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Manns MP, Bergquist A, Karlsen TH, Levy C, Muir AJ, Ponsioen C, Trauner M, Wong G, Younossi ZM. Primary sclerosing cholangitis. Nat Rev Dis Primers 2025; 11:17. [PMID: 40082445 DOI: 10.1038/s41572-025-00600-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/07/2025] [Indexed: 03/16/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic biliary inflammation associated with periductular fibrosis of the intrahepatic and extrahepatic bile ducts leading to strictures, bacterial cholangitis, decompensated liver disease and need for liver transplantation. This rare focal liver disease affects all races and ages, with a predominance of young males. There is an up to 88% association with inflammatory bowel disease. Although the aetiology is unknown and the pathophysiology is poorly understood, PSC is regarded as an autoimmune liver disease based on a strong immunogenetic background. Further, the associated risk for various malignancies, particularly cholangiocellular carcinoma, is also poorly understood. No medical therapy has been approved so far nor has been shown to improve transplant-free survival. However, ursodeoxycholic acid is widely used since it improves the biochemical parameters of cholestasis and is safe at low doses. MRI of the biliary tract is the primary imaging technology for diagnosis. Endoscopic interventions of the bile ducts should be limited to clinically relevant strictures for balloon dilatation, biopsy and brush cytology. End-stage liver disease with decompensation is an indication for liver transplantation with recurrent PSC in up to 38% of patients. Several novel therapeutic strategies are in various stages of development, including apical sodium-dependent bile acid transporter and ileal bile acid transporter inhibitors, integrin inhibitors, peroxisome proliferator-activated receptor agonists, CCL24 blockers, recombinant FGF19, CCR2/CCR5 inhibitors, farnesoid X receptor bile acid receptor agonists, and nor-ursodeoxycholic acid. Manipulation of the gut microbiome includes faecal microbiota transplantation. This article summarizes present knowledge and defines unmet medical needs to improve quality of life and survival.
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Affiliation(s)
- Michael P Manns
- Hannover Medical School (MHH) and Centre for Individualised Infection Medicine (CiiM), Hannover, Germany.
| | - Annika Bergquist
- Division of Hepatology, Department of Upper Gastrointestinal Disease, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Clinic of Surgery and Specialized medicine, Oslo University Hospital, Oslo, Norway
- Research Institute of Internal Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Cynthia Levy
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, FL, USA
| | - Andrew J Muir
- Division of Gastroenterology, Duke University School of Medicine, Durham, NC, USA
| | - Cyriel Ponsioen
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Grace Wong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Union Hospital, Hong Kong SAR, China
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Elzubeir A, High J, Hammond M, Shepstone L, Pond M, Walmsley M, Trivedi P, Culver E, Aithal G, Dyson J, Thorburn D, Alexandre L, Rushbrook S. Assessing brodalumab in the treatment of primary sclerosing cholangitis (SABR-PSC pilot study): protocol for a single-arm, multicentre, pilot study. BMJ Open Gastroenterol 2025; 12:e001596. [PMID: 40032516 PMCID: PMC11877274 DOI: 10.1136/bmjgast-2024-001596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 01/13/2025] [Indexed: 03/05/2025] Open
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a rare immune-mediated hepatobiliary disease, characterised by progressive biliary fibrosis, cirrhosis, and end-stage liver disease. As yet, no licensed pharmacological therapy exists. While significant advancements have been made in our understanding of the pathophysiology, the exact aetiology remains poorly defined. Compelling evidence from basic science and translational studies implicates the role of T helper 17 cells (Th17) and the interleukin 17 (IL-17) pro-inflammatory signalling pathway in the pathogenesis of PSC. However, exploration of the safety and efficacy of inhibiting the IL-17 pathway in PSC is lacking. METHODS AND ANALYSIS This is a phase 2a, open-label, multicentre pilot study, testing the safety of brodalumab, a recombinant human monoclonal antibody that binds with high affinity to interleukin-17RA, in adults with PSC. This study will enrol 20 PSC patients across five large National Health Service tertiary centres in the UK. The primary outcome of the study relates to determining the safety and feasibility of administering brodalumab in early, non-cirrhotic PSC patients. Secondary efficacy outcomes include non-invasive assessment of liver fibrosis, changes in alkaline phosphatase values and other liver biochemical readouts, assessment of biliary metrics through quantitative MR cholangiography+, and quality of life evaluation on completion of follow-up (using the 5D-itch tool, the PSC-patient-reported outcome and PSC-specific Chronic Liver Disease Questionnaire). ETHICS AND DISSEMINATION Ethical approval for this study has been obtained from the London Bridge Research Ethics Committee (REC23/LO/0718). Written informed consent will be obtained from all trial participants prior to undertaking any trial-specific examinations or investigations. On completion of the study, results will be submitted for publication in peer-reviewed journals and presented at national and international hepatology meetings. A summary of the findings will also be shared with participants and PSC communities. TRIAL REGISTRATION NUMBER ISRCTN15271834.
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MESH Headings
- Humans
- Cholangitis, Sclerosing/drug therapy
- Cholangitis, Sclerosing/immunology
- Pilot Projects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Interleukin-17/antagonists & inhibitors
- Interleukin-17/immunology
- Multicenter Studies as Topic
- Treatment Outcome
- Adult
- Clinical Trials, Phase II as Topic
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal/administration & dosage
- Quality of Life
- United Kingdom
- Male
- Female
- Th17 Cells/immunology
- Th17 Cells/drug effects
- Receptors, Interleukin-17/antagonists & inhibitors
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Affiliation(s)
- Amera Elzubeir
- University of East Anglia Norwich Medical School, Norwich, UK
- Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | - Juliet High
- Norwich Clinical Trials Unit, University of East Anglia, Norwich, UK
| | - Matthew Hammond
- Norwich Clinical Trials Unit, University of East Anglia, Norwich, UK
| | - Lee Shepstone
- Norwich Clinical Trials Unit, University of East Anglia, Norwich, UK
| | - Martin Pond
- Norwich Clinical Trials Unit, University of East Anglia, Norwich, UK
| | | | - Palak Trivedi
- NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Emma Culver
- Translational Gastroenterology Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Guruprasad Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Jessica Dyson
- Liver Unit, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK
| | - Douglas Thorburn
- University College London institute for Liver and Digestive Health, Royal Free Hospital, London, UK
| | - Leo Alexandre
- University of East Anglia Norwich Medical School, Norwich, UK
- Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | - Simon Rushbrook
- University of East Anglia Norwich Medical School, Norwich, UK
- Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
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Fossdal G, Braadland P, Hov JR, Husebye ES, Folseraas T, Ueland PM, Ulvik A, Karlsen TH, Berge RK, Vesterhus M. Mitochondrial dysfunction and lipid alterations in primary sclerosing cholangitis. Scand J Gastroenterol 2025; 60:165-173. [PMID: 39764583 DOI: 10.1080/00365521.2024.2447521] [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: 09/28/2023] [Revised: 12/17/2024] [Accepted: 12/22/2024] [Indexed: 02/05/2025]
Abstract
OBJECTIVES Indications of mitochondrial dysfunction are commonly seen in liver diseases, but data are scarce in primary sclerosing cholangitis (PSC). Analyzing circulating and liver-resident molecules indirectly reflecting mitochondrial dysfunction, we aimed to comprehensively characterize this deficit in PSC, and whether this was PSC specific or associated with cholestasis. MATERIALS AND METHODS We retrospectively included plasma from 191 non-transplant patients with large-duct PSC and 100 healthy controls and explanted liver tissue extracts from 24 PSC patients and 18 non-cholestatic liver disease controls. Using mass spectroscopy, we profiled lipids and fatty acids, carnitine, acylcarnitines, and metabolites in the tryptophan-kynurenine-nicotinamide pathway. RESULTS Hierarchal clustering of fatty acid levels identified patients with PSC and healthy controls as separate clusters. Compared to healthy controls, PSC patients had increased levels of monounsaturated fatty acids (MUFA) and palmitate (C16:0) in plasma, but reduced levels of long-chain saturated fatty acids (SFAs). These findings were more pronounced in PSC patients with cholestasis. Several n-3 polyunsaturated fatty acids were elevated in PSC but not associated with cholestasis. Acylcarnitine ratios C2/C5 and C2/C3 were elevated while C2/C16 was reduced in PSC, indicating impaired mitochondrial fatty acid oxidation of medium-long chained fatty acids. Levels of intermediates in the tryptophan-kynurenine pathway indicated impaired NAD biosynthesis, suggesting impaired energy supply to mitochondria in PSC. CONCLUSIONS We found that mitochondrial dysfunction was prominent in PSC and associated with increasing cholestasis. Whether this is merely a marker of liver disease and severity, or an underlying driver and potential therapeutic target in PSC remains to be explored.
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Affiliation(s)
- Guri Fossdal
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway
| | - Peder Braadland
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Johannes Roksund Hov
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | | | - Trine Folseraas
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Per Magne Ueland
- Department of Clinical Science, University of Bergen, Bergen, Norway
- BEVITAL AS, Bergen, Norway
| | | | - Tom Hemming Karlsen
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Rolf Kristian Berge
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Mitomega AS, Stavanger, Norway
| | - Mette Vesterhus
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway
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Färkkilä M, Åberg F, Alfthan H, Jokelainen K, Puustinen L, Kautiainen H, Tenca A. Surrogate markers of bile duct disease progression in primary sclerosing cholangitis - A prospective study with repeated ERCP examinations. JHEP Rep 2024; 6:101161. [PMID: 39290402 PMCID: PMC11405802 DOI: 10.1016/j.jhepr.2024.101161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/14/2024] [Accepted: 06/25/2024] [Indexed: 09/19/2024] Open
Abstract
Background & Aims Validated prognostic tools for estimating short-term bile duct disease progression in primary sclerosing cholangitis (PSC) are lacking. We evaluated the predictive value of serum and biliary biochemistry for the progression of bile duct disease in PSC using repeated endoscopic retrograde cholangiopancreatography (ERCP) examinations to identify surrogate markers for more personalized surveillance. Methods We conducted a prospective analysis including patients with PSC who underwent ERCP for confirmation of diagnosis, monitoring of disease progression, or dysplasia surveillance. ERCP findings were scored, and dilatation was performed if a dominant stricture was diagnosed or if a cytology brush could not be passed. Bile samples were aspirated for biliary IL8 and calprotectin. We analysed optimal cut-off values and AUCs for 20 laboratory markers and evaluated their association with the time to an ERCP score increase of ≥2 points or first dilatation, whichever came first. Of the 1,002 patients, 653 had ≥2 ERCP examinations and ≥3 years of follow-up. After excluding patients with PSC-overlap syndrome or initial dilatation, 398 patients were included. Results Of the patients included, 62% had mild or moderate and 38% had advanced bile duct disease. During follow-up, 41% of patients demonstrated progression of disease. Biliary calprotectin (AUC 0.76; 95% CI 0.69 to 0.82) and IL8 (AUC 0.76; 95% CI 0.69 to 0.84) were the only variables that demonstrated predictive value for disease progression and/or need for dilatation. Conclusions Biliary calprotectin and IL8 are promising surrogate markers for identifying patients with PSC at risk of progression and determining the timing for subsequent imaging. Conventional liver function tests may not be sensitive or specific enough to monitor PSC progression, particularly in the short term. Impact and implications Validated prognostic tools for estimating short-term bile duct disease progression in primary sclerosing cholangitis are lacking. In this prospective study, based on sequential endoscopic retrograde cholangiopancreatography examinations, biliary calprotectin and IL8 levels turned out to be more sensitive for predicting bile duct progression than traditional liver function tests, such as alkaline phosphatase, in the short term. These findings could lead to more personalized patient surveillance and improve clinical practice by providing a more accurate method for monitoring disease progression and treatment responses. Additionally, these markers have potential as surrogate endpoints in clinical drug trials. The limitation is that measurement of biliary IL8 and calprotectin requires endoscopic retrograde cholangiopancreatography with bile sampling.
