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Chen Y, Chen R, Li H, Shuai Z. Clinical management of autoimmune liver diseases: juncture, opportunities, and challenges ahead. Immunol Res 2025; 73:67. [PMID: 40195209 PMCID: PMC11976385 DOI: 10.1007/s12026-025-09622-9] [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: 11/27/2024] [Accepted: 03/14/2025] [Indexed: 04/09/2025]
Abstract
The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.
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MESH Headings
- Humans
- Hepatitis, Autoimmune/therapy
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/etiology
- Cholangitis, Sclerosing/therapy
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Animals
- Immunotherapy/methods
- Autoimmune Diseases/therapy
- Autoimmune Diseases/diagnosis
- Disease Management
- Genetic Predisposition to Disease
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Affiliation(s)
- Yangfan Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Ruofei Chen
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Haiyan Li
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China.
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, 230032, China.
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Boraschi P, Mazzantini V, Donati F, Coco B, Vianello B, Pinna A, Morganti R, Colombatto P, Brunetto MR, Neri E. Primary sclerosing cholangitis: Is qualitative and quantitative 3 T MR imaging useful for the evaluation of disease severity? Eur J Radiol Open 2024; 13:100595. [PMID: 39206437 PMCID: PMC11357777 DOI: 10.1016/j.ejro.2024.100595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/04/2024] Open
Abstract
Purpose To analyze the role of qualitative and quantitative 3 T MR imaging assessment as a non-invasive method for the evaluation of disease severity in patients with primary sclerosing cholangitis (PSC). Methods A series of 26 patients, with histological diagnosis of PSC undergoing 3 T MRI and hepatological evaluation, was retrospectively enrolled. All MR examinations included diffusion-weighted imaging (DWI), T2-weighted (T2w) and T1-weighted (T1w) sequences, before and after administration of Gd-EOB-DTPA with the acquisition of both dynamic and hepato-biliary phase (HBP). Qualitative analysis was performed by assessment of liver parenchyma and biliary tract changes, also including biliary excretion of gadoxetic acid on HBP. Quantitative evaluation was conducted on liver parenchyma by measurement of apparent diffusion coefficient (ADC) and relative enhancement (RE) on 3-minute delayed phase and on HBP. Results of blood tests (ALT, ALP, GGT, total and direct bilirubin, albumin, and platelets) and transient elastography-derived liver stiffness measurements (TE-LSM) were collected and correlated with qualitative and quantitative MRI findings. Results Among qualitative and quantitative findings, fibrosis visual assessment and RE had the best performance in estimating disease severity, showing a statistically significant correlation with both biomarkers of cholestasis and TE-LSM. Statistical analysis also revealed a significant correlation of gadoxetic acid biliary excretion with ALT and direct bilirubin, as well as of ADC with total bilirubin. Conclusion Qualitative and quantitative 3 T MR evaluation is a promising non-invasive method for the assessment of disease severity in patients with PSC.
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Affiliation(s)
- Piero Boraschi
- 2nd Unit of Radiology, Department of Radiological Nuclear and Laboratory Medicine - Pisa University Hospital, Via Paradisa 2, Pisa 56124, Italy
| | - Valentina Mazzantini
- Academic Radiology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 67, Pisa 56126, Italy
| | - Francescamaria Donati
- 2nd Unit of Radiology, Department of Radiological Nuclear and Laboratory Medicine - Pisa University Hospital, Via Paradisa 2, Pisa 56124, Italy
| | - Barbara Coco
- Hepatology Unit, Pisa University Hospital, Via Paradisa 2, Pisa 56124, Italy
| | - Barbara Vianello
- Hepatology Unit, Pisa University Hospital, Via Paradisa 2, Pisa 56124, Italy
| | - Andrea Pinna
- Hepatology Unit, Pisa University Hospital, Via Paradisa 2, Pisa 56124, Italy
| | - Riccardo Morganti
- Departmental Section of Statistical Support for Clinical Trials, Pisa University Hospital, Via Roma 67, Pisa 56126, Italy
| | - Piero Colombatto
- Hepatology Unit, Pisa University Hospital, Via Paradisa 2, Pisa 56124, Italy
| | | | - Emanuele Neri
- Academic Radiology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 67, Pisa 56126, Italy
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Abdelhamed W, El-Kassas M. Rare liver diseases in Egypt: Clinical and epidemiological characterization. Arab J Gastroenterol 2024; 25:75-83. [PMID: 38228442 DOI: 10.1016/j.ajg.2023.12.002] [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: 09/23/2022] [Revised: 12/04/2023] [Accepted: 12/16/2023] [Indexed: 01/18/2024]
Abstract
Illnesses that afflict a tiny number of individuals are referred to as rare diseases (RDs), sometimes called orphan diseases. The local healthcare systems are constantly under financial, psychological, and medical strain due to low incidence rates, unusual presentations, flawed diagnostic standards, and a lack of treatment alternatives for these RDs. The effective management of the once widely spread viral hepatitis B and C has altered the spectrum of liver diseases in Egypt during the last several years. The detection of uncommon disorders such as autoimmune, cholestatic, and hereditary liver diseases has also been made easier by the increasing knowledge and greater accessibility of specific laboratory testing. Finally, despite Egypt's large population, there are more uncommon liver disorders than previously thought. This review article discusses the clinical and epidemiological characteristics of a few uncommon liver disorders and the information currently accessible concerning these illnesses in Egypt.
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Affiliation(s)
- Walaa Abdelhamed
- Endemic Medicine Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt.
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Bokemeyer A, Lenze F, Stoica V, Sensoy TS, Kabar I, Schmidt H, Ullerich H. Digital single-operator video cholangioscopy improves endoscopic management in patients with primary sclerosing cholangitis-a retrospective observational study. World J Gastroenterol 2022; 28:2201-2213. [PMID: 35721887 PMCID: PMC9157616 DOI: 10.3748/wjg.v28.i20.2201] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/18/2022] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Patients with primary sclerosing cholangitis (PSC) are at a high risk of developing cholestatic liver disease and biliary cancer, and endoscopy is crucial for the complex management of these patients.
AIM To clarify the utility of recently introduced digital single-operator video cholangioscopy (SOVC) for the endoscopic management of PSC patients.
METHODS In this observational study, all patients with a history of PSC and in whom digital SOVC (using the SpyGlass DS System) was performed between 2015 and 2019 were included and retrospectively analysed. Examinations were performed at a tertiary referral centre in Germany. In total, 46 SOVCs performed in 38 patients with a history of PSC were identified. The primary endpoint was the evaluation of dominant biliary strictures using digital SOVC, and the secondary endpoints were the performance of selective guidewire passage across biliary strictures and the diagnosis and treatment of biliary stone disease in PSC patients.
RESULTS The 22 of 38 patients had a dominant biliary stricture (57.9%). In 4 of these 22 patients, a cholangiocellular carcinoma was diagnosed within the stricture (18.2%). Diagnostic evaluation of dominant biliary strictures using optical signs showed a sensitivity of 75% and a specificity of 94.4% to detect malignant strictures, whereas SOVC-guided biopsies to gain tissue for histopathological analysis showed a sensitivity of 50% and a specificity of 100%. In 13% of examinations, SOVC was helpful for guidewire passage across biliary strictures that could not be passed by conventional methods (technical success rate 100%). Biliary stone disease was observed in 17.4% of examinations; of these, in 37.5% of examinations, biliary stones could only be visualized by SOVC and not by standard fluoroscopy. Biliary stone treatment was successful in all cases (100%); 25% required SOVC-assisted electrohydraulic lithotripsy. Complications, such as postinterventional cholangitis and pancreatitis, occurred in 13% of examinations; however, no procedure-associated mortality occurred.
CONCLUSION Digital SOVC is effective and safe for the endoscopic management of PSC patients and may be regularly considered an additive tool for the complex endoscopic management of these patients.
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Affiliation(s)
- Arne Bokemeyer
- Department of Medicine B (Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology), University Hospital Muenster, Muenster 48149, Germany
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, Essen 45147, Germany
| | - Frank Lenze
- Department of Medicine B (Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology), University Hospital Muenster, Muenster 48149, Germany
| | - Viorelia Stoica
- Department of Medicine B (Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology), University Hospital Muenster, Muenster 48149, Germany
| | - Timur Selcuk Sensoy
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, Essen 45147, Germany
| | - Iyad Kabar
- Department of Medicine B (Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology), University Hospital Muenster, Muenster 48149, Germany
| | - Hartmut Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital Essen, Essen 45147, Germany
| | - Hansjoerg Ullerich
- Department of Medicine B (Gastroenterology, Hepatology, Endocrinology, Clinical Infectiology), University Hospital Muenster, Muenster 48149, Germany
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Cadamuro M, Strazzabosco M. Inflammatory pathways and cholangiocarcinoma risk mechanisms and prevention. Adv Cancer Res 2022; 156:39-73. [PMID: 35961707 PMCID: PMC10916841 DOI: 10.1016/bs.acr.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Cholangiocarcinoma (CCA), a neoplasm burdened by a poor prognosis and currently lacking adequate therapeutic treatments, can originate at different levels of the biliary tree, in the intrahepatic, hilar, or extrahepatic area. The main risk factors for the development of CCA are the presence of chronic cholangiopathies of various etiology. To date, the most studied prodromal diseases of CCA are primary sclerosing cholangitis, Caroli's disease and fluke infestations, but other conditions, such as metabolic syndrome, nonalcoholic fatty liver disease and obesity, are emerging as associated with an increased risk of CCA development. In this review, we focused on the analysis of the pro-inflammatory mechanisms that induce the development of CCA and on the role of cells of the immune response in cholangiocarcinogenesis. In very recent times, these cellular mechanisms have been the subject of emerging studies aimed at verifying how the modulation of the inflammatory and immunological responses can have a therapeutic significance and how these can be used as therapeutic targets.
