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1
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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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2
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Ott P, Eriksen PL, Kjærgaard K, Sørensen M, Thomsen KL, Vilstrup H. Down the road towards hepatic encephalopathy. The elusive ammonia- what determines the arterial concentration? Metab Brain Dis 2024; 40:48. [PMID: 39621139 PMCID: PMC11611965 DOI: 10.1007/s11011-024-01435-3] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 10/25/2024] [Indexed: 12/06/2024]
Abstract
Elevated arterial ammonia is associated with several complications of liver disease as it predicts mortality for in-patients and decompensation, hospitalization and death in out-patients with cirrhosis. In this review, our aim was to estimate how the individual organs contribute to arterial ammonia based on published data from human studies. The brain removes ammonia from arterial blood in a concentration-dependent fashion. Ammonia that is released from the gut to portal blood is mainly from metabolism of glutamine in the enterocytes using this as a source of energy. Ammonia produced by bacterial metabolism of urea and proteins only partially reach portal blood and is likely recycled into bacterial proteins. In general, the liver efficiently removes ammonia from arterial or portal blood in proportion to the delivered concentration. As a result,- and in some contrast to conventional wisdom-, the hepato-splanchnic region only contributes marginally to arterial ammonia; even during a simulated upper GI bleed. The only exception is acute liver failure where hepatocyte necrosis allows large quantities of portal ammonia to pass. The kidneys release ammonia from glutamine metabolism into systemic blood. The renal ammonia release increases during a simulated upper GI bleed or hypokalemia where it becomes a major source of elevated arterial ammonia. In the resting state, muscles remove ammonia in a concentration-dependent manner and muscles are the primary ammonia lowering organ in most situations with elevated arterial ammonia. During strenuous exercise, muscles produce large amounts of ammonia into systemic blood. Thus, the complete pattern of ammonia metabolism is very dynamic and illustrates the difficulties in designing ammonia lowering therapies.
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Affiliation(s)
- Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, DK-8200, Denmark.
| | - Peter Lykke Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, DK-8200, Denmark
| | - Kristoffer Kjærgaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, DK-8200, Denmark
| | - Michael Sørensen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, DK-8200, Denmark
- Department of Internal Medicine, Viborg Regional Hospital, Viborg, Denmark
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, DK-8200, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N, DK-8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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3
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Ntuli Y, Shawcross DL. Infection, inflammation and hepatic encephalopathy from a clinical perspective. Metab Brain Dis 2024; 39:1689-1703. [PMID: 39212845 PMCID: PMC11535002 DOI: 10.1007/s11011-024-01402-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024]
Abstract
Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.
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Affiliation(s)
- Yevedzo Ntuli
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK
| | - Debbie L Shawcross
- School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, King's College Hospital, 125 Coldharbour Lane, London, SE5 9NU, UK.
- Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.
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Gallego-Durán R, Hadjihambi A, Ampuero J, Rose CF, Jalan R, Romero-Gómez M. Ammonia-induced stress response in liver disease progression and hepatic encephalopathy. Nat Rev Gastroenterol Hepatol 2024; 21:774-791. [PMID: 39251708 DOI: 10.1038/s41575-024-00970-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 09/11/2024]
Abstract
Ammonia levels are orchestrated by a series of complex interrelated pathways in which the urea cycle has a central role. Liver dysfunction leads to an accumulation of ammonia, which is toxic and is strongly associated with disruption of potassium homeostasis, mitochondrial dysfunction, oxidative stress, inflammation, hypoxaemia and dysregulation of neurotransmission. Hyperammonaemia is a hallmark of hepatic encephalopathy and has been strongly associated with liver-related outcomes in patients with cirrhosis and liver failure. In addition to the established role of ammonia as a neurotoxin in the pathogenesis of hepatic encephalopathy, an increasing number of studies suggest that it can lead to hepatic fibrosis progression, sarcopenia, immune dysfunction and cancer. However, elevated systemic ammonia levels are uncommon in patients with metabolic dysfunction-associated steatotic liver disease. A clear causal relationship between ammonia-induced immune dysfunction and risk of infection has not yet been definitively proven. In this Review, we discuss the mechanisms by which ammonia produces its diverse deleterious effects and their clinical relevance in liver diseases, the importance of measuring ammonia levels for the diagnosis of hepatic encephalopathy, the prognosis of patients with cirrhosis and liver failure, and how our knowledge of inter-organ ammonia metabolism is leading to the development of novel therapeutic approaches.
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Affiliation(s)
- Rocío Gallego-Durán
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Anna Hadjihambi
- The Roger Williams Institute of Hepatology, Foundation for Liver Research, London, UK
- Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Javier Ampuero
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada
| | - Rajiv Jalan
- Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, London, UK
- European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Manuel Romero-Gómez
- UCM Digestive Diseases, Virgen del Rocío University Hospital. Instituto de Biomedicina de Sevilla (HUVR/CSIC/US), Department of Medicine, University of Seville, Seville, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
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Anand AC, Acharya SK. The Story of Ammonia in Liver Disease: An Unraveling Continuum. J Clin Exp Hepatol 2024; 14:101361. [PMID: 38444405 PMCID: PMC10910335 DOI: 10.1016/j.jceh.2024.101361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 02/03/2024] [Indexed: 03/07/2024] Open
Abstract
Hyperammonemia and liver disease are closely linked. Most of the ammonia in our body is produced by transamination and deamination activities involving amino acid, purine, pyrimidines, and biogenic amines, and from the intestine by bacterial splitting of urea. The only way of excretion from the body is by hepatic conversion of ammonia to urea. Hyperammonemia is associated with widespread toxicities such as cerebral edema, hepatic encephalopathy, immune dysfunction, promoting fibrosis, and carcinogenesis. Over the past two decades, it has been increasingly utilized for prognostication of cirrhosis, acute liver failure as well as acute on chronic liver failure. The laboratory assessment of hyperammonemia has certain limitations, despite which its value in the assessment of various forms of liver disease cannot be negated. It may soon become an important tool to make therapeutic decisions about the use of prophylactic and definitive treatment in various forms of liver disease.
