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Di Giorgio C, Urbani G, Marchianò S, Biagioli M, Bordoni M, Bellini R, Massa C, Lachi G, Cari L, Morretta E, Spinelli L, Monti MC, Sepe V, Zampella A, Distrutti E, Banales JM, Lapitz A, Milkiewicz P, Milkiewicz M, Fiorucci S. Liver GPBAR1 Associates With Immune Dysfunction in Primary Sclerosing Cholangitis and Its Activation Attenuates Cholestasis in Abcb4-/- Mice. Liver Int 2025; 45:e16235. [PMID: 39804015 PMCID: PMC11727439 DOI: 10.1111/liv.16235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/25/2024] [Accepted: 12/18/2024] [Indexed: 01/16/2025]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by progressive biliary inflammation and fibrosis, leading to liver cirrhosis and cholangiocarcinoma. GPBAR1 (TGR5) is a G protein-coupled receptor for secondary bile acids. In this study, we have examined the therapeutic potential of BAR501, a selective GPBAR1 agonist in a PSC model. METHODS Single-cell analysis of healthy human liver samples and gene expression analysis of PSC liver samples were conducted. In vitro studies on a human cholangiocyte cell line (NHC), U937 and human hepatic stellate cells (hSteCs) were performed. Additionally, Abcb4-/- mice were treated with BAR501 for 12-24 weeks. RESULTS Single-cell analysis demonstrated that GPBAR1 is expressed by macrophages, NK cells, sinusoidal cells and to a lesser extent by cholangiocytes. Total liver expression of GPBAR1 increases in PSC patients compared to that in healthy controls and positively correlates with markers for monocytes and NK cells and cytokeratin 19. In vitro treatment of NHCs with BAR501 reversed the acquisition of a pro-inflammatory phenotype and the downregulation of GPBAR1 expression promoted by LPS in an NF-κB-dependent manner. Treating Abcb4-/- mice reduced bile duct inflammation and liver fibrosis and prevented the downregulation of GPBAR1 expression. Treating mice with BAR501 also modulated the bile acid pool composition and reduced the dysbiosis-associated gut permeability, and intestinal and systemic inflammation. Ex vivo experiments using conditioned media from BAR501-treated cholangiocytes mitigated the activation of macrophages. CONCLUSIONS Our study provides evidence for the therapeutic potential of selective GPBAR1 agonists in intestinal inflammation-associated cholestasis, warranting the evaluation of BAR501 in PSC patients.
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MESH Headings
- Animals
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/drug therapy
- Cholangitis, Sclerosing/complications
- Cholangitis, Sclerosing/genetics
- Cholangitis, Sclerosing/metabolism
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/agonists
- Receptors, G-Protein-Coupled/genetics
- Humans
- Mice
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Mice, Knockout
- Cholestasis/immunology
- Cholestasis/drug therapy
- Liver/metabolism
- Liver/immunology
- Liver/pathology
- Disease Models, Animal
- Male
- Female
- Hepatic Stellate Cells/metabolism
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Affiliation(s)
| | - Ginevra Urbani
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Silvia Marchianò
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Michele Biagioli
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | | | - Rachele Bellini
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Carmen Massa
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Ginevra Lachi
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Luigi Cari
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Elva Morretta
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | - Lucio Spinelli
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | | | - Valentina Sepe
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | - Angela Zampella
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | | | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University HospitalUniversity of the Basque Country (UPV/EHU), CIBERehdDonostia‐San SebastianSpain
- IKERBASQUE, Basque Foundation for ScienceBilbaoSpain
- Department of Biochemistry and Genetics, School of SciencesUniversity of NavarraPamplonaSpain
| | - Ainhoa Lapitz
- Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University HospitalUniversity of the Basque Country (UPV/EHU), CIBERehdDonostia‐San SebastianSpain
| | - Piotr Milkiewicz
- Liver and Internal Medicine Unit, Department of General, Transplant and Liver SurgeryMedical University of WarsawWarsawPoland
- Translational Medicine GroupPomeranian Medical UniversitySzczecinPoland
| | - Malgorzata Milkiewicz
- Department of Medical BiologyPomeranian Medical University in SzczecinSzczecinPoland
| | - Stefano Fiorucci
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
