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Hu T, Tong J, Yang Y, Yuan C, Zhang J, Wang J. Ursodeoxycholic acid relieves clinical severity of COVID-19 in patients with chronic liver diseases. Front Med (Lausanne) 2025; 12:1494248. [PMID: 39981079 PMCID: PMC11839632 DOI: 10.3389/fmed.2025.1494248] [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] [Received: 09/10/2024] [Accepted: 01/24/2025] [Indexed: 02/22/2025] Open
Abstract
Background The potential effect of ursodeoxycholic acid (UDCA) on the clinical outcomes of SARS-CoV-2 in patients with chronic liver diseases has been a subject of ongoing debate since the onset of the SARS-CoV-2 pandemic in 2019. This study aims to investigate the effect of UDCA on the prognosis of SARS-CoV-2 infection in patients with chronic liver diseases. Methods A total of 926 patients with chronic liver diseases who contracted their first SARS-CoV-2 infection during December 2022 to January 2023, were included in this study. Participants were divided into two groups based on the use of UDCA: the UDCA cohort (n = 329) and the non-UDCA cohort (n = 597). After performing a 1:1 age-and sex-matching, the analysis proceeded with 309 patients from each group for further evaluation. Results In the UDCA-treated cohort, the incidence of asymptomatic SARS-CoV-2 infections was significantly higher, with 30.1% of patients affected, compared to 6.47% in the non-UDCA group (p < 0.0001). Multivariable analysis identified UDCA as a protective factor against symptomatic infections, yielding an odds ratio (OR) of 4.77 (95% CI: 2.70-8.44, p < 0.001). Furthermore, age over 50 was found to be a risk factor for asymptomatic infections in the UDCA cohort, with an adjusted OR of 1.51 (95% CI: 1.01-2.24, p = 0.05). Conclusion The study suggests that UDCA therapy may improve clinical outcomes in patients with chronic liver diseases patients who are infected with SARS-CoV-2, highlighting its potential role in improving prognosis within this vulnerable population. However, further research is required to validate these findings and to elucidate the mechanisms underlying UDCA's protective effect.
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Affiliation(s)
- Tiantian Hu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Fudan University School of Nursing, Fudan University, Shanghai, China
| | - Jie Tong
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yunhui Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Changrong Yuan
- Fudan University School of Nursing, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Infectious Diseases and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China
- Department of Infectious Diseases, Jing’An Branch of Huashan Hospital, Fudan University, Shanghai, China
| | - Jinyu Wang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Shanghai Institute of Infectious Diseases and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China
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2
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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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Faggiani I, Fanizza J, D’Amico F, Allocca M, Zilli A, Parigi TL, Barchi A, Danese S, Furfaro F. Extraintestinal Manifestations in Inflammatory Bowel Disease: From Pathophysiology to Treatment. Biomedicines 2024; 12:1839. [PMID: 39200303 PMCID: PMC11351332 DOI: 10.3390/biomedicines12081839] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/02/2024] [Accepted: 08/09/2024] [Indexed: 09/02/2024] Open
Abstract
The inflammatory bowel diseases (IBDs) are systemic conditions that affect not only the gastrointestinal tract but also other parts of the body. The presence of extraintestinal manifestations can significantly impact the quality of life in IBD patients. Peripheral arthritis, episcleritis, and erythema nodosum are frequently associated with active intestinal inflammation and often improve with standard treatment targeting intestinal inflammation. In contrast, anterior uveitis, ankylosing spondylitis, and primary sclerosing cholangitis typically occur independently of disease flares. The incidence of these conditions in individuals with IBD can reach up to 50% of patients over the course of their lifetime. In addition, some advanced therapies utilized for the treatment of IBD potentially result in side effects that may resemble extraintestinal manifestations. This review provides a thorough analysis of the pathophysiology and treatment of extraintestinal manifestations associated with Crohn's disease and ulcerative colitis.
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Affiliation(s)
- Ilaria Faggiani
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
- Gastroenterology and Endoscopy, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Jacopo Fanizza
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
- Gastroenterology and Endoscopy, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Ferdinando D’Amico
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
| | - Mariangela Allocca
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
| | - Alessandra Zilli
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
| | - Tommaso Lorenzo Parigi
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
- Gastroenterology and Endoscopy, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Alberto Barchi
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
- Gastroenterology and Endoscopy, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
- Gastroenterology and Endoscopy, Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Federica Furfaro
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, 20132 Milan, Italy; (I.F.); (J.F.); (F.D.); (M.A.); (A.Z.); (T.L.P.); (S.D.); (F.F.)
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Dai L, Ye Y, Mugaany J, Hu Z, Huang J, Lu C. Leveraging pQTL-based Mendelian randomization to identify new treatment prospects for primary biliary cholangitis and primary sclerosing cholangitis. Aging (Albany NY) 2024; 16:9228-9250. [PMID: 38809509 PMCID: PMC11164478 DOI: 10.18632/aging.205867] [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: 12/26/2023] [Accepted: 04/15/2024] [Indexed: 05/30/2024]
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune disorders characterized by progressive and chronic damage to the bile ducts, presenting clinicians with significant challenges. The objective of this study is to identify potential druggable targets to offer new avenues for treatment. A Mendelian randomization analysis was performed to identify druggable targets for PBC and PSC. This involved obtaining Cis-protein quantitative trait loci (Cis-pQTL) data from the deCODE database to serve as exposure. Outcome data for PBC (557 cases and 281,127 controls) and PSC (1,715 cases and 330,903 controls) were obtained from the FINNGEN database. Colocalization analysis was conducted to determine whether these features share the same associated SNPs. Validation of the expression level of druggable targets was done using the GSE119600 dataset and immunohistochemistry for clinical samples. Lastly, the DRUGBANK database was used to predict potential drugs. The MR analysis identified eight druggable targets each for PBC and PSC. Subsequent summary-data-based MR and colocalization analyses showed that LEFTY2 had strong evidence as a therapeutic candidate for PBC, while HSPB1 had moderate evidence. For PSC, only FCGR3B showed strong evidence as a therapeutic candidate. Additionally, upregulated expression of these genes was validated in PBC and PSC groups by GEO dataset and clinical samples. This study identifies two novel druggable targets with strong evidence for therapeutic candidates for PBC (LEFTY2 and HSPB1) and one for PSC (FCGR3B). These targets offer new therapeutic opportunities to address the challenging nature of PBC and PSC treatment.