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Holeček M. Origin and Roles of Alanine and Glutamine in Gluconeogenesis in the Liver, Kidneys, and Small Intestine under Physiological and Pathological Conditions. Int J Mol Sci 2024; 25:7037. [PMID: 39000145 PMCID: PMC11241752 DOI: 10.3390/ijms25137037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/21/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Alanine and glutamine are the principal glucogenic amino acids. Most originate from muscles, where branched-chain amino acids (valine, leucine, and isoleucine) are nitrogen donors and, under exceptional circumstances, a source of carbons for glutamate synthesis. Glutamate is a nitrogen source for alanine synthesis from pyruvate and a substrate for glutamine synthesis by glutamine synthetase. The following differences between alanine and glutamine, which can play a role in their use in gluconeogenesis, are shown: (i) glutamine appearance in circulation is higher than that of alanine; (ii) the conversion to oxaloacetate, the starting substance for glucose synthesis, is an ATP-consuming reaction for alanine, which is energetically beneficial for glutamine; (iii) most alanine carbons, but not glutamine carbons, originate from glucose; and (iv) glutamine acts a substrate for gluconeogenesis in the liver, kidneys, and intestine, whereas alanine does so only in the liver. Alanine plays a significant role during early starvation, exposure to high-fat and high-protein diets, and diabetes. Glutamine plays a dominant role in gluconeogenesis in prolonged starvation, acidosis, liver cirrhosis, and severe illnesses like sepsis and acts as a substrate for alanine synthesis in the small intestine. Interactions among muscles and the liver, kidneys, and intestine ensuring optimal alanine and glutamine supply for gluconeogenesis are suggested.
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Affiliation(s)
- Milan Holeček
- Department of Physiology, Faculty of Medicine, Charles University, 500 03 Hradec Kralove, Czech Republic
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Nadinskaia MY, Maevskaya MV, Bakulin IG, Bessonova EN, Bueverov AO, Zharkova MS, Okovityi SV, Ostrovskaya AS, Gulyaeva KA, Ivashkin VT. Diagnostic and Prognostic Value of Hyperammonemia in Patients with Liver Cirrhosis, Hepatic Encephalopathy, and Sarcopenia (Experts’ Agreement). RUSSIAN JOURNAL OF GASTROENTEROLOGY, HEPATOLOGY, COLOPROCTOLOGY 2024; 34:85-100. [DOI: 10.22416/1382-4376-2024-34-1-85-100] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Introduction. In cirrhotic patients, hyperammonemia develops due to impaired ammonia detoxification and portosystemic blood shunting and is most commonly associated with hepatic encephalopathy and sarcopenia. Currently, there are questions regarding the diagnosis of hyperammonemia and the effect of ammonia-lowering therapy on disease outcomes.Materials and methods. The Russian Scientific Liver Society selected a panel of seven experts in liver cirrhosis research and management of patients with this disease to make reasoned statements and recommendations on the issue of diagnostic and prognostic value of hyperammonemia in patients with liver cirrhosis, hepatic encephalopathy and sarcopenia.Results. The Delphi panel identified the most relevant topics, in the form of PICO questions (patient or population, intervention, comparison, outcome). The Delphi panel made six questions relevant to clinical practice and gave reasoned answers, framed as ‘clinical practice recommendations and statements’ with evidence-based comments. The questions and statements were based on the search and critical analysis of medical literature by keywords in Englishand Russian-language databases. The formulated questions could be combined into four categories: hepatic encephalopathy, sarcopenia, hyperammonemia, and ammonia-lowering therapy.Conclusions. The results of the experts' work are directly relevant to the quality management of patients with liver cirrhosis, and their recommendations and statements can be used in clinical practice.
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Affiliation(s)
- M. Yu. Nadinskaia
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - M. V. Maevskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - I. G. Bakulin
- North-Western State Medical University named after I.I. Mechnikov
| | | | - A. O. Bueverov
- I.M. Sechenov First Moscow State Medical University (Sechenov University);
M.F. Vladimirsky Moscow Regional Research and Clinical Institute
| | - M. S. Zharkova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - S. V. Okovityi
- Saint Petersburg State Chemical Pharmaceutical University
| | - A. S. Ostrovskaya
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - K. A. Gulyaeva
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
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Hill KL, Haddad JA, Ali RO, Zhang GY, Quinn GM, Townsend E, Everson GT, Helmke SM, Bagheri M, Schoenfeld M, Yang S, Koh C, Levy EB, Kleiner DE, Sacks DB, Etzion O, Heller T. Dynamic Elevation of Aromatic Amino Acids in Hepatitis C Virus-Induced Cirrhosis After a Standard Meal. Clin Transl Gastroenterol 2024; 15:e00666. [PMID: 38088382 PMCID: PMC10962898 DOI: 10.14309/ctg.0000000000000666] [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: 08/24/2023] [Accepted: 11/18/2023] [Indexed: 03/27/2024] Open
Abstract
INTRODUCTION Perturbations in aromatic (AAAs) and branched-chain amino acids (BCAAs) are seen in decompensated liver disease. The aim of this study was to evaluate the dynamic, postprandial relationship between hepatitis C virus-induced liver disease and amino acid concentrations in patients with compensated liver disease. METHODS Patients infected with hepatitis C virus underwent a baseline liver biopsy to determine Ishak Fibrosis Score and evaluate the liver transcriptome. Patients ate a standard meal and underwent peripheral vein sampling at defined intervals. Quantitative analysis of amino acids was performed using liquid chromatography-tandem mass spectrometry. RESULTS At baseline, there was no difference in AAA and BCAA concentrations between patients with cirrhosis and non-cirrhotic patients. After a standard meal, AAAs, but not BCAAs, were elevated in patients with cirrhosis compared with non-cirrhotic patients at every time point. The HepQuant SHUNT fraction was significantly higher in patients with cirrhosis and positively correlated with AAA concentration at all time points, but not BCAA. Analysis of the hepatic transcriptome demonstrated greater downregulation of the AAA degradation pathways than the BCAA degradation pathways. DISCUSSION At baseline, cirrhotic patients with compensated liver disease have adequate reserve liver function to metabolize AAAs and BCAAs. When faced with a metabolic stressor, such as a standard meal, patients with cirrhosis are less able to metabolize the increased load of AAAs. This impairment correlates with portosystemic shunting. Further evaluation of AAA levels in compensated liver disease might further the understanding of the liver-muscle axis and the role it may play in the development of sarcopenia in liver disease.