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Affiliation(s)
- Martti Färkkilä
- Helsinki University, Finland
- Department of Gastroenterology, Helsinki University Hospital, Abdominal Center, Helsinki, Finland
| | - Fredrik Åberg
- Transplantation and Liver Surgery, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Henrik Alfthan
- Department of Clinical Chemistry, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kalle Jokelainen
- Department of Gastroenterology, Helsinki University Hospital, Abdominal Center, Helsinki, Finland
| | - Lauri Puustinen
- Department of Gastroenterology, Helsinki University Hospital, Abdominal Center, Helsinki, Finland
| | - Hannu Kautiainen
- Folkhälsan Research Center, Helsinki, Finland and Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Andrea Tenca
- Department of Gastroenterology, Helsinki University Hospital, Abdominal Center, Helsinki, Finland
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Kim MN, Han JW, An J, Kim BK, Jin YJ, Kim SS, Lee M, Lee HA, Cho Y, Kim HY, Shin YR, Yu JH, Kim MY, Choi Y, Chon YE, Cho EJ, Lee EJ, Kim SG, Kim W, Jun DW, Kim SU. KASL clinical practice guidelines for noninvasive tests to assess liver fibrosis in chronic liver disease. Clin Mol Hepatol 2024; 30:S5-S105. [PMID: 39159947 PMCID: PMC11493350 DOI: 10.3350/cmh.2024.0506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 08/21/2024] Open
Affiliation(s)
- Mi Na Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Ji Won Han
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jihyun An
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Seung-seob Kim
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Minjong Lee
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
| | - Han Ah Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
| | - Hee Yeon Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Yu Rim Shin
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jung Hwan Yu
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Young Eun Chon
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Joo Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Won Kim
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
| | - on behalf of The Korean Association for the Study of the Liver (KASL)
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Gastroenterology and Hepatology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
- Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
- Department of Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Institute of Gastroenterology, CHA Bundang Medical Center, CHA University, Seongnam, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
- Department of Internal Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea
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Berg T, Aehling NF, Bruns T, Welker MW, Weismüller T, Trebicka J, Tacke F, Strnad P, Sterneck M, Settmacher U, Seehofer D, Schott E, Schnitzbauer AA, Schmidt HH, Schlitt HJ, Pratschke J, Pascher A, Neumann U, Manekeller S, Lammert F, Klein I, Kirchner G, Guba M, Glanemann M, Engelmann C, Canbay AE, Braun F, Berg CP, Bechstein WO, Becker T, Trautwein C. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:1397-1573. [PMID: 39250961 DOI: 10.1055/a-2255-7246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Affiliation(s)
- Thomas Berg
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Niklas F Aehling
- Bereich Hepatologie, Medizinischen Klinik II, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Tony Bruns
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martin-Walter Welker
- Medizinische Klinik I Gastroent., Hepat., Pneum., Endokrin. Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Tobias Weismüller
- Klinik für Innere Medizin - Gastroenterologie und Hepatologie, Vivantes Humboldt-Klinikum, Berlin, Deutschland
| | - Jonel Trebicka
- Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Deutschland
| | - Frank Tacke
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Pavel Strnad
- Medizinische Klinik III, Universitätsklinikum Aachen, Aachen, Deutschland
| | - Martina Sterneck
- Medizinische Klinik und Poliklinik I, Universitätsklinikum Hamburg, Hamburg, Deutschland
| | - Utz Settmacher
- Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Universitätsklinikum Jena, Jena, Deutschland
| | - Daniel Seehofer
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Eckart Schott
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie und Diabetolgie, Helios Klinikum Emil von Behring, Berlin, Deutschland
| | | | - Hartmut H Schmidt
- Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Essen, Deutschland
| | - Hans J Schlitt
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg, Regensburg, Deutschland
| | - Johann Pratschke
- Chirurgische Klinik, Charité Campus Virchow-Klinikum - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Andreas Pascher
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Münster, Münster, Deutschland
| | - Ulf Neumann
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
| | - Steffen Manekeller
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Bonn, Deutschland
| | - Frank Lammert
- Medizinische Hochschule Hannover (MHH), Hannover, Deutschland
| | - Ingo Klein
- Chirurgische Klinik I, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | - Gabriele Kirchner
- Klinik und Poliklinik für Chirurgie, Universitätsklinikum Regensburg und Innere Medizin I, Caritaskrankenhaus St. Josef Regensburg, Regensburg, Deutschland
| | - Markus Guba
- Klinik für Allgemeine, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Universitätsklinikum München, München, Deutschland
| | - Matthias Glanemann
- Klinik für Allgemeine, Viszeral-, Gefäß- und Kinderchirurgie, Universitätsklinikum des Saarlandes, Homburg, Deutschland
| | - Cornelius Engelmann
- Charité - Universitätsmedizin Berlin, Medizinische Klinik m. S. Hepatologie und Gastroenterologie, Campus Virchow-Klinikum (CVK) und Campus Charité Mitte (CCM), Berlin, Deutschland
| | - Ali E Canbay
- Medizinische Klinik, Universitätsklinikum Knappschaftskrankenhaus Bochum, Bochum, Deutschland
| | - Felix Braun
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
| | - Christoph P Berg
- Innere Medizin I Gastroenterologie, Hepatologie, Infektiologie, Universitätsklinikum Tübingen, Tübingen, Deutschland
| | - Wolf O Bechstein
- Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Deutschland
| | - Thomas Becker
- Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schlewswig-Holstein, Kiel, Deutschland
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Trivedi PJ, Arndtz K, Abbas N, Telford A, Young L, Banerjee R, Eddowes P, Jhaveri KS, Hirschfield GM. Quantitative MRCP and metrics of bile duct disease over time in patients with primary sclerosing cholangitis: A prospective study. Aliment Pharmacol Ther 2024; 59:1366-1375. [PMID: 38571284 DOI: 10.1111/apt.17944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/13/2024] [Accepted: 02/28/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND Imaging markers of biliary disease in primary sclerosing cholangitis (PSC) have potential for use in clinical and trial disease monitoring. Herein, we evaluate how quantitative magnetic resonance cholangiopancreatography (MRCP) metrics change over time, as per the natural history of disease. METHODS Individuals with PSC were prospectively scanned using non-contrast MRCP. Quantitative metrics were calculated using MRCP+ post-processing software to assess duct diameters and dilated and strictured regions. Additionally, a hepatopancreatobiliary radiologist (blinded to clinical details, biochemistry and quantitative biliary metrics) reported each scan, including ductal disease assessment according to the modified Amsterdam Cholangiographic Score (MAS). RESULTS At baseline, 14 quantitative MRCP+ metrics were found to be significantly different in patients with PSC (N = 55) compared to those with primary biliary cholangitis (N = 55), autoimmune hepatitis (N = 57) and healthy controls (N = 18). In PSC specifically, baseline metrics quantifying the number of strictures and the number and length of bile ducts correlated with the MAS, transient elastography and serum ALP values (p < 0.01 for all correlations). Over a median 371-day follow-up (range: 364-462), 29 patients with PSC underwent repeat MRCP, of whom 15 exhibited quantitative changes in MRCP+ metrics. Compared to baseline, quantitative MRCP+ identified an increasing number of strictures over time (p < 0.05). Comparatively, no significant differences in biochemistry, elastography or the MAS were observed between timepoints. Quantitative MRCP+ metrics remained stable in non-PSC liver disease. CONCLUSION Quantitative MRCP+ identifies changes in ductal disease over time in PSC, despite stability in biochemistry, liver stiffness and radiologist-derived cholangiographic assessment (trial registration: ISRCTN39463479).
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Affiliation(s)
- Palak J Trivedi
- National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research and Gastrointestinal Research, National Institute of Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), University of Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Katherine Arndtz
- National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research and Gastrointestinal Research, National Institute of Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), University of Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
- Institute of Applied Health Research, University of Birmingham, Birmingham, UK
| | - Nadir Abbas
- National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research and Gastrointestinal Research, National Institute of Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), University of Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- Liver Unit, University Hospitals Birmingham Queen Elizabeth, Birmingham, UK
| | | | | | | | - Peter Eddowes
- National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research and Gastrointestinal Research, National Institute of Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), University of Birmingham, Birmingham, UK
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
- NIHR Nottingham BRC, University of Nottingham, Nottingham, UK
- Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Kartik S Jhaveri
- Division of Radiology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Gideon M Hirschfield
- University Health Network and Department of Medicine, Toronto Centre for Liver Disease, University of Toronto, Toronto, Ontario, Canada
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8
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Greenman R, Snir T, Katav A, Aricha R, Mishalian I, Hay O, Frankel M, Lawler J, Saffioti F, Pinzani M, Thorburn D, Peled A, Mor A, Vaknin I. The Role of CCL24 in Primary Sclerosing Cholangitis: Bridging Patient Serum Proteomics to Preclinical Data. Cells 2024; 13:209. [PMID: 38334601 PMCID: PMC10854794 DOI: 10.3390/cells13030209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/10/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is an inflammatory and fibrotic biliary disease lacking approved treatment. We studied CCL24, a chemokine shown to be overexpressed in damaged bile ducts, and its involvement in key disease-related mechanisms. Serum proteomics of PSC patients and healthy controls (HC) were analyzed using the Olink® proximity extension assay and compared based on disease presence, fibrosis severity, and CCL24 levels. Disease-related canonical pathways, upstream regulators, and toxicity functions were elevated in PSC patients compared to HC and further elevated in patients with high CCL24 levels. In vitro, a protein signature in CCL24-treated hepatic stellate cells (HSCs) differentiated patients by disease severity. In mice, CCL24 intraperitoneal injection selectively recruited neutrophils and monocytes. Treatment with CM-101, a CCL24-neutralizing antibody, in an α-naphthylisothiocyanate (ANIT)-induced cholestasis mouse model effectively inhibited accumulation of peribiliary neutrophils and macrophages while reducing biliary hyperplasia and fibrosis. Furthermore, in PSC patients, CCL24 levels were correlated with upregulation of monocyte and neutrophil chemotaxis pathways. Collectively, these findings highlight the distinct role of CCL24 in PSC, influencing disease-related mechanisms, affecting immune cells trafficking and HSC activation. Its blockade with CM-101 reduces inflammation and fibrosis and positions CCL24 as a promising therapeutic target in PSC.
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Affiliation(s)
| | - Tom Snir
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Avi Katav
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | | | - Inbal Mishalian
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | - Ophir Hay
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | | | - John Lawler
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Francesca Saffioti
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Douglas Thorburn
- UCL Institute for Liver and Digestive Health, University College of London, London NW3 2PF, UK
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London NW3 2QG, UK
| | - Amnon Peled
- Goldyne Savad Institute of Gene Therapy, Hebrew University Hospital Jerusalem, Jerusalem 91120, Israel
| | - Adi Mor
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Ilan Vaknin
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
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9
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Gee MFW, Palladino A, Levy HR, De Vol E, Kiaei D. Derivation and validation of Transform equations to convert historical Enhanced liver fibrosis (ELF) scores to modern equivalents. Clin Chim Acta 2024; 552:117696. [PMID: 38070667 DOI: 10.1016/j.cca.2023.117696] [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: 10/23/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 12/19/2023]
Abstract
BACKGROUND AND AIMS The Siemens Healthineers ELF™ Test was designed in 2004 with 2 algorithms to allow choice in histological alignment. Consequently, historical and modern algorithms are not fully harmonized, complicating comparisons involving early datasets. We derived transform equations to equate all ELF score versions, allowing historical data to be used in systematic reviews and meta-analyses. METHODS Historical ELF equations were graphed pairwise versus their modern equivalent to assess correlation and derive four transforms. Transforms were validated using multiple datasets and evaluated for median absolute bias, number of samples reflecting clinically significant bias, number of discordant samples, bias at established cutoffs, and regression slope and y-intercept. RESULTS Three transforms were validated equating Scheuer-aligned and/or age-included historical ELF equations (Immuno 1) to later equations aligned to Ishak and omitting age. A fourth transform corrected ADVIA Centaur® / Atellica® IM ELF scores miscalculated using the Scheuer Immuno 1 equation. Transformed data were well within allowable ELF bias limits. CONCLUSIONS All transforms enabled accurate comparison of ELF scores generated by all historical algorithms to the current ADVIA Centaur / Atellica IM Analyzer ELF score. The transforms presented in this report should be used in systematic reviews and meta-analyses to facilitate comparisons to historical data.
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Affiliation(s)
- Matthew F W Gee
- Siemens Healthcare Diagnostics Inc., 511 Benedict Ave, Tarrytown, NY, United States.
| | - Agostino Palladino
- Siemens Healthcare Diagnostics Inc., 511 Benedict Ave, Tarrytown, NY, United States.
| | - H Roma Levy
- Siemens Healthcare Diagnostics Inc., 511 Benedict Ave, Tarrytown, NY, United States.
| | - Edward De Vol
- Siemens Healthcare Diagnostics Inc., 511 Benedict Ave, Tarrytown, NY, United States.
| | - David Kiaei
- Siemens Healthcare Diagnostics Inc., 511 Benedict Ave, Tarrytown, NY, United States.
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10
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D'Amato D, Carbone M. Prognostic models and autoimmune liver diseases. Best Pract Res Clin Gastroenterol 2023; 67:101878. [PMID: 38103932 DOI: 10.1016/j.bpg.2023.101878] [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: 09/07/2023] [Revised: 10/18/2023] [Accepted: 11/24/2023] [Indexed: 12/19/2023]
Abstract
Autoimmune liver diseases (AILDs) are complex diseases with unknown causes and immune-mediated pathophysiology. In primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) disease modifying drugs are available which improve patient quality and quantity of life. In primary sclerosing cholangitis (PSC) no medical therapy is available and the only accepted treatment is liver transplantation (LT). PBC, PSC and AIH possess features that describe the archetype of patients within each disorder. On the other hand, the classical disorders are not homogeneous, and patients within each diagnosis may present with a range of clinical, biochemical, serological, and histological findings. Singularly, they are considered rare diseases, but together, they account for approximately 20% of LTs in Europe and USA. Management of these patients is complex, as AILDs are relatively uncommon in clinical practice with challenges in developing expertise, disease presentation can be sneaky, clinical phenotypes and disease course are heterogeneous. Prognostic models are key tools for clinicians to assess patients' risk and to provide personalized care to patients. Aim of this review is to discuss challenges of the management of AILDs and how the available prognostic models can help. We will discuss the prognostic models developed in AILDs, with a special focus on the prognostic models that can support the clinical management of patients with AILDs: in PBC models based on ursodeoxycholic acid (UDCA) response and markers of liver fibrosis; in PSC several markers including biochemistry, disease stage and radiological semiquantitative markers; and finally in AIH, markers of disease stage and disease activity.
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Affiliation(s)
- Daphne D'Amato
- Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy.
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11
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Fuchs CD, Sroda N, Scharnagl H, Gupta R, Minto W, Stojakovic T, Liles JT, Budas G, Hollenback D, Trauner M. Non-steroidal FXR agonist cilofexor improves cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis. JHEP Rep 2023; 5:100874. [PMID: 37841639 PMCID: PMC10568427 DOI: 10.1016/j.jhepr.2023.100874] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 06/30/2023] [Accepted: 07/18/2023] [Indexed: 10/17/2023] Open
Abstract
Background & Aims The nuclear receptor farnesoid X receptor (FXR) is a key regulator of hepatic bile acid (BA) and lipid metabolism, inflammation and fibrosis. Here, we aimed to explore the potential of cilofexor (GS-9674), a non-steroidal FXR agonist, as a therapeutic approach for counteracting features of cholestatic liver injury by evaluating its efficacy and mechanisms in the Mdr2/Abcb4 knockout (-/-) mouse model of sclerosing cholangitis. Methods FVB/N wild-type and Mdr2-/- or BALB/c wild-type and Mdr2-/- mice were treated with 0, 10, 30 or 90 mg/kg cilofexor by gavage every 24 h for 10 weeks. Serum biochemistry, gene expression profile, hydroxyproline content, and picrosirius red and F4/80 immunostaining, were investigated. Bile flow, biliary bicarbonate and BA output, and hepatic BA profile, were assessed. Results Cilofexor treatment improved serum levels of aspartate aminotransferase, alkaline phosphatase as well as BAs in Mdr2-/- animals. Hepatic fibrosis was improved, as reflected by the reduced picrosirius red-positive area and hydroxyproline content in liver sections of cilofexor-treated Mdr2-/- mice. Intrahepatic BA concentrations were lowered in cilofexor-treated Mdr2-/- mice, while hepatobiliary bile flow and bicarbonate output were increased. Conclusion Collectively the current data show that cilofexor treatment improves cholestatic liver injury and decreases hepatic fibrosis in the Mdr2-/- mouse model of sclerosing cholangitis. Impact and implications Treatment with cilofexor, a non-steroidal farnesoid X receptor (FXR) agonist, improved histological features of sclerosing cholangitis, cholestasis and hepatic fibrosis in the Mdr2-/- mouse model. These findings indicate, that pharmacological stimulation of intestinal FXR-mediated gut-liver signaling, via fibroblast growth factor 15 (thereby reducing bile acid synthesis), may be sufficient to attenuate cholestatic liver injury in the Mdr2-/- mouse model of sclerosing cholangitis, thus arguing for potential therapeutic properties of cilofexor in cholestatic liver diseases.
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Affiliation(s)
- Claudia D. Fuchs
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | | | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria
| | | | | | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Austria
| | | | | | | | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
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12
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Tan N, Lubel J, Kemp W, Roberts S, Majeed A. Current Therapeutics in Primary Sclerosing Cholangitis. J Clin Transl Hepatol 2023; 11:1267-1281. [PMID: 37577219 PMCID: PMC10412694 DOI: 10.14218/jcth.2022.00068s] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 01/01/2023] [Accepted: 01/20/2023] [Indexed: 07/03/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is an orphan, cholestatic liver disease that is characterized by inflammatory biliary strictures with variable progression to end-stage liver disease. Its pathophysiology is poorly understood. Chronic biliary inflammation is likely driven by immune dysregulation, gut dysbiosis, and environmental exposures resulting in gut-liver crosstalk and bile acid metabolism disturbances. There is no proven medical therapy that alters disease progression in PSC, with the commonly prescribed ursodeoxycholic acid being shown to improve liver biochemistry at low-moderate doses (15-23 mg/kg/day) but not alter transplant-free survival or liver-related outcomes. Liver transplantation is the only option for patients who develop end-stage liver disease or refractory complications of PSC. Immunosuppressive and antifibrotic agents have not proven to be effective, but there is promise for manipulation of the gut microbiome with fecal microbiota transplantation and antibiotics. Bile acid manipulation via alternate synthetic bile acids such as norursodeoxycholic acid, or interaction at a transcriptional level via nuclear receptor agonists and fibrates have shown potential in phase II trials in PSC with several leading to larger phase III trials. In view of the enhanced malignancy risk, statins, and aspirin show potential for reducing the risk of colorectal cancer and cholangiocarcinoma in PSC patients. For patients who develop clinically relevant strictures with cholestatic symptoms and worsening liver function, balloon dilatation is safer compared with biliary stent insertion with equivalent clinical efficacy.
