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Piano S, Mahmud N, Caraceni P, Tonon M, Mookerjee RP. Mechanisms and treatment approaches for ACLF. Liver Int 2025; 45:e15733. [PMID: 37715608 PMCID: PMC12036731 DOI: 10.1111/liv.15733] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/03/2023] [Accepted: 09/02/2023] [Indexed: 09/17/2023]
Abstract
Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by decompensation of cirrhosis, severe systemic inflammation and organ failures. ACLF is frequently triggered by intra- and/or extrahepatic insults, such as bacterial infections, alcohol-related hepatitis or flares of hepatic viruses. The imbalance between systemic inflammation and immune tolerance causes organ failures through the following mechanisms: (i) direct damage of immune cells/mediators; (ii) worsening of circulatory dysfunction resulting in organ hypoperfusion and (iii) metabolic alterations with prioritization of energetic substrates for inflammation and peripheral organ 'energetic crisis'. Currently, the management of ACLF includes the support of organ failures, the identification and treatment of precipitating factors and expedited assessment for liver transplantation (LT). Early LT should be considered in patients with ACLF grade 3, who are unlikely to recover with the available treatments and have a mortality rate > 70% at 28 days. However, the selection of transplant candidates and their prioritization on the LT waiting list need standardization. Future challenges in the ACLF field include a better understanding of pathophysiological mechanisms leading to inflammation and organ failures, the development of specific treatments for the disease and personalized treatment approaches. Herein, we reviewed the current knowledge and future perspectives on mechanisms and treatment of ACLF.
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Affiliation(s)
- Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine –DIMED, University and Hospital of Padova, Padova, Italy
| | - Nadim Mahmud
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Leonard Davis Institute of Health Economics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Gastroenterology Section, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
| | - Paolo Caraceni
- Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
- Unit of Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marta Tonon
- Unit of Internal Medicine and Hepatology, Department of Medicine –DIMED, University and Hospital of Padova, Padova, Italy
| | - Rajeshwar Prosad Mookerjee
- Institute for Liver and Digestive Health, University College London, London, UK
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C, Denmark
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2
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Engelmann C, Zhang IW, Clària J. Mechanisms of immunity in acutely decompensated cirrhosis and acute-on-chronic liver failure. Liver Int 2025; 45:e15644. [PMID: 37365995 PMCID: PMC11815630 DOI: 10.1111/liv.15644] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/26/2023] [Accepted: 05/31/2023] [Indexed: 06/28/2023]
Abstract
The identification of systemic inflammation (SI) as a central player in the orchestration of acute-on-chronic liver failure (ACLF) has opened new avenues for the understanding of the pathophysiological mechanisms underlying this disease condition. ACLF, which develops in patients with acute decompensation of cirrhosis, is characterized by single or multiple organ failure and high risk of short-term (28-day) mortality. Its poor outcome is closely associated with the severity of the systemic inflammatory response. In this review, we describe the key features of SI in patients with acutely decompensated cirrhosis and ACLF, including the presence of a high blood white cell count and increased levels of inflammatory mediators in systemic circulation. We also discuss the main triggers (i.e. pathogen- and damage-associated molecular patterns), the cell effectors (i.e. neutrophils, monocytes and lymphocytes), the humoral mediators (acute phase proteins, cytokines, chemokines, growth factors and bioactive lipid mediators) and the factors that influence the systemic inflammatory response that drive organ failure and mortality in ACLF. The role of immunological exhaustion and/or immunoparalysis in the context of exacerbated inflammatory responses that predispose ACLF patients to secondary infections and re-escalation of end-organ dysfunction and mortality are also reviewed. Finally, several new potential immunogenic therapeutic targets are debated.
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Affiliation(s)
- Cornelius Engelmann
- Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow‐KlinikumCharité ‐ Universitätsmedizin BerlinBerlinGermany
- Berlin Institute of HealthBerlinGermany
- Institute for Liver and Digestive HealthUniversity College LondonLondonUK
| | - Ingrid W. Zhang
- Medical Department, Division of Hepatology and Gastroenterology, Campus Virchow‐KlinikumCharité ‐ Universitätsmedizin BerlinBerlinGermany
- Berlin Institute of HealthBerlinGermany
- European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols ChairBarcelonaSpain
| | - Joan Clària
- European Foundation for the Study of Chronic Liver Failure (EF CLIF) and Grifols ChairBarcelonaSpain
- Biochemistry and Molecular Genetics ServiceHospital Clínic‐IDIBAPS CIBERehdBarcelonaSpain
- Department of Biomedical SciencesUniversity of BarcelonaBarcelonaSpain
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3
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Gallego JJ, Ballester MP, Fiorillo A, Casanova-Ferrer F, López-Gramaje A, Urios A, Arenas YM, Ríos MP, Durbán L, Megías J, San-Miguel T, Benlloch S, Lluch P, Jalan R, Montoliu C. Ammonia and beyond - biomarkers of hepatic encephalopathy. Metab Brain Dis 2025; 40:100. [PMID: 39812958 PMCID: PMC11735499 DOI: 10.1007/s11011-024-01512-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 12/17/2024] [Indexed: 01/16/2025]
Abstract
Ammonia is a product of amino acid metabolism that accumulates in the blood of patients with liver cirrhosis, leading to neurotoxic effects and hepatic encephalopathy (HE). HE manifestations can range from mild, subclinical disturbances in cognition, or minimal HE (mHE) to gross disorientation and coma, a condition referred to as overt HE. Many blood-based biomarkers reflecting these neurotoxic effects of ammonia and liver disease can be measured in the blood allowing the development of new biomarkers to diagnose cirrhosis patients at risk of developing HE. The effect of ammonia on the brain is modulated by severity of systemic inflammation, and both hyperammonemia and inflammation can induce oxidative stress, which may mediate the neurological alterations associated to HE. This review aims to provide the latest evidence on biomarkers of HE beyond ammonia. We present different approaches to predict overt HE based on the combination of blood ammonia with some analytical and clinical parameters. Magnetic resonance analysis of brain images could also provide sensitive diagnostic biomarkers based on neuroimaging parameters. Some reports suggest that markers of systemic inflammation, oxidative stress, and central nervous system-derived components, may serve as additional biomarkers of HE. The involvement of extracellular vesicles and microbiota in the pathophysiology of mHE and HE has recently acquired importance and it would be interesting to explore their usefulness as early biomarkers of the disease. It is important to have a biomarker or a combination of them for early diagnosis of mHE to improve its treatment and prevent progression to overt HE.
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Affiliation(s)
- Juan-José Gallego
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - María-Pilar Ballester
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, 46010, Spain
| | - Alessandra Fiorillo
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | - Franc Casanova-Ferrer
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | | | - Amparo Urios
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain
| | - Yaiza María Arenas
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - María-Pilar Ríos
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
| | - Lucía Durbán
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
| | - Javier Megías
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - Teresa San-Miguel
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain
| | - Salvador Benlloch
- Servicio de Medicina Digestiva, Hospital Arnau de Vilanova, 46015, Valencia, Spain
- CIBERehd. Instituto de Salud Carlos III, Madrid, 28029, Spain
- Universidad Cardenal Herrera-CEU Universities, Valencia, 46115, Spain
| | - Paloma Lluch
- Servicio de Medicina Digestiva, Hospital Clínico Universitario de Valencia, Valencia, 46010, Spain
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.
- European Foundation for the Study of Chronic Liver Failure (EF Clif), Barcelona, 08021, Spain.
| | - Carmina Montoliu
- Fundación de Investigación Hospital Clínico Universitario de Valencia-INCLIVA, Valencia, 46010, Spain.
- Departamento de Patología, Universidad de Valencia, Valencia, 46010, Spain.
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4
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Rodríguez-Negrete EV, Gálvez-Martínez M, Sánchez-Reyes K, Fajardo-Felix CF, Pérez-Reséndiz KE, Madrigal-Santillán EO, Morales-González Á, Morales-González JA. Liver Cirrhosis: The Immunocompromised State. J Clin Med 2024; 13:5582. [PMID: 39337069 PMCID: PMC11432654 DOI: 10.3390/jcm13185582] [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: 07/26/2024] [Revised: 09/11/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024] Open
Abstract
Systemic inflammation and immunodeficiency are important components of cirrhosis-associated immune dysfunction (CAID), the severity of which is dynamic, progressive, and associated with the greater deterioration of liver function. Two inflammation phenotypes have been described: low-grade and high-grade systemic inflammation. Both of these phenotypes are related to liver cirrhosis function; thus, high-grade inflammation is correlated with the severity of hepatic insufficiency, bacterial translocation, and organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation (BT) plays a relevant role in persistent systemic inflammation in patients with cirrhosis, and the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.
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Affiliation(s)
- Elda Victoria Rodríguez-Negrete
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
| | - Marisol Gálvez-Martínez
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | - Karina Sánchez-Reyes
- Servicio de Cirugía General, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico;
| | - Carlos Fernando Fajardo-Felix
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | - Karla Erika Pérez-Reséndiz
- Servicio de Gastroenterología, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Ciudad de México 06720, Mexico; (E.V.R.-N.); (M.G.-M.); (C.F.F.-F.); (K.E.P.-R.)
| | | | - Ángel Morales-González
- Escuela Superior de Cómputo, Instituto Politécnico Nacional, Unidad Profesional “A. López Mateos”, Ciudad de México 07738, Mexico
| | - José Antonio Morales-González
- Laboratorio de Medicina de Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11340, Mexico;
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5
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Wong YJ, Abraldes JG. Pharmacologic Treatment of Portal Hypertension. Clin Liver Dis 2024; 28:417-435. [PMID: 38945635 DOI: 10.1016/j.cld.2024.03.002] [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: 07/02/2024]
Abstract
Portal hypertension is the key mechanism driving the transition from compensated to decompensated cirrhosis. In this review, the authors described the pathophysiology of portal hypertension in cirrhosis and the rationale of pharmacologic treatment of portal hypertension. We discussed both etiologic and nonetiologic treatment of portal hypertension and the specific clinical scenarios how nonselective beta-blocker can be used in patients with cirrhosis. Finally, the authors summarized the evidence for emerging alternatives for portal hypertension in patients with cirrhosis.
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Affiliation(s)
- Yu Jun Wong
- Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada; Liver Unit, Division of Gastroenterology, University of Alberta, 1-38 Zeidler Ledcor Centre, 8540 112 Street Northwest, Edmonton, Alberta T6G 2X8, Canada
| | - Juan G Abraldes
- Liver Unit, Division of Gastroenterology, University of Alberta, 1-38 Zeidler Ledcor Centre, 8540 112 Street Northwest, Edmonton, Alberta T6G 2X8, Canada.
