|
1
|
Kotsifa E, Saffioti F, Mavroeidis VK. Cholangiocarcinoma: The era of liquid biopsy. World J Gastroenterol 2025; 31:104170. [PMID: 40124277 PMCID: PMC11924015 DOI: 10.3748/wjg.v31.i11.104170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/14/2025] [Indexed: 03/13/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive and heterogeneous malignancy arising from the epithelial cells of the biliary tract. The limitations of the current methods in the diagnosis of CCA highlight the urgent need for new, accurate tools for early cancer detection, better prognostication and patient monitoring. Liquid biopsy (LB) is a modern and non-invasive technique comprising a diverse group of methodologies aiming to detect tumour biomarkers from body fluids. These biomarkers include circulating tumour cells, cell-free DNA, circulating tumour DNA, RNA and extracellular vesicles. The aim of this review is to explore the current and potential future applications of LB in CCA management, with a focus on diagnosis, prognostication and monitoring. We examine both its significant potential and the inevitable limitations associated with this technology. We conclude that LB holds considerable promise, but further research is necessary to fully integrate it into precision oncology for CCA.
Collapse
Affiliation(s)
- Evgenia Kotsifa
- The Second Propaedeutic Department of Surgery, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens 11527, Greece
| | - Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom
- University College London Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and University College London, London NW3 2QG, United Kingdom
- Division of Clinical and Molecular Hepatology, Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina 98124, Italy
| | - Vasileios K Mavroeidis
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of Gastrointestinal Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of HPB Surgery, Bristol Royal Infirmary, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS2 8HW, United Kingdom
| |
Collapse
|
|
2
|
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.
Collapse
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
| | | |
Collapse
|
|
3
|
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.
Collapse
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
| |
Collapse
|
|
4
|
Fiorucci S, Urbani G, Di Giorgio C, Biagioli M, Distrutti E. Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments. Cells 2024; 13:1650. [PMID: 39404413 PMCID: PMC11475195 DOI: 10.3390/cells13191650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 10/19/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease with no approved therapies. The ursodeoxycholic acid (UDCA) has been widely used, although there is no evidence that the use of UDCA delays the time to liver transplant or increases survival. Several candidate drugs are currently being developed. The largest group of these new agents is represented by FXR agonists, including obeticholic acid, cilofexor, and tropifexor. Other agents that target bile acid metabolism are ASTB/IBAP inhibitors and fibroblasts growth factor (FGF)19 analogues. Cholangiocytes, the epithelial bile duct cells, play a role in PSC development. Recent studies have revealed that these cells undergo a downregulation of GPBAR1 (TGR5), a bile acid receptor involved in bicarbonate secretion and immune regulation. Additional agents under evaluation are PPARs (elafibranor and seladelpar), anti-itching agents such as MAS-related G-protein-coupled receptors antagonists, and anti-fibrotic and immunosuppressive agents. Drugs targeting gut bacteria and bile acid pathways are also under investigation, given the strong link between PSC and gut microbiota.
Collapse
Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Cristina Di Giorgio
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy;
| |
Collapse
|
|
5
|
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
| |
Collapse
|
|
6
|
Nierath WF, Leitner E, Reimann S, Schwarz R, Hinz B, Bleich A, Vollmar B, Zechner D. GSK805 inhibits alpha-smooth muscle expression and modulates liver inflammation without impairing the well-being of mice. FASEB J 2024; 38:e23889. [PMID: 39157975 DOI: 10.1096/fj.202400733r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/21/2024] [Accepted: 08/05/2024] [Indexed: 08/20/2024]
Abstract
Cholestatic liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), lead to inflammation and severe hepatic damage with limited therapeutic options. This study assessed the efficacy of the inverse RORγt agonist, GSK805, both in vitro using the hepatic stellate cell-line LX-2 and in vivo using male bile duct-ligated BALB/c mice. In vitro, 0.3 μM GSK805 reduced alpha-smooth muscle actin expression in LX-2 cells. In vivo, GSK805 significantly decreased IL-23R, TNF-α, and IFN-γ expression in cholestatic liver. Despite high concentrations of GSK805 in the liver, no significant reduction in fibrosis was noticed. GSK805 significantly increased aspartate aminotransferase and alanine aminotransferase activity in the blood, while levels of glutamate dehydrogenase, alkaline phosphatase, and bilirubin were not substantially increased. Importantly, GSK805 did neither increase an animal distress score nor substantially reduce body weight, burrowing activity, or nesting behavior. These results suggest that a high liver concentration of GSK805 is achieved by daily oral administration and that this drug modulates inflammation in cholestatic mice without impairing animal well-being.
Collapse
Affiliation(s)
- Wiebke-Felicitas Nierath
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Emily Leitner
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Sabrina Reimann
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Rico Schwarz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| | - Burkhard Hinz
- Institute of Pharmacology and Toxicology, Rostock University Medical Center, Rostock, Germany
| | - André Bleich
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Brigitte Vollmar
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Dietmar Zechner
- Rudolf-Zenker-Institute of Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| |
Collapse
|
|
7
|
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).
Collapse
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
| |
Collapse
|
|
8
|
Snir T, Greenman R, Aricha R, Frankel M, Lawler J, Saffioti F, Pinzani M, Thorburn D, Mor A, Vaknin I. Machine Learning Identifies Key Proteins in Primary Sclerosing Cholangitis Progression and Links High CCL24 to Cirrhosis. Int J Mol Sci 2024; 25:6042. [PMID: 38892228 PMCID: PMC11173115 DOI: 10.3390/ijms25116042] [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: 05/05/2024] [Revised: 05/28/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare, progressive disease, characterized by inflammation and fibrosis of the bile ducts, lacking reliable prognostic biomarkers for disease activity. Machine learning applied to broad proteomic profiling of sera allowed for the discovery of markers of disease presence, severity, and cirrhosis and the exploration of the involvement of CCL24, a chemokine with fibro-inflammatory activity. Sera from 30 healthy controls and 45 PSC patients were profiled with proximity extension assay, quantifying the expression of 2870 proteins, and used to train an elastic net model. Proteins that contributed most to the model were tested for correlation to enhanced liver fibrosis (ELF) score and used to perform pathway analysis. Statistical modeling for the presence of cirrhosis was performed with principal component analysis (PCA), and receiver operating characteristics (ROC) curves were used to assess the useability of potential biomarkers. The model successfully predicted the presence of PSC, where the top-ranked proteins were associated with cell adhesion, immune response, and inflammation, and each had an area under receiver operator characteristic (AUROC) curve greater than 0.9 for disease presence and greater than 0.8 for ELF score. Pathway analysis showed enrichment for functions associated with PSC, overlapping with pathways enriched in patients with high levels of CCL24. Patients with cirrhosis showed higher levels of CCL24. This data-driven approach to characterize PSC and its severity highlights potential serum protein biomarkers and the importance of CCL24 in the disease, implying its therapeutic potential in PSC.
Collapse
Affiliation(s)
- Tom Snir
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, 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
| | - Adi Mor
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| | - Ilan Vaknin
- Chemomab Therapeutics Ltd., Tel Aviv 6158002, Israel
| |
Collapse
|
|
9
|
Cornillet M, Villard C, Rorsman F, Molinaro A, Nilsson E, Kechagias S, von Seth E, Bergquist A. The Swedish initiative for the st udy of Primary sclerosing cholangitis (SUPRIM). EClinicalMedicine 2024; 70:102526. [PMID: 38500838 PMCID: PMC10945116 DOI: 10.1016/j.eclinm.2024.102526] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 03/20/2024] Open
Abstract
Background Despite more than 50 years of research and parallel improvements in hepatology and oncology, there is still today neither a treatment to prevent disease progression in primary sclerosing cholangitis (PSC), nor reliable early diagnostic tools for the associated hepatobiliary cancers. Importantly, the limited understanding of the underlying biological mechanisms in PSC and its natural history not only affects the identification of new drug targets but implies a lack of surrogate markers that hampers the design of clinical trials and the evaluation of drug efficacy. The lack of easy access to large representative well-characterised prospective resources is an important contributing factor to the current situation. Methods We here present the SUPRIM cohort, a national multicentre prospective longitudinal study of unselected PSC patients capturing the representative diversity of PSC phenotypes. We describe the 10-year effort of inclusion and follow-up, an intermediate analysis report including original results, and the associated research resource. All included patients gave written informed consent (recruitment: November 2011-April 2016). Findings Out of 512 included patients, 452 patients completed the five-year follow-up without endpoint outcomes. Liver transplantation was performed in 54 patients (10%) and hepatobiliary malignancy was diagnosed in 15 patients (3%). We draw a comprehensive landscape of the multidimensional clinical and biological heterogeneity of PSC illustrating the diversity of PSC phenotypes. Performances of available predictive scores are compared and perspectives on the continuation of the SUPRIM cohort are provided. Interpretation We envision the SUPRIM cohort as an open-access collaborative resource to accelerate the generation of new knowledge and independent validations of promising ones with the aim to uncover reliable diagnostics, prognostic tools, surrogate markers, and new treatment targets by 2040. Funding This work was supported by the Swedish Cancer Society, Stockholm County Council, and the Cancer Research Funds of Radiumhemmet.
