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1
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Burra P, Zanetto A, Schnabl B, Reiberger T, Montano-Loza AJ, Asselta R, Karlsen TH, Tacke F. Hepatic immune regulation and sex disparities. Nat Rev Gastroenterol Hepatol 2024; 21:869-884. [PMID: 39237606 DOI: 10.1038/s41575-024-00974-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/07/2024]
Abstract
Chronic liver disease is a major cause of morbidity and mortality worldwide. Epidemiology, clinical phenotype and response to therapies for gastrointestinal and liver diseases are commonly different between women and men due to sex-specific hormonal, genetic and immune-related factors. The hepatic immune system has unique regulatory functions that promote the induction of intrahepatic tolerance, which is key for maintaining liver health and homeostasis. In liver diseases, hepatic immune alterations are increasingly recognized as a main cofactor responsible for the development and progression of chronic liver injury and fibrosis. In this Review, we discuss the basic mechanisms of sex disparity in hepatic immune regulation and how these mechanisms influence and modify the development of autoimmune liver diseases, genetic liver diseases, portal hypertension and inflammation in chronic liver disease. Alterations in gut microbiota and their crosstalk with the hepatic immune system might affect the progression of liver disease in a sex-specific manner, creating potential opportunities for novel diagnostic and therapeutic approaches to be evaluated in clinical trials. Finally, we identify and propose areas for future basic, translational and clinical research that will advance our understanding of sex disparities in hepatic immunity and liver disease.
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Affiliation(s)
- Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy.
| | - Alberto Zanetto
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA, USA
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Aldo J Montano-Loza
- Division of Gastroenterology and Liver Unit, Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Tom Hemming Karlsen
- Department of Transplantation Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
- Research Institute of Internal Medicine, Clinic of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
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Guixé-Muntet S, Quesada-Vázquez S, Gracia-Sancho J. Pathophysiology and therapeutic options for cirrhotic portal hypertension. Lancet Gastroenterol Hepatol 2024; 9:646-663. [PMID: 38642564 DOI: 10.1016/s2468-1253(23)00438-7] [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: 10/09/2023] [Revised: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 04/22/2024]
Abstract
Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension. Data also suggest that the phenotype of hepatic cells could be further impaired due to the altered mechanical properties of the cirrhotic liver itself, creating a deleterious cycle that worsens portal hypertension in the advanced stages of liver disease. In this Review, we discuss recent discoveries in the pathophysiology and treatment of cirrhotic portal hypertension, a condition with few pharmacological treatment options.
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Affiliation(s)
- Sergi Guixé-Muntet
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Sergio Quesada-Vázquez
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Hospital Clínic de Barcelona, Barcelona, Spain; Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
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Giorgi M, Pellegrini M, Massimi M. Role of Phosphodiesterases in Biology and Pathology 2.0. Int J Mol Sci 2024; 25:5339. [PMID: 38791377 PMCID: PMC11121124 DOI: 10.3390/ijms25105339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/28/2024] [Accepted: 04/28/2024] [Indexed: 05/26/2024] Open
Abstract
Phosphodiesterases (PDEs) are ubiquitous enzymes that hydrolyse cAMP and cGMP second messengers temporally, spatially, and integratedly according to their expression and compartmentalization inside the cell [...].
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Affiliation(s)
- Mauro Giorgi
- Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy;
| | - Manuela Pellegrini
- Institute of Biochemistry and Cell Biology, IBBC-CNR, Via E. Ramarini 32, 00015 Monterotondo (RM), Italy
| | - Mara Massimi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy
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Fareed MM, Khalid H, Khalid S, Shityakov S. Deciphering Molecular Mechanisms of Carbon Tetrachloride- Induced Hepatotoxicity: A Brief Systematic Review. Curr Mol Med 2024; 24:1124-1134. [PMID: 37818557 DOI: 10.2174/0115665240257603230919103539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/07/2023] [Accepted: 08/11/2023] [Indexed: 10/12/2023]
Abstract
The liver plays a critical role in metabolic processes, making it vulnerable to injury. Researchers often study carbon tetrachloride (CCl4)-induced hepatotoxicity in model organisms because it closely resembles human liver damage. This toxicity occurs due to the activation of various cytochromes, including CYP2E1, CYP2B1, CYP2B2, and possibly CYP3A, which produce the trichloromethyl radical (CCl3*). CCl3* can attach to biological molecules such as lipids, proteins, and nucleic acids, impairing lipid metabolism and leading to fatty degeneration. It can also combine with DNA to initiate hepatic carcinogenesis. When exposed to oxygen, CCl3* generates more reactive CCl3OO*, which leads to lipid peroxidation and membrane damage. At the molecular level, CCl4 induces the release of several inflammatory cytokines, including TNF-α and NO, which can either help or harm hepatotoxicity through cellular apoptosis. TGF-β contributes to fibrogenesis, while IL-6 and IL-10 aid in recovery by minimizing anti-apoptotic activity and directing cells toward regeneration. To prevent liver damage, different interventions can be employed, such as antioxidants, mitogenic agents, and the maintenance of calcium sequestration. Drugs that prevent CCl4- induced cytotoxicity and proliferation or enhance CYP450 activity may offer a protective response against hepatic carcinoma.
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Affiliation(s)
- Muhammad Mazhar Fareed
- School of Science and Engineering, Department of Computer Science, Università degli Studi di Verona, Verona, Italy
- Laboratorio di Bioinformatica Applicata, Department of Biotechnology, Università degli Studi di Verona, Verona, Italy
| | - Hina Khalid
- Faculty of Life Sciences, Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Sana Khalid
- School of Life Science and Medicine, Shandong University of Technology, Zibo, China
| | - Sergey Shityakov
- Laboratory of Chemoinformatics, Infochemistry Scientific Center, ITMO University, Saint-Petersburg, Russian Federation
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Shalaby S, Ronzoni L, Hernandez-Gea V, Valenti L. The genetics of portal hypertension: Recent developments and the road ahead. Liver Int 2023; 43:2592-2603. [PMID: 37718732 DOI: 10.1111/liv.15732] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/07/2023] [Accepted: 09/02/2023] [Indexed: 09/19/2023]
Abstract
Portal hypertension (PH), defined as a pathological increase in the portal vein pressure, has different aetiologies and causes. Intrahepatic PH is mostly secondary to the presence of underlying liver disease leading to cirrhosis, characterized by parenchymal changes with deregulated accumulation of extracellular matrix and vascular abnormalities; liver sinusoidal endothelial cells and hepatic stellate cells are key players in PH progression, able to influence each other. However, PH may also develop independently of parenchymal damage, as occur in portosinusoidal vascular disorder (PSVD), a group of clinical and histological entities characterized by portal vasculature dysfunctions. In this particular group of disorders, the pathophysiology of PH is still poorly understood. In the last years, several genetic studies, based on genome-wide association studies or whole-exome sequencing analysis, have highlighted the importance of genetic heritability in PH pathogenesis, both in cirrhotic and non-cirrhotic cases. The common PNPLA3 p.I148M variant, one of the main determinants of the susceptibility to steatotic liver disease, has also been associated with decompensation in patients with PH. Genetic variations at loci influencing coagulation, mainly the ABO locus, may directly contribute to the pathogenesis of PH. Rare genetic variants have been associated with familiar cases of progressive PSVD. In this review, we summarize the recent knowledges on genetic variants predisposing to PH development, contributing to better understand the role of genetic factors in PH pathogenesis.
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Grants
- Commissioner for Universities and Research from the Department of Economy and Knowledge" of the "Generalitat de Catalunya" (AGAUR SGR2017_517) (VHG)
- Fondazione Patrimonio Ca' Granda, "Liver BIBLE" (PR-0361) (LV)
- Gilead_IN-IT-989-5790 (LV)
- Innovative Medicines Initiative 2 joint undertaking of European Union's Horizon 2020 research and innovation programme and EFPIA European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS (LV)
- Instituto de Salud Carlos III" FIS PI20/00569 FEDER from the European Union (Fondos FEDER, "Una manera de hacer Europa") (VHG)
- Italian Ministry of Health (Ministero della Salute), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Ricerca Corrente (LV)
- Italian Ministry of Health (Ministero della Salute), Rete Cardiologica "CV-PREVITAL" (LV)
- Italian Ministry of Health (Ministero della Salute), Ricerca Finalizzata 2016, RF-2016-02364358 ("Impact of whole exome sequencing on the clinical management of patients with advanced nonalcoholic fatty liver and cryptogenic liver disease"), Ricerca Finalizzata 2021 RF-2021-12373889, Italian Ministry of Health, Ricerca Finalizzata PNRR 2022 "RATIONAL: Risk strAtificaTIon Of Nonalcoholic fAtty Liver" PNRR-MAD-2022-12375656 (LV)
- Italian Ministry of Health (Ministero della Salute). PNRR PNC-E3-2022-23683266 PNC-HLS-DA, INNOVA (LV)
- The European Union, H2020-ICT-2018-20/H2020-ICT-2020-2 programme "Photonics" under grant agreement No. 101016726 - REVEAL (LV)
- The European Union, HORIZON-MISS-2021-CANCER-02-03 programme "Genial" under grant agreement "101096312" (LV)
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Affiliation(s)
- Sarah Shalaby
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, CIBEREHD, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain
- Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Padua, Italy
| | - Luisa Ronzoni
- Precision Medicine Lab, Biological Resource Center Unit, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
| | - Virginia Hernandez-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, CIBEREHD, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN-Liver), Barcelona, Spain
| | - Luca Valenti
- Precision Medicine Lab, Biological Resource Center Unit, Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
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Pashayee-Khamene F, Hatami B, Cheraghpour M, Yari Z. Keeping an eye on the nutrition: The importance of nutrition management on cardiometabolic risk factors in cirrhotic patients. Clin Nutr ESPEN 2023; 58:186-192. [PMID: 38057004 DOI: 10.1016/j.clnesp.2023.09.927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 08/26/2023] [Accepted: 09/26/2023] [Indexed: 11/07/2023]
Abstract
Chronic liver diseases, especially cirrhosis, are associated with significant morbidity and mortality. Besides predisposing to chronic liver disease per se, diabetes, hypertension, and dyslipidemia worsen the prognosis of patients with cirrhosis induced by other causes. There is no standard of care in the management of these factors in patients with cirrhosis. Also, in particular, it is not known whether nutritional interventions in the modification of cardiometabolic factors can improve the course of cirrhosis or not. This narrative review aimed to investigate the clinical significance of diabetes, hypertension, and dyslipidemia and appropriate nutritional interventions in cirrhotic patients. A comprehensive literature search of the published data was performed in regard to the association of cirrhosis with cardiometabolic factors and the management of cirrhosis and its complications. There is limited evidence on the association of cirrhosis with cardiometabolic risk factors. Cirrhotic cardiometabolic abnormalities are associated with an increased risk of complications, such that the coexistence of diabetes, hypertension, and dyslipidemia increases the risk of clinical decompensation in cirrhosis. Dietary management of cirrhotic patients with risk factors such as diabetes, hypertension, or dyslipidemia does not seem to be considerably different from non-cirrhotic patients.