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Affiliation(s)
- Lei Dai
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Centre Lihuili Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315040, China
| | - Yunyan Ye
- Department of Ophthalmology, Ningbo Medical Centre Lihuili Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315040, China
| | - Joseph Mugaany
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Centre Lihuili Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315040, China
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Zetong Hu
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Centre Lihuili Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315040, China
- Health Science Center, Ningbo University, Ningbo 315211, China
| | - Jing Huang
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Centre Lihuili Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315040, China
| | - Changjiang Lu
- Department of Hepato-Pancreato-Biliary Surgery, Ningbo Medical Centre Lihuili Hospital, The Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315040, China
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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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Gordon H, Burisch J, Ellul P, Karmiris K, Katsanos K, Allocca M, Bamias G, Barreiro-de Acosta M, Braithwaite T, Greuter T, Harwood C, Juillerat P, Lobaton T, Müller-Ladner U, Noor N, Pellino G, Savarino E, Schramm C, Soriano A, Michael Stein J, Uzzan M, van Rheenen PF, Vavricka SR, Vecchi M, Zuily S, Kucharzik T. ECCO Guidelines on Extraintestinal Manifestations in Inflammatory Bowel Disease. J Crohns Colitis 2024; 18:1-37. [PMID: 37351850 DOI: 10.1093/ecco-jcc/jjad108] [Citation(s) in RCA: 74] [Impact Index Per Article: 74.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Indexed: 06/24/2023]
Affiliation(s)
- Hannah Gordon
- Department of Gastroenterology, Barts Health NHS Trust, London, Centre for Immunobiology, Blizard Institute, Faculty of Medicine, Barts & The London Medical School, Queen Mary University of London, UK
| | - Johan Burisch
- Gastrounit, medical division, Hvidovre Hospital, University of Copenhagen, Copenhagen Center for Inflammatory Bowel Disease in Children, Adolescents and Adults, Hvidovre Hospital, University of Copenhagen, Denmark
| | - Pierre Ellul
- Department of Medicine, Division of Gastroenterology, Mater Dei Hospital, Msida, Malta
| | | | - Konstantinos Katsanos
- Department of Gastroenterology and Hepatology, Division of Internal Medicine, University and Medical School of Ioannina, Ioannina, Greece
| | - Mariangela Allocca
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Giorgos Bamias
- GI Unit, 3rd Academic Department of Internal Medicine, National and Kapodistrian University of Athens, Sotiria Hospital, Athens, Greece
| | - Manuel Barreiro-de Acosta
- University Hospital Santiago De Compostela CHUS, Department of Gastroenterology - IBD Unit, Santiago De Compostela, Spain
| | - Tasanee Braithwaite
- School of Immunology and Microbiology, King's College London, The Medical Eye Unit, Guy's and St Thomas' Hospital NHS Foundation Trust, London, UK
| | - Thomas Greuter
- Division of Gastroenterology and Hepatology, GZO - Zurich Regional Health Center, Wetzikon, Division of Gastroenterology and Hepatology, University Hospital Lausanne - CHUV, Lausanne, Switzerland; Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Catherine Harwood
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London; Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, UK
| | - Pascal Juillerat
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland; Crohn and Colitis Center, Gastro-entérologie Beaulieu SA, Lausanne, Switzerland
| | - Triana Lobaton
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent; Department of Gastroenterology, Ghent University Hospital, Ghent, Belgium
| | - Ulf Müller-Ladner
- Department of Rheumatology and Clinical Immunology, Campus Kerckhoff, Justus Liebig University Giessen, Bad Nauheim, Germany
| | - Nurulamin Noor
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Gianluca Pellino
- Vall d'Hebron University Hospital, Universitat Autonoma de Barcelona UAB, Barcelona, Spain; Department of Advanced Medical and Surgical Sciences, Università degli Studi della Campania 'Luigi Vanvitelli', Naples, Italy
| | - Edoardo Savarino
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy; Gastroenterology Unit, Azienda Ospedale Università di Padova, Padua, Italy
| | - Christoph Schramm
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology (HCTI), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandra Soriano
- Gastroenterology Division and IBD Center, Internal Medicine Department, Azienda Unità Sanitaria Locale - IRCCS, 42122 Reggio Emilia, Italy
| | - Jürgen Michael Stein
- Interdisciplinary Crohn Colitis Centre Rhein-Main, Frankfurt/Main, Department of Gastroenterology and Clinical Nutrition, DGD Clinics Sachsenhausen, Frankfurt/Main, Germany
| | - Mathieu Uzzan
- Department of Gastroenterology, Hôpital Henri Mondor, APHP, Créteil, France
| | - Patrick F van Rheenen
- Department of Paediatric Gastroenterology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital, Zurich, Switzerland
| | - Maurizio Vecchi
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Stephane Zuily
- Vascular Medicine Division and French Referral Center for Rare Auto-Immune Diseases, Université de Lorraine, INSERM, DCAC and CHRU-Nancy, Nancy, France
| | - Torsten Kucharzik
- Department of Gastroenterology, Lüneburg Hospital, University of Münster, Lüneburg, Germany
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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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Shah YR, Nombera-Aznaran N, Guevara-Lazo D, Calderon-Martinez E, Tiwari A, Kanumilli S, Shah P, Pinnam BSM, Ali H, Dahiya DS. Liver transplant in primary sclerosing cholangitis: Current trends and future directions. World J Hepatol 2023; 15:939-953. [PMID: 37701917 PMCID: PMC10494561 DOI: 10.4254/wjh.v15.i8.939] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/23/2023] [Accepted: 08/11/2023] [Indexed: 08/22/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic and progressive immune-mediated cholangiopathy causing biliary tree inflammation and scarring, leading to liver cirrhosis and end-stage liver disease. Diagnosis of PSC is challenging due to its nonspecific symptoms and overlap with other liver diseases. Despite the rising incidence of PSC, there is no proven medical therapy that can alter the natural history of the disease. While liver transplantation (LT) is the most effective approach for managing advanced liver disease caused by PSC, post-transplantation recurrence of PSC remains a challenge. Therefore, ongoing research aims to develop better therapies for PSC, and continued efforts are necessary to improve outcomes for patients with PSC. This article provides an overview of PSC's pathogenesis, clinical presentation, and management options, including LT trends and future aspects. It also highlights the need for improved therapeutic options and ethical considerations in providing equitable access to LT for patients with PSC. Additionally, the impact of liver transplant on the quality of life and psychological outcomes of patients with PSC is discussed. Ongoing research into PSC's pathogenesis and post-transplant recurrence is crucial for improved understanding of the disease and more effective treatment options.
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Affiliation(s)
- Yash R Shah
- Department of Internal Medicine, Trinity Health Oakland, Pontiac, MI 48341, United States
| | | | - David Guevara-Lazo
- Faculty of Medicine, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
| | - Ernesto Calderon-Martinez
- Department of Internal Medicine, Universidad Nacional Autonoma de Mexico, Ciudad De Mexico 04510, Mexico
| | - Angad Tiwari
- Department of Internal Medicine, Maharani Laxmi Bai Medical College, Jhansi 284001, India
| | | | - Purva Shah
- Department of Postgraduate Education, Harvard Medical School, Boston, MA 02115, United States
| | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger Hospital of Cook County, Chicago, IL 60612, United States
| | - Hassam Ali
- Department of Internal Medicine, East Carolina University/Brody School of Medicine, Greenville, NC 27858, United States
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology and Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, United States.
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9
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Méndez-Sánchez N, Coronel-Castillo CE, Ordoñez-Vázquez AL. Current Therapies for Cholestatic Diseases. Biomedicines 2023; 11:1713. [PMID: 37371808 PMCID: PMC10296345 DOI: 10.3390/biomedicines11061713] [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: 04/14/2023] [Revised: 06/03/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Cholestasis is a condition characterized by decrease in bile flow due to progressive pathological states that lead to chronic cholestatic liver diseases which affect the biliary tree at the intrahepatic level and extrahepatic level. They induce complications such as cirrhosis, liver failure, malignancies, bone disease and nutritional deficiencies that merit close follow-up and specific interventions. Furthermore, as those conditions progress to liver cirrhosis, there will be an increase in mortality but also an important impact in quality of life and economic burden due to comorbidities related with liver failure. Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. With a general view of therapeutic options and their molecular targets, this review addresses the pathophysiology of cholangiopathies. The objective is to provide clinicians with an overview of the safety and efficacy of the treatment of cholangiopathies based on the current evidence.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Unit Liver Research, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Mexico City 14050, Mexico;
- Faculty of Medicine, National Autonomous University of Mexico, Av. Universidad 3004, Copilco Universidad, Coyoacán, Mexico City 04510, Mexico
| | - Carlos E. Coronel-Castillo
- Internal Medicine Section, Central Military Hospital, Manuel Ávila Camacho s/n, Militar, Miguel Hidalgo, Ciudad de México 11200, Mexico;
| | - Ana L. Ordoñez-Vázquez
- Unit Liver Research, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Mexico City 14050, Mexico;
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10
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 162] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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11
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Hatami B, Mosala M, Hassani AH, Ardakani MJE, Gholami S, Zali MR. Fenofibrate in primary sclerosing cholangitis; a randomized, double-blind, placebo-controlled trial. Pharmacol Res Perspect 2022; 10:e00984. [PMID: 35822553 PMCID: PMC9277608 DOI: 10.1002/prp2.984] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 11/12/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with no medical treatment proven to improve survival and postpone liver transplantation. Previous studies have shown the effectiveness of fibrates in primary biliary cholangitis. The current study prospectively evaluated the effect of fenofibrate on PSC patients. We administered 200 mg of fenofibrate to PSC patients in the intervention arm and a placebo in the control arm once per day for 6 months and evaluated liver biochemistries (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin, and albumin) and the Mayo Risk Score at the start and end of the study. The primary endpoint was defined as a reduction greater than 50% or normalization of ALP levels. Secondary endpoints were an improvement in the Mayo Risk Score and serum bilirubin levels. Thirty patients were included (19 female, 11 male, 40.2 ± 9.2 years old), all under treatment with Ursodeoxycholic acid prior to this study. ALP and ALT levels significantly decreased in the fenofibrate group, by 64.7% (mean difference = 557, p = 0.004, 95% CI = 208.72, 905.27) and 52.78%, (p = 0.006), respectively. The primary endpoint was achieved in 66.7% of patients (10 in 15) in the fenofibrate group versus 20% of patients (3 in 15) in the placebo group (p = 0.009). Other endpoints were not met. As studies have demonstrated lower levels of ALP may improve outcomes for PSC, our study resulted in significantly lower levels of ALP in the fenofibrate group, which could translate into better disease prognosis in PSC.
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Affiliation(s)
- Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhde Mosala
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Hassani
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Ehsani Ardakani
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Gholami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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12
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He Q, Liu L, Wei J, Jiang J, Rong Z, Chen X, Zhao J, Jiang K. Roles and action mechanisms of bile acid-induced gastric intestinal metaplasia: a review. Cell Death Dis 2022; 8:158. [PMID: 35379788 PMCID: PMC8979943 DOI: 10.1038/s41420-022-00962-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/11/2022] [Accepted: 03/17/2022] [Indexed: 12/13/2022]
Abstract
Gastric intestinal metaplasia (IM) is a precancerous lesion that increases the risk of subsequent gastric cancer (GC) development. Therefore, the mechanism of IM has been the focus of basic and clinical research. Helicobacter pylori (H. pylori) infection has been recognized as the main pathogenesis of gastric IM. However, more and more studies have shown that chronic inflammation of gastric mucosa caused by bile reflux is the key pathogenic factor of gastric IM. Bile reflux activates the expression of IM biomarkers via the bile acid receptor. In addition, microRNAs, exosomes, and epigenetics are also involved in the occurrence and development of bile acid-induced gastric IM. Currently, the relevant research is still very few. The molecular mechanism of the phenotypic transformation of gastrointestinal epithelial cells induced by bile acids has not been fully understood. This article mainly reviews the physiology and pathology of bile acid, mechanism of gastric IM induced by bile acid, bile acid receptors, and so on, in order to provide reference for further research.