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Affiliation(s)
- Kareen L. Hill
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - James A. Haddad
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Rabab O. Ali
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Grace Y. Zhang
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Gabriella M. Quinn
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Elizabeth Townsend
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Gregory T. Everson
- Section of Hepatology, Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- HepQuant LLC, Greenwood Village, Colorado, USA
| | - Steve M. Helmke
- Section of Hepatology, Division of Gastroenterology and Hepatology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- HepQuant LLC, Greenwood Village, Colorado, USA
| | - Mohammadhadi Bagheri
- Clinical Image Processing Service, Radiology and Imaging Sciences, National Institutes of Health, Bethesda, Maryland, USA
| | - Megan Schoenfeld
- Nutrition Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Shanna Yang
- Nutrition Department, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Elliot B. Levy
- Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - David E. Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - David B. Sacks
- Clinical Chemistry Service, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
| | - Ohad Etzion
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Translational Hepatology Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Deng Y, Hui Y, Cui B, Xie W, Sun C. Accumulating awareness on the clinical significance and relevance of frailty in cirrhosis: Time to dig deeper into mechanistic basis! Liver Int 2023; 43:1629-1643. [PMID: 37288711 DOI: 10.1111/liv.15639] [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: 12/10/2022] [Revised: 04/03/2023] [Accepted: 05/25/2023] [Indexed: 06/09/2023]
Abstract
Frailty corresponds to an emerging construct in the hepatology which is originally introduced as a validated geriatric syndrome regarding increased vulnerability to pathophysiological stressors. As for patients with cirrhosis, the presence of frailty is indicative of debilitating conditions that subjects are prone to deleterious acute insults and have difficulties to restore even if the underlying liver function partially returned to normal levels. Since this conceptual development, a variety of tools assessing frailty have been proposed and evaluated in the context of cirrhosis. A recent performance-based metric for frailty, designated as Liver Frailty Index, has broadly been applied in patients with cirrhosis and exhibited acceptable predictive ability in relation to disease progression, mortality and hospitalization. However, those functional tests measuring frailty may be impossible to perform in circumstance that patients are critically ill or undergoing detrimental events. An interesting modality indicates the use of alternative tests to evaluate frailty, which may be more adaptable and of choice for specific subgroups. The interrelation between frailty and various cirrhosis-associated pathological entities is of clinical importance and implication. Noticeably, it is imperative to clarify these complex linkages to highlight novel therapeutic targets or interventional endpoints. The efficient and effective management of frailty is still challenging, but many attempts have been made to overcome barriers of affordability and availability. Some clinical trials on small scale revealed that home-based exercise and individualized nutrition therapy show benefits in patients with cirrhosis, and high adherence to the treatment regimen may direct better efficacy and performance.
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Affiliation(s)
- You Deng
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yangyang Hui
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
| | - Binxin Cui
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Chao Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin, China
- Department of Gastroenterology, Tianjin Medical University General Hospital Airport Hospital, Tianjin, China
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10
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Swansson WD, Anderson BM, Yeoh SW, Lewis DJ. Management of minimal and overt hepatic encephalopathy with branched-chain amino acids: a review of the evidence. Eur J Gastroenterol Hepatol 2023; 35:812-821. [PMID: 37395232 DOI: 10.1097/meg.0000000000002595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Hepatic encephalopathy (HE) is a challenging complication of liver disease that is associated with substantial morbidity and mortality. Branched-chain amino acid (BCAA) supplementation in the management of HE is a debated topic. This narrative review aims to provide an up-to-date review of the topic and includes studies featuring patients with hepatocellular carcinoma. A review of the literature was performed using the online databases MEDLINE and EMBASE for studies between 2002 and December 2022. Keywords 'branched-chain amino acids', 'liver cirrhosis' and 'hepatic encephalopathy' were used. Studies were assessed for inclusion and exclusion criteria. Of 1045 citations, 8 studies met the inclusion criteria. The main outcomes reported for HE was changed in minimal HE (MHE) (n = 4) and/or incidence of overt HE (OHE) (n = 7). Two of the 4 studies reporting on MHE had improvement in psychometric testing in the BCAA group, but there was no change in the incidence of OHE in any of the 7 papers in the BCAA group. There were few adverse effects of BCAA supplementation. This review found weak evidence for BCAA supplementation for MHE, and no evidence for BCAAs for OHE. However, given the relative paucity and methodological heterogeneity of the current research, there is scope for future studies to examine the effects of varying timing, dosage, and frequency of BCAAs on outcomes such as HE. Importantly, research is also needed to examine BCAAs in conjunction with standard therapies for HE such as rifaximin and/or lactulose.