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Affiliation(s)
- Fereshteh Pashayee-Khamene
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Makan Cheraghpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Zahra Yari
- Department of Nutrition Research, National Nutrition and Food Technology Research Institute and Faculty of Nutrition Sciences and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Lawitz EJ, Reiberger T, Schattenberg JM, Schoelch C, Coxson HO, Wong D, Ertle J. Safety and pharmacokinetics of BI 685509, a soluble guanylyl cyclase activator, in patients with cirrhosis: A randomized Phase Ib study. Hepatol Commun 2023; 7:e0276. [PMID: 37889522 PMCID: PMC10615399 DOI: 10.1097/hc9.0000000000000276] [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: 03/03/2023] [Accepted: 07/29/2023] [Indexed: 10/28/2023] Open
Abstract
BACKGROUND Portal hypertension is a severe complication of cirrhosis. This Phase Ib study (NCT03842761) assessed the safety, tolerability, and pharmacokinetics of soluble guanylyl cyclase activator BI 685509 in patients with mild or moderate hepatic impairment (Child-Pugh [CP] A or B cirrhosis) and healthy volunteers (HVs). METHODS In this single-center, randomized, placebo-controlled study, patients received BI 685509 (maximum doses: 1, 2, or 3 mg, twice daily [BID]) or placebo for 28 days. HVs received one 0.5 mg dose of BI 685509 or placebo. RESULTS In total, 64 participants (CP-A, n=24; CP-B, n=25; HVs, n=15) were included; most commonly with NAFLD (36.7%), alcohol-associated (30.6%), or chronic viral hepatitis-related cirrhosis (28.6%). In patients with CP-A cirrhosis, drug-related adverse events (AEs) occurred in 5.6% of BI 685509-treated patients and 16.7% of placebo recipients. In patients with CP-B cirrhosis, drug-related AEs occurred in 26.3% of BI 685509-treated patients only. No serious AEs occurred in patients with CP-A cirrhosis; in patients with CP-B cirrhosis, serious AEs (not drug-related) occurred in 10.5% of BI 685509-treated patients and 16.7% of patients receiving placebo. BI 685509 was rapidly absorbed; exposure increased with dosage and was similar between etiologies and between patients with CP-A cirrhosis and patients with CP-A cirrhosis but lower in HVs. The mean percentage portal-systemic shunt fraction was measured in patients with CP-A cirrhosis and decreased at the end of treatment in the 2 mg BID (-11.2 ± 11.9%) and 3 mg BID (-14.0 ± 8.4%) BI 685509 dose groups, but not in the placebo group (+1.0 ± 27.3%). CONCLUSION BI 685509 was generally well tolerated, with 3 serious, not drug-related AEs reported in patients with CP-B cirrhosis. In patients with CP-A cirrhosis, portal-systemic shunt fraction in the exploratory efficacy analysis was reduced by 2 mg BID and 3 mg BID BI 685509.
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Affiliation(s)
- Eric J. Lawitz
- The Texas Liver Institute, University of Texas Health, San Antonio, Texas, USA
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Jörn M. Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center Mainz, Mainz, Rhineland Palatinate, Germany
| | | | | | - Diane Wong
- Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA
| | - Judith Ertle
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
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Torre A, Cisneros-Garza LE, Castillo-Barradas M, Navarro-Alvarez N, Sandoval-Salas R, González-Huezo MS, Pérez-Hernández JL, Méndez-Guerrero O, Ruiz-Manríquez JA, Trejo-Estrada R, Chavez-Tapia NC, Solís-Gasca LC, Moctezuma-Velázquez C, Aguirre-Valádez J, Flores-Calderón J, Higuera-de-la-Tijera F, García-Juárez I, Canedo-Castillo NA, Malé-Velázquez R, Montalvo-Gordon I, Vilatobá M, Márquez-Guillén E, Córdova-Gallardo J, Flores-García NC, Miranda-Zazueta G, Martínez-Saldívar BI, Páez-Zayas VM, Muñoz-Espinosa LE, Solís-Galindo FA. Consensus document on acute-on-chronic liver failure (ACLF) established by the Mexican Association of Hepatology. Ann Hepatol 2023; 28:101140. [PMID: 37482299 DOI: 10.1016/j.aohep.2023.101140] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 07/25/2023]
Abstract
Acute-on chronic liver failure (ACLF) has been an intensively debated topic mainly due to the lack of a unified definition and diagnostic criteria. The growing number of publications describing the mechanisms of ACLF development, the progression of the disease, outcomes and treatment has contributed to a better understanding of the disease, however, it has also sparked the debate about this condition. As an attempt to provide medical professionals with a more uniform definition that could be applied to our population, the first Mexican consensus was performed by a panel of experts in the area of hepatology in Mexico. We used the most relevant and impactful publications along with the clinical and research experience of the consensus participants. The consensus was led by 4 coordinators who provided the most relevant bibliography by doing an exhaustive search on the topic. The entire bibliography was made available to the members of the consensus for consultation at any time during the process and six working groups were formed to develop the following sections: 1.- Generalities, definitions, and criteria, 2.- Pathophysiology of cirrhosis, 3.- Genetics in ACLF, 4.- Clinical manifestations, 5.- Liver transplantation in ACLF, 6.- Other treatments.
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Affiliation(s)
- Aldo Torre
- Metabolic Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
| | - Laura Esthela Cisneros-Garza
- Gastroenterology and Hepatology Department, Hospital Christus Muguerza Alta Especialidad, Monterrey, Nuevo León, Mexico
| | | | - Nalu Navarro-Alvarez
- Gastroenterology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | | | - Osvely Méndez-Guerrero
- Gastroenterology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | | | - Luis Carlos Solís-Gasca
- Gastroenterology Department, Hospital General de Zona #12 Benito Juárez del Instituto Mexicano del Seguro Social, Mérida, Yucatán, Mexico
| | - Carlos Moctezuma-Velázquez
- Gastroenterology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; Department of Medicine - Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Alberta, Canada
| | | | - Judith Flores-Calderón
- Pediatrics Department, Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Mexico City, Mexico
| | | | - Ignacio García-Juárez
- Gastroenterology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - Iaarah Montalvo-Gordon
- Clinic of Gastrointestinal and Hepatic Specialties, Hospital Faro del Mayab, Mérida, Yucatán, Mexico
| | - Mario Vilatobá
- Transplant Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Ernesto Márquez-Guillén
- Gastroenterology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico; Hospital Ángeles del Pedregal, Mexico City, Mexico
| | - Jacqueline Córdova-Gallardo
- Hepatology Department - General Surgery Service, Hospital General Dr. Manuel Gea González, Mexico City, Mexico
| | - Nayeli Cointa Flores-García
- Gastroenterology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Godolfino Miranda-Zazueta
- Gastroenterology Department, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - Linda Elsa Muñoz-Espinosa
- Universidad Autónoma de Nuevo León. Liver Unit, Department of Internal Medicine, University Hospital 'Dr. José E. González', Monterrey, Nuevo León, Mexico
| | - Francisco Alfonso Solís-Galindo
- Gastroenterology Department, Unidad Médica de Alta Especialidad # 71 Instituto Mexicano del Seguro Social, Torreón, Coahuila, Mexico
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9
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Shaffer LR, Mahmud N. Statins in Cirrhosis: Hope or Hype? J Clin Exp Hepatol 2023; 13:1032-1046. [PMID: 37975036 PMCID: PMC10643276 DOI: 10.1016/j.jceh.2023.05.002] [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: 02/04/2023] [Accepted: 05/01/2023] [Indexed: 11/19/2023] Open
Abstract
In recent years, studies have demonstrated the benefits of statins in a range of chronic diseases separate from cardiovascular outcomes. Early studies in the context of chronic liver disease have suggested favorable effects of statins leading to slowed fibrosis progression, reduced portal pressures, decreased rates of hepatic decompensation, and improved survival. This has increased interest in the potential role that statins may have in the management of chronic liver disease and cirrhosis, though many questions remain unanswered, including concerns regarding the safety of higher dose statins in patients with advanced decompensated cirrhosis. In this review, we provide an update on the current literature addressing the use of statins in patients with cirrhosis and highlight areas in which additional studies are needed.
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Affiliation(s)
- Lauren R. Shaffer
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Gastroenterology Section, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Leonard David Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA
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10
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Huang XY, Zhang YH, Yi SY, Lei L, Ma T, Huang R, Yang L, Li ZM, Zhang D. Potential contribution of the gut microbiota to the development of portal vein thrombosis in liver cirrhosis. Front Microbiol 2023; 14:1217338. [PMID: 37965548 PMCID: PMC10641681 DOI: 10.3389/fmicb.2023.1217338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 10/09/2023] [Indexed: 11/16/2023] Open
Abstract
Background Portal vein thrombosis (PVT) is a serious complication of liver cirrhosis (LC) and is closely related to gut homeostasis. The study aimed to investigate the composition of gut microbiota and its putative role in PVT development in LC. Methods 33 patients with LC admitted between January 2022 and December 2022 were enrolled in this study. Based on imaging findings, they were categorized into LC without PVT (n = 21) and LC with PVT (n = 12) groups. Fecal samples were collected from each participant and underwent 16S rDNA sequencing. Results D-Dimer and platelet elevations were the main clinical features of LC with PVT. The alpha and beta diversity of the gut microbiota in LC with PVT group was found to be significantly higher compared to the control group. The structure of the gut microbiota was significantly different between the two groups. Based on LEfSe data, the genera Akkermansia, Eubacterium hallii group, Fusicatenibacter, and Anaerostipes were enriched in the LC with PVT, while Enterococcus, Weissella, Bacteroides, and Subdoligranulum were enriched in those of the LC subjects. Changes in microbiota structure result in significant differences in gut microbiota metabolism between the two groups. Altered levels of the microbiota genera were shown to be correlated with coagulation factor parameters. In animal experiments, the addition of Bacteroides reversed the CCl4-induced PVT. Conclusion Liver cirrhosis with PVT led to a disorder in the gut microbiota, which was characterized by an increase in pathogenic bacteria and a decrease in beneficial bacteria. Furthermore, modulating the gut microbiota, especially Bacteroides, may be a promising therapeutic approach to reduce the progression of PVT in LC.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Di Zhang
- Department of Gastroenterology and Hepatology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
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Bedair AF, Wahid A, El-Mezayen NS, El-Yazbi AF, Khalil HA, Hassan NW, Afify EA. Nicorandil/ morphine crosstalk accounts for antinociception and hepatoprotection in hepatic fibrosis in rats: Distinct roles of opioid/cGMP and NO/KATP pathways. Biomed Pharmacother 2023; 165:115068. [PMID: 37392650 DOI: 10.1016/j.biopha.2023.115068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/20/2023] [Accepted: 06/23/2023] [Indexed: 07/03/2023] Open
Abstract
Previous report indicated that nicorandil potentiated morphine antinociception and attenuated hepatic injury in liver fibrotic rats. Herein, the underlying mechanisms of nicorandil/morphine interaction were investigated using pharmacological, biochemical, histopathological, and molecular docking studies. Male Wistar rats were injected intraperitoneally (i.p.) with carbon tetrachloride (CCl4, 40%, 2 ml/kg) twice weekly for 5 weeks to induce hepatic fibrosis. Nicorandil (15 mg/kg/day) was administered per os (p.o.) for 14 days in presence of the blockers; glibenclamide (KATP channel blocker, 5 mg/kg, p.o.), L-NG-nitro-arginine methyl ester (L-NAME, nitric oxide synthase inhibitor, 15 mg/kg, p.o.), methylene blue (MB, guanylyl cyclase inhibitor, 2 mg/kg, i.p.) and naltrexone (opioid antagonist, 20 mg/kg, i.p.). At the end of the 5th week, analgesia was evaluated using tail flick and formalin tests along with biochemical determinations of liver function tests, oxidative stress markers and histopathological examination of liver tissues. Naltrexone and MB inhibited the antinociceptive activity of the combination. Furthermore, combined nicorandil/morphine regimen attenuated the release of endogenous peptides. Docking studies revealed a possible interaction of nicorandil on µ, κ and δ opioid receptors. Nicorandil/morphine combination protected against liver damage as evident by decreased liver enzymes, liver index, hyaluronic acid, lipid peroxidation, fibrotic insults, and increased superoxide dismutase activity. Nicorandil/morphine hepatoprotection and antioxidant activity were inhibited by glibenclamide and L-NAME but not by naltrexone or MB. These findings implicate opioid activation/cGMP versus NO/KATP channels in the augmented antinociception, and hepatoprotection, respectively, of the combined therapy and implicate provoked cross talk by nicorandil and morphine on opioid receptors and cGMP signaling pathway. That said, nicorandil/morphine combination provides a potential multitargeted therapy to alleviate pain and preserve liver function.
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Affiliation(s)
- Asser F Bedair
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Ahmed Wahid
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Nesrine S El-Mezayen
- Department of Pharmacology, Faculty of Pharmacy, Pharos University in Alexandria, Alexandria, Egypt
| | - Amira F El-Yazbi
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Hadeel A Khalil
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Nayera W Hassan
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
| | - Elham A Afify
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt.