Collapse
Affiliation(s)
- Martin Cornillet
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Christina Villard
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Transplantation Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Fredrik Rorsman
- Department of Gastroenterology and Hepatology, Akademiska University Hospital, Uppsala, Sweden
| | - Antonio Molinaro
- Department of Hepatology, Sahlgrenska University Hospital, Göteborg, Sweden
| | - Emma Nilsson
- Gastroenterology Clinic, Skåne University Hospital, Sweden
| | - Stergios Kechagias
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Erik von Seth
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Annika Bergquist
- Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| |
Collapse
|
|
10
|
Trauner M, Halilbasic E, Tatscher E, Fickert P. [Primary sclerosing cholangitis-Diagnosis and treatment 2024]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2024; 65:347-356. [PMID: 38498179 PMCID: PMC10959807 DOI: 10.1007/s00108-024-01697-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/05/2024] [Indexed: 03/20/2024]
Abstract
The etiology of primary sclerosing cholangitis (PSC) remains unclear, which explains in part the lack of a causal treatment. The differential diagnostic distinction from the even rarer immunoglobulin 4 (IgG4)-associated cholangitis (IAC) is becoming increasingly more successful. Advances in the understanding of different clinical courses, improvements in noninvasive diagnostics through modern magnetic resonance imaging (MRI) and the introduction of liver elastography have led to the development of improved prognostic models. The evidence for recommendations on medicinal (e.g., ursodeoxycholic acid) or endoscopic treatment (e.g., balloon dilatation and/or stent insertion) for PSC is still low. In contrast, the long-term results of liver transplantation in PSC patients are constantly improving. Due to the lack of highly sensitive and specific screening methods the early recognition of cholangiocellular carcinoma (CCC) as the most important complication is rarely successful. The continuous improvement of endoscopic retrograde cholangiopancreatography (ERCP) and direct cholangioscopy in combination with molecular biological and fluorescence in situ hybridization (FISH) analyses of bile duct tissue samples are promising for refined diagnostics. Due to the significantly increased risk of colorectal cancer, an annual colonoscopy is recommended in the presence of inflammatory bowel disease. Improvement of the early diagnostics of PSC and successful testing of new treatment strategies raise hope for a continuous improvement in the medical support of these complex patients.
Collapse
Affiliation(s)
- Michael Trauner
- Klinische Abteilung für Gastroenterologie und Hepatologie, Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, Währinger Gürtel 18-20, 1090, Wien, Österreich.
| | - Emina Halilbasic
- Klinische Abteilung für Gastroenterologie und Hepatologie, Universitätsklinik für Innere Medizin III, Medizinische Universität Wien, Währinger Gürtel 18-20, 1090, Wien, Österreich
| | - Elisabeth Tatscher
- Klinische Abteilung für Gastroenterologie und Hepatologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz, Auenbruggerplatz 15, 8036, Graz, Österreich
| | - Peter Fickert
- Klinische Abteilung für Gastroenterologie und Hepatologie, Universitätsklinik für Innere Medizin, Medizinische Universität Graz, Auenbruggerplatz 15, 8036, Graz, Österreich.
| |
Collapse
|
|
11
|
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.
Collapse
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
| |
Collapse
|
|
12
|
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.
Collapse
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.
| |
Collapse
|
|
13
|
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.
Collapse
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
| |
Collapse
|
|
14
|
Russo MW. Noninvasive prognostic models, imaging, and elastography to predict clinical events in primary sclerosing cholangitis: A review. World J Hepatol 2023; 15:1013-1020. [PMID: 37900215 PMCID: PMC10600698 DOI: 10.4254/wjh.v15.i9.1013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 07/17/2023] [Accepted: 08/23/2023] [Indexed: 09/22/2023] Open
Abstract
Surrogate endpoints are needed to estimate clinical outcomes in primary sclerosing cholangitis (PSC). Serum alkaline phosphatase was among the first markers studied, but there is substantial variability in alkaline phosphatase levels during the natural history of PSC without intervention. The Mayo risk score incorporates noninvasive variables and has served as a surrogate endpoint for survival for more than two decades. Newer models have better test performance than the Mayo risk score, including the primary sclerosing risk estimate tool (PREsTo) model and UK-PSC score that estimate hepatic decompensation and transplant free survival, respectively. The c-statistics for transplant-free survival for the Mayo risk model and the long-term UK-PSC model are 0.68 and 0.85, respectively. The c-statistics for hepatic decompensation for the Mayo risk model and PREsTo model are 0.85 and 0.90, respectively. The Amsterdam-Oxford model included patients with large duct and small duct PSC and patients with PSC-autoimmune hepatitis overlap and had a c-statistic of 0.68 for transplant-free survival. Other noninvasive tests that warrant further validation include magnetic resonance imaging, elastography and the enhanced liver fibrosis score. Prognostic models, noninvasive tests or a combination of these surrogate endpoints may not only serve to be useful in clinical trials of investigational agents, but also serve to inform our patients about their prognosis.
Collapse
Affiliation(s)
- Mark W Russo
- Division of Hepatology, Atrium Health Wake Forest, Charlotte, NC 28204, United States.
| |
Collapse
|
|
15
|
Wentworth BJ, Khot R, Caldwell SH. The Many Faces of Primary Sclerosing Cholangitis: Controversy Abounds. Dig Dis Sci 2023; 68:3514-3526. [PMID: 37358638 DOI: 10.1007/s10620-023-08003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/10/2023] [Indexed: 06/27/2023]
Abstract
Primary sclerosing cholangitis (PSC) is notoriously challenging to manage given its heterogeneity with regard to diagnosis, management, and progression. The lack of disease-modifying therapy and variable rate of onset of cirrhosis, portal hypertension-related decompensating events, jaundice, pruritus, biliary complications, and need for liver transplantation is deeply unsettling to clinicians and patients alike. Recent updated practice guidance by the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver endeavored to highlight some of these challenges. However, these references only briefly address clinical dilemmas that providers face on a daily basis. This review aims to further discuss these controversial topics, including providing insight into the utility of ursodeoxycolic acid, the significance of alkaline phosphatase normalization, when to consider PSC variants and mimickers, and the implications of continuous hepatobiliary malignancy screening. In particular, there has been a growing body of literature raising concern about repeat exposure to gadolinium-containing contrast. Patients with PSC are potentially at risk for large lifetime exposure to gadolinium related to frequent magnetic resonance imaging scans and whether this carries any negative long-term adverse effects remains unknown.
Collapse
Affiliation(s)
- Brian J Wentworth
- Division of Gastroenterology and Hepatology, School of Medicine, University of Virginia, PO Box 800708, Charlottesville, VA, 22908, USA.
| | - Rachita Khot
- Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, VA, USA
| | - Stephen H Caldwell
- Division of Gastroenterology and Hepatology, School of Medicine, University of Virginia, PO Box 800708, Charlottesville, VA, 22908, USA
| |
Collapse
|
|
16
|
Assis DN, Bowlus CL. Recent Advances in the Management of Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol 2023; 21:2065-2075. [PMID: 37084929 DOI: 10.1016/j.cgh.2023.04.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/05/2023] [Accepted: 04/10/2023] [Indexed: 04/23/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by fibroinflammatory damage to the biliary tree, typically in the setting of inflammatory bowel disease, with an increased risk of liver failure and cholangiocarcinoma. A complex pathophysiology, heterogeneity in clinical features, and the rare nature of the disease have contributed to the lack of effective therapy to date. However, recent innovations in the characterization and prognostication of patients with PSC, in addition to new tools for medical management and emerging pharmacologic agents, give rise to the potential for meaningful progress in the next several years. This review summarizes current concepts in PSC and highlights particular areas in need of further study.