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Affiliation(s)
| | | | - Sern Wei Yeoh
- Melbourne Medical School, The University of Melbourne
- Department of Gastroenterology, Northern Health, Melbourne, VIC, Australia
| | - Diana J Lewis
- Melbourne Medical School, The University of Melbourne
- Department of Gastroenterology, Northern Health, Melbourne, VIC, Australia
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Coelho MPP, de Castro PASV, de Vries TP, Colosimo EA, Bezerra JMT, Rocha GA, Silva LD. Sarcopenia in chronic viral hepatitis: From concept to clinical relevance. World J Hepatol 2023; 15:649-665. [PMID: 37305369 PMCID: PMC10251280 DOI: 10.4254/wjh.v15.i5.649] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 02/17/2023] [Accepted: 04/06/2023] [Indexed: 05/24/2023] Open
Abstract
Although the frequency of metabolic risk factors for cirrhosis and hepatocellular carcinoma (HCC) is increasing, chronic hepatitis B (CHB) and chronic hepatitis C (CHC) remain the most relevant risk factors for advanced liver disease worldwide. In addition to liver damage, hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are associated with a myriad of extrahepatic manifestations including mixed cryoglobulinaemia, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis-like polyarthritis, and autoantibody production. Recently, the list has grown to include sarcopenia. Loss of muscle mass or muscle function is a critical feature of malnutrition in cirrhotic patients and has been found in approximately 23.0%-60.0% of patients with advanced liver disease. Nonetheless, among published studies, there is significant heterogeneity in the aetiologies of hepatic diseases and measurement methods used to determine sarcopenia. In particular, the interaction between sarcopenia, CHB and CHC has not been completely clarified in a real-world setting. Sarcopenia can result from a complex and multifaceted virus-host-environment interplay in individuals chronically infected with HBV or HCV. Thus, in the present review, we provide an overview of the concept, prevalence, clinical relevance, and potential mechanisms of sarcopenia in patients with chronic viral hepatitis, with an emphasis on clinical outcomes, which have been associated with skeletal muscle loss in these patients. A comprehensive overview of sarcopenia in individuals chronically infected with HBV or HCV, independent of the stage of the liver disease, will reinforce the necessity of an integrated medical/nutritional/physical education approach in the daily clinical care of patients with CHB and CHC.
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Affiliation(s)
- Marta Paula Pereira Coelho
- Sciences Applied to Adult Health Care Post-Graduate Programme, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil
| | - Pedro Alves Soares Vaz de Castro
- Medical Undergraduate Student, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil
| | - Thaís Pontello de Vries
- Sciences Applied to Adult Health Care Post-Graduate Programme, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil
| | - Enrico Antônio Colosimo
- Department of Statistics, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil
| | - Juliana Maria Trindade Bezerra
- Department of Biological Sciences, Universidade Estadual do Maranhão, Açailândia 65715-000, Maranhão, Brazil
- Post-Graduate Programme of Animal Science, Universidade Estadual do Maranhão, São Luiz do Maranhão 65.055-310, Maranhão, Brazil
| | - Gifone Aguiar Rocha
- Laboratory of Research in Bacteriology, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil
| | - Luciana Diniz Silva
- Department of Internal Medicine, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 30130-100, Minas Gerais, Brazil.
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Low adipose tissue index as an indicator of hepatic encephalopathy in cirrhotic patients following transjugular intrahepatic portosystemic shunt. ABDOMINAL RADIOLOGY (NEW YORK) 2023; 48:1454-1467. [PMID: 36735033 DOI: 10.1007/s00261-023-03813-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 01/10/2023] [Accepted: 01/10/2023] [Indexed: 02/04/2023]
Abstract
PURPOSE We aimed to investigate the predictive value of body compositions measured by CT, including skeletal muscle and adipose tissue, for hepatic encephalopathy (HE) in cirrhotic patients following transjugular intrahepatic portosystemic shunt (TIPS). METHODS Patients who underwent TIPS between November 2015 and April 2021 were included in this retrospective study. CT images taken at L3 were quantified for three body composition indexes (cm2/m2), visceral fat area index (VFAI), subcutaneous fat area index (SFAI), and skeletal muscle index (SMI) at baseline. Multivariable logistic regression models were conducted to assess associations between post-TIPS HE and body compositions. Nomograms based on the multivariable logistic regression models were developed and were evaluated from Calibration curves. RESULTS Male patients had greater SMI, whereas SFAI and VFAI were higher in females (p < 0.001 for each). In sex stratified multivariate analyses after adjustment for other confounding variables, VFAI in males (p = 0.033) and SFAI in females (p = 0.003) were significant predictors of post-TIPS HE. Male patients with low VFAI (< 53.52 cm2/m2) (OR 6.44; 95% CI 1.72-23.59; p = 0.006) and female patients with low SFAI (< 70.05 cm2/m2) (OR 10.55; 95% CI 2.36-46.23; p = 0.002) had a higher risk of post-TIPS HE. Risk factors in the nomogram contributing to the male model included age, height, Child-Pugh score, and low VFAI; pre-albumin and low SFAI were contributed to female model. CONCLUSION Body compositions could not only be noninvasively used for nutritional assessment, but also be utilized to predict HE risk of cirrhotic patients after TIPS.