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12
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Jones AK, Chen H, Ng KJ, Villalona J, McHugh M, Zeveleva S, Wilks J, Brilisauer K, Bretschneider T, Qian HS, Fryer RM. Soluble Guanylyl Cyclase Activator BI 685509 Reduces Portal Hypertension and Portosystemic Shunting in a Rat Thioacetamide-Induced Cirrhosis Model. J Pharmacol Exp Ther 2023; 386:70-79. [PMID: 37230799 DOI: 10.1124/jpet.122.001532] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 04/03/2023] [Accepted: 04/10/2023] [Indexed: 05/27/2023] Open
Abstract
Portal hypertension (PT) commonly occurs in cirrhosis. Nitric oxide (NO) imbalance contributes to PT via reduced soluble guanylyl cyclase (sGC) activation and cGMP production, resulting in vasoconstriction, endothelial cell dysfunction, and fibrosis. We assessed the effects of BI 685509, an NO-independent sGC activator, on fibrosis and extrahepatic complications in a thioacetamide (TAA)-induced cirrhosis and PT model. Male Sprague-Dawley rats received TAA twice-weekly for 15 weeks (300-150 mg/kg i.p.). BI 685509 was administered daily for the last 12 weeks (0.3, 1, and 3 mg/kg p.o.; n = 8-11 per group) or the final week only (Acute, 3 mg/kg p.o.; n = 6). Rats were anesthetized to measure portal venous pressure. Pharmacokinetics and hepatic cGMP (target engagement) were measured by mass spectrometry. Hepatic Sirius Red morphometry (SRM) and alpha-smooth muscle actin (αSMA) were measured by immunohistochemistry; portosystemic shunting was measured using colored microspheres. BI 685509 dose-dependently increased hepatic cGMP at 1 and 3 mg/kg (3.92 ± 0.34 and 5.14 ± 0.44 versus 2.50 ± 0.19 nM in TAA alone; P < 0.05). TAA increased hepatic SRM, αSMA, PT, and portosystemic shunting. Compared with TAA, 3 mg/kg BI 685509 reduced SRM by 38%, αSMA area by 55%, portal venous pressure by 26%, and portosystemic shunting by 10% (P < 0.05). Acute BI 685509 reduced SRM and PT by 45% and 21%, respectively (P < 0.05). BI 685509 improved hepatic and extrahepatic cirrhosis pathophysiology in TAA-induced cirrhosis. These data support the clinical investigation of BI 685509 for PT in patients with cirrhosis. SIGNIFICANCE STATEMENT: BI 685509 is an NO-independent sGC activator that was tested in a preclinical rat model of TAA-induced nodular, liver fibrosis, portal hypertension, and portal systemic shunting. BI 685509 reduced liver fibrosis, portal hypertension, and portal-systemic shunting in a dose-dependent manner, supporting its clinical assessment to treat portal hypertension in patients with cirrhosis.
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Affiliation(s)
- Amanda K Jones
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Hongxing Chen
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Khing Jow Ng
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Jorge Villalona
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Mark McHugh
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Svetlana Zeveleva
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - James Wilks
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Klaus Brilisauer
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Tom Bretschneider
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Hu Sheng Qian
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
| | - Ryan M Fryer
- Department of Cardiometabolic Diseases Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut (A.K.J., H.C., K.J.N., J.V., M.M., S.Z., J.W., H.S.Q., R.M.F.); and Department of Drug Discovery Sciences, Discovery Science Technologies, Boehringer Ingelheim Pharma GmbH & Co., Biberach an der Riss, Germany (K.B., T.B.)
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Ristovska EC, Genadieva-Dimitrova M, Todorovska B, Milivojevic V, Rankovic I, Samardziski I, Bojadzioska M. The Role of Endothelial Dysfunction in the Pathogenesis of Pregnancy-Related Pathological Conditions: A Review. Pril (Makedon Akad Nauk Umet Odd Med Nauki) 2023; 44:113-137. [PMID: 37453122 DOI: 10.2478/prilozi-2023-0032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
In the recent decades, endothelial dysfunction (ED) has been recognized as a significant contributing factor in the pathogenesis of many pathological conditions. In interaction with atherosclerosis, hypercholesterolemia, and hypertension, ED plays a crucial role in the pathogenesis of coronary artery disease, chronic renal disease, and microvascular complications in diabetes mellitus. Although ED plays a significant role in the pathogenesis of several pregnancy-related disorders such as preeclampsia, HELLP syndrome, fetal growth restriction, and gestational diabetes mellitus, the exact pathogenetic mechanisms are still a matter of debate. The increased prevalence of these entities in patients with preexisting vascular diseases highlights the essential pathological role of the preexisting ED in these patients. The abnormal uteroplacental circulation and the release of soluble factors from the ischemic placenta into the maternal bloodstream are the main causes of the maternal ED underlying the characteristic preeclamptic phenotype. Besides the increased risk for maternal and fetal poor outcomes, the preexisting ED also increases the risk of development of future cardiovascular diseases in these patients. This study aimed to look deeper into the role of ED in the pathogenesis of several pregnancy-related hypertensive and liver diseases. Hopefully, it could contribute to improvement of the awareness, knowledge, and management of these conditions and also to the reduction of the adverse outcomes and additional long-term cardiovascular complications.
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Affiliation(s)
- Elena Curakova Ristovska
- 1University Clinic for Gastroenterohepatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
| | - Magdalena Genadieva-Dimitrova
- 1University Clinic for Gastroenterohepatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
| | - Beti Todorovska
- 1University Clinic for Gastroenterohepatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
| | - Vladimir Milivojevic
- 2Section for Internal Medicine, Medcompass Alliance, School of Medicine, Belgrade University, Belgrade, Serbia
| | - Ivan Rankovic
- 3Section for Internal Medicine, Medcompass Alliance, Belgrade, Serbia
| | - Igor Samardziski
- 4University Clinic for Gynecology and Obstetrics, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
| | - Maja Bojadzioska
- 5University Clinic for Rheumatology, Faculty of Medicine, Ss. Cyril and Methodius University in Skopje, Skopje, RN Macedonia
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14
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Akbari Aghdam M, Romecín P, García-Estañ J, Atucha NM. Role of Nitric Oxide in the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis. Int J Mol Sci 2023; 24:10948. [PMID: 37446122 DOI: 10.3390/ijms241310948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 06/26/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
INTRODUCTION Previously, we found that intracellular calcium (Ca2+) homeostasis is altered in platelets from an experimental model of liver cirrhosis, namely the bile-duct-ligated (BDL) rat. These alterations are compatible with the existence of a hypercoagulable state. OBJECTIVE In the present study, we analyzed the role of nitric oxide in the abnormal calcium signaling responses of an experimental cirrhosis model, the bile duct-ligated rat. METHODS Chronic treatment with L-NAME was used to inhibit NO production in a group of control and BDL animals, and the responses compared to those obtained in a control and BDL untreated group (n = 6 each). The experiments were conducted on isolated platelets loaded with fura-2, using fluorescence spectrometry. RESULTS Chronic treatment with L-NAME increased thrombin-induced Ca2+ release from internal stores in both control and BDL rats. However, the effect was significantly greater in the BDL rats (p < 0.05). Thrombin-induced calcium entry from the extracellular space was also elevated but at lower doses and, similarly in both control and BDL platelets, treated with the NO synthesis inhibitor. Capacitative calcium entry was also enhanced in the control platelets but not in platelets from BDL rats treated with L-NAME. Total calcium in intracellular stores was elevated in untreated platelets from BDL rats, and L-NAME pretreatment significantly (p < 0.05) elevated these values both in controls and in BDL but significantly more in the BDL rats (p < 0.05). CONCLUSIONS Our results suggest that nitric oxide plays a role in the abnormal calcium signaling responses observed in platelets from BDL rats by interfering with the mechanism that releases calcium from the internal stores.
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Affiliation(s)
- Masoud Akbari Aghdam
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Paola Romecín
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Joaquín García-Estañ
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
| | - Noemí M Atucha
- Departamento de Fisiología, Facultad de Medicina, Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, 30120 Murcia, Spain
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15
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Sánchez-Meza J, Campos-Valdez M, Domínguez-Rosales JA, Godínez-Rubí JM, Rodríguez-Reyes SC, Martínez-López E, Zúñiga-González GM, Sánchez-Orozco LV. Chronic Administration of Diethylnitrosamine and 2-Acetylaminofluorene Induces Hepatocellular Carcinoma in Wistar Rats. Int J Mol Sci 2023; 24:ijms24098387. [PMID: 37176094 PMCID: PMC10179122 DOI: 10.3390/ijms24098387] [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: 03/24/2023] [Revised: 04/30/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
This study aimed to analyze the biochemical, histological, and gene expression alterations produced in a hepatocarcinogenesis model induced by the chronic administration of diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) in Wistar rats. Thirteen rats weighing 180 to 200 g were divided into two groups: control and treated. Rats in the treated group were administered an intraperitoneal (i.p.) injection of DEN (50 mg/kg/week) and an intragastric (i.g.) dose of 2-AAF (25 mg/kg/week) for 18 weeks. The treated group had significant increases in their total cholesterol, HDL-C, AST, ALT, ALKP, and GGT levels. Furthermore, a histological analysis showed the loss of normal liver architecture with nuclear pleomorphism in the hepatocytes, atypical mitosis, and fibrous septa that were distributed between the portal triads and collagen fibers through the hepatic sinusoids. The gene expressions of 24 genes related to fibrosis, inflammation, apoptosis, cell growth, angiogenesis, lipid metabolism, and alpha-fetoprotein (AFP) were analyzed; only TGFβ, COL1α1, CYP2E1, CAT, SOD, IL6, TNF-α, and ALB showed significant differences when both groups were compared. Additionally, lung histopathological alterations were found in the treated group, suggesting metastasis. In this model, the chronic administration of DEN+2-AAF induces characteristic alterations of hepatocellular carcinoma in Wistar rats without AFP gene expression changes, highlighting different signatures in hepatocellular carcinoma heterogeneity.
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Affiliation(s)
- Jaime Sánchez-Meza
- Instituto de Enfermedades Crónico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Marina Campos-Valdez
- Instituto de Enfermedades Crónico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - José Alfredo Domínguez-Rosales
- Instituto de Enfermedades Crónico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Juliana Marisol Godínez-Rubí
- Laboratorio de Patología Diagnóstica e Inmunohistoquímica, Departamento de Microbiología y Patología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
| | - Sarai Citlalic Rodríguez-Reyes
- Instituto de Nutrigenética y Nutrigenómica Traslacional, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico
| | - Erika Martínez-López
- Instituto de Nutrigenética y Nutrigenómica Traslacional, Centro Universitario de Ciencias de la Salud, Guadalajara 44340, Mexico
| | - Guillermo M Zúñiga-González
- Laboratorio de Mutagénesis, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Mexico
| | - Laura Verónica Sánchez-Orozco
- Instituto de Enfermedades Crónico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Mexico
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Reiberger T, Berzigotti A, Trebicka J, Ertle J, Gashaw I, Swallow R, Tomisser A. The rationale and study design of two phase II trials examining the effects of BI 685,509, a soluble guanylyl cyclase activator, on clinically significant portal hypertension in patients with compensated cirrhosis. Trials 2023; 24:293. [PMID: 37095557 PMCID: PMC10123479 DOI: 10.1186/s13063-023-07291-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 04/03/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Clinically significant portal hypertension (CSPH) drives cirrhosis-related complications (i.e. hepatic decompensation). Impaired nitric oxide (NO) bioavailability promotes sinusoidal vasoconstriction, which is the initial pathomechanism of CSPH development. Activation of soluble guanylyl cyclase (sGC), a key downstream effector of NO, facilitates sinusoidal vasodilation, which in turn may improve CSPH. Two phase II studies are being conducted to assess the efficacy of the NO-independent sGC activator BI 685,509 in patients with CSPH due to various cirrhosis aetiologies. METHODS The 1366.0021 trial (NCT05161481) is a randomised, placebo-controlled, exploratory study that will assess BI 685,509 (moderate or high dose) for 24 weeks in patients with CSPH due to alcohol-related liver disease. The 1366.0029 trial (NCT05282121) is a randomised, open-label, parallel-group, exploratory study that will assess BI 685,509 (high dose) alone in patients with hepatitis B or C virus infection or non-alcoholic steatohepatitis (NASH) and in combination with 10 mg empagliflozin in patients with NASH and type 2 diabetes mellitus for 8 weeks. The 1366.0021 trial will enrol 105 patients, and the 1366.0029 trial will enrol 80 patients. In both studies, the primary endpoint is the change from baseline in hepatic venous pressure gradient (HVPG) until the end of treatment (24 or 8 weeks, respectively). Secondary endpoints include the proportion of patients with an HVPG reduction of > 10% from baseline, the development of decompensation events and the change from baseline in HVPG after 8 weeks in the 1366.0021 trial. In addition, the trials will assess changes in liver and spleen stiffness by transient elastography, changes in hepatic and renal function and the tolerability of BI 685,509. DISCUSSION These trials will enable the assessment of the short-term (8 weeks) and longer-term (24 weeks) effects and safety of sGC activation by BI 685,509 on CSPH due to various cirrhosis aetiologies. The trials will use central readings of the diagnostic gold standard HVPG for the primary endpoint, as well as changes in established non-invasive biomarkers, such as liver and spleen stiffness. Ultimately, these trials will provide key information for developing future phase III trials. TRIAL REGISTRATION 1366.0021: EudraCT no. 2021-001,285-38; ClinicalTrials.gov NCT05161481. Registered on 17 December 2021, https://www. CLINICALTRIALS gov/ct2/show/NCT05161481 . 1366.0029: EudraCT no. 2021-005,171-40; ClinicalTrials.gov NCT05282121. Registered on 16 March 2022, https://www. CLINICALTRIALS gov/ct2/show/NCT05282121 .