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Affiliation(s)
- Natassia Tan
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - John Lubel
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - William Kemp
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Stuart Roberts
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
| | - Ammar Majeed
- Department of Gastroenterology and Hepatology, Alfred Health; Central Clinical School, Monash University, Melbourne, Australia
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13
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Vuppalanchi R, Are V, Telford A, Young L, Mouchti S, Ferreira C, Kettler C, Gromski M, Akisik F, Chalasani N. A composite score using quantitative magnetic resonance cholangiopancreatography predicts clinical outcomes in primary sclerosing cholangitis. JHEP Rep 2023; 5:100834. [PMID: 37663118 PMCID: PMC10472223 DOI: 10.1016/j.jhepr.2023.100834] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 02/14/2023] [Accepted: 06/16/2023] [Indexed: 09/05/2023] Open
Abstract
Background & Aims Magnetic resonance cholangiopancreatography (MRCP) for evaluation of biliary disease currently relies on subjective assessment with limited prognostic value because of the lack of quantitative metrics. Artificial intelligence-enabled quantitative MRCP (MRCP+) is a novel technique that segments biliary anatomy and provides quantitative biliary tree metrics. This study investigated the utility of MRCP+ as a prognostic tool for the prediction of clinical outcomes in primary sclerosing cholangitis (PSC). Methods MRCP images of patients with PSC were post-processed using MRCP+ software. The duration between the MRCP and clinical event (liver transplantation or death) was calculated. Survival analysis and stepwise Cox regression were performed to investigate the optimal combination of MRCP+ metrics for the prediction of clinical outcomes. The resulting risk score was validated in a separate validation cohort and compared with an existing prognostic score (Mayo risk score). Results In this retrospective study, 102 patients were included in a training cohort and a separate 50 patients formed a validation cohort. Between the two cohorts, 34 patients developed clinical outcomes over a median duration of 3 years (23 liver transplantations and 11 deaths). The proportion of bile ducts with diameter 3-5 mm, total bilirubin, and aspartate aminotransferase were independently associated with transplant-free survival. Combined as a risk score, the overall discriminative performance of the MRCP+ risk score (M+BA) was excellent; area under the receiver operator curve 0.86 (95% CI: 0.77, 0.95) at predicting clinical outcomes in the validation cohort with a hazard ratio 5.8 (95% CI: 1.5, 22.1). This was superior to the Mayo risk score. Conclusions A composite score combining MRCP+ with total bilirubin and aspartate aminotransferase (M+BA) identified PSC patients at high risk of liver transplantation or death. Prospective studies are warranted to evaluate the clinical utility of this novel prognostic tool. Impact and Implications Primary sclerosis cholangitis (PSC) is a disease of the biliary tree where inflammation and fibrosis cause areas of narrowing (strictures) and expansion (dilatations) within the biliary ducts leading to liver failure and/or cancer (cholangiocarcinoma). In this study, we demonstrate that quantitative assessment of the biliary tree can better identify patients with PSC who are at high risk of either death or liver transplantation than a current blood-based risk score (Mayo risk score).
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Affiliation(s)
- Raj Vuppalanchi
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Vijay Are
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | | | | | | | | | - Carla Kettler
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Mark Gromski
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Fatih Akisik
- Department of Radiology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
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14
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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15
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Braadland PR, Schneider KM, Bergquist A, Molinaro A, Lövgren-Sandblom A, Henricsson M, Karlsen TH, Vesterhus M, Trautwein C, Hov JR, Marschall HU. Suppression of bile acid synthesis as a tipping point in the disease course of primary sclerosing cholangitis. JHEP REPORTS : INNOVATION IN HEPATOLOGY 2022; 4:100561. [PMID: 36176935 PMCID: PMC9513776 DOI: 10.1016/j.jhepr.2022.100561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/08/2022] [Accepted: 08/03/2022] [Indexed: 11/16/2022]
Abstract
Background & Aims Farnesoid X receptor (FXR) agonists and fibroblast growth factor 19 (FGF19) analogues suppress bile acid synthesis and are being investigated for their potential therapeutic efficacy in cholestatic liver diseases. We investigated whether bile acid synthesis associated with outcomes in 2 independent populations of people with primary sclerosing cholangitis (PSC) not receiving such therapy. Methods Concentrations of individual bile acids and 7α-hydroxy-4-cholesten-3-one (C4) were measured in blood samples from 330 patients with PSC attending tertiary care hospitals in the discovery and validation cohorts and from 100 healthy donors. We used a predefined multivariable Cox proportional hazards model to evaluate the prognostic value of C4 to predict liver transplantation-free survival and evaluated its performance in the validation cohort. Results The bile acid synthesis marker C4 was negatively associated with total bile acids. Patients with fully suppressed bile acid synthesis had strongly elevated total bile acids and short liver transplantation-free survival. In multivariable models, a 50% reduction in C4 corresponded to increased hazards for liver transplantation or death in both the discovery (adjusted hazard ratio [HR] = 1.24, 95% CI 1.06–1.43) and validation (adjusted HR = 1.23, 95% CI 1.03–1.47) cohorts. Adding C4 to established risk scores added value to predict future events, and predicted survival probabilities were well calibrated externally. There was no discernible impact of ursodeoxycholic acid treatment on bile acid synthesis. Conclusions Bile acid accumulation-associated suppression of bile acid synthesis was apparent in patients with advanced PSC and associated with reduced transplantation-free survival. In a subset of the patients, bile acid synthesis was likely suppressed beyond a tipping point at which any further pharmacological suppression may be futile. Implications for patient stratification and inclusion criteria for clinical trials in PSC warrant further investigation. Lay summary We show, by measuring the level of the metabolite C4 in the blood from patients with primary sclerosing cholangitis (PSC), that low production of bile acids in the liver predicts a more rapid progression to severe disease. Many people with PSC appear to have fully suppressed bile acid production, and both established and new drugs that aim to reduce bile acid production may therefore be futile for them. We propose C4 as a test to find those likely to respond to these treatments.
The bile acid synthesis marker C4 associated negatively with bile acid levels in patients with PSC. Suppression of bile acid synthesis was likely nearly complete in advanced PSC. UDCA treatment contributed significantly to total circulating bile acids but did not appear to affect bile acid synthesis. Attempts to inhibit bile acid synthesis in patients with low C4 may be futile, and such drugs may be contraindicated. Patients with PSC and low circulating C4 had shorter liver transplantation-free survival in two independent cohorts.
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Key Words
- 7α-Hydroxy-4-cholesten-3-one
- AOM, Amsterdam–Oxford model
- ASBT, apical sodium-dependent bile acid cotransporter
- Biliary disease
- C4
- C4, 7α-hydroxy-4-cholesten-3-one
- CYP7A1, cytochrome P450 family 7 subfamily A member 1
- Cholestasis
- Cholestatic liver disease
- FGF19, fibroblast growth factor 19
- FXR, farnesoid X receptor
- GUDCA, glycooursodeoxycholic acid
- HR, hazard ratio
- IBAT, ileal bile acid transporter
- Liver transplantation
- Liver transplantation-free survival
- MELD, model for end-stage liver disease
- PBC, primary biliary cholangitis
- PSC, primary sclerosing cholangitis
- STROBE, Strengthening the Reporting of Observational Studies in Epidemiology
- TUDCA, tauroursodeoxycholic acid
- UDCA, ursodeoxycholic acid
- UPLC-MS/MS, ultraperformance liquid chromatography–tandem mass spectrometry
- Ursodeoxycholic acid
- c-index, concordance index
- liver
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Affiliation(s)
- Peder Rustøen Braadland
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Kai Markus Schneider
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.,Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Annika Bergquist
- Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Antonio Molinaro
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital Gothenburg, Gothenburg, Sweden
| | | | - Marcus Henricsson
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Christian Trautwein
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Johannes Roksund Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.,Department of Medicine, Section of Gastroenterology and Hepatology, Sahlgrenska University Hospital Gothenburg, Gothenburg, Sweden
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16
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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17
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Trauner M, Bowlus CL, Gulamhusein A, Hameed B, Caldwell SH, Shiffman ML, Landis C, Muir AJ, Billin A, Xu J, Liu X, Lu X, Chung C, Myers RP, Kowdley KV. Safety and sustained efficacy of the farnesoid X receptor (FXR) agonist cilofexor over a 96-week open-label extension in patients with PSC. Clin Gastroenterol Hepatol 2022; 21:1552-1560.e2. [PMID: 35934287 DOI: 10.1016/j.cgh.2022.07.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 06/09/2022] [Accepted: 07/18/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is a major unmet medical need in clinical hepatology. Cilofexor is a nonsteroidal farnesoid X receptor agonist being evaluated for the treatment of PSC. Here, we describe the safety and preliminary efficacy of cilofexor in a 96-week, open-label extension (OLE) of a phase II trial. METHODS Noncirrhotic subjects with large-duct PSC who completed the 12-week, blinded phase of a phase II study (NCT02943460) were eligible, after a 4-week washout period, for a 96-week OLE with cilofexor 100 mg daily. Safety, liver biochemistry, and serum markers of fibrosis, cellular injury, and pharmacodynamic effects of cilofexor (fibroblast growth factor 19, C4, and bile acids [BAs]) were evaluated. RESULTS Among 52 subjects enrolled in the phase II study, 47 (90%) continued in the OLE phase (median age, 44 years; 60% male patients, 60% with inflammatory bowel disease, and 45% on ursodeoxycholic acid [UDCA]). At OLE baseline (BL), the median serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were 368 U/L (interquartile range [IQR], 277-468 U/L) and 417 U/L (IQR, 196-801 U/L), respectively. Of the 47 subjects enrolled, 15 (32%) discontinued treatment prematurely (pruritus [n = 5], other adverse events [n = 5], subject decision/investigator discretion [n = 5]). At week 96, reductions in liver biochemistry parameters occurred, including serum ALP (median, -8.3% [IQR, -25.9% to 11.0%]; P = .066), GGT (-29.8% [IQR, -42.3% to -13.9%]; P < .001), alanine aminotransaminase (ALT) (-29.8% [IQR, -43.7% to -6.6%]; P = .002), and aspartate aminotransaminase (AST) (-16.7% [IQR, -35.3% to 1.0%]; P = .010), and rebounded after 4 weeks of untreated follow-up. ALP response (≥20% reduction from BL to week 96) was similar in the presence or absence of UDCA therapy (29% vs 39%; P = .71). At week 96, cilofexor treatment was associated with a significant reduction in serum 7α-hydroxy-4-cholesten-3-one (C4) (-29.8% [IQR, -64.3% to -8.5%]; P = .001). In subjects with detectable serum BAs at BL (n = 40), BAs decreased -23.9% (IQR, -44.4% to -0.6%; P = .006) at week 48 (n = 28) and -25.7% (IQR, -35.9% to 53.7%; P = .91) at week 96 (n = 26). Serum cytokeratin 18 (CK18) M30 and M65 were reduced throughout the OLE; significant reductions were observed at week 72 (CK18 M30, -17.3% [IQR, -39.3% to 8.8%]; P = .018; CK18 M65, -43.5% [IQR, -54.9% to 15.3%]; P = .096). At week 96, a small, but statistically significant absolute increase of 0.15 units in Enhanced Liver Fibrosis score was observed compared with BL (median, 9.34 vs 9.53; P = .028). CONCLUSIONS In this 96-week OLE of a phase II study of PSC, cilofexor was safe and improved liver biochemistry and biomarkers of cholestasis and cellular injury. CLINICALTRIALS gov identifier: NCT02943460.
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Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis School of Medicine, Sacramento, California
| | | | - Bilal Hameed
- Division of Gastroenterology, University of California, San Francisco School of Medicine, San Francisco, California
| | - Stephen H Caldwell
- Division of Gastroenterology and Hepatology, University of Virginia School of Medicine, Charlottesville, Virginia
| | | | - Charles Landis
- Division of Gastroenterology & Hepatology, University of Washington School of Medicine, Seattle, Washington
| | - Andrew J Muir
- Division of Gastroenterology, Duke University School of Medicine, Durham, North Carolina
| | | | - Jun Xu
- Gilead Sciences, Inc, Foster City, California
| | - Xiangyu Liu
- Gilead Sciences, Inc, Foster City, California
| | - Xiaomin Lu
- Gilead Sciences, Inc, Foster City, California
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18
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Tornai D, Ven PL, Lakatos PL, Papp M. Serological biomarkers for management of primary sclerosing cholangitis. World J Gastroenterol 2022; 28:2291-2301. [PMID: 35800183 PMCID: PMC9185217 DOI: 10.3748/wjg.v28.i21.2291] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/01/2022] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
Clinical manifestations and progression of primary sclerosing cholangitis (PSC) are heterogeneous, and its pathogenesis is poorly understood. The importance of gut-liver interactions in the pathogenesis has been clinically confirmed and highlighted in different theories. Recent advances regarding biomarkers of biliary-gut crosstalk may help to identify clinically relevant PSC subgroups assisting everyday clinical work-up (e.g., diagnosis, disease stratification, or surveillance) and the exploration of potential therapeutic targets. Alkaline phosphatase produced by the biliary epithelium is consistently associated with prognosis. However, its level shows natural fluctuation limiting its use in individual patients. Inflammatory, cell activation, and tissue remodeling markers have been reported to predict clinical outcome. Elevated immunoglobulin (Ig) G4 level is associated with a shorter transplantation-free survival. IgG type atypical perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCAs) are non-specific markers of various autoimmune liver diseases and may reflect an abnormal B-cell response to gut microbial antigens. IgG type atypical P-ANCA identifies PSC patients with particular clinical and genetic (for human leukocyte antigens) characteristics. The presence of IgA type anti-F-actin antibody (AAA) may predict a progressive disease course, and it is associated with enhanced mucosal immune response to various microbial antigens and enterocyte damage. IgA type anti-glycoprotein 2 (GP2) antibodies identify patients with a severe disease phenotype and poor survival due to enhanced fibrogenesis or development of cholangiocarcinoma. Elevated soluble vascular adhesion protein-1 (sVAP-1) level is associated with adverse disease outcomes in PSC. High sVAP-1 levels correlate with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in the liver that contributes to gut activated T-cell homing to the hepatobiliary tract. In the present paper, we review the evidence on these possible serological markers that could potentially help address the unmet clinical needs in PSC.