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Affiliation(s)
| | - Mario Strazzabosco
- Liver Center, Department of Internal Medicine, Yale University, New Haven, CT, United States.
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Mehta TI, Weissman S, Fung BM, Sotiriadis J, Lindor KD, Tabibian JH. Global incidence, prevalence and features of primary sclerosing cholangitis: A systematic review and meta-analysis. Liver Int 2021; 41:2418-2426. [PMID: 34224208 DOI: 10.1111/liv.15007] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 06/03/2021] [Accepted: 06/08/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is an idiopathic, cholestatic liver disease with a diverse range of clinical manifestations. Inter-regional data on PSC are variable, but its global geoepidemiology has not been well-studied. We aimed to examine the worldwide incidence, prevalence and features of PSC and PSC-inflammatory bowel disease (PSC-IBD). METHODS A systematic search of multiple databases was conducted to identify all original, full-text studies until December 2020 with data regarding the incidence rate (IR) and/or prevalence of PSC. Outcomes were PSC IR, prevalence, features and IBD concurrence. Additionally, a meta-analysis of PSC IR was performed. The study was registered in PROSPERO (CRD42021224550). RESULTS Of the 1003 studies identified, 17 studies spanning three continents were included. PSC IR was 0.60 per 100 000 person-years (PY) (95% confidence interval: 0.37-0.88 per 100 000 PY). In pooled subgroup analysis for studies conducted in Europe and North America, PSC IR was 0.62 and 0.53 per 100 000 PY, respectively. PSC prevalence ranged 0-31.7 per 100 000 persons, with notable inter-regional differences. Mean age at PSC diagnosis was bimodally distributed, with relative peaks at 15 and 35 years. Mean concurrence of IBD with PSC was 50%, with 76% having ulcerative colitis, 17% Crohn's disease and 8% indeterminate/unspecified IBD. CONCLUSION While considerable heterogeneity exists in the geoepidemiology of PSC, overall, the classical dogmata of male predilection, bimodal distribution of mean age and high PSC-IBD concurrence appear to hold true. Despite a seemingly stable IR over time, further studies are needed to better understand the geoepidemiology of PSC.
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Affiliation(s)
- Tej I Mehta
- Department of Radiology, Johns Hopkins University Hospital, Baltimore, MD, USA
| | - Simcha Weissman
- Department of Medicine, Hackensack University-Palisades Medical Center, North Bergen, NJ, USA
| | - Brian M Fung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA
| | - John Sotiriadis
- Division of Gastroenterology and Hepatology, Hackensack University-Palisades Medical Center, North Bergen, NJ, USA
| | - Keith D Lindor
- College of Health Solutions, Arizona State University, Phoenix, AZ, USA
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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7
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Ali AH, Juran BD, Schlicht EM, Bianchi JK, McCauley BM, Atkinson EJ, Lazaridis KN. The PSC scientific community resource: an asset for multi-omics interrogation of primary sclerosing cholangitis. BMC Gastroenterol 2021; 21:353. [PMID: 34563121 PMCID: PMC8465725 DOI: 10.1186/s12876-021-01930-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/15/2021] [Indexed: 11/16/2022] Open
Abstract
Background Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease that often progresses to end-stage liver disease and/or the development of hepatobiliary neoplasia. Lack of prognostic tools and treatment options for PSC is driven in part by our poor understanding of its pathogenesis, which is thought to be complex, the interaction of genetic variants, environmental influences and biological response throughout the course of disease. The PSC Scientific Community Resource (PSC-SCR) seeks to overcome previous shortcomings by facilitating novel research in PSC with the ultimate goals of individualizing patient care and improving patient outcomes. Methods PSC patients who receive their health care at Mayo Clinic or a collaborating site are identified by chart review and invited in person or by mail to participate. Non-Mayo patients are offered enrollment if they provide sufficient access to their medical records to evaluate inclusion/exclusion criteria. Controls without liver disease are identified with assistance of the Mayo Clinic Biobank. Participant consent is obtained at the beginning of the recruitment process by mail-in, electronic or face-to-face protocols. Clinical data is extracted from the medical record by qualified physicians and entered in a custom designed database. Participants fill out a custom-designed, comprehensive questionnaire, which collects scientifically relevant demographic and clinical information. Biospecimens are collected using mail-in kits thar are returned via overnight carrier service and processed by the biospecimen accessioning and processing facility at Mayo Clinic, which coordinates sample transfers and provides required sample preparation services. The resource is currently being utilized to perform omics-scale projects investigating the exposome, metabolome, methylome, immunome and microbiome in PSC. Datasets and residual biospecimens will be shared with researchers proposing scientifically sound PSC-focused research with approval of the appropriate review boards. Discussion Patient-based studies leveraging the latest technologies for targeted and wide-scale interrogation of multiple omics layers offer promise to accelerate PSC research through discovery of unappreciated aspects of disease pathogenesis. However, the rarity of PSC severely limits such studies. Here we describe our effort to overcome this limitation, the PSC-SCR, a repository of patient biospecimens coupled with clinical and omics data for use by the broader PSC research community. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-021-01930-2.
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Affiliation(s)
- Ahmad Hassan Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Brian D Juran
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Erik M Schlicht
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Jackie K Bianchi
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA
| | - Bryan M McCauley
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Elizabeth J Atkinson
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Konstantinos N Lazaridis
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Mehta TI, Weissman S, Fung BM, Tabibian JH. Geoepidemiologic variation in outcomes of primary sclerosing cholangitis. World J Hepatol 2020; 12:116-124. [PMID: 32685104 PMCID: PMC7336294 DOI: 10.4254/wjh.v12.i4.116] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/15/2020] [Accepted: 03/24/2020] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, progressive, hepatobiliary disease characterized by inflammation and fibrosis of the intra- and extra-hepatic bile ducts. Its natural history is one that generally progresses towards cirrhosis, liver failure, cholangiocarcinoma, and ultimately disease-related death, with a median liver transplantation-free survival time of approximately 15-20 years. However, despite its lethal nature, PSC remains a heterogenous disease with significant variability in outcomes amongst different regions of the world. There are also many regions where the outcomes of PSC have not been studied, limiting the overall understanding of this disease worldwide. In this review, we present the geoepidemiologic variations in outcomes of PSC, with a focus on survival pre- and post-liver transplantation as well as the concurrence of inflammatory bowel disease and hepatobiliary neoplasia.
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Affiliation(s)
- Tej I Mehta
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, SD 57108, United States
| | - Simcha Weissman
- Department of Medicine, Hackensack University-Palisades Medical Center, North Bergen, NJ 07047, United States
| | - Brian M Fung
- Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA 91342, United States
| | - James H Tabibian
- Department of Medicine, UCLA-Olive View Medical Center, Sylmar, CA 91342, and Health Sciences Clinical Associate Professor, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States.
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Nicoletti A, Maurice JB, Thorburn D. Guideline review: British Society of Gastroenterology/UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Frontline Gastroenterol 2020; 12:62-66. [PMID: 33456743 PMCID: PMC7789993 DOI: 10.1136/flgastro-2019-101343] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 02/08/2020] [Accepted: 02/12/2020] [Indexed: 02/04/2023] Open
Abstract
New British Society of Gastroenterology/UK-PSC guidelines have recently discussed the current state-of-the-art on primary sclerosing cholangitis and outlined key elements for the management of this disease. The current lack of effective pharmacological treatments to prevent progression of liver fibrosis to cirrhosis limits our ability to modify the natural history of the disease. However, a personalised approach and structured follow-up could allow earlier diagnosis and management of complications and favour access to liver transplantation, which remains the only available treatment. Our commentary overviews the updates and summarises the key recommendations of the recent guidelines for the management of primary sclerosing cholangitis.
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Affiliation(s)
- Alberto Nicoletti
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK,Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - James B Maurice
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, Royal Free London NHS Foundation Trust, London, UK
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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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11
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Fung BM, Tabibian JH. Biliary endoscopy in the management of primary sclerosing cholangitis and its complications. LIVER RESEARCH (BEIJING, CHINA) 2019; 3:106-117. [PMID: 31341699 PMCID: PMC6656407 DOI: 10.1016/j.livres.2019.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, cholestatic liver disease characterized by inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts. It can affect individuals of all age groups and gender, has no established pharmacotherapy, and is associated with a variety of neoplastic (e.g. cholangiocarcinoma) and non-neoplastic (e.g. dominant strictures) hepatobiliary complications. Given these considerations, endoscopy plays a major role in the care of patients with PSC. In this review, we discuss and provide updates regarding endoscopic considerations in the management of hepatobiliary manifestations and complications of PSC. Where evidence is limited, we suggest pragmatic approaches based on currently available data and expert opinion.