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6
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Bartimoccia S, Praktiknjo M, Nocella C, Schierwagen R, Cammisotto V, Jansen C, Cristiano L, Castellani V, Chang J, Carnevale R, Maiucci S, Uschner FE, Pignatelli P, Brol MJ, Trebicka J, Violi F. Association between endotoxemia and blood no in the portal circulation of cirrhotic patients: results of a pilot study. Intern Emerg Med 2024; 19:713-720. [PMID: 38409619 DOI: 10.1007/s11739-024-03534-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 01/08/2024] [Indexed: 02/28/2024]
Abstract
Pathophysiology of portal vein thrombosis (PVT) in cirrhosis is still not entirely understood. Elevated levels of lipopolysaccharides (LPS) in portal circulation are significantly associated with hypercoagulation, increased platelet activation and endothelial dysfunction. The aim of the study was to investigate if LPS was associated with reduced portal venous flow, the third component of Virchow's triad, and the underlying mechanism. Serum nitrite/nitrate, as a marker of nitric oxide (NO) generation, and LPS were measured in the portal and systemic circulation of 20 patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedure; portal venous flow velocity (PVV) was also measured in each patient and correlated with NO and LPS levels. Serum nitrite/nitrate and LPS were significantly higher in the portal compared to systemic circulation; a significant correlation was found between LPS and serum nitrite/nitrate (R = 0.421; p < 0.01). Median PVV before and after TIPS was 15 cm/s (6-40) and 31 cm/s (14-79), respectively. Correlation analysis of PVV with NO and LPS showed a statistically significant negative correlation of PVV with portal venous NO concentration (R = - 0.576; p = 0.020), but not with LPS. In vitro study with endothelial cells showed that LPS enhanced endothelial NO biosynthesis, which was inhibited by L-NAME, an inhibitor of NO synthase, or TAK-242, an inhibitor of TLR4, the LPS receptor; this effect was accomplished by up-regulation of eNOS and iNOS. The study shows that in cirrhosis, endotoxemia may be responsible for reduced portal venous flow via overgeneration of NO and, therefore, contribute to the development of PVT.
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Affiliation(s)
- Simona Bartimoccia
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Cristina Nocella
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Christian Jansen
- Department of Medicine I, University Hospital Bonn, Bonn, Germany
| | | | - Valentina Castellani
- Department of General Surgery and Surgical Speciality, Sapienza University of Rome, Rome, Italy
| | - Johannes Chang
- Department of Medicine I, University Hospital Bonn, Bonn, Germany
| | - Roberto Carnevale
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- IRCCS Neuromed, Località Camerelle, 86077, Pozzilli, IS, Italy
| | - Sofia Maiucci
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro-Napoli, Via Orazio, 2, 80122, Naples, Italy
| | | | - Jonel Trebicka
- Department of Medicine B, University Hospital Münster, Münster, Germany
- European Foundation for the Study of Chronic Liver Failure, EF Clif, Barcelona, Spain
| | - Francesco Violi
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
- IRCCS Neuromed, Località Camerelle, 86077, Pozzilli, IS, Italy.
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7
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Efremova I, Maslennikov R, Poluektova E, Medvedev O, Kudryavtseva A, Krasnov G, Fedorova M, Romanikhin F, Bakhitov V, Aliev S, Sedova N, Kuropatkina T, Ivanova A, Zharkova M, Pervushova E, Ivashkin V. Gut Microbiota and Biomarkers of Endothelial Dysfunction in Cirrhosis. Int J Mol Sci 2024; 25:1988. [PMID: 38396668 PMCID: PMC10888218 DOI: 10.3390/ijms25041988] [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: 12/28/2023] [Revised: 01/30/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Our aim was to study the association of endothelial dysfunction biomarkers with cirrhosis manifestations, bacterial translocation, and gut microbiota taxa. The fecal microbiome was assessed using 16S rRNA gene sequencing. Plasma levels of nitrite, big endothelin-1, asymmetric dimethylarginine (ADMA), presepsin, and claudin were measured as biomarkers of endothelial dysfunction, bacterial translocation, and intestinal barrier dysfunction. An echocardiography with simultaneous determination of blood pressure and heart rate was performed to evaluate hemodynamic parameters. Presepsin, claudin 3, nitrite, and ADMA levels were higher in cirrhosis patients than in controls. Elevated nitrite levels were associated with high levels of presepsin and claudin 3, the development of hemodynamic circulation, hypoalbuminemia, grade 2-3 ascites, overt hepatic encephalopathy, high mean pulmonary artery pressure, increased abundance of Proteobacteria and Erysipelatoclostridium, and decreased abundance of Oscillospiraceae, Subdoligranulum, Rikenellaceae, Acidaminococcaceae, Christensenellaceae, and Anaerovoracaceae. Elevated ADMA levels were associated with higher Child-Pugh scores, lower serum sodium levels, hypoalbuminemia, grade 2-3 ascites, milder esophageal varices, overt hepatic encephalopathy, lower mean pulmonary artery pressure, and low abundance of Erysipelotrichia and Erysipelatoclostridiaceae. High big endothelin-1 levels were associated with high levels of presepsin and sodium, low levels of fibrinogen and cholesterol, hypocoagulation, increased Bilophila and Coprobacillus abundances, and decreased Alloprevotella abundance.
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Affiliation(s)
- Irina Efremova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Pogodinskaya Str. 1-1, 119435 Moscow, Russia; (I.E.); (E.P.)
| | - Roman Maslennikov
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Pogodinskaya Str. 1-1, 119435 Moscow, Russia; (I.E.); (E.P.)
- Scientific Community for the Promotion of the Clinical Study of the Human Microbiome, Pogodinskaya Str. 1-1, 119435 Moscow, Russia
- Consultative and Diagnostic Center 2 of the Moscow Health Department, Millionnaya Str. 6, 107564 Moscow, Russia (N.S.)
| | - Elena Poluektova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Pogodinskaya Str. 1-1, 119435 Moscow, Russia; (I.E.); (E.P.)
- Scientific Community for the Promotion of the Clinical Study of the Human Microbiome, Pogodinskaya Str. 1-1, 119435 Moscow, Russia
| | - Oleg Medvedev
- Pharmacology Department, Lomonosov Moscow State University, Leninskie Gori 1, 119991 Moscow, Russia; (O.M.)
| | - Anna Kudryavtseva
- Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
| | - George Krasnov
- Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
| | - Maria Fedorova
- Post-Genomic Research Laboratory, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova Str. 32, 119991 Moscow, Russia
| | - Filipp Romanikhin
- Pharmacology Department, Lomonosov Moscow State University, Leninskie Gori 1, 119991 Moscow, Russia; (O.M.)
| | - Vyacheslav Bakhitov
- Consultative and Diagnostic Center 2 of the Moscow Health Department, Millionnaya Str. 6, 107564 Moscow, Russia (N.S.)
| | - Salekh Aliev
- Consultative and Diagnostic Center 2 of the Moscow Health Department, Millionnaya Str. 6, 107564 Moscow, Russia (N.S.)
- First Hospital Surgery Department, Pirogov Russian National Research Medical University, Ostrovityanova Str. 1-7, 117997 Moscow, Russia
| | - Natalia Sedova
- Consultative and Diagnostic Center 2 of the Moscow Health Department, Millionnaya Str. 6, 107564 Moscow, Russia (N.S.)
- Department of Clinical Laboratory Diagnostics, FGBOU DPO “Russian Medical Academy of Continuing Professional Education of the Ministry of Health of the Russian Federation”, Barricadnaya Str. 2/1-2, 125993 Moscow, Russia
| | - Tatiana Kuropatkina
- Pharmacology Department, Lomonosov Moscow State University, Leninskie Gori 1, 119991 Moscow, Russia; (O.M.)
| | - Anastasia Ivanova
- Pharmacology Department, Lomonosov Moscow State University, Leninskie Gori 1, 119991 Moscow, Russia; (O.M.)
| | - Maria Zharkova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Pogodinskaya Str. 1-1, 119435 Moscow, Russia; (I.E.); (E.P.)
| | - Ekaterina Pervushova
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Pogodinskaya Str. 1-1, 119435 Moscow, Russia; (I.E.); (E.P.)
| | - Vladimir Ivashkin
- Department of Internal Medicine, Gastroenterology and Hepatology, Sechenov University, Pogodinskaya Str. 1-1, 119435 Moscow, Russia; (I.E.); (E.P.)
- Scientific Community for the Promotion of the Clinical Study of the Human Microbiome, Pogodinskaya Str. 1-1, 119435 Moscow, Russia
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8
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Simbrunner B, Caparrós E, Neuwirth T, Schwabl P, Königshofer P, Bauer D, Marculescu R, Trauner M, Scheiner B, Stary G, Mandorfer M, Reiberger T, Francés R. Bacterial translocation occurs early in cirrhosis and triggers a selective inflammatory response. Hepatol Int 2023; 17:1045-1056. [PMID: 36881247 PMCID: PMC10386924 DOI: 10.1007/s12072-023-10496-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 02/04/2023] [Indexed: 03/08/2023]
Abstract
BACKGROUND Experimental data suggest that bacterial translocation (BT) promotes systemic inflammation, portal hypertension, and circulatory dysfunction in advanced chronic liver disease (ACLD). METHODS Patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement and absence of acute decompensation or infections were included (n = 249). Serum biomarkers of BT (lipopolysaccharide [LPS], lipoteichoic acid [LTA], bacterial DNA [bactDNA]), systemic inflammation and markers of circulatory dysfunction were assessed. T-cell subsets in intestinal biopsies (n = 7 ACLD, n = 4 controls) were analyzed by flow cytometry. RESULTS Patients had a median HVPG of 18 (12-21) mmHg and 56% had decompensated ACLD. LPS (0.04 [0.02-0.06] vs. 0.64 [0.30-1.06] EU/mL), LTA (4.53 [3.58-5.97] vs. 43.2 [23.2-109] pg/mL), and detection of bactDNA (≥ 5 pg/mL; 5% vs. 41%) were markedly higher in patients with ACLD than healthy controls (n = 40; p < 0.001) but were similar between different clinical stages of compensated and decompensated ACLD and displayed no meaningful correlation with HVPG and systemic hemodynamics. TNF-α and IL-10 correlated with LPS (Spearman's rs = 0.523, p < 0.001/rs = 0.143, p = 0.024) but not with LTA. Presence of bactDNA was associated with higher LPS (0.54 [0.28-0.95] vs. 0.88 [0.32-1.31] EU/mL, p = 0.001) and TNF-α (15.3 [6.31-28.1] vs. 20.9 [13.8-32.9] pg/mL). Patients with ACLD exhibited a decreased CD4:CD8-ratio and increased TH1-cells in the intestinal mucosa as compared to controls. During a median FU of 14.7 (8.20-26.5) months, bacterial antigens did not predict decompensation or liver-related death (in contrast to HVPG, IL-6, and MAP) as well as infections at 24 months. CONCLUSION BT occurs already in early ACLD stages and triggers a systemic inflammatory response via TNF-α and IL-10. Interestingly, BT markers showed no clear correlation with portal hypertension and circulatory dysfunction in patients with stable ACLD. CLINICAL TRIAL NUMBER NCT03267615.