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Affiliation(s)
- Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
- Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria.
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
| | - Annalisa Berzigotti
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
- European Foundation for the Study of Chronic Liver Failure, EFCLIF, Barcelona, Spain
| | - Judith Ertle
- Boehringer Ingelheim International GmbH, Ingelheim Am Rhein, Germany
| | - Isabella Gashaw
- Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim Am Rhein, Germany
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Sepehrinezhad A, Stolze Larsen F, Ashayeri Ahmadabad R, Shahbazi A, Sahab Negah S. The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review. Cells 2023; 12:cells12070979. [PMID: 37048052 PMCID: PMC10093707 DOI: 10.3390/cells12070979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, 999017 Copenhagen, Denmark
| | | | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1449614535, Iran
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Hristov B, Andonov V, Doykov D, Doykova K, Valova S, Nacheva-Georgieva E, Uchikov P, Kostov G, Doykov M, Tilkian E. Evaluation of Liver Stiffness Measurement by Means of 2D-SWE for the Diagnosis of Esophageal Varices. Diagnostics (Basel) 2023; 13:diagnostics13030356. [PMID: 36766459 PMCID: PMC9914861 DOI: 10.3390/diagnostics13030356] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 01/21/2023] Open
Abstract
Portal hypertension (PH) and esophageal varices (EVs) are a matter of extensive research. According to current Baveno VII guidelines, in patients with compensated advanced chronic liver disease (cACLD), liver stiffness measurement (LSM) < 15 kPa and PLT count > 150 × 109/L, upper endoscopy (UE) is not mandatory, and the emphasis should be set on non-invasive methods for evaluation of clinically significant portal hypertension (CSPH). The aim of this study is to establish whether liver stiffness (LS) measured by 2D-SWE could be used as a predictor for the presence and severity of EVs in cirrhotic patients. In total, 86 patients of whom 32 with compensated liver cirrhosis (cLC) and 54 with decompensated liver cirrhosis (dLC) were examined in the Gastroenterology clinic of University hospital "Kaspela", Plovdiv, Bulgaria. Each patient underwent LS assessment by 2D-SWE and EVs grading by UE. EVs were detected in 47 (54.7%) patients, 23 (49%) of them were stage 4-high-risk EVs (HREV). The cut-off value for LS that differentiates HREV from the rest was set at 2.49 m/s with 100% sensitivity and 100% specificity (AUC 1.000, CI 0.925). Conclusions: 2D-SWE can be used as a non-invasive method in the assessment of only high-grade esophageal varices. For the other grades, upper endoscopy remains the method of choice.
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Affiliation(s)
- Bozhidar Hristov
- Second Department of Internal Diseases, Section “Gastroenterology”, Medical Faculty, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Gastroenterology Clinic, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
- Correspondence: Correspondence: ; Tel.: +359-88-4278187
| | - Vladimir Andonov
- Second Department of Internal Diseases, Section “Gastroenterology”, Medical Faculty, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Gastroenterology Clinic, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
| | - Daniel Doykov
- Second Department of Internal Diseases, Section “Gastroenterology”, Medical Faculty, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Gastroenterology Clinic, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
| | - Katya Doykova
- Department of Diagnostic Imaging, Medical Faculty, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Department of Diagnostic Imaging, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
| | - Siyana Valova
- Second Department of Internal Diseases, Section “Nephrology”, Medical Faculty, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Clinic of Nephrology, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
| | - Emiliya Nacheva-Georgieva
- Second Department of Internal Diseases, Section “Gastroenterology”, Medical Faculty, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Gastroenterology Clinic, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
| | - Petar Uchikov
- Department of Special Surgery, Faculty of Medicine, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- St. George University Hospital, 4000 Plovdiv, Bulgaria
| | - Gancho Kostov
- Department of Special Surgery, Faculty of Medicine, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Department of Surgery, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
| | - Mladen Doykov
- Department of Urology and General Medicine, Medical Faculty, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Clinic of Urology, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
| | - Eduard Tilkian
- Second Department of Internal Diseases, Section “Nephrology”, Medical Faculty, Medical University of Plovdiv, 6000 Plovdiv, Bulgaria
- Clinic of Nephrology, University Hospital “Kaspela”, 4001 Plovdiv, Bulgaria
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19
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Sauerbruch T, Hennenberg M, Trebicka J, Schierwagen R. Beta-blockers in patients with liver cirrhosis: Pragmatism or perfection? Front Med (Lausanne) 2023; 9:1100966. [PMID: 36743678 PMCID: PMC9891090 DOI: 10.3389/fmed.2022.1100966] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 12/12/2022] [Indexed: 01/11/2023] Open
Abstract
With increasing decompensation, hyperdynamic circulatory disturbance occurs in liver cirrhosis despite activation of vasoconstrictors. Here, the concept of a therapy with non-selective beta-blockers was established decades ago. They lower elevated portal pressure, protect against variceal hemorrhage, and may also have pleiotropic immunomodulatory effects. Recently, the beneficial effect of carvedilol, which blocks alpha and beta receptors, has been highlighted. Carvedilol leads to "biased-signaling" via recruitment of beta-arrestin. This effect and its consequences have not been sufficiently investigated in patients with liver cirrhosis. Also, a number of questions remain open regarding the expression of beta-receptors and its intracellular signaling and the respective consequences in the intra- and extrahepatic tissue compartments. Despite the undisputed role of non-selective beta-blockers in the treatment of liver cirrhosis, we still can improve the knowledge as to when and how beta-blockers should be used in which patients.
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Affiliation(s)
- Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Martin Hennenberg
- Department of Urology, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
| | - Jonel Trebicka
- Department of Internal Medicine B, University of Münster, Münster, Germany
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Robert Schierwagen
- Department of Internal Medicine B, University of Münster, Münster, Germany
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20
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Santopaolo F, Coppola G, Giuli L, Gasbarrini A, Ponziani FR. Influence of Gut–Liver Axis on Portal Hypertension in Advanced Chronic Liver Disease: The Gut Microbiome as a New Protagonist in Therapeutic Management. MICROBIOLOGY RESEARCH 2022; 13:539-555. [DOI: 10.3390/microbiolres13030038] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Clinically significant portal hypertension is associated with most complications of advanced chronic liver disease (ACLD), including variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. Gut dysbiosis is a hallmark of ACLD with portal hypertension and consists of the overgrowth of potentially pathogenic bacteria and a decrease in autochthonous bacteria; additionally, congestion makes the intestinal barrier more permeable to bacteria and their products, which contributes to the development of complications through inflammatory mechanisms. This review summarizes current knowledge on the role of the gut–liver axis in the pathogenesis of portal hypertension, with a focus on therapies targeting portal hypertension and the gut microbiota. The modulation of the gut microbiota on several levels represents a major challenge in the upcoming years; in-depth characterization of the molecular and microbiological mechanisms linking the gut–liver axis to portal hypertension in a bidirectional relationship could pave the way to the identification of new therapeutic targets for innovative therapies in the management of ACLD.
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Affiliation(s)
- Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Gaetano Coppola
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Lucia Giuli
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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21
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Lesmana CRA, Paramitha MS, Gani RA, Lesmana LA. The role of endoscopic ultrasound for portal hypertension in liver cirrhosis. J Med Ultrason (2001) 2022; 49:359-370. [PMID: 34797476 DOI: 10.1007/s10396-021-01165-4] [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: 06/01/2021] [Accepted: 08/14/2021] [Indexed: 10/19/2022]
Abstract
Chronic liver disease is still a major problem because disease progression will ultimately lead to liver cirrhosis. Portal hypertension is the hallmark in advanced liver disease management. By establishing portal vein access, endoscopic ultrasound (EUS) has been utilized in various clinical applications. In comparison to standard upper gastrointestinal endoscopy, EUS-Doppler has been shown to be a better modality for detecting esophageal and gastric varices along with peri-esophageal collateral veins, para-esophageal collateral veins, and perforating veins, and may be used to objectively predict the recurrence of bleeding. EUS-guided portal vein catheterization has also been proposed to overcome the limitations of trans-jugular approaches. The combination of EUS-elastography and azygos vein evaluation can also enhance the diagnostic accuracy of each modality. Another well-known implementation of EUS-guided procedures is in the management of ascites; particularly in paracentesis and ascitic fluid analysis. In addition, the most common clinical application of EUS in the treatment of portal hypertension is through vascular therapy or creation of intrahepatic portosystemic shunts. Major drawbacks of EUS mainly revolve around technical difficulties, the high cost of the procedure, as well as the requirement of more studies in humans to evaluate EUS-guided advanced therapeutic modalities in portal hypertension.
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Affiliation(s)
- Cosmas Rinaldi Adithya Lesmana
- Hepatobiliary Division, Department of Internal Medicine, Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia.
- Digestive Disease and GI Oncology Center, Medistra Hospital, Jakarta, Indonesia.
| | - Maria Satya Paramitha
- Hepatobiliary Division, Department of Internal Medicine, Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
| | - Rino A Gani
- Hepatobiliary Division, Department of Internal Medicine, Dr. Cipto Mangunkusumo National General Hospital, Medical Faculty Universitas Indonesia, Jakarta, Indonesia
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22
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Papagiouvanni I, Theodorakopoulou MP, Sarafidis PA, Sinakos E, Goulis I. Peripheral endothelial and microvascular damage in liver cirrhosis: A systematic review and meta-analysis. Microcirculation 2022; 29:e12773. [PMID: 35652811 DOI: 10.1111/micc.12773] [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: 02/18/2022] [Revised: 04/13/2022] [Accepted: 05/25/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVE This is the first systematic review and meta-analysis of studies using any available functional method to examine differences in peripheral endothelial function between cirrhotic and non-cirrhotic individuals. METHODS Literature search involved PubMed, Web-of-Science, and Scopus databases, as well as gray literature sources. We included studies in adult subjects evaluating endothelial function with any semi-invasive or non-invasive functional method in patients with and without liver cirrhosis. RESULTS From 3378 records initially retrieved, 15 studies with a total of 570 participants were included in the final quantitative meta-analysis. In six studies examining endothelial function with flow-mediated-dilatation, no differences between patients with cirrhosis and controls were evident (WMD: 1.33, 95%CI [-2.87, 5.53], I2 = 97%, p < .00001). Among studies assessing differences in endothelial-dependent or endothelial-independent vasodilation with venous-occlusion-plethysmography, there were no significant differences between the two groups. When pooling all studies together, regardless of the technique used, no significant difference in endothelial function between cirrhotic patients and controls was observed(SMD: 0.79, 95%CI[-0.04, 1.63], I2 = 94%, p < .00001). CONCLUSIONS No differences in peripheral endothelial function assessed with semi-invasive or non-invasive functional methods exist between cirrhotic and non-cirrhotic subjects. The increasing co-existence of cardiovascular risk factors leading to impaired vascular reactivity in cirrhotic patients may partly explain these findings.