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Affiliation(s)
- David Tornai
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hajdu-Bihar, Hungary
- European Reference Network on Hepatological Diseases, ERN RARE-LIVER, Debrecen H-4032, Hajdu-Bihar, Hungary
| | - Peter Laszlo Ven
- The First Department of Medicine, Division of Gastroenterology, University of Pécs, Pécs H-7624, Baranya, Hungary
- Kálmán Laki Doctoral School of Biomedical and Clinical Sciences, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hajdu-Bihar, Hungary
| | - Peter Laszlo Lakatos
- Division of Gastroenterology, McGill University Health Centre, Montreal QC H4A 3J1, Quebec, Canada
- The First Department of Medicine, Semmelweis University, Budapest H-1083, Pest, Hungary
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hajdu-Bihar, Hungary
- European Reference Network on Hepatological Diseases, ERN RARE-LIVER, Debrecen H-4032, Hajdu-Bihar, Hungary
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19
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Sjöblom N, Boyd S, Kautiainen H, Arola J, Färkkilä M. Novel histological scoring for predicting disease outcome in primary sclerosing cholangitis. Histopathology 2022; 81:192-204. [PMID: 35510514 PMCID: PMC9544993 DOI: 10.1111/his.14677] [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: 08/21/2021] [Revised: 04/24/2022] [Accepted: 05/03/2022] [Indexed: 12/01/2022]
Abstract
Background Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease that may lead to liver cirrhosis or cholangiocarcinoma. Liver histology and fibrosis stage are predictive markers of disease progression, and histological cirrhosis is defined as a significant endpoint. PSC‐specific histological scoring methods are lacking at present. We aimed to develop a tailored classification system for PSC, the PSC histoscore, based on histological features associated with disease progression. Methods In total, 300 PSC patients diagnosed between 1988 and 2018 were enrolled; their data were collected from the PSC registry (Helsinki University Hospital), and liver specimens were obtained from the Biobank of Helsinki. Five histological features included in the adapted Nakanuma scoring system and three additional parameters typical for PSC histology were evaluated and compared with the clinical and laboratory data. A compound endpoint consisting of liver transplantation, development of cholangiocarcinoma, or death was used as outcome measurement. Results Stage (fibrosis, bile duct loss, ductular reaction, and chronic cholestasis) and grade (portal inflammation, portal edema, hepatitis activity, and cholangitis activity) parameters were found to be independent predictive risk factors for the compound endpoint (P < 0.001). High disease grade (2–6) and stage (2–4) better correlated with clinical endpoints when evaluated with the PSC histoscore system compared to the adapted Nakanuma classification. The risk for disease progression in sequential endoscopic retrograde cholangiography (ERC) examinations was increased with elevated total PSC histoscores. Conclusion The PSC histoscore is a novel histological classification system for PSC. Our findings support the applicability of liver histology as a marker for disease progression.
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Affiliation(s)
- Nelli Sjöblom
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00290, Helsinki, Finland
| | - Sonja Boyd
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00290, Helsinki, Finland
| | - Hannu Kautiainen
- Folkhälsan Research Center, Helsinki, Finland.,Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 3, 00290, Helsinki, Finland
| | - Martti Färkkilä
- Department of Gastroenterology, University of Helsinki and Helsinki University Hospital, 00290, Helsinki, Finland
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20
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Peerani F, Du L, Lytvyak E, Bain VG, Mason AL, Bailey RJ, Montano-Loza AJ. Serum IgG4 cut-off of 70 mg/dL is associated with a shorter time to cirrhosis decompensation and liver transplantation in primary sclerosing cholangitis patients. CANADIAN LIVER JOURNAL 2022; 5:31-42. [PMID: 35990785 PMCID: PMC9231426 DOI: 10.3138/canlivj-2021-0023] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 09/05/2021] [Indexed: 10/11/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is an immune-mediated biliary disorder of unknown etiology with no effective treatment. The purpose of this study was to better prognosticate the development of cirrhosis, decompensation, and requirement for liver transplantation (LT) in PSC patients based on serum immunoglobulin G4 (IgG4) levels. METHODS A retrospective chart review was conducted on PSC patients seen at the University of Alberta Hospital between 2002 and 2017. PSC patients were categorized as high IgG4 group (≥70 mg/dL) or normal IgG4 group (<70 mg/dL). Laboratory parameters, clinical characteristics, and outcomes were compared between the groups. RESULTS One hundred and ten patients were followed over a mean period of 7.3 (SD 5) years. Seventy-two patients (66%) were male, the mean age at diagnosis of PSC was 35 (SD 15) years, and inflammatory bowel disease (IBD) was present in 80 patients (73%). High IgG4 levels were found in 37 patients (34%). PSC patients with high IgG4 had a shorter mean cholangitis-free survival time (5.3 versus 10.4 years, p = 0.02), cirrhosis-free survival time (8.7 versus 13.0 years, p = 0.02), and LT-free survival time (9.3 years versus 18.9 years, p <0.001). IgG4 ≥70 mg/dL was independently associated with liver decompensation and LT-free outcomes. A cut-off IgG4 value of ≥70 mg/dL performed better than a cut-off value of ≥140 mg/dL to predict time to LT (area under the curve [AUC] 0.68, p = 0.03, sensitivity 72%, specificity 78%). CONCLUSIONS Serum IgG4 ≥70 mg/dL in PSC predicts a shorter time to cirrhosis decompensation and LT.
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Affiliation(s)
- Farhad Peerani
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Lillian Du
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Ellina Lytvyak
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Vincent G Bain
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Andrew L Mason
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Robert J Bailey
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Aldo J Montano-Loza
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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21
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Chazouillères O, Potier P, Bouzbib C, Hanslik B, Heurgue A, NGuyen-Khac E, Gournay J, Tanne F, Bureau C, Bourlière M, Ganne-Carrié N, de Lédinghen V. Non-invasive diagnosis and follow-up of primary sclerosing cholangitis. Clin Res Hepatol Gastroenterol 2022; 46:101775. [PMID: 34332142 DOI: 10.1016/j.clinre.2021.101775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 07/23/2021] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare and chronic cholestatic liver disease of unknown cause commonly associated with inflammatory bowel disease (IBD) and characterized by progressive obliterative fibro-inflammation of the biliary tree. Although the natural course is highly variable, PSC is often progressive, leading to biliary cirrhosis and its complications. In addition, PSC is a condition harbouring broad neoplastic potential with increased susceptibility for the development of both biliary and colon cancer. As in other chronic liver diseases, non-invasive methods play a major role in the diagnosis and monitoring of PSC. MR cholangiography is the key exam for the diagnosis and has replaced diagnostic endoscopic retrograde cholangiopancreatography (ERCP). A strict and standardised protocol for carrying out MR cholangiography is recommended. Liver stiffness measured by FibroScan® correlates with the degree of liver fibrosis, has a prognostic value and should be repeated during follow-up. Invasive methods still play an important role, especially ERCP which is indicated for therapeutic purposes or for endo-biliary sample collection in suspected cholangiocarcinoma (following discussion in a multidisciplinary team meeting) and total colonoscopy which is recommended at the initial diagnosis of any PSC and annually in patients with IBD.
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Affiliation(s)
- Olivier Chazouillères
- Service d'hépato-gastroentérologie, Hôpital Saint Antoine, APHP, 184 Rue du Faubourg Saint-Antoine, 75012 Paris, France.
| | - Pascal Potier
- Service d'hépato-gastroentérologie et oncologie digestive, CHR Orléans, Orléans, France
| | - Charlotte Bouzbib
- Service d'Hépatologie, Hopital Pitié Salpêtrière, APHP, Paris, France
| | - Bertrand Hanslik
- Centre Montpelliérain des maladies du foie et de l'appareil digestif, Montpellier, France
| | - Alexandra Heurgue
- Service d'hépato-gastroentérologie et cancérologie digestive, CHU Reims, Reims, France
| | - Eric NGuyen-Khac
- Service d'hépato-gastroentérologie, CHU Amiens-Picardie, Amiens, France
| | - Jérôme Gournay
- Service d'hépato-gastro-entérologie, cancérologie digestive et assistance nutritionnelle, CHU Nantes, Nantes, France
| | - Florence Tanne
- Service d'hépato-gastro-entérologie, CHRU Brest Cavale Blanche, Brest, France
| | - Christophe Bureau
- Service d'hépatologie, Hôpital Rangueil, CHU Toulouse, Toulouse, France
| | - Marc Bourlière
- Service d'hépato-gastroentérologie, Hôpital Saint Joseph & INSERM UMR 1252 IRD SESSTIM Aix Marseille Université, Marseille, France
| | - Nathalie Ganne-Carrié
- Service d'hépatologie, Hôpital Avicenne, APHP, Université Sorbonne Paris Nord, INSERM UMR 1138, Centre de Recherche des Cordeliers, Université de Paris, Bobigny, France
| | - Victor de Lédinghen
- Service d'hépato-gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, pessac & INSERM U1053, Université de Bordeaux, Bordeaux, France
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22
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Ströbel S, Kostadinova R, Fiaschetti-Egli K, Rupp J, Bieri M, Pawlowska A, Busler D, Hofstetter T, Sanchez K, Grepper S, Thoma E. A 3D primary human cell-based in vitro model of non-alcoholic steatohepatitis for efficacy testing of clinical drug candidates. Sci Rep 2021; 11:22765. [PMID: 34815444 PMCID: PMC8611054 DOI: 10.1038/s41598-021-01951-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a progressive and severe liver disease, characterized by lipid accumulation, inflammation, and downstream fibrosis. Despite its increasing prevalence, there is no approved treatment yet available for patients. This has been at least partially due to the lack of predictive preclinical models for studying this complex disease. Here, we present a 3D in vitro microtissue model that uses spheroidal, scaffold free co-culture of primary human hepatocytes, Kupffer cells, liver endothelial cells and hepatic stellate cells. Upon exposure to defined and clinically relevant lipotoxic and inflammatory stimuli, these microtissues develop key pathophysiological features of NASH within 10 days, including an increase of intracellular triglyceride content and lipids, and release of pro-inflammatory cytokines. Furthermore, fibrosis was evident through release of procollagen type I, and increased deposition of extracellular collagen fibers. Whole transcriptome analysis revealed changes in the regulation of pathways associated with NASH, such as lipid metabolism, inflammation and collagen processing. Importantly, treatment with anti-NASH drug candidates (Selonsertib and Firsocostat) decreased the measured specific disease parameter, in accordance with clinical observations. These drug treatments also significantly changed the gene expression patterns of the microtissues, thus providing mechanisms of action and revealing therapeutic potential. In summary, this human NASH model represents a promising drug discovery tool for understanding the underlying complex mechanisms in NASH, evaluating efficacy of anti-NASH drug candidates and identifying new approaches for therapeutic interventions.
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Affiliation(s)
- Simon Ströbel
- InSphero AG, Wagistrasse 27A, 8952 Schlieren, CH, Switzerland.
| | | | | | - Jana Rupp
- InSphero AG, Wagistrasse 27A, 8952 Schlieren, CH Switzerland
| | - Manuela Bieri
- InSphero AG, Wagistrasse 27A, 8952 Schlieren, CH Switzerland
| | | | - Donna Busler
- InSphero AG, Wagistrasse 27A, 8952 Schlieren, CH Switzerland
| | | | | | - Sue Grepper
- InSphero AG, Wagistrasse 27A, 8952 Schlieren, CH Switzerland
| | - Eva Thoma
- InSphero AG, Wagistrasse 27A, 8952 Schlieren, CH Switzerland
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23
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Selvaraj EA, Ba-Ssalamah A, Poetter-Lang S, Ridgway GR, Brady JM, Collier J, Culver EL, Bailey A, Pavlides M. A Quantitative Magnetic Resonance Cholangiopancreatography Metric of Intrahepatic Biliary Dilatation Severity Detects High-Risk Primary Sclerosing Cholangitis. Hepatol Commun 2021; 6:795-808. [PMID: 34802195 PMCID: PMC8948671 DOI: 10.1002/hep4.1860] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/13/2021] [Accepted: 10/26/2021] [Indexed: 11/23/2022] Open
Abstract
Magnetic resonance imaging with magnetic resonance cholangiopancreatography (MRI‐MRCP) in primary sclerosing cholangitis (PSC) is currently based on qualitative assessment and has high interobserver variability. We investigated the utility and performance of quantitative metrics derived from a three‐dimensional biliary analysis tool in adult patients with PSC. MRI‐MRCP, blood‐based biomarkers, and FibroScan were prospectively performed in 80 participants with large‐duct PSC and 20 healthy participants. Quantitative analysis was performed using MRCP+ (Perspectum Ltd., United Kingdom), and qualitative reads were performed by radiologists. Inter‐reader agreements were compared. Patients were classified into high risk or low risk for disease progression, using Mayo risk score (MRS), Amsterdam‐Oxford model (AOM), upper limit of normal (ULN) alkaline phosphatase (ALP), disease distribution, and presence of dominant stricture. Performance of noninvasive tools was assessed using binomial logistic regressions and receiver operating characteristic curve analyses. Quantitative biliary metrics performed well to distinguish abnormal from normal bile ducts (P < 0.0001). Interobserver agreements for MRCP+ dilatation metrics (intraclass correlation coefficient, 0.90‐0.96) were superior to modified Amsterdam intrahepatic stricture severity score (κ = 0.74) and Anali score (κ = 0.38). MRCP+ intrahepatic dilatation severity showed excellent performance to classify patients into high‐risk and low‐risk groups, using predictors of disease severity as the reference (MRS, P < 0.0001; AOM, P = 0.0017; 2.2 × ULN ALP, P = 0.0007; 1.5 × ULN ALP, P = 0.0225; extrahepatic disease, P = 0.0331; dominant stricture, P = 0.0019). MRCP+ intrahepatic dilatation severity was an independent predictor of MRS >0 (odds ratio, 31.3; P = 0.035) in the multivariate analysis. Conclusion: Intrahepatic biliary dilatation severity calculated using MRCP+ is elevated in patients with high‐risk PSC and may be used as an adjunct for risk stratification in PSC. This exploratory study has provided the groundwork for examining the utility of novel quantitative biliary metrics in multicenter studies.