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Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 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
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Esther Caparrós
- CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Elche, Spain
- Instituto IDIBE, Miguel Hernández University, Elche, Spain
| | - Teresa Neuwirth
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 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
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Philipp Königshofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 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
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - David Bauer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Rodrig Marculescu
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Georg Stary
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 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
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, 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
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Rubén Francés
- CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Elche, Spain
- Instituto IDIBE, Miguel Hernández University, Elche, Spain
- Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
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9
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Maccauro V, Airola C, Santopaolo F, Gasbarrini A, Ponziani FR, Pompili M. Gut Microbiota and Infectious Complications in Advanced Chronic Liver Disease: Focus on Spontaneous Bacterial Peritonitis. Life (Basel) 2023; 13:life13040991. [PMID: 37109520 PMCID: PMC10145455 DOI: 10.3390/life13040991] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/28/2023] [Accepted: 04/01/2023] [Indexed: 04/29/2023] Open
Abstract
Liver cirrhosis is a chronic disease that can be complicated by episodes of decompensation such as variceal bleeding, hepatic encephalopathy, ascites, and jaundice, with subsequent increased mortality. Infections are also among the most common complications in cirrhotic patients, mostly due to a defect in immunosurveillance. Among them, one of the most frequent is spontaneous bacterial peritonitis (SBP), defined as the primary infection of ascitic fluid without other abdominal foci. SBP is mainly induced by Gram-negative bacteria living in the intestinal tract, and translocating through the intestinal barrier, which in cirrhotic patients is defective and more permeable. Moreover, in cirrhotic patients, the intestinal microbiota shows an altered composition, poor in beneficial elements and enriched in potentially pathogenic ones. This condition further promotes the development of leaky gut and increases the risk of SBP. The first-line treatment of SBP is antibiotic therapy; however, the antibiotics used have a broad spectrum of action and may adversely affect the composition of the gut microbiota, worsening dysbiosis. For this reason, the future goal is to use new therapeutic agents that act primarily on the gut microbiota, selectively modulating it, or on the intestinal barrier, reducing its permeability. In this review, we aim to describe the reciprocal relationship between gut microbiota and SBP, focusing on pathogenetic aspects but also on new future therapies.
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Affiliation(s)
- Valeria Maccauro
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Carlo Airola
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
- Department of Translational Medicine and Surgery, Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
- Department of Translational Medicine and Surgery, Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology-Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Roma, Italy
- Department of Translational Medicine and Surgery, Catholic University, Largo Francesco Vito 1, 00168 Roma, Italy
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10
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Koirala A, Pourafshar N, Daneshmand A, Wilcox CS, Mannemuddhu SS, Arora N. Etiology and Management of Edema: A Review. ADVANCES IN KIDNEY DISEASE AND HEALTH 2023; 30:110-123. [PMID: 36868727 DOI: 10.1053/j.akdh.2022.12.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 04/18/2023]
Abstract
The development of peripheral edema can often pose a significant diagnostic and therapeutic challenge for practitioners due to its association with a wide variety of underlying disorders ranging in severity. Updates to the original Starling's principle have provided new mechanistic insights into edema formation. Additionally, contemporary data highlighting the role of hypochloremia in the development of diuretic resistance provide a possible new therapeutic target. This article reviews the pathophysiology of edema formation and discusses implications for treatment.
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Affiliation(s)
- Abbal Koirala
- Division of Nephrology, University of Washington, Seattle, WA
| | - Negiin Pourafshar
- Division of Nephrology, MedStar Georgetown University Hospital, Washington DC
| | - Arvin Daneshmand
- Division of Nephrology, MedStar Georgetown University Hospital, Washington DC
| | | | | | - Nayan Arora
- Division of Nephrology, University of Washington, Seattle, WA.
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11
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Violi F, Carnevale R, Pignatelli P. "The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study": comment from Violi et al. JOURNAL OF THROMBOSIS AND HAEMOSTASIS : JTH 2023; 21:186-187. [PMID: 36695386 DOI: 10.1016/j.jtha.2022.09.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/17/2022] [Indexed: 01/11/2023]
Affiliation(s)
- Francesco Violi
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy; Mediterranea Cardiocentro-Napoli, Naples, Italy.
| | - Roberto Carnevale
- Mediterranea Cardiocentro-Napoli, Naples, Italy; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy; Mediterranea Cardiocentro-Napoli, Naples, Italy
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12
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Violi F, Pignatelli P, Castellani V, Carnevale R, Cammisotto V. Gut dysbiosis, endotoxemia and clotting activation: A dangerous trio for portal vein thrombosis in cirrhosis. Blood Rev 2023; 57:100998. [PMID: 35985881 DOI: 10.1016/j.blre.2022.100998] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/04/2022] [Accepted: 08/06/2022] [Indexed: 01/28/2023]
Abstract
Liver cirrhosis (LC) is associated with portal venous thrombosis (PVT) in roughly 20% of cirrhotic patients but the underlying mechanism is still unclear. Low-grade endotoxemia by lipopolysaccharides (LPS), a component of outer gut microbiota membrane, is detectable in the portal circulation of LC and could predispose to PVT. LPS may translocate into systemic circulation upon microbiota dysbiosis-induced gut barrier dysfunction, that is a prerequisite for enhanced gut permeability and ensuing endotoxemia. Experimental and clinical studies provided evidence that LPS behaves a pro-thrombotic molecule so promoting clotting and platelet activation. Experiments conducted in the portal circulation of cirrhotic patients showed the existence of LPS-related enhanced thrombin generation as well as endothelial dysfunction, venous stasis, and platelet activation. The review will analyze 1) the pro-thrombotic role of endotoxemia in the context of LC 2) the biological plausibility linking endotoxemia with PVT and 3) the potentially interventional tools to lower endotoxemia and eventually hypercoagulation.
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Affiliation(s)
- Francesco Violi
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, Rome 00161, Italy; Mediterranea Cardiocentro-Napoli, Via Orazio, 2, 80122, Naples, Italy.
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, Rome 00161, Italy; Mediterranea Cardiocentro-Napoli, Via Orazio, 2, 80122, Naples, Italy
| | - Valentina Castellani
- Department of General and Specialized Surgery "Paride Stefanini", Sapienza University of Rome, Italy
| | - Roberto Carnevale
- Mediterranea Cardiocentro-Napoli, Via Orazio, 2, 80122, Naples, Italy; Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 40100, Latina, Italy
| | - Vittoria Cammisotto
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico, 155, Rome 00161, Italy
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13
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Escherichia/ Shigella, SCFAs, and Metabolic Pathways-The Triad That Orchestrates Intestinal Dysbiosis in Patients with Decompensated Alcoholic Cirrhosis from Western Mexico. Microorganisms 2022; 10:microorganisms10061231. [PMID: 35744749 PMCID: PMC9229093 DOI: 10.3390/microorganisms10061231] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/07/2022] [Accepted: 06/13/2022] [Indexed: 11/16/2022] Open
Abstract
Gut microbiota undergoes profound alterations in alcohol cirrhosis. Microbiota-derived products, e.g., short chain fatty acids (SCFA), regulate the homeostasis of the gut-liver axis. The objective was to evaluate the composition and functions of the intestinal microbiota in patients with alcohol-decompensated cirrhosis. Fecal samples of 18 patients and 18 healthy controls (HC) were obtained. Microbial composition was characterized by 16S rRNA amplicon sequencing, SCFA quantification was performed by gas chromatography (GC), and metagenomic predictive profiles were analyzed by PICRUSt2. Gut microbiota in the cirrhosis group revealed a significant increase in the pathogenic/pathobionts genera Escherichia/Shigella and Prevotella, a decrease in beneficial bacteria, such as Blautia, Faecalibacterium, and a decreased α-diversity (p < 0.001) compared to HC. Fecal SCFA concentrations were significantly reduced in the cirrhosis group (p < 0.001). PICRUSt2 analysis indicated a decrease in acetyl-CoA fermentation to butyrate, as well as an increase in pathways related to antibiotics resistance, and aromatic amino acid biosynthesis. These metabolic pathways have been poorly described in the progression of alcohol-related decompensated cirrhosis. The gut microbiota of these patients possesses a pathogenic/inflammatory environment; therefore, future strategies to balance intestinal dysbiosis should be implemented. These findings are described for the first time in the population of western Mexico.
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14
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Chen T, Huang Z, Chen W, Ding R, Li N, Cui H, Wu F, Liang C, Cong X. Potential cardioprotective influence of bupropion against CCl4-triggered cirrhotic cardiomyopathy. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2021.103599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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15
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Albillos A, Martin-Mateos R, Van der Merwe S, Wiest R, Jalan R, Álvarez-Mon M. Cirrhosis-associated immune dysfunction. Nat Rev Gastroenterol Hepatol 2022; 19:112-134. [PMID: 34703031 DOI: 10.1038/s41575-021-00520-7] [Citation(s) in RCA: 202] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 02/08/2023]
Abstract
The term cirrhosis-associated immune dysfunction (CAID) comprises the distinctive spectrum of immune alterations associated with the course of end-stage liver disease. Systemic inflammation and immune deficiency are the key components of CAID. Their severity is highly dynamic and progressive, paralleling cirrhosis stage. CAID involves two different immune phenotypes: the low-grade systemic inflammatory phenotype and the high-grade systemic inflammatory phenotype. The low-grade systemic inflammatory phenotype can be found in patients with compensated disease or clinical decompensation with no organ failure. In this phenotype, there is an exaggerated immune activation but the effector response is not markedly compromised. The high-grade systemic inflammatory phenotype is present in patients with acute-on-chronic liver failure, a clinical situation characterized by decompensation, organ failure and high short-term mortality. Along with high-grade inflammation, this CAID phenotype includes intense immune paralysis that critically increases the risk of infections and worsens prognosis. The intensity of CAID has important consequences on cirrhosis progression and correlates with the severity of liver insufficiency, bacterial translocation and organ failure. Therapies targeting the modulation of the dysfunctional immune response are currently being evaluated in preclinical and clinical studies.
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Affiliation(s)
- Agustín Albillos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. .,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.
| | - Rosa Martin-Mateos
- Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.,Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Schalk Van der Merwe
- Laboratory of Hepatology, Department of Chronic Diseases, Metabolism and Aging (CHROMETA), University of Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospital Gasthuisberg, Leuven, Belgium
| | - Reiner Wiest
- Department of Visceral Surgery and Medicine, University Inselspital, Bern, Switzerland
| | - Rajiv Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Melchor Álvarez-Mon
- Departamento de Medicina y Especialidades Médicas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Department of Internal Medicine, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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16
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Influence of Probiotics Administration Before Liver Resection in Patients with Liver Disease: A Randomized Controlled Trial. World J Surg 2021; 46:656-665. [PMID: 34837121 DOI: 10.1007/s00268-021-06388-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND By inhibiting the growth of pathogenic bacteria and modulating the local intestinal immune system, probiotics may reduce bacterial translocation and systemic endotoxaemia, factors partially responsible for post-operative complications following liver resection for hepatocellular carcinoma in patients with cirrhosis. METHODS Patients with resectable hepatocellular carcinoma developed in the setting of chronic liver disease were prospectively divided into two equal-sized groups: one receiving probiotic treatment 14 days prior to surgery and the other receiving placebo. The primary endpoint was the level of circulating endotoxins after hepatectomy. Secondary endpoints were systemic inflammation (inflammatory cytokine levels), post-operative liver function and overall post-operative complication rate. RESULTS From May 2013 to December 2018, 64 patients were randomized, and 54 patients were included in the analysis, 27 in each arm. No significant change in endotoxin levels was observed over time in either group (P = 0.299). No difference between the groups in terms of post-operative liver function and overall complication rates was observed. The only differences observed were significant increases in the levels of TNFalpha (P = 0.019) and interleukin 1-b (P = 0.028) in the probiotic group in the post-operative period. CONCLUSION Contrary to the modest data reported in the literature, the administration of probiotics before minor liver resection for hepatocellular carcinoma developed in the setting of compensated chronic liver disease does not seem to have an impact on circulating endotoxin levels or post-operative complication rates. TRIAL REGISTRATION Trial registration: NCT02021253.
