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Pose E, Jiménez C, Zaccherini G, Campion D, Piano S, Uschner FE, de Wit K, Roux O, Gananandan K, Laleman W, Solé C, Alonso S, Cuyàs B, Ariza X, Juanola A, Ma AT, Napoleone L, Gratacós-Ginès J, Tonon M, Pompili E, Sánchez-Delgado J, Allegretti AS, Morales-Ruiz M, Carol M, Pérez-Guasch M, Fabrellas N, Pich J, Martell C, Joyera M, Domenech G, Ríos J, Torres F, Serra-Burriel M, Hernáez R, Solà E, Graupera I, Watson H, Soriano G, Bañares R, Mookerjee RP, Francoz C, Beuers U, Trebicka J, Angeli P, Alessandria C, Caraceni P, Vargas VM, Abraldes JG, Kamath PS, Ginès P. Simvastatin and Rifaximin in Decompensated Cirrhosis: A Randomized Clinical Trial. JAMA 2025; 333:864-874. [PMID: 39908052 PMCID: PMC11800124 DOI: 10.1001/jama.2024.27441] [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] [Received: 04/25/2024] [Accepted: 12/10/2024] [Indexed: 02/06/2025]
Abstract
Importance There are no useful treatments to prevent the development of severe complications of liver cirrhosis. Simvastatin and rifaximin have shown beneficial effects in liver cirrhosis. Objective To assess whether simvastatin combined with rifaximin improves outcomes in patients with decompensated cirrhosis. Design, Setting, and Participants Double-blind, placebo-controlled, phase 3 trial conducted among patients with decompensated cirrhosis in 14 European hospitals between January 2019 and December 2022. The last date of follow-up was December 2022. Interventions Patients were randomly assigned to receive simvastatin, 20 mg/d, plus rifaximin, 1200 mg/d (n = 117), or identical-appearing placebo (n = 120) for 12 months in addition to standard therapy, stratified according to Child-Pugh class B or C. Main Outcomes and Measures The primary end point was incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for acute-on-chronic liver failure. Secondary outcomes included transplant or death and a composite end point of complications of cirrhosis (ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection). Results Among the 237 participants randomized (Child-Pugh class B: n = 194; Child-Pugh class C: n = 43), 72% were male and the mean age was 57 years. There were no differences between the 2 groups in terms of development of acute-on-chronic liver failure (21 [17.9%] vs 17 [14.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 1.23; 95% CI, 0.65-2.34; P = .52); transplant or death (22 [18.8%] vs 29 [24.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.75; 95% CI, 0.43-1.32; P = .32); or development of complications of cirrhosis (50 [42.7%] vs 55 [45.8%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.93; 95% CI, 0.63-1.36; P = .70). Incidence of adverse events was similar in both groups (426 vs 419; P = .59), but 3 patients in the treatment group (2.6%) developed rhabdomyolysis. Conclusions and Relevance The addition of simvastatin plus rifaximin to standard therapy does not improve outcomes in patients with decompensated liver cirrhosis. Trial Registration ClinicalTrials.gov Identifier: NCT03780673.
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Affiliation(s)
- Elisa Pose
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
| | - César Jiménez
- Liver Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain
- Vall d’Hebron Institut de Recerca, Liver Unit, Universitat Autonoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Giacomo Zaccherini
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna, Italy
| | - Daniela Campion
- Division of Gastroenterology and Hepatology, A. O. U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine–DIMED, University and Hospital of Padova, Padova, Italy
| | - Frank Erhard Uschner
- Department of Internal Medicine I, University Hospital Frankfurt, Frankfurt am Main, Germany
- Department of Internal Medicine B, University Hospital Münster, Münster, Germany
| | - Koos de Wit
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Olivier Roux
- Service d’Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, Clichy, France
- Centre de Recherche sur l’Inflammation, Inserm, UMR, Paris, France
| | - Kohilan Gananandan
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Wim Laleman
- Department of Internal Medicine B, University Hospital Münster, Münster, Germany
- Department of Gastroenterology and Hepatology, Cluster of Liver and Biliopancreatic Disorders and Liver Transplantation, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Cristina Solé
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Department of Gastroenterology and Hepatology, Parc Tauli Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Sonia Alonso
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Digestive Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Berta Cuyàs
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Xavier Ariza
- Digestive Diseases Unit, Hospital Moisès Broggi, Sant Joan Despí, Barcelona, Spain
| | - Adrià Juanola
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
| | - Ann T. Ma
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Laura Napoleone
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
| | - Jordi Gratacós-Ginès
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine–DIMED, University and Hospital of Padova, Padova, Italy
| | - Enrico Pompili
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Jordi Sánchez-Delgado
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Department of Gastroenterology and Hepatology, Parc Tauli Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
| | - Andrew S. Allegretti
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Manuel Morales-Ruiz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Barcelona, Spain
- Biomedicine Department, University of Barcelona, Barcelona, Spain
| | - Marta Carol
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Faculty of Nursing, University of Barcelona, Barcelona, Spain
| | - Martina Pérez-Guasch
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
| | - Núria Fabrellas
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Faculty of Nursing, University of Barcelona, Barcelona, Spain
| | - Judit Pich
- Clinical Trial Unit, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Claudia Martell
- Clinical Trial Unit, Hospital Clínic of Barcelona, Barcelona, Spain
| | - María Joyera
- Clinical Trial Unit, Hospital Clínic of Barcelona, Barcelona, Spain
| | - Gemma Domenech
- Biostatistics and Data Management Core Facility, Institut D’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Hospital Clínic of Barcelona, Barcelona, Spain
| | - José Ríos
- Biostatistics and Data Management Core Facility, Institut D’Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Hospital Clínic of Barcelona, Barcelona, Spain
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ferrán Torres
- Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Miquel Serra-Burriel
- Epidemiology, Biostatistics, and Prevention Institute, University of Zurich, Zurich, Switzerland
| | - Rubén Hernáez
- Section of Gastroenterology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
- VA Health Services Research and Development, Center for Innovations in Quality, Effectiveness, and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Elsa Solà
- Institute for Immunity, Transplantation, and Infection, Stanford University, Stanford, California
| | - Isabel Graupera
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Hugh Watson
- Medical Development and Translational Science, Evotec, Lyon, France
- Department of Hepatology and Gastroenterology, Aarhus University, Aarhus, Denmark
| | - Germán Soriano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rafael Bañares
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Digestive Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain
- Instituto de Investigación Sanitaria Gregorio Marañón (IISGM), Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Rajeshwar P. Mookerjee
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
- Department of Hepatology and Gastroenterology, Aarhus University, Aarhus, Denmark
| | - Claire Francoz
- Service d’Hépatologie, AP-HP, Hôpital Beaujon, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, Clichy, France
- Centre de Recherche sur l’Inflammation, Inserm, UMR, Paris, France
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Jonel Trebicka
- Department of Internal Medicine B, University Hospital Münster, Münster, Germany
| | - Paolo Angeli
- Unit of Internal Medicine and Hepatology, Department of Medicine–DIMED, University and Hospital of Padova, Padova, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, A. O. U. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Unit of Semeiotics, Liver and Alcohol-Related Diseases, IRCCS Azienda Ospedaliero–Universitaria di Bologna, Bologna, Italy
| | - Víctor M. Vargas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- Liver Unit, Hospital Universitari Vall d’Hebron, Barcelona, Spain
| | - Juan G. Abraldes
- Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Canada
| | - Patrick S. Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Pere Ginès
- Liver Unit, Hospital Clínic de Barcelona, Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Madrid, Spain
- School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
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Morrison MA, Artru F, Trovato FM, Triantafyllou E, McPhail MJ. Potential therapies for acute-on-chronic liver failure. Liver Int 2025; 45:e15545. [PMID: 36800487 PMCID: PMC11815631 DOI: 10.1111/liv.15545] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 02/19/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.
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Affiliation(s)
- Maura A. Morrison
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Florent Artru
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Francesca M. Trovato
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
| | - Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and ReproductionImperial College LondonLondonUK
| | - Mark J. McPhail
- Institute of Liver StudiesKing's College HospitalLondonUK
- Department of Inflammation Biology, School of Immunology and Microbial SciencesKing's College LondonLondonUK
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Porada M, Bułdak Ł. From Pathophysiology to Practice: Evolving Pharmacological Therapies, Clinical Complications, and Pharmacogenetic Considerations in Portal Hypertension. Metabolites 2025; 15:72. [PMID: 39997697 PMCID: PMC11857179 DOI: 10.3390/metabo15020072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 01/07/2025] [Accepted: 01/18/2025] [Indexed: 02/26/2025] Open
Abstract
Background: Portal hypertension is a major complication of chronic liver diseases, leading to serious issues such as esophageal variceal bleeding. The increase in portal vein pressure is driven by both an organic component and a functional component, including tonic contraction of hepatic stellate cells. These processes result in a pathological rise in intrahepatic vascular resistance, stemming from partial impairment of hepatic microcirculation, which is further exacerbated by abnormalities in extrahepatic vessels, including increased portal blood flow. Objectives: This review aims to provide a comprehensive overview of the evolving pharmacological therapies for portal hypertension, with consideration and discussion of pathophysiological mechanisms, clinical complications, and pharmacogenetic considerations, highlighting potential directions for future research. Methods: A review of recent literature was performed to evaluate current knowledge and potential therapeutic strategies in portal hypertension. Results: For over 35 years, non-selective beta-blockers have been the cornerstone therapy for portal hypertension by reducing portal vein inflow as an extrahepatic target, effectively preventing decompensation and variceal hemorrhages. However, since not all patients exhibit an adequate response to non-selective beta-blockers (NSBBs), and some may not tolerate NSBBs, alternative or adjunctive therapies that enhance the effects of NSBBs on portal pressure are being investigated in preclinical and early clinical studies. Conclusions: A better understanding of pharmacogenetic factors and pathophysiological mechanisms could lead to more individualized and effective treatments for portal hypertension. These insights highlight potential directions for future research.
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Affiliation(s)
- Michał Porada
- Students’ Scientific Society, Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland;
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
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Song DS, Yang JM, Jung YK, Yim HJ, Kim HY, Kim CW, Kim SS, Cheong JY, Lee HL, Lee SW, Yoo JJ, Kim SG, Kim YS. Rifaximin treatment in patients with severe alcoholic hepatitis: A multicenter, randomized controlled, open-label, pilot trial. Ann Hepatol 2024; 30:101749. [PMID: 39662593 DOI: 10.1016/j.aohep.2024.101749] [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: 06/18/2024] [Revised: 08/10/2024] [Accepted: 09/30/2024] [Indexed: 12/13/2024]
Abstract
INTRODUCTION AND OBJECTIVES The short-term mortality of severe alcoholic-associated hepatitis (SAH) is high, but there are no effective treatments to improve short-term mortality other than corticosteroids. This study investigated the effects of adding rifaximin to standard treatment in patients with SAH. MATERIAL AND METHODS In this randomized controlled open-label trial, patients with SAH (Maddrey's discriminant function≥32) were randomized to the rifaximin or control group. Patients were simultaneously treated with corticosteroid or pentoxifylline as standard treatment for 4 weeks. Randomization was stratified by SAH treatment. RESULTS A total of 50 patients were enrolled in this study (29 in the control group and 21 in the rifaximin group). The mean Model for End-stage Liver Disease (MELD) scores were 24.4 and 27.5 in the control and rifaximin groups, respectively (P = 0.106). There were no significant differences in 6-month Liver Transplantation (LT)-free survival rate between the two groups (P = 0.502). When stratified by SAH treatment, there was no significant difference in 6-month LT-free survival rate between the control and rifaximin treatment groups (P = 0.186 in the corticosteroid group and P = 0.548 in the pentoxifylline group). There were no significant differences in the occurrence of liver-related complications between the two groups (all Ps>0.05). The MELD score was the only independent factor for 6-month LT-free survival (hazard ratio 1.188, 95 % confidence interval 1.094-1.289, P<0.001), and rifaximin was not. CONCLUSIONS In patients with SAH, adding rifaximin to corticosteroid or pentoxifylline had no survival benefit and no preventive effect on the development of liver-related complications. The MELD score was the only significant factor for short-term mortality. CLINICAL TRIAL REGISTRATION The study was registered on ClinicalTrials.gov (number: NCT02485106).