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Affiliation(s)
- Qijin He
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Limin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Jingge Wei
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Jiaying Jiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Zheng Rong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China.
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China.
| | - Kui Jiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, No. 154 Anshan Road, Tianjin, 300052, China.
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13
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Cariello M, Gadaleta RM, Moschetta A. The gut-liver axis in cholangiopathies: focus on bile acid based pharmacological treatment. Curr Opin Gastroenterol 2022; 38:136-143. [PMID: 35034082 PMCID: PMC10826921 DOI: 10.1097/mog.0000000000000807] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW This review analyses the main features of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and provides an overview of the currently available (bile acid) bile acid related treatments. RECENT FINDINGS In PBC, biliary injury is the consequence of a dysregulated intrahepatic and systemic immune response. Given the close association between PSC and inflammatory bowel disease (IBD), the microbiota represents an important factor in the development of PSC. Bile acid based pharmacological treatments could represent promising therapeutic strategies in the management of cholangiopathies. SUMMARY Cholangiopathies include a spectrum of diseases resulting in cholestasis, an impairment of bile flow in the biliary tree, leading to biliary obstruction and damage as well as liver inflammation and fibrosis. PSC and PBC are highly heterogeneous cholangiopathies and progressive disorders with defined pathophysiological mechanisms. Curative treatments have not been established, and although their prevalence is low, they are a frequent indication for liver transplantation in the advanced stages of cholangiopathies. These diseases still present with unmet therapeutic strategies, also taking into account that on average 30-40% of patients undergoing liver transplantation will have recurrence of the original illness.
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Affiliation(s)
- Marica Cariello
- INBB, National Institute for Biostructures and Biosystems, Rome
| | - Raffaella M. Gadaleta
- Department of Interdisciplinary Medicine, ‘Aldo Moro’ University of Bari, Bari, Italy
| | - Antonio Moschetta
- INBB, National Institute for Biostructures and Biosystems, Rome
- Department of Interdisciplinary Medicine, ‘Aldo Moro’ University of Bari, Bari, Italy
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14
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Gao W, Li Z, Chu H, Yuan H, Hu L, Yao L, Zhang L, Wang W, Lin R, Yang L. Ursodeoxycholic Acid in Liver Cirrhosis: A Chinese Perspective. PHARMACOTHERAPY FOR LIVER CIRRHOSIS AND ITS COMPLICATIONS 2022:81-111. [DOI: 10.1007/978-981-19-2615-0_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Mazza S, Soro S, Verga MC, Elvo B, Ferretti F, Cereatti F, Drago A, Grassia R. Liver-side of inflammatory bowel diseases: Hepatobiliary and drug-induced disorders. World J Hepatol 2021; 13:1828-1849. [PMID: 35069993 PMCID: PMC8727201 DOI: 10.4254/wjh.v13.i12.1828] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/16/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases (IBD), both in Crohn’s disease and ulcerative colitis (UC), and therefore represent a diagnostic challenge. Immune-mediated conditions include primary sclerosing cholangitis (PSC) as the main form, variant forms of PSC (namely small-duct PSC, PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis) and granulomatous hepatitis. PSC is by far the most common, presenting in up to 8% of IBD patients, more frequently in UC. Several genetic foci have been identified, but environmental factors are preponderant on disease pathogenesis. The course of the two diseases is typically independent. PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies. Risk of cholangiocarcinoma is significantly increased in PSC, as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis. No disease-modifying drugs are approved to date. Thus, PSC management is directed against symptoms and complications and includes medical therapies for pruritus, endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease. Other non-immune-mediated hepatobiliary disorders are gallstone disease, whose incidence is higher in IBD and reported in up to one third of IBD patients, non-alcoholic fatty liver disease, pyogenic liver abscess and portal vein thrombosis. Drug-induced liver injury (DILI) is an important issue in IBD, since most IBD therapies may cause liver toxicity; however, the incidence of serious adverse events is low. Thiopurines and methotrexate are the most associated with DILI, while the risk related to anti-tumor necrosis factor-α and anti-integrins is low. Data on hepatotoxicity of newer drugs approved for IBD, like anti-interleukin 12/23 and tofacitinib, are still scarce, but the evidence from other rheumatic diseases is reassuring. Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD, and adequate screening and vaccination is warranted. On the other hand, hepatitis C reactivation does not seem to be a real risk, and hepatitis C antiviral treatment does not influence IBD natural history. The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis, but it is of paramount importance to make a quick and accurate diagnosis, as it may influence the therapeutic management.
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Affiliation(s)
- Stefano Mazza
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Sara Soro
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Maria Chiara Verga
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Biagio Elvo
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Francesca Ferretti
- Gastroenterology Unit, ASST Fatebenefratelli-Sacco, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan 20157, Italy
| | - Fabrizio Cereatti
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Andrea Drago
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Roberto Grassia
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
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16
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The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities. J Clin Med 2021; 10:jcm10081763. [PMID: 33919600 PMCID: PMC8073106 DOI: 10.3390/jcm10081763] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/12/2021] [Accepted: 04/15/2021] [Indexed: 02/07/2023] Open
Abstract
Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two chronic cholestatic liver diseases affecting bile ducts that may progress to biliary cirrhosis. In the past few years, the increasing knowledge in the pathogenesis of both diseases led to a growing number of clinical trials and possible new targets for therapy. In this review, we provide an update on the treatments in clinical use and summarize the new drugs in trials for PBC and PSC patients. Farnesoid X Receptor (FXR) agonists and Pan-Peroxisome Proliferator-Activated Receptor (PPAR) agonists are the most promising agents and have shown promising results in both PBC and PSC. Fibroblast Growth Factor 19 (FGF19) analogues also showed good results, especially in PBC, while, although PBC and PSC are autoimmune diseases, immunosuppressive drugs had disappointing effects. Since the gut microbiome could have a potential role in the pathogenesis of PSC, recent research focused on molecules that could change the microbiome, with good results. The near future of the medical management of these diseases may include new treatments or a combination of multiple drugs targeting different signaling pathways at different stages of the diseases.
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17
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Rabiee A, Silveira MG. Primary sclerosing cholangitis. Transl Gastroenterol Hepatol 2021; 6:29. [PMID: 33824933 DOI: 10.21037/tgh-20-266] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/19/2020] [Indexed: 12/15/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by inflammatory destruction of the intrahepatic and/or extrahepatic bile ducts, leading to bile stasis, fibrosis, and ultimately to cirrhosis, and often requires liver transplantation (LT). PSC occurs more commonly in men, and is typically diagnosed between the ages of 30 and 40. Most cases occur in association with inflammatory bowel disease (IBD), which often precedes the development of PSC. PSC is usually diagnosed after detection of cholestasis during health evaluation or screening of patients with IBD. When symptomatic, the most common presenting symptoms are abdominal pain, pruritus, jaundice or fatigue. The etiology of PSC is poorly understood, but an increasing body of evidence supports the concept of cholangiocyte injury as a result of environmental exposure and an abnormal immune response in genetically susceptible individuals. PSC is a progressive disease, yet no effective medical therapy for halting disease progression has been identified. Management of PSC is mainly focused on treatment of symptoms and addressing complications. PSC can be complicated by bacterial cholangitis, dominant strictures (DSs), gallbladder polyps and adenocarcinoma, cholangiocarcinoma (CCA) and, in patients with IBD, colorectal malignancy. CCA is the most common malignancy in PSC with a cumulative lifetime risk of 10-20%, and accounts for a large proportion of mortality in PSC. LT is currently the only life-extending therapeutic approach for eligible patients with end-stage PSC, ultimately required in approximately 40% of patients. LT secondary to PSC has an excellent outcome compared to other LT indications, although the disease can recur and result in morbidity post-transplant.
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Affiliation(s)
- Anahita Rabiee
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Marina G Silveira
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
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18
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Samec MJ, Ramos GP, Simonetto DA. 59-Year-Old Man With Fever and Abdominal Pain. Mayo Clin Proc 2020; 95:2535-2539. [PMID: 33153638 DOI: 10.1016/j.mayocp.2020.03.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/02/2020] [Accepted: 03/12/2020] [Indexed: 10/23/2022]
Affiliation(s)
- Matthew J Samec
- Resident in Internal Medicine, Mayo Clinic School of Graduate Medical Education, Rochester, MN
| | - Guilherme Piovezani Ramos
- Resident in Internal Medicine, Mayo Clinic School of Graduate Medical Education, Rochester, MN. https://twitter.com/@GuiRamosMD
| | - Douglas A Simonetto
- Advisor to residents and Consultant in Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.