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17
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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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18
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Midodrine Helps Early Discharge of Patients From the ICU, Though Results in Higher Rate of Natural Death. Crit Care Med 2020; 48:e79. [PMID: 31833992 DOI: 10.1097/ccm.0000000000004067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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19
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Yeboah MM, Hye Khan MA, Chesnik MA, Skibba M, Kolb LL, Imig JD. Role of the cytochrome P-450/ epoxyeicosatrienoic acids pathway in the pathogenesis of renal dysfunction in cirrhosis. Nephrol Dial Transplant 2019; 33:1333-1343. [PMID: 29361048 DOI: 10.1093/ndt/gfx354] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Accepted: 11/24/2017] [Indexed: 02/06/2023] Open
Abstract
Background Hepatorenal syndrome (HRS) is a life-threatening complication of advanced liver cirrhosis that is characterized by hemodynamic alterations in the kidney and other vascular beds. Cytochrome P(CYP)-450 enzymes metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acids. These eicosanoids regulate blood pressure, vascular tone and renal tubular sodium transport under both physiological and pathophysiological states. Methods Experiments were performed to investigate the role of the CYP system in the pathogenesis of renal dysfunction during cirrhosis. Rats underwent bile duct ligation (BDL) or sham surgery and were studied at 2, 4 and 5 weeks post-surgery. In additional experiments, post-BDL rats were treated with three daily intraperitoneal doses of either the selective epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH) or a vehicle, starting on Day 22 after surgery. Results BDL led to progressive renal dysfunction that was associated with reduced renal cortical perfusion but without any overt histologic changes, consistent with HRS. CYP isoform enzyme expression was significantly altered in BDL rats. In the kidney, CYP2C23 expression was upregulated at both the mRNA and protein levels in BDL rats, while CYP2C11 was downregulated. Histologically, the changes in CYP2C23 and CYP2C11 expression were localized to the renal tubules. EET production was increased in the kidneys of BDL rats as assessed by urinary eicosanoid levels. Finally, treatment with the selective epoxygenase inhibitor MSPPOH significantly reduced renal function and renal cortical perfusion in BDL rats, suggesting a homeostatic role for epoxygenase-derived eicosanoids. Conclusions The CYP/EET pathway might represent a novel therapeutic target for modulating renal dysfunction in advanced cirrhosis.
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Affiliation(s)
- Michael M Yeboah
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Md Abdul Hye Khan
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Marla A Chesnik
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Melissa Skibba
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Lauren L Kolb
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - John D Imig
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
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Abstract
This review chapter describes the current knowledge about the nature of pericytes in the gut, their interaction with endothelial cells in blood vessels, and their pathophysiological functions in the setting of chronic liver disease. In particular, it focuses on the role of these vascular cell types and related molecular signaling pathways in pathological angiogenesis associated with liver disease and in the establishment of the gut-vascular barrier and the potential implications in liver disease through the gut-liver axis.
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21
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Abstract
Purpose of review Patients with cirrhosis are at high risk of developing serious infections. Bacterial infections remain the most common cause of morbidity and mortality in these patients. This review is focused on the prevalence of infections in those with cirrhosis, including multidrug-resistant (MDR) pathogens, pathogenesis of infection-related acute-on-chronic liver failure (ACLF), current treatment recommendations, and prophylactic strategies in patients with cirrhosis. Recent findings Recent epidemiological studies have noted an emerging prevalence of MDR bacterial infections and associated with poor prognosis, and a high rate of treatment failure and mortality. Therefore, new recommendations on empirical antibiotic use based on epidemiological data have been developed in order to improve outcomes. Summary Spontaneous bacterial peritonitis (SBP) and urinary tract infection (UTI) are the most frequent infections followed by pneumonia, cellulitis, and bacteremia, while pneumonia carries the highest risk of mortality. The incidence of MDR bacterial infections has been increasing, especially in healthcare-associated settings. Second infections that develop during hospitalization, multiple organ failures, and high MELD score are associated with poor survival. Preventive measures, early diagnosis, and adequate treatment of infections are essential key concepts in minimizing morbidity and mortality in patients with cirrhosis.
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22
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Suraj J, Kurpińska A, Sternak M, Smolik M, Niedzielska-Andres E, Zakrzewska A, Sacha T, Kania A, Chlopicki S, Walczak M. Quantitative measurement of selected protein biomarkers of endothelial dysfunction in plasma by micro-liquid chromatography-tandem mass spectrometry based on stable isotope dilution method. Talanta 2018; 194:1005-1016. [PMID: 30609507 DOI: 10.1016/j.talanta.2018.10.067] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 10/15/2018] [Accepted: 10/18/2018] [Indexed: 12/12/2022]
Abstract
The aim of this study was to develop and validate the novel microLC/MS-MRM method for the simultaneous quantification of six proteins: angiopoietin 2 (Angpt-2), soluble form of fms-like tyrosine kinase 1 (sFLT-1), plasminogen activator inhibitor 1 (PAI-1), tissue plasminogen activator (t-PA), endocan (ESM-1), soluble form of E-selectin (sE-sel), and one peptide: adrenomedullin (ADM) in mouse plasma. Two approaches were compared: a stable isotope dilution (SID) method- used as a reference and a modified SID (mSID) procedure. In SID strategy the calibration curves were used, whereas in mSID the ratio between the chromatogram peak area of endogenous tryptic peptides at unknown concentration to chromatogram peak area of exogenous, stable isotope-labelled internal standards (SISs) added to the sample at known concentration was calculated. The microLC/MS-MRM method in the SID approach was linear from 0.250 pmol/mL to 250 pmol/mL for Angpt-2; 5 pmol/mL to 5000 pmol/mL for sFLT-1; 2.5 pmol/mL to 5000 pmol/mL for PAI-1; 0.375 pmol/mL to 250 pmol/mL for t-PA; 0.375 pmol/mL to 187.5 pmol/mL for ESM-1; 2.5 pmol/mL to 5000 pmol/mL for sE-sel and 0.375 pmol/mL to 250 pmol/mL for ADM. LPS-induced changes in plasma assessed based on SID and mSID approaches gave comparable quantitative results and featured LPS-induced dysregulation of endothelial permeability (Angpt-2, sFLT-1), glycocalyx injury (SDC-1) accompanied by a pro-thrombotic response (PAI-1). In addition, we applied microLC/MS-MRM method with mSID strategy to analyze human plasma samples from patients with chronic myeloid leukemia (CML) and obstructive sleep apnoea (OSA) and demonstrated usefulness of the method to characterize endothelial function in humans. In conclusion, the microLC/MS-MRM method with mSID strategy applied for simultaneous quantification of protein biomarkers of endothelial function in plasma represents a novel targeted proteomic platform for the comprehensive evaluation of endothelial function in mice and humans.
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Affiliation(s)
- Joanna Suraj
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland; Jagiellonian University Medical College, Faculty of Pharmacy, Chair and Department of Toxicology, Medyczna 9, 30-688 Krakow, Poland
| | - Anna Kurpińska
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Magdalena Sternak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Magdalena Smolik
- Jagiellonian University Medical College, Faculty of Pharmacy, Chair and Department of Toxicology, Medyczna 9, 30-688 Krakow, Poland
| | - Ewa Niedzielska-Andres
- Jagiellonian University Medical College, Faculty of Pharmacy, Chair and Department of Toxicology, Medyczna 9, 30-688 Krakow, Poland
| | - Agnieszka Zakrzewska
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland
| | - Tomasz Sacha
- Jagiellonian University Medical College, Faculty of Medicine, Chair and Department of Haematology, Kopernika 17, 31-501 Krakow, Poland
| | - Aleksander Kania
- Jagiellonian University Medical College, Faculty of Medicine, Department of Pulmonology, II Chair of Internal Medicine, Skawinska 8, 31-066 Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland; Jagiellonian University Medical College, Faculty of Medicine, Chair of Pharmacology, Grzegorzecka 16, 31-531 Krakow, Poland.
| | - Maria Walczak
- Jagiellonian University, Jagiellonian Centre for Experimental Therapeutics, Bobrzynskiego 14, 30-348 Krakow, Poland; Jagiellonian University Medical College, Faculty of Pharmacy, Chair and Department of Toxicology, Medyczna 9, 30-688 Krakow, Poland.
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Arai N, Mine Y, Kagami H, Inaba M. Rush progression and fatal result of septic shock related to central line catheter infection in cirrhosis patient with brain stroke. BMC Neurol 2018; 18:158. [PMID: 30268118 PMCID: PMC6162877 DOI: 10.1186/s12883-018-1166-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 09/25/2018] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Catheter-related blood stream infection (CRBSI) is one of the most common intractable healthcare-associated infections because catheters can be easily contaminated by resistant bacteria, and is associated with a high mortality. Central lines are currently used for administering medication to patients with severe stroke, and may thus cause CRBSI. CASE PRESENTATION A 71-year-old woman with cirrhosis presented with subarachnoid hemorrhage (SAH) that was treated by clipping surgery. On postoperative day (POD) 38, sudden high fever (40.3 °C) was detected; the patient died a few hours later. Blood and central line cultures were positive for Klebsiella pneumoniae that may have caused CRBSI and endotoxin shock. In this case, the duration from fever detection to death was notably short. Additionally, inflammatory markers such as white blood cells (WBC) or C-reactive protein (CRP) were almost within normal ranges, even a few hours after fever was detected and before death. Cirrhosis was considered to be the cause of these phenomena. CONCLUSION The timely diagnosis and complete treatment of patients with liver cirrhosis who develop CRBSI are highly challenging. We suggest that clinicians should rigorously apply preventive measures and strengthen CRBSI monitoring, especially in cirrhosis-associated cases.
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Affiliation(s)
- Nobuhiko Arai
- Department of Neurosurgery, Saiseikai Yokohamashi Tobu hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku, Yokohama, Kanagawa 230-8765 Japan
| | - Yutaka Mine
- Department of Neurosurgery, Saiseikai Yokohamashi Tobu hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku, Yokohama, Kanagawa 230-8765 Japan
- Department of Endovascular Surgery, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Kanagawa 230-8765 Japan
- Department of Physiology, Keio University School of Medicine, Tokyo, 160-8582 Japan
- Department of Clinical Research, Tochigi Medical Center, National Hospital Organization, Utsunomiya, Tochigi, 320-8580 Japan
| | - Hiroshi Kagami
- Department of Endovascular Surgery, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Kanagawa 230-8765 Japan
| | - Makoto Inaba
- Department of Neurosurgery, Saiseikai Yokohamashi Tobu hospital, 3-6-1 Shimosueyoshi, Tsurumi-ku, Yokohama, Kanagawa 230-8765 Japan
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24
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Jang CM, Jung YK. [Hyponatremia in Liver Cirrhosis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018; 72:74-78. [PMID: 30145859 DOI: 10.4166/kjg.2018.72.2.74] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Hyponatremia is a commonly observed complication that is related to hypoalbuminemia and portal hypertension in patients with advanced liver cirrhosis. Hyponatremia in patients with liver cirrhosis is mostly dilutional hyponatremia and is defined when the serum sodium concentration is below 130 meq/L. The risk of complications increases significantly in cirrhotic patients with hyponatremia, which includes spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. In addition, hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic factor before and after liver transplantation. The conventional therapies of hyponatremia are albumin infusion, fluid restriction and loop diuretics, but these are frequently ineffective. This review investigates the pathophysiology and various therapeutic modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with liver cirrhosis.
