel disease, compared to PSC-normal IgG4 and the disease mimic IgG4-SC. Distinguishing PSC-high IgG4 from IgG4-SC remains challenging, requiring careful assessment of clinical features, organ involvement and tissue morphology. Calculation of serum IgG4:IgG1 ratios and use of a novel IgG4:IgG RNA ratio have been reported to have excellent specificity to distinguish IgG4-SC and PSC-high IgG4 but require validation in larger cohorts. A role for corticosteroid therapy in PSC-high IgG4 remains unanswered, with concerns of increased toxicity and lack of outcome data. The immunological drivers underlying prominent IgG4 antibodies in PSC are incompletely defined. An association with PSC-high IgG4 and HLA class-II haplotypes (B*07, DRB1*15), T-helper2 and T-regulatory cytokines (IL4, IL10, IL13) and chemokines (CCL1, CCR8) have been described. PSC-high IgG4 have a distinct clinical phenotype and need careful discrimination from IgG4-SC, although response to immunosuppressive treatments and long-term outcome remains unresolved. The presence of IgG4 likely represents chronic activation to persistent antigenic exposure in genetically predisposed individuals.
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Affiliation(s)
- Charis D Manganis
- Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Roger W Chapman
- Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Emma L Culver
- Translational Gastroenterology Unit and Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
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16
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Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities. J Gastroenterol 2020; 55:588-614. [PMID: 32222826 PMCID: PMC7242240 DOI: 10.1007/s00535-020-01681-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 03/05/2020] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics.
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17
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Gilligan LA, Trout AT, Lam S, Singh R, Tkach JA, Serai SD, Miethke AG, Dillman JR. Differentiating pediatric autoimmune liver diseases by quantitative magnetic resonance cholangiopancreatography. Abdom Radiol (NY) 2020; 45:168-176. [PMID: 31422438 DOI: 10.1007/s00261-019-02184-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE Autoimmune liver diseases (AILD), including primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC), and autoimmune hepatitis (AIH), have overlapping clinical features but distinct management strategies and outcomes. The purpose of this study was to assess the diagnostic performance of quantitative magnetic resonance cholangiopancreatography (MRCP) parameters for distinguishing PSC/ASC from AIH in children and young adults. MATERIALS AND METHODS This IRB-approved, cross-sectional study included participants from an institutional AILD registry that underwent baseline serum liver biochemistry testing and 3D fast spin-echo MRCP. The biliary tree was extracted and modeled from MRCP images using novel proprietary software (MRCP+ ™; Perspectum Diagnostics; Oxford, United Kingdom), and quantitative parameters were generated (e.g., biliary tree volume; number and length of bile ducts, strictures, and dilations; bile duct median/maximum diameters). Mann-Whitney U tests were performed to compare laboratory values and MRCP metrics between patient cohorts (clinical diagnosis of PSC/ASC versus AIH). Receiver operating characteristic (ROC) curves and multivariable logistic regression were used to assess diagnostic performance of serum biochemistry values and MRCP parameters for discriminating PSC/ASC from AIH. RESULTS Thirty percent (14/47) of MRCP exams failed post-processing due to motion artifact. The remaining 33 patients included 20 males and 13 females, with a mean age of 15.1 ± 3.9 years. Eighteen patients were assigned the clinical diagnosis of PSC or ASC and 15 of AIH. All but one quantitative MRCP parameter were significantly different between cohorts (p < 0.05) and predictive of diagnosis (ROC p < 0.05), including numbers of bile duct strictures (area under curve [AUC] = 0.86, p < 0.0001) and dilations (AUC = 0.87, p < 0.0001) and total length of dilated ducts (AUC = 0.89, p < 0.0001). Laboratory values were not significantly different between cohorts (p > 0.05). The best multivariable model for distinguishing PSC/ASC from AIH included total length of dilated ducts (odds ratio [OR], 1.08; 95% CI 1.02-1.14) and maximum left hepatic duct diameter (OR, 1.21; 95% CI 0.57-2.56) [AUC = 0.92]. CONCLUSION Quantitative MRCP parameters provide good discrimination of PSC/ASC from AIH.
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Affiliation(s)
- Leah A Gilligan
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
| | - Andrew T Trout
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Simon Lam
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Ruchi Singh
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Jean A Tkach
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Suraj D Serai
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Alexander G Miethke
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jonathan R Dillman
- Department of Radiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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18
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Sundaram S, Jearth V. Primary Sclerosing Cholangitis: A Clinical Update. EUROPEAN MEDICAL JOURNAL 2019. [DOI: 10.33590/emj/10313809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic disorder of the liver, with strictures in the bile ducts leading to cirrhosis of the liver in a proportion of patients. PSC is commonly associated with inflammatory bowel disease and increased risk of cholangiocarcinoma, gall bladder cancer, colorectal cancer, and hepatocellular carcinoma. Medical therapies are primarily aimed at symptom management and disease-modifying therapies are limited. Endoscopic therapies are used in patients with dominant strictures and liver transplantation is a last resort. In this article, the authors aim to comprehensively review the epidemiology, diagnosis, and management of PSC with emphasis on risk of malignancies and management of PSC. The authors also survey the advances in pathogenesis understanding and novel medical therapies for PSC.
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Affiliation(s)
- Sridhar Sundaram
- Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, India
| | - Vaneet Jearth
- Department of Digestive Diseases and Clinical Nutrition, Tata Memorial Centre, Mumbai, India
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19
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Zhang C, Hussaini T, Yoshida EM. Review of pharmacotherapeutic treatments for primary sclerosing cholangitis. CANADIAN LIVER JOURNAL 2019; 2:58-70. [PMID: 35990218 PMCID: PMC9202752 DOI: 10.3138/canlivj-2018-0016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 08/15/2018] [Indexed: 11/13/2023]
Abstract
BACKGROUND The objective of this review was to evaluate pharmacotherapeutic treatments for primary sclerosing cholangitis (PSC) through a literature search of current published data. A review of the current clinical data for each treatment is discussed. METHODS We conducted a systematic literature search for articles using EMBASE (1980 to April 1, 2018), and MEDLINE (1948 to April 1, 2018) using Ovid, to identify studies investigating various therapies in PSC. Search terms included the following: primary sclerosing cholangitis, cholangitis, sclerosing cholangitis; ursodeoxycholic acid, glucocorticoids, cyclosporine, tacrolimus, methotrexate, azathioprine, 6-mercaptopurine, penicillamine, anti-TNF, antibiotics, and probiotics. We also performed a review of current clinical trials using ClinicalTrials.gov. We considered for review relevant studies published in English, pilot studies, and randomized controlled trials involving human subjects. RESULTS Therapies that have been investigated in the management of PSC include those used in search terms and others that were not included in our search parameters. Analysis of published data involving each therapy was explored and none have shown any sustained, significant benefit in the treatment of PSC. In terms of relevance to patient care and clinical practice, this review evaluates and compares various pharmacotherapeutic treatments for PSC where liver transplantation remains the only definitive treatment. CONCLUSIONS To date, no clinical study of any drug has demonstrated effectiveness in terms of survival benefit or a decreased need for liver transplantation. More clinical studies are needed, and patients need to be adequately informed before any medical therapy for PSC is undertaken.