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Improvement of sarcopenia is beneficial for prognosis in cirrhotic patients after TIPS placement. Dig Liver Dis 2023:S1590-8658(23)00003-8. [PMID: 36682922 DOI: 10.1016/j.dld.2023.01.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 12/14/2022] [Accepted: 01/01/2023] [Indexed: 01/24/2023]
Abstract
BACKGROUND The relationship between the improvement of sarcopenia and post-TIPS prognosis has not been fully investigated. AIMS To assess what level of sarcopenia improvement is required for potential benefits to post-TIPS prognosis. METHODS In this retrospective study, 109 cirrhotic patients with sarcopenia who underwent TIPS between February 2016 and January 2021 were included. The change in skeletal muscle index (SMI) at 6 months post-TIPS was assessed and the correlations of SMI improvement with clinical outcomes were analyzed. RESULTS During follow up, 59 (65.6%) patients reversed from sarcopenic to non-sarcopenic, and the cumulative mortality (8.5 % vs. 26.0%, log rank P = 0.013) and incidence of overt hepatic encephalopathy (OHE) (18.6% vs. 44.0%, log rank P = 0.004) in patients who reversed were significantly lower than who did not. SMI improvement rate was identified as an independent risk factor for mortality and OHE. In addition, the cumulative survival rate of patients with sarcopenia reversal or SMI improvement rate > 10.4% was significantly higher than that of patients with an SMI improvement rate ≤ 10.4% (92.5% vs. 58.6%, log rank P < 0.001). CONCLUSION Reversal of sarcopenia or significant SMI improvement by TIPS could reduce the risk of death and OHE.
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Ni B, Qin M, Zhao J, Guo Q. A glance at transient hyperammonemia of the newborn: Pathophysiology, diagnosis, and treatment: A review. Medicine (Baltimore) 2022; 101:e31796. [PMID: 36482558 PMCID: PMC9726343 DOI: 10.1097/md.0000000000031796] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hyperammonemia is the excessive accumulation of ammonia in the blood, and is usually defined as a plasma level above 100 µmol/L in neonates or above 50 µmol/L in term infants, children, and adolescents. Patients with hyperammonemia usually experience life-threatening neuropsychiatric symptoms, especially newborns. It is routinely caused by inherited metabolic diseases and also by acquired disorders, such as liver failure, portosystemic shunting, gastrointestinal hemorrhage, ureterosigmoidostomy, renal tubular acidosis, hypoxic ischemic encephalopathy, infections with urea-metabolizing organisms, and some drugs. Transient hyperammonemia of the newborn (THAN) is a special type of hyperammonemia acknowledged in the field of metabolic disease as an inwell-defined or well-understood entity, which can be diagnosed only after the exclusion of genetic and acquired causes of hyperammonemia. Although the prognosis for THAN is good, timely identification and treatment are essential. Currently, THAN is underdiagnosed and much less is mentioned for early diagnosis and vigorous treatment. Herein, we present common themes that emerge from the pathogenesis, diagnosis, and management of THAN, based on current evidence. When a newborn presents with sepsis, intracranial hemorrhage, or asphyxia that cannot explain coma and seizures, doctors should always keep this disease in mind.
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Affiliation(s)
- Beibei Ni
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Miao Qin
- Department of Neonatology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jun Zhao
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qie Guo
- Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, China
- * Correspondence: Qie Guo, Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Qingdao, Shandong 266003, China (e-mail: )
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15
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Tranah TH, Ballester MP, Carbonell-Asins JA, Ampuero J, Alexandrino G, Caracostea A, Sánchez-Torrijos Y, Thomsen KL, Kerbert AJC, Capilla-Lozano M, Romero-Gómez M, Escudero-García D, Montoliu C, Jalan R, Shawcross DL. Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis. J Hepatol 2022; 77:1554-1563. [PMID: 35872326 DOI: 10.1016/j.jhep.2022.07.014] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 07/07/2022] [Accepted: 07/08/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND & AIMS Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. METHODS We studied 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analyses using fast unified random forests were performed to predict complications and mortality. External validation was carried out using prospective data from 130 patients with cirrhosis in an independent tertiary liver centre. RESULTS Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (hazard ratio 2.13; 95% CI 1.89-2.40; p <0.001) and mortality (hazard ratio 1.45; 95% CI 1.20-1.76; p <0.001). The AUROC of AMM-ULN was 77.9% for 1-year liver-related complications, which is higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p <0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation. CONCLUSION Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications. LAY SUMMARY We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients.
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Affiliation(s)
- Thomas H Tranah
- Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - María-Pilar Ballester
- Digestive Disease Department, Hospital Clínico Universitario de Valencia, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain
| | | | - Javier Ampuero
- Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Ciberehd, Spain
| | - Gonçalo Alexandrino
- Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom; Gastroenterology and Hepatology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal
| | - Andra Caracostea
- Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Yolanda Sánchez-Torrijos
- Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Ciberehd, Spain
| | - Karen L Thomsen
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, United Kingdom; Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus, Denmark
| | - Annarein J C Kerbert
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, United Kingdom
| | | | - Manuel Romero-Gómez
- Hospital Universitario Virgen del Rocio, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Ciberehd, Spain
| | | | - Carmina Montoliu
- INCLIVA Biomedical Research Institute, Valencia, Spain; Department of Pathology, Faculty of Medicine, University of Valencia, Spain
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, United Kingdom; European Foundation for the Study of Chronic Liver Failure (EF Clif), Spain.