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van Rheenen PF, Kolho K, Russell RK, Aloi M, Deganello A, Hussey S, Junge N, De Laffolie J, Deneau MR, Fitzpatrick E, Griffiths AM, Hojsak I, Nicastro E, Nita A, Pakarinen M, Ricciuto A, de Ridder L, Sonzogni A, Tenca A, Samyn M, Indolfi G. Primary sclerosing cholangitis in children with inflammatory bowel disease: An ESPGHAN position paper from the Hepatology Committee and the IBD Porto group. J Pediatr Gastroenterol Nutr 2025; 80:374-393. [PMID: 39741383 PMCID: PMC11788976 DOI: 10.1002/jpn3.12378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 07/31/2024] [Accepted: 08/21/2024] [Indexed: 01/03/2025]
Abstract
OBJECTIVE We aimed to provide an evidence-supported approach to diagnose, monitor, and treat children with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC). METHODS The core group formulated seven PICO-structured clinical questions. A systematic literature search from inception to December 2022 was conducted by a medical librarian using MEDLINE and EMBASE. Core messages from the literature were phrased as position statements and then circulated to a sounding board composed of international experts in pediatric gastroenterology and hepatology, histopathology, adult gastroenterology and hepatology, radiology, and surgery. Statements reaching at least 80% agreement were considered as final. The other statements were refined and then subjected to a second online vote or rejection. RESULTS Regular screening for gamma-glutamyltransferase (GGT) is essential for detecting possible biliary disease in children with IBD. MR cholangiopancreatography is the radiological modality of choice for establishing the diagnosis of PSC. Liver biopsy is relevant in the evaluation of small duct PSC or autoimmune hepatitis. Children who do not have known IBD at the time of PSC diagnosis should undergo initial screening with fecal calprotectin for asymptomatic colitis, and then at least once yearly thereafter. Children with a cholestatic liver enzyme profile can be considered for treatment with ursodeoxycholic acid and can continue if there is a meaningful reduction or normalization in GGT. Oral vancomycin may have a beneficial effect on GGT and intestinal inflammation, but judicious use is recommended due to the lack of long-term studies. Children with PSC-IBD combined with convincing features of autoimmune hepatitis may benefit from corticosteroids and antimetabolites. CONCLUSIONS We present state-of-the-art guidance on the diagnostic criteria, follow-up strategies, and therapeutic strategies and point out research gaps in children and adolescents with PSC-IBD.
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Affiliation(s)
- Patrick F. van Rheenen
- Department of Paediatric Gastroenterology, Hepatology, and NutritionUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | | | - Richard K. Russell
- Department of Paediatric Gastroenterology, and NutritionRoyal Hospital for Children and Young PeopleEdinburghUK
| | - Marina Aloi
- Sapienza University of Rome ‐ Umberto I HospitalRomeItaly
| | - Annamaria Deganello
- Department of RadiologyKing's College Hospital, School of Biomedical Engineering and Imaging Sciences, King's College LondonLondonUK
| | - Séamus Hussey
- Children's Health Ireland and University College DublinDublinIreland
| | - Norman Junge
- Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic DiseasesHannover Medical SchoolHannoverGermany
| | - Jan De Laffolie
- General Paediatrics and Neonatology, GastroenterologyJustus Liebig University GiessenGiessenGermany
| | - Mark R. Deneau
- University of Utah and Intermountain Healthcare Primary Children's HospitalSalt Lake CityUtahUSA
| | - Emer Fitzpatrick
- Children's Health Ireland and University College DublinDublinIreland
| | - Anne M. Griffiths
- Faculty of Medicine, IBD Centre, SickKids HospitalUniversity of TorontoTorontoOntarioCanada
| | - Iva Hojsak
- Children's Hospital ZagrebUniversity of Zagreb Medical SchoolZagrebCroatia
| | - Emanuele Nicastro
- Pediatric HepatologyGastroenterology and Transplantation, Hospital Papa Giovanni XXIIIBergamoItaly
| | - Andreia Nita
- Department of Paediatric GastroenterologyGreat Ormond Street HospitalLondonUK
| | - Mikko Pakarinen
- Department of Pediatric SurgeryThe New Children's HospitalUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Amanda Ricciuto
- Faculty of Medicine, IBD Centre, SickKids HospitalUniversity of TorontoTorontoOntarioCanada
| | - Lissy de Ridder
- Department of Paediatric GastroenterologyErasmus University Medical Center Sophia Children's HospitalRotterdamThe Netherlands
| | | | - Andrea Tenca
- Helsinki University and Helsinki University Hospital HUS, Abdominal CenterHelsinkiFinland
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition ServiceKing's College HospitalLondonUK
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3
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Fiorucci S, Marchianò S, Urbani G, Di Giorgio C, Distrutti E, Zampella A, Biagioli M. Immunology of bile acids regulated receptors. Prog Lipid Res 2024; 95:101291. [PMID: 39122016 DOI: 10.1016/j.plipres.2024.101291] [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: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | | | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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4