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Affiliation(s)
- Emmanuel A Selvaraj
- Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.,Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.,National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.,Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom
| | - Ahmed Ba-Ssalamah
- Medical University of Vienna, Department of Biomedical Imaging and Image-Guided Therapy, General Hospital of Vienna, Vienna, Austria
| | - Sarah Poetter-Lang
- Medical University of Vienna, Department of Biomedical Imaging and Image-Guided Therapy, General Hospital of Vienna, Vienna, Austria
| | | | - J Michael Brady
- Perspectum Ltd., Oxford, United Kingdom.,Department of Oncology, Medical Sciences Division, University of Oxford, Oxford, United Kingdom
| | - Jane Collier
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Emma L Culver
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.,National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.,Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom
| | - Adam Bailey
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.,National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.,Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom
| | - Michael Pavlides
- Oxford Centre for Clinical Magnetic Resonance Research, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.,Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.,National Institute for Health Research Oxford Biomedical Research Centre, University of Oxford, Oxford, United Kingdom.,Oxford University Hospitals National Health Service Foundation Trust, Oxford, United Kingdom
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24
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Saffioti F, Hall A, de Krijger M, Verheij J, Hübscher SG, Maurice J, Luong TV, Pinzani M, Ponsioen CY, Thorburn D. Collagen proportionate area correlates with histological stage and predicts clinical events in primary sclerosing cholangitis. Liver Int 2021; 41:2681-2692. [PMID: 34051052 DOI: 10.1111/liv.14979] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 04/25/2021] [Accepted: 05/25/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease in need of accurate biomarkers for stratification and as surrogates for clinical endpoints in trials. Quantitative liver fibrosis assessment by collagen proportionate area (CPA) measurement has been demonstrated to correlate with clinical outcomes in chronic hepatitis C, alcohol-related and non-alcoholic fatty liver disease. We aimed to investigate the ability of CPA to quantify liver fibrosis and predict clinical events in PSC. METHODS Biopsies from 101 PSC patients from two European centres were retrospectively assessed by two expert pathologists in tandem, using grading (Ishak and Nakanuma) and staging (Ishak, Nakanuma, Ludwig) systems recently validated to predict clinical events in PSC. CPA was determined by image analysis of picro-Sirius red-stained sections following a standard protocol. We assessed the correlations between CPA, staging and grading and their associations with three outcomes: (1) time to PSC-related death, liver transplant or primary liver cancer; (2) liver transplant-free survival; (3) occurrence of cirrhosis-related clinical manifestations. RESULTS CPA correlated strongly with histological stage determined by each scoring system (P < .001) and was significantly associated with the three endpoints. Median time to endpoint-1, endpoint-2 and endpoint-3 was shorter in patients with higher CPA, on Kaplan-Meier analyses (P = .011, P = .034 and P = .001, respectively). CONCLUSION Quantitative fibrosis assessment by CPA has utility in PSC. It correlates with established histological staging systems and predicts clinical events. CPA may be a useful tool for staging fibrosis and for risk stratification in PSC and should be evaluated further within prospective clinical trials.
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Affiliation(s)
- Francesca Saffioti
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK.,Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Andrew Hall
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK.,Department of Cellular Pathology, Royal Free Hospital, London, UK
| | - Manon de Krijger
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Joanne Verheij
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Stefan G Hübscher
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, UK
| | - James Maurice
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK
| | - Tu Vinh Luong
- Department of Cellular Pathology, Royal Free Hospital, London, UK
| | - Massimo Pinzani
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK
| | - Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust and UCL Institute for Liver and Digestive Health, University College of London, London, UK
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25
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Fossdal G, Mjelle AB, Wiencke K, Bjørk I, Gilja OH, Folseraas T, Karlsen TH, Rosenberg W, Giil LM, Vesterhus M. Fluctuating biomarkers in primary sclerosing cholangitis: A longitudinal comparison of alkaline phosphatase, liver stiffness, and ELF. JHEP Rep 2021; 3:100328. [PMID: 34485881 PMCID: PMC8403583 DOI: 10.1016/j.jhepr.2021.100328] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 05/25/2021] [Accepted: 06/16/2021] [Indexed: 02/08/2023] Open
Abstract
Background & Aims Primary sclerosing cholangitis (PSC) is a progressive liver disease characterised by fluctuating liver biochemistries and highly variable disease progression. The Enhanced Liver Fibrosis (ELF®) test and liver stiffness measurements (LSMs) reflect fibrosis and predict clinical outcomes in PSC; however, longitudinal assessments are missing. We aimed to characterise the systematic change in ELF and LSM over time in a prospective cohort of patients with PSC, along with their longitudinal relationship to alkaline phosphatase (ALP) and bilirubin. Methods We included 113 non-transplant PSC patients (86 males [76.1%]; mean age 43.3 ± 15.7 years) with annual study visits between 2013 and 2019 at 2 Norwegian centres. ELF test, LSM, clinical data, liver biochemistries, and revised Mayo risk score were measured. We used linear mixed-effects models to estimate change over time, intraclass correlations (ICCs), and their relationship with ALP and bilirubin. Results At baseline, the median (range) ELF test was 9.3 (7.5–12.9) and median LSM 1.26 m/s (0.66–3.04 m/s). ELF and LSM increased over time (0.09 point/year, 95% CI [0.03, 0.15], p = 0.005, vs. 0.12 point/year, 95% CI [0.03, 0.21], p = 0.009). Between-patient effects explained 78% of ELF variation (ICC 0.78) and 56% of LSM variation (ICC 0.56). ALP also increased and showed the highest ICC (0.86). Conclusions ELF and LSM increased over a 5-year period. Longitudinal analyses demonstrated differences regarding within- and between-patient effects, suggesting that the ELF test may have superior reliability for risk stratification compared with LSM in PSC. Lay summary Primary sclerosing cholangitis (PSC) is characterised by substantial disease variability between patients and fluctuating liver biochemistries. Hence, new biomarkers are needed to identify individuals with an increased risk of developing end-stage liver disease. We explore the change over time of 2 putative prognostic biomarkers in PSC, the serum Enhanced Liver Fibrosis (ELF®) test and LSMs by ultrasound, demonstrating differences that may reflect differing abilities to discriminate risk.
ELF and LSM increased in patients with PSC, but only in patients with ALP >1.5× ULN. ELF may be more reliable for PSC risk stratification (low within-patient variation). A subgroup showed concomitant spontaneous reduction in ALP, ELF, and LSM.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- Alkaline phosphatase
- Biomarker
- CRP, C-reactive protein
- ELF, enhanced liver fibrosis
- Elastography
- Enhanced liver fibrosis test
- FIB-4, Fibrosis-4 Index for Liver Fibrosis
- GGT, gamma-glutamyl transferase
- HA, hyaluronic acid
- ICC, intraclass correlation
- INR, international normalised ratio
- IgG4, immunoglobulin G4
- LSM, liver stiffness measurement
- Liver stiffness
- PIIINP, propeptide of type III procollagen
- PSC, primary sclerosing cholangitis
- Primary sclerosing cholangitis
- ROI, region of interest
- Risk stratification
- TE, transient elastography
- TIMP-1, tissue inhibitor of metalloproteinases-1
- UDCA, ursodeoxycholic acid
- ULN, upper limit of normal
- pSWE, point shear wave elastography
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Affiliation(s)
- Guri Fossdal
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway
| | - Anders B Mjelle
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Kristine Wiencke
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Ida Bjørk
- Department of Radiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Odd Helge Gilja
- Department of Clinical Medicine, University of Bergen, Bergen, Norway.,National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Trine Folseraas
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Tom Hemming Karlsen
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - William Rosenberg
- UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, UK
| | - Lasse M Giil
- Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway
| | - Mette Vesterhus
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway
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26
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Berzigotti A, Tsochatzis E, Boursier J, Castera L, Cazzagon N, Friedrich-Rust M, Petta S, Thiele M. EASL Clinical Practice Guidelines on non-invasive tests for evaluation of liver disease severity and prognosis - 2021 update. J Hepatol 2021; 75:659-689. [PMID: 34166721 DOI: 10.1016/j.jhep.2021.05.025] [Citation(s) in RCA: 998] [Impact Index Per Article: 249.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 05/28/2021] [Indexed: 02/07/2023]
Abstract
Non-invasive tests are increasingly being used to improve the diagnosis and prognostication of chronic liver diseases across aetiologies. Herein, we provide the latest update to the EASL Clinical Practice Guidelines on the use of non-invasive tests for the evaluation of liver disease severity and prognosis, focusing on the topics for which relevant evidence has been published in the last 5 years.
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27
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Abdel-Hameed EA, Rouster SD, Kottilil S, Sherman KE. The Enhanced Liver Fibrosis Index Predicts Hepatic Fibrosis Superior to FIB4 and APRI in HIV/HCV Infected Patients. Clin Infect Dis 2021; 73:450-459. [PMID: 32459305 DOI: 10.1093/cid/ciaa646] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 05/22/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Accurate noninvasive biomarkers of fibrotic progression are important for hepatitis C virus (HCV) management, but commonly used modalities may have decreased efficacy in human immunodeficiency virus (HIV)/HCV-coinfected persons. The enhanced liver fibrosis (ELF) index is a highly sensitive noninvasive marker of hepatic fibrosis that has had limited assessment in the HIV/HCV population. We compared ELF index performance to FIB4 and aspartate to platelet ratio index (APRI) at different stages of liver fibrosis as determined by liver histology, and validated the efficacy of the three noninvasive biomarkers in HIV/HCV-coinfected versus HCV-monoinfected. METHODS The ELF index was determined in 147 HIV/HCV-coinfected and 98 HCV-monoinfected persons using commercial ELISA assays for the component elements of the index. Area under the receiver-operator curve was used to validate ELF and to compare its performance to liver histology as well as to other noninvasive biomarkers of liver fibrosis, FIB4, and APRI. RESULTS The ELF index increased with histological stage of liver fibrosis and exhibited a linear relationship with Metavir score in all subjects. ELF performance was comparable between HIV/HCV and HCV with advanced liver fibrosis/cirrhosis. In the HIV/HCV cohort ELF cutoffs of 8.45 and 9.23 predicted mild and moderate fibrosis with 85% sensitivity, whereas the ELF cutoff of 9.8 had the highest specificity for advanced fibrosis and the cutoff of 10.4 was 99% specific for cirrhosis. ELF performance was superior to FIB4 and APRI in all subjects regardless of HIV status. CONCLUSIONS ELF index demonstrated excellent characteristics toward accurate prediction of liver fibrosis and cirrhosis with superior performance to APRI and FIB4 in HIV/HCV coinfection. Applying this noninvasive biomarker index for diagnosis of liver fibrosis and progression in HIV/HCV is warranted.
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Affiliation(s)
| | - Susan D Rouster
- University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland, Baltimore, Maryland, USA
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28
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Sharma C, Cococcia S, Ellis N, Parkes J, Rosenberg W. Systematic review: Accuracy of the enhanced liver fibrosis test for diagnosing advanced liver fibrosis and cirrhosis. J Gastroenterol Hepatol 2021; 36:1788-1802. [PMID: 33668077 DOI: 10.1111/jgh.15482] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 02/02/2021] [Accepted: 02/22/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS The rising incidence of chronic liver disease (CLD) has increased the need for early recognition. This systematic review assesses the diagnostic accuracy of the enhanced liver fibrosis (ELF) test in cases of advanced fibrosis and cirrhosis due to multiple etiologies in at-risk populations. METHODS Studies evaluating the ELF accuracy in identifying advanced fibrosis or cirrhosis, defined as METAVIR stage F ≥ 3 and F = 4 or equivalent, in patients with non-alcoholic fatty liver disease (NAFLD), alcohol liver disease (ALD), or viral hepatitis were included. Liver biopsy was used as the reference standard. Medline and Embase databases were searched. The QUADAS-2 tool was used as a framework to assess risk of bias and applicability. The area under the receiver operator curve (AUROC) was extracted as a summary measure of diagnostic accuracy. RESULTS Thirty-six studies were included: 11 hepatitis C, 4 hepatitis B, 9 NAFLD, 2 ALD, and 10 mixed. The ELF test showed good diagnostic performance in detecting advanced fibrosis in patients with viral hepatitis (AUROC 0.69 to 0.98) and excellent performance in NAFLD (AUROC 0.78 to 0.97) and ALD (AUROC from 0.92 to 0.94). There is also evidence of good diagnostic performance for detecting cirrhosis in patients with viral hepatitis (AUROC 0.63 to 0.99), good performance in NAFLD (AUROC 0.85 to 0.92), and excellent performance in patients with ALD (AUROC 0.93 to 0.94). CONCLUSION This systematic review supports the use of the ELF test across a range of CLD as a possible alternative to liver biopsy in selected cases.
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Affiliation(s)
- Chetanya Sharma
- Institute for Liver and Digestive Health, University College London, Division of Medicine and Royal Free London NHS Foundation Trust, London, UK
| | - Sara Cococcia
- Institute for Liver and Digestive Health, University College London, Division of Medicine and Royal Free London NHS Foundation Trust, London, UK.,First Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Nicola Ellis
- Institute for Liver and Digestive Health, University College London, Division of Medicine and Royal Free London NHS Foundation Trust, London, UK
| | - Julie Parkes
- Department of Public Health and Medical Statistics, Faculty of Medicine, University of Southampton, Southampton, UK
| | - William Rosenberg
- Institute for Liver and Digestive Health, University College London, Division of Medicine and Royal Free London NHS Foundation Trust, London, UK
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29
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Abstract
Cholestatic liver disease is a disease that causes liver damage and fibrosis owing to bile stasis. It is represented by primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), but the pathophysiological pathways that cause bile stasis in both diseases are different. The pathogenesis of the disease is still unclear, although autoimmune mechanisms have been postulated and partially elucidated. Although the disease may progress slowly with only mild liver dysfunction, it may progress to liver cirrhosis or liver failure, which require liver transplantation. As a medical treatment, ursodeoxycholic acid is widely used for PBC and has proved to be very effective against disease progression in cases of PBC. On the other hand, its efficacy is limited in cases of PSC, and the research and development of various drugs are underway. Furthermore, the clinical course of both diseases is quite variable, making the design of clinical trials fairly difficult. In this review, we present the general natural history of PBC and PSC, and provide information on the latest drug therapies currently available and those that are under investigation.
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30
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Dhillon AK, Rupp C, Bergquist A, Voitl R, Folseraas T, Trøseid M, Midttun Ø, Ueland PM, Karlsen TH, Vesterhus M, Kummen M, Hov JR. Associations of neopterin and kynurenine-tryptophan ratio with survival in primary sclerosing cholangitis. Scand J Gastroenterol 2021; 56:443-452. [PMID: 33583308 DOI: 10.1080/00365521.2021.1880627] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Biomarkers of inflammation may be of clinical utility in primary sclerosing cholangitis (PSC). We aimed to investigate the interferon gamma-related biomarkers neopterin and kynurenine-tryptophanratio (KT-ratio) in PSC. METHODS Circulating neopterin, tryptophan and kynurenine were measured with LC-MS/MS in multiple cross-sectional cohorts comprising in total of 524 PSC patients and 100 healthy controls from Norway, Germany and Sweden. RESULTS Neopterin and KT-ratio were significantly increased in PSC patients compared with controls in both a discovery and a validation cohort from Norway. Furthermore, high neopterin and KT-ratio levels were associated with a shorter transplantation-free survival in the PSC patients in the Norwegian discovery cohort and the German validation cohort. However, in the validation PSC cohort from Sweden, no relationship between neopterin and KT-ratio and liver transplantation-free survival was observed. The correlations between neopterin and KT-ratio were moderate to strong and similar in all cohorts (rho 0.50-0.67). Neopterin and KT-ratio also correlated with C-reactive protein (rho 0.17-0.63) and revised Mayo risk score (rho 0.23-0.42) in all cohorts. CONCLUSIONS Neopterin and KT-ratio were elevated in PSC and associated with liver transplantation-free survival in two independent PSC cohorts, highlighting a possible role of interferon gamma-driven inflammation in the pathogenesis. However, the lack of association with survival in one of the cohorts reduces the potential clinical value of neopterin and KT-ratioas biomarkers and highlights the need to validate new biomarkers in PSC in multiple cohorts.