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19
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Raine T, Thomas JP, Brais R, Godfrey E, Carroll NR, Metz AJ. Test performance and predictors of accuracy of endoscopic ultrasound-guided fine-needle aspiration for diagnosing biliary strictures or masses. Endosc Int Open 2020; 8:E1537-E1544. [PMID: 33140008 PMCID: PMC7577792 DOI: 10.1055/a-1231-4948] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 06/05/2020] [Indexed: 12/11/2022] Open
Abstract
Background and study aims Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has emerged as an important method for obtaining a preoperative tissue diagnosis for suspected cholangiocarcinoma. However, doubts remain about test sensitivity. This study assessed the value and limitations of EUS-FNA in clinical practice. Patients and methods Patients undergoing EUS-FNA for biliary strictures/masses at a UK tertiary referral center from 2005 to 2014 were prospectively enrolled. Data on EUS-FNA findings, histology, and endoscopy and patient outcomes were collected to evaluate test performance and identify factors predictive of an inaccurate diagnostic result. Results Ninety-seven patients underwent a total of 112 EUS-FNA procedures. Overall test sensitivity for an initial EUS-FNA for suspected cholangiocarcinoma was 75 % (95 % CI 64 %-84 %), with specificity 100 % (95 % CI 85 %-100 %) and negative predictive value 0.62 (95 % CI 0.47-0.75). Hilar lesions, the presence of a biliary stent, and a diagnosis of PSC were significantly independently associated with an inaccurate result. For the most difficult cases, repeat sampling and use of the Papanicolaou cytopathology grading scale led to an increase in test sensitivity from 17 % to 100 % ( P = 0.015) with no loss of specificity. Conclusions EUS-FNA was found to be a useful method for obtaining a preoperative tissue diagnosis for patients with suspected cholangiocarcinoma. This study identified markers that can reduce test accuracy and measures that can improve test performance of EUS-FNA.
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Affiliation(s)
- Tim Raine
- Division of Gastroenterology, Department of Medicine, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK
| | - John P. Thomas
- Department of Gastroenterology, Norfolk and Norwich University Hospital, Norwich, UK
| | - Rebecca Brais
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Edmund Godfrey
- Department of Endoscopy, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Nicholas R. Carroll
- Department of Endoscopy, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Andrew J. Metz
- Department of Gastroenterology, Royal Melbourne Hospital, Melbourne, Australia
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20
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Ye HL, Zhang JW, Chen XZ, Wu PB, Chen L, Zhang G. Ursodeoxycholic acid alleviates experimental liver fibrosis involving inhibition of autophagy. Life Sci 2019; 242:117175. [PMID: 31843528 DOI: 10.1016/j.lfs.2019.117175] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 12/04/2019] [Accepted: 12/12/2019] [Indexed: 12/12/2022]
Abstract
AIMS Ursodeoxycholic acid (UDCA) has been widely used in the treatment of primary biliary cholangitis (PBC) with chronic liver fibrosis, but its detailed mechanism remains unclear. This study was aimed to determine whether autophagic signaling is involved in the therapeutic effect of UDCA on liver fibrosis. METHODS By using hepatic stellate cell (HSC) line LX2 and CCl4-induced fibrotic rat model, autophagy signaling was investigated by western blotting and mRFP-EGFP-LC3 tandem fluorescent tagged plasmid (ptfLC3) transfection technique. Anti-fibrotic profile was determined by western blotting, qRT-PCR, MTT assay, trypan blue, hydroxyproline assay and Masson staining. KEY FINDINGS TGFβ1 treatment decreased P62 accumulation and increased both autophagosomes and autolysosomes in LX2 cells, thereby elevated autophagic flux. Hydroxychloroquine (HCQ), antagonist of autophagy, was found to dramatically inhibit COL1A2 mRNA expression and cell proliferation in a dose-dependent manner. This coincides with the effect of UDCA intervention on collagen aggradation and cell viability. Meanwhile, UDCA inhibited TGFβ1-induced autophagy flux. And rapamycin, agonist of autophagy, was found to impair the anti-fibrotic effect of UDCA. Moreover, study in vivo showed that UDCA alone or in combination with HCQ restored the CCl4-induced liver fibrosis in rodent models with autophagy inhibited profile. SIGNIFICANCE Taken together, our study revealed that UDCA displays anti-fibrotic role by protecting HSC against production of collagen and inhibiting cellular viability involving autophagy inhibition and provide a new insight into the pharmacological basis of UDCA treatment for hepatic fibrosis.
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Affiliation(s)
- Hui-Lan Ye
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China; Department of Internal Medicine, Liuzhou Maternity and Child Healthcare Hospital, Liuzhou, Guangxi, PR China
| | - Ji-Wang Zhang
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China
| | - Xing-Zhou Chen
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China
| | - Peng-Bo Wu
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China; Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, PR China
| | - Li Chen
- New Drug Research & Development Center, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, PR China
| | - Guo Zhang
- Department of Gastroenterology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, PR China.
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21
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Koya Y, Shibata M, Shinohara N, Nebuya S, Oe S, Honma Y, Senju M, Sato N, Harada M. Secondary sclerosing cholangitis with hemobilia induced by pembrolizumab: Case report and review of published work. Hepatol Res 2019; 49:950-956. [PMID: 30861263 DOI: 10.1111/hepr.13329] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 02/22/2019] [Accepted: 03/02/2019] [Indexed: 12/13/2022]
Abstract
A 66-year-old man was admitted to our department due to cholestatic liver injury. He had received five cycles of pembrolizumab for small-cell lung cancer. Imaging showed the possibility of sclerosing cholangitis (SC) with hemobilia. Histologically, CD8+ T cells had infiltrated the biliary epithelium of the extrahepatic bile duct. We reached the diagnosis of secondary SC induced by pembrolizumab. Although we treated him with high-dose corticosteroids, laboratory data showed only a moderate response. Clinicians should recognize that immune checkpoint inhibitors can sometimes cause severe and irreversible SC.
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Affiliation(s)
- Yudai Koya
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Michihiko Shibata
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Nobuhiko Shinohara
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Satoru Nebuya
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Shinji Oe
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yuichi Honma
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Michio Senju
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Naoko Sato
- Department of Pathology, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Masaru Harada
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
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22
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Chapman MH, Thorburn D, Hirschfield GM, Webster GGJ, Rushbrook SM, Alexander G, Collier J, Dyson JK, Jones DE, Patanwala I, Thain C, Walmsley M, Pereira SP. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut 2019; 68:1356-1378. [PMID: 31154395 PMCID: PMC6691863 DOI: 10.1136/gutjnl-2018-317993] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 02/21/2019] [Accepted: 03/24/2019] [Indexed: 12/11/2022]
Abstract
These guidelines on the management of primary sclerosing cholangitis (PSC) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included medical representatives from hepatology and gastroenterology groups as well as patient representatives from PSC Support. The guidelines aim to support general physicians, gastroenterologists and surgeons in managing adults with PSC or those presenting with similar cholangiopathies which may mimic PSC, such as IgG4 sclerosing cholangitis. It also acts as a reference for patients with PSC to help them understand their own management. Quality of evidence is presented using the AGREE II format. Guidance is meant to be used as a reference rather than for rigid protocol-based care as we understand that management of patients often requires individual patient-centred considerations.
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Affiliation(s)
- Michael Huw Chapman
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Liver Unit, Royal Free London NHS Foundation Trust, London, UK
| | | | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network and University of Toronto, Toronto, Canada
| | | | - Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | | | | | - Jessica K Dyson
- Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - David Ej Jones
- Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Imran Patanwala
- Gastroenterology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK
- University of Liverpool, Liverpool, UK
| | | | | | - Stephen P Pereira
- GI Division, UCL Hospitals NHS Foundation Trust, London, UK
- Institute for Liver & Digestive Health, University College London, London, UK
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23
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Kerkar N, Chan A. Autoimmune Hepatitis, Sclerosing Cholangitis, and Autoimmune Sclerosing Cholangitis or Overlap Syndrome. Clin Liver Dis 2018; 22:689-702. [PMID: 30266157 DOI: 10.1016/j.cld.2018.06.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Autoimmune hepatitis (AIH) is characterized by elevated serum aminotransferases, immunoglobulin G, autoantibodies, and interface hepatitis, in the absence of a known diagnosis. Presentation is varied. Therapy is with immunosuppression. There is inflammation of the intrahepatic and/or extrahepatic bile ducts in Sclerosing cholangitis (SC) and when associated with inflammatory bowel disease, it is known as primary SC, with Ursodeoxycholic acid used for therapy. The overlap of clinical, biochemical and histological features of AIH and PSC is known as autoimmune sclerosing cholangitis (ASC) or overlap syndrome. Liver transplantation is performed when medical treatment fails and both AIH and PSC may recur post-transplantation.