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Affiliation(s)
- Chaoran Zhang
- Internal Medicine Residency Training Program, Department of Medicine, University of British Columbia, Vancouver, British Columbia;
| | - Trana Hussaini
- Department of Pharmaceutical Sciences Medicine, Vancouver General Hospital, Vancouver, British Columbia;
| | - Eric M Yoshida
- Division of Gastroenterology, University of British Columbia, Vancouver, British Columbia
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20
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Malik A, Kardashian AA, Zakharia K, Bowlus CL, Tabibian JH. Preventative care in cholestatic liver disease: Pearls for the specialist and subspecialist. LIVER RESEARCH (BEIJING, CHINA) 2019; 3:118-127. [PMID: 32042471 PMCID: PMC7008979 DOI: 10.1016/j.livres.2019.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cholestatic liver diseases (CLDs) encompass a variety of disorders of abnormal bile formation and/or flow. CLDs often lead to progressive hepatic insult and injury and following the development of cirrhosis and associated complications. Many such complications are clinically silent until they manifest with severe sequelae, including but not limited to life-altering symptoms, metabolic disturbances, cirrhosis, and hepatobiliary diseases as well as other malignancies. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are the most common CLDs, and both relate to mutual as well as unique complications. This review provides an overview of PSC and PBC, with a focus on preventive measures aimed to reduce the incidence and severity of disease-related complications.
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Affiliation(s)
- Adnan Malik
- Department of Public Health and Business Administration, The University of Alabama at Birmingham, Birmingham, AL, USA
- Department of Internal Medicine, Beaumont Hospital, Dearborn, MI, USA
| | - Ani A. Kardashian
- University of California Los Angeles Gastroenterology Fellowship Training Program, Vatche and Tamar Manoukian Division of Digestive Diseases, Los Angeles, CA, USA
| | - Kais Zakharia
- Division of Gastroenterology and Hepatology, University of Iowa, Iowa, IA, USA
| | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA
| | - James H. Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-University of California Los Angeles Medical Center, Sylmar, CA, USA
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21
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Laborda TJ, Jensen MK, Kavan M, Deneau M. Treatment of primary sclerosing cholangitis in children. World J Hepatol 2019; 11:19-36. [PMID: 30705716 PMCID: PMC6354124 DOI: 10.4254/wjh.v11.i1.19] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 12/19/2018] [Accepted: 01/06/2019] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare disease of stricturing and destruction of the biliary tree with a complex genetic and environmental etiology. Most patients have co-occurring inflammatory bowel disease. Children generally present with uncomplicated disease, but undergo a variable progression to end-stage liver disease. Within ten years of diagnosis, 50% of children will develop clinical complications including 30% requiring liver transplantation. Cholangiocarcinoma is a rare but serious complication affecting 1% of children. Ursodeoxycholic acid and oral vancomycin therapy used widely in children as medical therapy, and may be effective in a subset of patients. Gamma glutamyltransferase is a potential surrogate endpoint for disease activity, with improved survival in patients who achieve a normal value. Endoscopic retrograde cholangiopancreatography is a necessary adjunct to medical therapy to evaluate mass lesions or dominant strictures for malignancy, and also to relieve biliary obstruction. Liver transplantation remains the only option for patients who progress to end-stage liver disease. We review special considerations for patients before and after transplant, and in patients with inflammatory bowel disease. There is presently no published treatment algorithm or guideline for the management of children with PSC. We review the evidence for drug efficacy, dosing, duration of therapy, and treatment targets in PSC, and provide a framework for endoscopic and medical management of this complex problem.
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Affiliation(s)
- Trevor J Laborda
- Department of Pediatrics, University of Utah, Salt Lake City, UT 84113, United States
| | - M Kyle Jensen
- Department of Pediatrics, University of Utah, Salt Lake City, UT 84113, United States
| | - Marianne Kavan
- Department of Pediatrics, University of Utah, Salt Lake City, UT 84113, United States
| | - Mark Deneau
- Department of Pediatrics, University of Utah, Salt Lake City, UT 84113, United States
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22
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Goldstein J, Levy C. Novel and emerging therapies for cholestatic liver diseases. Liver Int 2018; 38:1520-1535. [PMID: 29758112 DOI: 10.1111/liv.13880] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023]
Abstract
While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.
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Affiliation(s)
- Jordan Goldstein
- Division of Internal Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Cynthia Levy
- Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA
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23
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Isayama H, Tazuma S, Kokudo N, Tanaka A, Tsuyuguchi T, Nakazawa T, Notohara K, Mizuno S, Akamatsu N, Serikawa M, Naitoh I, Hirooka Y, Wakai T, Itoi T, Ebata T, Okaniwa S, Kamisawa T, Kawashima H, Kanno A, Kubota K, Tabata M, Unno M, Takikawa H. Clinical guidelines for primary sclerosing cholangitis 2017. J Gastroenterol 2018; 53:1006-1034. [PMID: 29951926 PMCID: PMC8930933 DOI: 10.1007/s00535-018-1484-9] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 06/11/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is relatively rare disease and pathogenesis and methods of treatments were still not established. Then, we had conducted the making clinical guidelines to manage patients with PSC based on the literature review and expert opinions. These clinical guidelines were made for the medical doctors on the management of PSC, except child case of PSC. METHODS We had employed modified Delphi method. The production committee decided guidelines, strength of recommendations and evidence level after reviewed literatures systematically, and The Expert panel evaluated those. The Scientific Committee of the Japan Biliary Association (JBA) evaluated revised guidelines, and the Public comments were collected on web site of JBA. RESULTS We had made 16 guidelines about epidemiology/pathophysiology, diagnostics, therapy and prognosis. Also, we had made both diagnostic and therapeutic flow chart. CONCLUSIONS We hope that these guidelines will contribute to the improvement and development of the medical care of PSC.