Collapse
|
|
17
|
Saarinen K, Färkkilä M, Jula A, Erlund I, Vihervaara T, Lundqvist A, Åberg F. Enhanced liver Fibrosis® test predicts liver-related outcomes in the general population. JHEP Rep 2023; 5:100765. [PMID: 37333973 PMCID: PMC10276292 DOI: 10.1016/j.jhepr.2023.100765] [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: 12/09/2022] [Revised: 03/03/2023] [Accepted: 03/22/2023] [Indexed: 06/20/2023] Open
Abstract
Background & Aims The Enhanced Liver Fibrosis® (ELF) test exhibits good discriminative performance in detecting advanced liver fibrosis and in predicting liver-related outcomes in patients with specific liver diseases, but large population-based studies are missing. We analysed the predictive performance of the ELF test in a general population cohort. Methods Data were sourced from the Health 2000 study, a Finnish population-based health examination survey conducted in 2000-2001. Subjects with baseline liver disease were excluded. The ELF test was performed on blood samples collected at baseline. Data were linked with national healthcare registers for liver-related outcomes (hospitalisation, cancer, and death). Results The cohort comprised 6,040 individuals (mean age 52.7. 45.6% men) with 67 liver-related outcomes during a median 13.1-year follow-up. ELF predicted liver outcomes (unadjusted hazards ratio 2.70, 95% CI 2.16-3.38). with 5- and 10-year AUCs of 0.81 (95% CI 0.71-0.91) and 0.71 (95% CI 0.63-0.79) by competing-risk methodology. The 10-year risks for liver outcomes increased from 0.5% at ELF <9.8 to 7.1% at ELF ≥11.3, being higher among men than women at any given ELF level. Among individuals with body mass index ≥30 kg/m2, diabetes, or alanine aminotransferase >40 U/L. Five-year AUCs for ELF were 0.85, 0.87, and 0.88, respectively. The predictive ability of the ELF test decreased with time: the 10-year AUCs were 0.78, 0.69, and 0.82, respectively. Conclusions The ELF test shows good discriminative performance in predicting liver-related outcomes in a large general population cohort and appears particularly useful for predicting 5-year outcomes in persons with risk factors. Impact and implications The Enhanced Liver Fibrosis test exhibits good performance for predicting liver-related outcomes (hospitalisation, liver cancer, or liver-related death) in the general population, especially in those with risk factors.
Collapse
Affiliation(s)
- Kustaa Saarinen
- Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Martti Färkkilä
- Abdominal Center, Helsinki University Hospital, Helsinki, Finland
- University of Helsinki, Helsinki, Finland
| | - Antti Jula
- Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Iris Erlund
- Finnish Institute for Health and Welfare, Helsinki, Finland
| | | | | | - Fredrik Åberg
- Transplantation and Liver Surgery, Helsinki University Hospital, Helsinki, Finland
| |
Collapse
|
|
18
|
Nielsen MJ, Dolman GE, Harris R, Frederiksen P, Chalmers J, Grove JI, Irving WL, Karsdal MA, Patel K, Leeming DJ, Guha IN. PRO-C3 is a predictor of clinical outcomes in distinct cohorts of patients with advanced liver disease. JHEP Rep 2023; 5:100743. [PMID: 37284140 PMCID: PMC10240276 DOI: 10.1016/j.jhepr.2023.100743] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/24/2023] [Accepted: 03/15/2023] [Indexed: 06/08/2023] Open
Abstract
Background & Aims Fibroblast activity is a key feature of fibrosis progression and organ function loss, leading to liver-related complications and mortality. The fibrogenesis marker, PRO-C3, has been shown to have prognostic significance in relation to fibrosis progression and as a treatment efficacy marker. We investigated whether PRO-C3 was prognostic for clinical outcome and mortality in two distinct cohorts of compensated cirrhosis. Methods Cohort 1 was a rapid fibrosis progression cohort including 104 patients with HCV and biopsy-proven Ishak fibrosis stage ≥3 without prior clinical events. Cohort 2 was a prospective cohort including 172 patients with compensated cirrhosis of mixed aetiology. Patients were assessed for clinical outcomes. PRO-C3 was assessed in serum at baseline in cohorts 1 and 2, and compared with model for end-stage liver disease and albumin-bilirubin (ALBI) scores. Results In cohort 1, a 2-fold increase in PRO-C3 was associated with 2.7-fold increased hazard of liver-related events (95% CI 1.6-4.6), whereas a one unit increase in ALBI score was associated with a 6.5-fold increased hazard (95% CI 2.9-14.6). In cohort 2, a 2-fold increase in PRO-C3 was associated with a 2.7-fold increased hazard (95% CI 1.8-3.9), whereas a one unit increase in ALBI score was associated with a 6.3-fold increased hazard (95% CI 3.0-13.2). A multivariable Cox regression analysis identified PRO-C3 and ALBI as being independently associated with the hazard of liver-related outcomes. Conclusions PRO-C3 and ALBI were independent prognostic factors for predicting liver-related clinical outcomes. Understanding the dynamic range of PRO-C3 might enhance its use for both drug development and clinical practice. Impact and Implications We tested novel proteins of liver scarring (PRO-C3) in two groups of liver patients with advanced disease to see if they could predict clinical events. We found that this marker and an established test called ALBI were both independently associated with future liver-related clinical outcomes.
Collapse
Affiliation(s)
| | - Grace E. Dolman
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Rebecca Harris
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | | | - Jane Chalmers
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Jane I. Grove
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| | - William L. Irving
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | | | - Keyur Patel
- Division of Gastroenterology and Hepatology, University of Toronto Health Network, Toronto, ON, Canada
| | | | - Indra Neil Guha
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK
| |
Collapse
|
|
19
|
Wang J, Huang R, Liu J, Lai R, Liu Y, Zhu C, Qiu Y, He Z, Yin S, Chen Y, Yan X, Ding W, Zheng Q, Li J, Wu C. A novel non-invasive model for the prediction of advanced liver fibrosis in chronic hepatitis B patients with NAFLD. J Viral Hepat 2023; 30:287-296. [PMID: 36696366 DOI: 10.1111/jvh.13808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/26/2023]
Abstract
There are still lack of non-invasive models to evaluate liver fibrosis in chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD). We aimed to establish a predictive model for advanced fibrosis in these patients. A total of 504 treatment-naive CHB patients with NAFLD who underwent liver biopsy were enrolled and randomly divided into a training set (n = 336) and a validation set (n = 168). Receiver operating characteristic (ROC) curve was used to compare predicting accuracy for the different models. One hundred fifty-six patients (31.0%) had advanced fibrosis. In the training set, platelet, prothrombin time, type 2 diabetes, HBeAg positivity and globulin were significantly associated with advanced fibrosis by multivariable analysis. A predictive model namely PPDHG for advanced fibrosis was developed based on these parameters. The areas under the ROC curve (AUROC) of PPDHG with an optimal cut-off value of -0.980 in predicting advanced fibrosis was 0.817 (95% confidence interval 0.772 to 0.862), with a sensitivity of 81.82% and a specificity of 66.81%. The predicting accuracy of PPDHG for advanced fibrosis was significantly superior to AST to platelet ratio index (APRI), fibrosis-4 score (FIB-4) and NAFLD fibrosis score (NFS). Further analysis revealed that the AUROC of PPDHG remained significantly higher than FIB-4 and NFS indexes, while it was comparable with APRI for predicting advanced fibrosis in the validation set. PPDHG had a better predicting performance than established models for advanced fibrosis in CHB patients with NAFLD. The application of PPDHG can reduce the necessary for liver biopsy in these patients.