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Özdirik B, Schnabl B. Microbial Players in Primary Sclerosing Cholangitis: Current Evidence and Concepts. Cell Mol Gastroenterol Hepatol 2023; 17:423-438. [PMID: 38109970 PMCID: PMC10837305 DOI: 10.1016/j.jcmgh.2023.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/12/2023] [Accepted: 12/12/2023] [Indexed: 12/20/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease with progressive biliary inflammation, destruction of the biliary tract, and fibrosis, resulting in liver cirrhosis and end-stage liver disease. To date, liver transplantation is the only definitive treatment option for PSC. The precise etiology of PSC remains elusive, but it is widely accepted to involve a complex interplay between genetic predisposition, immunologic dysfunction, and environmental influence. In recent years, the gut-liver axis has emerged as a crucial pathway contributing to the pathogenesis of PSC, with particular focus on the role of gut microbiota. However, the role of the fungal microbiome or mycobiome has been overlooked for years, resulting in a lack of comprehensive studies on its involvement in PSC. In this review, we clarify the present clinical and mechanistic data and concepts concerning the gut bacterial and fungal microbiota in the context of PSC. This review sheds light on the role of specific microbes and elucidates the dynamics of bacterial and fungal populations. Moreover, we discuss the latest insights into microbe-altering therapeutic approaches involving the gut-liver axis and bile acid metabolism.
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Affiliation(s)
- Burcin Özdirik
- Department of Medicine, University of California San Diego, La Jolla, California
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California; Department of Medicine, VA San Diego Healthcare System, San Diego, California.
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Shah YR, Nombera-Aznaran N, Guevara-Lazo D, Calderon-Martinez E, Tiwari A, Kanumilli S, Shah P, Pinnam BSM, Ali H, Dahiya DS. Liver transplant in primary sclerosing cholangitis: Current trends and future directions. World J Hepatol 2023; 15:939-953. [PMID: 37701917 PMCID: PMC10494561 DOI: 10.4254/wjh.v15.i8.939] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/23/2023] [Accepted: 08/11/2023] [Indexed: 08/22/2023] Open
Abstract
Primary sclerosing cholangitis (PSC) is a chronic and progressive immune-mediated cholangiopathy causing biliary tree inflammation and scarring, leading to liver cirrhosis and end-stage liver disease. Diagnosis of PSC is challenging due to its nonspecific symptoms and overlap with other liver diseases. Despite the rising incidence of PSC, there is no proven medical therapy that can alter the natural history of the disease. While liver transplantation (LT) is the most effective approach for managing advanced liver disease caused by PSC, post-transplantation recurrence of PSC remains a challenge. Therefore, ongoing research aims to develop better therapies for PSC, and continued efforts are necessary to improve outcomes for patients with PSC. This article provides an overview of PSC's pathogenesis, clinical presentation, and management options, including LT trends and future aspects. It also highlights the need for improved therapeutic options and ethical considerations in providing equitable access to LT for patients with PSC. Additionally, the impact of liver transplant on the quality of life and psychological outcomes of patients with PSC is discussed. Ongoing research into PSC's pathogenesis and post-transplant recurrence is crucial for improved understanding of the disease and more effective treatment options.
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Affiliation(s)
- Yash R Shah
- Department of Internal Medicine, Trinity Health Oakland, Pontiac, MI 48341, United States
| | | | - David Guevara-Lazo
- Faculty of Medicine, Universidad Peruana Cayetano Heredia, Lima 15102, Peru
| | - Ernesto Calderon-Martinez
- Department of Internal Medicine, Universidad Nacional Autonoma de Mexico, Ciudad De Mexico 04510, Mexico
| | - Angad Tiwari
- Department of Internal Medicine, Maharani Laxmi Bai Medical College, Jhansi 284001, India
| | | | - Purva Shah
- Department of Postgraduate Education, Harvard Medical School, Boston, MA 02115, United States
| | - Bhanu Siva Mohan Pinnam
- Department of Internal Medicine, John H. Stroger Hospital of Cook County, Chicago, IL 60612, United States
| | - Hassam Ali
- Department of Internal Medicine, East Carolina University/Brody School of Medicine, Greenville, NC 27858, United States
| | - Dushyant Singh Dahiya
- Division of Gastroenterology, Hepatology and Motility, The University of Kansas School of Medicine, Kansas City, KS 66160, United States.