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Affiliation(s)
- Do Seon Song
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Jin Mo Yang
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea.
| | - Hyung Joon Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea
| | - Hee Yeon Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Chang Wook Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Soon Sun Kim
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Jae Youn Cheong
- Department of Internal Medicine, Ajou University School of Medicine, Suwon, South Korea
| | - Hae Lim Lee
- Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Sung Won Lee
- Department of Internal Medicine, Bucheon St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
| | - Young Seok Kim
- Department of Internal Medicine, Bucheon Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, Bucheon, South Korea
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Yang W, Guo G, Sun C. Therapeutic potential of rifaximin in liver diseases. Biomed Pharmacother 2024; 178:117283. [PMID: 39126775 DOI: 10.1016/j.biopha.2024.117283] [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: 06/14/2024] [Revised: 08/05/2024] [Accepted: 08/08/2024] [Indexed: 08/12/2024] Open
Abstract
Rifaximin, derived from rifamycin, is a broad-spectrum antibiotic by inhibiting bacterial RNA synthesis. Rifaximin has a very low intestinal absorption and exerts its antimicrobial activity primarily in the intestinal tract. It regulates the gut microbiota with limited side effects systemically. Rifaximin has been recommended for the treatment of hepatic encephalopathy but some studies shed light on its medicinal effects in many other diseases. For instance, rifaximin may suppress the progression of liver fibrosis and its related complications, and ameliorate metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease, etc. Rifaximin can also mediate anti-inflammation, antiproliferation, and proapoptotic events by activating pregnane X receptor, which is efficious in cancers such as colon cancer. In addition, some investigations have shown rifaximin may play a therapeutic role in various autoimmune and neurological disorders. However, these findings still need more real-world practices and in-depth investigations to obtain more precise indications and fully elucidate the multifaceted potentials of rifaximin.
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Affiliation(s)
- Wanting Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Gaoyue Guo
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Anshan Road 154, Heping District, Tianjin 300052, China; Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, East Street 6, Tianjin Airport Economic Area, Tianjin 300308, China.
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Li M, Wang L, Lin D, Liu Z, Wang H, Yang Y, Sun C, Ye J, Liu Y. Advanced Bioinspired Multifunctional Platforms Focusing on Gut Microbiota Regulation. ACS NANO 2024; 18:20886-20933. [PMID: 39080827 DOI: 10.1021/acsnano.4c05013] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2025]
Abstract
Gut microbiota plays a crucial role in maintaining host homeostasis, impacting the progression and therapeutic outcomes of diseases, including inflammatory bowel disease, cancer, hepatic conditions, obesity, cardiovascular pathologies, and neurologic disorders, via immune, neural, and metabolic mechanisms. Hence, the gut microbiota is a promising target for disease therapy. The safety and precision of traditional microbiota regulation methods remain a challenge, which limits their widespread clinical application. This limitation has catalyzed a shift toward the development of multifunctional delivery systems that are predicated on microbiota modulation. Guided by bioinspired strategies, an extensive variety of naturally occurring materials and mechanisms have been emulated and harnessed for the construction of platforms aimed at the monitoring and modulation of gut microbiota. This review outlines the strategies and advantages of utilizing bioinspired principles in the design of gut microbiota intervention systems based on traditional regulation methods. Representative studies on the development of bioinspired therapeutic platforms are summarized, which are based on gut microbiota modulation to confer multiple pharmacological benefits for the synergistic management of diseases. The prospective avenues and inherent challenges associated with the adoption of bioinspired strategies in the refinement of gut microbiota modulation platforms are proposed to augment the efficacy of disease treatment.
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Affiliation(s)
- Muqing Li
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
| | - LuLu Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
| | - Demin Lin
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
| | - Zihan Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
| | - Hongliang Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
| | - Yanfang Yang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
| | - Chunmeng Sun
- Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, P.R. China
| | - Jun Ye
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
| | - Yuling Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, P.R. China
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7
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Harshal R. Severe Alcoholic Hepatitis-optimizing Medical Management: Whether we need a Liver Transplant. ANNALS OF CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2024; 8:006-016. [DOI: 10.29328/journal.acgh.1001045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Severe alcoholic hepatitis is an ethical and clinical conundrum, wherein a liver transplant is often recommended. The adequacy of medical treatment versus the risk of recidivism after transplant is often debated. Complete recovery in 26 of 27 patients with severe alcoholic hepatitis was observed, and hence the data was retrospectively analysed. Methods: 27 patients, with severe alcoholic hepatitis, with Maddrey's discriminant function between 59.7 to 165.2 (mean 107.53), from June 2017 to May 2022, were followed up for between 11 months to 6 years. INR ranged from 1.99 to 3.7 (mean 2.709), and bilirubin was between 7.6 to 37.01, (mean 20.859). 8 patients had pre-existing liver cirrhosis. All patients received probiotics, nutritional support, physical rehabilitation, saturated fat (clarified butter/ desi ghee) supplementation, and anti-oxidant support. At 90 days, total bilirubin improved to between 1.0 to 6.8 (mean 2.625). ALT (Alanine Transaminase/ SGPT) ranged from 65 to 550 (mean ALT – 197); and AST (Aspartate Transaminase / SGOT) ranged from 58 to 810 (mean AST – 271.51). Both the AST and ALT were near normal after 90 days. One patient died due to bacterial pneumonia and sepsis; the remaining 26 patients made a complete recovery. All patients including those with diagnosed liver cirrhosis, had complete resolution of their ascites, and near-normal liver function. At the last outpatient visit, none had ascites, edema, or encephalopathy, and had normal albumin levels and INR values. Conclusion: Probiotics, nutrition, a saturated fat diet, and exercise; all have shown benefits in patients with severe alcoholic hepatitis when tested individually. Concomitant use of all the above has not been reported in the treatment of alcoholic hepatitis. The role of nutrition alone versus the contribution of nutritional deficiencies and the role of gut-derived endotoxemia need to be studied in detail. How to identify patients who need a transplant, if it is needed at all, remains a challenge.
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8
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Nie G, Zhang H, Xie D, Yan J, Li X. Liver cirrhosis and complications from the perspective of dysbiosis. Front Med (Lausanne) 2024; 10:1320015. [PMID: 38293307 PMCID: PMC10824916 DOI: 10.3389/fmed.2023.1320015] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 12/26/2023] [Indexed: 02/01/2024] Open
Abstract
The gut-liver axis refers to the intimate relationship and rigorous interaction between the gut and the liver. The intestinal barrier's integrity is critical for maintaining liver homeostasis. The liver operates as a second firewall in this interaction, limiting the movement of potentially dangerous compounds from the gut and, as a result, contributing in barrier management. An increasing amount of evidence shows that increased intestinal permeability and subsequent bacterial translocation play a role in liver damage development. The major pathogenic causes in cirrhotic individuals include poor intestinal permeability, nutrition, and intestinal flora dysbiosis. Portal hypertension promotes intestinal permeability and bacterial translocation in advanced liver disease, increasing liver damage. Bacterial dysbiosis is closely related to the development of cirrhosis and its related complications. This article describes the potential mechanisms of dysbiosis in liver cirrhosis and related complications, such as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, and hepatocellular carcinoma, using dysbiosis of the intestinal flora as an entry point.
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Affiliation(s)
- Guole Nie
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Honglong Zhang
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Danna Xie
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Jun Yan
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
- Cancer Prevention and Control Center of Lanzhou University Medical School, Lanzhou, China
- Gansu Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou, China
- Gansu Clinical Medical Research Center of General Surgery, Lanzhou, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
- Cancer Prevention and Control Center of Lanzhou University Medical School, Lanzhou, China
- Gansu Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou, China
- Gansu Clinical Medical Research Center of General Surgery, Lanzhou, China
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9
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Gilbert MC, Setayesh T, Wan YJY. The contributions of bacteria metabolites to the development of hepatic encephalopathy. LIVER RESEARCH 2023; 7:296-303. [PMID: 38221945 PMCID: PMC10786625 DOI: 10.1016/j.livres.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Over 20% of mortality during acute liver failure is associated with the development of hepatic encephalopathy (HE). Thus, HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels. Thus, the brain is exposed to intestinal-derived toxic substances. Moreover, the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation. This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE. Together, the significance of the gut-liver-brain axis in human health warrants attention. This review paper focuses on the roles of bacteria metabolites, mainly ammonia and bile acids (BAs) as well as BA receptors in HE. The literature search conducted for this review included searches for phrases such as BA receptors, BAs, ammonia, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy. PubMed, as well as Google Scholar, was the search engines used to find relevant publications.
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Affiliation(s)
- Miranda Claire Gilbert
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
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10
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Ward JA, Yerke J, Lumpkin M, Kapoor A, Lindenmeyer CC, Bass S. Evaluation of a protocol for rifaximin discontinuation in critically ill patients with liver disease receiving broad-spectrum antibiotic therapy. World J Hepatol 2023; 15:1226-1236. [DOI: 10.4254/wjh.v15.i11.1226] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 09/05/2023] [Accepted: 10/23/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Rifaximin is frequently administered to critically ill patients with liver disease and hepatic encephalopathy, but patients currently or recently treated with antibiotics were frequently excluded from studies of rifaximin efficacy. Due to overlapping spectrums of activity, combination therapy with broad-spectrum antibiotics and rifaximin may be unnecessary. A pharmacist-driven protocol was piloted to reduce potentially overlapping therapy in critically ill patients with liver disease. It was hypothesized that withholding rifaximin during broad-spectrum antibiotic therapy would be safe and reduce healthcare costs.
AIM To determine the clinical, safety, and financial impact of discontinuing rifaximin during broad-spectrum antibiotic therapy in critically ill liver patients.
METHODS This was a single-center, quasi-experimental, pre-post study based on a pilot pharmacist-driven protocol. Patients in the protocol group were prospectively identified via the medical intensive care unit (ICU) (MICU) protocol to have rifaximin withheld during broad-spectrum antibiotic treatment. These were compared to a historical cohort who received combination therapy with broad-spectrum antibiotics and rifaximin. All data were collected retrospectively. The primary outcome was days alive and free of delirium and coma (DAFD) to 14 d. Safety outcomes included MICU length of stay, 48-h change in vasopressor dose, and ICU mortality. Secondary outcomes characterized rifaximin cost savings and protocol adherence. Multivariable analysis was utilized to evaluate the association between group assignment and the primary outcome while controlling for potential confounding factors.
RESULTS Each group included 32 patients. The median number of delirium- and coma-free days was similar in the control and protocol groups [3 interquartile range (IQR 0, 8) vs 2 (IQR 0, 9.5), P = 0.93]. In multivariable analysis, group assignment was not associated with a reduced ratio of days alive and free of delirium or coma at 14 d. The protocol resulted in a reduced median duration of rifaximin use during broad-spectrum antibiotic therapy [6 d control (IQR 3, 9.5) vs 1 d protocol (IQR 0, 1); P < 0.001]. Rates of other secondary clinical and safety outcomes were similar including ICU mortality and 48-h change in vasopressor requirements. Overall adherence to the protocol was 91.4%. The median estimated total cost of rifaximin therapy per patient was reduced from $758.40 (IQR $379.20, $1200.80) to $126.40 (IQR $0, $126.40), P < 0.01.
CONCLUSION The novel pharmacist-driven protocol for rifaximin discontinuation was associated with significant cost savings and no differences in safety outcomes including DAFD.
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Affiliation(s)
- Jessica A Ward
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Jason Yerke
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Mollie Lumpkin
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Aanchal Kapoor
- Department of Critical Care Medicine, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Christina C Lindenmeyer
- Department of Gastroenterology, Hepatology, and Nutrition, Cleveland Clinic, Cleveland, OH 44195, United States
| | - Stephanie Bass
- Department of Pharmacy, Cleveland Clinic, Cleveland, OH 44195, United States
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11
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Greinert R, Zipprich A, Casper M, Reichert MC, Lammert F, Ripoll C. Presence of NOD2 mutations is not associated with hepatic or systemic hemodynamic abnormalities of cirrhosis. Dig Liver Dis 2023; 55:1362-1367. [PMID: 37321912 DOI: 10.1016/j.dld.2023.05.016] [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: 02/27/2023] [Revised: 04/25/2023] [Accepted: 05/15/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Patients with cirrhosis who carry NOD2 mutations are susceptible to bacterial infections. The aim was to evaluate the association of NOD2 mutations with hepatic and systemic hemodynamics in cirrhosis. PATIENTS AND METHODS This is a secondary analysis of a prospectively collected database in the context of the screening for the INCA trial (EudraCT 2013-001626-26). This cross-sectional study compared hemodynamic findings according to NOD2 status in 215 patients. Patients were genotyped for NOD2 variants (p.N289S, p.R702W, p.G908R, c.3020insC, rs72796367). Hepatic hemodynamic study and right heart catheterization were performed. RESULTS Patients had a median age of 59 (IQR 53-66) years, and 144 (67%) were men. Most patients (64%) were Child-Pugh stage B. Sixty-six patients (31%) carried a NOD2 mutation, which was slightly more common among Child-Pugh stage C (p = 0.05), without differences in MELD [wild-type: 13 (10-16); NOD2 variants 13 (10-18)]. No differences in hepatic and systemic hemodynamics were observed according to NOD2 status. If excluding patients on prophylactic or therapeutic antibiotics, again no association between hepatic or systemic hemodynamics and NOD2 status could be observed. CONCLUSION NOD2 mutations are not associated with hepatic or systemic hemodynamic abnormalities in patients with decompensated cirrhosis, suggesting that other mechanisms leading to bacterial translocation predominate.