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Affiliation(s)
- Brian M. Fung
- University of California Los Angeles-Olive View Internal Medicine Residency Program, Sylmar, CA, USA
| | - James H. Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-University of California Los Angeles Medical Center, Sylmar, CA, USA
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12
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Annese V. A Review of Extraintestinal Manifestations and Complications of Inflammatory Bowel Disease. SAUDI JOURNAL OF MEDICINE & MEDICAL SCIENCES 2019; 7:66-73. [PMID: 31080385 PMCID: PMC6503692 DOI: 10.4103/sjmms.sjmms_81_18] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Extraintestinal manifestations (EIMs) are common in inflammatory bowel disease (IBD), in both Crohn's disease and ulcerative colitis. Almost any organ system can be affected, including the musculoskeletal, dermatologic, renal, hepatopancreatobiliary, pulmonary and ocular systems. However, the musculoskeletal and dermatologic systems are the most commonly involved sites of manifestations. While some manifestations such as peripheral arthritis and erythema nodosum have an association with IBD activity, others such as axial arthropathy, pyoderma gangrenosum and primary sclerosing cholangitis have an independent disease course. This review provides a summary of the most common EIMs in IBD and their prevalence and management.
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Affiliation(s)
- Vito Annese
- Department of Gastroenterology, Valiant Clinic, Dubai, United Arab Emirates
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Chi ZC. Intestinal microbiome and autoimmune liver disease. Shijie Huaren Xiaohua Zazhi 2019; 27:50-62. [DOI: 10.11569/wcjd.v27.i1.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
At present, it has been proved that intestinal microbial-related disorders are involved in the development and progression of multi-organ system diseases. Intestinal microflora is the accumulation of microbial antigens and activated immune cells. Changes in the composition of intestinal microflora (biological disorders) can destroy the systemic immune tolerance of intestinal and symbiotic bacteria. Toll-like receptors in the intestine recognize microbial-related molecular patterns and T helper lymphocyte subpopulations that can cross-react with host antigens (molecular mimics). Activated enterogenous lymphocytes can migrate to lymph nodes, and enterogenous microbial antigens can migrate to extraintestinal sites. Inflammasomes can form in hepatocytes and hepatic stellate cells, which can drive inflammatory, immune-mediated and fibrotic responses. This article reviews and evaluates the role of intestinal microorganisms in the pathogenesis and treatment of autoimmune liver disease.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Affiliated Hospital of Shandong University Medical College, Qingdao 266011, Shandong Province, China
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14
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Tietz-Bogert PS, Kim M, Cheung A, Tabibian JH, Heimbach JK, Rosen CB, Nandakumar M, Lazaridis KN, LaRusso NF, Sung J, O'Hara SP. Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis. Int J Mol Sci 2018; 19:3188. [PMID: 30332763 PMCID: PMC6214107 DOI: 10.3390/ijms19103188] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 10/11/2018] [Accepted: 10/13/2018] [Indexed: 02/08/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann⁻Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.
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Affiliation(s)
- Pamela S Tietz-Bogert
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA.
| | - Minsuk Kim
- Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
- Division of Surgical Research, Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.
| | - Angela Cheung
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
| | - James H Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA 91342, USA.
| | - Julie K Heimbach
- Division of Transplant Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
| | - Charles B Rosen
- Division of Transplant Surgery, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
| | | | - Konstantinos N Lazaridis
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA.
| | - Nicholas F LaRusso
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA.
| | - Jaeyun Sung
- Microbiome Program, Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
- Division of Surgical Research, Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA.
| | - Steven P O'Hara
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
- Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA.
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15
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Staufer K, Kivaranovic D, Rasoul-Rockenschaub S, Soliman T, Trauner M, Berlakovich G. Waitlist mortality and post-transplant survival in patients with cholestatic liver disease - Impact of changes in allocation policy. HPB (Oxford) 2018; 20:916-924. [PMID: 29937419 DOI: 10.1016/j.hpb.2018.03.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 02/26/2018] [Accepted: 03/30/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND This study investigated the impact of Model of end-stage liver disease (MELD)-score introduction (MELDi) on waitlist mortality and post-liver transplant (LT) survival in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). METHODS LT candidates with PSC or PBC listed between January 1983 and March 2016 were included and followed until December 2016. After MELDi in 2004, PBC patients were listed according to labMELD, PSC patients according to the highest MELD during active cholangitis (chMELD). RESULTS In total, 100 PBC and 76 PSC patients were included. Waitlist mortality in PBC was significantly higher than in PSC (16% vs. 5.3%, p = 0.031), whereas PSC patients were significantly more often withdrawn from the waitlist due to improved condition (3.0% vs. 13.2%, p = 0.017). Competing risks analysis identified MELDi (HR = 4.12) and PBC (HR = 2.95) as significant predictors of waitlist mortality. Yet, overall 10 y-patient survival increased after MELDi by 18.8% leading to a 1 y-, 5 y-, and 10 y-patient survival of 98.2%, 70.6% and 70.6% in PBC, and 83.3%, 83.3%, and 80.6% in PSC, respectively. CONCLUSIONS PSC patients showed significantly lower waitlist mortality irrespective of MELDi, whereas in PBC waitlist mortality further increased after MELDi. Utility of MELD and chMELD did not impair post LT outcome.
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Affiliation(s)
- Katharina Staufer
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Austria.
| | - Danijel Kivaranovic
- Department of Statistics and Operations Research, University of Vienna, Vienna, Austria
| | | | - Thomas Soliman
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Gabriela Berlakovich
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Austria
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16
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Kalani A, Tabibian JH, Lindor KD. Emerging therapeutic targets for primary sclerosing cholangitis. Expert Opin Orphan Drugs 2018; 6:393-401. [DOI: 10.1080/21678707.2018.1490643] [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: 10/28/2022]
Affiliation(s)
- Amir Kalani
- Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA Gastroenterology Fellowship Training Program, Los Angeles, CA, USA
| | - James H. Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
| | - Keith D. Lindor
- Professor of Medicine and Senior Advisor to the Provost, College of Health Solutions, Arizona State University, USA
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17
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Tabibian JH, Baron TH. Endoscopic management of primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol 2018; 12:693-703. [PMID: 29883229 DOI: 10.1080/17474124.2018.1483719] [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] [Received: 03/29/2018] [Accepted: 05/30/2018] [Indexed: 12/14/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare but clinically important cholestatic liver disease. Histopathologically and cholangiographically, PSC is characterized by intra- and/or extra-hepatic bile duct inflammation and fibro-obliteration, which ultimately leads to biliary cirrhosis and related sequelae, including development of hepatobiliary and colorectal carcinomata. PSC can be diagnosed at essentially any age and carries a median survival of 15-20 years, regardless of age at diagnosis, and is a foremost risk factor for cholangiocarcinoma. Given the chronic and progressive nature of PSC, its inherent association with both neoplastic and non-neoplastic biliary tract complications, and the lack of effective pharmacotherapies, alimentary and biliary tract endoscopy plays a major role in the care of patients with PSC. Areas covered: Here, we provide a narrative review on endoscopic management of PSC, including established and evolving applications to the diagnosis and treatment of both its benign and malignant complications. Expert commentary: Due to the rarity of PSC and the considerable patient-years required to rigorously study major endpoints, there remains a paucity of high-quality evidence regarding its management. As the advanced endoscopic repertoire expands, so has the interest in developing best practices in PSC, which we discuss herein.
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Affiliation(s)
- James H Tabibian
- a Division of Gastroenterology, Department of Medicine , Olive View-UCLA Medical Center , Sylmar , CA , USA
| | - Todd H Baron
- b Division of Gastroenterology and Hepatology , University of North Carolina at Chapel Hill , Chapel Hill , NC , USA
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18
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Dyson JK, Beuers U, Jones DEJ, Lohse AW, Hudson M. Primary sclerosing cholangitis. Lancet 2018; 391:2547-2559. [PMID: 29452711 DOI: 10.1016/s0140-6736(18)30300-3] [Citation(s) in RCA: 273] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 11/24/2017] [Accepted: 01/03/2018] [Indexed: 12/13/2022]
Abstract
Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by intrahepatic or extrahepatic stricturing, or both, with bile duct fibrosis. Inflammation and fibrosis of bile ducts and the liver are followed by impaired bile formation or flow and progressive liver dysfunction. Patients might be asymptomatic at presentation or might have pruritus, fatigue, right upper quadrant pain, recurrent cholangitis, or sequelae of portal hypertension. The key diagnostic elements are cholestatic liver biochemistry and bile duct stricturing on cholangiography. Genetic and environmental factors are important in the cause of the disease, with the intestinal microbiome increasingly thought to play a pathogenetic role. Approximately 70% of patients have concurrent inflammatory bowel disease and patients require colonoscopic screening and surveillance. Primary sclerosing cholangitis is associated with increased malignancy risk and surveillance strategies for early cholangiocarcinoma detection are limited. No single drug has been proven to improve transplant-free survival. Liver transplantation is effective for advanced disease but at least 25% of patients develop recurrent disease in the graft.
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Affiliation(s)
- Jessica K Dyson
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK.