Collapse
Affiliation(s)
- Jian Wang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| | - Rui Huang
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| | - Jiacheng Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Ruimin Lai
- Department of Hepatology, Hepatology Research institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yilin Liu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chuanwu Zhu
- Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, China
| | - Yuanwang Qiu
- Department of Infectious Diseases, The Fifth People's Hospital of Wuxi, Wuxi, China
| | - Zebao He
- Department of Infectious Diseases, Taizhou Enze Medical Center (Group) Enze Hospital, Taizhou, China
| | - Shengxia Yin
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| | - Yuxin Chen
- Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China.,Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiaomin Yan
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Weimao Ding
- Department of Hepatology, Huai'an No. 4 People's Hospital, Huai'an, China
| | - Qi Zheng
- Department of Hepatology, Hepatology Research institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Jie Li
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| | - Chao Wu
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
| |
Collapse
|
|
20
|
Trauner M, Chung C, Sterling K, Liu X, Lu X, Xu J, Tempany-Afdhal C, Goodman ZD, Färkkilä M, Tanaka A, Trivedi P, Kowdley KV, Bowlus CL, Levy C, Myers RP. PRIMIS: design of a pivotal, randomized, phase 3 study evaluating the safety and efficacy of the nonsteroidal farnesoid X receptor agonist cilofexor in noncirrhotic patients with primary sclerosing cholangitis. BMC Gastroenterol 2023; 23:75. [PMID: 36922785 PMCID: PMC10015541 DOI: 10.1186/s12876-023-02653-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/13/2023] [Indexed: 03/17/2023] Open
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a chronic progressive liver disease leading to biliary fibrosis and cirrhosis. Cilofexor is a nonsteroidal farnesoid X receptor agonist that demonstrated significant improvements in liver biochemistry and markers of cholestasis in patients with PSC in a phase 2 study. We describe here the rationale, design, and implementation of the phase 3 PRIMIS trial, the largest placebo-controlled trial in PSC. METHODS Adults with large-duct PSC without cirrhosis are randomized 2:1 to receive oral cilofexor 100 mg once daily or placebo for up to 96 weeks during the blinded phase. Patients completing the blinded phase are eligible to receive open-label cilofexor 100 mg daily for up to 96 weeks. The primary objective is to evaluate whether cilofexor reduces the risk of fibrosis progression compared with placebo. Liver biopsy is performed at screening and Week 96 of the blinded phase for histologic assessment of fibrosis. The primary endpoint-chosen in conjunction with guidance from the U.S. Food and Drug Administration-is the proportion of patients with ≥ 1-stage increase in fibrosis according to Ludwig histologic classification at week 96. Secondary objectives include evaluation of changes in liver biochemistry, serum bile acids, liver fibrosis assessed by noninvasive methods, health-related quality of life, and safety of cilofexor. CONCLUSION The phase 3 PRIMIS study is the largest randomized, double-blind, placebo-controlled trial in PSC to date and will allow for robust evaluation of the efficacy and safety of cilofexor in noncirrhotic patients with large-duct PSC. TRIAL REGISTRATION ClinicalTrials.gov NCT03890120; registered 26/03/2019.
Collapse
Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
| | | | - Kate Sterling
- Gilead Sciences, Inc., 333 Lakeside Dr, Foster City, CA, 94404, USA
| | - Xiangyu Liu
- Gilead Sciences, Inc., 333 Lakeside Dr, Foster City, CA, 94404, USA
| | - Xiaomin Lu
- Gilead Sciences, Inc., 333 Lakeside Dr, Foster City, CA, 94404, USA.
| | - Jun Xu
- Gilead Sciences, Inc., 333 Lakeside Dr, Foster City, CA, 94404, USA
| | - Clare Tempany-Afdhal
- Department of Radiology, Ferenc Jolesz National Center for Image Guided Therapy, Brigham and Women's Hospital, 75 Francis St, L1 Rm 050, Boston, MA, 02115, USA
| | - Zachary D Goodman
- Hepatic Pathology Consultation and Research, Inova Fairfax Hospital, 8110 Gatehouse Rd, Falls Church, VA, 22042, USA
| | - Martti Färkkilä
- Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Atsushi Tanaka
- Department of Medicine, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-Ku, Tokyo, 173-8605, Japan
| | - Palak Trivedi
- National Institute for Health Research Birmingham Biomedical Research Centre, Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, ITM Building, Mindelsohn Way, Edgbaston, Birmingham, B15 2TT, UK
| | - Kris V Kowdley
- Liver Institute Northwest, 3216 NE 45 Pl #212, Seattle, WA, 98105, USA
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, UC Davis School of Medicine, 4150 V Street, Sacramento, CA, 95817, USA
| | - Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami, Jackson Medical Towers, 1500 NW 12 Ave, Suite 1101 ET, Miami, FL, 33136, USA
| | | |
Collapse
|
|
21
|
Helgadottir H, Vesterhus M. Noninvasive evaluation of fibrosis in adult biliary diseases. Curr Opin Gastroenterol 2023; 39:83-88. [PMID: 36821455 DOI: 10.1097/mog.0000000000000909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
PURPOSE OF REVIEW Liver fibrosis is highly associated with disease progression and clinical outcome in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), the major chronic biliary diseases in adults. Establishment of validated tools for the noninvasive evaluation of liver fibrosis in PBC and PSC for use in patient follow-up, and effect evaluation in clinical trials, has been a top research priority over recent years. RECENT FINDINGS Two studies in large PBC patient panels investigated liver stiffness measurement by vibration-controlled transient elastography (VCTE) and two studies in PSC demonstrated enhanced liver fibrosis (ELF) variation over time, confirming VCTE and ELF as good prognostic markers. Currently, magnetic resonance elastography (MRE), quantitative MRI mapping and novel serum extracellular matrix and extracellular vesicle markers show promising results for fibrosis and prognostic assessment in biliary diseases. SUMMARY In this article, we will briefly review recent studies supporting recommendations to assess liver fibrosis and prognosis using the ELF test and VCTE during clinical follow-up in both PBC and PSC. We will discuss emerging evidence for MRE and other imaging techniques, and novel serum fibrosis markers, for which sufficient data or availability is currently limited precluding recommendations for clinical use.
Collapse
Affiliation(s)
- Holmfridur Helgadottir
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo.,Department of Medicine, Haraldsplass Deaconess Hospital
| | - Mette Vesterhus
- Norwegian PSC Research Centre, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo.,Department of Medicine, Haraldsplass Deaconess Hospital.,Department of Clinical Science, University of Bergen, Bergen, Norway
| |
Collapse
|
|
22
|
Mulinacci G, Cristoferi L, Palermo A, Luca M, Gerussi A, Invernizzi P, Carbone M. Risk stratification in primary sclerosing cholangitis. Minerva Gastroenterol (Torino) 2023; 69:84-94. [PMID: 33300753 DOI: 10.23736/s2724-5985.20.02821-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic liver disorder commonly affecting young patients and associated with uncertain prognosis and elevated risk of end-stage liver disease and hepatobiliary cancer. Rate of progression in PSC is heterogeneous and accurately predicting the disease course is of paramount importance to clinical practice and interventional trial design. So far, efforts have brought to the development of models looking at short-to-middle-term outcome using composite models including clinical, laboratory, radiological and histological parameters with limited performance. In the era of whole genome sequencing and digital innovation, the time is ripe for the development of stratified medicine in PSC. Efforts should be directed toward developing well-phenotyped cohorts of patients with longitudinal follow-up across sustained periods of time, application of novel image-processing technology, and biomarker discovery using multiomics platforms.
Collapse
Affiliation(s)
- Giacomo Mulinacci
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milan Bicocca, Milan, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Laura Cristoferi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milan Bicocca, Milan, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Andrea Palermo
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milan Bicocca, Milan, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Martina Luca
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milan Bicocca, Milan, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milan Bicocca, Milan, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milan Bicocca, Milan, Italy.,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology, Department of Medicine and Surgery, Center for Autoimmune Liver Diseases, University of Milan Bicocca, Milan, Italy - .,European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| |
Collapse
|
|
23
|
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: 124] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [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
| |
Collapse
|
|
24
|
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.
Collapse
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
Collapse
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
| |
Collapse
|
|
25
|
Laursen TL, Bossen L, Pihl R, Troldborg A, Sandahl TD, Hansen AG, Folserass T, Vesterhus M, Grønbæk H, Thiel S. Highly Increased Levels of Inter-α-inhibitor Heavy Chain 4 (ITIH4) in Autoimmune Cholestatic Liver Diseases. J Clin Transl Hepatol 2022; 10:796-802. [PMID: 36304505 PMCID: PMC9547247 DOI: 10.14218/jcth.2021.00515] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 01/26/2022] [Accepted: 02/16/2022] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND AND AIMS There is an unmet need for new biomarkers to improve diagnostics and prognostics in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Inter-α-inhibitor heavy chain 4 (ITIH4) is an abundant, liver-produced protein, and its synthesis may be altered in liver diseases. We investigated whether ITIH4 plasma concentrations were affected in PBC and PSC patients. METHODS We developed an immunoassay specific for ITIH4 and determined ITIH4 plasma concentrations in 66 PBC, 126 PSC, 92 autoimmune hepatitis (AIH), 67 chronic hepatitis C (CHC), 33 alcoholic hepatitis (AH) patients and 138 healthy controls (HCs). Hepatic ITIH4 expression was investigated by immunohistochemistry in PBC. RESULTS The mean plasma concentration of ITIH4 was almost doubled in PBC [409 µg/mL (95% CI: 388-431)] and 35% higher in PSC [308 µg/mL, (95% CI: 296-319)] compared with HCs [226 µg/mL (95% CI: 221-231); p<0.001]. In PBC patients, ITIH4 correlated with IgM (rho=0.49, p<0.001). Responders to ursodeoxycholic acid treatment (UDCA) had lower levels of ITIH4 than incomplete responders [395 µg/mL (95% CI: 364-425)] vs. 460 µg/mL (95% CI: 421-498); p=0.02]. Four weeks of UDCA treatment had no effect (p=0.19). Increased ITIH4 immunohistochemical staining was seen in a liver biopsy from a PBC patient. ITIH4 levels in AIH [224 µg/mL (95% CI: 208-241)] and HCs were similar (p=0.8). ITIH4 levels were lower in AH [199 µg/mL (95% CI: 175-223)] and CHC [202 µg/mL (192-212)] patients than in HCs (p<0.05). CONCLUSIONS The plasma concentration of ITIH4 was highly elevated in patients with PBC and PSC, suggesting that ITIH4 should be further investigated as a biomarker in cholestatic liver disease.