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Affiliation(s)
- Robin Greinert
- Department of Internal Medicine I, Martin-Luther University Halle Wittenberg, Halle, Germany
| | | | - Markus Casper
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | | | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany; Health Sciences, Hannover Medical School MHH, Hannover, Germany
| | - Cristina Ripoll
- Internal Medicine IV, Jena University Hospital, Jena, Germany.
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12
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Stojic J, Kukla M, Grgurevic I. The Intestinal Microbiota in the Development of Chronic Liver Disease: Current Status. Diagnostics (Basel) 2023; 13:2960. [PMID: 37761327 PMCID: PMC10528663 DOI: 10.3390/diagnostics13182960] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/06/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic liver disease (CLD) is a significant global health burden, leading to millions of deaths annually. The gut-liver axis plays a pivotal role in this context, allowing the transport of gut-derived products directly to the liver, as well as biological compounds from the liver to the intestine. The gut microbiota plays a significant role in maintaining the health of the digestive system. A change in gut microbiome composition as seen in dysbiosis is associated with immune dysregulation, altered energy and gut hormone regulation, and increased intestinal permeability, contributing to inflammatory mechanisms and damage to the liver, irrespective of the underlying etiology of CLD. The aim of this review is to present the current knowledge about the composition of the intestinal microbiome in healthy individuals and those with CLD, including the factors that affect this composition, the impact of the altered microbiome on the liver, and the mechanisms by which it occurs. Furthermore, this review analyzes the effects of gut microbiome modulation on the course of CLD, by using pharmacotherapy, nutrition, fecal microbiota transplantation, supplements, and probiotics. This review opens avenues for the translation of knowledge about gut-liver interplay into clinical practice as an additional tool to fight CLD and its complications.
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Affiliation(s)
- Josip Stojic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
| | - Michał Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagellonian University Medical College, 31-688 Kraków, Poland;
- Department of Endoscopy, University Hospital, 30-688 Kraków, Poland
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10000 Zagreb, Croatia;
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, 10000 Zagreb, Croatia
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13
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Adebayo D, Wong F. Pathophysiology of Hepatorenal Syndrome - Acute Kidney Injury. Clin Gastroenterol Hepatol 2023; 21:S1-S10. [PMID: 37625861 DOI: 10.1016/j.cgh.2023.04.034] [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: 02/05/2023] [Revised: 03/14/2023] [Accepted: 04/06/2023] [Indexed: 08/27/2023]
Abstract
Hepatorenal syndrome is a complication of liver cirrhosis with ascites that results from the complex interplay of many pathogenetic mechanisms. Advanced cirrhosis is characterized by the development of hemodynamic changes of splanchnic and systemic arterial vasodilatation, with paradoxical renal vasoconstriction and renal hypoperfusion. Cirrhosis is also an inflammatory state. The inflammatory cascade is initiated by a portal hypertension-induced increased translocation of bacteria, bacterial products, and endotoxins from the gut to the splanchnic and then to the systemic circulation. The inflammation, whether sterile or related to infection, is responsible for renal microcirculatory dysfunction, microthrombi formation, renal tubular oxidative stress, and tubular damage. Of course, many of the bacterial products also have vasodilatory properties, potentially exaggerating the state of vasodilatation and worsening the hemodynamic instability in these patients. The presence of cardiac dysfunction, related to cirrhotic cardiomyopathy, with its associated systolic incompetence, can aggravate the mismatch between the circulatory capacitance and the circulation volume, worsening the extent of the effective arterial underfilling, with lower renal perfusion pressure, contributing to renal hypoperfusion and increasing the risk for development of acute kidney injury. The presence of tense ascites can exert an intra-abdominal compartmental syndrome effect on the renal circulation, causing renal congestion and hampering glomerular filtration. Other contributing factors to renal dysfunction include the tubular damaging effects of cholestasis and adrenal dysfunction. Future developments include the use of metabolomics to identify metabolic pathways that can lead to the development of renal dysfunction, with the potential of identifying biomarkers for early diagnosis of renal dysfunction and the development of treatment strategies.
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Affiliation(s)
- Danielle Adebayo
- Department of Gastroenterology, Royal Berkshire National Health Service Foundation Trust, Reading, United Kingdom
| | - Florence Wong
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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14
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Zhang D, Liu Z, Bai F. Roles of Gut Microbiota in Alcoholic Liver Disease. Int J Gen Med 2023; 16:3735-3746. [PMID: 37641627 PMCID: PMC10460590 DOI: 10.2147/ijgm.s420195] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Accepted: 08/10/2023] [Indexed: 08/31/2023] Open
Abstract
Alcoholic liver disease (ALD)-one of the most common liver diseases - involves a wide range of disorders, including asymptomatic hepatic steatosis, alcoholic hepatitis (AH), liver fibrosis, and cirrhosis. Alcohol consumption induces a weakened gut barrier and changes in the composition of the gut microbiota. The presence of CYP2E1 and its elevated levels in the gastrointestinal tract after alcohol exposure lead to elevated levels of ROS and acetaldehyde, inducing inflammation and oxidative damage in the gut. At the same time, the influx of harmful molecules such as the bacterial endotoxin LPS and peptidogly from gut dysbiosis can induce intestinal inflammation and oxidative damage, further compromising the intestinal mucosal barrier. In this process, various oxidative stress-mediated post-translational modifications (PTMs) play an important role in the integrity of the barrier, eg, the presence of acetaldehyde will result in the sustained phosphorylation of several paracellular proteins (occludin and zona occludens-1), which can lead to intestinal leakage. Eventually, persistent oxidative stress, LPS infiltration and hepatocyte damage through the enterohepatic circulation will lead to hepatic stellate cell activation and hepatic fibrosis. In addition, probiotics, prebiotics, synbiotics, fecal microbial transplantation (FMT), bioengineered bacteria, gut-restricted FXR agonists and others are promising therapeutic approaches that can alter gut microbiota composition to improve ALD. In the future, there will be new challenges to study the interactions between the genetics of individuals with ALD and their gut microbiome, to provide personalized interventions targeting the gut-liver axis, and to develop better techniques to measure microbial communities and metabolites in the body.
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Affiliation(s)
- Daya Zhang
- Graduate School, Hainan Medical University, Haikou, People’s Republic of China
| | - ZhengJin Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China
| | - Feihu Bai
- Department of Gastroenterology, The Second Affiliated Hospital of Hainan Medical University, Haikou, People’s Republic of China
- The Gastroenterology Clinical Medical Center of Hainan Province, Haikou, People’s Republic of China
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15
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Zhao M, Saab S, Craw C, Lee EW. The Impact of Renal Function on Hepatic Encephalopathy Following TIPS Placement for Refractory Ascites. Biomedicines 2023; 11:2171. [PMID: 37626668 PMCID: PMC10452451 DOI: 10.3390/biomedicines11082171] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 07/26/2023] [Accepted: 07/29/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND The impact of renal function on hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) placement for refractory ascites is poorly understood. We investigated the role of renal function on HE following TIPS placement. METHODS A retrospective study was performed for patients undergoing TIPS for refractory ascites from 2007-2019. Patients were stratified by GFR at time of TIPS placement and by whether they were on hemodialysis (HD). Chronic kidney disease (CKD) stage 3 or higher was defined as pre-TIPS GFR < 60 for at least 3 months. Logistic regression analyses were used to identify the role of GFR and CKD at time of TIPS placement on HE within 60 days post TIPS placement. RESULTS Among 201 TIPS patients for refractory ascites (61% male; mean age 59.1), 78 (39%) patients were in CKD, and 16 (21%) were on HD. Mean GFR at time of TIPS placement was 62.7 ± 28.2 for all non-HD patients (n = 185). Compared with the GFR ≥ 90 group, GFR < 30 or HD (OR, 3.56; 95%CI, 1.19-10.7; p = 0.023) and CKD (OR, 2.52; 95%CI, 1.40-4.53; p = 0.002) at time of TIPS placement were significant predictors of post-TIPS placement HE within 60 days. GFRs between 30-60 and 60-90 were not significant predictors. CONCLUSIONS In TIPS patients for recurrent ascites, patients with acutely impaired renal function or chronic renal dysfunction were at an increased risk for HE after TIPS.
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Affiliation(s)
- Matthew Zhao
- Division of Hepatology, Department of Medicine, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (M.Z.); (S.S.); (C.C.)
| | - Sammy Saab
- Division of Hepatology, Department of Medicine, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (M.Z.); (S.S.); (C.C.)
- Division of Liver and Pancreas Transplantation Surgery, Department of Surgery, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Chloe Craw
- Division of Hepatology, Department of Medicine, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; (M.Z.); (S.S.); (C.C.)
| | - Edward Wolfgang Lee
- Division of Liver and Pancreas Transplantation Surgery, Department of Surgery, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Division of Interventional Radiology, Department of Radiology, UCLA Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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16
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Abstract
Globally, liver disease caused by alcohol is becoming more prevalent each year. Misuse of alcohol causes a spectrum of liver diseases, such as liver steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The cornerstone of treatment is abstinence from alcohol. In spite of this, available treatment for alcohol-associated liver disease (ALD) shows limited effectiveness currently. There are numerous ways in which alcohol disrupts the gut-liver axis, including dysbiosis of the gut microbiome, disruption of mucus and epithelial cell barriers, impaired production of antimicrobial molecules, and dysfunction of the immune system, causing translocation of viable microbes and microbial products to the liver and systemic circulation. Microbial exposure results in not only inflammation and progression of liver disease but also infections in late-stage ALD. This led scientists to focus their therapeutic strategies and targets for ALD on the gut microbiome. Throughout this review, we address the role of gut microbiome-centered therapeutic approaches for ALD focusing predominantly on randomized controlled trials. We will summarize the latest clinical trials using probiotics, antibiotics, and fecal microbial transplants in modulating the gut-liver axis and for improvement of ALD.
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Affiliation(s)
- Tannaz Ranjbarian
- 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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17
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Zacharias HD, Kamel F, Tan J, Kimer N, Gluud LL, Morgan MY. Rifaximin for prevention and treatment of hepatic encephalopathy in people with cirrhosis. Cochrane Database Syst Rev 2023; 7:CD011585. [PMID: 37467180 PMCID: PMC10360160 DOI: 10.1002/14651858.cd011585.pub2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/21/2023]
Abstract
BACKGROUND Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia. OBJECTIVES To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023. SELECTION CRITERIA We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone. DATA COLLECTION AND ANALYSIS Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay. MAIN RESULTS We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting. Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I2 = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I2 = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I2 = 0%; 14 trials, 1946 participants; moderate-certainty evidence). There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I2 = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I2 = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I2 = 60%; 7 trials, 1076 participants). Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I2 = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I2 = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I2 = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome. There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I2 = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I2 = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I2 = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I2 = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I2 = 62%; 17 trials, 2332 participants; low-certainty evidence). AUTHORS' CONCLUSIONS Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed.
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Affiliation(s)
- Harry D Zacharias
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Fady Kamel
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Jaclyn Tan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
| | - Nina Kimer
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Lise Lotte Gluud
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UK
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18
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Rifaximin Improves Liver Functional Reserve by Regulating Systemic Inflammation. J Clin Med 2023; 12:jcm12062210. [PMID: 36983211 PMCID: PMC10054398 DOI: 10.3390/jcm12062210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/01/2023] [Accepted: 03/07/2023] [Indexed: 03/18/2023] Open
Abstract
Rifaximin, a non-absorbable antibiotic, has been demonstrated to be effective against hepatic encephalopathy (HE); however, its efficacy on liver functional reserve remains unknown. Here, we evaluated the efficacy of rifaximin on the liver functional reserve and serological inflammation-based markers in patients with cirrhosis. A retrospective study was conducted on patients who received rifaximin for more than three months at our hospital between November 2016 and October 2021. The recurrence and grade of HE, serological ammonia levels, Child–Pugh score (CPS), and serological inflammation-based markers such as the neutrophil–lymphocyte ratio (NLR), lymphocyte–monocyte ratio (LMR), platelet–lymphocyte ratio (PLR), C-reactive protein (CRP), and CRP to albumin ratio (CAR) were evaluated. The correlations between serological inflammation-based markers and liver functional reserve were evaluated. HE grades, serum ammonia levels, and inflammation-based markers significantly improved at three months compared with those at baseline. Patients with improved albumin levels showed significantly higher CRP improvement rates at both 3 and 12 months. Patients with an improvement in CAR at 3 months demonstrated a significant improvement in CPS at 12 months. Rifaximin improved the liver functional reserve in patients with cirrhosis. Improvements in inflammation-based markers, particularly CRP and albumin, may be involved in this process.