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - David E J Jones
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK
| | - Ansgar W Lohse
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mark Hudson
- Department of Hepatology, Newcastle upon Tyne Hospitals NHS Foundation Trust and Institute of Cellular Medicine, Newcastle University, Newcastle, UK
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19
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Tedesco D, Thapa M, Chin CY, Ge Y, Gong M, Li J, Gumber S, Speck P, Elrod EJ, Burd EM, Kitchens WH, Magliocca JF, Adams AB, Weiss DS, Mohamadzadeh M, Grakoui A. Alterations in Intestinal Microbiota Lead to Production of Interleukin 17 by Intrahepatic γδ T-Cell Receptor-Positive Cells and Pathogenesis of Cholestatic Liver Disease. Gastroenterology 2018; 154:2178-2193. [PMID: 29454797 PMCID: PMC5985208 DOI: 10.1053/j.gastro.2018.02.019] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 01/16/2018] [Accepted: 02/07/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Variants at the ABCB4 or MDR2 locus, which encodes a biliary transport protein, are associated with a spectrum of cholestatic liver diseases. Exacerbation of liver disease has been linked to increased hepatic levels of interleukin (IL) 17, yet the mechanisms of this increase are not understood. We studied mice with disruption of Mdr2 to determine how defects in liver and alteration in the microbiota contribute to production of IL17 by intrahepatic γδ T cells. METHODS We performed studies with Mdr2-/- and littermate FVB/NJ (control) mice. IL17 was measured in serum samples by an enzyme-linked immunosorbent assay. Mice were injected with neutralizing antibodies against the γδ T-cell receptor (TCR; anti-γδ TCR) or mouse IL17A (anti-IL17A). Livers were collected and bacteria were identified in homogenates by culture procedures; TCRγδ+ cells were isolated by flow cytometry. Fecal samples were collected from mice and analyzed by 16S ribosomal DNA sequencing. Cells were stimulated with antibodies or bacteria, and cytokine production was measured. We obtained tissues from 10 patients undergoing liver transplantation for primary sclerosing cholangitis or chronic hepatitis C virus infection. Tissues were analyzed for cytokine production by γδ TCR+ cells. RESULTS Mdr2-/- mice had collagen deposition around hepatic bile ducts and periportal-bridging fibrosis with influx of inflammatory cells and increased serum levels of IL17 compared with control mice. Administration of anti-IL17A reduced hepatic fibrosis. Livers from Mdr2-/- mice had increased numbers of IL17A+ γδTCR+ cells-particularly of IL17A+ Vγ6Jγ1 γδ TCR+ cells. Fecal samples from Mdr2-/- mice were enriched in Lactobacillus, and liver tissues were enriched in Lactobacillus gasseri compared with control mice. Mdr2-/- mice also had increased intestinal permeability. The γδ TCR+ cells isolated from Mdr2-/- livers produced IL17 in response to heat-killed L gasseri. Intraperitoneal injection of control mice with L gasseri led to increased serum levels of IL17 and liver infiltration by inflammatory cells; injection of these mice with anti-γδ TCR reduced serum level of IL17. Intravenous injections of Mdr2-/- mice with anti-γδ TCR reduced fibrosis; liver levels of IL17, and inflammatory cells; and serum levels of IL17. γδTCR+ cells isolated from livers of patients with primary sclerosing cholangitis, but not hepatitis C virus infection, produced IL17. CONCLUSIONS In Mdr2-/- mice, we found development of liver fibrosis and inflammation to require hepatic activation of γδ TCR+ cells and production of IL17 mediated by exposure to L gasseri. This pathway appears to contribute to development of cholestatic liver disease in patients.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Adult
- Aged
- Animals
- Bile Ducts/cytology
- Bile Ducts/immunology
- Bile Ducts/microbiology
- Cells, Cultured
- Cholangitis, Sclerosing/microbiology
- Cholangitis, Sclerosing/pathology
- Cholangitis, Sclerosing/surgery
- Cholestasis/immunology
- Cholestasis/microbiology
- Cholestasis/pathology
- Cholestasis/surgery
- Disease Models, Animal
- End Stage Liver Disease/microbiology
- End Stage Liver Disease/pathology
- End Stage Liver Disease/surgery
- Female
- Gastrointestinal Microbiome
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/surgery
- Hepatitis C, Chronic/virology
- Humans
- Interleukin-17/antagonists & inhibitors
- Interleukin-17/blood
- Interleukin-17/immunology
- Interleukin-17/metabolism
- Intraepithelial Lymphocytes/metabolism
- Lactobacillus gasseri/immunology
- Liver/cytology
- Liver/immunology
- Liver/microbiology
- Liver/pathology
- Liver Cirrhosis/immunology
- Liver Cirrhosis/microbiology
- Liver Cirrhosis/pathology
- Liver Cirrhosis/surgery
- Liver Transplantation
- Male
- Mice
- Mice, Knockout
- Middle Aged
- Receptors, Antigen, T-Cell, gamma-delta/antagonists & inhibitors
- Receptors, Antigen, T-Cell, gamma-delta/metabolism
- Young Adult
- ATP-Binding Cassette Sub-Family B Member 4
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Affiliation(s)
- Dana Tedesco
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes Research Primate Center, Emory University School of Medicine, Atlanta, Georgia
| | - Manoj Thapa
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes Research Primate Center, Emory University School of Medicine, Atlanta, Georgia
| | - Chui Yoke Chin
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Emory Antibiotic Resistance Center, Atlanta, Georgia
| | - Yong Ge
- Department of Infectious Disease and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Minghao Gong
- Department of Infectious Disease and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Jing Li
- Department of Infectious Disease and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, Florida
| | - Sanjeev Gumber
- Division of Pathology and Laboratory Medicine, Yerkes Research Primate Center, Emory University School of Medicine, Atlanta, Georgia
| | - Patrick Speck
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes Research Primate Center, Emory University School of Medicine, Atlanta, Georgia
| | - Elizabeth J Elrod
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes Research Primate Center, Emory University School of Medicine, Atlanta, Georgia
| | - Eileen M Burd
- Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Emory Antibiotic Resistance Center, Atlanta, Georgia; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia
| | - William H Kitchens
- Department of Surgery, Transplant, Emory University School of Medicine, Atlanta, Georgia
| | - Joseph F Magliocca
- Department of Surgery, Transplant, Emory University School of Medicine, Atlanta, Georgia
| | - Andrew B Adams
- Department of Surgery, Transplant, Emory University School of Medicine, Atlanta, Georgia
| | - David S Weiss
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes Research Primate Center, Emory University School of Medicine, Atlanta, Georgia; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Emory Antibiotic Resistance Center, Atlanta, Georgia
| | - Mansour Mohamadzadeh
- Department of Infectious Disease and Pathology, College of Veterinary Medicine, University of Florida, Gainesville, Florida; Division of Hepatology, Gastroenterology, and Nutrition; University of Florida, Gainesville, Florida
| | - Arash Grakoui
- Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes Research Primate Center, Emory University School of Medicine, Atlanta, Georgia; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
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20
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Tabibian JH, Bowlus CL. WITHDRAWN: Primary sclerosing cholangitis: A review and update. LIVER RESEARCH 2018. [DOI: 10.1016/j.livres.2017.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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21
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Damman JL, Rodriguez EA, Ali AH, Buness CW, Cox KL, Carey EJ, Lindor KD. Review article: the evidence that vancomycin is a therapeutic option for primary sclerosing cholangitis. Aliment Pharmacol Ther 2018; 47:886-895. [PMID: 29411404 DOI: 10.1111/apt.14540] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 11/06/2017] [Accepted: 01/08/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS PSC is an autoimmune biliary inflammatory disorder that is often associated with inflammatory bowel disease (IBD), with 50%-75% of patients with PSC having coexisting IBD, most commonly ulcerative colitis. Currently, no medical therapies have been shown to improve the disease course or slow its progression. However, ongoing research has resulted in a growing interest in the use of antibiotics for treatment of PSC, of which vancomycin is the most studied. In this review, we summarise the current evidence on the use of vancomycin in PSC and comment on future research areas of interest. METHODS A comprehensive PUBMED and EMBASE literature search for articles on vancomycin, PSC, therapeutic options and microbiome was performed. RESULTS Two randomised clinical trials, three case series and two case reports were included in the study. These include uncontrolled data from at least 98 patients that include promising improvements in biochemistry and imaging. Optimal dosing regimens are unclear. CONCLUSION Vancomycin is one of the most studied antibiotics used in the treatment of PSC with promising results. There is not currently sufficient evidence to support treatment recommendations. Further research is needed to establish if vancomycin is a PSC treatment.