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Affiliation(s)
- Nanda Kerkar
- Division of Gastroenterology, Hepatology and Nutrition, Golisano Children's Hospital, University of Rochester Medical Center, 601 Elmwood Avenue, Box 667, Rochester, NY 14642, USA.
| | - Albert Chan
- Division of Gastroenterology, Hepatology and Nutrition, Golisano Children's Hospital, University of Rochester Medical Center, 601 Elmwood Avenue, Box 667, Rochester, NY 14642, USA; Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Florida, PO Box 100296, Gainesville, FL 32610, USA
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Santiago P, Scheinberg AR, Levy C. Cholestatic liver diseases: new targets, new therapies. Therap Adv Gastroenterol 2018; 11:1756284818787400. [PMID: 30159035 PMCID: PMC6109852 DOI: 10.1177/1756284818787400] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 06/14/2018] [Indexed: 02/04/2023] Open
Abstract
Cholestatic liver diseases result from gradual destruction of bile ducts, accumulation of bile acids and self-perpetuation of the inflammatory process leading to damage to cholangiocytes and hepatocytes. If left untreated, cholestasis will lead to fibrosis, biliary cirrhosis, and ultimately end-stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are the two most common chronic cholestatic liver diseases affecting adults, and their etiologies remain puzzling. While treatment with ursodeoxycholic acid (UDCA) has significantly improved outcomes and prolonged transplant-free survival for patients with PBC, treatment options for UDCA nonresponders remain limited. Furthermore, there is no available medical therapy for PSC. With recent advances in molecular biochemistry specifically related to bile acid regulation and understanding of immunologic pathways, novel pharmacologic treatments have emerged. In this review, we discuss the standard of care and emphasize the various emerging treatments for PBC and PSC.
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Affiliation(s)
- Priscila Santiago
- Department of Medicine, University of Miami/Jackson Memorial Hospital
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25
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Gitto S, Guarneri V, Sartini A, Andreone P. The use of obeticholic acid for the management of non-viral liver disease: current clinical practice and future perspectives. Expert Rev Gastroenterol Hepatol 2018; 12:165-171. [PMID: 29082798 DOI: 10.1080/17474124.2018.1399060] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Farnesoid X nuclear receptor is involved in the regulation of lipid and glucose metabolism, though mainly in the homeostasis of bile acids. Indeed, the agonists of farnesoid X nuclear receptor represent promising drugs. Areas covered: Obeticholic acid, a novel semisynthetic analogue of the naturally occurring bile acid, has led to encouraging preliminary results in both cholestatic and metabolic liver disease. In patients with primary biliary cholangitis, obeticholic acid determines a significant biochemical improvement although the effects on liver fibrosis are lacking. Obeticholic acid has been suggested for the treatment of nonalcoholic liver disease with good laboratory results. In cirrhotic animal models, the drug seems to reduce both portal hypertension and gut bacterial translocation. Expert commentary: The use of obeticholic acid for the treatment of primary biliary cholangitis shows satisfying results. However, some open questions remain unresolved. Herein, we provide an overview of the current knowledge about the use of obeticholic acid in the field of nonviral chronic liver diseases. We tried to give a global point of view using a translational approach.
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Affiliation(s)
- Stefano Gitto
- a Department of Medical and Surgical Sciences , University of Bologna and Azienda Ospedaliero-Universitaria di Bologna , Bologna , Italy
- b Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche , University of Bologna , Bologna , Italy
| | - Valeria Guarneri
- a Department of Medical and Surgical Sciences , University of Bologna and Azienda Ospedaliero-Universitaria di Bologna , Bologna , Italy
- b Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche , University of Bologna , Bologna , Italy
| | - Alessandro Sartini
- c Department of Gastroenterology , University of Modena and Reggio Emilia and Azienda Ospedaliero-Universitaria di Modena , Modena , Italy
| | - Pietro Andreone
- a Department of Medical and Surgical Sciences , University of Bologna and Azienda Ospedaliero-Universitaria di Bologna , Bologna , Italy
- b Centro di Ricerca per lo Studio delle Epatiti, Dipartimento di Scienze Mediche e Chirurgiche , University of Bologna , Bologna , Italy
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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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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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28
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Kumar N, Thompson CC. Remnant gastropathy due to bile reflux after Roux-en-Y gastric bypass: a unique cause of abdominal pain and successful treatment with ursodiol. Surg Endosc 2017; 31:5399-5402. [PMID: 28799115 DOI: 10.1007/s00464-017-5621-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 05/16/2017] [Indexed: 01/22/2023]
Abstract
BACKGROUND Chronic abdominal pain can occur after Roux-en-Y gastric bypass (RYGB), and can remain unexplained despite extensive investigation. Bile can pool in the gastric remnant and create a bile reflux gastropathy. The aim of this study was to assess gastric remnant findings in patients with RYGB and chronic abdominal pain of unclear etiology, and to determine the effectiveness of ursodiol therapy for patients with confirmed remnant gastropathy. METHODS All consecutive patients with RYGB and a diagnosis of chronic abdominal pain, and a negative diagnostic workup (including physical examination, routine laboratory work, cross-sectional imaging, and standard upper endoscopy), who underwent device-assisted enteroscopy for evaluation of the gastric remnant, were included. Pathology reports, treatments, and clinical follow-up were recorded. RESULTS 28 post-RYGB patients (all female) with chronic abdominal pain and negative evaluation were included. Pooling of bile with gastric erythema was noted in 22/28 patients. All 22 patients with endoscopic erythema had pathology consistent with bile reflux chemical gastropathy. Of these patients, 12 were started on a proton pump inhibitor (PPI) alone, and 10 were started on ursodiol. Of the ursodiol group, 8/10 (80%) patients reported substantial improvement or resolution of abdominal pain at clinical follow-up. All three ursodiol patients with repeat endoscopic examination of the gastric remnant had endoscopic and histologic resolution of gastropathy. Of the PPI patients, 1/12 reported improvement in abdominal pain at clinical follow-up (p = 0.002), and both patients with repeat endoscopic examination of the gastric remnant had persistent remnant gastropathy. CONCLUSIONS Roux-en-Y gastric bypass patients with unexplained chronic pain, and biopsy-confirmed chemical gastropathy, had a significantly higher rate of abdominal pain resolution with ursodiol treatment compared to PPI. Remnant gastropathy due to bile reflux is a treatable cause of chronic abdominal pain in RYGB patients, and ursodiol should be considered for empiric treatment in RYGB patients with unexplained chronic abdominal pain.
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Affiliation(s)
- Nitin Kumar
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham & Women's Hospital, 75 Francis St., Thorn 1404, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Christopher C Thompson
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham & Women's Hospital, 75 Francis St., Thorn 1404, Boston, MA, 02115, USA.
- Harvard Medical School, Boston, MA, 02115, USA.
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29
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Smolka V, Karaskova E, Tkachyk O, Aiglova K, Ehrmann J, Michalkova K, Konecny M, Volejnikova J. Long-term follow-up of children and adolescents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis. Hepatobiliary Pancreat Dis Int 2016; 15:412-8. [PMID: 27498582 DOI: 10.1016/s1499-3872(16)60088-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Sclerosing cholangitis (SC) is a chronic cholestatic hepatobiliary disease with uncertain long-term prognosis in pediatric patients. This study aimed to evaluate long-term results in children with SC according to the types of SC. METHODS We retrospectively followed up 25 children with SC over a period of 4-17 years (median 12). The diagnosis of SC was based on biochemical, histological and cholangiographic findings. Patients fulfilling diagnostic criteria for probable or definite autoimmune hepatitis at the time of diagnosis were defined as having autoimmune sclerosing cholangitis (ASC); other patients were included in a group of primary sclerosing cholangitis (PSC). The incidence of the following complications was studied: obstructive cholangitis, portal hypertension, advanced liver disease and death associated with the primary disease. RESULTS Fourteen (56%) patients had PSC and 11 (44%) had ASC. Patients with ASC were significantly younger at the time of diagnosis (12.3 vs 15.4 years, P=0.032) and had higher IgG levels (22.7 vs 17.2 g/L, P=0.003). The mentioned complications occurred in 4 (16%) patients with SC, exclusively in the PSC group: one patient died from colorectal cancer, one patient underwent liver transplantation and two patients, in whom severe bile duct stenosis was present at diagnosis, were endoscopically treated for acute cholangitis. Furthermore, two other children with ASC and 2 children with PSC had elevated aminotransferase levels. The 10-year overall survival was 95.8% in all patients, 100% in patients without complicated liver disease, and 75.0% in patients with complications. CONCLUSION In children, ASC is a frequent type of SC, whose prognosis may be better than that in patients with PSC.
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Affiliation(s)
- Vratislav Smolka
- Department of Pediatrics, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, Olomouc 779 00, Czech Republic.
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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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31
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Drapkina OM, Bueverova EL. [Ursodeoxycholic acid: A therapeutic niche in an internist's practice]. TERAPEVT ARKH 2015; 87:84-90. [PMID: 26087640 DOI: 10.17116/terarkh201587484-90] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The paper shows more than 40 years' experience with ursodeoxycholic acid (UDCA) used as a drug; during this period it has demonstrated its rather high clinical efficacy. Due to the range of its inherent pleiotropic (choleretic, cytoprotective, immunomodulatory, antiapoptotic, hypocholesterolemic, and litholytic) properties, UDCA has a broad spectrum of therapeutic activity. The paper considers the issues associated with the mechanism of action and with the clinical effects of this bile acid. It gives the results of the most important randomized controlled trials determining currently the evidence base for the efficiency and safety of using UDCA in the clinical picture of visceral diseases.