Collapse
Affiliation(s)
- Tea Lund Laursen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- Correspondence to: Tea Lund Laursen, Department of Hepatology and Gastroenterology, Aarhus University Hospital, 99 Palle Juul-Jensens Boulevard, DK-8200 Aarhus N, Denmark. ORCID: https://orcid.org/0000-0003-2494-0526. Tel: +45-23715703, Fax: +45-78462860, E-mail: ,
| | - Lars Bossen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Rasmus Pihl
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Anne Troldborg
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | | | | | - Trine Folserass
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Haraldsplass Deaconess Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Steffen Thiel
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| |
Collapse
|
|
26
|
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: 146] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
Collapse
|
|
27
|
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.
Collapse
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
| | | | | | | |
Collapse
|
|
28
|
Owen T, Francis H, Alpini G, Kennedy L. What the duct: Imaging ductular reaction spanning the fibrotic areas in primary sclerosing cholangitis (PSC). Biochim Biophys Acta Mol Basis Dis 2022; 1868:166392. [PMID: 35314350 PMCID: PMC10646949 DOI: 10.1016/j.bbadis.2022.166392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Travis Owen
- 702 Rotary Circle, Rm. 007, Indianapolis, IN 46202, United States of America
| | - Heather Francis
- 702 Rotary Circle, Rm. 007, Indianapolis, IN 46202, United States of America
| | - Gianfranco Alpini
- 702 Rotary Circle, Rm. 007, Indianapolis, IN 46202, United States of America
| | - Lindsey Kennedy
- 702 Rotary Circle, Rm. 007, Indianapolis, IN 46202, United States of America.
| |
Collapse
|
|
29
|
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: 10] [Impact Index Per Article: 3.3] [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.
Collapse
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
| |
Collapse
|
|
30
|
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.
Collapse
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
| |
Collapse
|
|
31
|
Ponsioen CY, Assis DN, Boberg KM, Bowlus CL, Deneau M, Thorburn D, Aabakken L, Färkkilä M, Petersen B, Rupp C, Hübscher SG. Defining Primary Sclerosing Cholangitis: Results From an International Primary Sclerosing Cholangitis Study Group Consensus Process. Gastroenterology 2021; 161:1764-1775.e5. [PMID: 34384749 DOI: 10.1053/j.gastro.2021.07.046] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 07/29/2021] [Indexed: 12/24/2022]
Affiliation(s)
- Cyriel Y Ponsioen
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Location Academic Medical Center, Amsterdam, the Netherlands
| | - David N Assis
- Department of Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Kirsten M Boberg
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; ERN RARE Liver, Hamburg, Germany
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento, California
| | - Mark Deneau
- University of Utah and Intermountain Primary Children's Hospital, Salt Lake City, Utah
| | - Douglas Thorburn
- Sheila Sherlock Liver Centre, Royal Free Hospital and Institute for Liver and Digestive Health, University College London, London, United Kingdom; ERN RARE Liver, Hamburg, Germany
| | - Lars Aabakken
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine, and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; ERN RARE Liver, Hamburg, Germany
| | - Martti Färkkilä
- Abdominal Center, Helsinki University Hospital, Helsinki, Finland; ERN RARE Liver, Hamburg, Germany
| | - Bret Petersen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Christian Rupp
- Department of Internal Medicine IV, Gastroenterology, and Hepatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Stefan G Hübscher
- Institute of Immunology and Immunotherapy, University of Birmingham and, Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, United Kingdom
| | | |
Collapse
|
|
32
|
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.
Collapse
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
| |
Collapse
|
|
33
|
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.
Collapse
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
| |
Collapse
|
|
34
|
Saffioti F, Mavroeidis VK. Review of incidence and outcomes of treatment of cholangiocarcinoma in patients with primary sclerosing cholangitis. World J Gastrointest Oncol 2021; 13:1336-1366. [PMID: 34721770 PMCID: PMC8529934 DOI: 10.4251/wjgo.v13.i10.1336] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 07/05/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a premalignant condition and a well-documented risk factor for cholangiocarcinoma (CCA) which is the most common malignancy in this setting and the leading cause of deaths in the recent years, with an increasing incidence. PSC-associated CCA has a geographical distribution that follows the incidence of PSC, with an observed ascending gradient from the Eastern to the Western and from the Southern to the Northern countries. It may arise at any location along the biliary tree but is most common in the perihilar area. Patients with PSC and intrahepatic or perihilar CCA are typically not suitable for liver resection, which is otherwise the treatment of choice with curative intent in patients with resectable tumours, providing a radical resection with clear margins can be achieved. This largely relates to the commonly advanced stage of liver disease at presentation, which allows consideration for liver resection only for a very limited number of suitable patients with PSC. On the other hand, remarkable progress has been reached in the last decades with the implementation of a protocol combining neoadjuvant chemoradiation and orthotopic liver transplantation (OLT) for the treatment of perihilar CCA, within specific criteria. Excellent results have been achieved particularly for PSC patients with this cancer, who seem to benefit the most from this treatment, having converted this into an accepted indication for transplantation and the standard of care in several experienced centres. Intrahepatic CCA as an indication for OLT remains controversial and has not been accepted given disappointing previous results. However, as recent studies have shown favourable outcomes in early intrahepatic CCA, it may be that under defined criteria, OLT may play a more prominent role in the future. Distal CCA in the context of PSC requires aggressive surgical treatment with curative intent, when feasible. This review provides insight about particular features of CCA in the setting of PSC, with a main focus on its incidence, considerations relating to its anatomical location and implications to treatment and outcomes, through the viewpoint of historical evolution of management, and future perspectives.
Collapse
Affiliation(s)
- Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, Oxfordshire, United Kingdom
- UCL Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital, University College London, London NW3 2QG, United Kingdom
| | - Vasileios K Mavroeidis
- Department of Surgery, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, United Kingdom
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
| |
Collapse
|
|
35
|
Schmeltzer PA, Russo MW. Systematic Review of Prognostic Models Compared to the Mayo Risk Score for Primary Sclerosing Cholangitis. J Clin Med 2021; 10:jcm10194476. [PMID: 34640494 PMCID: PMC8509587 DOI: 10.3390/jcm10194476] [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: 08/18/2021] [Revised: 09/17/2021] [Accepted: 09/26/2021] [Indexed: 11/16/2022] Open
Abstract
Background: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease with a variable clinical course that can ultimately lead to end-stage liver disease, cholangiocarcinoma, and the need for liver transplantation. Several prognostic models have been developed to predict clinical outcomes and have been compared to the revised Mayo Risk Score (rMRS). Aim: To conduct a systematic review comparing the rMRS to other non-invasive prognostic tests for PSC. Methods: A systematic review of studies from 2000 to 2020 was performed that compared non-invasive biochemical prognostic models to the rMRS in predicting outcomes in patients with PSC. Results: Thirty-seven studies were identified, of which five studies that collectively included 3230 patients were reviewed. Outcomes included transplant-free survival or composite clinical outcomes. The rMRS was better than the Amsterdam–Oxford model for predicting 1-year transplant-free survival, c-statistics 0.75 and 0.70, respectively. The UK-PSC score outperformed the rMRS for 10-year transplant-free survival, c-statistics 0.85 and 0.69, respectively. An enhanced liver fibrosis score was independently associated with transplant-free survival after adjusting for rMRS. PREsTo predicts 5-year hepatic decompensation with a c-statistic modestly higher than rMRS; 0.90 and 0.85, respectively. Conclusion: Newer prognostic models, including the UK-PSC score and PREsTo, are more accurate at predicting clinical endpoints in PSC compared to the rMRS. Time frames and clinical endpoints are not standard among studies.