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Affiliation(s)
- J L Damman
- Pediatrics/Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - E A Rodriguez
- Gastroenterology and Hepatology, Mayo Clinic, Arizona, USA
| | - A H Ali
- Hepatology, Mayo Clinic, Arizona, USA
| | - C W Buness
- National Patient Advocate Foundation, Paradise Valley, AZ, USA
| | - K L Cox
- Pediatric Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - E J Carey
- Gastroenterology and Hepatology, Mayo Clinic, Arizona, USA
| | - K D Lindor
- Gastroenterology and Hepatology, Arizona State University and Mayo Clinic, Arizona, USA
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22
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Tabibian JH, Bowlus CL. Primary sclerosing cholangitis: A review and update. LIVER RESEARCH (BEIJING, CHINA) 2017; 1:221-230. [PMID: 29977644 PMCID: PMC6028044 DOI: 10.1016/j.livres.2017.12.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare, chronic, cholestatic liver disease of uncertain etiology characterized biochemically by cholestasis and histologically and cholangiographically by fibro-obliterative inflammation of the bile ducts. In a clinically significant proportion of patients, PSC progresses to cirrhosis, end-stage liver disease, and/or hepatobiliary cancer, though the disease course can be highly variable. Despite clinical trials of numerous pharmacotherapies over several decades, safe and effective medical therapy remains to be established. Liver transplantation is an option for select patients with severe complications of PSC, and its outcomes are generally favorable. Periodic surveillance testing for pre- as well as post-transplant patients is a cornerstone of preventive care and health maintenance. Here we provide an overview of PSC including its epidemiology, etiopathogenesis, clinical features, associated disorders, surveillance, and emerging potential therapies.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA
- Division of Gastroenterology, Olive View-UCLA Medical Center, Sylmar, CA, USA
| | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis, Sacramento, CA, USA
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23
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Cardile S, Alterio T, Candusso M, Pietrobattista A, Liccardo D, Basso MS, Papadatou B, Bracci F, Knafelz D, Torre G. Autoimmune liver diseases and inflammatory bowel diseases in children: current issues and future perspectives. Scand J Gastroenterol 2017; 52:662-667. [PMID: 28281846 DOI: 10.1080/00365521.2017.1298833] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Inflammatory bowel diseases (IBDs) represent a group of intestinal disorders with a chronic and relapsing inflammation of the gut, and with a potential risk of systemic involvement of other organs and systems. Over the pediatric age, an incidence higher than 20% of developing extraintestinal manifestation during follow-up has been reported. The liver and the biliary system are frequently involved, and primary sclerosing cholangitis (PSC) is the most predominant entity with an incidence rate of 6.4-7.8% in children. PSC recognizes a multifactorial pathogenesis, and so far a not fully known mechanism for this association. The peculiar phenotype and the distinct clinical course of patients with IBD and PSC-associated make this 'linkage' an attractive study model to better understand mechanisms underlying these diseases. Approaching to these patients is complex and multidisciplinary, and a unique therapeutic strategy has not been standardized yet. New medications are being studied; however, further studies are needed to fully understand the pathogenesis and to improve the care of these patients. The aim of this paper is to review the recent literature regarding hepatobiliary involvement in IBD patients, with particular attention to PSC, and to provide the latest information for a correct diagnosis and appropriate management.
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Affiliation(s)
- Sabrina Cardile
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
| | - Tommaso Alterio
- b Department of Pediatrics , University of Messina , Messina , Italy
| | - Manila Candusso
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
| | - Andrea Pietrobattista
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
| | - Daniela Liccardo
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
| | - Maria Sole Basso
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
| | - Bronislava Papadatou
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
| | - Fiammetta Bracci
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
| | - Daniela Knafelz
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
| | - Giuliano Torre
- a Hepatology, Gastroenterology and Nutrition Unit , Bambino Gesù Children's Hospital , Rome , Italy
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24
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic, cholestatic, idiopathic liver disease that can progress to end-stage liver disease, cirrhosis and cholangiocarcinoma. PSC is an uncommon and highly heterogeneous disease, associated with inflammatory bowel disease and a complex pathophysiology. To date, no medical therapies have proved effective. The only available treatment for end-stage PSC is liver transplant, but recurrence is a significant complication. Areas covered: This review will explore previously tested treatments, discuss current treatment strategies and present viewpoints about future emerging therapies in PSC. We searched PubMed using the noted keywords. We included data from full-text articles published in English. Further relevant articles were identified from the reference lists of review articles. Expert commentary: The development of new therapies in PSC has been challenging. However, with greater awareness of the disease nowadays, new insights into the disease may help in the design of future therapeutic agents in PSC and ultimately in effective therapies.
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Affiliation(s)
- Eduardo A Rodriguez
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA
| | - Elizabeth J Carey
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA
| | - Keith D Lindor
- a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.,b College of Health Solutions , Arizona State University , Phoenix , AZ , USA
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Gidwaney NG, Pawa S, Das KM. Pathogenesis and clinical spectrum of primary sclerosing cholangitis. World J Gastroenterol 2017; 23:2459-2469. [PMID: 28465630 PMCID: PMC5394509 DOI: 10.3748/wjg.v23.i14.2459] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 01/21/2017] [Accepted: 03/20/2017] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a disease of the biliary tract, which has been documented in the literature since 1867. This disease has a strong predilection for affecting men and can be seen in individuals as young as 2 years of age. PSC has a strong associated with inflammatory bowel disease, more commonly with ulcerative colitis, and is also part of the clinical spectrum of IgG4-related diseases. Small-duct PSC, a variant of PSC, also has an association with inflammatory bowel disease. The exact pathogenesis of PSC is not well understood at present, however, is likely a combination of a genetic predisposition with alteration of the molecular structure of the gut. Abnormal serum liver chemistry and presence of certain autoimmune markers are usually the first indicators leading to a diagnosis of PCS, however, these may often be normal in early stages of this disease. The diagnosis is made by cholangiography, which is now considered the gold standard. PSC is a known pre-malignant condition. Such patients have an increased risk of developing cholangiocarcinoma, gallbladder neoplasia, and colon cancer. Many new treatment modalities have emerged in the recent past, including anti-tumor necrosis factor- α and anti-integrins; however, liver transplantation is the only known cure for PSC. Despite past and present research, PSC remains an enigmatic biliary disease with few viable treatment options.
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Ali AH, Carey EJ, Lindor KD. The management of autoimmunity in patients with cholestatic liver diseases. Expert Rev Gastroenterol Hepatol 2016; 10:73-91. [PMID: 26523975 DOI: 10.1586/17474124.2016.1095088] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cholestatic liver diseases are rare diseases that often lead to cirrhosis and its consequent complications. In addition to liver-related morbidity, patients with cholestatic liver diseases often suffer from autoimmune diseases that affect several organs and tissues. The robust and efficient data collection and collaboration between hepatologists and rheumatologists have led to significant advancements in understanding the relationship between the cholestatic liver diseases and associated autoimmune diseases. In this paper, we discuss the cholestatic liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis and immunoglobulin G4 associated cholangitis) and associated autoimmune diseases.
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Affiliation(s)
- Ahmad H Ali
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Elizabeth J Carey
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.,b 2 Arizona State University, College of Health Solutions, Phoenix, AZ, USA
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Kumar A, Wheatley D, Puttanna A. Primary Sclerosing Cholangitis: Therapeutic Options and Surveillance Management. CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2016; 9:25-9. [PMID: 27330336 PMCID: PMC4902039 DOI: 10.4137/cgast.s38451] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 05/01/2016] [Accepted: 05/03/2016] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis is a chronic immune-mediated liver disease. Though rare, it poses several clinical concerns for the managing physician. There are currently limited therapeutic options in the management of the condition and weak evidence base behind them. Endoscopic intervention is limited to those patients with obstructing stricture-related disease, and even liver transplantation has a risk of disease recurrence. Surveillance for inflammatory bowel disorders, metabolic bone disease, and malignancy is paramount when managing such patients. This article provides an overview of the condition with further focus on current therapeutic options and guidance on surveillance management.
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Affiliation(s)
| | | | - Amar Puttanna
- University Hospital North Midlands, Stoke-on-Trent, England, UK
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Andersen IM, Fosby B, Boberg KM, Clausen OPF, Jebsen P, Melum E, Line PD, Foss A, Schrumpf E, Karlsen TH. Indications and Outcomes in Liver Transplantation in Patients With Primary Sclerosing Cholangitis in Norway. Transplant Direct 2015; 1:e39. [PMID: 27500239 PMCID: PMC4946487 DOI: 10.1097/txd.0000000000000548] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 08/03/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is 1 of the leading causes of liver transplantation (LTX) in Scandinavia, and an increasing number of PSC patients have been transplanted in Norway during the last 2 decades. This trend is partly attributable to the recently established practice in Norway of offering LTX to PSC patients with cholangiocellular dysplasia. Based on the controversy associated with this practice, we herein aimed to report the main features and outcomes of our LTX program in PSC. METHODS The primary indication for LTX (quality of life/end-stage liver disease or suspected neoplasia) was retrospectively determined for 222 patients undergoing LTX for PSC or other autoimmune liver diseases (primary biliary cirrhosis/autoimmune hepatitis) with at least 5 years of follow-up. RESULTS In PSC patients impaired quality of life (43.5%) and end-stage liver disease (38.4%) were the most frequent indications for LTX, whereas suspected neoplasia accounted for 18.1%. The proportion of PSC patients with manifest encephalopathy, variceal bleeding, or ascites declined over time. In patients with suspected neoplasia as the primary indication for LTX (n = 25), neoplasia was confirmed in the explanted liver in 20 patients (80%). Five-year survival rates for PSC patients transplanted between 2001 and 2009 were 91.9% for patients receiving LTX due to impaired quality of life or end-stage liver disease and 83.3% for suspected neoplasia. CONCLUSIONS The PSC patients are increasingly listed for LTX at an earlier stage of their liver disease. In patients with suspected neoplasia before LTX, 5-year survival was acceptable, despite confirmation of neoplasia in 80% of the liver explants.