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Affiliation(s)
- Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Susumu Tazuma
- Department of General Internal Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University Hospital, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Norihiro Kokudo
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Toshio Tsuyuguchi
- Department of Medicine and Gastroenterology, Chiba University, Chiba, Japan
| | - Takahiro Nakazawa
- Department of Gastroenterology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
| | - Kenji Notohara
- Department of Anatomic Pathology, Kurashiki Central Hospital, Kurashiki, Japan
| | - Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masahiro Serikawa
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Itaru Naitoh
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan
| | - Yoshiki Hirooka
- Department of Endoscopy, Nagoya University Hospital, Nagoya, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takao Itoi
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Tomoki Ebata
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shinji Okaniwa
- Department of Gastroenterology, Iida Municipal Hospital, Nagano, Japan
| | - Terumi Kamisawa
- Department of Internal Medicine, Tokyo Komagome Metropolitan Hospital, Tokyo, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Atsushi Kanno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Keiichi Kubota
- Second Department of Surgery, Dokkyo Medical University, Tochigi, Japan
| | - Masami Tabata
- Department of Surgery, Matsusaka Central General Hospital, Matsusaka, Mie, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Hajime Takikawa
- Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan
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24
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Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet 2018; 391:2547-2559. [PMID: 29452711 DOI: 10.1016/s0140-6736(18)30300-3] [Citation(s) in RCA: 282] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 11/24/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022]
Abstract
Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by intrahepatic or extrahepatic stricturing, or both, with bile duct fibrosis. Inflammation and fibrosis of bile ducts and the liver are followed by impaired bile formation or flow and progressive liver dysfunction. Patients might be asymptomatic at presentation or might have pruritus, fatigue, right upper quadrant pain, recurrent cholangitis, or sequelae of portal hypertension. The key diagnostic elements are cholestatic liver biochemistry and bile duct stricturing on cholangiography. Genetic and environmental factors are important in the cause of the disease, with the intestinal microbiome increasingly thought to play a pathogenetic role. Approximately 70% of patients have concurrent inflammatory bowel disease and patients require colonoscopic screening and surveillance. Primary sclerosing cholangitis is associated with increased malignancy risk and surveillance strategies for early cholangiocarcinoma detection are limited. No single drug has been proven to improve transplant-free survival. Liver transplantation is effective for advanced disease but at least 25% of patients develop recurrent disease in the graft.
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Affiliation(s)
- Jessica K Dyson
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - David E J Jones
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mark Hudson
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK
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25
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Fousekis FS, Theopistos VI, Katsanos KH, Tsianos EV, Christodoulou DK. Hepatobiliary Manifestations and Complications in Inflammatory Bowel Disease: A Review. Gastroenterology Res 2018; 11:83-94. [PMID: 29707074 PMCID: PMC5916631 DOI: 10.14740/gr990w] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 03/12/2018] [Indexed: 12/12/2022] Open
Abstract
Liver and biliary track diseases are common extraintestinal manifestations of inflammatory bowel disease (IBD), reported both in Crohn’s disease and ulcerative colitis, and may occur at any time during the natural course of the disease. Their etiology is mainly related to pathophysiological changes induced by IBD, and secondary, due to drugs used in IBD. Fatty liver is considered as the most frequent hepatobiliary manifestation in IBD, while primary sclerosing cholangitis (PSC) is the most correlated hepatobiliary disorder and is more prevalent in patients with ulcerative colitis. PSC can cause serious complications from the liver, biliary tree, and gallbladder and can lead to liver failure. Less frequently, IBD-associated hepatobiliary manifestations include cholelithiasis, granulomatous hepatitis, portal vein thrombosis, IgG4-related cholangiopathy, pyogenic liver abscess, hepatic amyloidosis and primary biliary cirrhosis. Most of the drugs used for IBD treatment may cause liver toxicity. Methotrexate and thiopurines carry the higher risk for hepatotoxicity, and in many cases, dose adjustment may normalize the liver biochemical tests. Reactivation of hepatitis B and C virus during immunosuppressive use, especially during use of biological agents, is a major concern, and adequate screening, vaccination and prophylactic treatment is warranted.
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Affiliation(s)
- Fotios S Fousekis
- Department of Gastroenterology and Hepatology, Medical School of Ioannina, Greece
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26
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Chen JH, Deshpande V. Inflammatory Nodules Identify Steroid-Responsive Primary Sclerosing Cholangitis. Int J Surg Pathol 2018; 26:402-409. [PMID: 29464971 DOI: 10.1177/1066896918758451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a cholangiopathy-usually associated with inflammatory bowel disease-that leads to cirrhosis and liver failure. Based on a multitude of clinical trials, there is general consensus that PSC progression is unchanged by current therapies, including steroids. However, there are scattered reports in the literature of PSC patients responsive to steroids. Recently, several steroid-responsive PSC mimics have been described, most notably immunoglobulin G4-related sclerosing cholangitis. Following these discoveries, many assume that cases in the literature previously reported as steroid-responsive PSC would now be classified as one of these mimics. We reviewed liver biopsies and the medical histories of patients diagnosed with PSC with documented response to steroids. We identified 3 cases of steroid-responsive PSC in patients with inflammatory bowel disease that do not fit criteria of known PSC mimics. All 3 were adults (age range = 18-44 years) with inflammatory bowel disease, and included 2 males and 1 female. All 3 patients had abnormal liver function tests that normalized on prednisone. Histologically, these 3 cases share a common feature, hepatic fibroinflammatory nodules in a collagen-rich background. They lacked clinical, serologic, and histologic features of immunoglobulin G4-related sclerosing cholangitis. These cases suggest that fibroinflammatory nodules may identify a unique subset of PSC patients who are responsive to steroids.
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Affiliation(s)
- Jonathan H Chen
- 1 Massachusetts General Hospital, Boston, MA, USA.,2 Harvard Medical School, Boston, MA, USA
| | - Vikram Deshpande
- 1 Massachusetts General Hospital, Boston, MA, USA.,2 Harvard Medical School, Boston, MA, USA
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27
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic immune-mediated disease affecting intra- and extrahepatic bile ducts, primarily the large biliary ducts. Clinical manifestations are broad, and the spectrum encompasses asymptomatic cholestasis, icteric cholangitis with pruritis, cirrhosis, and cholangiocarcinoma. Though rare, PSC has a propensity to affect young to middle-aged males and is strongly associated with inflammatory bowel disease. There is an unmet need for effective medical treatments for PSC, and to date, the only curative therapy is liver transplantation reserved for those with end-stage liver disease. This article addresses the diagnostic and management challenges of PSC, with a succinct analysis of existing therapies, their limitations, and a glimpse into the future of the management of this multifaceted pathologic entity.