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Affiliation(s)
- Ioanna Papagiouvanni
- Fourth Department of Internal Medicine, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Marieta P Theodorakopoulou
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pantelis A Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Emmanouil Sinakos
- Fourth Department of Internal Medicine, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Goulis
- Fourth Department of Internal Medicine, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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23
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Abstract
Hepatorenal syndrome (HRS) is defined as a functional renal failure without major histologic changes in individuals with severe liver disease and it is associated with a high mortality rate. Renal hypoperfusion due to marked vasoconstriction as a result of complex circulatory dysfunction has been suggested to be the cornerstone of HRS. Splanchnic and peripheral arterial vasodilation and cirrhotic cardiomyopathy result in effective arterial hypovolemia and compensatory activation of vasoconstrictor mechanisms. The efficacy of current therapeutic strategies targeting this circulatory dysfunction is limited. Increasing evidence suggests a substantial role of systemic inflammation in HRS via either vascular or direct renal effects. Here we summarize the current understanding of HRS pathophysiology.
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Affiliation(s)
- Timea Csak
- Sandra Atlas Bass Center for Liver Diseases, Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA.
| | - David Bernstein
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 400 Community Drive, Manhasset, NY 11030, USA
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24
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Iwahashi N, Horii M, Tamura K, Kimura K. Worsening Dyspnea in Patients With Idiopathic Portal Hypertension. Chest 2022; 161:e245-e248. [DOI: 10.1016/j.chest.2021.05.077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/06/2021] [Accepted: 05/29/2021] [Indexed: 10/18/2022] Open
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25
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Huang HC, Hsu SJ, Chang CC, Kao YC, Chuang CL, Hou MC, Lee FY. Lycopene treatment improves intrahepatic fibrosis and attenuates pathological angiogenesis in biliary cirrhotic rats. J Chin Med Assoc 2022; 85:414-420. [PMID: 35120355 DOI: 10.1097/jcma.0000000000000699] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Liver cirrhosis is characterized by liver fibrosis and pathological angiogenesis, which results in hyperdynamic circulation, portal-systemic collateral vascular formation, and abnormal angiogenesis. Lycopene is a nutrient mostly found in tomatoes. The beneficial effects of lycopene include anti-inflammation, anti-oxidation, anti-fibrosis, and anti-angiogenesis; however, the association between liver cirrhosis and pathological angiogenesis has yet to be studied. This study aimed to investigate the effects of lycopene on biliary cirrhotic rats. METHODS The efficacy of lycopene treatment in common bile duct ligation (BDL)-induced biliary cirrhotic rats was evaluated. Sham-operated rats served as surgical controls. Lycopene (20 mg/kg/day, oral gavage) or vehicle was administered to BDL or sham-operated rats for 4 weeks, after which the hemodynamics, liver biochemistry, portal-systemic shunting, liver and mesenteric angiogenesis, and hepatic angiogenesis-related protein expressions were examined. RESULTS Lycopene alleviated hyperdynamic circulation as evidenced by decreased cardiac index and increased peripheral vascular resistance (p < 0.05), but it did not affect portal pressure or liver biochemistry in the BDL rats (p > 0.05). Lycopene significantly diminished the shunting degree of portal-systemic collaterals (p = 0.04) and mesenteric vascular density (p = 0.01), and also ameliorated intrahepatic angiogenesis and liver fibrosis. In addition, lycopene upregulated endothelial nitric oxide synthase, protein kinase B (Akt) and phosphatidylinositol 3-kinases (PI3K), and downregulated vascular endothelial growth factor receptor 2 (VEGFR-2) protein expressions (p < 0.05) in the livers of the BDL rats. CONCLUSION Lycopene ameliorated liver fibrosis, hyperdynamic circulation, and pathological angiogenesis in biliary cirrhotic rats, possibly through the modulation of intrahepatic Akt/PI3K/eNOS and VEGFR-2 pathways.
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Affiliation(s)
- Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yun-Chieh Kao
- Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chiao-Lin Chuang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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26
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Schreier B, Zipprich A, Uhlenhaut H, Gekle M. Mineralocorticoid receptor in non-alcoholic fatty liver disease. Br J Pharmacol 2021; 179:3165-3177. [PMID: 34935140 DOI: 10.1111/bph.15784] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/12/2021] [Accepted: 11/30/2021] [Indexed: 11/30/2022] Open
Abstract
Liver diseases are the fourth common death in Europe responsible for about 2 million death per year worldwide. Among the known detrimental causes for liver dysfunction are virus infections, intoxications and obesity. The mineralocorticoid receptor (MR) is a ligand-dependent transcription factor activated by aldosterone or glucocorticoids but also by pathological milieu factors. Canonical actions of the MR take place in epithelial cells of kidney, colon and sweat glands and contribute to sodium reabsorption, potassium secretion and extracellular volume homeostasis. The non-canonical functions can be initiated by inflammation or an altered micro milieu leading to fibrosis, hypertrophy and remodeling in various tissues. This narrative review summarizes the evidence regarding the role of MR in portal hypertension, non-alcoholic fatty liver disease, liver fibrosis and cirrhosis, demonstrating that inhibition of the MR in vivo seems to be beneficial for liver function and not just for volume regulation. Unfortunately, the underlying molecular mechanisms are still not completely understood.
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Affiliation(s)
- Barbara Schreier
- Julius-Bernstein-Institute of Physiology, Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
| | - Alexander Zipprich
- Department of Internal Medicine IV, Friedrich-Schiller-University Jena, Jena, Germany
| | - Henriette Uhlenhaut
- TUM School of Life Sciences, Technical University of Munich, Freising-Weihenstephan, Germany
| | - Michael Gekle
- Julius-Bernstein-Institute of Physiology, Medical Faculty of the Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
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27
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The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer. Cancers (Basel) 2021; 13:cancers13225719. [PMID: 34830874 PMCID: PMC8616349 DOI: 10.3390/cancers13225719] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary During the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development. Abstract The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
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28
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Huang HC, Ho HL, Chang CC, Chuang CL, Pun CK, Lee FY, Huang YH, Hou MC, Hsu SJ. Matrix metalloproteinase-9 inhibition or deletion attenuates portal hypertension in rodents. J Cell Mol Med 2021; 25:10073-10087. [PMID: 34647412 PMCID: PMC8572799 DOI: 10.1111/jcmm.16940] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 12/29/2022] Open
Abstract
Liver cirrhosis and portal hypertension are accompanied by hyperdynamic circulation, angiogenesis and portosystemic collaterals. Matrix metalloproteinases (MMPs) participate in fibrogenesis and angiogenesis, however, whether they can be targeted in cirrhosis treatment is unclear. Therefore, we performed three series of experiments to investigate this issue. Liver cirrhosis was induced by common bile duct ligation (BDL) in Sprague‐Dawley rats. Sham‐operated rats served as controls. Rats were randomly allocated to receive vehicle, minocycline (a nonselective MMP inhibitor) or SB‐3CT (MMP‐2 and −9 inhibitor) for 28 days in the first and second series, respectively. MMP‐9 knockout mice were used in the third series. The results showed that minocycline ameliorated portal hypertension, hemodynamic abnormalities, reduced collateral shunting, mesenteric vascular density, plasma VEGF level and alleviated liver fibrosis. SB‐3CT attenuated portal hypertension, hemodynamic derangements, reduced shunting, mesenteric vascular density, mesenteric VEGF protein expression, and liver fibrosis. Knockout BDL mice had significantly alleviated portal hypertension, liver fibrosis, liver α‐SMA and mesenteric eNOS protein expressions compared to wild‐type BDL mice. Liver SMAD2 phosphorylation was down‐regulated in all series with MMP inhibition or knock‐out. In conclusion, MMP‐9 inhibition or deletion ameliorated the severity of cirrhosis, portal hypertension, and associated derangements. MMP‐9 may be targeted in the treatment of liver cirrhosis.
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Affiliation(s)
- Hui-Chun Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsin-Ling Ho
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Lo-Hsu Medical Foundation, Lotung Poh-Ai Hospital, Yilan, Taiwan
| | - Ching-Chih Chang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chiao-Lin Chuang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chon Kit Pun
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Fa-Yauh Lee
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ming-Chih Hou
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shao-Jung Hsu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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29
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Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet 2021; 398:1359-1376. [PMID: 34543610 DOI: 10.1016/s0140-6736(21)01374-x] [Citation(s) in RCA: 769] [Impact Index Per Article: 192.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 06/02/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023]
Abstract
Cirrhosis is widely prevalent worldwide and can be a consequence of different causes, such as obesity, non-alcoholic fatty liver disease, high alcohol consumption, hepatitis B or C infection, autoimmune diseases, cholestatic diseases, and iron or copper overload. Cirrhosis develops after a long period of inflammation that results in replacement of the healthy liver parenchyma with fibrotic tissue and regenerative nodules, leading to portal hypertension. The disease evolves from an asymptomatic phase (compensated cirrhosis) to a symptomatic phase (decompensated cirrhosis), the complications of which often result in hospitalisation, impaired quality of life, and high mortality. Progressive portal hypertension, systemic inflammation, and liver failure drive disease outcomes. The management of liver cirrhosis is centred on the treatment of the causes and complications, and liver transplantation can be required in some cases. In this Seminar, we discuss the disease burden, pathophysiology, and recommendations for the diagnosis and management of cirrhosis and its complications. Future challenges include better screening for early fibrosis or cirrhosis, early identification and reversal of causative factors, and prevention of complications.
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Affiliation(s)
- Pere Ginès
- Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; Institute of Biomedical Investigation August Pi I Sunyer, Barcelona, Spain; Hepatic and Digestive Diseases Biomedical Investigation Center, Madrid, Spain.
| | - Aleksander Krag
- Centre for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Juan G Abraldes
- Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, AB, Canada
| | - Elsa Solà
- Liver Unit, Hospital Clinic of Barcelona, Barcelona, Spain; Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA
| | - Núria Fabrellas
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; Institute of Biomedical Investigation August Pi I Sunyer, Barcelona, Spain; Hepatic and Digestive Diseases Biomedical Investigation Center, Madrid, Spain
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Sauerbruch T, Hennenberg M, Trebicka J, Beuers U. Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction. Front Physiol 2021; 12:718783. [PMID: 34393832 PMCID: PMC8358446 DOI: 10.3389/fphys.2021.718783] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.
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Affiliation(s)
- Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Martin Hennenberg
- Department of Urology I, University Hospital, LMU Munich, Munich, Germany
| | - Jonel Trebicka
- Translational Hepatology, Medical Department, University of Frankfurt, Frankfurt, Germany
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands
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Baiocchi L, Glaser S, Francis H, Kennedy L, Felli E, Alpini G, Gracia‐Sancho J. Impact of Aging on Liver Cells and Liver Disease: Focus on the Biliary and Vascular Compartments. Hepatol Commun 2021; 5:1125-1137. [PMID: 34278165 PMCID: PMC8279468 DOI: 10.1002/hep4.1725] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 02/26/2021] [Accepted: 03/16/2021] [Indexed: 12/11/2022] Open
Abstract
The aging process is represented by the time-dependent decay in physiologic functions of living beings. Major interest has been focused in recent years on the determinants of this progressive condition due to its correlative relationship with the onset of diseases. Several hallmark features have been observed in aging, such as genetic alterations, mitochondrial impairment, and telomere shortening. At the cellular level, a senescent phenotype has been identified in response to aging that is characterized by a flat appearance, proliferative arrest, and production of specific molecules. The net effect of these cells in the course of diseases is an argument of debate. In fact, while the onset of a senescent phenotype may prevent tumor spreading, these cells appear to support pathological processes in some conditions. Several studies are now focused on clarifying the specific molecular pathways of aging/senescence in different cells, tissues, or organs. Biliary and vascular components, within the liver, have emerged as important determinants of some form of liver disease. In this review we summarize the most recent achievements on aging/senescence, focusing on the biliary and vascular liver system. Conclusion: Several findings, in both preclinical animal models and on human liver specimens, converge in supporting the presence of specific aging hallmarks in the diseases involving these hepatic compartments.