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19
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Saifi S, Swaminathan A, Devi P, Chattopadhyay P, Gupta S, Garg A, Saxena S, Parveen S, Pandey R. A Tour-d’Horizon of microbiota therapeutics for metabolic disorders. MICROBIOME THERAPEUTICS 2023:231-253. [DOI: 10.1016/b978-0-323-99336-4.00006-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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20
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Sakiani S, Heller T, Koh C. Current and investigational drugs in early clinical development for portal hypertension. Front Med (Lausanne) 2022; 9:974182. [PMID: 36300180 PMCID: PMC9589453 DOI: 10.3389/fmed.2022.974182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction The development of portal hypertension leads to a majority of complications associated with chronic liver disease. Therefore, adequate treatment of portal hypertension is crucial in the management of such patients. Current treatment options are limited and consist mainly of medications that decrease the hyperdynamic circulation, such as non-selective beta blockers, and treatment of hypervolemia with diuretics. Despite these options, mortality rates have not improved over the last two decades. Newer, more effective treatment options are necessary to help improve survival and quality of life in these patients. Areas covered Multiple preclinical models and clinical studies have demonstrated potential efficacy of a variety of new treatment modalities. We introduce treatment options including the use of vasodilation promotors, vasoconstriction inhibitors, anticoagulants, antiangiogenics, and anti-inflammatory drugs. We examine the most recent studies for treatment options within these drug classes and offer insights as to which show the most promise in this field. Methodology Published studies that identified novel medical treatment options of portal hypertension were searched using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Clinical trials listed in Clinicaltrials.gov were also searched with a focus on more recent and ongoing studies, including those with completed recruitment. Searching with key terms including "portal hypertension" as well as individually searching specific treatment medications that were listed in other publications was carried out. Finally, current societal guidelines and recent review articles relevant to the management of portal hypertension were evaluated, and listed references of interest were included. Conclusion Many ongoing early phase studies demonstrate promising results and may shape the field of portal hypertension management in future. As concrete results become available, larger RCTs will be required before making definitive conclusions regarding safety and efficacy and whether or not they can be incorporated into routine clinical practice. Statins, anticoagulants, and PDE inhibitors have been among the most studied and appear to be most promising.
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Affiliation(s)
- Sasan Sakiani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Baltimore, MD, United States
| | - Theo Heller
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Christopher Koh
- Liver Diseases Branch, Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
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21
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Yokoyama K, Fukuda H, Yamauchi R, Higashi M, Miyayama T, Higashi T, Uchida Y, Shibata K, Tsuchiya N, Fukunaga A, Umeda K, Takata K, Tanaka T, Shakado S, Sakisaka S, Hirai F. Long-Term Effects of Rifaximin on Patients with Hepatic Encephalopathy: Its Possible Effects on the Improvement in the Blood Ammonia Concentration Levels, Hepatic Spare Ability and Refractory Ascites. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58091276. [PMID: 36143954 PMCID: PMC9501622 DOI: 10.3390/medicina58091276] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/09/2022] [Accepted: 09/11/2022] [Indexed: 11/20/2022]
Abstract
Background and Objectives: To investigate the long-term efficacy of rifaximin (RFX) for hyperammonemia and efficacy for refractory ascites in patients with cirrhosis. Materials and Methods: We enrolled 112 patients with liver cirrhosis who were orally administered RFX in this study. Changes in the clinical data of patients were evaluated up to 36 months after RFX administration. The primary endpoint was a change in blood ammonia levels. Secondary endpoints included changes in clinical symptoms, Child−Pugh (CP) score, number of hospitalizations, degree of refractory ascites, adverse events, and the relationship between RFX administration and the renin-angiotensin-aldosterone system. Results: An improved rate of overt hepatic encephalopathy (HE) of 82.7% was observed 3 months after RFX administration, which significantly induced a progressive decrease in blood ammonia concentration and an improved CP score up to 36 months. No serious RFX treatment-related adverse events were observed. 36.5% in patients after RFX administration improved refractory ascites. After RFX administration, patients with satisfactory control of hepatic ascites without addition of diuretic had lower renin concentration than those with poor control (p < 0.01). At less than 41 pg/mL renin concentration, the control of refractory ascites was significantly satisfactory (p < 0.0001). Conclusions: RFX reduced blood ammonia concentration and improved hepatic spare ability and the quality of life of patients with long-term HE to up to 36 months. Our study revealed the effects of RFX against refractory ascites, suggesting that renin concentration may be a predictive marker for assessing ascites control.
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Affiliation(s)
- Keiji Yokoyama
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
- Correspondence: ; Tel.: +81-92-801-1011 (ext. 3355)
| | - Hiromi Fukuda
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Ryo Yamauchi
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Masashi Higashi
- Higashi Hospital, 593-1 Hirotsu, Yositomi-machi, Chikujo-gun 871-0811, Fukuoka, Japan
| | - Takashi Miyayama
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Tomotaka Higashi
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Yotaro Uchida
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kumiko Shibata
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Naoaki Tsuchiya
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Atsushi Fukunaga
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kaoru Umeda
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Kazuhide Takata
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Takashi Tanaka
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Satoshi Shakado
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Shotaro Sakisaka
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
| | - Fumihito Hirai
- Department of Gastroenterology and Medicine, Faculty of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka-shi 814-0180, Fukuoka, Japan
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22
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Hyun JY, Kim SK, Yoon SJ, Lee SB, Jeong JJ, Gupta H, Sharma SP, Oh KK, Won SM, Kwon GH, Cha MG, Kim DJ, Ganesan R, Suk KT. Microbiome-Based Metabolic Therapeutic Approaches in Alcoholic Liver Disease. Int J Mol Sci 2022; 23:8749. [PMID: 35955885 PMCID: PMC9368757 DOI: 10.3390/ijms23158749] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 07/21/2022] [Accepted: 08/03/2022] [Indexed: 11/21/2022] Open
Abstract
Alcohol consumption is a global healthcare problem. Chronic alcohol consumption generates a wide spectrum of hepatic lesions, the most characteristic of which are steatosis, hepatitis, fibrosis, and cirrhosis. Alcoholic liver diseases (ALD) refer to liver damage and metabolomic changes caused by excessive alcohol intake. ALD present several clinical stages of severity found in liver metabolisms. With increased alcohol consumption, the gut microbiome promotes a leaky gut, metabolic dysfunction, oxidative stress, liver inflammation, and hepatocellular injury. Much attention has focused on ALD, such as alcoholic fatty liver (AFL), alcoholic steatohepatitis (ASH), alcoholic cirrhosis (AC), hepatocellular carcinoma (HCC), a partnership that reflects the metabolomic significance. Here, we report on the global function of inflammation, inhibition, oxidative stress, and reactive oxygen species (ROS) mechanisms in the liver biology framework. In this tutorial review, we hypothetically revisit therapeutic gut microbiota-derived alcoholic oxidative stress, liver inflammation, inflammatory cytokines, and metabolic regulation. We summarize the perspective of microbial therapy of genes, gut microbes, and metabolic role in ALD. The end stage is liver transplantation or death. This review may inspire a summary of the gut microbial genes, critical inflammatory molecules, oxidative stress, and metabolic routes, which will offer future promising therapeutic compounds in ALD.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Raja Ganesan
- Institute for Liver and Digestive Disease, College of Medicine, Hallym University, Chuncheon 24253, Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive Disease, College of Medicine, Hallym University, Chuncheon 24253, Korea
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23
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Jung JH, Kim SE, Suk KT, Kim DJ. Gut microbiota-modulating agents in alcoholic liver disease: Links between host metabolism and gut microbiota. Front Med (Lausanne) 2022; 9:913842. [PMID: 35935787 PMCID: PMC9354621 DOI: 10.3389/fmed.2022.913842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/04/2022] [Indexed: 11/13/2022] Open
Abstract
Alcoholic liver disease (ALD) involves a wide spectrum of diseases, including asymptomatic hepatic steatosis, alcoholic hepatitis, hepatic fibrosis, and cirrhosis, which leads to morbidity and mortality and is responsible for 0.9% of global deaths. Alcohol consumption induces bacterial translocation and alteration of the gut microbiota composition. These changes in gut microbiota aggravate hepatic inflammation and fibrosis. Alteration of the gut microbiota leads to a weakened gut barrier and changes host immunity and metabolic function, especially related to bile acid metabolism. Modulation and treatment for the gut microbiota in ALD has been studied using probiotics, prebiotics, synbiotics, and fecal microbial transplantation with meaningful results. In this review, we focused on the interaction between alcohol and gut dysbiosis in ALD. Additionally, treatment approaches for gut dysbiosis, such as abstinence, diet, pro-, pre-, and synbiotics, antibiotics, and fecal microbial transplantation, are covered here under ALD. However, further research through human clinical trials is warranted to evaluate the appropriate gut microbiota-modulating agents for each condition related to ALD.
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Affiliation(s)
- Jang Han Jung
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
| | - Sung-Eun Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, South Korea
| | - Ki Tae Suk
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, South Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, South Korea
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon, South Korea
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24
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Rodrigues SG, Mendoza YP, Bosch J. Investigational drugs in early clinical development for portal hypertension. Expert Opin Investig Drugs 2022; 31:825-842. [PMID: 35758843 DOI: 10.1080/13543784.2022.2095259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Advanced chronic liver disease is considered a reversible condition after removal of the primary aetiological factor. This has led to a paradigm shift in which portal hypertension (PH) is a reversible complication of cirrhosis. The pharmacologic management of PH is centered on finding targets to modify the natural history of cirrhosis and PH. AREAS COVERED This paper offers an overview of the use of pharmacological strategies in early clinical development that modify PH. Papers included were selected from searching clinical trials sites and PubMed from the last 10 years. EXPERT OPINION A paradigm shift has generated a new concept of PH in cirrhosis as a reversible complication of a potentially curable disease. Decreasing portal pressure to prevent decompensation and further complications of cirrhosis that may lead liver transplantation or death is a goal. Therapeutic strategies also aspire achieve total or partial regression of fibrosis thus eliminating the need for treatment or screening of PH.
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Affiliation(s)
- Susana G Rodrigues
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
| | - Yuly P Mendoza
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland.,Graduate School for Health Sciences (GHS), University of Bern
| | - Jaime Bosch
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland.,Department for BioMedical Research, Visceral Surgery and Medicine, University of Bern, Switzerland
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25
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The heart and gut relationship: a systematic review of the evaluation of the microbiome and trimethylamine-N-oxide (TMAO) in heart failure. Heart Fail Rev 2022; 27:2223-2249. [PMID: 35726110 DOI: 10.1007/s10741-022-10254-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/31/2022] [Indexed: 02/08/2023]
Abstract
There is an expanding body of research on the bidirectional relationship of the human gut microbiome and cardiovascular disease, including heart failure (HF). Researchers are examining the microbiome and gut metabolites, primarily trimethylamine-N-oxide (TMAO), to understand clinically observed outcomes. This systematic review explored the current state of the science on the evaluation and testing of the gut biome in persons with HF. Using electronic search methods of Medline, Embase, CINAHL, and Web of Science, until December 2021, we identified 511 HF biome investigations between 2014 and 2021. Of the 30 studies included in the review, six were 16S rRNA and nineteen TMAO, and three both TMAO and 16S rRNA, and two bacterial cultures. A limited range of study designs were represented, the majority involving single cohorts (n = 10) and comparing individuals with HF to controls (n = 15). Patients with HF had less biodiversity in fecal samples compared to controls. TMAO is associated with age, BNP, eGFR, HF severity, and poor outcomes including hospitalizations and mortality. Inconsistent across studies was the ability of TMAO to predict HF development, the independent prognostic value of TMAO when controlling for renal indices, and the relationship of TMAO to LVEF and CRP. Gut microbiome dysbiosis is associated with HF diagnosis, disease severity, and prognostication related to hospitalizations and mortality. Gut microbiome research in patients with HF is developing. Further longitudinal and multi-centered studies are required to inform interventions to promote clinical decision-making and improved patient outcomes.
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26
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Pose E, Solà E, Lozano JJ, Juanola A, Sidorova J, Zaccherini G, de Wit K, Uschner F, Tonon M, Kazankov K, Jiménez C, Campion D, Napoleone L, Ma AT, Carol M, Morales-Ruiz M, Alessandria C, Beuers U, Caraceni P, Francoz C, Durand F, Mookerjee RP, Trebicka J, Vargas V, Piano S, Watson H, Abraldes JG, Kamath PS, Davis MM, Ginès P. Treatment With Simvastatin and Rifaximin Restores the Plasma Metabolomic Profile in Patients With Decompensated Cirrhosis. Hepatol Commun 2022; 6:1100-1112. [PMID: 34964311 PMCID: PMC9035579 DOI: 10.1002/hep4.1881] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/13/2021] [Accepted: 10/27/2021] [Indexed: 12/18/2022] Open
Abstract
Patients with decompensated cirrhosis, particularly those with acute-on-chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE-SAFETY randomized, double-blind, placebo-controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography-tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan-kynurenine and carnitine beta-oxidation pathways. An ACLF-specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan-kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.