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Affiliation(s)
- Amandeep Kaur Dhillon
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Christian Rupp
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany
| | - Annika Bergquist
- Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Robert Voitl
- Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Marius Trøseid
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Clinical Immunology and Infectious diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | | | - Per M Ueland
- Bevital AS, Bergen, Norway.,Laboratory of Clinical Chemistry, Haukeland University Hospital, Bergen, Norway
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Martin Kummen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Johannes R Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
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31
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Eksteen B, Bowlus CL, Montano-Loza AJ, Lefebvre E, Fischer L, Vig P, Martins EB, Ahmad J, Yimam KK, Pockros PJ, Feld JJ, Minuk G, Levy C. Efficacy and Safety of Cenicriviroc in Patients With Primary Sclerosing Cholangitis: PERSEUS Study. Hepatol Commun 2021; 5:478-490. [PMID: 33681680 PMCID: PMC7917279 DOI: 10.1002/hep4.1619] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 06/10/2020] [Accepted: 07/09/2020] [Indexed: 12/14/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic disease with no approved treatments. C-C chemokine receptor types 2 and 5 (CCR2/CCR5) play an important role in inflammation and fibrosis and are potential therapeutic targets for PSC. We evaluated the efficacy and safety of cenicriviroc (CVC), a dual antagonist of CCR2 and CCR5, for the treatment of PSC. This was a single-arm, open-label, exploratory study of CVC in adults with a clinical diagnosis of PSC, serum alkaline phosphatase (ALP) ≥1.5 times the upper limit of normal (ULN), with or without inflammatory bowel disease, across eight sites in the United States and Canada. The primary endpoint was percent change in ALP over 24 weeks; key secondary efficacy endpoints were proportion of participants who achieved ALP normalization and overall response (decrease to <1.5 times the ULN or 50% decrease). Of the 24 participants, 20 completed the study. The mean age was 43 years, 50% were female, and the mean body mass index was 25 kg/m2. From a median ALP baseline of 369 U/L (range: 173, 1,377 U/L), a median absolute reduction of 49.5 U/L (range: -460, 416 U/L) was achieved at week 24, corresponding to a median reduction of 18.0% (range: -46%, 89%). No participant achieved ALP normalization or a 50% decrease; 2 participants (10%) achieved a reduction in ALP to < 1.5 times the ULN, and 4 had ≥25% increase. Twenty participants (83.3%) reported at least one adverse event; most were mild to moderate in severity. The most frequent events were rash, fatigue, and dizziness. Conclusion: After 24 weeks of CVC treatment, adults with PSC achieved a modest reduction (median 18%) in the surrogate endpoint of ALP. CVC was well tolerated, and no new safety signals were observed. ClinicalTrials.gov identifier: NCT02653625.
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Affiliation(s)
| | | | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver UnitUniversity of AlbertaEdmontonABCanada
| | | | | | | | | | - Jawad Ahmad
- Division of Liver DiseasesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Kidist K Yimam
- Department of Hepatology and Liver TransplantationCalifornia Pacific Medical CenterSan FranciscoCAUSA
| | - Paul J Pockros
- Scripps Clinic and Scripps Translational Science InstituteLa JollaCAUSA
| | - Jordan J Feld
- Toronto Center for Liver DiseaseToronto General HospitalUniversity of TorontoTorontoONCanada
| | - Gerald Minuk
- John Buhler Research CenterUniversity of ManitobaWinnipegMBCanada
| | - Cynthia Levy
- Schiff Center for Liver DiseasesUniversity of MiamiMiamiFLUSA
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32
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Prokopič M, Beuers U. Management of primary sclerosing cholangitis and its complications: an algorithmic approach. Hepatol Int 2020; 15:6-20. [PMID: 33377990 PMCID: PMC7886831 DOI: 10.1007/s12072-020-10118-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease, characterized by multiple strictures and dilatations of the intra- and extrahepatic bile ducts, leading to progressive liver fibrosis, in 10–15% cholangiocarcinoma, and ultimately end-stage liver disease. The pathogenesis is poorly understood, but (epi-)genetic factors, mechanisms of innate and adaptive immunity, toxic effects of hydrophobic bile acids, and possibly intestinal dysbiosis appear to be involved. The strong link with inflammatory bowel disease (IBD) is associated with a markedly enhanced risk of colorectal cancer which next to cholangiocarcinoma represents the most serious diagnostic challenge in long-term PSC management. Despite extensive research, no medical treatment has been proven so far to prolong the time to liver transplantation (LTx), which remains the effective treatment in late-stage disease. Recurrence of PSC after LTx is observed in up to 20% of patients. Here, we briefly summarize actual views on PSC pathogenesis and provide an algorithmic approach to diagnostic procedures and recommendations for the management of PSC and its complications. We describe promising treatment options subject to current clinical trials.
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Affiliation(s)
- Michal Prokopič
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, AGEM, C2-327, Meibergdreef 9, 1100 DE, Amsterdam, The Netherlands.,Department of Gastroenterology, Comenius University Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, Location AMC, AGEM, C2-327, Meibergdreef 9, 1100 DE, Amsterdam, The Netherlands.
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33
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Angioni R, Calì B, Vigneswara V, Crescenzi M, Merino A, Sánchez-Rodríguez R, Liboni C, Hoogduijn MJ, Newsome PN, Muraca M, Russo FP, Viola A. Administration of Human MSC-Derived Extracellular Vesicles for the Treatment of Primary Sclerosing Cholangitis: Preclinical Data in MDR2 Knockout Mice. Int J Mol Sci 2020; 21:8874. [PMID: 33238629 PMCID: PMC7700340 DOI: 10.3390/ijms21228874] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/05/2020] [Accepted: 11/11/2020] [Indexed: 12/12/2022] Open
Abstract
Primary Sclerosing Cholangitis (PSC) is a progressive liver disease for which there is no effective medical therapy. PSC belongs to the family of immune-mediated biliary disorders and it is characterized by persistent biliary inflammation and fibrosis. Here, we explored the possibility of using extracellular vesicles (EVs) derived from human, bone marrow mesenchymal stromal cells (MSCs) to target liver inflammation and reduce fibrosis in a mouse model of PSC. Five-week-old male FVB.129P2-Abcb4tm1Bor mice were intraperitoneally injected with either 100 µL of EVs (± 9.1 × 109 particles/mL) or PBS, once a week, for three consecutive weeks. One week after the last injection, mice were sacrificed and liver and blood collected for flow cytometry analysis and transaminase quantification. In FVB.129P2-Abcb4tm1Bor mice, EV administration resulted in reduced serum levels of alkaline phosphatase (ALP), bile acid (BA), and alanine aminotransferase (ALT), as well as in decreased liver fibrosis. Mechanistically, we observed that EVs reduce liver accumulation of both granulocytes and T cells and dampen VCAM-1 expression. Further analysis revealed that the therapeutic effect of EVs is accompanied by the inhibition of NFkB activation in proximity of the portal triad. Our pre-clinical experiments suggest that EVs isolated from MSCs may represent an effective therapeutic strategy to treat patients suffering from PSC.
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Affiliation(s)
- Roberta Angioni
- Department of Biomedical Sciences, University of Padova and Fondazione Istituto di Ricerca Pediatrica—Città della Speranza, 35127 Padova, Italy; (R.A.); (B.C.); (R.S.-R.); (C.L.)
| | - Bianca Calì
- Department of Biomedical Sciences, University of Padova and Fondazione Istituto di Ricerca Pediatrica—Città della Speranza, 35127 Padova, Italy; (R.A.); (B.C.); (R.S.-R.); (C.L.)
| | - Vasanthy Vigneswara
- National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham; Centre for Liver and GI Research, Institute of Immunology and Immunotherapy, University of Birmingham; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK; (V.V.); (P.N.N.)
| | - Marika Crescenzi
- Department of Surgery, Oncology and Gastroenterology—DiSCOG, Gastroenterology and Multivisceral Transplant Unit, 35128 Padova, Italy; (M.C.); (F.P.R.)
| | - Ana Merino
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands; (A.M.); (M.J.H.)
| | - Ricardo Sánchez-Rodríguez
- Department of Biomedical Sciences, University of Padova and Fondazione Istituto di Ricerca Pediatrica—Città della Speranza, 35127 Padova, Italy; (R.A.); (B.C.); (R.S.-R.); (C.L.)
| | - Cristina Liboni
- Department of Biomedical Sciences, University of Padova and Fondazione Istituto di Ricerca Pediatrica—Città della Speranza, 35127 Padova, Italy; (R.A.); (B.C.); (R.S.-R.); (C.L.)
| | - Martin J. Hoogduijn
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands; (A.M.); (M.J.H.)
| | - Philip Noel Newsome
- National Institute for Health Research Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham; Centre for Liver and GI Research, Institute of Immunology and Immunotherapy, University of Birmingham; Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK; (V.V.); (P.N.N.)
| | - Maurizio Muraca
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, Padova, and Stem Cell and Regenerative Medicine Laboratory, Department of Women’s and Children’s Health, University of Padova, 35128 Padova, Italy;
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology—DiSCOG, Gastroenterology and Multivisceral Transplant Unit, 35128 Padova, Italy; (M.C.); (F.P.R.)
| | - Antonella Viola
- Department of Biomedical Sciences, University of Padova and Fondazione Istituto di Ricerca Pediatrica—Città della Speranza, 35127 Padova, Italy; (R.A.); (B.C.); (R.S.-R.); (C.L.)
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Vesterhus M, Nielsen MJ, Hov JR, Saffioti F, Manon-Jensen T, Leeming DJ, Moum B, Boberg KM, Pinzani M, Karlsen TH, Karsdal MA, Thorburn D. Comprehensive assessment of ECM turnover using serum biomarkers establishes PBC as a high-turnover autoimmune liver disease. JHEP Rep 2020; 3:100178. [PMID: 33225252 PMCID: PMC7666353 DOI: 10.1016/j.jhepr.2020.100178] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 08/21/2020] [Accepted: 08/25/2020] [Indexed: 02/08/2023] Open
Abstract
Background & Aims Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated the extracellular matrix (ECM) profiles of patients with PSC, PBC, and AIH to establish whether the diseases display differential patterns of ECM turnover. Methods Serum samples were retrospectively collected from the UK (test cohort; PSC n = 78; PBC n = 74; AIH n = 58) and Norway (validation cohort; PSC n = 138; PBC n = 28; AIH n = 27). Patients with ulcerative colitis without liver disease (n = 194) served as controls. We assessed specific serological biomarkers of ECM turnover: type III and V collagen formation (PRO-C3, PRO-C5), degradation of type III and IV collagen (C3M, C4M), biglycan (BGM) and citrullinated vimentin (VICM). Results Most of the ECM markers showed elevated serum levels in PBC compared with PSC or AIH (p <0.01). PRO-C3 correlated well with liver stiffness and showed the most striking differences between advanced and non-advanced liver disease; several of the other ECM markers were also associated with stage. PRO-C3 and other ECM markers were inversely associated with ursodeoxycholic acid treatment response in PBC and remission in AIH. All ECM remodelling markers were significantly elevated (p <0.05) in patients with PSC, PBC, or AIH compared with ulcerative colitis. Conclusions In this first study comparing ECM turnover in autoimmune liver diseases, we found increased ECM turnover in PBC compared with either PSC or AIH. The study indicates that ECM remodelling is different in PSC, PBC, and AIH, suggesting differing opportunities for therapeutic intervention. Lay summary The level of scarring is linked to prognosis in autoimmune liver diseases such as primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis; hence, the scarring process is a possible target for novel therapy. Investigating the scarring process using highly specific technology, we show that the scarring process is different between the 3 autoimmune liver diseases, and this may have important implications for the development of medical treatment.
Serological biomarkers specifically targeting extracellular matrix remodelling enable evaluation of the dynamics of fibrosis evolution. ECM turnover was increased in PBC compared with PSC and AIH. ECM markers, particularly PRO-C3, were associated with disease stage in the autoimmune liver diseases and with clinical outcome in PSC.
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Key Words
- AIH, autoimmune hepatitis
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- APRI, AST to platelet ratio index
- AST, aspartate aminotransferase
- AUROC, area under the receiver operator characteristics curve
- BGM, marker of biglycan degradation
- Biomarker
- C3M, marker of type III collagen degradation
- C4M, marker of type IV collagen degradation
- CI, confidence interval
- ECM, extracellular matrix
- ELF, enhanced liver fibrosis
- Fibrosis
- GGT, gamma glutamyltransferase
- HYA, hyaluronic acid
- IBD, inflammatory bowel disease
- INR, international normalised ratio
- LSM, liver stiffness measurement
- PBC, primary biliary cholangitis
- PIIINP, N-terminal procollagen type III
- PRO-C3
- PRO-C3, marker of type III collagen formation
- PRO-C5, marker of type V collagen formation
- PSC, primary sclerosing cholangitis
- Primary biliary cholangitis
- Primary sclerosing cholangitis
- TE, transient elastography
- TIMP-1, tissue inhibitor of metalloproteinase
- UC, ulcerative colitis
- VICM, marker of citrullinated vimentin degradation
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Affiliation(s)
- Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | | | - Johannes Roksund Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Francesca Saffioti
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Royal Free Hospital, London, UK.,Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy
| | | | | | - Bjørn Moum
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Division of Medicine, Department of Gastroenterology, Oslo University Hospital, Oslo, Norway
| | - Kirsten Muri Boberg
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Massimo Pinzani
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Royal Free Hospital, London, UK
| | - Tom Hemming Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | | | - Douglas Thorburn
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Royal Free Hospital, London, UK
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Mjelle AB, Fossdal G, Gilja OH, Vesterhus M. Liver Elastography in Primary Sclerosing Cholangitis Patients Using Three Different Scanner Systems. ULTRASOUND IN MEDICINE & BIOLOGY 2020; 46:1854-1864. [PMID: 32507342 DOI: 10.1016/j.ultrasmedbio.2020.03.025] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 03/17/2020] [Accepted: 03/24/2020] [Indexed: 06/11/2023]
Abstract
The aim of the study described here was to characterize three different liver elastography methods in primary sclerosing cholangitis (PSC) patients, for the first time exploring 2-D shear wave elastography (2-D-SWE) in PSC patients and its putative advantages over point shear wave elastography (pSWE). Sixty-six adult PSC patients (51 males, 77%) underwent liver elastography: Transient elastography (TE), pSWE and 2-D-SWE were applied head-to-head after B-mode ultrasonography and blood tests. Liver stiffness measurements (LSMs) by pSWE yielded lower values than those by TE; 2-D-SWE had less steep slope but was overall not significantly different from TE. Correlation between LSMs by pSWE and TE was excellent (intraclass correlation coefficient = 0.92); correlation for 2-D-SWE with either pSWE or TE was moderate but improved with exclusion of overweight individuals. LSMs correlated with the Enhanced Liver Fibrosis test (ELF) across all scanner systems. Our study indicates that LSM by different systems is feasible in PSC patients and that 2-D-SWE tends to underestimate stiffness compared with TE.