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Affiliation(s)
- Sanjeev Sirpal
- Department of Medicine, Centre Hospitalier de l’Université de Montréal (CHUM), University of Montreal, Montreal, QC
| | - Natasha Chandok
- Department of Medicine, University of Western Ontario, London, ON, Canada
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28
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Gossard AA, Gores GJ. Primary Sclerosing Cholangitis: What the Gastroenterologist and Hepatologist Needs to Know. Clin Liver Dis 2017; 21:725-737. [PMID: 28987259 DOI: 10.1016/j.cld.2017.06.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic biliary tract disease characterized by segmental strictures. The disease is progressive with no proven treatments and may eventually lead to cirrhosis and end-stage liver disease. Abrupt changes in liver biochemistries, pain, and/or cholangitis may suggest a dominant stricture amenable to endoscopic therapy or the development of cholangiocarcinoma. Patients with PSC are at increased risk of cholangiocarcinoma. There is a strong association with inflammatory bowel disease, and an associated increased risk of colorectal cancer. Colonoscopy every 1 to 2 years is appropriate.
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Affiliation(s)
- Andrea A Gossard
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55901, USA.
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street Southwest, Rochester, MN 55901, USA
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29
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Mizuno S, Isayama H, Hirano K, Watanabe T, Takahara N, Kogure H, Matsubara S, Nakai Y, Tada M, Koike K. Factors predictive of the efficacy of bezafibrate therapy in patients with primary sclerosing cholangitis. Hepatol Res 2017; 47:1102-1107. [PMID: 27874998 DOI: 10.1111/hepr.12846] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 11/17/2016] [Accepted: 11/20/2016] [Indexed: 12/13/2022]
Abstract
AIM Primary sclerosing cholangitis (PSC) is a rare cholestatic disease. We previously reported the effects of bezafibrate on elevated hepatobiliary enzyme levels in patients with this disease both retrospectively and prospectively. In this study, we assessed factors predictive of bezafibrate efficacy. METHODS Twenty-five patients with PSC, who underwent bezafibrate therapy (400 mg per day) from November 2006 to June 2015, were evaluated. Treatment was judged as being effective if the levels of all of the hepatobiliary enzymes decreased after 12 weeks. We investigated the patients' characteristics, disease history, concomitant medications, liver function, and liver stiffness. RESULTS The efficacy rate of bezafibrate was 60% (15/25 patients). The efficacy rate in patients graded as Child-Pugh class A was significantly higher (75% [15/20]) than that in patients graded as class B (0% [0/5], P < 0.01). Non-responders had higher liver stiffness values (18.0 vs. 8.8 kPa, P = 0.19), and concomitantly used ursodeoxycholic acid more frequently (100% vs. 73%, P = 0.12) than responders. CONCLUSIONS We could not elucidate the factors predictive for bezafibrate efficacy for the treatment of PSC. However, bezafibrate was more effective for patients with preserved liver function (Child-Pugh class A) when it was prescribed before progression of liver fibrosis and failure of ursodeoxycholic acid therapy.
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Affiliation(s)
- Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Kenji Hirano
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Takeo Watanabe
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Naminatsu Takahara
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Hirofumi Kogure
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Saburo Matsubara
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Minoru Tada
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease that can progress to end-stage liver disease, cirrhosis and cholangiocarcinoma. PSC is an uncommon and highly heterogeneous disease, associated with inflammatory bowel disease and a complex pathophysiology. To date, no medical therapies have proved effective. The only available treatment for end-stage PSC is liver transplant, but recurrence is a significant complication. Areas covered: This review will explore previously tested treatments, discuss current treatment strategies and present viewpoints about future emerging therapies in PSC. We searched PubMed using the noted keywords. We included data from full-text articles published in English. Further relevant articles were identified from the reference lists of review articles. Expert commentary: The development of new therapies in PSC has been challenging. However, with greater awareness of the disease nowadays, new insights into the disease may help in the design of future therapeutic agents in PSC and ultimately in effective therapies.
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Affiliation(s)
- Eduardo A Rodriguez
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA
| | - Elizabeth J Carey
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA
| | - Keith D Lindor
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.,b College of Health Solutions , Arizona State University , Phoenix , AZ , USA
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Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees. J Pediatr Gastroenterol Nutr 2017; 64:639-652. [PMID: 27984347 DOI: 10.1097/mpg.0000000000001492] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatobiliary disorders are common in patients with inflammatory bowel disease (IBD), and persistent abnormal liver function tests are found in approximately 20% to 30% of individuals with IBD. In most cases, the cause of these elevations will fall into 1 of 3 main categories. They can be as a result of extraintestinal manifestations of the disease process, related to medication toxicity, or the result of an underlying primary hepatic disorder unrelated to IBD. This latter possibility is beyond the scope of this review article, but does need to be considered in anyone with elevated liver function tests. This review is provided as a clinical summary of some of the major hepatic issues that may occur in patients with IBD.
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de Vries E, Beuers U. Management of cholestatic disease in 2017. Liver Int 2017; 37 Suppl 1:123-129. [PMID: 28052628 DOI: 10.1111/liv.13306] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 10/27/2016] [Indexed: 12/13/2022]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the most frequent chronic cholestatic liver diseases and serve as model diseases to discuss the management of cholestasis in 2017 in the lecture that is summarized in this report. PBC and PSC are characterized by inflammation and fibrosis of small intrahepatic (PBC) or larger intra- and/or extrahepatic (PSC) bile ducts. Bile duct damage leads to cholestasis and can progress to liver fibrosis and even cirrhosis. Various genetic, environmental and endogenous factors may contribute to the development of chronic cholestatic liver diseases, but the exact pathogenesis of PBC and PSC has not been clarified. Ursodeoxycholic acid (UDCA) is the standard treatment of PBC and is used also for other cholestatic conditions including PSC, and it exerts anticholestatic effects at adequate doses. Novel anticholestatic therapeutic options for patients not adequately responding to UDCA are under development or have, like obeticholic acid, already been proven to have efficacy when combined with UDCA in the treatment of PBC. The future role of immunomodulating/immunosuppressive drug regimens must be critically reviewed.