| | - Debbie L Shawcross
- Institute of Liver Studies, Dept of Inflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
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Pichon C, Nachit M, Gillard J, Vande Velde G, Lanthier N, Leclercq IA. Impact of L-ornithine L-aspartate on non-alcoholic steatohepatitis-associated hyperammonemia and muscle alterations. Front Nutr 2022; 9:1051157. [PMID: 36466421 PMCID: PMC9709200 DOI: 10.3389/fnut.2022.1051157] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 10/31/2022] [Indexed: 12/13/2023] Open
Abstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease in the world. Progression toward non-alcoholic steatohepatitis (NASH) is associated with alterations of skeletal muscle. One plausible mechanism for altered muscle compartment in liver disease is changes in ammonia metabolism. In the present study, we explored the hypothesis that NASH-associated hyperammonemia drives muscle changes as well as liver disease progression. MATERIALS AND METHODS In Alms1-mutant mice (foz/foz) fed a 60% fat diet (HFD) for 12 weeks; we investigated hepatic and muscular ammonia detoxification efficiency. We then tested the effect of an 8 week-long supplementation with L-ornithine L-aspartate (LOLA), a known ammonia-lowering treatment, given after either 4 or 12 weeks of HFD for a preventive or a curative intervention, respectively. We monitored body composition, liver and muscle state by micro computed tomography (micro-CT) as well as muscle strength by four-limb grip test. RESULTS According to previous studies, 12 weeks of HFD induced NASH in all foz/foz mice. Increase of hepatic ammonia production and alterations of urea cycle efficiency were observed, leading to hyperammonemia. Concomitantly mice developed marked myosteatosis. First signs of myopenia occurred after 20 weeks of diet. Early LOLA treatment given during NASH development, but not its administration in a curative regimen, efficiently prevented myosteatosis and muscle quality, but barely impacted liver disease or, surprisingly, ammonia detoxification. CONCLUSION Our study confirms the perturbation of hepatic ammonia detoxification pathways in NASH. Results from the interventional experiments suggest a direct beneficial impact of LOLA on skeletal muscle during NASH development, though it does not improve ammonia metabolism or liver disease.
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Affiliation(s)
- Camille Pichon
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Maxime Nachit
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Justine Gillard
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Greetje Vande Velde
- Department of Imaging and Pathology, Molecular Small Animal Imaging Center, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Nicolas Lanthier
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
- Service d’Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Isabelle A. Leclercq
- Laboratory of Hepato-Gastroenterology (GAEN), Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
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Mahmoud MS, El-Kott AF, AlGwaiz HIM, Fathy SM. Protective effect of Moringa oleifera Lam. leaf extract against oxidative stress, inflammation, depression, and apoptosis in a mouse model of hepatic encephalopathy. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:83783-83796. [PMID: 35771324 DOI: 10.1007/s11356-022-21453-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 06/10/2022] [Indexed: 06/15/2023]
Abstract
The present study aimed to assess the antioxidative, anti-inflammatory, antiapoptotic, and anti-depression impacts of Moringa oleifera Lam. leaf ethanolic extract (MOLE) in the hippocampus and cerebral cortex of CCl4-induced hepatic encephalopathy mouse model. High-performance liquid chromatography was used to detect marker compounds: rutin and β-sitosterol. Animals were divided into four groups: vehicle group, CCl4-treated group, MOLE-treated group, and (CCl4 + MOLE) group treated with MOLE for 14 days before CCl4-induced neurotoxicity. MOLE decreased alanine aminotransferase, aspartate aminotransferase, corticosterone, and ammonia levels in serum and improved the antioxidant status of CCl4-treated mice in the hippocampus and cerebral cortex. It reduced the expression of toll-like receptor 4 (TLR4), TLR2, myeloid differentiation primary response 88 (MYD88), and nuclear factor-kappa B (NF-κB) genes and the protein levels of the pro-inflammatory cytokines. MOLE also attenuated apoptosis, as revealed by the reduced expression of caspase3, and prevented histological deterioration. Furthermore, MOLE attenuated CCl4-induced anxiety and depression-like behavioral changes. Collectively, MOLE modulates neuroinflammation, oxidative stress, TLR4/2-MyD88/NF-κB signaling, and apoptosis in the hippocampus and cerebral cortex of the hepatic encephalopathy experimental model.
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Affiliation(s)
- Mohammed S Mahmoud
- Zoology Department, Faculty of Science, Fayoum University, Fayoum, 63514, Egypt.
| | - Attalla F El-Kott
- Department of Biology, College of Science, King Khalid University, Abha, 61421, Saudi Arabia
- Department of Zoology, Faculty of Science, Damanhour University, Damanhour, 22511, Egypt
| | - Hussah I M AlGwaiz
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, 11474, Riyadh, Saudi Arabia
| | - Samah M Fathy
- Zoology Department, Faculty of Science, Fayoum University, Fayoum, 63514, Egypt
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Du JY, Shu L, Zhou YT, Zhang L. Branched-chain amino acids supplementation has beneficial effects on the progression of liver cirrhosis: A meta-analysis. World J Clin Cases 2022; 10:10984-10996. [PMID: 36338230 PMCID: PMC9631141 DOI: 10.12998/wjcc.v10.i30.10984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/19/2022] [Accepted: 09/19/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Liver cirrhosis (LC) is currently the 11th most common cause of death and 15th cause of morbidity globally. The treatment of LC is mainly aimed at etiological intervention, lifestyle intervention, prevention and treatment of complications and nutritional treatment. Nutritional treatment of LC mainly includes increasing dietary intake, food intake time and branched-chain amino acids (BCAAs). Despite the recommendation of BCAAs in some guidelines, adverse effects have been reported in studies so the efficacy and safety of BCAAs remain controversial. Currently, BCAAs have been widely used in chronic liver disease, while the summary of the effect of BCAAs on long-term prognosis is rare.
AIM To determine the effects of BCAAs in patients with LC.
METHODS The PubMed, Cochrane Library, Embase and Web of Science databases were searched. The retrieval deadline was 1 October 2021 and there were no language restrictions set in the retrieval. The study was performed in strict accordance with the inclusion and exclusion criteria. Nine studies were finally included. The primary outcome was complications of LC. The secondary outcomes were nutritional status and liver function. This meta-analysis used the Review Manager, version 5 statistical package (Cochrane Collaboration, Oxford, England) for analysis.