Collapse
|
|
36
|
Garantziotis S. Modulation of hyaluronan signaling as a therapeutic target in human disease. Pharmacol Ther 2021; 232:107993. [PMID: 34587477 DOI: 10.1016/j.pharmthera.2021.107993] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/08/2021] [Accepted: 09/09/2021] [Indexed: 12/14/2022]
Abstract
The extracellular matrix is an active participant, modulator and mediator of the cell, tissue, organ and organismal response to injury. Recent research has highlighted the role of hyaluronan, an abundant glycosaminoglycan constituent of the extracellular matrix, in many fundamental biological processes underpinning homeostasis and disease development. From this basis, emerging studies have demonstrated the therapeutic potential of strategies which target hyaluronan synthesis, biology and signaling, with significant promise as therapeutics for a variety of inflammatory and immune diseases. This review summarizes the state of the art in this field and discusses challenges and opportunities in what could emerge as a new class of therapeutic agents, that we term "matrix biologics".
Collapse
Affiliation(s)
- Stavros Garantziotis
- Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
| |
Collapse
|
|
37
|
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.
Collapse
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
Collapse
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
| |
Collapse
|
|
38
|
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: 945] [Impact Index Per Article: 236.3] [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.
Collapse
|
|
39
|
Mousa OY, Juran BD, McCauley BM, Vesterhus MN, Folseraas T, Turgeon CT, Ali AH, Schlicht EM, Atkinson EJ, Hu C, Harnois D, Carey EJ, Gossard AA, Oglesbee D, Eaton JE, LaRusso NF, Gores GJ, Karlsen TH, Lazaridis KN. Bile Acid Profiles in Primary Sclerosing Cholangitis and Their Ability to Predict Hepatic Decompensation. Hepatology 2021; 74:281-295. [PMID: 33226645 PMCID: PMC8141059 DOI: 10.1002/hep.31652] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 09/10/2020] [Accepted: 10/23/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility. APPROACH AND RESULTS Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86). CONCLUSIONS Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.
Collapse
Affiliation(s)
- Omar Y. Mousa
- Division of Gastroenterology and Hepatology, Mayo Clinic, Mankato, MN,Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Brian D. Juran
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Bryan M. McCauley
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN
| | - Mette N. Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway,Department of Clinical Science, University of Bergen, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Coleman T. Turgeon
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Ahmad H. Ali
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Erik M. Schlicht
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | | | - Chang Hu
- University of Illinois Urbana-Champagne, IL
| | - Denise Harnois
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL
| | - Elizabeth J. Carey
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ
| | - Andrea A. Gossard
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Devin Oglesbee
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - John E. Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | | | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Tom H. Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | | |
Collapse
|
|
40
|
Trivedi PJ, Muir AJ, Levy C, Bowlus CL, Manns MP, Lu X, Crans G, Chung C, Subramanian GM, Myers RP, Goodman Z, Chalasani N, Vierling JM, Guha IN, Hirschfield GM. Inter- and Intra-individual Variation, and Limited Prognostic Utility, of Serum Alkaline Phosphatase in a Trial of Patients With Primary Sclerosing Cholangitis. Clin Gastroenterol Hepatol 2021; 19:1248-1257. [PMID: 32707342 DOI: 10.1016/j.cgh.2020.07.032] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 06/05/2020] [Accepted: 07/14/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Serum alkaline phosphatase (ALP) and the enhanced liver fibrosis (ELF) score are used as endpoints in trials of patients with primary sclerosing cholangitis (PSC). We aimed to quantify inter- and intra-individual variation in levels of ALP and the ELF score over time, and evaluated their association with fibrosis progression. METHODS We analyzed data from 234 patients with large-duct PSC enrolled in a 2-year, phase 2b placebo-controlled trial of simtuzumab. Participants were assessed by laboratory tests every 4 weeks, and liver biopsies collected at time of screening, week 48, and week 96. RESULTS Serum levels of ALP and ELF scores did not differ significantly between simtuzumab and placebo groups, so the data were pooled. Median per-patient variations in ALP between clinic visits were approximately 12% over 12 weeks, 20% over 48 weeks, and 20% over 96 weeks. Reductions, unrelated to study intervention, of more than 40% in ALP were observed in 10.9% of patients with baseline activity greater than 2-fold the upper limit of normal (ULN) and 12.5% of patients with more than 3-fold the ULN at 1 year. At 2 years, reductions of more than 40% in ALP were observed in 15.8% of patients with baseline activity greater than 2-fold the ULN and 17.9% of patients with more than 3-fold the ULN. Among the 209 patients with Ishak fibrosis stage 0-4 at baseline, serum ALP activity did not associate with development of cirrhosis or with a 2-point increase in fibrosis stage at 2 years. In contrast, the median per-patient variation in ELF scores between clinic visits was approximately 3% over 12 weeks, 4% over 48 weeks, and 4% over 96 weeks. Elevated ELF scores at baseline and at weeks 12, 24 and 48, each associated with development of cirrhosis at 2 years (odds ratio >2.75; P < .01 for all timepoints). ELF scores at baseline and weeks 12, 24 and 48, also associated with a 2-point increase in fibrosis stage at 2 years (odds ratios all greater than 2; P < .01 for all timepoints). CONCLUSIONS In an analysis of data from patients with large-duct PSC enrolled in a prospective trial, we found large interindividual and intraindividual variations in serum ALP activity. Serum ALP activity did not associate with disease progression over a 2-year period. Variations in ELF score were smaller, and scores determined at multiple timepoints associated with fibrosis progression and development of cirrhosis.
Collapse
Affiliation(s)
- Palak J Trivedi
- 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; Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom.
| | - Andrew J Muir
- Duke Clinical Research Institute, Durham, North Carolina
| | | | | | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Xiaomin Lu
- Gilead Sciences, Inc, Foster City, California
| | | | | | | | | | | | - Naga Chalasani
- Indiana University School of Medicine, Indianapolis, Indiana
| | | | - Indra Neil Guha
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Gideon M Hirschfield
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
41
|
Rabiee A, Silveira MG. Primary sclerosing cholangitis. Transl Gastroenterol Hepatol 2021; 6:29. [PMID: 33824933 DOI: 10.21037/tgh-20-266] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 10/19/2020] [Indexed: 12/15/2022] Open
Abstract
Primary sclerosing cholangitis (PSC) is a rare chronic cholestatic liver disease characterized by inflammatory destruction of the intrahepatic and/or extrahepatic bile ducts, leading to bile stasis, fibrosis, and ultimately to cirrhosis, and often requires liver transplantation (LT). PSC occurs more commonly in men, and is typically diagnosed between the ages of 30 and 40. Most cases occur in association with inflammatory bowel disease (IBD), which often precedes the development of PSC. PSC is usually diagnosed after detection of cholestasis during health evaluation or screening of patients with IBD. When symptomatic, the most common presenting symptoms are abdominal pain, pruritus, jaundice or fatigue. The etiology of PSC is poorly understood, but an increasing body of evidence supports the concept of cholangiocyte injury as a result of environmental exposure and an abnormal immune response in genetically susceptible individuals. PSC is a progressive disease, yet no effective medical therapy for halting disease progression has been identified. Management of PSC is mainly focused on treatment of symptoms and addressing complications. PSC can be complicated by bacterial cholangitis, dominant strictures (DSs), gallbladder polyps and adenocarcinoma, cholangiocarcinoma (CCA) and, in patients with IBD, colorectal malignancy. CCA is the most common malignancy in PSC with a cumulative lifetime risk of 10-20%, and accounts for a large proportion of mortality in PSC. LT is currently the only life-extending therapeutic approach for eligible patients with end-stage PSC, ultimately required in approximately 40% of patients. LT secondary to PSC has an excellent outcome compared to other LT indications, although the disease can recur and result in morbidity post-transplant.
Collapse
Affiliation(s)
- Anahita Rabiee
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Marina G Silveira
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| |
Collapse
|
|
42
|
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.