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Affiliation(s)
- Elsemieke de Vries
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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Kumar A, Wheatley D, Puttanna A. Primary Sclerosing Cholangitis: Therapeutic Options and Surveillance Management. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2016; 9:25-9. [PMID: 27330336 PMCID: PMC4902039 DOI: 10.4137/cgast.s38451] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 05/01/2016] [Accepted: 05/03/2016] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis is a chronic immune-mediated liver disease. Though rare, it poses several clinical concerns for the managing physician. There are currently limited therapeutic options in the management of the condition and weak evidence base behind them. Endoscopic intervention is limited to those patients with obstructing stricture-related disease, and even liver transplantation has a risk of disease recurrence. Surveillance for inflammatory bowel disorders, metabolic bone disease, and malignancy is paramount when managing such patients. This article provides an overview of the condition with further focus on current therapeutic options and guidance on surveillance management.
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Affiliation(s)
| | | | - Amar Puttanna
- University Hospital North Midlands, Stoke-on-Trent, England, UK
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Ponsioen CY, Chapman RW, Chazouillères O, Hirschfield GM, Karlsen TH, Lohse AW, Pinzani M, Schrumpf E, Trauner M, Gores GJ. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process. Hepatology 2016; 63:1357-67. [PMID: 26418478 DOI: 10.1002/hep.28256] [Citation(s) in RCA: 136] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Accepted: 09/24/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. CONCLUSION At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials.
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Affiliation(s)
- Cyriel Y Ponsioen
- Department of Gastroenterology & Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Roger W Chapman
- Department of Gastroenterology & Hepatology, John Radcliffe Hospital, Headington, Oxford, United Kingdom
| | - Olivier Chazouillères
- AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie and Sorbonne Universités, UPMC Univ Paris, France
| | - Gideon M Hirschfield
- Center for Liver Research and NIHR Biomedical Research Unit University of Birmingham, Birmingham, United Kingdom
| | - Tom H Karlsen
- Norwegian PSC Research Center, Oslo University Hospital, Oslo, Norway
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg, Eppendorf, Germany
| | - Massimo Pinzani
- Division of Medicine, University College London, UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | - Erik Schrumpf
- Norwegian PSC Research Center, Oslo University Hospital, Oslo, Norway
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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de Vries EMG, Verheij J, Hubscher SG, Leeflang MMG, Boonstra K, Beuers U, Ponsioen CY. Applicability and prognostic value of histologic scoring systems in primary sclerosing cholangitis. J Hepatol 2015; 63:1212-9. [PMID: 26095184 DOI: 10.1016/j.jhep.2015.06.008] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 05/13/2015] [Accepted: 06/08/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. At present, there is no appropriate histologic scoring system available for PSC, evaluating both degree of necroinflammatory activity (grade) and fibrosis (stage). The aim of this study was to assess if three scoring systems, commonly used in different liver diseases could be applied for grading and/or staging of PSC. METHODS Sixty-four PSC patients from a Dutch cohort, who underwent diagnostic liver biopsy, were included. Staging was scored using Ishak, Nakanuma, and Ludwig systems. Grading was scored using Ishak and Nakanuma systems. Three measures of outcome were defined; transplant-free survival, time to liver transplantation (LTx) and occurrence of cirrhosis related symptoms (CRS). Association of grade and stage with outcome was estimated using Kaplan-Meier log-rank test, and Cox regression analysis. Correlation with biochemistry was assessed by Spearman's rank test. RESULTS There were strong associations between disease stage measured by Ishak, Nakanuma, and Ludwig staging systems with both outcome measuring transplant-free survival (Hazard ratio (HR) 2.56; 95% CI 1.11-5.89, HR 6.53; 95% CI 2.01-21.22, HR 1.94; 95% CI 1.00-3.79, respectively), and time to LTx (HR 4.18; 95%CI 1.51-11.56, HR 7.05; 95% CI 1.77-28.11, HR 3.13; 95%CI 1.42-6.87, respectively). Ishak and Nakanuma grading systems were not associated with CRS. Weak correlations between histopathology and liver biochemistry were shown. CONCLUSION Applying the Nakanuma, Ishak, and Ludwig histopathological staging systems is feasible and clinically relevant given their association with transplant-free survival and time to LTx. This suggests that these staging systems could be likely candidates for surrogate endpoints and stratification purposes in clinical trials in PSC.
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Affiliation(s)
- Elisabeth M G de Vries
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Stefan G Hubscher
- School of Cancer Sciences, University of Birmingham and Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | - Mariska M G Leeflang
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands
| | - Kirsten Boonstra
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
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Zhu GQ, Shi KQ, Huang GQ, Wang LR, Lin YQ, Braddock M, Chen YP, Zhou MT, Zheng MH. A network meta-analysis of the efficacy and side effects of UDCA-based therapies for primary sclerosing cholangitis. Oncotarget 2015; 6:26757-26769. [PMID: 26378046 PMCID: PMC4694950 DOI: 10.18632/oncotarget.5610] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 08/28/2015] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES Therapies for treatment of patients with primary sclerosing cholangitis (PSC) include administration of ursodeoxycholic acid (UDCA) alone, or combination with metronidazole (MTZ) or mycophenolate mofetil (MMF), respectively. However, the optimum regimen still remains inconclusive. We aimed to compare interventions in terms of patient mortality or liver transplantation (MOLT), progression of liver histological stage (POLHS), serum bilirubin, alkaline phosphatase (ALP) levels and adverse events (AE). METHODS We searched PubMed, Embase and the Cochrane Library for randomized controlled trials until 31, Jan 2015. We estimated hazard ratios (HRs), odds ratios (ORs) and mean difference (MD) between treatments on clinical outcomes. Sensitivity analyses based on the dose of UDCA, quality of trials or treatment duration were also performed. RESULTS Ten RCTs were included. Compared with UDCA plus MTZ, UDCA (HR 0.28, 95%CI 0.01-3.41), UDCA plus MMF (HR 0.08, 95%CI 0.00-4.18), or OBS (HR 0.28, 95%CI 0.01-3.98) all provided an increased risk of MOLT. UDCA provided a significant reduction in bilirubin and ALP levels compared with OBS (MD -13.92, P < 0.001; MD -484.34, P < 0.001; respectively). With respect to POLHS, although differing not significantly, UDCA plus MTZ had a tendency to improve LHS more than UDCA (OR 1.33), UDCA plus MMF (OR 3.24) or OBS (OR 1.08). Additionally, UDCA plus MTZ (MD -544.66, P < 0.001) showed a significant reduction in ALP levels compared with OBS, but appeared to be associated with more AEs compared with UDCA (OR 5.09), UDCA plus MMF (OR 4.80) or OBS (OR 7.21). CONCLUSIONS MTZ plus UDCA was the most effective therapy in survival rates and liver histological progression.