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Affiliation(s)
- Ina M. Andersen
- Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Bjarte Fosby
- Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Kirsten M. Boberg
- Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ole P. F. Clausen
- Department of Pathology, Clinic for Diagnostics and Intervention, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Peter Jebsen
- Department of Pathology, Clinic for Diagnostics and Intervention, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Espen Melum
- Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Pål D. Line
- Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Aksel Foss
- Section for Transplantation Surgery, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Erik Schrumpf
- Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Tom H. Karlsen
- Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Tabibian JH, Moradkhani A, Topazian MD. Colorectal cancer surveillance in primary sclerosing cholangitis and inflammatory bowel disease. Ann Hepatol 2015; 14:564-566. [PMID: 26019046 DOI: 10.1016/s1665-2681(19)31181-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/14/2025]
Affiliation(s)
- James H Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Ania Moradkhani
- University of Massachusetts Medical School, Nurse Practitioner Program, Worcester, MA, USA
| | - Mark D Topazian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Fosby B, Melum E, Bjøro K, Bennet W, Rasmussen A, Andersen IM, Castedal M, Olausson M, Wibeck C, Gotlieb M, Gjertsen H, Toivonen L, Foss S, Makisalo H, Nordin A, Sanengen T, Bergquist A, Larsson ME, Soderdahl G, Nowak G, Boberg KM, Isoniemi H, Keiding S, Foss A, Line PD, Friman S, Schrumpf E, Ericzon BG, Höckerstedt K, Karlsen TH. Liver transplantation in the Nordic countries - An intention to treat and post-transplant analysis from The Nordic Liver Transplant Registry 1982-2013. Scand J Gastroenterol 2015; 50:797-808. [PMID: 25959101 PMCID: PMC4487534 DOI: 10.3109/00365521.2015.1036359] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 03/28/2015] [Accepted: 03/29/2015] [Indexed: 02/04/2023]
Abstract
AIM AND BACKGROUND The Nordic Liver Transplant Registry (NLTR) accounts for all liver transplants performed in the Nordic countries since the start of the transplant program in 1982. Due to short waiting times, donor liver allocation has been made without considerations of the model of end-stage liver disease (MELD) score. We aimed to summarize key outcome measures and developments for the activity up to December 2013. MATERIALS AND METHODS The registry is integrated with the operational waiting-list and liver allocation system of Scandiatransplant (www.scandiatransplant.org) and accounted at the end of 2013 for 6019 patients out of whom 5198 were transplanted. Data for recipient and donor characteristics and relevant end-points retransplantation and death are manually curated on an annual basis to allow for statistical analysis and the annual report. RESULTS Primary sclerosing cholangitis, acute hepatic failure, alcoholic liver disease, primary biliary cirrhosis and hepatocellular carcinoma are the five most frequent diagnoses (accounting for 15.3%, 10.8%, 10.6%, 9.3% and 9.0% of all transplants, respectively). Median waiting time for non-urgent liver transplantation during the last 10-year period was 39 days. Outcome has improved over time, and for patients transplanted during 2004-2013, overall one-, five- and 10-year survival rates were 91%, 80% and 71%, respectively. In an intention-to-treat analysis, corresponding numbers during the same time period were 87%, 75% and 66%, respectively. CONCLUSION The liver transplant program in the Nordic countries provides comparable outcomes to programs with a MELD-based donor liver allocation system. Unique features comprise the diagnostic spectrum, waiting times and the availability of an integrated waiting list and transplant registry (NLTR).
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Affiliation(s)
- Bjarte Fosby
- Section for Transplantation Surgery, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Espen Melum
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine and Norwegian PSC Research Centre, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Kristian Bjøro
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - William Bennet
- Department of Transplantation, Sahlgrenska Academy at University of Gothenburg and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Allan Rasmussen
- Department of Surgical Gastroenterology and Liver Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Ina Marie Andersen
- Research Institute of Internal Medicine and Norwegian PSC Research Centre, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Maria Castedal
- Department of Transplantation, Sahlgrenska Academy at University of Gothenburg and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Michael Olausson
- Department of Transplantation, Sahlgrenska Academy at University of Gothenburg and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Christina Wibeck
- Department of Transplantation, Sahlgrenska Academy at University of Gothenburg and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mette Gotlieb
- Department of Surgical Gastroenterology and Liver Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Henrik Gjertsen
- Department of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Leena Toivonen
- Department of Transplantation and Liver Surgery, University Hospital, Helsinki, Finland
| | - Stein Foss
- Section for Transplantation Surgery, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Heikki Makisalo
- Department of Transplantation and Liver Surgery, University Hospital, Helsinki, Finland
| | - Arno Nordin
- Department of Transplantation and Liver Surgery, University Hospital, Helsinki, Finland
| | - Truls Sanengen
- Department of Pediatrics, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Annika Bergquist
- Department of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Marie E. Larsson
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Gunnar Soderdahl
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Greg Nowak
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Kirsten Muri Boberg
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine and Norwegian PSC Research Centre, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Helena Isoniemi
- Department of Transplantation and Liver Surgery, University Hospital, Helsinki, Finland
| | - Susanne Keiding
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Aksel Foss
- Section for Transplantation Surgery, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Pål-Dag Line
- Section for Transplantation Surgery, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Styrbjörn Friman
- Department of Transplantation, Sahlgrenska Academy at University of Gothenburg and The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Erik Schrumpf
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine and Norwegian PSC Research Centre, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
| | - Bo-Göran Ericzon
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Krister Höckerstedt
- Department of Transplantation and Liver Surgery, University Hospital, Helsinki, Finland
| | - Tom H. Karlsen
- Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Research Institute of Internal Medicine and Norwegian PSC Research Centre, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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Abstract
Research related to primary sclerosing cholangitis (PSC) has since 1980 been a major activity at the Oslo University Hospital Rikshospitalet. The purpose of this publication is to describe the development of this research, the impact of this research on the clinical handling of the patients, and finally to describe what we believe are the most urgent, remaining problems to be solved. During the early years, our research dealt primarily with clinical aspects of the disease. The concomitant inflammatory bowel disease (IBD) seen in most patients with PSC was a major interest and we also started looking into genetic associations of PSC. Prognosis, malignancy development and treatment with special emphasis on transplantation have later been dealt with. These activities has had impact on several aspects of PSC management; when and how to diagnose PSC and variant forms of PSC, how to handle IBD in PSC and how to deal with the increased rate of malignancy? The problems remaining to be solved are many. What is the role of the gut and the gut microbiota in the development of PSC? Do the PSC patients have an underlying disturbance in the bile homeostasis? And how does the characteristic type of fibrosis in PSC develop? The genetic studies have supported a role for the adaptive immune system in the disease development, but how should this be dealt with? Importantly, the development of malignancy in PSC is still not understood, and we lack appropriate medical treatment for our patients.
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Affiliation(s)
- Erik Schrumpf
- Norwegian PSC research center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet , Oslo , Norway
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32
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Aabakken L. Scandinavian Journal of Gastroenterology - the editors-in-chief. Scand J Gastroenterol 2015; 50:630-5. [PMID: 25803744 DOI: 10.3109/00365521.2015.1028995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The SJG has enjoyed a sequence of active and dynamic editors-in-chief following the initial period with Professor Myren in charge. This paper gives a short overview of the subsequent editors including their clinical and scientific merits.
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Affiliation(s)
- Lars Aabakken
- Department of Med Gastroenterology, Rikshospitalet University Hospital , Oslo , Norway
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33
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Ali AH, Carey EJ, Lindor KD, Chen Y, Lin Y, Zheng Q, Zhu K, Pan J. Recent advances in the development of farnesoid X receptor agonists. ANNALS OF TRANSLATIONAL MEDICINE 2015. [PMID: 25705637 DOI: 10.3978/j.issn.2305-5839] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.
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Affiliation(s)
- Ahmad H Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Yuanmei Chen
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
| | - Yu Lin
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
| | - Qingfeng Zheng
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
| | - Kunshou Zhu
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
| | - Jianji Pan
- 1 Department of Oncological Surgery, 2 Department of Radiation Oncology, 3 Department of Pathology, The Teaching Hospital of Fujian Medical University, Fujian Provincial Cancer Hospital, Fuzhou 350014, China
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Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:5. [PMID: 25705637 DOI: 10.3978/j.issn.2305-5839.2014.12.06] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 11/21/2014] [Indexed: 12/13/2022]
Abstract
Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.
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Affiliation(s)
- Ahmad H Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA
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Ali AH, Carey EJ, Lindor KD. Current research on the treatment of primary sclerosing cholangitis. Intractable Rare Dis Res 2015; 4:1-6. [PMID: 25674381 PMCID: PMC4322589 DOI: 10.5582/irdr.2014.01018] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 11/10/2014] [Accepted: 11/10/2014] [Indexed: 12/13/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a progressive disease of the liver characterized by inflammation and destruction of the intra- and/or extra-hepatic bile ducts, leading to fibrosis and ultimately liver failure, cirrhosis and an increased risk of malignancy. The etiology of PSC is unclear. It is often associated with the inflammatory bowel diseases (IBD), particularly Ulcerative Colitis (UC); up to 75% of PSC patients have UC. PSC is more prevalent in men than in women. Ursodeoxycholic acid (UDCA) has been extensively studied in PSC in randomized clinical trials but failed to show a positive impact on the natural course of the disease. Currently, there is no effective medical therapy for PSC, and the majority of patients will eventually require liver transplantation. PSC is one of the leading indications for liver transplantation. In this paper, we review the current research on the potential therapeutic agents for the treatment of PSC.