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Affiliation(s)
- Anders Batman Mjelle
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway.
| | - Guri Fossdal
- Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway; Norwegian PSC Research Center (NoPSC), Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Odd Helge Gilja
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Mette Vesterhus
- National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen, Norway; Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway; Norwegian PSC Research Center (NoPSC), Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway
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Trembling PM, Apostolidou S, Gentry-Maharaj A, Parkes J, Ryan A, Tanwar S, Burnell M, Harris S, Menon U, Rosenberg WM. The Enhanced Liver Fibrosis test is associated with liver-related outcomes in postmenopausal women with risk factors for liver disease. BMC Gastroenterol 2020; 20:104. [PMID: 32293289 PMCID: PMC7158048 DOI: 10.1186/s12876-020-01251-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Accepted: 03/30/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Chronic liver disease (CLD) is usually asymptomatic but earlier detection is critical to permit life-saving interventions for those at risk due to high alcohol consumption and increased body mass index (BMI). The aim of this study was to estimate the association between the Enhanced Liver Fibrosis (ELF) test and liver-related events (LRE) and its performance in predicting LRE in postmenopausal women with risk factors in a nested case-control study within the United Kingdom Trial of Ovarian Cancer Screening (UKCTOCS). METHODS In a cohort of 95,126 we performed a case-control study measuring ELF in blinded samples from 173 participants with self-reported high alcohol use and / or BMI ≥25 kg/m2 comprising all 58 cases who developed LRE and 115 controls matched for age, alcohol and BMI who did not develop LRE during median follow-up of 8.5 years. RESULTS Using Cox regression at an ELF threshold of 10.51 hazard ratios (HR) for LRE were 4.88 (95% confidence interval (CI) 2.37-10.03) (unadjusted model) and 4.62 (95% CI 2.12-10.08) (adjusted for deprivation and self-reported hypertension, heart disease, hypercholesterolaemia and diabetes). At a threshold of 9.8 HR for LRE were 2.21 (95% CI 1.22-3.97) (unadjusted model) and 2.18 (95% CI 1.19-4.01) (adjusted). ELF was evaluated as a time dependent variable by generating time-dependent Cox models; HRs at an ELF threshold of 10.51 were 1.94 (95% CI 1.10-3.39) (unadjusted) and 2.05 (95% CI 1.16-3.64) (adjusted) and at a threshold of 9.8 HRs were 1.85 (95% CI 1.09-3.15) (unadjusted) and 1.80 (95% CI 1.04-3.13) (adjusted). Area under the receiver operating characteristic curve for recruitment ELF predicting LRE was 0.58 (95% CI 0.49-0.68), and for second subsequent ELF 0.61 (95% CI 0.52-0.71). CONCLUSION This study demonstrates the association between ELF and CLD in postmenopausal women with risk factors for liver disease, creating the opportunity to intervene to reduce liver-related mortality and morbidity. Although larger studies are required, these results demonstrate the potential of ELF as a prognostic tool in health checks in primary care. TRIAL REGISTRATION This study is nested in UKCTOCS. UKCTOCS is registered as an International Standard Randomised Controlled Trial, number ISRCTN22488978. Registered 06/04/2000.
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Affiliation(s)
- Paul M. Trembling
- Division of Medicine, University College London, Institute for Liver and Digestive Health, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF UK
| | - Sophia Apostolidou
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Faculty of Population Health Sciences, University College London, 2nd Floor, 90 High Holborn, London, WC1V 6LJ UK
| | - Aleksandra Gentry-Maharaj
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Faculty of Population Health Sciences, University College London, 2nd Floor, 90 High Holborn, London, WC1V 6LJ UK
| | - Julie Parkes
- Primary Care and Population Sciences Academic Unit, Faculty of Medicine, University of Southampton, Level C, South Academic Block, University Hospital Southampton, Southampton, SO16 6YD UK
| | - Andy Ryan
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Faculty of Population Health Sciences, University College London, 2nd Floor, 90 High Holborn, London, WC1V 6LJ UK
| | - Sudeep Tanwar
- Division of Medicine, University College London, Institute for Liver and Digestive Health, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF UK
| | - Matthew Burnell
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Faculty of Population Health Sciences, University College London, 2nd Floor, 90 High Holborn, London, WC1V 6LJ UK
| | - Scott Harris
- Primary Care and Population Sciences Academic Unit, Faculty of Medicine, University of Southampton, Level C, South Academic Block, University Hospital Southampton, Southampton, SO16 6YD UK
| | - Usha Menon
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, Faculty of Population Health Sciences, University College London, 2nd Floor, 90 High Holborn, London, WC1V 6LJ UK
| | - William M. Rosenberg
- Division of Medicine, University College London, Institute for Liver and Digestive Health, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF UK
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Patel PJ, Connoley D, Rhodes F, Srivastava A, Rosenberg W. A review of the clinical utility of the Enhanced Liver Fibrosis test in multiple aetiologies of chronic liver disease. Ann Clin Biochem 2020; 57:36-43. [PMID: 31529981 DOI: 10.1177/0004563219879962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The rising incidence of chronic liver disease continues to be an increasing health burden. The morbidity and mortality associated with chronic liver disease typically occur in patients with advanced fibrosis. Hence, early identification of those at-risk is of vital importance to ensure appropriate ongoing management. Currently, tools for appropriate risk stratification remain limited. Increasing awareness of the limitations of liver biopsy has driven research into alternative non-invasive methods of fibrosis assessment including serological markers assessing functional changes. One such biomarker, the Enhanced Liver Fibrosis test, was initially validated in a cohort of 1021 patients with mixed aetiology chronic liver disease and shown to perform well. Since this pathfinder study, it has been independently validated in cohorts of hepatitis C, non-alcoholic fatty liver disease, alcoholic liver disease, primary biliary cirrhosis and primary sclerosing cholangitis. In addition to performing well as a diagnostic tool, the Enhanced Liver Fibrosis test has been shown to outperform liver biopsy in prognostic studies and is the only non-invasive marker to do so. However, questions remain regarding the use of this test, particularly regarding the possible effect age and alcohol may have on test scores. This review examines the current literature published in relation to the Enhanced Liver Fibrosis test and its clinical utility and highlights areas requiring further study.
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Affiliation(s)
- Preya Janubhai Patel
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK
| | - Declan Connoley
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK.,Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia
| | - Freya Rhodes
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK
| | - Ankur Srivastava
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK.,Department of Gastroenterology & Hepatology, Southmead Hospital, North Bristol Trust, Bristol, UK
| | - William Rosenberg
- The Institute for Liver and Digestive Health, UCL Division of Medicine, UCL, London, UK
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38
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Deneau MR, Valentino PL, Mack C, Alqoaer K, Amin M, Amir AZ, Aumar M, Auth M, Broderick A, DiGuglielmo M, Draijer LG, El-Matary W, Ferrari F, Furuya KN, Gottrand F, Gupta N, Homan M, Jensen MK, Kamath BM, Kim KM, Kolho KL, Koot B, Iorio R, Martinez M, Miloh T, Mohan P, Palle S, Papadopoulou A, Ricciuto A, Saubermann L, Sathya P, Shteyer E, Smolka V, Tanaka A, Varier R, Venkat V, Vitola B, Woynarowski M, Guthery S. Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children. J Pediatr Gastroenterol Nutr 2020; 70:e12-e17. [PMID: 31651664 DOI: 10.1097/mpg.0000000000002522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC. METHODS We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic. RESULTS Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy. CONCLUSIONS All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.
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Affiliation(s)
| | | | - Cara Mack
- University of Colorado School of Medicine, Aurora, CO
| | | | - Mansi Amin
- Phoenix Children's Hospital, Phoenix, AZ
| | - Achiya Z Amir
- The Dana-Dwek Children's Hospital, The Tel-Aviv Medical Center, Tel-Aviv University, Tel Aviv, Israel
| | | | - Marcus Auth
- Alder Hey Children's Hospital, Liverpool, United Kingdom
| | | | | | | | | | | | | | | | - Nitika Gupta
- Emory University School of Medicine, Atlanta, GA
| | | | | | | | | | | | - Bart Koot
- Academic Medical Centre, Amsterdam, The Netherlands
| | | | - Mercedes Martinez
- Columbia University College of Physicians and Surgeons, New York, NY
| | | | | | - Sirish Palle
- Emory University School of Medicine, Atlanta, GA
| | | | | | | | - Pushpa Sathya
- Memorial University, St. John's, Newfoundland and Labrador, Canada
| | | | | | | | - Raghu Varier
- Northwest Pediatric Gastroenterology LLC, Portland, OR
| | - Veena Venkat
- University of Pittsburgh Medical Center, Pittsburgh, PA
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Emerging therapies in primary sclerosing cholangitis: pathophysiological basis and clinical opportunities. J Gastroenterol 2020; 55:588-614. [PMID: 32222826 PMCID: PMC7242240 DOI: 10.1007/s00535-020-01681-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 03/05/2020] [Indexed: 02/04/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a progressive liver disease, histologically characterized by inflammation and fibrosis of the bile ducts, and clinically leading to multi-focal biliary strictures and with time cirrhosis and liver failure. Patients bear a significant risk of cholangiocarcinoma and colorectal cancer, and frequently have concomitant inflammatory bowel disease and autoimmune disease manifestations. To date, no medical therapy has proven significant impact on clinical outcomes and most patients ultimately need liver transplantation. Several treatment strategies have failed in the past and whilst prescription of ursodeoxycholic acid (UDCA) prevails, controversy regarding benefits remains. Lack of statistical power, slow and variable disease progression, lack of surrogate biomarkers for disease severity and other challenges in trial design serve as critical obstacles in the development of effective therapy. Advances in our understanding of PSC pathogenesis and biliary physiology over recent years has however led to a surge of clinical trials targeting various mechanistic compartments and currently raising hopes for imminent changes in patient management. Here, in light of pathophysiology, we outline and critically evaluate emerging treatment strategies in PSC, as tested in recent or ongoing phase II and III trials, stratified per a triad of targets of nuclear and membrane receptors regulating bile acid metabolism, immune modulators, and effects on the gut microbiome. Furthermore, we revisit the UDCA trials of the past and critically discuss relevant aspects of clinical trial design, including how the choice of endpoints, alkaline phosphatase in particular, may affect the future path to novel, effective PSC therapeutics.
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Trauner M, Gindin Y, Jiang Z, Chung C, Subramanian GM, Myers RP, Gulamhusein A, Kowdley KV, Levy C, Goodman Z, Manns MP, Muir AJ, Bowlus CL. Methylation signatures in peripheral blood are associated with marked age acceleration and disease progression in patients with primary sclerosing cholangitis. JHEP Rep 2019; 2:100060. [PMID: 32039401 PMCID: PMC7005566 DOI: 10.1016/j.jhepr.2019.11.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/08/2019] [Accepted: 11/14/2019] [Indexed: 02/06/2023] Open
Abstract
Background & Aims A DNA methylation (DNAm) signature derived from 353 CpG sites (the Horvath clock) has been proposed as an epigenetic measure of chronological and biological age. This epigenetic signature is accelerated in diverse tissue types in various disorders, including non-alcoholic steatohepatitis, and is associated with mortality. Here, we assayed whole blood DNAm to explore age acceleration in patients with primary sclerosing cholangitis (PSC). Methods Using the MethylationEPIC BeadChip (850K) array, DNAm signatures in whole blood were analyzed in 36 patients with PSC enrolled in a 96-week trial of simtuzumab (Ishak F0-1, n = 13; F5-6, n = 23). Age acceleration was calculated as the difference between DNAm age and chronological age. Comparisons between patients with high and low age acceleration (≥ vs. < the median) were made and Cox regression evaluated the association between age acceleration and PSC-related clinical events (e.g. decompensation, cholangitis, transplantation). Results Age acceleration was significantly higher in patients with PSC compared to a healthy reference cohort (median, 11.1 years, p <2.2 × 10-16). In PSC, demographics, presence of inflammatory bowel disease, and ursodeoxycholic acid use were similar between patients with low and high age acceleration. However, patients with high age acceleration had increased serum alkaline phosphatase, gamma glutamyltransferase, alanine aminotransferase, enhanced liver fibrosis test scores, and greater hepatic collagen and α-smooth muscle actin expression on liver biopsy (all p <0.05). Moreover, patients with high age acceleration had an increased prevalence of cirrhosis (89% vs. 39%; p = 0.006) and greater likelihood of PSC-related events (hazard ratio 4.19; 95% CI 1.15–15.24). Conclusion This analysis of blood DNAm profiles suggests that compared with healthy controls, patients with PSC – particularly those with cirrhosis - exhibit significant acceleration of epigenetic age. Future studies are required to evaluate the prognostic implications and effect of therapies on global methylation patterns and age acceleration in PSC. Lay summary An epigenetic clock based on DNA methylation has been proposed as a marker of age. In liver diseases such as non-alcoholic steatohepatitis, age acceleration based on this epigenetic clock has been observed. Herein, we show that patients with primary sclerosing cholangitis have marked age acceleration, which is further accentuated by worsening fibrosis. This measure of age acceleration could be a useful marker for prognostication or risk stratification in primary sclerosing cholangitis.
A peripheral blood DNA methylation (DNAm) score identifies age acceleration in PSC patients vs. healthy controls. PSC patients with high age acceleration had significantly more PSC-related events than those with low age acceleration. These findings may enable stratification of at-risk PSC patients based on a DNAm score from peripheral blood.
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Key Words
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- Aging
- BMI, body mass index
- DNAm, DNA methylation
- ELF, enhanced liver fibrosis
- FDR, false discovery rate
- GGT, gamma-glutamyltransferase
- IBD, inflammatory bowel disease
- IL, interleukin
- LOXL2, lysyl oxidase-like-2
- NASH, non-alcoholic steatohepatitis
- PSC, primary sclerosing cholangitis
- SMA, smooth muscle actin
- UDCA, ursodeoxycholic acid
- biomarker
- inflammatory bowel disease
- primary sclerosing cholangitis
- prognosis
- ursodeoxycholic acid
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Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Corresponding author. Address: Division of Gastroenterology & Hepatology, Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
| | | | | | | | | | | | - Aliya Gulamhusein
- Division of Gastroenterology, University of Toronto, Toronto, ON, Canada
| | | | | | | | | | | | - Christopher L. Bowlus
- Division of Gastroenterology and Hepatology, University of California at Davis, Sacramento, CA, USA
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Chascsa DM, Lindor KD. Cancer risk, screening and surveillance in primary sclerosing cholangitis. MINERVA GASTROENTERO 2019; 65:214-228. [PMID: 31220911 DOI: 10.23736/s1121-421x.19.02586-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory condition mainly of the large bile ducts, affecting predominantly young men, and is associated with the presence of inflammatory bowel disease. There is no known cure for PSC, which progresses to cirrhosis or death over 10-20 years. Hepatobiliary malignancy, especially cholangiocarcinoma, is a feared complication associated with poor overall survival. Screening and surveillance appear to improve overall outcomes. To capture as many relevant studies, broad search criteria were employed within the PubMed database. Given the high prevalence of IBD and its own associations with the development of malignancy two separate search strategies were employed. Results were filtered by English language. The first search identified the risks, epidemiological factors and surveillance strategies for patients with PSC at risk for developing malignancy. MeSH terms included: cholangitis, sclerosing, digestive system neoplasms, liver neoplasms, biliary tract neoplasms, cholangiocarcinoma, gallbladder neoplasms, colonic neoplasms, rectal neoplasms, or pancreatic neoplasms, risk factors, risk, surveillance, epidemiology and screen. The second included inflammatory bowel diseases, Crohn's, or colitis, and assessed for additional malignancies such as lymphoma and skin neoplasms. A total of 288 results returned with 21 duplicates; 267 remaining abstracts were assessed for relevance for inclusion by the authors. Patients with PSC show significantly higher than average risk for the development of hepatobiliary and colonic malignancies including cholangiocarcinoma, gallbladder carcinoma and colorectal carcinoma. Yearly ultrasound surveillance followed with more definitive cross-sectional imaging is prudent to arrive in a timely diagnosis of carcinoma, reducing morbidity and mortality.