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Affiliation(s)
- Gui-Qi Zhu
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ke-Qing Shi
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou China
| | - Gui-Qian Huang
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Renji School of Wenzhou Medical University, Wenzhou China
| | - Li-Ren Wang
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Yi-Qian Lin
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Renji School of Wenzhou Medical University, Wenzhou China
| | - Martin Braddock
- Global Medicines Development, AstraZeneca R&D, Loughborough, United Kingdom
| | - Yong-Ping Chen
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou China
| | - Meng-Tao Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ming-Hua Zheng
- Department of Infection and Liver Diseases, Liver Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou China
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Lindor KD, Kowdley KV, Harrison ME. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol 2015; 110:646-59; quiz 660. [PMID: 25869391 DOI: 10.1038/ajg.2015.112] [Citation(s) in RCA: 330] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Accepted: 03/02/2015] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis is a chronic cholestatic liver disease that can shorten life and may require liver transplantation. The cause is unknown, although it is commonly associated with colitis. There is no approved or proven therapy, although ursodeoxycholic acid is used by many on an empiric basis. Complications including portal hypertension, fat-soluble vitamin deficiency, metabolic bone diseases, and development of cancers of the bile duct or colon can occur.
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Affiliation(s)
- Keith D Lindor
- 1] College of Health Solutions, Arizona State University, Phoenix, Arizona, USA [2] Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | - Kris V Kowdley
- Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle, Washington, USA
| | - M Edwyn Harrison
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
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Abstract
PURPOSE OF REVIEW Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin. There is no medical treatment of proven benefit on survival; once patients have progressed to end-stage liver disease, the only treatment option is liver transplantation. RECENT FINDINGS Over the last years, some progress has been made in identifying biomarkers of PSC disease progression. Categories that can be distinguished include clinical and biochemical biomarkers, histology, imaging, prognostic modelling and genetics. With this review, we summarize biomarkers for progression of PSC from these six categories, which have been studied to date. SUMMARY Biomarkers for the progression of PSC disease course can be used for several purposes. First of all, they can be implemented as surrogate endpoints for clinical trials. Second, biomarkers of disease progression form the basis of prognostic modelling, which is needed for proper patient counselling and management. Lastly, these biomarkers may yield a better understanding of PSC pathogenesis.
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Benito de Valle M, Müller T, Björnsson E, Otten M, Volkmann M, Guckelberger O, Wiedenmann B, Sadik R, Schott E, Andersson M, Berg T, Lindkvist B. The impact of elevated serum IgG4 levels in patients with primary sclerosing cholangitis. Dig Liver Dis 2014; 46:903-8. [PMID: 25091876 DOI: 10.1016/j.dld.2014.06.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2014] [Revised: 05/24/2014] [Accepted: 06/28/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Elevated IgG4 levels have been reported among patients with primary sclerosing cholangitis. Epidemiological data has only been provided from tertiary centres. AIMS To investigate the prevalence of elevated IgG4 levels and to compare prognosis between patients with and without elevated IgG4 levels in serum in two European cohorts of patients with primary sclerosing cholangitis. METHODS Serum IgG4-levels were measured in a consecutive series of patients from Berlin, and retrospectively collected in a population-based cohort from Sweden (total N=345). Cox's proportional hazard analysis was used to calculate relative risks for liver-related death or liver transplantation and cholangiocarcinoma. RESULTS Elevated IgG4 values were demonstrated in 10% of patients. A previous history of pancreatitis, combined intra- and extrahepatic biliary involvement and jaundice were independently associated with elevated IgG4 in multivariate analysis. IgG4 status was not associated with an increased risk for the combined endpoint liver-related death or liver transplantation or cholangiocarcinoma. CONCLUSION The prevalence of elevated IgG4 values among European patients with primary sclerosing cholangitis is similar to what previously has been reported from the United States. Elevated IgG4 was not associated with an increased risk of liver transplantation or liver-related death or cholangiocarcinoma.
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Affiliation(s)
| | - Tobias Müller
- Institute of Medicine, Hepatology and Gastroenterology, University Hospital Charité, Campus Virchow Clinic, Berlin, Germany
| | - Einar Björnsson
- Department of Internal Medicine, Section of Gastroenterology and Hepatology, The National University Hospital, Reykjavik, Iceland
| | - Morgane Otten
- Occupational Health Centrum, University Hospital The Charité, Campus Virchow Clinic, Berlin, Germany
| | | | - Olaf Guckelberger
- General and Transplantation Surgery Clinic, University Hospital The Charité, Campus Virchow Clinic, Berlin, Germany
| | - Bertram Wiedenmann
- Institute of Medicine, Hepatology and Gastroenterology, University Hospital Charité, Campus Virchow Clinic, Berlin, Germany
| | - Riadh Sadik
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Eckart Schott
- Institute of Medicine, Hepatology and Gastroenterology, University Hospital Charité, Campus Virchow Clinic, Berlin, Germany
| | - Mats Andersson
- Department of Radiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Thomas Berg
- Gastroenterology and Reumatology Clinic, Hepatology Section, University Hospital Leipzig, Germany
| | - Björn Lindkvist
- Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
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40
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Abstract
Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.
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Affiliation(s)
- Hanh D Vo
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital at Downstate, SUNY-Downstate Medical Center, Brooklyn, NY
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Ali AH, Carey EJ, Lindor KD. An overview of current and future therapeutic strategies for the treatment of primary sclerosing cholangitis. Expert Opin Orphan Drugs 2014. [DOI: 10.1517/21678707.2014.908701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Eksteen B. Advances and controversies in the pathogenesis and management of primary sclerosing cholangitis. Br Med Bull 2014; 110:89-98. [PMID: 24795363 DOI: 10.1093/bmb/ldu008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a chronic immune-mediated liver disease that results in end-stage liver disease requiring liver transplantation. PSC is closely associated with inflammatory bowel disease (IBD) with 70% of patients with PSC also suffering from IBD. SOURCES OF DATA Data for this review were obtained from PubMed. AREAS OF AGREEMENT Historical and genome-wide association studies have established a strong human leukocyte antigen (HLA) linkage to PSC and defined specific haplotypes associated with enhanced PSC risk. Fifteen non-HLA loci have been defined in PSC. AREAS OF CONTROVERSY The biological role of risk loci in PSC and their place in PSC pathogenesis remain speculative but suggest significant interactions with the host microbiome and therapeutic opportunities. GROWING POINTS Genetics provides a platform to systematically target emerging therapies in PSC. AREAS TIMELY FOR DEVELOPING RESEARCH Linking PSC genotypes with biology and disease phenotypes paves the way for a personalized medicine approach to manage PSC.