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Affiliation(s)
- Leonardo Baiocchi
- Hepatology UnitDepartment of MedicineUniversity of Tor VergataRomeItaly
| | - Shannon Glaser
- Medical PhysiologyTexas A&M College of MedicineBryanTXUSA
| | - Heather Francis
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Lindsey Kennedy
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Eric Felli
- HepatologyDepartment of Biomedical ResearchInselspitalBernSwitzerland
| | - Gianfranco Alpini
- Hepatology and MedicineIndiana UniversityIndianapolisINUSA
- Richard L. Roudebush VA Medical CenterIndianapolisINUSA
| | - Jordi Gracia‐Sancho
- Liver Vascular BiologyIDIBAPS Biomedical Research Institute and CIBEREHDBarcelonaSpain
- HepatologyDepartment of Biomedical ResearchInselspitalBernSwitzerland
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Engelmann C, Clària J, Szabo G, Bosch J, Bernardi M. Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction. J Hepatol 2021; 75 Suppl 1:S49-S66. [PMID: 34039492 PMCID: PMC9272511 DOI: 10.1016/j.jhep.2021.01.002] [Citation(s) in RCA: 203] [Impact Index Per Article: 50.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acute-on-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure(s). The pathomechanisms involved in decompensation and disease progression are still not well understood, and as specific disease-modifying treatments do not exist, research to identify novel therapeutic targets is of the utmost importance. This review amalgamates the latest knowledge on disease mechanisms that lead to tissue injury and extrahepatic organ failure - such as systemic inflammation, mitochondrial dysfunction, oxidative stress and metabolic changes - and marries these with the classical paradigms of acute decompensation to form a single paradigm. With this detailed breakdown of pathomechanisms, we identify areas for future research. Novel disease-modifying strategies that break the vicious cycle are urgently required to improve patient outcomes.
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Affiliation(s)
- Cornelius Engelmann
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany; Institute for Liver and Digestive Health, University College London, London, United Kingdom; Section Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany; Berlin Institute of Health (BIH), Berlin, Germany.
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain,Biochemistry and Molecular Genetics Service, Hospital ClínicIDIBAPS and CIBERehd, Spain,Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain
| | - Gyongyi Szabo
- Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
| | - Jaume Bosch
- IDIBAPS and CIBERehd, University of Barcelona, Barcelona, Spain,Department for Biomedical Research (DBMR), Bern University, Bern, Switzerland
| | - Mauro Bernardi
- Department of Medical and Surgical Sciences; Alma Mater Studiorum – University of Bologna; Italy
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Serum Amyloid Beta42 Is Not Eliminated by the Cirrhotic Liver: A Pilot Study. J Clin Med 2021; 10:jcm10122669. [PMID: 34204545 PMCID: PMC8235170 DOI: 10.3390/jcm10122669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Amyloid-beta (Aβ) deposition in the brain is the main pathological hallmark of Alzheimer disease. Peripheral clearance of Aβ may possibly also lower brain levels. Recent evidence suggested that hepatic clearance of Aβ42 is impaired in liver cirrhosis. To further test this hypothesis, serum Aβ42 was measured by ELISA in portal venous serum (PVS), systemic venous serum (SVS), and hepatic venous serum (HVS) of 20 patients with liver cirrhosis. Mean Aβ42 level was 24.7 ± 20.4 pg/mL in PVS, 21.2 ± 16.7 pg/mL in HVS, and 19.2 ± 11.7 pg/mL in SVS. Similar levels in the three blood compartments suggested that the cirrhotic liver does not clear Aβ42. Aβ42 was neither associated with the model of end-stage liver disease score nor the Child–Pugh score. Patients with abnormal creatinine or bilirubin levels or prolonged prothrombin time did not display higher Aβ42 levels. Patients with massive ascites and patients with large varices had serum Aβ42 levels similar to patients without these complications. Serum Aβ42 was negatively associated with connective tissue growth factor levels (r = −0.580, p = 0.007) and a protective role of Aβ42 in fibrogenesis was already described. Diabetic patients with liver cirrhosis had higher Aβ42 levels (p = 0.069 for PVS, p = 0.047 for HVS and p = 0.181 for SVS), which is in accordance with previous reports. Present analysis showed that the cirrhotic liver does not eliminate Aβ42. Further studies are needed to explore the association of liver cirrhosis, Aβ42 levels, and cognitive dysfunction.
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Hartl L, Jachs M, Desbalmes C, Schaufler D, Simbrunner B, Paternostro R, Schwabl P, Bauer DJM, Semmler G, Scheiner B, Bucsics T, Eigenbauer E, Marculescu R, Szekeres T, Peck-Radosavljevic M, Kastl S, Trauner M, Mandorfer M, Reiberger T. The differential activation of cardiovascular hormones across distinct stages of portal hypertension predicts clinical outcomes. Hepatol Int 2021; 15:1160-1173. [PMID: 34021479 PMCID: PMC8514393 DOI: 10.1007/s12072-021-10203-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023]
Abstract
Background and aims The cardiovascular hormones renin/angiotensin/aldosterone (RAA), brain-type natriuretic peptide (BNP)and arginine-vasopressin (AVP) are key regulators of systemic circulatory homeostasis in portal hypertension (PH). We assessed (i) the activation of renin, BNP and AVP across distinct stages of PH and (ii) whether activation of these hormones correlates with clinical outcomes. Methods Plasma levels of renin, proBNP and copeptin (AVP biomarker) were determined in 663 patients with advanced chronic liver disease (ACLD) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital between 11/2011 and 02/2019. We stratified for Child stage (A–C), HVPG (6–9 mmHg, 10–15 mmHg, ≥ 16 mmHg) and compensated vs. decompensated ACLD. Results With increasing PH, hyperdynamic state was indicated by higher heart rates (6–9 mmHg: median 71.0 [IQR 18.0] bpm, 10–15 mmHg: 76.0 [19.0] bpm, ≥ 16 mmHg: 80.0 [22.0] bpm; p < 0.001), lower mean arterial pressure (6–9 mmHg: 103.0 [13.5] mmHg, 10–15 mmHg: 101.0 [19.5] mmHg, ≥ 16 mmHg: 99.0 [21.0] mmHg; p = 0.032) and lower serum sodium (6–9 mmHg: 139.0 [3.0] mmol/L, 10–15 mmHg: 138.0 [4.0] mmol/L, ≥ 16 mmHg: 138.0 [5.0] mmol/L; p < 0.001). Across HVPG strata (6–9 mmHg vs. 10–15 mmHg vs ≥ 16 mmHg), median plasma levels of renin (21.0 [50.5] vs. 25.1 [70.9] vs. 65.4 [219.6] µIU/mL; p < 0.001), proBNP (86.1 [134.0] vs. 63.6 [118.0], vs. 132.2 [208.9] pg/mL; p = 0.002) and copeptin (7.8 [7.7] vs. 5.6 [8.0] vs. 10.7 [18.6] pmol/L; p = 0.024) increased with severity of PH. Elevated renin levels independently predicted first hepatic decompensation (adjusted hazard ratio [aHR]: 1.69; 95% confidence interval [95% CI] 1.07–2.68; p = 0.025) and mortality in compensated patients (aHR: 3.15; 95% CI 1.70–5.84; p < 0.001) and the overall cohort aHR: 1.42; 95% CI 1.01–2.01; p = 0.046). Elevated copeptin levels predicted mortality in decompensated patients (aHR: 5.77; 95% CI 1.27–26.33; p = 0.024) and in the overall cohort (aHR: 3.29; 95% CI 1.36–7.95; p = 0.008). ProBNP levels did not predict clinical outcomes. Conclusions The cardiovascular hormones renin, proBNP and AVP are activated with progression of ACLD and PH. Renin activation is a risk factor for hepatic decompensation and mortality, especially in compensated patients. Increased plasma copeptin is a risk factor for mortality, in particular in decompensated patients. Supplementary Information The online version contains supplementary material available at 10.1007/s12072-021-10203-9.
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Affiliation(s)
- Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Christopher Desbalmes
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Dunja Schaufler
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria.,Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria.,Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - David Josef Maria Bauer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Theresa Bucsics
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Ernst Eigenbauer
- IT-Systems and Communications, Medical University of Vienna, Vienna, Austria
| | - Rodrig Marculescu
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Thomas Szekeres
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria.,Department of Internal Medicine and Gastroenterology (IMuG), Hepatology, Endocrinology, Rheumatology and Nephrology, Central Emergency Medicine (ZAE), Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Stefan Kastl
- Division of Cardiology, Department of Medicine II, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria. .,Vienna Hepatic Hemodynamic Lab, Medical University of Vienna, Vienna, Austria. .,Christian Doppler Lab for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
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Dourakis SP, Geladari E, Geladari C, Vallianou N. Cirrhotic Cardiomyopathy: The Interplay Between Liver and Cardiac Muscle. How Does the Cardiovascular System React When the Liver is Diseased? Curr Cardiol Rev 2021; 17:78-84. [PMID: 31072296 PMCID: PMC8142364 DOI: 10.2174/1573403x15666190509084519] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 04/21/2019] [Accepted: 04/22/2019] [Indexed: 12/03/2022] Open
Abstract
It is widely known that liver cirrhosis, regardless of the etiologies is accompanied by severe hemodynamic changes. The principal pathophysiological mechanisms are the hyperdynamic circulation with increased cardiac output, heart rate along with reduced systemic vascular resistance. Thus, counteractive mechanisms may develop that eventually lead to systolic as well as diastolic dysfunction and rhythm disturbances, in order to keep a steady homeostasis in the human body. Literally, blunted contractile responsiveness to physical or pharmacological stress, impaired diastolic relaxation and electrophysiological changes, primarily QT interval prolongation, do occur progressively in a cirrhotic patient with no known preexisting cardiac disease. This condition is identified as cirrhotic cardiomyopathy (CCM), an entity different from that seen in alcoholic cardiac muscle disease. For the past decades, clinicians did study and attempt to understand the pathophysiology and clinical significance of this process. Indeed, various factors have been identified acting at the molecular and cellular level. Electrocardiography, echocardiography and various serum biomarkers are the main tools that help healthcare practitioners to point to the correct diagnosis. Noteworthy, the subjects that suffer from cirrhotic cardiomyopathy may progress to heart failure during invasive procedures such as surgery, insertion of a transjugular intrahepatic portosystemic shunting (TIPS) and liver transplantation. Besides, several studies have illustrated that CCM is a contributing factor, or even a precipitant, of hepatorenal syndrome (HRS), a conceivable reversible kidney failure in patients with liver cirrhosis and ascites. The treatment is the same as it is in the patients with liver cirrhosis and heart failure and there is no particular treatment for cirrhotic cardiomyopathy. Hence, it is of utmost importance to clearly comprehend the pathophysiology of this disease in order to design more accurate diagnostic tools and definitive treatments in a way to prevent the complications of cirrhosis and overt heart failure. The objective of this review is to describe in a comprehensive way the pathological alterations that occur in the cardiovascular system of cirrhotic patients. It will also point the limitations that remain in the diagnosis and treatment strategies and more importantly, this review will alert the clinicians in the modern era to further observe and record additional pathological changes in this subset of patients.