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Affiliation(s)
- O M Drapkina
- Department of Internal Propedeutics, Faculty of Therapeutics, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow
| | - E L Bueverova
- Department of Internal Propedeutics, Faculty of Therapeutics, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow
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Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol 2015; 62:S25-37. [PMID: 25920087 DOI: 10.1016/j.jhep.2015.02.023] [Citation(s) in RCA: 376] [Impact Index Per Article: 37.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 02/16/2015] [Accepted: 02/16/2015] [Indexed: 02/08/2023]
Abstract
Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent norUDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases.
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Affiliation(s)
- Ulrich Beuers
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands.
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Peter Jansen
- Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands
| | - Raoul Poupon
- UPMC Université Paris 06, INSERM, UMR_S 938, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie, F-75012 Paris, France
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Watanabe T, Hirano K, Tada M, Isayama H, Mizuno S, Arizumi T, Toda N, Sugawara Y, Kokudo N, Koike K. Short-term prognostic factors for primary sclerosing cholangitis. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:486-90. [PMID: 25826613 DOI: 10.1002/jhbp.238] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND It was recently reported that alkaline phosphatase (ALP) levels below 1.5 upper limit of normal (ULN) predicted better prognosis in primary sclerosing cholangitis (PSC). We evaluated whether ALP as well as other laboratory values were useful for the short-term prognosis of PSC in a Japanese cohort. METHODS In 78 patients with PSC (41 males and 37 females, mean onset age 41.9 years), the relationship between nine parameters (albumin, bilirubin, international normalized ratio of prothrombin time [PT-INR], ALP, aspartate aminotransferase [AST], alanine aminotransferase [ALT], γ-glutamyl transpeptidase [γ-GTP], platelet, and calculated Model for End-Stage Liver Disease [MELD] score), and liver related clinical endpoints (death due to liver failure, variceal bleeding, liver transplantation, and biliary carcinoma) were retrospectively examined. Using receiver operating characteristic (ROC) analysis, we investigated which parameter was useful for predicting the short-term prognosis. RESULTS Average follow-up period was 8.6 years. The endpoints were evaluated in 40 patients. Seven patients died of liver failure, three patients developed variceal bleeding, nine patients received liver transplantation from a living donor, 13 patients received certified brain-dead liver transplantation, and eight patients developed biliary carcinoma. The parameters with an area under the curve (AUC) of more than 0.8 were albumin, bilirubin, PT-INR, ALP, and MELD score. AUC for ALP was 0.85. The optimal cutoff value was 2.3 ULN. Despite the use or non-use of ursodeoxycholic acid, short-term prognosis of patients with an ALP level below 2.3 ULN was good. CONCLUSIONS We confirmed that keeping ALP low is associated with better short-term prognosis in a Japanese cohort. In addition, Alb, Bil, PT-INR, and MELD score were good predictors.
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Affiliation(s)
- Takeo Watanabe
- Department of Gastroenterology, Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, 6-25-1 Kamiyouga, Setagaya-ku, Tokyo, 158-8531, Japan. .,Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Kenji Hirano
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Gastroenterology, Tokyo Takanawa Hospital, Tokyo, Japan
| | - Minoru Tada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Gastroenterology, Toshiba General Hospital, Tokyo, Japan
| | - Toshihiko Arizumi
- Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Nobuo Toda
- Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan
| | - Yasuhiko Sugawara
- Artificial Organ and Transplantation Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Artificial Organ and Transplantation Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Rojas-Feria M, Castro M, Suárez E, Ampuero J, Romero-Gómez M. Hepatobiliary manifestations in inflammatory bowel disease: The gut, the drugs and the liver. World J Gastroenterol 2013; 19:7327-7340. [PMID: 24259964 PMCID: PMC3831215 DOI: 10.3748/wjg.v19.i42.7327] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/07/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
Abnormal liver biochemical tests are present in up to 30% of patients with inflammatory bowel disease (IBD), and therefore become a diagnostic challenge. Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn’s disease and ulcerative colitis (UC), and typically do not correlate with intestinal activity. Primary sclerosing cholangitis (PSC) is the most common hepatobiliary manifestation of IBD, and is more prevalent in UC. Approximately 5% of patients with UC develop PSC, with the prevalence reaching up to 90%. Cholangiocarcinoma and colon cancer risks are increased in these patients. Less common disorders include autoimmune hepatitis/PSC overlap syndrome, IgG4-associated cholangiopathy, primary biliary cirrhosis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis, liver abscess, and non-alcoholic fatty liver disease. Hepatitis B reactivation during immunosuppressive therapy is a major concern, with screening and vaccination being recommended in serologically negative cases for patients with IBD. Reactivation prophylaxis with entecavir or tenofovir for 6 to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen (HBsAg) positive, independently from viral load. HBsAg negative and anti-HBc positive patients, with or without anti-HBs, should be closely monitored, measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy, and should be treated if the viral load increases. On the other hand, immunosuppressive therapy does not seem to promote reactivation of hepatitis C, and hepatitis C antiviral treatment does not influence IBD natural history either. Most of the drugs used for IBD treatment may induce hepatotoxicity, although the incidence of serious adverse events is low. Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant. Methotrexate-related hepatotoxicity has been described in 14% of patients with IBD, in a dose-dependent manner. Liver biopsy is not routinely recommended. Biologics-related hepatotoxicity is rare, but has been shown most frequently in patients treated with infliximab. Thiopurines have been associated with veno-occlusive disease, regenerative nodular hyperplasia, and liver peliosis. Routine liver biochemical tests are recommended, especially during the first month of treatment. All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement. Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.
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Fickert P, Pollheimer MJ, Silbert D, Moustafa T, Halilbasic E, Krones E, Durchschein F, Thüringer A, Zollner G, Denk H, Trauner M. Differential effects of norUDCA and UDCA in obstructive cholestasis in mice. J Hepatol 2013; 58:1201-8. [PMID: 23369794 PMCID: PMC3650580 DOI: 10.1016/j.jhep.2013.01.026] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2012] [Revised: 01/08/2013] [Accepted: 01/17/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS The quest for effective drugs to treat cholangiopathies led to the development of norUDCA previously shown to have potent choleretic effects and to heal cholangiopathy in Abcb4 knockout (Abcb4(-/-)) mice. Its mother compound UDCA had detrimental effects in common bile duct ligated (CBDL) mice, presumably related to its choleretic effects. norUDCA choleretic effects may therefore raise safety concerns when used in cholangiopathies with biliary obstruction. We therefore aimed at comparing the effects of UDCA and norUDCA in clear-cut obstructive cholestasis. METHODS 0.5% UDCA- or norUDCA-fed wild type and Abcb4(-/-) mice were subjected to CBDL or selective bile duct ligation (SBDL) and compared to controls with regard to liver injury. Bile flow, bile composition, and biliary manometry were compared in UDCA-fed, norUDCA-fed and control mice. Toxicity of UDCA and norUDCA was compared in vitro. RESULTS Compared to UDCA, liver injury in CBDL mice was significantly lower in almost all norUDCA groups. In SBDL mice, only UDCA induced bile infarcts in the ligated lobes, whereas norUDCA even ameliorated liver injury. In vitro, UDCA induced cellular ATP depletion and was significantly more toxic than norUDCA in HepG2 cells, mouse bile duct epithelial cells, and primary human hepatocytes. CONCLUSIONS Compared to norUDCA, UDCA is significantly more toxic in CBDL mice. norUDCA, in contrast to UDCA, significantly ameliorates liver injury in SBDL mice. Our findings uncover profound differences in metabolism and therapeutic mechanisms of both bile acids with important clinical consequences.
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Affiliation(s)
- Peter Fickert
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
- Institute of Pathology, Medical University of Graz, Austria
- Corresponding authors. Addressess: Department of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. Tel.: +43 (0) 316/385 17104; fax: +43 (0) 316/385 17560 (P. Fickert). Department of Medicine III, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43 (0) 1/40400 4741; fax: +43 (0) 1/40400 4735 (M. Trauner).
| | - Marion J. Pollheimer
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
- Institute of Pathology, Medical University of Graz, Austria
| | - Dagmar Silbert
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Tarek Moustafa
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Emina Halilbasic
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Elisabeth Krones
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Franziska Durchschein
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | | | - Gernot Zollner
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Helmut Denk
- Institute of Pathology, Medical University of Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
- Corresponding authors. Addressess: Department of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. Tel.: +43 (0) 316/385 17104; fax: +43 (0) 316/385 17560 (P. Fickert). Department of Medicine III, Waehringer Guertel 18-20, A-1090 Vienna, Austria. Tel.: +43 (0) 1/40400 4741; fax: +43 (0) 1/40400 4735 (M. Trauner).