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Affiliation(s)
- Bertus Eksteen
- Division of Gastroenterology and Hepatology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
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Wells MM, Croome KP, Boyce E, Chandok N. Roux-en-Y choledochojejunostomy versus duct-to-duct biliary anastomosis in liver transplantation for primary sclerosing cholangitis: a meta-analysis. Transplant Proc 2014; 45:2263-71. [PMID: 23953538 DOI: 10.1016/j.transproceed.2013.01.066] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Accepted: 01/14/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Roux-en-Y choledochojejunostomy and duct-to-duct anastomosis are potential methods for biliary reconstruction in liver transplantation (LT) for recipients with primary sclerosing cholangitis (PSC). However, there is controversy over which method yields superior outcomes. The purpose of this study was to evaluate the outcomes of duct-to-duct versus Roux-en-Y biliary anastomosis in patients undergoing LT for PSC. METHODS Studies comparing Roux-en-Y versus duct-to-duct anastomosis during LT for PSC were identified based on systematic searches of 9 electronic databases and multiple sources of gray literature. RESULTS The search identified 496 citations, including 7 retrospective series, and 692 patients met eligibility criteria. The use of duct-to-duct anastomosis was not associated with a significant difference in clinical outcomes, including 1-year recipient survival rates (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.65-1.60; P = .95), 1-year graft survival rates (OR, 1.11; 95% CI, 0.72-1.71; P = .64), risk of biliary leaks (OR, 1.23; 95% CI, 0.59-2.59; P = .33), risk of biliary strictures (OR, 1.99; 95% CI, 0.98-4.06; P = .06), or rate of recurrence of PSC (OR, 0.94; 95% CI, 0.19-4.78; P = .94). CONCLUSIONS There were no significant differences in 1-year recipient survival, 1-year graft survival, risk of biliary complications, and PSC recurrence between Roux-en-Y and duct-to-duct biliary anastomosis in LT for PSC.
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Affiliation(s)
- M M Wells
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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Saadi M, Yu C, Othman MO. A Review of the Challenges Associated with the Diagnosis and Therapy of Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2014; 2:45-52. [PMID: 26357617 PMCID: PMC4548359 DOI: 10.14218/jcth.2013.00021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 02/01/2014] [Accepted: 02/04/2014] [Indexed: 12/12/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disease that often leads to the development of cirrhosis. Complications of PSC include pruritus, fatigue, vitamin deficiencies, metabolic bone disease, dominant biliary strictures, gallstones, and hepatobiliary malignancies, most commonly cholangiocarcinoma (CCA). Despite the presumed autoimmune etiology of PSC, a clear benefit from immunosuppressive agents has not yet been established, and their use is limited by their side effects. Endoscopy is required in evaluation of biliary strictures in PSC to rule out the possibility of CCA. Liver transplantation is currently the only life-extending therapy for patients with end-stage disease. However, disease recurrence can be a source of morbidity and mortality as transplanted patients survive longer. Further studies are needed to develop an optimal therapeutic strategy for patients with PSC to decrease the incidence of complications of the disease, to decrease the need for transplantation, and to extend life expectancy.
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Affiliation(s)
- Mohammed Saadi
- Department of Medicine, Division of Gastroenterology and Hepatology, Texas Tech University Health Science Center-Paul L. Foster School of Medicine, El Paso, TX, USA
| | - Christine Yu
- Department of Medicine, Division of Gastroenterology and Hepatology, Texas Tech University Health Science Center-Paul L. Foster School of Medicine, El Paso, TX, USA
| | - Mohamed O Othman
- Department of Medicine, Division of Gastroenterology and Hepatology, Texas Tech University Health Science Center-Paul L. Foster School of Medicine, El Paso, TX, USA
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45
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Yimam KK, Bowlus CL. Diagnosis and classification of primary sclerosing cholangitis. Autoimmun Rev 2014; 13:445-50. [PMID: 24424180 DOI: 10.1016/j.autrev.2014.01.040] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/13/2013] [Indexed: 12/14/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease of the liver and that is characterized by progressive inflammation, fibrosis, and stricturing of the intrahepatic and extrahepatic bile ducts. It is progressive in most patients and leads to cirrhosis. It is a rare disease, mostly affecting people of northern European descent, males greater than females. The diagnosis is best established by contrast cholangiography, which reveals a characteristic picture of diffuse, multifocal strictures and focal dilation of the bile ducts, leading to a beaded appearance. Inflammatory bowel disease (IBD) is present in ~75% of the patients with PSC, mostly ulcerative colitis (~85% of the cases). In addition to biliary cirrhosis, complications of PSC include dominant strictures of the bile ducts, cholangitis, cholangiocarcinoma, colon dysplasia and cancer in patients with IBD, gallbladder polyps and cancer, and hepatic osteodystrophy. The etiology of PSC is not clear, but studies are ongoing. The median survival without liver transplantation is 12 to 15 years after diagnosis. Currently there are no effective treatments except liver transplantation. Immunosuppressive medications have not been shown to be effective but antibiotics and anti-fibrotic agents seem promising.
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Affiliation(s)
- Kidist K Yimam
- Division of Hepatology and Liver Transplant, California Pacific Medical Center, San Francisco, CA, United States
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, United States.
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Longman RS, Scherl EJ. Medical Management of Extraintestinal Manifestations of Ulcerative Colitis. MEDICAL THERAPY OF ULCERATIVE COLITIS 2014:377-391. [DOI: 10.1007/978-1-4939-1677-1_35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Abstract
Primary sclerosing cholangitis is the classic hepatobiliary manifestation of inflammatory bowel disease and is generally chronic and progressive. Patients frequently present with asymptomatic, anicteric cholestasis, but many develop progressive biliary strictures with time, leading to recurrent cholangitis, biliary cirrhosis, and end-stage liver disease. Medical treatment does not slow the progression of disease, and many patients need liver transplantation, after which recurrent disease is a risk. The increased incidence of hepatobiliary cancer, which is not related to the underlying severity of biliary fibrosis, is of particular concern. Risk of colorectal cancer is also increased in patients with coexistent inflammatory bowel disease. Mechanistic insights have arisen from studies of secondary sclerosing cholangitis, in which a similar clinical profile is associated with a specific cause, and genomic studies have elucidated potential disease-initiating pathways in the primary form. The close association between inflammatory bowel disease and primary sclerosing cholangitis underscores the need to further understand the role of environmental factors in generation of lymphocytes that are postulated to be retargeted, deleteriously, to the biliary tree. Treatment of primary sclerosing cholangitis is confined to supportive measures, but advances in pathobiology suggest that new stratified approaches will soon be available.