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Affiliation(s)
- Ahmad H Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, Arizona, USA
- Address correspondence to: Dr. Ahmad H Ali, Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA. E-mail: ;
| | - Elizabeth J Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Arizona, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Arizona, USA
- Arizona State University, College of Health Solutions, Phoenix, Arizona, USA
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36
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Hoffmann K, Hinz U, Hillebrand N, Ganten T, Gotthardt D, Longerich T, Schirmacher P, Schemmer P. The MELD score predicts the short-term and overall survival after liver transplantation in patients with primary sclerosing cholangitis or autoimmune liver diseases. Langenbecks Arch Surg 2014; 399:1001-1009. [PMID: 25106131 DOI: 10.1007/s00423-014-1237-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 07/28/2014] [Indexed: 12/21/2022]
Abstract
PURPOSE Liver transplantation (LT) is well established in patients with autoimmune liver disease. Despite excellent outcomes, organ scarcity demands careful patients' selection and timing of transplantation. METHODS This retrospective study analyzes data of 79 consecutive patients with primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and overlap syndrome, undergoing LT between 2001 and 2012. Overall survival (OS) and graft survival were assessed using Kaplan-Meier estimate. Multivariate survival analysis was performed to identify prognostic factors by using Cox regression model. RESULTS After 59.6-month median follow-up, the 5-year OS and graft survival were 75.3 and 68.8%, respectively. The 5-year survival rates for patients with PSC (n=57), AIH (n=17), and overlap syndrome (n=5) were 76.3, 76.0, and 60.0%. The 90-day mortality rate of 70.0% was significantly higher in patients with a labMELD score≥20 (n=10) compared to 26.1% in 69 patients with a labMELD<20 (p=0.009). A lab Model for End-Stage Liver Disease (MELD) score≥20 was an independent predictor of impaired OS (p=0.050, hazard ratio 2.5). The 5-year OS was 55.7% in patients with a labMELD score≥20 compared to 84.7% in patients with a labMELD score<20. CONCLUSION The recipients' MELD score is a predictor for the short-term outcome after LT in patients with autoimmune liver disease. Meticulous selection for transplant listing remains necessary to safe scarce donor organs.
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Affiliation(s)
- Katrin Hoffmann
- Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
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Mogl MT, Albert K, Pascher A, Sauer I, Puhl G, Gül S, Schönemann C, Neuhaus P, Guckelberger O. Survival without biliary complications after liver transplant for primary sclerosing cholangitis. EXP CLIN TRANSPLANT 2014; 11:510-21. [PMID: 24344944 DOI: 10.6002/ect.2013.0051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Patients who have a liver transplant for primary sclerosing cholangitis may develop recurrent disease and biliary complications, organ loss necessitating revision liver transplant, or death. We evaluated long-term outcomes in patients who had liver transplant for primary sclerosing cholangitis. MATERIALS AND METHODS In 71 patients who had a liver transplant for end-stage liver disease because of primary sclerosing cholangitis, a retrospective review was done to evaluate biliary complication-free survival, transplanted organ survival, and death. Human leukocyte antigen typing and matching were reviewed. RESULTS There were 39 patients (55%) who had biliary complications, loss of the liver transplant, or death at a mean 12.1 years after transplant. The 5- and 10-year event-free survival reached 74.6% and 45% (53 patients after 5 years, and 32 patients after 10 years). Male sex of transplant recipients was a significant risk factor for biliary complications, revision liver transplant, or death. Most patients had inflammatory bowel disease, primarily ulcerative colitis. The human leukocyte antigen profile or number of mismatches had no effect on complication-free survival. CONCLUSIONS Biliary complications, revision liver transplant, and death are a useful combined primary endpoint for recurrent primary sclerosing cholangitis after liver transplant.
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Affiliation(s)
- Martina T Mogl
- Department of General, Visceral and Transplantation Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany
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Tabibian JH, Lindor KD. Ursodeoxycholic acid in primary sclerosing cholangitis: if withdrawal is bad, then administration is good (right?). Hepatology 2014; 60:785-788. [PMID: 24752961 DOI: 10.1002/hep.27180] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 04/13/2014] [Indexed: 12/13/2022]
Affiliation(s)
- James H Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN; Center for Clinical and Translational Sciences, Mayo Clinic, Rochester, MN
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Tabibian JH, Talwalkar JA, Lindor KD. Role of the microbiota and antibiotics in primary sclerosing cholangitis. BIOMED RESEARCH INTERNATIONAL 2013; 2013:389537. [PMID: 24232746 PMCID: PMC3819830 DOI: 10.1155/2013/389537] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 09/05/2013] [Indexed: 12/18/2022]
Abstract
Primary sclerosing cholangitis (PSC) is an idiopathic, progressive, cholestatic liver disease with considerable morbidity and mortality and no established pharmacotherapy. In addition to the long-recognized association between PSC and inflammatory bowel disease, several lines of preclinical and clinical evidence implicate the microbiota in the etiopathogenesis of PSC. Here we provide a concise review of these data which, taken together, support further investigation of the role of the microbiota and antibiotics in PSC as potential avenues toward elucidating safe and effective pharmacotherapy for patients afflicted by this illness.
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Affiliation(s)
- James H. Tabibian
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Sreet SW, Rochester, MN 55905, USA
| | - Jayant A. Talwalkar
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Sreet SW, Rochester, MN 55905, USA
| | - Keith D. Lindor
- Executive Vice Provost & Dean, College of Health Solutions, Arizona State University, 550 North 3rd Street, Phoenix, AZ 85004, USA
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Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013; 145:521-36. [PMID: 23827861 PMCID: PMC3815445 DOI: 10.1053/j.gastro.2013.06.052] [Citation(s) in RCA: 282] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 05/18/2013] [Accepted: 06/24/2013] [Indexed: 02/08/2023]
Abstract
Primary sclerosing cholangitis (PSC), first described in the mid-1850s, is a complex liver disease that is heterogeneous in its presentation. PSC is characterized by chronic cholestasis associated with chronic inflammation of the biliary epithelium, resulting in multifocal bile duct strictures that can affect the entire biliary tree. Chronic inflammation leads to fibrosis involving the hepatic parenchyma and biliary tree, which can lead to cirrhosis and malignancy. The etiology of PSC is not fully understood, which in part explains the lack of effective medical therapy for this condition. However, we have begun to better understand the molecular pathogenesis of PSC. The recognition of specific clinical subtypes and their pattern of progression could improve phenotypic and genotypic classification of the disease. We review our current understanding of this enigmatic disorder and discuss important topics for future studies.
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Affiliation(s)
- John E. Eaton
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
| | - Jayant A. Talwalkar
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN,Corresponding Author: Jayant A. Talwalkar, M.D., M.P.H., Professor of Medicine, Division of Gastroenterology & Hepatology, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, Secretary: 507-284-4823, Fax: 507-284-0538,
| | | | - Gregory J. Gores
- Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, MN
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Yao Y, Xu ZY, Gao JP, Shen LJ, Wang H, Long Y, Yang JH. Histopathological changes in the liver of patients with autoimmune liver diseases: an analysis of 109 cases. Shijie Huaren Xiaohua Zazhi 2012; 20:605-609. [DOI: 10.11569/wcjd.v20.i7.605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze and compare the histopathological characteristics of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and their overlap syndromes.
METHODS: The histopathological changes in the liver of 27 patients with AIH, 67 patients with PBC, 4 patients with PSC, 1 patient with AIH-PSC overlap syndrome, and 10 patients with AIH-PBC overlap syndrome were investigated retrospectively.
RESULTS: Autoimmune liver diseases most frequently affected middle-aged women (73.3%). The main histological change in the liver was interface hepatitis (77.7%), and bridging necrosis was observed in severe AIH cases. Approximately 28.3% of PBC patients had early disease (stages I and II) and late disease (stages III and IV). The AIH-PBC overlap syndrome is not rare, and its pathological characteristics showed both characteristics of PBC and AIH.
CONCLUSION: Autoimmune liver diseases are not rare in China, and their diagnosis should be based on clinical presentations, biochemical, immunological and histological changes.
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Krones E, Graziadei I, Trauner M, Fickert P. Evolving concepts in primary sclerosing cholangitis. Liver Int 2012; 32:352-69. [PMID: 22097926 DOI: 10.1111/j.1478-3231.2011.02607.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 06/27/2011] [Indexed: 02/13/2023]
Abstract
Patients suffering from primary sclerosing cholangitis (PSC) show considerable differences regarding clinical manifestations (i.e. large duct versus small-duct PSC, presence or absence of concomitant inflammatory bowel disease), disease progression, risk for malignancy and response to therapy, raising the question whether PSC may represent a mixed bag of diseases of different aetiologies. The growing list of secondary causes and diseases 'mimicking' or even overlapping with PSC (e.g. IgG4-associated sclerosing cholangitis), which frequently causes problems in clear-cut discrimination from classic PSC and the emerging knowledge about potential disease modifier genes (e.g. variants of CFTR, TGR5 and MDR3) support such a conceptual view. In addition, PSC in children differs significantly from PSC in adults in several aspects resulting in distinct therapeutic concepts. From a clinical perspective, appropriate categorization and careful differential diagnosis are essential for the management of concerned patients. Therefore, the aim of the current review is to summarize current and evolving pathophysiological concepts and to provide up-to-date perspectives including future treatment strategies for PSC.