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Affiliation(s)
- Elisa Pose
- Liver UnitHospital Clinic de Barcelona, School of Medicine and Health SciencesUniversity of BarcelonaBarcelonaSpain.,Institut d'Investigacions Biomediques August Pi i SunyerBarcelonaSpain.,Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Elsa Solà
- Liver UnitHospital Clinic de Barcelona, School of Medicine and Health SciencesUniversity of BarcelonaBarcelonaSpain.,Institut d'Investigacions Biomediques August Pi i SunyerBarcelonaSpain.,Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Juan J Lozano
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Adrià Juanola
- Liver UnitHospital Clinic de Barcelona, School of Medicine and Health SciencesUniversity of BarcelonaBarcelonaSpain.,Institut d'Investigacions Biomediques August Pi i SunyerBarcelonaSpain.,Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Julia Sidorova
- Instituto de Tecnología del ConocimientoCampus de SomosaguasUniversidad Complutense de MadridPozuelo de AlarconSpain
| | - Giacomo Zaccherini
- Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly.,Bologna University Hospital Authority St. Orsola-Malpighi PolyclinicBolognaItaly
| | - Koos de Wit
- Department of Gastroenterology and HepatologyAcademic Medical CenterUniversity of AmsterdamAmsterdamthe Netherlands
| | - Frank Uschner
- Department of Internal MedicineGoethe University FrankfurtFrankfurtGermany
| | - Marta Tonon
- Unit of Internal Medicine and HepatologyDepartment of MedicineUniversity of PadovaPadovaItaly
| | - Konstantin Kazankov
- Institute for Liver and Digestive HealthDivision of MedicineRoyal Free HospitalUniversity College LondonLondonUnited Kingdom
| | - Cesar Jiménez
- Liver Unit, Hospital Vall d'Hebron and Vall d'Hebron Research UnitUniversitat Autònoma de BarcelonaBarcelonaSpain
| | - Daniela Campion
- Division of Gastroenterology and HepatologyCittà della Salute e della Scienza HospitalUniversity of TurinTurinItaly
| | - Laura Napoleone
- Liver UnitHospital Clinic de Barcelona, School of Medicine and Health SciencesUniversity of BarcelonaBarcelonaSpain.,Institut d'Investigacions Biomediques August Pi i SunyerBarcelonaSpain.,Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Ann T Ma
- Liver UnitHospital Clinic de Barcelona, School of Medicine and Health SciencesUniversity of BarcelonaBarcelonaSpain.,Institut d'Investigacions Biomediques August Pi i SunyerBarcelonaSpain.,Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Marta Carol
- Liver UnitHospital Clinic de Barcelona, School of Medicine and Health SciencesUniversity of BarcelonaBarcelonaSpain.,Institut d'Investigacions Biomediques August Pi i SunyerBarcelonaSpain.,Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Manuel Morales-Ruiz
- Institut d'Investigacions Biomediques August Pi i SunyerBarcelonaSpain.,Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
| | - Carlo Alessandria
- Division of Gastroenterology and HepatologyCittà della Salute e della Scienza HospitalUniversity of TurinTurinItaly
| | - Ulrich Beuers
- Department of Gastroenterology and HepatologyAcademic Medical CenterUniversity of AmsterdamAmsterdamthe Netherlands
| | - Paolo Caraceni
- Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly.,Bologna University Hospital Authority St. Orsola-Malpighi PolyclinicBolognaItaly
| | - Claire Francoz
- Hepatology and Liver Intensive Care Unit, Hospital BeaujonAssistance Publique-Hôpitaux de ParisClichyUniversity Paris DiderotParisFrance
| | - François Durand
- Hepatology and Liver Intensive Care Unit, Hospital BeaujonAssistance Publique-Hôpitaux de ParisClichyUniversity Paris DiderotParisFrance
| | - Rajeshwar P Mookerjee
- Institute for Liver and Digestive HealthDivision of MedicineRoyal Free HospitalUniversity College LondonLondonUnited Kingdom
| | - Jonel Trebicka
- Department of Internal MedicineGoethe University FrankfurtFrankfurtGermany
| | - Victor Vargas
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain.,Liver Unit, Hospital Vall d'Hebron and Vall d'Hebron Research UnitUniversitat Autònoma de BarcelonaBarcelonaSpain
| | - Salvatore Piano
- Unit of Internal Medicine and HepatologyDepartment of MedicineUniversity of PadovaPadovaItaly
| | - Hugh Watson
- Evotec IDVirology, LyonFrance.,Department of Clinical PharmacologyAarhus UniversityAarhusDenmark
| | - Juan G Abraldes
- Division of Gastroenterology, Liver UnitUniversity of AlbertaEdmontonABCanada
| | - Patrick S Kamath
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Mark M Davis
- Institute for Immunity, Transplantation and InfectionStanford UniversityStanfordCAUSA.,Department of Microbiology and ImmunologyStanford UniversityStanfordCAUSA.,Howard Hughes Medical InstituteStanford UniversityStanfordCAUSA
| | - Pere Ginès
- Liver UnitHospital Clinic de Barcelona, School of Medicine and Health SciencesUniversity of BarcelonaBarcelonaSpain.,Institut d'Investigacions Biomediques August Pi i SunyerBarcelonaSpain.,Centro de Investigación Biomédica en Red Enfermedades Hepáticas y DigestivasBarcelonaSpain
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Kimer N, Meldgaard M, Hamberg O, Kronborg TM, Lund AM, Møller HJ, Bendtsen F, Ytting H. The impact of rifaximin on inflammation and metabolism in alcoholic hepatitis: A randomized clinical trial. PLoS One 2022; 17:e0264278. [PMID: 35286322 PMCID: PMC8920190 DOI: 10.1371/journal.pone.0264278] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 02/05/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS Alcoholic hepatitis (AH) is characterized by acute liver failure, neurocognitive impairment and renal failure. Severe inflammatory reactions are also known to occur in AH. Inflammation and bacterial translocation in the gut are thought to have major impact on disease development and progression. The mortality rate for AH is close to 50%. We aimed to assess the efficacy of rifaximin in treating AH and its impact on inflammation and metabolism. METHODS The trial was approved by relevant authorities (EudraCT no: 2014-02264-33, Scientific Ethics Committee, jr. no: H-1-2014-056). Primary outcomes were changes in metabolic and inflammatory markers. Secondary outcomes were portal hypertension, kidney and neurocognitive function. RESULTS Thirty-two patients were randomized to standard medical therapy (SMT) or SMT plus rifaximin, allocation was concealed. Four patients in the SMT group and five patients in the SMT + rifaximin group died due to AH and liver failure. No adverse events related to the study medication were observed. We found no significant differences in amino acids or inflammation markers (IL-2, IL-6, IL-8, IL-10, TNF-α, interferon-γ) between the groups after 28 and 90 days. CONCLUSION Rifaximin does not alter inflammation or metabolism in patients with AH.
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Affiliation(s)
- Nina Kimer
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Mads Meldgaard
- Department of Internal Medicine, Zealand University Hospital, Koege, Denmark
| | - Ole Hamberg
- Department of Internal Medicine, Zealand University Hospital, Koege, Denmark
- Department of Hepatology and Gastroenterology, Rigshospitalet, Copenhagen, Denmark
| | - Thit Mynster Kronborg
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Allan M. Lund
- Center for Inherited Metabolic Diseases, Departments of Clinical Genetics and Pediatrics, Rigshospitalet, Copenhagen, Denmark
| | - Holger Jon Møller
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
| | - Henriette Ytting
- Gastro Unit, Medical Division, Amager-Hvidovre University Hospital, Hvidovre, Denmark
- Department of Hepatology and Gastroenterology, Rigshospitalet, Copenhagen, Denmark
- * E-mail:
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28
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Liu SY, Huang CC, Huang SF, Liao TL, Kuo NR, Yang YY, Li TH, Liu CW, Hou MC, Lin HC. Pioglitazone Ameliorates Acute Endotoxemia-Induced Acute on Chronic Renal Dysfunction in Cirrhotic Ascitic Rats. Cells 2021; 10:3044. [PMID: 34831270 PMCID: PMC8616474 DOI: 10.3390/cells10113044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 01/23/2023] Open
Abstract
Endotoxemia-activated tumor necrosis factor (TNFα)/nuclear factor kappa B (NFκB) signals result in acute on chronic inflammation-driven renal dysfunction in advanced cirrhosis. Systemic activation of peroxisome proliferator-activated receptor gamma (PPARγ) with pioglitazone can suppress inflammation-related splanchnic and pulmonary dysfunction in cirrhosis. This study explored the mechanism and effects of pioglitazone treatment on the abovementioned renal dysfunction in cirrhotic rats. Cirrhotic ascitic rats were induced with renal dysfunction by bile duct ligation (BDL). Then, 2 weeks of pioglitazone treatment (Pio, PPAR gamma agonist, 12 mg/kg/day, using the azert osmotic pump) was administered from the 6th week after BDL. Additionally, acute lipopolysaccharide (LPS, Escherichia coli 0111:B4; Sigma, 0.1 mg/kg b.w, i.p. dissolved in NaCl 0.9%) was used to induce acute renal dysfunction. Subsequently, various circulating, renal arterial and renal tissue pathogenic markers were measured. Cirrhotic BDL rats are characterized by decreased mean arterial pressure, increased cardiac output and portal venous pressure, reduced renal arterial blood flow (RABF), increased renal vascular resistance (RVR), increased relative renal weight/hydroxyproline, downregulated renal PPARγ expression, upregulated renal inflammatory markers (TNFα, NFκB, IL-6, MCP-1), increased adhesion molecules (VCAM-1 and ICAM-1), increased renal macrophages (M1, CD68), and progressive renal dysfunction (increasing serum and urinary levels of renal injury markers (lipocalin-2 and IL-18)). In particular, acute LPS administration induces acute on chronic renal dysfunction (increasing serum BUN/creatinine, increasing RVR and decreasing RABF) by increased TNFα-NFκB-mediated renal inflammatory markers as well as renal M1 macrophage infiltration. In comparison with the BDL+LPS group, chronic pioglitazone pre-treatment prevented LPS-induced renal pathogenic changes in the BDL-Pio+LPS group. Activation of systemic, renal vessel and renal tissue levels of PPARγ by chronic pioglitazone treatment has beneficial effects on the endotoxemia-related TNFα/NFκB-mediated acute and chronic renal inflammation in cirrhosis. This study revealed that normalization of renal and renal arterial levels of PPARγ effectively prevented LPS-induced acute and chronic renal dysfunction in cirrhotic ascitic rats.
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Affiliation(s)
- Szu-Yu Liu
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Chia-Chang Huang
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Shiang-Fen Huang
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Tsai-Ling Liao
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 11217, Taiwan
| | - Nai-Rong Kuo
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Ying-Ying Yang
- Department of Medical Education, Medical Innovation and Research Office (MIRO), Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-Y.L.); (C.-C.H.); (N.-R.K.)
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Tzu-Hao Li
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
- Division of Allergy, Immunology, and Rheumatology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Foundation, Taipei 11217, Taiwan
| | - Chih-Wei Liu
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Ming-Chih Hou
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
| | - Han-Chieh Lin
- Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan; (S.-F.H.); (M.-C.H.)
- Faculty of Medicine, School of Medicine, National Yang-Ming Chiao Tung University, Taipei 11217, Taiwan; (T.-L.L.); (T.-H.L.); (C.-W.L.)
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Fu X, Chen T, Cai J, Liu B, Zeng Y, Zhang X. The Microbiome-Gut-Brain Axis, a Potential Therapeutic Target for Substance-Related Disorders. Front Microbiol 2021; 12:738401. [PMID: 34690981 PMCID: PMC8526971 DOI: 10.3389/fmicb.2021.738401] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/31/2021] [Indexed: 12/31/2022] Open
Abstract
Substance addiction is a complex worldwide public health problem. It endangers both personal life and social stability, causing great loss on economy. Substance-related disorder is considered to be a complicated chronic brain disorder. It resulted from interactions among pharmacological properties of addictive substances, individual susceptibility, and social–environmental factors. Unfortunately, there is still no ideal treatment for this disorder. Recent lines of evidence suggest that gut microbiome may play an important role in the pathogenesis of neuropsychiatric disorders, including substance-related disorders. This review summarizes the research on the relationship between gut microbiome and substance-related disorders, including different types of substance, different individual susceptibility, and the occurrence and development of substance-induced mental disorders. We also discuss the potentiation of gut microbiome in the treatment of substance-related disorders, especially in the treatment of substance-induced mental disorders and manipulation on individuals’ responsiveness to addictive substances.