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Affiliation(s)
- Cheol Min Jang
- Department of Internal Medicine, Korea Universty College of Medicine, Seoul, Korea
| | - Young Kul Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Korea
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25
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Ponziani FR, Zocco MA, Cerrito L, Gasbarrini A, Pompili M. Bacterial translocation in patients with liver cirrhosis: physiology, clinical consequences, and practical implications. Expert Rev Gastroenterol Hepatol 2018; 12:641-656. [PMID: 29806487 DOI: 10.1080/17474124.2018.1481747] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 05/24/2018] [Indexed: 02/07/2023]
Abstract
The gut liver axis is an operative unit that works to protect the human body against potentially harmful substances and microorganisms, maintaining the homeostasis of the immune system. Liver cirrhosis profoundly alters this complex system. The intestine becomes more permeable allowing the translocation of bacteria, bacterial products and fragments into the portal circulation, triggering an abnormal local and systemic inflammatory response and a condition of perpetual immunologic alarm. This immune-inflammatory disorder related to dysbiosis is involved in the development of liver damage and liver cirrhosis complications and increases intestinal permeability in a vicious circle. Areas covered: The most relevant studies on bacterial translocation, the mechanism of intestinal barrier dysfunction and its consequences in patients with liver cirrhosis have been revised through a PubMed search. Data have been discussed with particular regard to their significance in clinical practice. Expert commentary: The assessment of bacterial translocation and intestinal permeability is not currently used in clinical practice but may be useful to stratify patients' prognosis.
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Affiliation(s)
- Francesca Romana Ponziani
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maria Assunta Zocco
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Lucia Cerrito
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Antonio Gasbarrini
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
| | - Maurizio Pompili
- a Internal Medicine, Gastroenterology and Hepatology , Fondazione Agostino Gemelli Hospital , Rome , Italy
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26
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Moharem HA, Fetouh FA, Darwish HM, Ghaith D, Elayashy M, Hussein A, Elsayed R, Khalil MM, Abdelaal A, ElMeteini M, Mukhtar A. Effects of bacterial translocation on hemodynamic and coagulation parameters during living-donor liver transplant. BMC Anesthesiol 2018; 18:46. [PMID: 29699477 PMCID: PMC5921288 DOI: 10.1186/s12871-018-0507-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 04/13/2018] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Bacterial translocation (BT) has been proposed as a trigger for stimulation of the immune system with consequent hemodynamic alteration in patients with liver cirrhosis. However, no information is available regarding its hemodynamic and coagulation consequences during liver transplantation. METHODS We screened 30 consecutive adult patients undergoing living-donor liver transplant for the presence of BT. Bacterial DNA, Anti factor Xa (aFXa), thromboelastometry, tumor necrosis factor-α TNF-α, and interleukin-17 (IL-17) values were measured in sera before induction of anesthesia. Systemic hemodynamic data were recorded throughout the procedures. RESULTS Bacterial DNA was detected in 10 patients (33%) (bactDNA(+)). Demographic, clinical, and hemodynamic data were similar in patients with presence or absence of bacterial DNA. BactDNA(+) patients showed significantly higher circulating values of TNF-α and IL-17, and had significantly higher clotting times and clot formation times as well as significantly lower alpha angle and maximal clot firmness than bactDNA(-) patients, P < 0.05. We found no statistically significant difference in aFXa between the groups, P = 0.4. Additionally, 4 patients in each group needed vasopressor agents, P = 0.2. And, the amount of transfused blood and blood products used were similar between both groups. CONCLUSION Bacterial translocation was found in one-third of patients at the time of transplantation and was largely associated with increased markers of inflammation along with decreased activity of coagulation factors. TRIAL REGISTRATION Trial Registration Number: NCT03230214 . (Retrospective registered). Initial registration date was 20/7/2017.
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Affiliation(s)
- Heba A. Moharem
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Fawzia Aboul Fetouh
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Cairo University, 1 Alsaray st, Almanial, Cairo, Egypt
| | - Hamed M. Darwish
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Doaa Ghaith
- Department of clinical and chemical pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Elayashy
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Cairo University, 1 Alsaray st, Almanial, Cairo, Egypt
| | - Amr Hussein
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Cairo University, 1 Alsaray st, Almanial, Cairo, Egypt
| | - Riham Elsayed
- Department of clinical and chemical pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohammad M. Khalil
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Amr Abdelaal
- Department of surgery, Ainshams University, Cairo, Egypt
| | | | - Ahmed Mukhtar
- Department of Anesthesia, Surgical Intensive Care and Pain Management, Faculty of Medicine, Cairo University, 1 Alsaray st, Almanial, Cairo, Egypt
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27
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Abd-Elsalam S, El-Kalla F, Kobtan A, Elhendawy M, Badawi R, Mansour L. Response. Gastrointest Endosc 2018; 87:904-905. [PMID: 29454457 DOI: 10.1016/j.gie.2017.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 12/05/2017] [Indexed: 02/08/2023]
Affiliation(s)
- Sherief Abd-Elsalam
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Ferial El-Kalla
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Abdelrahman Kobtan
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Elhendawy
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rehab Badawi
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Loai Mansour
- Department of Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
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28
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Affiliation(s)
- A Santoro
- Nephrology and Dialysis Unit, Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
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29
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Lin SH, Chung PH, Wu YY, Fung CP, Hsu CM, Chen LW. Inhibition of nitric oxide production reverses diabetes-induced Kupffer cell activation and Klebsiella pneumonia liver translocation. PLoS One 2017; 12:e0177269. [PMID: 28493939 PMCID: PMC5426676 DOI: 10.1371/journal.pone.0177269] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 04/25/2017] [Indexed: 02/06/2023] Open
Abstract
Klebsiella pneumoniae (KP) is the most common pathogen of pyogenic liver abscess in East and Southeast Asia and diabetes mellitus (DM) is a major risk factor. The effect and mechanism of diabetes on KP liver abscess was examined in streptozotocin-induced diabetic mice and Akita mice (C57BL/6J-Ins2Akita). KP translocation to liver and plasma alaine transaminase levels were increased and liver clearance of KP was decreased in DM mice. Diabetic mice exhibited overgrowth of Enterococcus as well as E.coli and decreased lactobacilli/bifidas growth in intestine, increased intestinal iNOS protein and nitrite levels in portal vein, and increased IL-1β and TNF-α expression of Kupffer cells. Fructooligosaccharides (FOS) or dead L. salivarius (dLac) supplementation reversed diabetes-induced enteric dysbiosis, NO levels in portal vein, and KP translocation to liver. L-NAME treatment decreased intestinal iNOS protein expression as well as Kupffer cell activation and increased liver clearance of KP in DM mice. Dead E.coli (2×108 CFU/ml) feeding for one week induced iNOS and TLR4 expression of intestine in germ-free (GF) mice. Dead bacteria feeding induced IL-1β and TNF-α expression of Kupffer cells in GF mice but not in GF TLR4-/- mice. In conclusion, balance of intestinal microflora is important for preventing intestinal iNOS expression, Kupffer cell activation, and KP liver translocation in diabetes. Reversal of diabetes-induced enteric dysbiosis with FOS or dead L. salivarius decreases diabetes-induced intestinal iNOS expression and KP liver translocation. Diabetes induces Kupffer cell activation and KP liver translocation through enteric dysbiosis and nitric oxide production.
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Affiliation(s)
- Shu-Han Lin
- Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Nursing, National Taiwan University Hospital, Taipei, Taiwan
| | - Pei-Hsuan Chung
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Ying-Ying Wu
- Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chang-Phone Fung
- Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan
- Division of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ching-Mei Hsu
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Lee-Wei Chen
- Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan
- Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- * E-mail:
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30
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Noor MT, Manoria P. Immune Dysfunction in Cirrhosis. J Clin Transl Hepatol 2017; 5:50-58. [PMID: 28507927 PMCID: PMC5411357 DOI: 10.14218/jcth.2016.00056] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 01/20/2017] [Accepted: 02/08/2017] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis due to any etiology disrupts the homeostatic role of liver in the body. Cirrhosis-associated immune dysfunction leads to alterations in both innate and acquired immunity, due to defects in the local immunity of liver as well as in systemic immunity. Cirrhosis-associated immune dysfunction is a dynamic phenomenon, comprised of both increased systemic inflammation and immunodeficiency, and is responsible for 30% mortality. It also plays an important role in acute as well as chronic decompensation. Immune paralysis can accompany it, which is characterized by increase in anti-inflammatory cytokines and suppression of proinflammatory cytokines. There is also presence of increased gut permeability, reduced gut motility and altered gut flora, all of which leads to increased bacterial translocation. This increased bacterial translocation and consequent endotoxemia leads to increased blood stream bacterial infections that cause systemic inflammatory response syndrome, sepsis, multiorgan failure and death. The gut microbiota of cirrhotic patients has more pathogenic microbes than that of non-cirrhotic individuals, and this disturbs the homeostasis and favors gut translocation. Prompt diagnosis and treatment of such infections are necessary for better survival. We have reviewed the various mechanisms of immune dysfunction and its consequences in cirrhosis. Recognizing the exact pathophysiology of immune dysfunction will help treating clinicians in avoiding its complications in their patients and can lead to newer therapeutic interventions and reducing the morbidity and mortality rates.