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Affiliation(s)
- Elisabeth Krones
- Department of Internal Medicine, Medical University of Graz, Graz, Austria
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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: 102] [Impact Index Per Article: 7.8] [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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Culver EL, Chapman RW. Systematic review: management options for primary sclerosing cholangitis and its variant forms - IgG4-associated cholangitis and overlap with autoimmune hepatitis. Aliment Pharmacol Ther 2011; 33:1273-91. [PMID: 21501198 DOI: 10.1111/j.1365-2036.2011.04658.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) remains a challenging disease to manage. The main goals are prevention of disease progression and reduction of the increased cancer risk. AIMS To review the management strategies for PSC and its variant forms based on published studies. METHODS Publications were identified using Pubmed, Medline and Ovid search engines. RESULTS Distinguishing PSC from variants, such as IgG4-associated cholangitis, and overlap with autoimmune hepatitis is essential to guide treatment decisions. There is no proven efficacious medical treatment for PSC. Ursodeoxycholic acid has been disappointing in low and moderate doses, and potentially dangerous in higher doses, although its role and optimal dose in chemoprevention requires investigation. The novel bile acid, 24-norursodeoxycholic acid, has shown promise in mouse models; human trials are in progress. Dominant strictures are optimally managed by dilatation and stenting to relieve obstructive complications, although exclusion of biliary malignancy is essential. Liver transplantation is the only proven therapy for those with advanced disease. Cholangiocarcinoma remains the most unpredictable and feared complication. In highly selected groups, neo-adjuvant chemoradiation with liver transplantation seems promising, but requires further validation. Screening for inflammatory bowel disease and surveillance for colorectal carcinoma should not be overlooked. CONCLUSIONS The effective management of PSC and its variants is hindered by uncertainties regarding pathogenesis of disease and factors responsible for its progression. Genome studies may help to identify further targets for drug therapy and factors leading to malignant transformation.
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Parés A. [Primary sclerosing cholangitis: diagnosis, prognosis and treatment]. GASTROENTEROLOGIA Y HEPATOLOGIA 2011; 34:41-52. [PMID: 20435377 DOI: 10.1016/j.gastrohep.2010.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Accepted: 02/12/2010] [Indexed: 05/29/2023]
Abstract
Primary sclerosing cholangitis is a chronic cholestatic disease characterized by inflammation with fibrosis and obliteration of the intra- and extrahepatic bile ducts. This disease is usually associated with ulcerative colitis. The process of chronic cholestasis eventually leads to biliary cirrhosis. The prevalence of primary sclerosing cholangitis is low in southern Europe but is especially high in Scandinavian countries. The etiopathogenesis is unknown but immune disorders, potential toxic agents or intestinal infections, ischemic injury to the bile ducts, and possibly alterations in hepatobiliary transporters are known to play a role. The disease manifests at the age of approximately 40 years, mainly in men with clinical and laboratory features of cholestasis but may also be asymptomatic. There are specific forms in which the small intrahepatic bile ducts are involved, mainly affecting children, as well as overlap syndromes with autoimmune hepatitis. A form characterized by an increase in IgG4 has been described, which is usually associated with autoimmune pancreatitis. The key diagnostic procedure is endoscopic retrograde cholangiography, although magnetic resonance cholangiography is the first diagnostic procedure that should be used since it is equally informative and non-invasive. Liver biopsy is not essential for diagnosis. Primary sclerosing cholangitis is a progressive disease with a probability of transplant-free survival of 18 years in asymptomatic forms and of 8.5 years in symptomatic forms. Cholangiocarcinoma can result from the disease and confers a poor prognosis. There is no specific treatment although ursodeoxycholic acid improves the biochemical alterations of cholestasis. Liver transplantation is the last therapeutic resort with good results in terms of survival although the disease can recur in the transplanted liver.
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Affiliation(s)
- Albert Parés
- Unidad de Hepatología, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Universidad de Barcelona, Barcelona, Spain.
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Karlsen TH, Schrumpf E, Boberg KM. Primary sclerosing cholangitis. Best Pract Res Clin Gastroenterol 2010; 24:655-66. [PMID: 20955968 DOI: 10.1016/j.bpg.2010.07.005] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2010] [Revised: 07/15/2010] [Accepted: 07/16/2010] [Indexed: 01/31/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic bile duct disease leading to fibrotic biliary strictures and liver cirrhosis. The patient population is heterogeneous with regard to disease progression and the presence of co-morbidities, complicating the practical handling of patients as well as studies of pathogenetic mechanisms. The aetiology of PSC is unknown, but the recent findings of several robust susceptibility genes emphasise the importance of genetic risk factors. There is no effective medical treatment available to delay the disease progression, but endoscopic therapy of biliary stenoses may be indicated. Follow-up of patients includes management of the inflammatory bowel disease that is found in the majority of cases along with investigations aimed at the early detection of cholangiocarcinoma and colorectal cancer, which also occur at increased frequencies. In the present review, we aim to summarise the present knowledge of PSC with a particular emphasis on the possible basis of disease variability.
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Affiliation(s)
- Tom H Karlsen
- Norwegian PSC Research Center, Clinic for Specialized Medicine and Surgery, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway.
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Abstract
Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of intra-/extrahepatic bile ducts, leading to multifocal strictures. Primary sclerosing cholangitis exhibits a progressive course resulting in cirrhosis and the need for liver transplantation over a median period of 12 years. The disease is frequently associated with inflammatory bowel disease and carries an increased risk of colorectal cancer and cholangiocarcinoma. Despite extensive research, there is currently no effective medical treatment. Multiple drugs are shown to be ineffective in halting disease progression, including ursodeoxycholic acid, the most widely evaluated drug. High-dose ursodeoxycholic acid (28-30 mg/kg/day) was recently shown to increase the adverse events rate. Endoscopic or radiological dilatation of a 'dominant' stricture may lead to symptomatic and biochemical improvement. However, liver transplantation is the only life-prolonging treatment for patients with end-stage disease. Studies with promising drugs, such as antibiotics, antifibrotic agents and bile acid derivatives, are eagerly awaited.
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Affiliation(s)
- Emmanouil Sinakos
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905, USA
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48
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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: 83] [Impact Index Per Article: 5.5] [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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The natural history of inflammatory bowel disease and primary sclerosing cholangitis after liver transplantation--a single-centre experience. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2010; 24:40-6. [PMID: 20186355 DOI: 10.1155/2010/830291] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE To describe the natural history of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) after liver transplant, the predictors of PSC and IBD recurrence, and the interaction of these disease processes. METHODS Data regarding patients who received liver transplants for PSC at the University of Alberta Hospital (Edmonton, Alberta) from 1989 to 2006 were retrospectively reviewed. Recurrent PSC (rPSC) was defined by the Mayo Clinic criteria. Cox proportional hazards modelling and Kaplan-Meier statistics were used. RESULTS Fifty-nine patients were studied, with a median follow-up of 68 months. A total of 71.2% of patients were diagnosed with IBD pretransplant. Clinical IBD severity post-transplant compared with severity pretransplant was unchanged in 67%, worse in 26.5% and improved in 6.1% of patients. Twenty-five per cent of patients developed rPSC posttransplant. The occurrence of at least one episode of acute cellular rejection (hazard ratio 5.7; 95% CI 1.3 to 25.8) and cytomegalovirus mismatch (hazard ratio 4.2; 95% CI 1.1 to 15.4) were found to be significant predictors of rPSC. Although not statistically significant, there was no rPSC in patients without pre- or post-transplant IBD, and in only one patient with a colectomy. Actuarial patient survival rates at one, five and 10 years posttransplant were 97%, 86% and 79%, respectively. Although a significant proportion of patients experienced worsening IBD post-transplantation, the presence or severity of IBD did not influence rPSC or patient survival. CONCLUSION Acute cellular rejection and cytomegalovirus mismatch were both identified as independent predictors of rPSC. The impact of steroids and the ideal immunosuppressive regimen for the control of both IBD and PSC post-transplant requires further examination in prospective studies.
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Orthotopic liver transplantation and what to do during follow-up: recommendations for the practitioner. ACTA ACUST UNITED AC 2008; 6:23-36. [PMID: 19029996 DOI: 10.1038/ncpgasthep1312] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2008] [Accepted: 10/01/2008] [Indexed: 12/18/2022]
Abstract
Improvements in surgical technique and the introduction of several new immunosuppressive medications mean that outcome after orthotopic liver transplantation (OLT) has improved continuously over the past 15 years. Given the increasing longevity of patients after OLT, the recognition and prevention of long-term complications after transplantation have become ever more important. With respect to graft function, physicians responsible for the everyday care of patients following transplantation should be particularly aware of the risk of late and chronic rejection episodes and of recurrence of the underlying liver disease. The major challenge of post-transplant care is, however, how best to prevent and manage the long-term adverse effects caused by the immunosuppressive medications prescribed. Screening investigations for early diagnosis of malignancy, strict control of cardiovascular risk factors, preservation of renal function, and prevention of infections are, therefore, fundamental. This Review suggests guidelines for the management of OLT recipients to improve long-term survival, overall outcome and health-related quality of life.
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