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Karemera M, Verce M, Roumain M, Muccioli GG, Cani PD, Everard A, Stephenne X, Sokal E. Pediatric Autoimmune or Primary Sclerosing Cholangitis: Metronidazole Effectiveness on Biochemical Data, Bile Acid Profile, and Gut Microbiota: A Pilot Study. JPGN REPORTS 2023; 4:e334. [PMID: 37600615 PMCID: PMC10435019 DOI: 10.1097/pg9.0000000000000334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/25/2023] [Indexed: 08/22/2023]
Abstract
Objectives Autoimmune hepatitis and primary sclerosing cholangitis (PSC) can both be present, resulting in autoimmune sclerosing cholangitis (ASC). PSC physiopathology could be based on the cross-talk between gut microbiota and bile acids (BAs); antibiotics are an innovative therapy. This pilot study assesses metronidazole (MTZ)'s effectiveness in ASC or PSC patients according to the stage of the disease, and its effects on biochemical parameters, BA profiles, and gut microbiota. Methods ASC or PSC patients from Cliniques universitaires Saint-Luc's pediatric hepato-gastroenterology division were enrolled retrospectively and prospectively; both datasets were merged. MTZ was administered over at least 14 days on top of standard treatment (ursodeoxycholic acid, azathioprine, and steroids). Fecal and blood samples were collected before (T0) and at MTZ day 14 (T14). Sustained biochemical remission was defined by the reduction of transaminases (AST and ALT), gamma-glutamyl transferase (GGT), and CRP until 12 months post-MTZ. Results A total of 18 patients (mean age, 13.2 ± 4.5 years) were enrolled (13 ASC and 5 PSC), and divided in remission or relapse patients. CRP, AST, ALT, and GGT levels decreased post-MTZ in both groups (excepting GGT in relapse patients), with decreases between T0 and T14 being significant for AST and ALT. Relapse patients were older (P = 0.0351) and in late-disease stage, with mainly large-duct PSC (P = 0.0466). In remission patients, the mean plasma relative abundance of hydrophilic BA increased by +6.3% (P = 0.0391) after MTZ. Neither at baseline nor T14, there were significant differences in gut microbiota recorded. Conclusion These data are likely indicative of long-term benefits following MTZ therapy at early-stage ASC or PSC, with increased hydrophilic BA abundance. Multicenter prospective studies are needed.
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Affiliation(s)
- Manon Karemera
- From the Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Marko Verce
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Martin Roumain
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Giulio G. Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Patrice D. Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Amandine Everard
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Walloon Excellence in Life Sciences and Biotechnology (WELBIO), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Xavier Stephenne
- From the Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Cliniques universitaires Saint-Luc, Brussels, Belgium
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research - PEDI
| | - Etienne Sokal
- From the Department of Pediatrics, Division of Pediatric Gastroenterology and Hepatology, Cliniques universitaires Saint-Luc, Brussels, Belgium
- UCLouvain, Université catholique de Louvain, Institute of Experimental and Clinical Research - PEDI
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7
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Méndez-Sánchez N, Coronel-Castillo CE, Ordoñez-Vázquez AL. Current Therapies for Cholestatic Diseases. Biomedicines 2023; 11:1713. [PMID: 37371808 PMCID: PMC10296345 DOI: 10.3390/biomedicines11061713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/03/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Cholestasis is a condition characterized by decrease in bile flow due to progressive pathological states that lead to chronic cholestatic liver diseases which affect the biliary tree at the intrahepatic level and extrahepatic level. They induce complications such as cirrhosis, liver failure, malignancies, bone disease and nutritional deficiencies that merit close follow-up and specific interventions. Furthermore, as those conditions progress to liver cirrhosis, there will be an increase in mortality but also an important impact in quality of life and economic burden due to comorbidities related with liver failure. Therefore, it is important that clinicians understand the treatment options for cholestatic liver diseases. With a general view of therapeutic options and their molecular targets, this review addresses the pathophysiology of cholangiopathies. The objective is to provide clinicians with an overview of the safety and efficacy of the treatment of cholangiopathies based on the current evidence.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Unit Liver Research, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Mexico City 14050, Mexico;