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Affiliation(s)
- Mohd Talha Noor
- Department of Gastroenterology, Sri Aurobindo Medical College and Post Graduate Institute, Indore, India
- *Correspondence to: Mohd Talha Noor, Department of Gastroenterology, Sri Aurobindo Medical College and Post Graduate Institute, Indore 453 111, India. Tel: +91-7314231751, +91-8305421496, Fax: +91-7314231012, E-mail: ,
| | - Piyush Manoria
- Department of Gastroenterology, Sri Aurobindo Medical College and Post Graduate Institute, Indore, India
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31
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Mayyas F, Alzoubi KH, Bonyan R. The role of spironolactone on myocardial oxidative stress in rat model of streptozotocin-induced diabetes. Cardiovasc Ther 2017; 35. [DOI: 10.1111/1755-5922.12242] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 12/04/2016] [Accepted: 12/09/2016] [Indexed: 11/30/2022] Open
Affiliation(s)
- Fadia Mayyas
- Department of Clinical Pharmacy; Faculty of Pharmacy; Jordan University of Science and Technology; Irbid Jordan
| | - Karem H. Alzoubi
- Department of Clinical Pharmacy; Faculty of Pharmacy; Jordan University of Science and Technology; Irbid Jordan
| | - Ruwidah Bonyan
- Department of Clinical Pharmacy; Faculty of Pharmacy; Jordan University of Science and Technology; Irbid Jordan
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Betrapally NS, Gillevet PM, Bajaj JS. Gut microbiome and liver disease. Transl Res 2017; 179:49-59. [PMID: 27477080 PMCID: PMC5164947 DOI: 10.1016/j.trsl.2016.07.005] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 06/09/2016] [Accepted: 07/06/2016] [Indexed: 02/07/2023]
Abstract
Gut microbiota changes are important in determining the occurrence and progression of chronic liver disease related to alcohol, nonalcoholic fatty liver disease, and cirrhosis. Specifically, the systemic inflammation, endotoxemia, and the vasodilation that leads to complications such as spontaneous bacterial peritonitis and hepatic encephalopathy could be related to the gut milieu. Given the poor prognosis of these events, their prevention and early management are essential. Microbiota may be an essential component of the gut milieu that can impact these clinical events, and the study of their composition and function in a culture-independent manner could help understand the prognosis. Recent human and animal studies have shown that the relative abundance and the functional changes of microbiota in the stool, colonic mucosa, and saliva have varying consequences on the presence and prognosis of chronic liver disease and cirrhosis. The impact of therapies on the microbiota is slowly being understood and will likely lead to a more targeted approach to gut microbiota modification in chronic liver disease and cirrhosis.
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Affiliation(s)
| | | | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Va.
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33
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Sood S, Yu L, Visvanathan K, Angus PW, Gow PJ, Testro AG. Immune function biomarker QuantiFERON-monitor is associated with infection risk in cirrhotic patients. World J Hepatol 2016; 8:1569-1575. [PMID: 28050238 PMCID: PMC5165271 DOI: 10.4254/wjh.v8.i35.1569] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/06/2016] [Accepted: 10/22/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether a novel immune function biomarker QuantiFERON-Monitor (QFM) can identify cirrhotic patients at greatest risk of infection. METHODS Adult cirrhotic patients on the liver transplant waiting list were recruited for this observational cohort study from a tertiary liver transplant referral unit. The immune function biomarker, QFM was performed using the same method as the widely available Quantiferon-gold assay, and measures output in interferon gamma in IU/mL after dual stimulation of the innate and adaptive immune systems. Ninety-one cirrhotic patients were recruited, with 47 (52%) transplanted on the day of their QFM. The remaining 44 (48%) were monitored for infections until transplant, death, or census date of 1st February 2014. RESULTS Cirrhotic patients express a median QFM significantly lower than healthy controls (94.5 IU/mL vs 423 IU/mL), demonstrating that they are severely immunosuppressed. Several factors including model for end stage liver disease, presence of hepatocellular carcinoma, bilirubin, international normalized ratio and haemoglobin were associated with QFM on univariate analysis. Disease aetiology did not appear to impact QFM. On multivariate analysis, only Child-Pugh score and urea were significantly associated with a patient's immune function as objectively measured by QFM. In the 44 patients who were not transplanted immediately after their blood test and could be monitored for subsequent infection risk, 13 (29.5%) experienced a pre-transplant infection a median 20 d (range 2-182) post-test. QFM < 214 IU/mL was associated with HR = 4.1 (P = 0.01) for infection. A very low QFM < 30 IU/mL was significantly associated (P = 0.003) with death in three patients who died while awaiting transplantation (HR = 56.6). CONCLUSION QFM is lower in cirrhotics, allowing objective determinations of an individual's unique level of immune dysfunction. Low QFM was associated with increased susceptibility to infection.
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Affiliation(s)
- Siddharth Sood
- Siddharth Sood, Department of Gastroenterology and Hepatology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050, Australia
| | - Lijia Yu
- Siddharth Sood, Department of Gastroenterology and Hepatology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050, Australia
| | - Kumar Visvanathan
- Siddharth Sood, Department of Gastroenterology and Hepatology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050, Australia
| | - Peter William Angus
- Siddharth Sood, Department of Gastroenterology and Hepatology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050, Australia
| | - Paul John Gow
- Siddharth Sood, Department of Gastroenterology and Hepatology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050, Australia
| | - Adam Gareth Testro
- Siddharth Sood, Department of Gastroenterology and Hepatology, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC 3050, Australia
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Caro E, Francés R, Zapater P, Pascual S, Bellot P, Such J. Grade of soluble inflammatory response is mainly affected by circulating bacterial DNA concentrations in cirrhosis. Liver Int 2016; 36:1473-80. [PMID: 26991936 DOI: 10.1111/liv.13118] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 03/08/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Patients with decompensated cirrhosis show a marked innate immune response that shows a wide variability. The reasons for this fact have not been previously evaluated. This investigation was undertaken to study factors influencing the immune response intensity in both serum and ascitic fluid in patients with cirrhosis and ascites with presence of bactDNA. METHODS 77 patients with cirrhosis and presence of bactDNA fragments in blood and ascitic fluid were included. Identification of bactDNA was evaluated by 16SrRNA gene PCR followed by nucleotide sequencing and by species-specific PCR. Concentration of amplified bacterial-DNA, bacteria identification, LPS, TNF-alpha, IFN-gamma, Interleukin 12 and nitric oxide in serum and ascitic fluid were evaluated as factors related to intensity of the immune response. RESULTS Serum and AF levels of bactDNA, TNF-α, IFN-γ and nitric oxide concentration were higher in patients with presence of bactDNA from gram negative bacteria. Serum TNF-α levels showed a significant correlation with concentrations of bactDNA (r = 0.88; P = 0.001) and LPS (r = 0.28; P = 0.016). Serum nitric oxide levels were also significantly correlated with concentrations of bactDNA (r = 0.761; P = 0.001) but not with LPS levels. Levels of INF-γ and IL-12 were not significantly correlated with either bactDNA nor LPS levels. Plasmatic concentration of bactDNA was the most accurately correlated factor with the inflammatory response (ancova model included only levels of bactDNA (r(2) = 0.87, P = 0.047 for TNF-α; r(2) = 0.45, P = 0.03 for NOx). CONCLUSIONS Bacterial-DNA concentration is the most influencing variable associated with serum TNF-α and nitric oxide response.
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Affiliation(s)
- Elena Caro
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain
| | - Rubén Francés
- Departamento de Medicina Clínica, Universidad Miguel Hernández, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Pedro Zapater
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.,Unidad de Farmacología Clínica, Hospital General Universitario de Alicante y Universidad Miguel Hernández, Alicante, Spain
| | - Sonia Pascual
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Pablo Bellot
- Unidad Hepática, Hospital General Universitario de Alicante, Alicante, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - José Such
- Digestive Disease Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, UAE, Lerner School of medicine, Case Western Reserve University, Cleveland, OH, US.
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35
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Enescu A, Petrescu F, Mitruţ P, Petrescu IO, Pădureanu V, Enescu AŞ. Hepatorenal Syndrome: Diagnosis and Treatment - newsreel. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MEDECINE INTERNE 2016; 54:143-150. [PMID: 27658161 DOI: 10.1515/rjim-2016-0024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Indexed: 01/06/2023]
Abstract
Hepatorenal syndrome (HRS) is defined as renal failure that occurs in the presence of severe acute or chronic liver disease in the absence of underlying renal pathology. Due to the functional nature of the disease and the absence of specific diagnostic markers, HRS diagnosis is determined based on positive criteria associated with excluding other causes of renal failure in patients with liver cirrhosis and ascites. Differentiation from other types of acute or chronic renal disease is extremely difficult and therapeutic options are limited, prophylactic behavior is most appropriate in patients with severe hepatic disease and risk factors for the installation of hepatorenal syndrome. Highlighting all precipitating factors of acute renal insufficiency and therapeutic modalities in order to minimize adverse events is an important step in improving the follow-up of the patients with liver cirrhosis. The prognosis is reserved especially for type 1 HRS. Liver transplantation is the best option for patients without contraindications. The therapies introduced in recent years, such as vasoconstrictor drugs or transjugular intrahepatic portosystemic shunt are effective methods in the renal function improvement.
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Bernardi M, Moreau R, Angeli P, Schnabl B, Arroyo V. Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis. J Hepatol 2015; 63:1272-84. [PMID: 26192220 DOI: 10.1016/j.jhep.2015.07.004] [Citation(s) in RCA: 430] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Revised: 07/06/2015] [Accepted: 07/07/2015] [Indexed: 02/06/2023]
Abstract
The peripheral arterial vasodilation hypothesis has been most influential in the field of cirrhosis and its complications. It has given rise to hundreds of pathophysiological studies in experimental and human cirrhosis and is the theoretical basis of life-saving treatments. It is undisputed that splanchnic arterial vasodilation contributes to portal hypertension and is the basis for manifestations such as ascites and hepatorenal syndrome, but the body of research generated by the hypothesis has revealed gaps in the original pathophysiological interpretation of these complications. The expansion of our knowledge on the mechanisms regulating vascular tone, inflammation and the host-microbiota interaction require a broader approach to advanced cirrhosis encompassing the whole spectrum of its manifestations. Indeed, multiorgan dysfunction and failure likely result from a complex interplay where the systemic spread of bacterial products represents the primary event. The consequent activation of the host innate immune response triggers endothelial molecular mechanisms responsible for arterial vasodilation, and also jeopardizes organ integrity with a storm of pro-inflammatory cytokines and reactive oxygen and nitrogen species. Thus, the picture of advanced cirrhosis could be seen as the result of an inflammatory syndrome in contradiction with a simple hemodynamic disturbance.
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Affiliation(s)
- Mauro Bernardi
- Department of Medical and Surgical Sciences - Alma Mater Studiorum, University of Bologna, Italy; Semeiotica Medica, Policlinico S. Orsola-Malpighi, Bologna, Italy.
| | - Richard Moreau
- Inserm, U(1149), Centre de Recherche sur l'Inflammation (CRI), Paris, France; UMR_S(1149), Université Paris Diderot, Faculté de Médecine, Paris, France; Département Hospitalo-Universitaire (DHU) UNITY, Service d'Hépatologie, Hôpital Beaujon, AP-HP, Clichy, France
| | - Paolo Angeli
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine-DIMED, University of Padova, Padova, Italy
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, United States; Department of Medicine, VA San Diego Healthcare System, San Diego, CA, United States
| | - Vicente Arroyo
- Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques Agust Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
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Gut Microbiota and Host Reaction in Liver Diseases. Microorganisms 2015; 3:759-91. [PMID: 27682116 PMCID: PMC5023261 DOI: 10.3390/microorganisms3040759] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 10/08/2015] [Accepted: 10/21/2015] [Indexed: 02/07/2023] Open
Abstract
Although alcohol feeding produces evident intestinal microbial changes in animals, only some alcoholics show evident intestinal dysbiosis, a decrease in Bacteroidetes and an increase in Proteobacteria. Gut dysbiosis is related to intestinal hyperpermeability and endotoxemia in alcoholic patients. Alcoholics further exhibit reduced numbers of the beneficial Lactobacillus and Bifidobacterium. Large amounts of endotoxins translocated from the gut strongly activate Toll-like receptor 4 in the liver and play an important role in the progression of alcoholic liver disease (ALD), especially in severe alcoholic liver injury. Gut microbiota and bacterial endotoxins are further involved in some of the mechanisms of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). There is experimental evidence that a high-fat diet causes characteristic dysbiosis of NAFLD, with a decrease in Bacteroidetes and increases in Firmicutes and Proteobacteria, and gut dysbiosis itself can induce hepatic steatosis and metabolic syndrome. Clinical data support the above dysbiosis, but the details are variable. Intestinal dysbiosis and endotoxemia greatly affect the cirrhotics in relation to major complications and prognosis. Metagenomic approaches to dysbiosis may be promising for the analysis of deranged host metabolism in NASH and cirrhosis. Management of dysbiosis may become a cornerstone for the future treatment of liver diseases.