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Affiliation(s)
- Xuan Fu
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center on Mental Disorders, Changsha, China.,National Technology Institute on Mental Disorders, Changsha, China.,Hunan Medical Center for Mental Health, Changsha, China.,Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China.,Mental Health Institute of Central South University, Changsha, China
| | - Ti Chen
- Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Jingda Cai
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center on Mental Disorders, Changsha, China.,National Technology Institute on Mental Disorders, Changsha, China.,Hunan Medical Center for Mental Health, Changsha, China.,Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China.,Mental Health Institute of Central South University, Changsha, China
| | - Bo Liu
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center on Mental Disorders, Changsha, China.,National Technology Institute on Mental Disorders, Changsha, China.,Hunan Medical Center for Mental Health, Changsha, China.,Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China.,Mental Health Institute of Central South University, Changsha, China
| | - Yaohui Zeng
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center on Mental Disorders, Changsha, China.,National Technology Institute on Mental Disorders, Changsha, China.,Hunan Medical Center for Mental Health, Changsha, China.,Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China.,Mental Health Institute of Central South University, Changsha, China
| | - Xiaojie Zhang
- Department of Psychiatry, The Second Xiangya Hospital, Central South University, Changsha, China.,National Clinical Research Center on Mental Disorders, Changsha, China.,National Technology Institute on Mental Disorders, Changsha, China.,Hunan Medical Center for Mental Health, Changsha, China.,Hunan Key Laboratory of Psychiatry and Mental Health, Changsha, China.,Mental Health Institute of Central South University, Changsha, China
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30
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Nathwani R, Mullish B, Kockerling D, Cole A, Selvapatt N, Dhar A. Review of Rifaximin: A Summary of the Current Evidence and Benefits Beyond Licensed Use. EUROPEAN MEDICAL JOURNAL 2021. [DOI: 10.33590/emj/21-00026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Antibiotic resistance in patients with cirrhosis continues to draw significant attention. With a propensity to frequent hospitalisations, patients with cirrhosis are subject to frequent antibiotic prescription. This increases their risk of developing resistance to one or more antimicrobial agents, making management of their condition particularly challenging. Despite advancements being made in the management of liver disease, mortality rates continue to rise: almost 5-fold in those <65 years of age while remaining the leading cause of death in those 35–49 years of age. Alternative therapeutic options to prevent disease progression and cirrhosis-associated complications are urgently required; rifaximin is one such example. The medication use in patients with cirrhosis demonstrates additional benefits beyond current licensed use in the UK, that being for the prevention of hepatic encephalopathy and traveller’s diarrhoea; rifaximin has especially been explored beyond current licensed use in the context of enteric-driven pathologies. Through the therapy’s key central action as a broad-spectrum antimicrobial, rifaximin has the ability to modulate the gut–liver axis via removal of gut microbial products associated with the progression of cirrhosis and its sequalae.
The benefits of rifaximin use continues to gather momentum, given its non-absorbable nature and well-tolerated side-effect profile, and these require consideration. With broad-spectrum antimicrobial properties, its use may assist in overcoming the conundrum posed of antibiotic resistance amongst patients with cirrhosis. This literature review discusses the chemical and antimicrobial properties of rifaximin, its licenced indication for use, and its reported benefits beyond this, as well as concerns regarding rifaximin resistance.
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Affiliation(s)
- Rooshi Nathwani
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - Benjamin Mullish
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - David Kockerling
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - Alexander Cole
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - Nowlan Selvapatt
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - Ameet Dhar
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
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31
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Caraceni P, Vargas V, Solà E, Alessandria C, de Wit K, Trebicka J, Angeli P, Mookerjee RP, Durand F, Pose E, Krag A, Bajaj JS, Beuers U, Ginès P, Napoleone L, Carol M, Avitabile E, Thu AM, Cervera M, Pérez M, Belén Rubio‐Garcia A, Ardiaca A, Vives A, Pich J, Fabrellas N, Zaccherini G, Chiappa MT, Jiménez C, Palacio E, Campion D, Lanzillotti T, Piano S, Nicolao G, Uschner F, Graf_Dirmeier S, Francoz C, Roux O, Esnault V, Helder J, Aban M, Kazankov K, Korenjak M, Kamath P, Abraldes JG, Watson H. The Use of Rifaximin in Patients With Cirrhosis. Hepatology 2021; 74:1660-1673. [PMID: 33421158 PMCID: PMC8518409 DOI: 10.1002/hep.31708] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/10/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure, and mortality, are therefore eagerly awaited.
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Affiliation(s)
- Paolo Caraceni
- University of BolognaUniversity Hospital S. Orsola‐Malpighi di BolognaBolognaItaly
| | - Victor Vargas
- Hospital Vall d’HebronUniversitat Autònoma de BarcelonaCIEREHDBarcelonaCataloniaSpain
| | - Elsa Solà
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
| | - Carlo Alessandria
- Division of Gastroenterology and HepatologyCittà della Salute e della Scienza HospitalUniversity of TorinoTurinItaly
| | - Koos de Wit
- Amsterdam University Medical CentersAmsterdamthe Netherlands
| | - Jonel Trebicka
- Goethe‐University ‐ Frankfurt am MainFrankfurt am MainGermany,EF‐CLIFBarcelonaCataloniaSpain
| | | | | | | | - Elisa Pose
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
| | - Aleksander Krag
- Department of Gastroenterology and HepatologyOdense University HospitalOdenseDenmark,Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
| | | | - Ulrich Beuers
- Amsterdam University Medical CentersAmsterdamthe Netherlands
| | - Pere Ginès
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
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32
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Hepatorenal syndrome: pathophysiology and evidence-based management update. ROMANIAN JOURNAL OF INTERNAL MEDICINE 2021; 59:227-261. [DOI: 10.2478/rjim-2021-0006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Indexed: 11/20/2022] Open
Abstract
Abstract
Hepatorenal syndrome (HRS) is a functional renal failure that develops in patients with advanced hepatic cirrhosis with ascites and in those with fulminant hepatic failure. The prevalence of HRS varies among studies but in general it is the third most common cause of acute kidney injury (AKI) in cirrhotic patients after pre-renal azotemia and acute tubular necrosis. HRS carries a grim prognosis with a mortality rate approaching 90% three months after disease diagnosis. Fortunately, different strategies have been proven to be successful in preventing HRS. Although treatment options are available, they are not universally effective in restoring renal function but they might prolong survival long enough for liver transplantation, which is the ultimate treatment. Much has been learned in the last two decades regarding the pathophysiology and management of this disease which lead to notable evolution in the HRS definition and better understanding on how best to manage HRS patients. In the current review, we will summarize the recent advancement in epidemiology, pathophysiology, and management of HRS.
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Iwakiri Y, Trebicka J. Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy. JHEP Rep 2021; 3:100316. [PMID: 34337369 PMCID: PMC8318926 DOI: 10.1016/j.jhepr.2021.100316] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/19/2021] [Accepted: 05/12/2021] [Indexed: 12/14/2022] Open
Abstract
Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.
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Key Words
- ACE2, angiogenesis-converting enzyme 2
- ACLF, acute-on-chronic liver failure
- AT1R, angiotensin II type I receptor
- CCL2, chemokine (C-C motif) ligand 2
- CCl4, carbon tetrachloride
- CLD, chronic liver disease
- CSPH, clinically significant portal hypertension
- Dll4, delta like canonical Notch ligand 4
- ECM, extracellular matrix
- EUS, endoscopic ultrasound
- FXR
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- HRS, hepatorenal syndrome
- HSC
- HSCs, hepatic stellate cells
- HVPG, hepatic venous pressure gradient
- Hsp90, heat shock protein 90
- JAK2, Janus kinase 2
- KO, knockout
- LSEC
- LSEC, liver sinusoidal endothelial cells
- MLCP, myosin light-chain phosphatase
- NET, neutrophil extracellular trap
- NO
- NO, nitric oxide
- NSBB
- NSBBs, non-selective beta blockers
- PDE, phosphodiesterase
- PDGF, platelet-derived growth factor
- PIGF, placental growth factor
- PKG, cGMP-dependent protein kinase
- Rho-kinase
- TIPS
- TIPS, transjugular intrahepatic portosystemic shunt
- VCAM1, vascular cell adhesion molecule 1
- VEGF
- VEGF, vascular endothelial growth factor
- angiogenesis
- eNOS, endothelial nitric oxide synthase
- fibrosis
- liver stiffness
- statins
- β-Arr2, β-arrestin 2
- β1-AR, β1-adrenergic receptor
- β2-AR, β2-adrenergic receptor
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, University Clinic Frankfurt, Frankfurt, Germany
- European Foundation for the Study of Chronic Liver Failure-EF Clif, Barcelona, Spain
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Han JW, Kim DI, Nam HC, Chang UI, Yang JM, Song DS. Association between serum TNF-α and sarcopenia in liver cirrhosis. Clin Mol Hepatol 2021; 28:219-231. [PMID: 34281295 PMCID: PMC9013623 DOI: 10.3350/cmh.2021.0082] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/30/2021] [Indexed: 11/10/2022] Open
Abstract
Background/Aims Sarcopenia is an independent prognostic factor of liver cirrhosis (LC). However, the association between LC-related systemic inflammation and sarcopenia is unclear. Methods Sprague-Dawley rats were treated with thioacetamide (TAA) or saline as a control. Rifaximin was administered to TAA-induced LC rats. Enzyme-linked immunosorbent assay was performed to measure inflammatory mediators in rat serum. RT-PCR was performed to measure the molecular expression in tissues. Hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to investigate tissue pathology. Serum tumor necrosis factor-α levels, liver stiffness (LS), and the L3 skeletal muscle index (L3SMI) were measured in 60 patients with chronic liver disease. Results LC and sarcopenia were successfully induced by TAA. Serum TNF-α levels were increased in LC rats and correlated with myostatin expression, muscle weight, and myofiber diameter. The expression of intestinal occludin and zona occludens-1 was reduced in LC rats and associated with serum TNF-α levels and sarcopenia. In patients with LS ≥7 kPa or sarcopenia, serum TNF-α levels were significantly increased, which was also confirmed when we raised the LS cutoff to 10 kPa. The L3SMI was inversely correlated with serum TNF-α levels in patients with LS ≥7 kPa. TNF-α was reduced by rifaximin, which might have resulted in reduced expression of muscular MuRF1 and myostatin and improvements in myofiber diameters within muscle tissues. Conclusions These results suggest that serum TNF-α is associated with LC-related sarcopenia. Rifaximin might be effective in reducing serum TNF-α levels and improving sarcopenia in LC, but these results need to be validated in future studies.
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Affiliation(s)
- Ji Won Han
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Da In Kim
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hee Chul Nam
- Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - U Im Chang
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Mo Yang
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Do Seon Song
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Simbrunner B, Costa D, Reiberger T. Reply to: "Presepsin as a biomarker of inflammation and prognosis in decompensated liver disease". J Hepatol 2021; 75:234-236. [PMID: 33852949 DOI: 10.1016/j.jhep.2021.03.027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 12/04/2022]
Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Dalila Costa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; Gastroenterology Department, Braga Hospital, Braga, Portugal
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria; Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
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Bureau C, Thabut D, Jezequel C, Archambeaud I, D'Alteroche L, Dharancy S, Borentain P, Oberti F, Plessier A, De Ledinghen V, Ganne-Carrié N, Carbonell N, Rousseau V, Sommet A, Péron JM, Vinel JP. The Use of Rifaximin in the Prevention of Overt Hepatic Encephalopathy After Transjugular Intrahepatic Portosystemic Shunt : A Randomized Controlled Trial. Ann Intern Med 2021; 174:633-640. [PMID: 33524293 DOI: 10.7326/m20-0202] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The efficacy of rifaximin in the secondary prevention of overt hepatic encephalopathy (HE) is well documented, but its effectiveness in preventing a first episode in patients after transjugular intrahepatic portosystemic shunt (TIPS) has not been established. OBJECTIVE To determine whether rifaximin prevents overt HE after TIPS compared with placebo. DESIGN Randomized, double-blind, multicenter, placebo-controlled trial. (ClinicalTrials.gov: NCT02016196). PARTICIPANTS 197 patients with cirrhosis undergoing TIPS for intractable ascites or prevention of variceal rebleeding. INTERVENTION Patients were randomly assigned to receive rifaximin (600 mg twice daily) or placebo, beginning 14 days before TIPS and continuing for 168 days after the procedure. MEASUREMENTS The primary efficacy end point was incidence of overt HE within 168 days after the TIPS procedure. RESULTS An episode of overt HE occurred in 34% (95% CI, 25% to 44%) of patients in the rifaximin group (n = 93) and 53% (CI, 43% to 63%) in the placebo group (n = 93) during the postprocedure period (odds ratio, 0.48 [CI, 0.27 to 0.87]). Neither the incidence of adverse events nor transplant-free survival was significantly different between the 2 groups. LIMITATIONS The study's conclusion applies mainly to patients with alcoholic cirrhosis, who made up the study population. The potential benefit of rifaximin 6 months after TIPS and beyond remains to be investigated. CONCLUSION In patients with cirrhosis treated with TIPS, rifaximin was well tolerated and reduced the risk for overt HE. Rifaximin should therefore be considered for prophylaxis of post-TIPS HE. PRIMARY FUNDING SOURCE French Public Health Ministry.