RESULTS The analysis included nine studies that consisted of 1080 patients (554 in the BCAA groups and 526 in the control groups). The nine studies were randomized control trials (RCTs). The quality of the studies was assessed using the risk of bias method recommended by the Cochrane Collaboration. BCAAs reduced the rate of complications in LC patients [Risk ratio: 0.70, 95% confidence interval (CI): 0.56-0.88, P = 0.002] and improved patients’ albumin levels [std mean difference SMD: 0.26, 95%CI: 0.12-0.40, P = 0.0002]. Meanwhile, BCAAs significantly ameliorated the levels of alanine transaminase (SMD: -2.03, 95%CI: -2.52 to -1.53, P < 0.00001) and aspartate aminotransferase (SMD: -1.8, 95%CI: -2.14 to -1.46, P < 0.00001). Meanwhile, glucose in the LC was significantly increased in BCAA-treated patients (MD: 13.04, 95%CI: 6.81-19.89, P = 0.0002).
CONCLUSION BCAAs reduce the incidence of complications in patients with LC and ameliorate nutritional status.
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Affiliation(s)
- Jia-Yu Du
- School of Clinical Medicine, Chengdu Medical College, Chengdu 610000, Sichuan Province, China
| | - Liu Shu
- Department of Neuroscience, College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Hong Kong, China
| | - Yu-Tian Zhou
- Department of Geriatrics, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610000, Sichuan Province, China
| | - Li Zhang
- Department of Geriatrics, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu 610072, Sichuan Province, China
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19
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Fürschuß L, Rainer F, Effenberger M, Niederreiter M, Portugaller RH, Horvath A, Fickert P, Stadlbauer V. A novel score predicts mortality after transjugular intrahepatic portosystemic shunt: MOTS - Modified TIPS Score. Liver Int 2022; 42:1849-1860. [PMID: 35261130 PMCID: PMC9539997 DOI: 10.1111/liv.15236] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 02/04/2022] [Accepted: 03/02/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND AND AIMS The high risk for severe shunting-related post-interventional complications demands a stringent selection of candidates for transjugular intrahepatic portosystemic shunt (TIPS). We aimed to develop a simple and reliable tool to accurately predict early post-TIPS mortality. METHODS 144 cases of TIPS implantation were retrospectively analysed. Using univariate and multivariate Cox regression analysis of factors predicting mortality within 90 days after TIPS, a score integrating urea, international normalized ratio (INR) and bilirubin was developed. The Modified TIPS-Score (MOTS) ranges from 0 to 3 points: INR >1.6, urea >71 mg/dl and bilirubin >2.2 mg/dl account for one point each. Additionally, MOTS was tested in an external validation cohort (n = 187) and its performance was compared to existing models. RESULTS Modified TIPS-Score achieved a significant prognostic discrimination reflected by 90-day mortality of 8% in patients with MOTS 0-1 and 60% in patients with MOTS 2-3 (p < .001). Predictive performance (area under the curve) of MOTS was accurate (c = 0.845 [0.73-0.96], p < .001), also in patients with renal insufficiency (c = 0.830 [0.64-1.00], p = .02) and in patients with refractory ascites (c = 0.949 [0.88-1.00], p < .001), which are subgroups with particular room for improvement of post-TIPS mortality prediction. The results were reproducible in the validation cohort. CONCLUSIONS Modified TIPS-Score is a novel, practicable tool to predict post-TIPS mortality, that can significantly simplify clinical decision making. Its practical applicability should be further investigated.
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Affiliation(s)
- Luisa Fürschuß
- Department of Internal Medicine, Research Unit "Transplantation Research", Medical University of Graz, Graz, Austria
| | - Florian Rainer
- Department of Internal Medicine, Research Unit "Transplantation Research", Medical University of Graz, Graz, Austria
| | - Maria Effenberger
- Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Markus Niederreiter
- Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Rupert H Portugaller
- Division of Vascular and Interventional Radiology, Department of Radiology, Medical University of Graz, Graz, Austria
| | - Angela Horvath
- Department of Internal Medicine, Research Unit "Transplantation Research", Medical University of Graz, Graz, Austria
- Centre for Biomarker Research in Medicine (CBmed), Graz, Austria
| | - Peter Fickert
- Department of Internal Medicine, Research Unit "Transplantation Research", Medical University of Graz, Graz, Austria
| | - Vanessa Stadlbauer
- Department of Internal Medicine, Research Unit "Transplantation Research", Medical University of Graz, Graz, Austria
- Centre for Biomarker Research in Medicine (CBmed), Graz, Austria
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20
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Shaw J, Beyers L, Bajaj JS. Inadequate practices for hepatic encephalopathy management in the inpatient setting. J Hosp Med 2022; 17 Suppl 1:S8-S16. [PMID: 35972037 PMCID: PMC9542542 DOI: 10.1002/jhm.12897] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/23/2022] [Accepted: 05/27/2022] [Indexed: 11/18/2022]
Abstract
Hepatic encephalopathy (HE) is an important complication of decompensated liver disease. Hospital admission for episodes of HE are very common, with these patients being managed by the hospitalists. These admissions are costly and burdensome to the health-care system. Diagnosis of HE at times is not straightforward, particularly in patients who are altered and unable to provide any history. Precipitants leading to episodes of HE, should be actively sought and effectively tackled along with the overall management. This mandates timely diagnostics, appropriate initiation of pharmacological treatment, and supportive care. Infections are the most important precipitants leading to HE and should be aggressively managed. Lactulose is the front-line medication for primary treatment of HE episodes and for prevention of subsequent recurrence. However, careful titration in the hospital setting along with the appropriate route of administration should be established and supervised by the hospitalist. Rifaximin has established its role as an add-on medication, in those cases where lactulose alone is not working. Overall effective management of HE calls for attention to guideline-directed nutritional requirements, functional assessment, medication reconciliation, patient education/counseling, and proper discharge planning. This will potentially help to reduce readmissions, which are all too common for HE patients. Early specialty consultation may be warranted in certain conditions. Numerous challenges exist to optimal care of hospitalized OHE patients. However, hospitalists if equipped with knowledge about a systematic approach to taking care of these frail patients are in an ideal position to ensure good inpatient and transition of care outcomes.