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Lim TS, Park JY, Kim SI, Kang H, Chung MJ. A Case of Rapidly Progressive Primary Sclerosing Cholangitis Requiring Liver Transplantation. KOREAN JOURNAL OF TRANSPLANTATION 2013. [DOI: 10.4285/jkstn.2013.27.1.24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Tae Seop Lim
- Department of Internal Medicine, Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Soon Il Kim
- Department of Surgery, Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Huapyong Kang
- Department of Internal Medicine, Yonsei Institute of Gastroenterology, Seoul, Korea
| | - Moon Jae Chung
- Department of Internal Medicine, Yonsei Institute of Gastroenterology, Seoul, Korea
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Trivedi PJ, Chapman RW. PSC, AIH and overlap syndrome in inflammatory bowel disease. Clin Res Hepatol Gastroenterol 2012; 36:420-36. [PMID: 22306055 DOI: 10.1016/j.clinre.2011.10.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Revised: 10/08/2011] [Accepted: 10/14/2011] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive, cholestatic disorder characterised by chronic inflammation and stricture formation of the biliary tree. Symptoms include pruritus, fatigue and in advanced cases ascending cholangitis, cirrhosis and end-stage hepatic failure. Patients are at an increased risk of malignancy arising from the bile ducts, gallbladder, liver and colon. The majority (>80%) of Northern European patients with PSC also have inflammatory bowel disease (IBD), usually ulcerative colitis (UC). IBD commonly presents before the onset of PSC, although the opposite can occur and the onset of both conditions can be separated by many years. The colitis associated with PSC is characteristically mild although frequently involves the whole colon. Despite the majority of patients having relatively inactive colonic disease, paradoxically the risk of colorectal malignancy is substantially increased. Patients may also develop dominant, stenotic lesions of the biliary tree which may be difficult to differentiate from cholangiocarcinoma and the coexistence of IBD may influence the development of this complication. Ursodeoxycholic acid may offer a chemoprotective effect against colorectal malignancy and improve liver biochemical indices. Evidence of any beneficial effect on histological progression of hepatobiliary disease is less clear. High doses (∼25-30 mg/kg/d) may be harmful and should be avoided. Autoimmune hepatitis (AIH) is less common in patients with IBD than PSC, however, an association has been observed. A small subgroup may have an overlap syndrome between AIH and PSC and management should be individualised dependant on liver histology, serum immunoglobulin levels, autoantibodies, degree of biochemical cholestasis and cholangiography.
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Affiliation(s)
- P J Trivedi
- Centre for Liver Research and NIHR Biomedical Research Unit, University of Birmingham, Wolfson Drive, Edgbaston, Birmingham, B15 2TT United Kingdom.
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Urosdeoxycholic acid in primary sclerosing cholangitis: a meta-analysis and systematic review. Arab J Gastroenterol 2012; 13:103-10. [PMID: 23122450 DOI: 10.1016/j.ajg.2012.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 02/23/2012] [Accepted: 06/10/2012] [Indexed: 01/06/2023]
Abstract
BACKGROUND AND STUDY AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with no proven effective medical therapy. Ursodeoxycholic acid (UDCA) was proposed as a potential treatment for this disorder. However, several randomised controlled trials reported conflicting results regarding the usefulness of UDCA. The aim of this meta-analysis and systematic review is to investigate the efficacy of UDCA in PSC. PATIENTS AND METHODS Literature review was performed to include randomised controlled trials and non-randomised studies comparing UDCA to a placebo in PSC. The included controlled trials were assigned a quality score. Random effects model was used. Outcomes were measured with Weight Mean Difference, Risk Ratio or Risk Difference. Heterogeneity was measured by I(2) measure of inconsistency. RESULTS Seven RCTs satisfied the inclusion criteria with a total number of 553 patients. Low dose UDCA was used in 4 studies, high dose UDCA (17-30mg/kg) was used in three studies. UDCA did not decrease the risk of mortality compared to placebo (RR=1.04, 95% CI 0.46-2.35) or the need for liver transplant (RR=1.22, 95% CI 0.7-2.12). UDCA also had no effect on the clinical symptoms. Liver Function Tests (LFTs) were significantly improved in the UDCA treated patients. UDCA did not decrease the incidence of cholangiocarcinoma. CONCLUSION UDCA had no beneficial effect on the patients' survival, liver histology, prevention of cholangiocarcinoma, or improvement of clinical symptoms. High dose UDCA was associated with increased mortality in one of the large randomised trial included in this analysis.
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Imam MH, Gossard AA, Sinakos E, Lindor KD. Pathogenesis and management of pruritus in cholestatic liver disease. J Gastroenterol Hepatol 2012; 27:1150-1158. [PMID: 22413872 DOI: 10.1111/j.1440-1746.2012.07109.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.
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Affiliation(s)
- Mohamad H Imam
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, MN 55905, USA
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Fosby B, Karlsen TH, Melum E. Recurrence and rejection in liver transplantation for primary sclerosing cholangitis. World J Gastroenterol 2012; 18:1-15. [PMID: 22228965 PMCID: PMC3251800 DOI: 10.3748/wjg.v18.i1.1] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2011] [Revised: 06/15/2011] [Accepted: 06/22/2011] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic progressive inflammatory disease affecting the bile ducts, leading to fibrosis and eventually cirrhosis in most patients. Its etiology is unknown and so far no effective medical therapy is available. Liver transplantation (LTX) is the only curative treatment and at present PSC is the main indication for LTX in the Scandinavian countries. Close to half of the PSC patients experience one or more episodes of acute cellular rejection (ACR) following transplantation and approximately 1/5 of the transplanted patients develop recurrent disease in the graft. In addition, some reports indicate that ACR early after LTX for PSC can influence the risk for recurrent disease. For these important post-transplantation entities affecting PSC patients, we have reviewed the current literature on epidemiology, pathogenesis, treatment and the possible influence of rejection on the risk of recurrent disease in the allograft.
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Abstract
Improved medical management and the changing disease demographic mean that the majority of patients with chronic liver disease are living with the disease rather than dying from it. Historically, the perception has been that the impact of chronic liver disease is related entirely to the consequences of endstage liver disease; however, more recently a number of systemic symptoms have been recognised that can occur at any point in the natural history of chronic liver disease and which can be associated with functional impairment and reduced quality of life. The most characteristic of these systemic symptoms is fatigue, which frequently associates with sleep disturbance and autonomic dysfunction, particularly manifest as abnormality of blood pressure regulation. Cognitive symptoms can occur even in non-cirrhotic patients. Falls can present in patients with autonomic dysfunction, complicated by the presence of peripheral muscle strength problems. Importantly for clinicians managing chronic liver disease, the severity of these systemic symptoms is typically not related to liver disease severity, and therefore despite optimal liver disease management, patients can often continue to experience debilitating symptoms. The similarity in systemic symptoms between different chronic liver diseases (and indeed chronic inflammatory conditions affecting other organs) suggests the possibility of shared pathogenetic processes and raises the possibility of common management strategies, although further research is urgently needed to confirm this. In primary biliary cirrhosis, where our understanding of systemic symptoms is arguably most developed, structured management strategies have been shown to improve the quality of life of patients. It is highly likely that similar approaches will have comparable benefits for other chronic liver disease groups. Here, we review the current understanding of systemic symptoms in chronic liver disease and offer recommendations regarding the successful management of these symptoms. Critical for successful treatment is use of a structured and systematic approach to management in which all contributing factors are addressed in an organised fashion. We believe that such a systematic approach, when applied to research as well as to clinical management, will allow us to reduce the overall burden of chronic liver disease, improve quality of life and enhance functional ability.
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Affiliation(s)
- Julia L Newton
- UK NIHR Biomedical Research Centre in Ageing and Age Related Diseases, Newcastle University, Newcastle, UK.
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42
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Hepatobiliary disease associated with hypereosinophilia: a report of two patients and a review of the literature. Dig Dis Sci 2011; 56:3689-94. [PMID: 21647653 DOI: 10.1007/s10620-011-1764-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2010] [Accepted: 05/18/2011] [Indexed: 12/09/2022]
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Wong GLH, Wong VWS. Medical therapy for primary sclerosing cholangitis. Aliment Pharmacol Ther 2011; 34:1135-6; discussion 1136-7. [PMID: 21981734 DOI: 10.1111/j.1365-2036.2011.04845.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- G L-H Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
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Abstract
Several hepatobiliary abnormalities have been described in association with inflammatory bowel disease (IBD), including primary sclerosing cholangitis (PSC), small duct PSC, chronic hepatitis, cryptogenic cirrhosis, cholangiocarcinoma, and cholelithiasis. PSC is the most common biliary condition in patients with IBD, with an incidence ranging from 2.5% to 7.5%. PSC usually progresses insidiously and eventually leads to cirrhosis independent of inflammatory bowel disease activity. There is a very high incidence of cholangiocarcinoma and an elevated risk for developing colon cancer in patients with PSC. Medical therapy has not proven successful in slowing disease progression or prolonging survival. Treatment of symptoms due to cholestasis, such as pruritis and steatorrhea, is an important aspect of the medical care of patients with PSC. Our preferred treatment of pruritis due to cholestasis is with bile acid binding exchange resins, such as cholestyramine or colestipol. Endoscopic manipulation is recommended for treating complications of recurrent cholangitis or worsening jaundice in the setting of a dominant stricture, but endoscopic approaches have not been conclusively demonstrated to improve survival or decrease the need for liver transplantation. Liver transplantation remains the only effective treatment of advanced PSC, and should be considered in patients with complications of cirrhosis or intractable pruritis or fatigue.