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Affiliation(s)
- Christophe Bureau
- University Hospital of Toulouse and Toulouse III Paul Sabatier University, Toulouse, France (C.B., J.M.P., J.P.V.)
| | | | | | | | | | | | | | - Frédéric Oberti
- Centre Hospitalier Universitaire d'Angers, Angers, France (F.O.)
| | | | | | - Nathalie Ganne-Carrié
- Hôpitaux Universitaires Paris Seine-Saint-Denis, Bondy, and Université Paris 13, Sorbonne Paris Cité et INSERM UMR 1162, Paris, France (N.G.)
| | | | | | - Agnès Sommet
- Toulouse University Hospital, Toulouse, France (V.R., A.S.)
| | - Jean Marie Péron
- University Hospital of Toulouse and Toulouse III Paul Sabatier University, Toulouse, France (C.B., J.M.P., J.P.V.)
| | - Jean Pierre Vinel
- University Hospital of Toulouse and Toulouse III Paul Sabatier University, Toulouse, France (C.B., J.M.P., J.P.V.)
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Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol 2021; 18:167-180. [PMID: 33257833 DOI: 10.1038/s41575-020-00376-3] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 12/12/2022]
Abstract
The human gut microbiome has emerged as a major player in human health and disease. The liver, as the first organ to encounter microbial products that cross the gut epithelial barrier, is affected by the gut microbiome in many ways. Thus, the gut microbiome might play a major part in the development of liver diseases. The common end stage of liver disease is decompensated cirrhosis and the further development towards acute-on-chronic liver failure (ACLF). These conditions have high short-term mortality. There is evidence that translocation of components of the gut microbiota, facilitated by different pathogenic mechanisms such as increased gut epithelial permeability and portal hypertension, is an important driver of decompensation by induction of systemic inflammation, and thereby also ACLF. Elucidating the role of the gut microbiome in the aetiology of decompensated cirrhosis and ACLF deserves further investigation and improvement; and might be the basis for development of diagnostic and therapeutic strategies. In this Review, we focus on the possible pathogenic, diagnostic and therapeutic role of the gut microbiome in decompensation of cirrhosis and progression to ACLF.
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Affiliation(s)
- Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, Frankfurt, Germany. .,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain. .,Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark. .,Institute for Bioengineering of Catalonia, Barcelona, Spain.
| | - Peer Bork
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Manimozhiyan Arumugam
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark. .,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Changes of Gut-Microbiota-Liver Axis in Hepatitis C Virus Infection. BIOLOGY 2021; 10:biology10010055. [PMID: 33451143 PMCID: PMC7828638 DOI: 10.3390/biology10010055] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/02/2021] [Accepted: 01/08/2021] [Indexed: 12/12/2022]
Abstract
Simple Summary Gut microbiota alteration is linked to many health disorders including hepatitis C virus (HCV) infection. This dysbiosis in turn impacts the coordination between the gut and the liver that is known as the gut–liver-axis. Here, we discuss the latest findings regarding the changes in gut microbiota structure and functionality post HCV infection and its treatment regimens. In addition, we underline the contribution of the microbiota alterations to HCV associated liver complications. Abstract The gut–liver-axis is a bidirectional coordination between the gut, including microbial residents, the gut microbiota, from one side and the liver on the other side. Any disturbance in this crosstalk may lead to a disease status that impacts the functionality of both the gut and the liver. A major cause of liver disorders is hepatitis C virus (HCV) infection that has been illustrated to be associated with gut microbiota dysbiosis at different stages of the disease progression. This dysbiosis may start a cycle of inflammation and metabolic disturbance that impacts the gut and liver health and contributes to the disease progression. This review discusses the latest literature addressing this interplay between the gut microbiota and the liver in HCV infection from both directions. Additionally, we highlight the contribution of gut microbiota to the metabolism of antivirals used in HCV treatment regimens and the impact of these medications on the microbiota composition. This review sheds light on the potential of the gut microbiota manipulation as an alternative therapeutic approach to control the liver complications post HCV infection.
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Zyryanov SK, Baybulatova EA. Rifaximin-Alpha and Other Crystalline Forms of Rifaximin: Are There Any Differences? ANTIBIOTICS AND CHEMOTHERAPY 2020; 65:52-62. [DOI: 10.37489/0235-2990-2020-65-7-8-52-62] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Rifaximin is an antibiotic characterized by polymorphism. It has various crystalline forms with different pharmacological characteristics. Rifaximin acts locally in the digestive tract, therefore it is important for the absorption to be minimal and for concentration in the intestinal lumen to be high. The absorption of other crystalline forms of rifaximin in the intestine is greater than that of rifaximin-α (Alpha Normix®). Differences in pharmacokinetics of the crystalline forms of rifaximin may affect its effectiveness and safety, especially in patients with chronic diseases (immunodeficiency and leaky gut against the background of liver cirrhosis) who require long courses of therapy. Rifaximin-α (Alpha Normix®) is unique as it has eubiotic and anti-inflammatory properties in addition to local antibacterial effect. Given its diverse mechanisms of action, rifaximin-α positively modulates gut microbiota.
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Mendoza YP, Rodrigues SG, Bosch J, Berzigotti A. Effect of poorly absorbable antibiotics on hepatic venous pressure gradient in cirrhosis: A systematic review and meta-analysis. Dig Liver Dis 2020; 52:958-965. [PMID: 32736898 DOI: 10.1016/j.dld.2020.06.048] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 06/24/2020] [Accepted: 06/29/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The effects of poorly/non-absorbable antibiotics on hepatic venous pressure gradient (HVPG) are debated. AIM To analyze the effects of rifaximin or norfloxacin on HVPG and on markers of bacterial translocation and proinflammatory cytokines. METHODS We performed a systematic search of randomized clinical trials (RCTs) involving patients with cirrhosis and portal hypertension, assessing the effect of rifaximin or norfloxacin vs control on HVPG. Pooled analyses were based on random-effects models, heterogeneity was assessed by Cochran's Q, I2 statistic and subgroup analyses. RESULTS Five studies (215 patients) were included. Risk of bias was high in three. We found no significant differences using antibiotics versus control. The summary mean difference in HVPG was of -0.55 mmHg (95%CI:-1.52, 0.42; P = 0.27), with moderate heterogeneity (P = 0.15; I2 = 40%). RCTs with longer therapy (60-90 days) used non-selective-beta-blockers (NSBB) in both antibiotics and control arms. Subgroup analysis showed a significantly greater reduction in HVPG in the combination arm over controls (mean difference -1.46 mmHg [95%CI: -2.63, -0.28; P = 0.01]) with no heterogeneity (P = 0.46; I2 = 0%). Serum lipopolysaccharide-binding protein (LBP) significantly decreased with antibiotics, but with high heterogeneity (P < 0.001; I2 = 92%). CONCLUSIONS Rifaximin or norfloxacin did not significantly reduce HVPG in patients with cirrhosis and portal hypertension. Studies using antibiotic for longer periods on top of NSBB showed a significant decrease in HVPG.
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Affiliation(s)
- Yuly P Mendoza
- UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Switzerland
| | - Susana G Rodrigues
- UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Switzerland
| | - Jaime Bosch
- UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Switzerland
| | - Annalisa Berzigotti
- UVCM, Inselspital, Bern University Hospital, Department of Biomedical Research, University of Bern, Switzerland.
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Thomson MJ, Taylor A, Sharma P, Lok AS, Tapper EB. Limited Progress in Hepatorenal Syndrome (HRS) Reversal and Survival 2002-2018: A Systematic Review and Meta-Analysis. Dig Dis Sci 2020; 65:1539-1548. [PMID: 31571102 PMCID: PMC7103565 DOI: 10.1007/s10620-019-05858-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Accepted: 09/19/2019] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Type 1 hepatorenal syndrome (HRS) is a fatal complication of cirrhosis. Treatments trend toward HRS reversal, but few show clear mortality benefit. We sought to quantify the progress-or lack thereof-in improving outcomes of type 1 HRS over time. METHODS We performed a systematic review and meta-analysis for randomized controlled trials (RCTs) comparing type 1 HRS outcomes including (a) overall survival (liver transplant-free survival if reported) and (b) HRS reversal. Each study arm was analyzed separately to look at changes in outcomes over time. RCTs published comparing medical treatments for type 1 HRS were searched using several databases through July 31, 2019. RESULTS Fourteen RCTs (28 arms) involving 778 participants enrolled between 2002 and 2018 were included. Twelve RCTs measured HRS reversal. In conjunction with albumin (or plasma expander), the most common medications used were terlipressin (13 arms), antibiotics (7), norepinephrine (6), dopamine (4), and midodrine/octreotide (3). Pooled survival rate was 34.6% (95% CI 26.4-43.8), and pooled HRS reversal rate was 42.8% (95% CI 34.2-51.9). Regression analyzing the incremental effect of the year the RCT was initiated showed that more recent studies were not associated with improved survival (OR 1.02, 95% CI 0.94-1.11, p = 0.66) or HRS reversal rates (OR 1.03, 95% CI 0.96-1.11, p = 0.41). There was no survival improvement when RCTs with endpoints assessed ≤ or > 1 month were analyzed separately with respective OR of 1.07 (95% CI 0.95-1.20, p = 0.26) and 0.97 (95% CI 0.85-1.12, p = 0.70). CONCLUSION Outcomes have not improved for patients with type 1 HRS since 2002. There is a need to improve prevention and treatment of type 1 HRS.
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Affiliation(s)
- Mary J Thomson
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA.
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA.
| | - Arthur Taylor
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Pratima Sharma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA
| | - Elliot B Tapper
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109, USA
- Institute for Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA
- Veterans Affairs Hospital, Ann Arbor, MI, USA
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Méndez-Sánchez N, Valencia-Rodriguez A, Vera-Barajas A, Abenavoli L, Scarpellini E, Ponciano-Rodriguez G, Wang DQH. The mechanism of dysbiosis in alcoholic liver disease leading to liver cancer. HEPATOMA RESEARCH 2020; 6:5. [PMID: 32582865 PMCID: PMC7313221 DOI: 10.20517/2394-5079.2019.29] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Currently, alcoholic liver disease (ALD) is one of the most prevalent chronic liver diseases worldwide, representing one of the main etiologies of cirrhosis and hepatocellular carcinoma (HCC). Although we do not know the exact mechanisms by which only a selected group of patients with ALD progress to the final stage of HCC, the role of the gut microbiota within the progression to HCC has been intensively studied in recent years. To date, we know that alcohol-induced gut dysbiosis is an important feature of ALD with important repercussions on the severity of this disease. In essence, an increased metabolism of ethanol in the gut induced by an excessive alcohol consumption promotes gut dysfunction and bacterial overgrowth, setting a leaky gut. This causes the translocation of bacteria, endotoxins, and ethanol metabolites across the enterohepatic circulation reaching the liver, where the recognition of the pathogen-associated molecular patterns via specific Toll-like receptors of liver cells will induce the activation of the nuclear factor kappa-B pathway, which releases pro-inflammatory cytokines and chemokines. In addition, the mitogenic activity of hepatocytes will be promoted and cellular apoptosis will be inhibited, resulting in the development of HCC. In this context, it is not surprising that microbiota-regulating drugs have proven effectiveness in prolonging the overall survival of patients with HCC, making attractive the implementation of these drugs as co-adjuvant for HCC treatment.