Collapse
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
| |
Collapse
|
|
43
|
Kummen M, Thingholm LB, Rühlemann MC, Holm K, Hansen SH, Moitinho-Silva L, Liwinski T, Zenouzi R, Storm-Larsen C, Midttun Ø, McCann A, Ueland PM, Høivik ML, Vesterhus M, Trøseid M, Laudes M, Lieb W, Karlsen TH, Bang C, Schramm C, Franke A, Hov JR. Altered Gut Microbial Metabolism of Essential Nutrients in Primary Sclerosing Cholangitis. Gastroenterology 2021; 160:1784-1798.e0. [PMID: 33387530 PMCID: PMC7611822 DOI: 10.1053/j.gastro.2020.12.058] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 12/02/2020] [Accepted: 12/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS To influence host and disease phenotype, compositional microbiome changes, which have been demonstrated in patients with primary sclerosing cholangitis (PSC), must be accompanied by functional changes. We therefore aimed to characterize the genetic potential of the gut microbiome in patients with PSC compared with healthy controls (HCs) and patients with inflammatory bowel disease (IBD). METHODS Fecal DNA from 2 cohorts (1 Norwegian and 1 German), in total comprising 136 patients with PSC (58% with IBD), 158 HCs, and 93 patients with IBD without PSC, were subjected to metagenomic shotgun sequencing, generating 17 billion paired-end sequences, which were processed using HUMAnN2 and MetaPhlAn2, and analyzed using generalized linear models and random effects meta-analyses. RESULTS Patients with PSC had fewer microbial genes compared with HCs (P < .0001). Compared with HCs, patients with PSC showed enrichment and increased prevalence of Clostridium species and a depletion of, for example, Eubacterium spp and Ruminococcus obeum. Patients with PSC showed marked differences in the abundance of genes related to vitamin B6 synthesis and branched-chain amino acid synthesis (Qfdr < .05). Targeted metabolomics of plasma from an independent set of patients with PSC and controls found reduced concentrations of vitamin B6 and branched-chain amino acids in PSC (P < .0001), which strongly associated with reduced liver transplantation-free survival (log-rank P < .001). No taxonomic or functional differences were detected between patients with PSC with and without IBD. CONCLUSIONS The gut microbiome in patients with PSC exhibits large functional differences compared with that in HCs, including microbial metabolism of essential nutrients. Alterations in related circulating metabolites associated with disease course, suggesting that microbial functions may be relevant for the disease process in PSC.
Collapse
Affiliation(s)
- 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, Oslo University Hospital Rikshospitalet, Oslo, Norway,Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Louise B. Thingholm
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Malte C. Rühlemann
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Kristian Holm
- 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, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Simen H. Hansen
- 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, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Lucas Moitinho-Silva
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany,Department of Dermatology, Venereology and Allergy, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Timur Liwinski
- Institute of Medical Systems Biology, Center for Molecular Neurobiology, Hamburg, Germany,I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Roman Zenouzi
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christopher Storm-Larsen
- 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, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | | | | | | | - Marte L. Høivik
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway,Department of Gastroenterology, Oslo University Hospital Ullevål, 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
| | - Marius Trøseid
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway,Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Matthias Laudes
- Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine 1, University of Kiel, Germany
| | - Wolfgang Lieb
- Institute of Epidemiology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - 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, Oslo University Hospital Rikshospitalet, Oslo, Norway,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Corinna Bang
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Christoph Schramm
- I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,Martin Zeitz Centre for Rare Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,Hamburg Center for Translational Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - 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, Oslo University Hospital Rikshospitalet, Oslo, Norway,Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| |
Collapse
|
|
44
|
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.
Collapse
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
| |
Collapse
|
|
45
|
Bossen L, Vesterhus M, Hov JR, Färkkilä M, Rosenberg WM, Møller HJ, Boberg KM, Karlsen TH, Grønbæk H. Circulating Macrophage Activation Markers Predict Transplant-Free Survival in Patients With Primary Sclerosing Cholangitis. Clin Transl Gastroenterol 2021; 12:e00315. [PMID: 33646203 PMCID: PMC7925135 DOI: 10.14309/ctg.0000000000000315] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 01/13/2021] [Indexed: 02/08/2023] Open
Abstract
INTRODUCTION Primary sclerosing cholangitis (PSC) is a progressive liver disease characterized by bile duct inflammation and fibrosis. The role of macrophages in PSC development and progression is less studied. Macrophage activation markers soluble (s)CD163 and mannose receptor (sMR) are associated with disease severity and outcome in other liver diseases, but not previously investigated in PSC. We evaluated sCD163 and sMR regarding disease severity and prognosis in patients with PSC. METHODS We investigated 2 independent PSC cohorts from Oslo (n = 138) and Helsinki (n = 159) and analyzed blood sCD163 and sMR levels. The Mayo score, Enhanced Liver Fibrosis Test, and Amsterdam-Oxford model were assessed for comparison. RESULTS Median (interquartile range) sCD163 was 3.32 (2.27-5.60) and 1.96 (1.47-2.70) mg/L in the Oslo and Helsinki cohorts, respectively, reflecting differences in disease severity between cohorts. Median sMR was similar in both cohorts, 0.28 (0.22-0.44) and 0.28 mg/L (0.20-0.36), respectively. In both cohorts, sCD163 and sMR levels raised with increasing disease severity (liver enzymes, Mayo score, and enhanced liver fibrosis test). Patients with high baseline levels of sCD163 had shorter transplant-free survival than patients with low baseline levels. Furthermore, sCD163 was associated with transplant-free survival in univariate cox-regression analyses. Both sCD163 and sMR performed better in the Oslo cohort of more severely diseased patients than those in the Helsinki cohort of more mildly diseased patients. DISCUSSION Macrophage activation markers are elevated according to disease severity suggesting an important role of macrophages in PSC. Furthermore, sCD163 was identified as a prognostic marker and predictor of transplant-free survival in PSC (see Visual Abstract, Supplementary Digital Content 4, http://links.lww.com/CTG/A516).
Collapse
MESH Headings
- Adult
- Antigens, CD/analysis
- Antigens, CD/metabolism
- Antigens, Differentiation, Myelomonocytic/analysis
- Antigens, Differentiation, Myelomonocytic/metabolism
- Biomarkers/blood
- Biomarkers/metabolism
- Case-Control Studies
- Cholangitis, Sclerosing/blood
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/mortality
- Cholangitis, Sclerosing/surgery
- Disease Progression
- End Stage Liver Disease/blood
- End Stage Liver Disease/epidemiology
- End Stage Liver Disease/immunology
- End Stage Liver Disease/surgery
- Female
- Finland/epidemiology
- Humans
- Liver Transplantation/statistics & numerical data
- Macrophage Activation
- Macrophages/immunology
- Macrophages/metabolism
- Male
- Membrane Glycoproteins/analysis
- Membrane Glycoproteins/metabolism
- Middle Aged
- Norway/epidemiology
- Prognosis
- Receptors, Cell Surface/analysis
- Receptors, Cell Surface/metabolism
- Receptors, Immunologic/analysis
- Receptors, Immunologic/metabolism
- Registries/statistics & numerical data
- Retrospective Studies
- Risk Assessment/methods
- Severity of Illness Index
Collapse
Affiliation(s)
- Lars Bossen
- Department of Hepatology & Gastroenterology, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Aarhus University Hospital, Aarhus, Denmark;
| | - Mette Vesterhus
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), 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, Division of Surgery, Inflammatory Diseases and Transplantation, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Oslo University Hospital Rikshospitalet, Oslo, Norway;
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway;
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway;
| | - Martti Färkkilä
- Helsinki University, Clinic of Gastroenterology, Helsinki University Hospital, Helsinki, Finland;
| | - William M. Rosenberg
- UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Royal Free London, NHS Foundation Trust, London, UK;
| | - Holger J. Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.
| | - Kirsten M. Boberg
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Oslo University Hospital Rikshospitalet, Oslo, Norway;
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway;
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway;
| | - Tom H. Karlsen
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Oslo University Hospital Rikshospitalet, Oslo, Norway;
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway;
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Oslo, Norway;
- Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway;
| | - Henning Grønbæk
- Department of Hepatology & Gastroenterology, and European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Aarhus University Hospital, Aarhus, Denmark;
| |
Collapse
|
|
46
|
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.
Collapse
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
Collapse
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
| |
Collapse
|
|
47
|
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.