- Faculty of Medicine, National Autonomous University of Mexico, Av. Universidad 3004, Copilco Universidad, Coyoacán, Mexico City 04510, Mexico
| | - Carlos E. Coronel-Castillo
- Internal Medicine Section, Central Military Hospital, Manuel Ávila Camacho s/n, Militar, Miguel Hidalgo, Ciudad de México 11200, Mexico;
| | - Ana L. Ordoñez-Vázquez
- Unit Liver Research, Medica Sur Clinic & Foundation, Puente de Piedra 150, Toriello Guerra, Tlalpan, Mexico City 14050, Mexico;
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8
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Single Center Experience of Oral Vancomycin Therapy in Young Patients with Primary Sclerosing Cholangitis: A Case Series. LIVERS 2023. [DOI: 10.3390/livers3010009] [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: 03/08/2023] Open
Abstract
There is no single proven therapy that prolongs hepatic transplant-free survival in patients with primary sclerosing cholangitis (PSC). Oral vancomycin (OV) has shown some benefit in small pediatric and adult series. We describe the effect of OV on pediatric onset PSC at our tertiary hospital. This is a single-center, retrospective, descriptive case series involving patients (<21 years at diagnosis) with PSC on OV from 2001 till 2021. The therapy effect was assessed based on symptoms, biochemical labs, imaging and liver biopsy at six and twelve months, and then annually until therapy was discontinued. The inclusion criteria identified 17 patients. Baseline GGT (n = 17) was elevated among 88.2% which then normalized among 53.8% (n = 13) at six months and 55.6% (n = 9) at one year post-OV. Baseline ALT normalized in 58.8% (n = 17) at six months and 42.8% (n = 14) at one year. Imaging findings within one year of OV revealed improved/stable biliary findings among 66.7% (n = 8/12). No adverse events were reported. OV was associated with an improvement in bile duct injury marker (GGT) after at least six months of therapy, with no disease progression on imaging within one year of therapy.
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 125] [Impact Index Per Article: 62.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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10
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Fuchs Y, Valentino PL. Natural history and prognosis of pediatric PSC with updates on management. Clin Liver Dis (Hoboken) 2023; 21:47-51. [PMID: 36950306 PMCID: PMC10022853 DOI: 10.1097/cld.0000000000000006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 11/13/2022] [Indexed: 03/24/2023] Open
Affiliation(s)
- Yonathan Fuchs
- Section of Gastroenterology and Hepatology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Pamela L. Valentino
- Section of Gastroenterology and Hepatology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA
- Section of Gastroenterology and Hepatology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, Washington, USA
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11
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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12
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Stevens JP, Gupta NA. Recent Insights into Pediatric Primary Sclerosing Cholangitis. Clin Liver Dis 2022; 26:489-519. [PMID: 35868687 DOI: 10.1016/j.cld.2022.03.009] [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] [Indexed: 01/31/2023]
Abstract
This article reviews recent literature on the pathogenesis, presentation, diagnosis, comorbidities, natural history, and management of pediatric primary sclerosing cholangitis (PSC). The authors shed light on the role of genetic and environmental factors in PSC, although recognize the limitations in the understanding of PSC pathogenesis. They reflect on presenting disease phenotypes, including the association with inflammatory bowel disease and frequent histologic presence of autoimmune hepatitis features. The current lack of effective medications is discussed, and disease complications and prognosis are described. Finally, the authors highlight available evidence while acknowledging the paucity of prospective pediatric data.
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Affiliation(s)
- James P Stevens
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 1760 Haygood Drive, Atlanta GA 30322, USA
| | - Nitika A Gupta
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 1760 Haygood Drive, Atlanta GA 30322, USA.