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Affiliation(s)
- Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | | | | | - Ludovico Abenavoli
- Department of Health Sciences, University “Magna Graecia” Viale Europa, Catanzaro 88100, Italy
| | - Emidio Scarpellini
- Clinical Nutrition Unit, and Internal Medicine Unit, “Madonna del Soccorso” General Hospital, Via Luciano Manara 7, San Benedetto del Tronto (AP) 63074, Italy
| | - Guadalupe Ponciano-Rodriguez
- Public Health Department, Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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Lv XY, Ding HG, Zheng JF, Fan CL, Li L. Rifaximin improves survival in cirrhotic patients with refractory ascites: A real-world study. World J Gastroenterol 2020; 26:199-218. [PMID: 31988585 PMCID: PMC6962437 DOI: 10.3748/wjg.v26.i2.199] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/06/2019] [Accepted: 12/21/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Rifaximin has been shown to reduce the incidence of hepatic encephalopathy and other complications in patients with cirrhosis. However, few studies have investigated the effect of rifaximin in cirrhotic patients with refractory ascites. AIM To evaluate the effects of rifaximin in the treatment of refractory ascites and to preliminarily explore its possible mechanism. METHODS A total of 75 cirrhotic patients with refractory ascites were enrolled in the study (50 in a rifaximin and 25 in a control group). Patients in the rifaximin group were divided into two subgroups according to the presence of spontaneous bacterial peritonitis and treatment with or without other antibiotics (19 patients treated with rifaximin and 31 patients treated with rifaximin plus intravenous antibiotics). All patients received conventional treatment for refractory ascites, while patients in the rifaximin group received oral rifaximin-α 200 mg four times daily for at least 2 wk. The ascites grade, fasting weight, liver and kidney function, and inflammatory factors in the plasma were evaluated before and after treatment. In addition, the gut microbiota was determined by metagenomics sequencing to analyse the changes in the characteristics of the gut microbiota before and after rifaximin treatment. The patients were followed for 6 mo. RESULTS Compared with the control group, the fasting weight of patients significantly decreased and the ascites significantly subsided after treatment with rifaximin (P = 0.011 and 0.009, respectively). The 6-mo survival rate of patients in the rifaximin group was significantly higher than that in the control group (P = 0.048). The concentration of interferon-inducible protein 10 decreased significantly in the rifaximin group compared with that in the control group (P = 0.024). The abundance of Roseburia, Haemophilus, and Prevotella was significantly reduced after rifaximin treatment, while the abundance of Lachnospiraceae_noname, Subdoligranulum, and Dorea decreased and the abundance of Coprobacillus increased after treatment with rifaximin plus intravenous antibiotics. The gene expression of virulence factors was significantly reduced after treatment in both subgroups treated with rifaximin or rifaximin plus intravenous antibiotics. CONCLUSION Rifaximin mitigates ascites and improves survival of cirrhotic patients with refractory ascites. A possible mechanism is that rifaximin regulates the structure and function of intestinal bacteria, thus improving the systemic inflammatory state.
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Affiliation(s)
- Xin-Yue Lv
- Department of Gastroenterology and Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Hui-Guo Ding
- Department of Gastroenterology and Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Jun-Fu Zheng
- Department of Gastroenterology and Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Chun-Lei Fan
- Department of Gastroenterology and Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Lei Li
- Department of Gastroenterology and Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
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Coronel-Castillo C, Contreras-Carmona J, Frati-Munari A, Uribe M, Méndez-Sánchez N. Efficacy of rifaximin in the different clinical scenarios of hepatic encephalopathy. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2020. [DOI: 10.1016/j.rgmxen.2019.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Shibasaki M, Hatanaka T, Shimada Y, Nagashima T, Namikawa M, Saito S, Hosonuma K, Naganuma A, Takizawa D, Arai H, Kosone T, Takagi H, Sato K, Kakizaki S, Uraoka T. Efficacy and safety of rifaximin treatment in Japanese patients with hepatic encephalopathy. KANZO 2020; 61:1-10. [DOI: 10.2957/kanzo.61.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/28/2023]
Affiliation(s)
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital
| | | | - Tamon Nagashima
- Department of Gastroenterology, Shibukawa Medical Center, National Hospital Organization
| | | | - Shuichi Saito
- Department of Gastroenterology, Tomioka General Hospital
| | | | - Atsushi Naganuma
- Department of Gastroenterology, Takasaki General Medical Center, National Hospital Organization
| | | | - Hirotaka Arai
- Department of Gastroenterology, Maebashi Red Cross Hospital
| | - Takashi Kosone
- Department of Gastroenterology and Hepatology, Kusunoki Hospital
| | - Hitoshi Takagi
- Department of Gastroenterology and Hepatology, Kusunoki Hospital
| | - Ken Sato
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
| | - Toshio Uraoka
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine
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Coronel-Castillo CE, Contreras-Carmona J, Frati-Munari AC, Uribe M, Méndez-Sánchez N. Efficacy of rifaximin in the different clinical scenarios of hepatic encephalopathy. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2020; 85:56-68. [PMID: 31836274 DOI: 10.1016/j.rgmx.2019.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 08/21/2019] [Accepted: 09/04/2019] [Indexed: 06/10/2023]
Abstract
Hepatic encephalopathy is a frequent complication in patients with cirrhosis of the liver and is associated with a high mortality rate. Costs attributed to the management of patients with cirrhosis are especially high due to complications, such as hepatic encephalopathy, given that they increase the number of days of hospital stay. Different drugs are currently used to treat hepatic encephalopathy, and the main ones are lactulose, L-ornithine L-aspartate (LOLA), and certain antibiotics, especially rifaximin-α (RFX). Even though many of them have been shown to be effective to greater or lesser degrees, it is important to understand the differences between them, so that every patient receives individualized treatment and the best option is chosen, in accordance with the different clinical scenarios. Thus, the aim of the present study was to analyze the evidence on the advantages and disadvantages of the individual or combined use of the 3 main treatments for hepatic encephalopathy, specifically taking into consideration their different degrees of efficacy, their impact on quality of life, prophylaxis, and cost reduction.
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Affiliation(s)
- C E Coronel-Castillo
- Unidad de Investigación en Hígado, Fundación Clínica Médica Sur, Ciudad de México, México
| | - J Contreras-Carmona
- Unidad de Investigación en Hígado, Fundación Clínica Médica Sur, Ciudad de México, México
| | - A C Frati-Munari
- Departamento de Medicina Interna, Fundación Clínica Médica Sur, Ciudad de México, México
| | - M Uribe
- Unidad de Investigación en Hígado, Fundación Clínica Médica Sur, Ciudad de México, México
| | - N Méndez-Sánchez
- Unidad de Investigación en Hígado, Fundación Clínica Médica Sur, Ciudad de México, México; Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, México.
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Simbrunner B, Mandorfer M, Trauner M, Reiberger T. Gut-liver axis signaling in portal hypertension. World J Gastroenterol 2019; 25:5897-5917. [PMID: 31660028 PMCID: PMC6815800 DOI: 10.3748/wjg.v25.i39.5897] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 08/15/2019] [Accepted: 09/28/2019] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension (PHT) in advanced chronic liver disease (ACLD) results from increased intrahepatic resistance caused by pathologic changes of liver tissue composition (structural component) and intrahepatic vasoconstriction (functional component). PHT is an important driver of hepatic decompensation such as development of ascites or variceal bleeding. Dysbiosis and an impaired intestinal barrier in ACLD facilitate translocation of bacteria and pathogen-associated molecular patterns (PAMPs) that promote disease progression via immune system activation with subsequent induction of proinflammatory and profibrogenic pathways. Congestive portal venous blood flow represents a critical pathophysiological mechanism linking PHT to increased intestinal permeability: The intestinal barrier function is affected by impaired microcirculation, neoangiogenesis, and abnormal vascular and mucosal permeability. The close bidirectional relationship between the gut and the liver has been termed “gut-liver axis”. Treatment strategies targeting the gut-liver axis by modulation of microbiota composition and function, intestinal barrier integrity, as well as amelioration of liver fibrosis and PHT are supposed to exert beneficial effects. The activation of the farnesoid X receptor in the liver and the gut was associated with beneficial effects in animal experiments, however, further studies regarding efficacy and safety of pharmacological FXR modulation in patients with ACLD are needed. In this review, we summarize the clinical impact of PHT on the course of liver disease, discuss the underlying pathophysiological link of PHT to gut-liver axis signaling, and provide insight into molecular mechanisms that may represent novel therapeutic targets.
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Affiliation(s)
- Benedikt Simbrunner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| | - Mattias Mandorfer
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
| | - Thomas Reiberger
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna 1180, Austria
- Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna 1180, Austria
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Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Gastroenterol Hepatol 2019; 5:31-41. [PMID: 31607677 DOI: 10.1016/s2468-1253(19)30320-6] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 08/07/2019] [Accepted: 08/09/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Statins have beneficial effects on intrahepatic circulation and decrease portal hypertension and rifaximin modulates the gut microbiome and might prevent bacterial translocation in patients with cirrhosis. Therefore, this drug combination might be of therapeutic benefit in patients with decompensated cirrhosis. However, there is concern regarding the safety of statins in patients with decompensated cirrhosis. We assessed the safety of two different doses of simvastatin, in combination with rifaximin, in patients with decompensated cirrhosis. METHODS We did a double-blind, randomised, placebo-controlled, phase 2 trial in patients with decompensated cirrhosis and moderate-to-severe liver failure from nine university hospitals in six European countries (Italy, France, Holland, Germany, the UK, and Spain). Patients older than 18 years with Child-Pugh class B or C disease were eligible. We randomly assigned patients (1:1:1) to receive either simvastatin 40 mg/day plus rifaximin 1200 mg/day, simvastatin 20 mg/day plus rifaximin 1200 mg/day, or placebo of both medications for 12 weeks. Randomisation was stratified according to Child-Pugh class (B vs C) and restricted using blocks of multiples of three. The primary endpoint was development of liver or muscle toxicity, as defined by changes in liver aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]), alkaline phosphastase, and creatine kinase. The study is registered with the European Union Clinical Trials Register, 2016-004499-23, and with ClinicalTrials.gov, NCT03150459. FINDINGS The study recruitment period was between July 28, 2017, and Jan 2, 2018. Follow-up finished on March 12, 2018. 50 patients were randomly assigned to simvastatin 40 mg/day plus rifaximin 1200 mg/day (n=18), simvastatin 20 mg/day plus rifaximin 1200 mg/day (n=16), or placebo of both medications (n=16). Six patients (two from each group) were excluded. Therefore, the full analysis set included 44 patients (16 in the simvastatin 40 mg/day plus rifaximin 1200 mg/day group, 14 in the simvastatin 20 mg/day plus rifaximin mg/day group, and 14 in the placebo group). After a safety analyses when the first ten patients completed treatment, treatment was stopped prematurely in the simvastatin 40 mg/day plus rifaximin group due to recommendations by the data safety monitoring board. Patients in the simvastatin 40 mg/day plus rifaximin group showed a significant increase in AST and ALT compared with the placebo group (mean differences between the groups at the end of treatment for AST 130 IU/L [95% CI 54 to 205; p=0·0009] and for ALT 61 IU/L [22 to 100; p=0·0025]. We observed no significant differences at 12 weeks in AST and ALT between the simvastatin 20 mg/day plus rifaximin and placebo group (for AST -14 IU/L [-91 to 64; p=0·728] and for ALT -8 IU/L [-49 to 33; p=0·698]). We observed no significant differences in alkaline phosphatase between the the simvastatin 40 mg/day plus rifaximin or the simvastatin 20 mg/day plus rifaximin groups compared with placebo. Patients in the simvastatin 40 mg/day plus rifaximin group showed an increase in creatine kinase at the end of treatment compared with patients in the placebo group (1009 IU/L [208 to 1809]; p=0·014). We observed no significant changes in creatine kinase in the simvastatin 20 mg/day plus rifaximin group (4·2 IU/L [-804 to 813]; p=0·992). Three (19%) patients in the simvastatin 40 mg/day group developed liver and muscle toxicity consistent with rhabdomyolysis. The number of patients who stopped treatment because of adverse events was significantly higher in the simvastatin 40 mg/day plus rifaximin group (nine [56%] of 16 patients) compared with the other two groups (two [14%] of 14 for both groups; p=0·017). There were no serious unexpected adverse reactions reported during the study. INTERPRETATION Treatment with simvastatin 40 mg/day plus rifaximin in patients with decompensated cirrhosis was associated with a significant increase in adverse events requiring treatment withdrawal, particularly rhabdomyolysis, compared with simvastatin 20 mg/day plus rifaximin. We recommend simvastatin 20 mg/day as the dose to be used in studies investigating the role of statins in patients with decompensated cirrhosis. FUNDING Horizon 20/20 European programme.
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Abstract
Many studies have indicated that intestinal barrier dysfunction is the key mechanism of alcoholic liver disease (ALD). In this paper, we systematically review the causes of intestinal barrier dysfunction and the pathogenesis of ALD and discuss the treatment of intestinal barrier dysfunction.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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Cresci S, Pereira NL, Ahmad F, Byku M, de las Fuentes L, Lanfear DE, Reilly CM, Owens AT, Wolf MJ. Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association. CIRCULATION. GENOMIC AND PRECISION MEDICINE 2019; 12:458-485. [PMID: 31510778 DOI: 10.1161/hcg.0000000000000058] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The "omics"-genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics- of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.
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