Collapse
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
| |
Collapse
|
|
48
|
An P, Wei G, Huang P, Li W, Qi X, Lin Y, Vaid KA, Wang J, Zhang S, Li Y, Or YS, Jiang L, Popov YV. A novel non-bile acid FXR agonist EDP-305 potently suppresses liver injury and fibrosis without worsening of ductular reaction. Liver Int 2020; 40:1655-1669. [PMID: 32329946 PMCID: PMC7384094 DOI: 10.1111/liv.14490] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 04/06/2020] [Accepted: 04/20/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND EDP-305 is a novel and potent farnesoid X receptor (FXR) agonist, with no/minimal cross-reactivity to TGR5 or other nuclear receptors. Herein we report therapeutic efficacy of EDP-305, in direct comparison with the first-in-class FXR agonist obeticholic acid (OCA), in mouse models of liver disease. METHODS EDP-305 (10 and 30 mg/kg/day) or OCA (30mg/kg/day) was tested in mouse models of pre-established biliary fibrosis (BALBc.Mdr2-/-, n = 9-12/group) and steatohepatitis induced by methionine/choline-deficient diet (MCD, n = 7-12/group). Effects on biliary epithelium were evaluated in vivo and in primary EpCAM + hepatic progenitor cell (HPC) cultures. RESULTS In a BALBc.Mdr2-/- model, EDP-305 reduced serum transaminases by up to 53% and decreased portal pressure, compared to untreated controls. Periportal bridging fibrosis was suppressed by EDP-305 at both doses, with up to a 39% decrease in collagen deposition in high-dose EDP-305. In MCD-fed mice, EDP-305 treatment reduced serum ALT by 62% compared to controls, and profoundly inhibited perisinusoidal 'chicken wire' fibrosis, with over 80% reduction in collagen deposition. In both models, treatment with 30mg/kg OCA reduced serum transaminases up to 30%, but did not improve fibrosis. The limited impact on fibrosis was mediated by cholestasis-independent worsening of ductular reaction by OCA in both disease models; OCA but not EDP-305 at therapeutic doses promoted ductular proliferation in healthy mice and favoured differentiation of primary HPC towards cholangiocyte lineage in vitro. CONCLUSIONS EDP-305 potently improved pre-established liver injury and hepatic fibrosis in murine biliary and metabolic models of liver disease, supporting the clinical evaluation of EDP-305 in fibrotic liver diseases including cholangiopathies and non-alcoholic steatohepatitis.
Collapse
Affiliation(s)
- Ping An
- Divison of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA,Division of Gastroenterology and HepatologyRenmin HospitalWuhan UniversityWuhanChina
| | - Guangyan Wei
- Divison of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA,Department of Radiation OncologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Pinzhu Huang
- Divison of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA,Department of Colon and Rectum SurgeryThe Sixth Affiliated HospitalSun Yat-sen UniversityGuangzhouChina
| | - Wenda Li
- Divison of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA,Department of Hepatobiliary SurgerSun Yat-sen Memorial HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Xiaolong Qi
- Divison of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA,Institute of Portal HypertensionThe First Hospital of Lanzhou UniversityLanzhouChina
| | - Yi Lin
- Divison of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA
| | - Kahini A. Vaid
- Divison of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA
| | - Jun Wang
- Division of NeurosurgeryRenmin HospitalWuhan UniversityWuhanChina
| | | | - Yang Li
- Enanta Pharmaceuticals, Inc.WatertownMAUSA
| | - Yat Sun Or
- Enanta Pharmaceuticals, Inc.WatertownMAUSA
| | | | - Yury V. Popov
- Divison of Gastroenterology and HepatologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA
| |
Collapse
|
|
49
|
Simbrunner B, Marculescu R, Scheiner B, Schwabl P, Bucsics T, Stadlmann A, Bauer DJM, Paternostro R, Eigenbauer E, Pinter M, Stättermayer AF, Trauner M, Mandorfer M, Reiberger T. Non-invasive detection of portal hypertension by enhanced liver fibrosis score in patients with different aetiologies of advanced chronic liver disease. Liver Int 2020; 40:1713-1724. [PMID: 32358998 PMCID: PMC7383870 DOI: 10.1111/liv.14498] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/03/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS The enhanced liver fibrosis (ELF) score comprises serum markers of fibrogenesis and matrix remodelling and was developed to detect liver fibrosis, however, it may also be useful for the non-invasive detection of portal hypertension (PHT). METHODS ELF score and its single components (TIMP1/PIIINP/HA) were analysed in 201 patients with advanced chronic liver disease (ACLD; ie hepatic venous pressure gradient (HVPG) ≥6 mm Hg). Patients with pre-/post-hepatic PHT, hepatocellular carcinoma beyond Milan criteria, and history of TIPS implantation or liver transplantation were excluded. RESULTS ELF and its single components correlated with HVPG in the overall cohort: ELF: r = .443, TIMP1: r = .368, PIIINP:r = .332, and HA:r = .419 (all P < .001). The strength of the correlation between ELF and HVPG decreased in higher HVPG strata: 6-9 mm Hg:r = .569(P = .004), 10-19 mm Hg:r = .304 (P = .001) and ≥20 mm Hg:r = -.023(P = .853). Area under the receiver operating characteristics (AUROC) of ELF score to detect clinically significant PHT (CSPH; HVPG ≥ 10 mm Hg) was 0.833. Importantly, HA alone yielded an AUROC of 0.828. Detection of CSPH in strictly compensated ACLD (cACLD) patients was less accurate: AUROC: 0.759 (P < .001). CSPH was ruled-in by ELF ≥ 11.1 with a PPV of 98% (sensitivity: 61%/specificity: 92%/NPV:24%), but CSPH could not be ruled-out. ELF score had a low AUROC of 0.677 (0.60-0.75; P < .001) for the diagnosis of high-risk PHT (HRPH; HVPG ≥ 20mm Hg) and, thus, HRPH could not be ruled-in by ELF. However, ELF < 10.1 ruled-out HRPH with a NPV of 95% (sensitivity: 97%/specificity: 26%/PPV: 39%). CONCLUSION The ELF score correlates with HVPG at values <20 mm Hg. An ELF ≥ 11.1 identifies patients with a high probability of CSPH, while an ELF < 10.1 may be used to rule-out HRPH.
Collapse
Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Rodrig Marculescu
- Department of Laboratory MedicineMedical University of ViennaViennaAustria
| | - Bernhard Scheiner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Philipp Schwabl
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Theresa Bucsics
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Alexander Stadlmann
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria,Hospital HietzingViennaAustria
| | - David J. M. Bauer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Rafael Paternostro
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Ernst Eigenbauer
- IT‐Systems & CommunicationsMedical University of ViennaViennaAustria
| | - Matthias Pinter
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Albert Friedrich Stättermayer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Mattias Mandorfer
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LaboratoryMedical University of ViennaViennaAustria,Ludwig Boltzmann Institute for Rare and Undiagnosed DiseasesViennaAustria,CeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| |
Collapse
|
|
50
|
Nagelkerke SCJ, Draijer LG, Benninga MA, Koot BGP, Tabbers MM. The prevalence of liver fibrosis according to non-invasive tools in a pediatric home parenteral nutrition cohort. Clin Nutr 2020; 40:460-466. [PMID: 32636112 DOI: 10.1016/j.clnu.2020.05.039] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/12/2020] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Liver biopsy is no viable tool to routinely screen for liver fibrosis in children suffering from chronic intestinal failure (IF). We aim to assess the prevalence of liver fibrosis in a cohort of children with chronic IF by non-invasive tests: transient elastography (TE), aspartate-aminotransferase-to-platelet-ratio-index (APRI) and enhanced liver fibrosis (ELF) score. METHODS Cross sectional study where patients with chronic IF, receiving parenteral nutrition (PN) for at least 3 months, were enrolled. TE, APRI and ELF score were measured. Using Spearman's rank correlation coefficient and Kruskal-Wallis H test, the correlation between TE, APRI, ELF score and known risk factors for development of intestinal failure-associated liver disease (IFALD) were calculated. RESULTS 32 patients were included (50% female), median age was 8 years and 4 months, median PN duration was 45 months. Six patients (21%) had TE ≥6.5 kPa, indicating significant fibrosis. Twelve patients (38%) had APRI ≥.5, indicating fibrosis. ELF score indicated moderate fibrosis in 17 patients (63%) and significant fibrosis in 10 patients (37%). TE and APRI correlated significantly with known risk factors for IFALD, but ELF showed poor correlation with known risk factors for IFALD. CONCLUSION In a cohort of pediatric patients suffering from chronic IF, TE measurement, APRI and ELF test show a varying, but substantial proportion of subjects with fibrosis. The diagnostic value of these tests and their role in the management of pediatric IF must be determined in larger cohorts with liver biopsy as reference standard. TRIAL REGISTRATION Academic Medical Center medical ethics committee number: METC 2017_185.
Collapse
Affiliation(s)
- Sjoerd C J Nagelkerke
- Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Amsterdam, the Netherlands.
| | - Laura G Draijer
- Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Amsterdam, the Netherlands
| | - Marc A Benninga
- Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Amsterdam, the Netherlands
| | - Bart G P Koot
- Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Amsterdam, the Netherlands
| | - Merit M Tabbers
- Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Amsterdam, the Netherlands
| |
Collapse
|