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Affiliation(s)
- Spyros P Dourakis
- 2nd Department of Internal Medicine and Research Laboratory, Medical School, National and Kapodistrian University of Athens, Hippokration Hospital, Athens, Greece
| | - Eleni Geladari
- Internal Medicine Department, Evaggelismos General Hospital, Athens, Greece
| | | | - Natalia Vallianou
- Internal Medicine Department, Evaggelismos General Hospital, Athens, Greece
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The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol 2021; 74:670-685. [PMID: 33301825 DOI: 10.1016/j.jhep.2020.11.048] [Citation(s) in RCA: 263] [Impact Index Per Article: 65.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 11/24/2020] [Accepted: 11/30/2020] [Indexed: 12/11/2022]
Abstract
Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and left ventricular dysfunction, hepatic encephalopathy to hyperammonaemia, and variceal haemorrhage to portal hypertension. Recent large-scale European observational studies have shown that systemic inflammation is a hallmark of AD. Here we present a working hypothesis, the systemic inflammation hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or more of the major organ systems may be a common theme and act synergistically with the traditional mechanisms involved in the development of AD. Systemic inflammation may impair organ system function through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxide-mediated accentuation of the preexisting splanchnic vasodilation, resulting in the overactivation of the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in certain vascular beds, in particular the renal circulation. Second, systemic inflammation may cause immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritisation of metabolic fuels for inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result in decreased mitochondrial production of ATP (energy) and subsequently impaired organ function.
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Lu J, Zhao YL, Zhang XQ, Li LJ. The vascular endothelial growth factor signaling pathway regulates liver sinusoidal endothelial cells during liver regeneration after partial hepatectomy. Expert Rev Gastroenterol Hepatol 2021; 15:139-147. [PMID: 32902336 DOI: 10.1080/17474124.2020.1815532] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Liver regeneration after partial hepatectomy is a very complex and well-regulated procedure. It utilizes all liver cell types, which are associated with signaling pathways involving growth factors, cytokines, and stimulatory and inhibitory feedback of several growth-related signals. Liver sinusoidal endothelial cells (LSECs) contribute to liver regeneration after partial hepatectomy. Vascular endothelial growth factor (VEGF) has various functions in LSECs. In this review, we summarize the relationship between VEGF and LSECs involving VEGF regulatory activity in the vascular endothelium. AREAS COVERED Maintenance of the fenestrated LSEC phenotype requires two VEGF pathways: VEGF stimulated-NO acting through the cGMP pathway and VEGF independent of nitric oxide (NO). The results suggest that VEGF is a key regenerating mediator of LSECs in the partial hepatectomy model. NO-independent pathway was also essential to the maintenance of the LSEC in liver regeneration. EXPERT OPINION Liver regeneration remains a fascinating and significative research field in recent years. The liver involved of molecular pathways except for LSEC-VEGF pathways that make the field of liver further depth studies should be put into effect to elaborate the undetermined confusions, which will be better to understand liver regeneration.
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Affiliation(s)
- Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Ya-Lei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Xiao-Qian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
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Blanco-Rivero J, Xavier FE. Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases. Curr Pharm Des 2021; 26:3633-3651. [PMID: 32242780 DOI: 10.2174/1381612826666200403172736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/08/2020] [Indexed: 02/08/2023]
Abstract
Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.
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Affiliation(s)
- Javier Blanco-Rivero
- Departamento de Fisiologia, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain
| | - Fabiano E Xavier
- Departamento de Fisiologia e Farmacologia, Centro de Biociencias, Universidade Federal de Pernambuco, Recife, Brazil
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Brusilovskaya K, Königshofer P, Lampach D, Szodl A, Supper P, Bauer D, Beer A, Stift J, Timelthaler G, Oberhuber G, Podesser BK, Seif M, Zinober K, Rohr-Udilova N, Trauner M, Reiberger T, Schwabl P. Soluble guanylyl cyclase stimulation and phosphodiesterase-5 inhibition improve portal hypertension and reduce liver fibrosis in bile duct-ligated rats. United European Gastroenterol J 2020; 8:1174-1185. [PMID: 32878579 PMCID: PMC7724531 DOI: 10.1177/2050640620944140] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 06/22/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In cirrhosis, the nitric oxide-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is impaired, which contributes to increased intrahepatic vascular resistance (IHVR) and fibrogenesis. We investigated if sGC stimulation (riociguat (RIO)), sGC activation (cinaciguat (CINA)) or phosphodiesterase (PDE)-5 inhibition (tadalafil (TADA)) improves portal hypertension (PHT) and liver fibrosis. METHODS Fifty male Sprague-Dawley rats underwent bile-duct ligation (BDL) or sham operation. RIO (0.5 mg/kg), CINA (1 mg/kg), TADA (1.5 mg/kg) or vehicle (VEH) was administered from weeks 2 to 4 after BDL. At week 4, invasive haemodynamic measurements were performed, and liver fibrosis was assessed by histology (chromotrope-aniline blue (CAB), Picro-Sirius red (PSR)) and hepatic hydroxyproline content. RESULTS Cirrhotic bile duct-ligated rats presented with PHT (13.1 ± 1.0 mmHg) and increased IHVR (4.9 ± 0.5 mmHg⋅min/mL). Both RIO (10.0 ± 0.7 mmHg, p = 0.021) and TADA (10.3 ± 0.9 mmHg, p = 0.050) decreased portal pressure by reducing IHVR (RIO: -41%, p = 0.005; TADA: -21%, p = 0.199) while not impacting heart rate, mean arterial pressure and portosystemic shunting. Hepatic cGMP levels increased upon RIO (+239%, p = 0.006) and TADA (+32%, p = 0.073) therapy. In contrast, CINA dosed at 1 mg/kg caused weight loss, arterial hypotension and hyperlactataemia in bile duct-ligated rats. Liver fibrosis area was significantly decreased by RIO (CAB: -48%, p = 0.011; PSR: -27%, p = 0.121) and TADA (CAB: -21%, p = 0.342; PSR: -52%, p = 0.013) compared to VEH-treated bile duct-ligated rats. Hepatic hydroxyproline content was reduced by RIO (from 503 ± 20 to 350 ± 30 µg/g, p = 0.003) and TADA (282 ± 50 µg/g, p = 0.003), in line with a reduction of the hepatic stellate cell activation markers smooth-muscle actin and phosphorylated moesin. Liver transaminases decreased under RIO (AST: -36%; ALT: -32%) and TADA (AST: -24%; ALT: -27%) treatment. Hepatic interleukin 6 gene expression was reduced in the RIO group (-56%, p = 0.053). CONCLUSION In a rodent model of biliary cirrhosis, the sGC stimulator RIO and the PDE-5 inhibitor TADA improved PHT. The decrease of sinusoidal vascular resistance was paralleled by a reduction in liver fibrosis and hepatic inflammation, while systemic haemodynamics were not affected.
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Affiliation(s)
- Ksenia Brusilovskaya
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), 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,
Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian
Academy of Sciences, Vienna, Austria
| | - Philipp Königshofer
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), 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,
Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian
Academy of Sciences, Vienna, Austria
| | - Daniel Lampach
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), Medical University of
Vienna, Vienna, Austria
| | - Adrian Szodl
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), Medical University of
Vienna, Vienna, Austria
| | - Paul Supper
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), Medical University of
Vienna, Vienna, Austria
| | - David Bauer
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), Medical University of
Vienna, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver
Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Andrea Beer
- Department of Pathology, Medical University of Vienna, Vienna,
Austria
| | - Judith Stift
- Department of Pathology, Medical University of Vienna, Vienna,
Austria
| | - Gerald Timelthaler
- The Institute of Cancer Research, Department of Medicine I,
Medical University of Vienna, Vienna, Austria
| | | | - Bruno Karl Podesser
- Center for Biomedical Research, Medical University of Vienna,
Vienna, Austria
| | - Martha Seif
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), Medical University of
Vienna, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver
Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Kerstin Zinober
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), Medical University of
Vienna, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver
Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Nataliya Rohr-Udilova
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), Medical University of
Vienna, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver
Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), 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,
Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian
Academy of Sciences, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of
Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Haemodynamic Lab (HEPEX), 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,
Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian
Academy of Sciences, Vienna, Austria
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Gunarathne LS, Rajapaksha H, Shackel N, Angus PW, Herath CB. Cirrhotic portal hypertension: From pathophysiology to novel therapeutics. World J Gastroenterol 2020; 26:6111-6140. [PMID: 33177789 PMCID: PMC7596642 DOI: 10.3748/wjg.v26.i40.6111] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/28/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin II type receptor 1 blockers, which target the components of the classical renin angiotensin system (RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant off-target effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective -blockers (NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs. Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.
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Affiliation(s)
- Lakmie S Gunarathne
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
| | - Harinda Rajapaksha
- School of Molecular Science, College of Science, Health and Engineering, La Trobe University, Bundoora, VIC 3086, Australia
| | | | - Peter W Angus
- Department of Gastroenterology, Austin Health, Heidelberg, VIC 3084, Australia
| | - Chandana B Herath
- Department of Medicine, Melbourne Medical School, The University of Melbourne, Heidelberg, VIC 3084, Australia
- South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW 2170, Australia
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Clinical Decompensation and Outcomes in Patients With Compensated Cirrhosis and a Hepatic Venous Pressure Gradient ≥20 mm Hg. Am J Gastroenterol 2020; 115:1624-1633. [PMID: 32453061 DOI: 10.14309/ajg.0000000000000653] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Hepatic venous pressure gradient (HVPG) of ≥10 mm Hg predicts clinical decompensation (CD) in compensated cirrhosis. A proportion of cirrhotic patients at presentation have high HVPG (≥20 mm Hg) and are compensated. The natural history, spectrum of CD, and mortality in this group is largely unknown. METHODS Consecutive compensated cirrhotic patients with HVPG ≥6 mm Hg (n = 741) were followed up for 3-6 months for the development of any CD. Patients were classified based on the baseline HVPG (6 to <12 mm Hg [low HVPG, Gr.A, n = 163], 12 to <20 mm Hg [intermediate HVPG, Gr.B, n = 437] and ≥20 mm Hg [high HVPG, Gr.C, n = 141]). We analyzed the predictors of first CD, HVPG response to carvedilol, and mortality in these groups. RESULTS CD developed in 217 (29.3%) patients during a mean follow-up of 1.6 ± 0.4 years, and those who developed CD had higher baseline HVPG (17.02 ± 4.79 vs 14.28 ± 4.86; P < 0.001). First CD was seen earlier (1.3 ± 0.7 years vs 1.5 ± 0.6 years and 1.6 ± 0.5 years, P = 0.02) and more frequently (44.7% vs 11% and 31.1%, P < 0.01) in high HVPG groups compared with low and intermediate HVPG groups, with higher mortality rates. Patients in the high HVPG group compared with the low HVPG group more often had NASH-cirrhosis (35.5% vs 19.6%; P 0.001), higher liver stiffness values (45.06 ± 20.46 vs 20.09 ± 5.47 kPa, P < 0.001), and lower platelet counts (113.37 ± 72.57 vs 151.7 ± 87.30/cmm, P < 0.001). Patients with HVPG ≥12 mm Hg received carvedilol, and a repeat HVPG performed in a proportion after 9.3 ± 2.4 months showed response (≥20% reduction in HVPG or <12 mm Hg) in 31.6% patients (Gr. B, 44.9% > Gr. C, 22.2%, P < 0.05). Baseline HVPG (HVPG ≥12 to <20 mm Hg [Hazard ratio: 2.73] and HVPG ≥20 mm Hg [Hazard ratio: 4.48], P < 0.001) independently predicted CD. DISCUSSION HVPG ≥20 mm Hg in patients with compensated cirrhosis independently predicts early and more frequent CD and poor outcomes. These patients should be labeled as "high-risk compensated cirrhosis," and early and effective interventions to reduce portal pressure should be initiated to improve long-term outcomes.