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Affiliation(s)
- David R Lichtenstein
- Section of Gastroenterology, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA.
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Triantos CK, Koukias NM, Nikolopoulou VN, Burroughs AK. Meta-analysis: ursodeoxycholic acid for primary sclerosing cholangitis. Aliment Pharmacol Ther 2011; 34:901-10. [PMID: 21883323 DOI: 10.1111/j.1365-2036.2011.04822.x] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND There is no satisfactory medical treatment for patients with primary sclerosing cholangitis. There are conflicting data regarding the clinical benefit of high doses of ursodeoxycholic acid (UDCA) in primary sclerosing cholangitis. AIM To evaluate using meta-analysis, if UDCA (standard or high-dose) is useful in primary sclerosing cholangitis. METHODS We searched MEDLINE using the textwords 'PSC', 'treatment', 'UDCA' and retrieved all abstracts from the major Gastroenterology and Liver meetings. We included randomised clinical trials comparing standard or high-dose of UDCA (>15 mg/kg body weight per day) vs. placebo or no intervention. End-points: mortality or liver transplantation, pruritus, fatigue, cholangiocarcinoma and histological progression. RESULTS We identified eight randomised clinical trials comprising 567 patients. Five used standard doses and three high doses of UDCA. There was no significant difference in mortality [OR, 0.6 (95% CI, 0.4-1.4)], in pruritus [OR, 1.5 (95% CI, 0.3-7.2)], in fatigue [OR, 0.0 (95% CI, 0.1-7.7)], in cholangiocarcinoma [OR, 1.7 (95% CI, 0.6-5.1)] and in histology stage progression [OR, 0.9 (95% CI, 0.34-2.44)]. No differences were found in the subgroup analyses. CONCLUSION Neither standard nor high-dose UDCA influence favourably the progression of primary sclerosing cholangitis.
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Affiliation(s)
- C K Triantos
- Department of Gastroenterology, University Hospital of Patras, Patras, Greece.
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Osumi T, Ohno K, Kanemoto H, Nakashima K, Uchida K, Karasawa A, Fujino Y, Tsujimoto H. A case of recovery from canine destructive cholangitis in a Miniature Dachshund. J Vet Med Sci 2011; 73:937-9. [PMID: 21325741 DOI: 10.1292/jvms.10-0448] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
A 7-year-old Miniature Dachshund presented with severe chronic jaundice and elevated liver enzymes. Destructive cholangitis was diagnosed according to histopathological findings of remarkable ductopenia with inflammatory infiltrates and fibrosis in the portal areas. Supportive therapy with prednisolone, high-dose ursodeoxycholic acid, human placental extract and antibiotics was tried, and the patient showed recovery of clinical signs 3 months after diagnosis. A second liver biopsy was performed about 1 year after initial diagnosis, and bile duct restoration was confirmed with continuous inflammation around portal areas and inside the lobules. Although we could not determine which treatment was effective in this case, destructive cholangitis in dogs may be recoverable with long-term supportive therapies.
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Affiliation(s)
- Takafumi Osumi
- Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
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Poropat G, Giljaca V, Stimac D, Gluud C, Cochrane Hepato‐Biliary Group. Bile acids for primary sclerosing cholangitis. Cochrane Database Syst Rev 2011; 2011:CD003626. [PMID: 21249655 PMCID: PMC7163275 DOI: 10.1002/14651858.cd003626.pub2] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis is a progressive chronic cholestatic liver disease that usually leads to the development of cirrhosis. Studies evaluating bile acids in the treatment of primary sclerosing cholangitis have shown a potential benefit of their use. However, no influence on patients survival and disease outcome has yet been proven. OBJECTIVES To assess the beneficial and harmful effects of bile acids for patients with primary sclerosing cholangitis. SEARCH STRATEGY We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, MEDLINE, EMBASE and Science Citation Index Expanded generally from inception through to October 2010. SELECTION CRITERIA Randomised clinical trials comparing any dose of bile acids or duration of treatment versus placebo, no intervention, or another intervention were included irrespective of blinding, language, or publication status. DATA COLLECTION AND ANALYSIS Two authors extracted data independently. We evaluated the risk of bias of the trials using prespecified domains. We performed the meta-analysis according to the intention-to-treat principle. We presented outcomes as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI). MAIN RESULTS Eight trials evaluated ursodeoxycholic acid versus placebo or no intervention (592 patients). The eight randomised clinical trials have a high risk of bias. Patients were treated for three months to six years (median three years). The dosage of ursodeoxycholic acid used in the trials ranged from low (10 mg/kg body weight/day) to high (28 to 30 mg/kg body weight/day). Ursodeoxycholic acid did not significantly reduce the risk of death (RR 1.00; 95% CI 0.46 to 2.20); treatment failure including liver transplantation, varices, ascites, and encephalopathy (RR 1.22; 95% CI 0.91 to 1.64); liver histological deterioration (RR 0.89; 95% CI 0.45 to 1.74); or liver cholangiographic deterioration (RR 0.60; 95% CI 0.23 to 1.57). Ursodeoxycholic acid significantly improved serum bilirubin (MD -14.6 µmol/litre; 95% CI -18.7 to -10.6), alkaline phosphatases (MD -506 IU/litre; 95% CI -583 to -430), aspartate aminotransferase (MD -46 IU/litre; 95% CI -77 to -16), and gamma-glutamyltranspeptidase (MD -260 IU/litre; 95% CI -315 to -205), but not albumin (MD -0.20 g/litre; 95% CI -1.91 to 1.50). Ursodeoxycholic acid was safe and well tolerated by patients with primary sclerosing cholangitis. AUTHORS' CONCLUSIONS We did not find enough evidence to support or refute the use of bile acids in the treatment of primary sclerosing cholangitis. However, bile acids seem to lead to a significant improvement in liver biochemistry. Therefore, more randomised trials are needed before any of the bile acids can be recommended for this indication.
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Affiliation(s)
- Goran Poropat
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51000
| | - Vanja Giljaca
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51000
| | - Davor Stimac
- Clinical Hospital Centre RijekaDepartment of GastroenterologyKresimirova 42RijekaCroatia51000
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Abstract
Sclerosing cholangitis is a rare progressive cholestatic liver disease affecting the biliary tract. It may be associated with other diseases including autoimmune hepatitis, immunodeficiencies, cystic fibrosis, and sickle cell disease. Sclerosing cholangitis not associated with other diseases is termed "primary sclerosing cholangitis," which has a strong association with male gender, Caucasian race, and inflammatory bowel disease. Diagnosis is based on typical biochemical, radiologic, and histologic features. Medical management is directed mainly at managing complications (pruritus, cholangitis, strictures, and nutritional deficiencies). Administration of ursodeoxycholic acid results in biochemical improvement, but has not been proven to prolong transplant-free survival. Patients with autoimmune overlap respond to immunosuppression. The disease is typically progressive and evolves to biliary cirrhosis and possibly cholangiocarcinoma. Orthotopic liver transplantation remains the only life-extending alternative for patients with sclerosing cholangitis, with good long-term patient and graft survival, and recurrent graft primary sclerosing cholangitis in about 10% of children.
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Affiliation(s)
- Nanda Kerkar
- Department of Pediatrics, The Mount Sinai Medical Center, New York, NY, USA.
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Current world literature. Curr Opin Rheumatol 2010; 23:125-30. [PMID: 21124095 DOI: 10.1097/bor.0b013e3283422cce] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Karlsen TH, Schrumpf E, Boberg KM. Update on primary sclerosing cholangitis. Dig Liver Dis 2010; 42:390-400. [PMID: 20172772 DOI: 10.1016/j.dld.2010.01.011] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2009] [Accepted: 01/17/2010] [Indexed: 02/06/2023]
Abstract
Early studies in primary sclerosing cholangitis (PSC) were concerned with disease characterization, and were followed by epidemiological studies of PSC and clinical subsets of PSC as well as a large number of treatment trials. Recently, the molecular pathogenesis and the practical handling of the patients have received increasing attention. In the present review we aim to give an update on the pathogenesis of PSC and cholangiocarcinoma in PSC, as well as to discuss the current opinion on diagnosis and treatment of PSC in light of the recent European Association for the Study of the Liver and the American Association for the Study of Liver Diseases practice guidelines.
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Affiliation(s)
- Tom H Karlsen
- Norwegian PSC Research Center, Medical Department, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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