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Thomas DD, Heinecke JL, Ridnour LA, Cheng RY, Kesarwala AH, Switzer CH, McVicar DW, Roberts DD, Glynn S, Fukuto JM, Wink DA, Miranda KM. Signaling and stress: The redox landscape in NOS2 biology. Free Radic Biol Med 2015; 87:204-25. [PMID: 26117324 PMCID: PMC4852151 DOI: 10.1016/j.freeradbiomed.2015.06.002] [Citation(s) in RCA: 100] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 06/01/2015] [Accepted: 06/02/2015] [Indexed: 01/31/2023]
Abstract
Nitric oxide (NO) has a highly diverse range of biological functions from physiological signaling and maintenance of homeostasis to serving as an effector molecule in the immune system. However, deleterious as well as beneficial roles of NO have been reported. Many of the dichotomous effects of NO and derivative reactive nitrogen species (RNS) can be explained by invoking precise interactions with different targets as a result of concentration and temporal constraints. Endogenous concentrations of NO span five orders of magnitude, with levels near the high picomolar range typically occurring in short bursts as compared to sustained production of low micromolar levels of NO during immune response. This article provides an overview of the redox landscape as it relates to increasing NO concentrations, which incrementally govern physiological signaling, nitrosative signaling and nitrosative stress-related signaling. Physiological signaling by NO primarily occurs upon interaction with the heme protein soluble guanylyl cyclase. As NO concentrations rise, interactions with nonheme iron complexes as well as indirect modification of thiols can stimulate additional signaling processes. At the highest levels of NO, production of a broader range of RNS, which subsequently interact with more diverse targets, can lead to chemical stress. However, even under such conditions, there is evidence that stress-related signaling mechanisms are triggered to protect cells or even resolve the stress. This review therefore also addresses the fundamental reactions and kinetics that initiate signaling through NO-dependent pathways, including processes that lead to interconversion of RNS and interactions with molecular targets.
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Affiliation(s)
- Douglas D Thomas
- Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Julie L Heinecke
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Lisa A Ridnour
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Robert Y Cheng
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Aparna H Kesarwala
- Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Christopher H Switzer
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Daniel W McVicar
- Cancer and Inflammation Program, National Cancer Institute-Frederick, Frederick, MD 21702, USA
| | - David D Roberts
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Sharon Glynn
- Prostate Cancer Institute, NUI Galway, Ireland, USA
| | - Jon M Fukuto
- Department of Chemistry, Sonoma State University, Rohnert Park, CA 94928, USA
| | - David A Wink
- Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Katrina M Miranda
- Department of Chemistry, University of Arizona, 1306 E. University Blvd., Tucson, AZ 85721, USA.
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Sinha VK, Ko B. Hyponatremia in Cirrhosis--Pathogenesis, Treatment, and Prognostic Significance. Adv Chronic Kidney Dis 2015; 22:361-7. [PMID: 26311597 DOI: 10.1053/j.ackd.2015.02.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 02/06/2015] [Accepted: 02/12/2015] [Indexed: 01/14/2023]
Abstract
Cirrhosis is characterized by systemic and splanchnic vasodilation that leads to excessive nonosmotic secretion of vasopressin (antidiuretic hormone). Hyponatremia is a common electrolyte abnormality in advanced liver disease that results from the impaired ability of the kidney to excrete solute-free water that leads to "dilutional" hyponatremia-water retention disproportionate to the retention of sodium. Hyponatremia in liver diseases carries the prognostic burden, correlates with the severity of cirrhosis, and, in recent studies, has also been implicated in the pathogenesis of hepatic encephalopathy. The current treatment options are limited to conventional therapies like fluid restriction, and the outcomes are unsatisfactory. Although currently available vasopressin (V2 receptors) antagonists have been shown to increase serum sodium concentrations and improve ascites control, their role in the treatment of hyponatremia in liver disease patients remains questionable because of adverse effect profiles, high cost, and poor data on long-term mortality benefits. More information is needed to argue the benefits vs risks of short-term use of vaptans for correction of hyponatremia especially just hours-to-days before liver transplant.
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Abstract
There is an intricate relationship between the liver and the kidney, with renal physiology and function intimately involved in many primary disorders of pediatric liver disease. The hemodynamic changes of progressive cirrhosis affect and are directly affected by changes in renal blood flow and renal handling of sodium and free water excretion. Resulting complications of worsening ascites, hyponatremia, and acute kidney injury frequently complicate the care of children with advanced liver disease and contribute significant morbidity and mortality. While liver transplantation may restore hemodynamic stability, nearly 40% of pediatric liver transplant recipients develop chronic kidney disease post-transplant and approximately 25% are left with clinical hypertension. This review seeks to provide a basic understanding of this relationship to enable the provision of optimal care to children with liver disease.
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Affiliation(s)
- Robyn Greenfield Matloff
- Division of Pediatric Nephrology, Maria Fareri Children's Hospital of Westchester Medical Center, New York Medical College, Skyline Office # 1N-C12, 40 Sunshine Cottage Road, Valhalla, NY, 10595, USA,
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Angeli P, Tonon M, Pilutti C, Morando F, Piano S. Sepsis-induced acute kidney injury in patients with cirrhosis. Hepatol Int 2015; 10:115-23. [PMID: 26141259 DOI: 10.1007/s12072-015-9641-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Accepted: 05/19/2015] [Indexed: 12/13/2022]
Abstract
Acute kidney injury (AKI) is a common and life-threatening complication in patients with cirrhosis. Recently, new criteria for the diagnosis of AKI have been proposed in patients with cirrhosis by the International Club of Ascites. Almost all types of bacterial infections can induce AKI in patients with cirrhosis representing its most common precipitating event. The bacterial infection-induced AKI usually meets the diagnostic criteria of hepatorenal syndrome (HRS). Well in keeping with the "splanchnic arterial vasodilation hypothesis", it has been stated that HRS develops as a consequence of a severe reduction of effective circulating volume related to splanchnic arterial vasodilation and to an inadequate cardiac output. Nevertheless, the role of bacterial infections in precipitating organ failures, including renal failure, is enhanced when their course is characterized by the development of a systemic inflammatory response syndrome (SIRS), thus, when sepsis occurs. Sepsis has been shown to be capable to induce "per se" AKI in animals as well as in patients conditioning also the features of renal damage. This observation suggests that when precipitated by sepsis, the pathogenesis and the clinical course of AKI also in patients with cirrhosis may differentiate to a certain extent from AKI with another or no precipitating factor. The purpose of this review is to describe the features of AKI precipitated by bacterial infections and to highlight whether infection and/or the development of SIRS may influence its clinical course, and, in particular, the response to treatment.
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Affiliation(s)
- Paolo Angeli
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine, DIMED, University of Padova, Via Giustiniani 2, 35128, Padua, Italy.
| | - Marta Tonon
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine, DIMED, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Chiara Pilutti
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine, DIMED, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Filippo Morando
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine, DIMED, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
| | - Salvatore Piano
- Unit of Hepatic Emergencies and Liver Transplantation, Department of Medicine, DIMED, University of Padova, Via Giustiniani 2, 35128, Padua, Italy
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Fukui H. Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia. World J Hepatol 2015; 7:425-442. [PMID: 25848468 PMCID: PMC4381167 DOI: 10.4254/wjh.v7.i3.425] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 12/14/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023] Open
Abstract
A “leaky gut” may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin, activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.
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Nikoui V, Ejtemaei Mehr S, Jazaeri F, Ostadhadi S, Eftekhari G, Dehpour AR, Mani AR, Bakhtiarian A. Prostaglandin F₂α modulates atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats. Eur J Pharmacol 2015; 748:149-156. [PMID: 25446912 DOI: 10.1016/j.ejphar.2014.10.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Revised: 10/09/2014] [Accepted: 10/10/2014] [Indexed: 01/25/2023]
Abstract
Endotoxemia induces various physiological adaptive responses such as tachycardia. There is evidence to show that inflammatory tachycardia might be linked to a direct action of prostanoids on the cardiac pacemaker cells. Recent reports have indicated that systemic inflammation may uncouple of cardiac pacemaker from cholinergic neural control in experimental animals; however, the exact mechanism of this phenomenon is uncertain. This study was aimed to explore the hypothesis that prostanoids modulate atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats. Male albino rats were given intraperitoneal injection of either saline or lipopolysaccharide (LPS, 1 mg/kg). 3 h after saline or LPS injection, the atria were isolated and chronotropic responsiveness to cholinergic stimulation was evaluated in an organ bath. The expression of atrial cyclooxygenases (COX)-1, COX-2 and COX-3 mRNA was assessed by quantitative real-time RT-PCR and cytosocalcium-dependent phospholipase A₂ (cPLA₂) activity was measured in the atria. The expression of atrial COX-2 mRNA and cPLA₂ activity increased significantly in endotoxemic atria (P<0.05). Incubation with prostaglandin F₂α (PGF₂α, 100 pM) could significantly decrease chronotropic response to cholinergic stimulation in vitro. Likewise, LPS injection could induce a significant hyporesponsiveness to cholinergic stimulation, and incubation of isolated atria with either indomethacin (5 µM) or AL-8810 (a PGF₂α antagonist, 10 µM) could reverse it (P<0.01, P<0.05, respectively), while SQ29548 (a thromboxane A₂ antagonist, 10 nM) was failed (P>0.05). Our data showed that PGF₂α may contribute to the atrial chronotropic hyporesponsiveness to cholinergic stimulation in endotoxemic rats.