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Farooqui N, Elhence A, Shalimar. A Current Understanding of Bile Acids in Chronic Liver Disease. J Clin Exp Hepatol 2022; 12:155-173. [PMID: 35068796 PMCID: PMC8766695 DOI: 10.1016/j.jceh.2021.08.017] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 08/16/2021] [Indexed: 01/03/2023] Open
Abstract
Chronic liver disease (CLD) is one of the leading causes of disability-adjusted life years in many countries. A recent understanding of nuclear bile acid receptor pathways has increased focus on the impact of crosstalk between the gut, bile acids, and liver on liver pathology. While conventionally used in cholestatic disorders and to dissolve gallstones, the discovery of bile acids' influence on the gut microbiome and human metabolism offers a unique potential for their utility in early and advanced liver diseases because of diverse etiologies. Based on these findings, preclinical studies using bile acid-based molecules have shown encouraging results at addressing liver inflammation and fibrosis. Emerging data also suggest that bile acid profiles change distinctively across various causes of liver disease. We summarize the current knowledge and evidence related to bile acids in health and disease and discuss culminated and ongoing therapeutic trials of bile acid derivatives in CLD. In the near future, further evidence in this area might help clinicians better detect and manage liver diseases.
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Key Words
- AD, Acute decompensation
- ALP, Alkaline phosphatase
- AMACR, α-methylacyl-CoA racemase (AMACR)
- ASBT, Apical sodium dependent bile salt transporter
- BA, Bile acid
- BSEP, Bile salt export pump
- BSH, Bile salt hydrolase
- CA, Cholic acid
- CDCA, Chenodeoxycholic acid
- CLD
- CLD, Chronic Liver Disease
- CTP, Child-Turcotte-Pugh
- CYP7A1, Cholesterol 7 α hydroxylase
- DCA, Deoxycholic acid
- DR5, Death receptor 5
- ELF, Enhanced Liver Fibrosis
- FGF-19, Fibroblast growth factor-19
- FGFR4, FGF receptor 4
- FXR, Farnesoid X receptor
- GCA, Glycocholic acid
- GDCA, Glycodeoxycholic acid
- GLP-1, Glucagon-like peptide1
- HBV, Hepatitis B virus
- HCV, Hepatitis C virus
- HVPG, Hepatic Venous Pressure Gradient
- LCA, Lithocholic acid
- LPS, Lipopolysaccharide
- MELD, Model for End-Stage Liver Disease (MELD)
- MRI-PDFF, Magnetic resonance imaging derived proton density fat fraction
- NAFLD
- NAFLD, Non-alcoholic fatty liver disease
- NAS, NAFLD activity score
- NASH, Nonalcoholic steatohepatitis
- NTCP, Sodium taurocholate cotransporting polypeptide
- OCA, Obeticholic acid
- OST, Organic solute transporter
- PBC, Primary biliary cirrhosis
- PFIC, Progressive familial intrahepatic cholestasis
- PSC, Primary sclerosing cholangitis
- PXR, Pregnane X receptor
- SHP, Small heterodimer partner
- TBA, Total bile acids
- TGR5, Takeda G-protein coupled receptor 5
- TRAIL, TNF-related apoptosis-inducing ligand
- UDCA, Ursodeoxycholic acid
- UPLC-MS, Ultra-performance liquid chromatography with tandem mass spectrometry
- VDR, Vitamin D receptor
- bile acids
- cirrhosis
- microbiome
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Affiliation(s)
- Naba Farooqui
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Anshuman Elhence
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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Wang D, Yu H, Li Y, Xu Z, Shi S, Dou D, Sun L, Zheng Z, Shi X, Deng X, Zhong X. iTRAQ-based quantitative proteomics analysis of the hepatoprotective effect of melatonin on ANIT-induced cholestasis in rats. Exp Ther Med 2021; 22:1014. [PMID: 34373700 PMCID: PMC8343461 DOI: 10.3892/etm.2021.10446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 04/28/2021] [Indexed: 11/15/2022] Open
Abstract
The therapeutic effects of melatonin on cholestatic liver injury have received widespread attention recently. The aim of the present study was to investigate the mechanisms of the anti-cholestatic effects of melatonin against α-naphthyl isothiocyanate (ANIT)-induced liver injury in rats and to screen for potential biomarkers of cholestasis through isobaric tags for relative and absolute quantitation (iTRAQ) proteomics. Rats orally received melatonin (100 mg/kg body weight) or an equivalent volume of 0.25% carboxymethyl cellulose sodium salt 12 h after intraperitoneal injection of ANIT (75 mg/kg) and were subsequently sacrificed at 36 h after injection. Liver biochemical indices were determined and liver tissue samples were stained using hematoxylin-eosin staining, followed by iTRAQ quantitative proteomics to identify potential underlying therapeutic mechanisms and biomarkers. The results suggested that the expression levels of alanine transaminase, aspartate aminotransferase, total bilirubin and direct bilirubin were reduced in the rats treated with melatonin. Histopathological observation indicated that melatonin was effective in the treatment of ANIT-induced cholestasis. iTRAQ proteomics results suggested that melatonin-mediated reduction in ANIT-induced cholestasis may be associated with enhanced antioxidant function and relieving abnormal fatty acid metabolism. According to pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes, the major metabolic pathways for the metabolism of melatonin are fatty acid degradation, the peroxisome proliferator-activated receptor signaling pathway, fatty acid metabolism, chemical carcinogenesis, carbon metabolism, pyruvate metabolism, fatty acid biosynthesis and retinol metabolism, as well as drug metabolism via cytochrome P450. Malate dehydrogenase 1 and glutathione S-transferase Yb-3 may serve as potential targets in the treatment of ANIT-induced cholestasis with melatonin.