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Affiliation(s)
- David M Chascsa
- Departments of Gastroenterology and Hepatology and Transplant Center, Mayo Clinic, Phoenix, AZ, USA -
| | - Keith D Lindor
- Office of University Provost, Arizona State University, Phoenix, AZ, USA
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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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44
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Nagy N, Sunkari VG, Kaber G, Hasbun S, Lam DN, Speake C, Sanda S, McLaughlin TL, Wight TN, Long SR, Bollyky PL. Hyaluronan levels are increased systemically in human type 2 but not type 1 diabetes independently of glycemic control. Matrix Biol 2019; 80:46-58. [PMID: 30196101 PMCID: PMC6401354 DOI: 10.1016/j.matbio.2018.09.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 09/04/2018] [Accepted: 09/05/2018] [Indexed: 01/19/2023]
Abstract
Hyaluronan (HA), an extracellular matrix glycosaminoglycan, is implicated in the pathogenesis of both type 1 diabetes (T1D) as well as type 2 diabetes (T2D) and has been postulated to be increased in these diseases due to hyperglycemia. We have examined the serum and tissue distribution of HA in human subjects with T1D and T2D and in mouse models of these diseases and evaluated the relationship between HA levels and glycemic control. We found that serum HA levels are increased in T2D but not T1D independently of hemoglobin-A1c, C-peptide, body mass index, or time since diabetes diagnosis. HA is likewise increased in skeletal muscle in T2D subjects relative to non-diabetic controls. Analogous increases in serum and muscle HA are seen in diabetic db/db mice (T2D), but not in diabetic DORmO mice (T1D). Diabetes induced by the β-cell toxin streptozotozin (STZ) lead to an increase in blood glucose but not to an increase in serum HA. These data indicate that HA levels are increased in multiple tissue compartments in T2D but not T1D independently of glycemic control. Given that T2D but not T1D is associated with systemic inflammation, these patterns are consistent with inflammatory factors and not hyperglycemia driving increased HA. Serum HA may have value as a biomarker of systemic inflammation in T2D.
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Affiliation(s)
- Nadine Nagy
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
| | - Vivekananda G. Sunkari
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
| | - Gernot Kaber
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
| | - Sonia Hasbun
- Department of Cardiology, Good Samaritan Regional Medical Center, 3600 NW Samaritan Dr, Corvallis, OR, 97330
| | - Dung N. Lam
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
| | - Cate Speake
- Diabetes Clinical Research Program, Benaroya Research Institute, 1201 Ninth Ave, Seattle, WA, 98101
| | - Srinath Sanda
- Department of Pediatrics, UCSF School of Medicine, 513 Parnassus Avenue, San Francisco, CA, 94143
| | - Tracey L. McLaughlin
- Department of Medicine, Medicine – Endocrinology, Endocrine Clinic, Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA, 94305
| | - Thomas N. Wight
- Matrix Biology Program, Benaroya Research Institute, 1201 Ninth Ave, Seattle, WA, 98101
| | - Steven R. Long
- Department of Pathology, Stanford University School of Medicine, Lane 235, 300 Pasteur Drive, Stanford, CA, 94305
| | - Paul L. Bollyky
- Division of Infectious Diseases and Geographic Medicine, Dept. of Medicine, Stanford University School of Medicine, Beckman Center, 279 Campus Drive, Stanford, CA, 94305
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45
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Maurice JB, Thorburn D. Precision medicine in primary sclerosing cholangitis. J Dig Dis 2019; 20:346-356. [PMID: 31099965 DOI: 10.1111/1751-2980.12788] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Accepted: 05/07/2019] [Indexed: 12/11/2022]
Abstract
Primary sclerosing cholangitis is a rare, complex autoimmune disease in relatively young patients. There is currently no treatment for the disease, resulting in high rates of advanced liver disease leading to death or liver transplantation. However, advances have been made in our understanding of the pathophysiological mechanisms of the disease, particularly from breakthroughs in the underlying genetics. Moreover, large international collaborations have generated important clinical data that have given greater detail on the different disease phenotypes and natural history, generating new risk prediction models. As a result, drug development may be designed to target specific disease mechanisms at known points of the disease natural history. Therefore, more drugs are entering phase II and III development, giving hope that soon patient-specific treatments may be available to treat this difficult disease.
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Affiliation(s)
- James B Maurice
- Department of Hepatology and Liver Transplantation, Royal Free Hospital NHS Foundation Trust, London, UK
| | - Douglas Thorburn
- Department of Hepatology and Liver Transplantation, Royal Free Hospital NHS Foundation Trust, London, UK
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46
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Dhillon AK, Kremer AE, Kummen M, Boberg KM, Elferink RPO, Karlsen TH, Beuers U, Vesterhus M, Hov JR. Autotaxin activity predicts transplant-free survival in primary sclerosing cholangitis. Sci Rep 2019; 9:8450. [PMID: 31186435 PMCID: PMC6559994 DOI: 10.1038/s41598-019-44762-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 05/14/2019] [Indexed: 02/07/2023] Open
Abstract
Autotaxin has been associated with liver disease severity and transplant-free survival. This study aimed to validate autotaxin as a biomarker in two cohorts of Norwegian large-duct PSC patients, one discovery panel (n = 165) and one validation panel (n = 87). Serum activity of autotaxin was measured in diluted sera by a fluorometric enzymatic assay. Patients reaching an end-point, liver transplantation or death, (discovery panel: n = 118 [71.5%]; validation panel: n = 35 [40.2%]), showed higher autotaxin activity compared with the other patients, P < 0.001 and P = 0.004, respectively. Kaplan-Meier survival analyses showed a strong association between increasing autotaxin activity and shorter liver transplant-free survival (discovery panel: P < 0.001, validation panel: P = 0.001). There was no relationship between autotaxin activity and the presence of inflammatory bowel disease or occurrence of hepatobiliary malignancy. In a multivariable analysis, high autotaxin activity was associated with an increased risk of liver transplantation or death (hazard ratio 2.03 (95% confidence interval 1.21–3.40), P < 0.01), independent from Mayo risk score, an in-house enhanced liver fibrosis score and interleukin-8 in serum. In conclusion, increased serum autotaxin activity is associated with reduced liver transplant-free survival independent from Mayo risk score and markers of inflammation and fibrosis.
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Affiliation(s)
- Amandeep K Dhillon
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory diseases and Transplantation, Oslo University hospital Rikshospitalet, Oslo, Norway
| | - Andreas E Kremer
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg-Erlangen, Erlangen, Germany
| | - Martin Kummen
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory diseases and Transplantation, Oslo University hospital Rikshospitalet, Oslo, Norway
| | - Kirsten M Boberg
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Ronald P Oude Elferink
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Tom H Karlsen
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory diseases and Transplantation, Oslo University hospital Rikshospitalet, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Department of Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Johannes R Hov
- Norwegian PSC Research Center, Department of transplantation medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway. .,Research Institute of Internal Medicine, Division of Surgery, Inflammatory diseases and Transplantation, Oslo University hospital Rikshospitalet, Oslo, Norway. .,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
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47
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Saffioti F, Roccarina D, Vesterhus M, Hov JR, Rosenberg W, Pinzani M, Pereira SP, Boberg KM, Thorburn D. Cholangiocarcinoma is associated with a raised enhanced liver fibrosis score independent of primary sclerosing cholangitis. Eur J Clin Invest 2019; 49:e13088. [PMID: 30762236 DOI: 10.1111/eci.13088] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 02/11/2019] [Accepted: 02/12/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) complicates primary sclerosing cholangitis (PSC) in 10%-20% of cases, but current tools for prediction of a CCA diagnosis are inadequate. Recently, we demonstrated the utility of the enhanced liver fibrosis (ELF) test to stratify prognosis in PSC. We observed that patients with PSC + CCA had significantly higher ELF score than those with PSC alone. In this study, we aimed to investigate further this association in a larger cohort of PSC patients with CCA compared with patients with PSC or CCA alone. MATERIALS AND METHODS Stored sera from patients with PSC (n = 119), CCA without known chronic liver disease (n = 36) and PSC + CCA (n = 32) were tested for ELF. ELF score, gender, age, age at disease diagnosis, inflammatory bowel disease, PSC duration and severity, and CCA features were compared amongst the three cohorts. Factors related to an elevated ELF score were investigated. RESULTS Enhanced liver fibrosis score was significantly higher in patients with CCA without underlying chronic liver disease and in patients with PSC + CCA compared to those with PSC alone (P < 0.001). In multivariate analysis, elevated ELF score was associated with the diagnosis of CCA independently of age and PSC status (P < 0.001). CONCLUSIONS Enhanced liver fibrosis score was elevated in patients with CCA irrespective of the presence of PSC, and independently of liver disease stage. Our results indicate that the association between high ELF score and CCA may be related to the tumour's desmoplastic nature, independent of background liver fibrosis, suggesting that ELF score could be used to risk stratify for CCA in PSC.
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Affiliation(s)
- Francesca Saffioti
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, UK.,Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy
| | - Davide Roccarina
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, UK
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Johannes R Hov
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - William Rosenberg
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, UK
| | - Massimo Pinzani
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, UK
| | - Stephen P Pereira
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, UK
| | - Kirsten M Boberg
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre and UCL Institute for Liver and Digestive Health, University College London & Royal Free London NHS Foundation Trust, London, UK
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48
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Tabibian JH, Lindor KD. NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A nebulous matter. J Hepatol 2019; 70:348-350. [PMID: 30626486 DOI: 10.1016/j.jhep.2018.12.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Accepted: 12/09/2018] [Indexed: 12/12/2022]
Affiliation(s)
- 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, Phoenix, AZ, USA.
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49
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Hirschfield GM, Chazouillères O, Drenth JP, Thorburn D, Harrison SA, Landis CS, Mayo MJ, Muir AJ, Trotter JF, Leeming DJ, Karsdal MA, Jaros MJ, Ling L, Kim KH, Rossi SJ, Somaratne RM, DePaoli AM, Beuers U. Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial. J Hepatol 2019; 70:483-493. [PMID: 30414864 DOI: 10.1016/j.jhep.2018.10.035] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/09/2018] [Accepted: 10/29/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC. METHODS In this double-blind, placebo-controlled phase II trial, 62 patients who had PSC confirmed by cholangiography or biopsy and an elevated alkaline phosphatase (ALP) >1.5 × the upper limit of normal were randomly assigned 1:1:1 to receive NGM282 1 mg, 3 mg or placebo once daily for 12 weeks. The primary outcome was the change in ALP from baseline to week 12. Secondary and exploratory outcomes included changes in serum biomarkers of bile acid metabolism and fibrosis. Efficacy analysis was by intention-to-treat. RESULTS At 12 weeks, there were no significant differences in the mean change from baseline in ALP between the NGM282 and placebo groups, and therefore, the primary endpoint was not met. However, NGM282 significantly reduced levels of 7alpha-hydroxy-4-cholesten-3-one (a marker of hepatic CYP7A1 activity, LS mean differences -6.2 ng/ml (95% CI -10.7 to -1.7; p = 0.008) and -9.4 ng/ml (-14.0 to -4.9; p <0.001) in the NGM282 1 mg and 3 mg groups, respectively, compared with placebo) and bile acids. Importantly, fibrosis biomarkers that predict transplant-free survival, including Enhanced Liver Fibrosis score and Pro-C3, were significantly improved following NGM282 treatment. Most adverse events were mild to moderate in severity, with gastrointestinal symptoms more frequent in the NGM282 treatment groups. CONCLUSIONS In patients with PSC, NGM282 potently inhibited bile acid synthesis and decreased fibrosis markers, without significantly affecting ALP levels. LAY SUMMARY We present for the first time, the clinical and laboratory effects of a first-in-class, engineered analogue of the endocrine hormone FGF19 in patients with primary sclerosing cholangitis (PSC). By incorporating non-invasive markers of fibrosis, beyond standard liver injury markers, we show that NGM282 impacted on fibrosis turnover and hepatic inflammation without changing alkaline phosphatase. Our findings demonstrate the complexities of using highly potent rational agents in PSC, and furthermore challenge the dogma about what the appropriate endpoints should be for trials in PSC.
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Affiliation(s)
- Gideon M Hirschfield
- National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, United Kingdom; University Hospitals Birmingham, Birmingham, United Kingdom; Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom; Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Canada.
| | - Olivier Chazouillères
- Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, Hepatology and Gastroenterology Department, Saint-Antoine University Hospital, Assistance Publique-Hopitaux de Paris, and INSERM UMR S938, Sorbonne University, Paris, France
| | - Joost P Drenth
- Department of Gastroenterology and Hepatology, Radboud UMC, Nijmegen, the Netherlands
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre and UCL Institute of Liver and Digestive Health, Royal Free Hospital, London, United Kingdom
| | | | - Charles S Landis
- Division of Gastroenterology and Hepatology, University of Washington, Seattle, United States
| | - Marlyn J Mayo
- University Texas Southwestern Medical Center, Dallas, United States
| | - Andrew J Muir
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, United States
| | - James F Trotter
- Texas Digestive Disease Consultants, Clinical Research, Southlake, United States
| | | | | | | | - Lei Ling
- NGM Biopharmaceuticals, South San Francisco, United States
| | - Kathline H Kim
- NGM Biopharmaceuticals, South San Francisco, United States
| | | | | | - Alex M DePaoli
- NGM Biopharmaceuticals, South San Francisco, United States
| | - Ulrich Beuers
- Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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50
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Selvaraj EA, Culver EL, Bungay H, Bailey A, Chapman RW, Pavlides M. Evolving role of magnetic resonance techniques in primary sclerosing cholangitis. World J Gastroenterol 2019; 25:644-658. [PMID: 30783369 PMCID: PMC6378540 DOI: 10.3748/wjg.v25.i6.644] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 01/25/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Development of non-invasive methods to risk-stratify patients and predict clinical endpoints have been identified as one of the key research priorities in primary sclerosing cholangitis (PSC). In addition to serum and histological biomarkers, there has been much recent interest in developing imaging biomarkers that can predict disease course and clinical outcomes in PSC. Magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) continue to play a central role in the diagnosis and follow-up of PSC patients. Magnetic resonance (MR) techniques have undergone significant advancement over the last three decades both in MR data acquisition and interpretation. The progression from a qualitative to quantitative approach in MR acquisition techniques and data interpretation, offers the opportunity for the development of objective and reproducible imaging biomarkers that can potentially be incorporated as an additional endpoint in clinical trials. This review article will discuss how the role of MR techniques have evolved over the last three decades from emerging as an alternative diagnostic tool to endoscopic retrograde cholangiopancreatography, to being instrumental in the ongoing search for imaging biomarker of disease stage, progression and prognosis in PSC.
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Affiliation(s)
- Emmanuel A Selvaraj
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
- Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Emma L Culver
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
- Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Helen Bungay
- Department of Radiology, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Adam Bailey
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
- Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford OX3 9DU, United Kingdom
| | - Roger W Chapman
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Michael Pavlides
- Oxford Centre for Clinical Magnetic Resonance Research, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
- Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust and the University of Oxford, Oxford OX3 9DU, United Kingdom
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