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Affiliation(s)
- Gideon M Hirschfield
- Centre for Liver Research, National Institute for Health Research Biomedical Research Unit, University of Birmingham, Birmingham, UK.
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Kim JH, Byun JH, Kim SY, Lee SS, Kim HJ, Kim MH, Lee MG. Sclerosing cholangitis with autoimmune pancreatitis versus primary sclerosing cholangitis: comparison on endoscopic retrograde cholangiography, MR cholangiography, CT, and MRI. Acta Radiol 2013; 54:601-7. [PMID: 23528564 DOI: 10.1177/0284185113481018] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND It is essential to differentiate sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) from primary sclerosing cholangitis (PSC) as the treatment and prognosis of the two diseases are totally different. PURPOSE To compare image findings of SC-AIP and PSC on endoscopic retrograde cholangiography (ERC), magnetic resonance cholangiography (MRC), computed tomography (CT), and magnetic resonance imaging (MRI). MATERIAL AND METHODS Two radiologists retrospectively reviewed ERC, MRC, CT, and MRI in 28 SC-AIP and 23 PSC patients in consensus. Factors evaluated included the length, location, and multiplicity of bile duct stricture, the presence of characteristic cholangiographic features of PSC on ERC and MRC, and the presence, location, thickness, and pattern of bile duct wall thickening on CT and MRI. RESULTS On ERC, focal stricture, multifocal and intrahepatic bile duct stricture, and beaded, pruned-tree, and diverticulum-like appearance were more frequent in PSC than in SC-AIP patients (P ≤ 0.006). On MRC, multifocal and intrahepatic bile duct stricture and pruned-tree appearance were more frequent in PSC than in SC-AIP patients (P ≤ 0.044). On CT and MRI, the bile duct wall was thicker (5.1 mm vs. 3.1 mm; P = 0.033 and 4.3 mm vs. 3.0 mm; P = 0.01, respectively) in SC-AIP than in PSC patients. PSC was more frequently associated with intrahepatic bile duct wall thickening on both CT (93% vs. 50%; P = 0.024) and MRI (100% vs. 50%; P = 0.023) than SC-AIP. CONCLUSION The combination of ERC or MRC with cross-sectional images, including CT and MRI, may be helpful in differentiating between SC-AIP and PSC.
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Affiliation(s)
- Jin Hee Kim
- Department of Radiology and Research Institute of Radiology
| | - Jae Ho Byun
- Department of Radiology and Research Institute of Radiology
| | - So Yeon Kim
- Department of Radiology and Research Institute of Radiology
| | - Seung Soo Lee
- Department of Radiology and Research Institute of Radiology
| | | | - Myung-Hwan Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Moon-Gyu Lee
- Department of Radiology and Research Institute of Radiology
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Tabibian JH, Weeding E, Jorgensen RA, Petz JL, Keach JC, Talwalkar JA, Lindor KD. Randomised clinical trial: vancomycin or metronidazole in patients with primary sclerosing cholangitis - a pilot study. Aliment Pharmacol Ther 2013; 37:604-612. [PMID: 23384404 DOI: 10.1111/apt.12232] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2012] [Revised: 12/24/2012] [Accepted: 01/14/2013] [Indexed: 12/15/2022]
Abstract
BACKGROUND Emerging data suggest that oral antibiotics may have therapeutic effects in primary sclerosing cholangitis (PSC), but published studies are limited. AIMS To investigate the safety and efficacy of oral vancomycin and metronidazole in patients with PSC. METHODS Thirty-five patients with PSC were randomised in a double-blind manner into four groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks. The primary endpoint was decrease in alkaline phosphatase (ALK) at 12 weeks. Secondary end points included serum bilirubin and Mayo PSC risk score; pruritus; and adverse effects (AEs). Nonparametric tests were used for analysis. RESULTS The primary endpoint was reached in the low-dose (-43% change in ALK, P = 0.03) and high-dose (-40%, P = 0.02) vancomycin groups, with two patients in the former experiencing ALK normalisation. Bilirubin decreased significantly in the low-dose metronidazole group (-20%, P = 0.03) and trended towards significance in the low-dose vancomycin group (-33%, P = 0.06). Mayo PSC risk score decreased significantly in the low-dose vancomycin (-0.55, P = 0.02) and low-dose metronidazole group (-0.16, P = 0.03). Pruritus decreased significantly in the high-dose metronidazole group (-3.4, P = 0.03). AEs led to medication discontinuation in six patients, four of whom were receiving metronidazole. CONCLUSIONS Both vancomycin and metronidazole demonstrated efficacy; however, only patients in the vancomycin groups reached the primary endpoint, and with less adverse effects. Larger, longer-term studies are needed to further examine the safety and efficacy of antibiotics as a potential treatment for patients with primary sclerosing cholangitis (clinicaltrials.gov NCT01085760).
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Affiliation(s)
- J H Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Tabibian JH, Lindor KD. Primary sclerosing cholangitis: a review and update on therapeutic developments. Expert Rev Gastroenterol Hepatol 2013; 7:103-114. [PMID: 23363260 DOI: 10.1586/egh.12.80] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease characterized by fibro-obliterative inflammation of the hepatic bile ducts. In a clinically significant proportion of patients, PSC progresses to cirrhosis, end-stage liver disease, and in some cases, cholangiocarcinoma. Despite clinical trials of nearly 20 different pharmacotherapies over several decades, safe and effective medical therapy, albeit critically needed, remains to be established. PSC is pathogenically complex, with genetic, immune, enteric microbial, environmental and other factors being potentially involved and, thus, not surprisingly, it manifests as a clinically heterogeneous disease with a relatively unpredictable course. It is likely that this complexity and clinical heterogeneity are responsible for the negative results of clinical trials, but novel insights about and approaches to PSC may shift this trend. The authors herein provide a review of previously tested pharmacologic agents, discuss emerging fundamental concepts and present viewpoints regarding how identifying therapies for PSC may evolve over the next several years.
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Affiliation(s)
- James H Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.
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