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Affiliation(s)
- Dingnan Wang
- Synopsis of Golden Chamber Department, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Han Yu
- Synopsis of Golden Chamber Department, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China.,Formulas of Chinese Medicine, Basic Medical College of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China
| | - Yunzhou Li
- Synopsis of Golden Chamber Department, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Zongying Xu
- Synopsis of Golden Chamber Department, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Shaohua Shi
- Synopsis of Golden Chamber Department, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Dou Dou
- Synopsis of Golden Chamber Department, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Lili Sun
- Synopsis of Golden Chamber Department, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Zhili Zheng
- Department of Pharmacology, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xinghua Shi
- Department of Pharmacology, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xiulan Deng
- Department of Pharmacology, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
| | - Xianggen Zhong
- Synopsis of Golden Chamber Department, Chinese Medicine College, Beijing University of Chinese Medicine, Beijing 100029, P.R. China
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McCain JD, Chascsa DM, Lindor KD. Assessing and managing symptom burden and quality of life in primary sclerosing cholangitis patients. Expert Opin Orphan Drugs 2021. [DOI: 10.1080/21678707.2021.1898370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Josiah D. McCain
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
| | - David M. Chascsa
- Department of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona, USA
- Department of Transplant Center, Mayo Clinic, Phoenix, Arizona, USA
| | - Keith D. Lindor
- Office of University Provost, Arizona State University, Arizona, USA
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Deneau MR, Mack C, Mogul D, Perito ER, Valentino PL, Amir AZ, DiGuglielmo M, Draijer LG, El-Matary W, Furuya KN, Gupta N, Hochberg JT, Horslen S, Jensen MK, Jonas MM, Kerkar N, Koot BG, Laborda TJ, Lee CK, Loomes KM, Martinez M, Miethke A, Miloh T, Mohammad S, Ovchinsky N, Rao G, Ricciuto A, Sathya P, Schwarz KB, Shah U, Singh R, Vitola B, Zizzo A, Guthery SL. Oral Vancomycin, Ursodeoxycholic Acid, or No Therapy for Pediatric Primary Sclerosing Cholangitis: A Matched Analysis. Hepatology 2021; 73:1061-1073. [PMID: 32946600 PMCID: PMC8557636 DOI: 10.1002/hep.31560] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/21/2020] [Accepted: 08/27/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Many children with primary sclerosing cholangitis (PSC) receive oral vancomycin therapy (OVT) or ursodeoxycholic acid (UDCA). There is a paucity of data on whether these medications improve outcomes. APPROACH AND RESULTS We analyzed retrospective data from the Pediatric PSC Consortium. Children treated with OVT were matched 1:1:1 to those treated with UDCA or managed with observation (no treatment) based on the closest propensity score, ensuring similar baseline characteristics. Two hundred sixty-four patients (88 each with OVT, UDCA, or observation) had matching propensity scores and were similar in demographics, phenotype, immunosuppression, baseline biochemistry, and hepatic fibrosis. After 1 year in an intention-to-treat analysis, all outcome metrics were similar regardless of treatment group. In OVT, UDCA, and untreated groups, respectively: Gamma-glutamyltransferase normalized in 53%, 49%, and 52% (P = not significant [NS]), liver fibrosis stage was improved in 20%, 13%, and 18% and worsened in 11%, 29%, and 18% (P = NS), and the 5-year probability of liver transplant listing was 21%, 10%, and 12% (P = NS). Favorable outcome was associated with having a mild phenotype of PSC and minimal hepatic fibrosis. CONCLUSIONS We presented the largest-ever description of outcomes on OVT in PSC and compared them to carefully matched patients on UDCA or no therapy. Neither OVT nor UDCA showed improvement in outcomes compared to a strategy of observation. Patients progressed to end-stage liver disease at similar rates. Spontaneous normalization of biochemistry is common in children receiving no therapy, particularly in the majority of children with a mild phenotype and an early stage of disease. Placebo-controlled treatment trials are needed to identify effective treatments for pediatric PSC.