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Lin Z, Huang R, Zhou J, Chen Y, Xu L, Gao Y, Wang C, Wang Q. Fowl Adenovirus Serotype 4 Influences Arginine Metabolism to Benefit Replication. Avian Dis 2020; 64:16-22. [PMID: 32267121 DOI: 10.1637/0005-2086-64.1.16] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Accepted: 09/25/2019] [Indexed: 11/05/2022]
Abstract
Hydropericardium syndrome (HPS) is caused by fowl adenovirus serotype 4 (FAdV-4). HPS has caused outbreaks in Chinese populations of broiler chickens since 2015. However, little is known about the molecular mechanisms underlying HPS. In this study, we used transcriptomic analysis to screen differentially expressed genes (DEGs) in the livers of FAdV-4-infected and noninfected chicks. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the gene network associated with the arginine metabolism pathway was enriched in livers infected by FAdV-4; 10 genes were downregulated and 8 genes were upregulated in these livers when compared to noninfected livers. The DEGs identified in livers were reanalyzed by real-time fluorescence quantitative PCR (qPCR); results indicated that the mRNA levels of the DEGs concurred with the data derived from KEGG analysis. Next, we used qPCR to detect the DEGs of the arginine metabolism pathway in a hepatocellular carcinoma cell line (LMH) after infection with FAdV-4 for 24 hr; this also indicated that the mRNA levels of the DEGs concurred with that seen in the liver. We also used si-RNA oligonucleotides to knock down the mRNA levels of iNOS in LMH cells infected with FAdV-4 and found that the viral load of FAdV-4 was increased. Further investigation revealed that the addition of 240 µg/ml of arginine into the culture medium of LMH cells infected with FAdV-4 for 24 hr led to a significant increase in the mRNA levels of iNOS but a significant reduction in the viral load of FAdV-4. Therefore, our data indicated that when broiler chickens become infected with FAdV-4, the arginine metabolic pathway in the liver becomes dysfunctional and the iNOS mRNA level decreases. This will add benefit to the replication of FAdV-4 but can be inhibited by the addition of an appropriate amount of arginine.
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Affiliation(s)
- Zhixin Lin
- College of Animal Science (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China
| | - Ruiling Huang
- College of Animal Science (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China
| | - Jiaxin Zhou
- College of Animal Science (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China
| | - Yuan Chen
- College of Animal Science (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China
| | - Lihui Xu
- College of Animal Science (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China
| | - Yuyun Gao
- College of Animal Science (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China
| | - Changkang Wang
- College of Animal Science (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China,
| | - Quanxi Wang
- College of Animal Science (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China, .,Fujian Key Laboratory of Traditional Chinese Veterinary Medicine and Animal Health, Fujian Agriculture and Forestry University, Fuzhou, 350002, P.R. China,
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Kreisel W, Schaffner D, Lazaro A, Trebicka J, Merfort I, Schmitt-Graeff A, Deibert P. Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension. Int J Mol Sci 2020; 21:6223. [PMID: 32872119 PMCID: PMC7503357 DOI: 10.3390/ijms21176223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Denise Schaffner
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
- Department of Radiology–Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
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Indexes of nitric oxide system in experimental antiphospholipid syndrome. UKRAINIAN BIOCHEMICAL JOURNAL 2020. [DOI: 10.15407/ubj92.01.075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Bravo M, Raurell I, Hide D, Fernández-Iglesias A, Gil M, Barberá A, Salcedo MT, Augustin S, Genescà J, Martell M. Restoration of liver sinusoidal cell phenotypes by statins improves portal hypertension and histology in rats with NASH. Sci Rep 2019; 9:20183. [PMID: 31882668 PMCID: PMC6934751 DOI: 10.1038/s41598-019-56366-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 11/29/2019] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a common chronic liver disorder in developed countries, with the associated clinical complications driven by portal hypertension (PH). PH may precede fibrosis development, probably due to endothelial dysfunction at early stages of the disease. Our aim was to characterize liver sinusoidal endothelial cell (LSEC) dedifferentiation/capillarization and its contribution to PH in NASH, together with assessing statins capability to revert endothelial function improving early NASH stages. Sprague-Dawley rats were fed with high fat glucose-fructose diet (HFGFD), or control diet (CD) for 8 weeks and then treated with simvastatin (sim) (10 mg·kg−1·day−1), atorvastatin (ato) (10 mg·kg−1·day−1) or vehicle during 2 weeks. Biochemical, histological and hemodynamic determinations were carried out. Sinusoidal endothelial dysfunction was assessed in individualized sorted LSEC and hepatic stellate cells (HSC) from animal groups and in whole liver samples. HFGFD rats showed full NASH features without fibrosis but with significantly increased portal pressure compared with CD rats (10.47 ± 0.37 mmHg vs 8.30 ± 0.22 mmHg; p < 0.001). Moreover, HFGFD rats showed a higher percentage of capillarized (CD32b−/CD11b−) LSEC (8% vs 1%, p = 0.005) showing a contractile phenotype associated to HSC activation. Statin treatments caused a significant portal pressure reduction (sim: 9.29 ± 0.25 mmHg, p < 0.01; ato: 8.85 ± 0.30 mmHg, p < 0.001), NASH histology reversion, along with significant recovery of LSEC differentiation and a regression of HSC activation to a more quiescent phenotype. In an early NASH model without fibrosis with PH, LSEC transition to capillarization and HSC activation are reverted by statin treatment inducing portal pressure decrease and NASH features improvement.
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Affiliation(s)
- Miren Bravo
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Imma Raurell
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Diana Hide
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Anabel Fernández-Iglesias
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Liver Vascular Biology Research Group, Hepatic Hemodynamic Lab. IDIBAPS-Hospital Clínic, Barcelona, Spain
| | - Mar Gil
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Aurora Barberá
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain
| | | | - Salvador Augustin
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.
| | - Joan Genescà
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.
| | - María Martell
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autonoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
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The effects of valve leaflet mechanics on lymphatic pumping assessed using numerical simulations. Sci Rep 2019; 9:10649. [PMID: 31337769 PMCID: PMC6650476 DOI: 10.1038/s41598-019-46669-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 06/20/2019] [Indexed: 01/04/2023] Open
Abstract
The lymphatic system contains intraluminal leaflet valves that function to bias lymph flow back towards the heart. These valves are present in the collecting lymphatic vessels, which generally have lymphatic muscle cells and can spontaneously pump fluid. Recent studies have shown that the valves are open at rest, can allow some backflow, and are a source of nitric oxide (NO). To investigate how these valves function as a mechanical valve and source of vasoactive species to optimize throughput, we developed a mathematical model that explicitly includes Ca2+ -modulated contractions, NO production and valve structures. The 2D lattice Boltzmann model includes an initial lymphatic vessel and a collecting lymphangion embedded in a porous tissue. The lymphangion segment has mechanically-active vessel walls and is flanked by deformable valves. Vessel wall motion is passively affected by fluid pressure, while active contractions are driven by intracellular Ca2+ fluxes. The model reproduces NO and Ca2+ dynamics, valve motion and fluid drainage from tissue. We find that valve structural properties have dramatic effects on performance, and that valves with a stiffer base and flexible tips produce more stable cycling. In agreement with experimental observations, the valves are a major source of NO. Once initiated, the contractions are spontaneous and self-sustained, and the system exhibits interesting non-linear dynamics. For example, increased fluid pressure in the tissue or decreased lymph pressure at the outlet of the system produces high shear stress and high levels of NO, which inhibits contractions. On the other hand, a high outlet pressure opposes the flow, increasing the luminal pressure and the radius of the vessel, which results in strong contractions in response to mechanical stretch of the wall. We also find that the location of contraction initiation is affected by the extent of backflow through the valves.
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Urotensin II receptor antagonist reduces hepatic resistance and portal pressure through enhanced eNOS-dependent HSC vasodilatation in CCl4-induced cirrhotic rats. Front Med 2019; 13:398-408. [DOI: 10.1007/s11684-019-0689-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 12/27/2018] [Indexed: 12/11/2022]
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48
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Endocannabinoid System in Hepatic Glucose Metabolism, Fatty Liver Disease, and Cirrhosis. Int J Mol Sci 2019; 20:ijms20102516. [PMID: 31121839 PMCID: PMC6566399 DOI: 10.3390/ijms20102516] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/18/2019] [Accepted: 05/19/2019] [Indexed: 12/18/2022] Open
Abstract
There is growing evidence that glucose metabolism in the liver is in part under the control of the endocannabinoid system (ECS) which is also supported by its presence in this organ. The ECS consists of its cannabinoid receptors (CBRs) and enzymes that are responsible for endocannabinoid production and metabolism. ECS is known to be differentially influenced by the hepatic glucose metabolism and insulin resistance, e.g., cannabinoid receptor type 1(CB1) antagonist can improve the glucose tolerance and insulin resistance. Interestingly, our own study shows that expression patterns of CBRs are influenced by the light/dark cycle, which is of significant physiological and clinical interest. The ECS system is highly upregulated during chronic liver disease and a growing number of studies suggest a mechanistic and therapeutic impact of ECS on the development of liver fibrosis, especially putting its receptors into focus. An opposing effect of the CBRs was exerted via the CB1 or CB2 receptor stimulation. An activation of CB1 promoted fibrogenesis, while CB2 activation improved antifibrogenic responses. However, underlying mechanisms are not yet clear. In the context of liver diseases, the ECS is considered as a possible mediator, which seems to be involved in the synthesis of fibrotic tissue, increase of intrahepatic vascular resistance and subsequently development of portal hypertension. Portal hypertension is the main event that leads to complications of the disease. The main complication is the development of variceal bleeding and ascites, which have prognostic relevance for the patients. The present review summarizes the current understanding and impact of the ECS on glucose metabolism in the liver, in association with the development of liver cirrhosis and hemodynamics in cirrhosis and its complication, to give perspectives for development of new therapeutic strategies.
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Baffy G. Potential mechanisms linking gut microbiota and portal hypertension. Liver Int 2019; 39:598-609. [PMID: 30312513 DOI: 10.1111/liv.13986] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 10/01/2018] [Accepted: 10/04/2018] [Indexed: 12/11/2022]
Abstract
Gut microbiota is the largest collection of commensal micro-organisms in the human body, engaged in reciprocal cellular and molecular interactions with the liver. This mutually beneficial relationship may break down and result in dysbiosis, associated with disease phenotypes. Altered composition and function of gut microbiota has been implicated in the pathobiology of nonalcoholic fatty liver disease (NAFLD), a prevalent condition linked to obesity, insulin resistance and endothelial dysfunction. NAFLD may progress to cirrhosis and portal hypertension, which is the result of increased intrahepatic vascular resistance and altered splanchnic circulation. Gut microbiota may contribute to rising portal pressure from the earliest stages of NAFLD, although the significance of these changes remains unclear. NAFLD has been linked to lower microbial diversity and weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defence and inflammation. Moreover, disrupted host-microbial metabolic interplay alters bile acid signalling and the release of vasoregulatory gasotransmitters. These perturbations become prominent in cirrhosis, increasing the risk of clinically significant portal hypertension and leading to bacterial translocation, sepsis and acute-on-chronic liver failure. Better understanding of the gut-liver axis and identification of novel microbial molecular targets may yield specific strategies in the prevention and management of portal hypertension.
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Affiliation(s)
- Gyorgy Baffy
- Department of Medicine, VA Boston Healthcare System and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
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AbuHalimeh B, Krowka MJ, Tonelli AR. Treatment Barriers in Portopulmonary Hypertension. Hepatology 2019; 69:431-443. [PMID: 30063259 PMCID: PMC6460471 DOI: 10.1002/hep.30197] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 07/23/2018] [Indexed: 12/16/2022]
Abstract
Portopulmonary hypertension (PoPH) is a form of pulmonary arterial hypertension (PAH) that can develop as a complication of portal hypertension. Treatment of PoPH includes PAH-specific therapies, and in certain cases, such therapies are necessary to facilitate a successful liver transplantation. A significant number of barriers may limit the adequate treatment of patients with PoPH and explain the poorer survival of these patients when compared to patients with other types of PAH. Until recently, only one randomized controlled trial has included PoPH patients, and the majority of treatment data have been derived from relatively small observational studies. In the present article, we review some of the barriers in the treatment of patients with PoPH and implications for liver transplantation.
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Affiliation(s)
- Batool AbuHalimeh
- Pathobiology Division, Lerner Research Institute. Cleveland Clinic, OH, USA.
| | - Michael J Krowka
- Department of Gastroenterology and Hepatology and Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.
| | - Adriano R. Tonelli
- Department of Pulmonary, Allergy and Critical Care Medicine. Respiratory Institute, Cleveland Clinic, Cleveland, OH, USA.
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