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Affiliation(s)
- Vahid Nikoui
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Shahram Ejtemaei Mehr
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Farahnaz Jazaeri
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Sattar Ostadhadi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Golnar Eftekhari
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Ahmad-Reza Dehpour
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Ali R Mani
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Azam Bakhtiarian
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Pathophysiology of Portal Hypertension. PANVASCULAR MEDICINE 2015. [PMCID: PMC7153457 DOI: 10.1007/978-3-642-37078-6_144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The bases of our current knowledge on the physiology of the hepatic portal system are largely owed to the work of three pioneering vascular researchers from the sixteenth and the seventeenth centuries: A. Vesalius, W. Harvey, and F. Glisson. Vesalius is referred to as the founder of modern human anatomy, and in his influential book, De humani corporis fabrica libri septem, he elaborated the first anatomical atlas of the hepatic portal venous system (Vesalius 2013). Sir William Harvey laid the foundations of modern cardiovascular research with his Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (Harvey 1931) in which he established the nature of blood circulation. Finally, F. Glisson characterized the gastrointestinal-hepatic vascular system (Child 1955). These physiological descriptions were later complemented with clinical observations. In the eighteenth and nineteenth centuries, Morgagni, Puckelt, Cruveilhier, and Osler were the first to make the connection between common hepatic complications – ascites, splenomegaly, and gastrointestinal bleeding – and obstruction of the portal system (Sandblom 1993). These were the foundations that allowed Gilbert, Villaret, and Thompson to establish an early definition of portal hypertension at the beginning of the twentieth century. In this period, Thompson performed the first direct measurement of portal pressure by laparotomy in some patients (Gilbert and Villaret 1906; Thompson et al. 1937). Considering all these milestones, and paraphrasing Sir Isaac Newton, if hepatologists have seen further, it is by standing on the shoulders of giants. Nowadays, our understanding of the pathogenesis of portal hypertension has largely improved thanks to the progress in preclinical and clinical research. However, this field is ever-changing and hepatologists are continually identifying novel pathological mechanisms and developing new therapeutic strategies for this clinical condition. Hence, the aim of this chapter is to summarize the current knowledge about this clinical condition.
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Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance. J Hepatol 2014; 61:1385-96. [PMID: 25135860 DOI: 10.1016/j.jhep.2014.08.010] [Citation(s) in RCA: 825] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Revised: 07/27/2014] [Accepted: 08/09/2014] [Indexed: 02/06/2023]
Abstract
The term cirrhosis-associated immune dysfunction refers to the main syndromic abnormalities of immune function, immunodeficiency and systemic inflammation that are present in cirrhosis. The course of advanced cirrhosis, regardless of its aetiology, is complicated by cirrhosis-associated immune dysfunction and this constitutes the pathophysiological hallmark of an increased susceptibility to bacterial infection, distinctive of the disease. Cirrhosis impairs the homeostatic role of the liver in the systemic immune response. Damage to the reticulo-endothelial system compromises the immune surveillance function of the organ and the reduced hepatic synthesis of proteins, involved in innate immunity and pattern recognition, hinders the bactericidal ability of phagocytic cells. Systemic inflammation, in form of activated circulating immune cells and increased serum levels of pro-inflammatory cytokines, is the result of persistent episodic activation of circulating immune cells from damage-associated molecular patterns, released from necrotic liver cells and, as cirrhosis progresses, from pathogen-associated molecular patterns, released from the leaky gut. Cirrhosis-associated immune dysfunction phenotypes switch from predominantly "pro-inflammatory" to predominantly "immunodeficient" in patients with stable ascitic cirrhosis and in patients with severely decompensated cirrhosis and extra-hepatic organ failure (e.g. acute-on-chronic liver failure), respectively. These cirrhosis-associated immune dysfunction phenotypes represent the extremes of a spectrum of reversible dynamic events that take place during the course of cirrhosis. Systemic inflammation can affect the functions of tissue somatic cells and modify the clinical manifestation of cirrhosis. The best characterized example is the contribution of systemic inflammation to the haemodynamic derangement of cirrhosis, which correlates negatively with prognosis.
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Affiliation(s)
- Agustín Albillos
- Department of Medicine, Universidad de Alcalá, Madrid, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Service of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain.
| | - Margaret Lario
- Department of Medicine, Universidad de Alcalá, Madrid, Spain
| | - Melchor Álvarez-Mon
- Department of Medicine, Universidad de Alcalá, Madrid, Spain; CIBERehd, Instituto de Salud Carlos III, Madrid, Spain; Service of Immune Diseases and Oncology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
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Ghasemi M, Karimollah AR, Bakhtiari B, Ghasemi A, Moezi L, Bahremand A, Ziaei P, Dehpour AR. Effect of biliary cirrhosis on neurogenic relaxation of rat gastric fundus and anococcygeus muscle: role of nitric oxide pathway. Dig Dis Sci 2014; 59:2675-2681. [PMID: 24898099 DOI: 10.1007/s10620-014-3225-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 05/23/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cirrhosis, associated with a host of hemodynamic abnormalities, could affect the gastrointestinal (GI) tract motility. On the other hand, the nonadrenergic noncholinergic (NANC) neurotransmission has been shown to play a pivotal role in GI tract motility and has been linked with release of nitric oxide (NO) on electrical stimulation. In this study, we investigated the effect of biliary cirrhosis on the neurogenic relaxation of rat gastric fundus and anococcygeus muscle and also the possible role of nitric oxide system in this manner. METHODS Isolated gastric fundus and anococcygeus strips of sham-operated and biliary cirrhotic (4 weeks after bile duct ligation) rats were mounted under tension in a standard organ bath. Electrical stimulation was applied to obtain NANC-mediated relaxations in precontracted gastric fundus and anococcygeus muscle. The neurogenic relaxations were examined in the presence of different doses of NO synthase inhibitor, N (w)-Nitro-L-Arginine Methyl Ester (L-NAME). The concentration-dependent relaxant responses to the NO donor sodium nitroprusside were also evaluated. RESULTS The neurogenic relaxation of both gastric fundus and anococcygeus muscle was significantly (P < 0.001) increased in cirrhotic animals. L-NAME (0.03-1,000 µM) inhibited relaxations in both groups in a dose-dependent manner (P < 0.001), but cirrhotic groups were more resistant to the inhibitory effects of L-NAME (P < 0.01). Sodium nitroprusside-mediated relaxations were similar in two groups. CONCLUSIONS This study for the first time demonstrated that cirrhosis increases the NO-mediated neurogenic relaxation of both rat gastric fundus and anococcygeus muscle, suggesting a crucial role for the neurogenic NO in the pathophysiology of disturbed GI motility in cirrhosis.
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Affiliation(s)
- Mehdi Ghasemi
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Gustot T. New findings about an 'old' drug: immunomodulatory effects of norfloxacin in cirrhosis. J Hepatol 2014; 61:725-6. [PMID: 24996045 DOI: 10.1016/j.jhep.2014.06.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 06/26/2014] [Indexed: 01/16/2023]
Affiliation(s)
- Thierry Gustot
- Department of Gastroenterology and Hepato-Pancreatology, Erasme Hospital, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.
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Acevedo J, Fernández J. New determinants of prognosis in bacterial infections in cirrhosis. World J Gastroenterol 2014; 20:7252-7259. [PMID: 24966596 PMCID: PMC4064071 DOI: 10.3748/wjg.v20.i23.7252] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2013] [Revised: 02/09/2014] [Accepted: 05/12/2014] [Indexed: 02/06/2023] Open
Abstract
Despite major advances in the knowledge and management of liver diseases achieved in recent decades, decompensation of cirrhosis still carries a high burden of morbidity and mortality. Bacterial infections are one of the main causes of decompensation. It is very important for clinical management to be aware of the population with the highest risk of poor outcome. This review deals with the new determinants of prognosis in patients with cirrhosis and bacterial infections reported recently. Emergence of multiresistant bacteria has led to an increasing failure rate of the standard empirical antibiotic therapy recommended by international guidelines. Moreover, it has been recently reported that endothelial dysfunction is associated with the degree of liver dysfunction and, in infected patients, with the degree of sepsis. It has also been reported that relative adrenal insufficiency is frequent in the non-critically ill cirrhotic population and it is associated with a higher risk of developing infection, severe sepsis, hepatorenal syndrome and death. We advise a change in the standard empirical antibiotic therapy in patients with high risk for multiresistant infections and also to take into account endothelial and adrenal dysfunction in prognostic models in hospitalized patients with decompensated cirrhosis.
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Could serum nitrate and nitrite levels possibly predict hepatorenal syndrome in hepatitis C virus-related liver cirrhosis? Indian J Gastroenterol 2014; 33:274-80. [PMID: 24287875 DOI: 10.1007/s12664-013-0427-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 10/14/2013] [Indexed: 02/04/2023]
Abstract
PURPOSE This study aimed to determine whether serum levels of nitric oxide metabolites (nitrates and nitrites) correlate with renal dysfunction in patients with liver cirrhosis and, moreover, to assess nitric oxide metabolite (NOx) power for predicting hepatorenal syndrome (HRS) in such patients. METHODS Among patients admitted to the Tropical Medicine Department, Ain Shams University Hospital, a total of 60 patients with chronic hepatitis C-related liver cirrhosis were included in this study. Patients were divided into three groups. Group I included 20 patients with compensated liver cirrhosis (CLC). Group II included 20 patients with decompensated liver cirrhosis (DLC). Group III included 20 patients with decompensated liver cirrhosis and HRS. Twenty healthy subjects with no clinical or laboratory evidence of liver disease were enrolled as a control group (group IV). RESULTS Patients with HRS had a higher mean nitrite levels followed by DLC, then CLC, and then controls. The sensitivity and specificity of NO metabolites (nitrites) were 100 % and 93.3 %, respectively, with accuracy of 95 % at cutoff value of 387 μmol/L for diagnosing patients with HRS. There was a highly significant statistical difference between patients positive and negative for nitrites as regards renal profile (p = 0.000). CONCLUSION A strong relation between nitrite cutoff value and renal dysfunction in liver cirrhosis has been found. Also, patients with HRS had higher mean serum nitrite levels than decompensated liver cirrhosis or compensated liver cirrhosis, raising the possibility of using nitrate and nitrite levels as a predictor for HRS in HCV-related liver cirrhosis.
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Jayakumar S, Carbonneau M, Hotte N, Befus AD, St Laurent C, Owen R, McCarthy M, Madsen K, Bailey RJ, Ma M, Bain V, Rioux K, Tandon P. VSL#3 ® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis. Liver Int 2013; 33:1470-7. [PMID: 23968203 DOI: 10.1111/liv.12280] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Accepted: 06/20/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS In patients with decompensated cirrhosis, bacterial translocation can contribute to splanchnic vasodilatation, decreased effective circulating volume, and portal hypertension. The primary objective of this randomized, double blind placebo controlled trial was to evaluate the effect of the probiotic VSL#3(®) on the hepatic venous pressure gradient (HVPG). METHODS Seventeen patients with decompensated cirrhosis and an HVPG of ≥ 10 mmHg were randomized to receive 2 months of VSL#3(®) or an identical placebo. HVPG, endotoxin, interleukin (IL)-6, IL-8, IL-10, renin, aldosterone, nitric oxide and stool microbiota were measured at baseline and study end. RESULTS Two of the 17 patients were taken off the trial before completion (one for alcohol abuse and the second for SBP - both in placebo arm). Data were analysed on the remaining 15 patients. The median model for end-stage liver disease score was 12, and 80% of patients had Child Pugh B disease. The treatment arm had a greater decrease in HVPG from baseline to study end than the placebo arm (median change from baseline -11.6% vs +2.8%), although this reduction was not statistically significant in either group. There was a significant reduction in the plasma aldosterone level in the VSL#3(®) group, but no significant changes in the other measured parameters, including the stool microflora analysis. CONCLUSIONS Within the limitations of our sample size, VSL#3(®) therapy does not appear to have a significant impact on portal pressure reduction in patients with decompensated cirrhosis.
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Affiliation(s)
- Saumya Jayakumar
- Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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