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Affiliation(s)
- Mark R. Deneau
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
| | - Cara Mack
- University of Colorado School of Medicine, Aurora, CO
| | | | | | | | - Achiya Z. Amir
- The Dana-Dwek Children’s Hospital, The Tel-Aviv Medical Center, Tel-Aviv University, Tel Aviv, Israel
| | | | | | | | - Katryn N. Furuya
- Mayo Clinic, Rochester, MN
- University of Wisconsin–Madison School of Medicine and Public Health, Madison, WI
| | - Nitika Gupta
- Emory University School of Medicine, Atlanta, GA
| | | | | | - M. Kyle Jensen
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
| | - Maureen M. Jonas
- Boston Children’s Hospital and Harvard Medical School, Boston, MA
| | - Nanda Kerkar
- University of Rochester Medical Center, Rochester, NY
| | - Bart G.P. Koot
- Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Trevor J. Laborda
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
| | - Christine K. Lee
- Boston Children’s Hospital and Harvard Medical School, Boston, MA
| | | | | | | | | | | | - Nadia Ovchinsky
- Children’s Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY
| | | | | | - Pushpa Sathya
- Memorial University, St. John’s, Newfoundland and Labrador, Canada
| | - Kathleen B. Schwarz
- Johns Hopkins University, Baltimore, MD
- University of California San Diego, San Diego, CA
| | - Uzma Shah
- Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Ruchi Singh
- Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
| | | | - Andréanne Zizzo
- London Health Sciences Center, Western University, London, Ontario, Canada
| | - Stephen L. Guthery
- University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, UT
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17
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Assis DN, Levy C. Oral Vancomycin or Ursodeoxycholic Acid for Pediatric Primary Sclerosing Cholangitis? The Uncontroversial Need for Randomized Controlled Trials. Hepatology 2021; 73:887-889. [PMID: 33403699 DOI: 10.1002/hep.31702] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/23/2020] [Accepted: 12/23/2020] [Indexed: 12/14/2022]
Affiliation(s)
- David N Assis
- Department of Medicine, Section of Digestive DiseasesYale School of MedicineNew HavenCT
| | - Cynthia Levy
- Division of Digestive Health and Liver DiseasesUniversity of MiamiMiamiFL
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Kriegermeier A, Green R. Pediatric Cholestatic Liver Disease: Review of Bile Acid Metabolism and Discussion of Current and Emerging Therapies. Front Med (Lausanne) 2020; 7:149. [PMID: 32432119 PMCID: PMC7214672 DOI: 10.3389/fmed.2020.00149] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 04/06/2020] [Indexed: 02/06/2023] Open
Abstract
Cholestatic liver diseases are a significant cause of morbidity and mortality and the leading indication for pediatric liver transplant. These include diseases such as biliary atresia, Alagille syndrome, progressive intrahepatic cholestasis entities, ductal plate abnormalities including Caroli syndrome and congenital hepatic fibrosis, primary sclerosing cholangitis, bile acid synthesis defects, and certain metabolic disease. Medical management of these patients typically includes supportive care for complications of chronic cholestasis including malnutrition, pruritus, and portal hypertension. However, there are limited effective interventions to prevent progressive liver damage in these diseases, leaving clinicians to ultimately rely on liver transplantation in many cases. Agents such as ursodeoxycholic acid, bile acid sequestrants, and rifampicin have been mainstays of treatment for years with the understanding that they may decrease or alter the composition of the bile acid pool, though clinical response to these medications is frequently insufficient and their effects on disease progression remain limited. Recently, animal and human studies have identified potential new therapeutic targets which may disrupt the enterohepatic circulation of bile acids, alter the expression of bile acid transporters or decrease the production of bile acids. In this article, we will review bile formation, bile acid signaling, and the relevance for current and newer therapies for pediatric cholestasis. We will also highlight further areas of potential targets for medical intervention for pediatric cholestatic liver diseases.
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Affiliation(s)
- Alyssa Kriegermeier
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, United States
| | - Richard Green
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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