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Affiliation(s)
- Jawaid Shaw
- Department of Internal Medicine, Division of Hospital MedicineVirginia Commonwealth UniversityRichmondVirginiaUSA
| | - Lisa Beyers
- Department of Internal Medicine, Strong Memorial HospitalUniversity of RochesterRochesterNew YorkUSA
| | - Jasmohan S. Bajaj
- Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth University and Central Virginia Veterans Healthcare SystemRichmondVirginiaUSA
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21
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Yang C, Chen Y, Wang C, Liu J, Huang S, Zhou C, Wang Y, Ju S, Li T, Bai Y, Yao W, Xiong B. Portal flow diversion based on portography is superior than puncture site in the prediction of overt hepatic encephalopathy after TIPS creation. BMC Gastroenterol 2022; 22:363. [PMID: 35906529 PMCID: PMC9336111 DOI: 10.1186/s12876-022-02447-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022] Open
Abstract
Background Targeted puncture of an appropriate portal venous branch during transjugular intrahepatic portosystemic shunt (TIPS) procedure may reduce the risk of postprocedural overt hepatic encephalopathy (HE). This study aimed to describe blood distribution under portography and combined it with puncture site to determine portal flow diversion, and to evaluate its prognostic value in predicting post-TIPS overt HE. Methods In this retrospective analysis of patients with cirrhosis undergoing TIPS, we included 252 patients to describe blood distribution under portography and 243 patients to assess the association between portal flow diversion and post-TIPS overt HE. Results At the first stage, 51 (20.2%) patients were identified as type A (unilateral type with the right portal branch receives blood from splenic vein [SV]), 16 (6.4%) as type B (unilateral type with the right branch receives blood from superior mesenteric vein [SMV]) and 185 (73.4%) as type C (fully mixed type). At the second stage, 40 patients were divided into the SV group, 25 into the SMV group and 178 into the mixed group. Compared with the mixed group, the risk of post-TIPS overt HE was significantly higher in the SMV group (adjusted HR 3.70 [95% CI 2.01–6.80]; p < 0.001), whereas the SV group showed a non-significantly decreased risk (adjusted HR 0.57 [95% CI 0.22–1.48]; p = 0.25). Additionally, the SMV group showed a substantial increase in ammonia level at 3 days and 1 month after procedure. Conclusions Our results support the clinical use of portal flow diversion for risk stratification and decision-making in the management of post-TIPS overt HE. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02447-y.
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Affiliation(s)
- Chongtu Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yang Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chaoyang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Songjiang Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Tongqiang Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Wei Yao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China.,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China
| | - Bin Xiong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China. .,Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
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22
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Arjunan A, Sah DK, Jung YD, Song J. Hepatic Encephalopathy and Melatonin. Antioxidants (Basel) 2022; 11:837. [PMID: 35624703 PMCID: PMC9137547 DOI: 10.3390/antiox11050837] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/06/2022] [Accepted: 04/24/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatic encephalopathy (HE) is a severe metabolic syndrome linked with acute/chronic hepatic disorders. HE is also a pernicious neuropsychiatric complication associated with cognitive decline, coma, and death. Limited therapies are available to treat HE, which is formidable to oversee in the clinic. Thus, determining a novel therapeutic approach is essential. The pathogenesis of HE has not been well established. According to various scientific reports, neuropathological symptoms arise due to excessive accumulation of ammonia, which is transported to the brain via the blood-brain barrier (BBB), triggering oxidative stress and inflammation, and disturbing neuronal-glial functions. The treatment of HE involves eliminating hyperammonemia by enhancing the ammonia scavenging mechanism in systemic blood circulation. Melatonin is the sole endogenous hormone linked with HE. Melatonin as a neurohormone is a potent antioxidant that is primarily synthesized and released by the brain's pineal gland. Several HE and liver cirrhosis clinical studies have demonstrated impaired synthesis, secretion of melatonin, and circadian patterns. Melatonin can cross the BBB and is involved in various neuroprotective actions on the HE brain. Hence, we aim to elucidate how HE impairs brain functions, and elucidate the precise molecular mechanism of melatonin that reverses the HE effects on the central nervous system.
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Affiliation(s)
- Archana Arjunan
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Dhiraj Kumar Sah
- Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea;
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 Seoyangro, Hwasun 58128, Korea
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23
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Kroupina K, Bémeur C, Rose CF. Amino acids, ammonia, and hepatic encephalopathy. Anal Biochem 2022; 649:114696. [PMID: 35500655 DOI: 10.1016/j.ab.2022.114696] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 03/30/2022] [Accepted: 04/21/2022] [Indexed: 11/30/2022]
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24
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Nardelli S, Gioia S, Ridola L, Carlin M, Cioffi AD, Merli M, Spagnoli A, Riggio O. Risk of falls in patients with cirrhosis evaluated by timed up and go test: Does muscle or brain matter more? Dig Liver Dis 2022; 54:371-377. [PMID: 34233863 DOI: 10.1016/j.dld.2021.06.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Minimal hepatic encephalopathy (MHE) is considered a risk factor for falls in patients with liver cirrhosis. However, MHE is prevalent in patients with muscle alterations (sarcopenia and myosteatosis) probably due to the role of muscle in ammonia handling. AIM To assess the respective role of muscle alterations and MHE on the risk of falls in cirrhotic patients. METHODS Fifty cirrhotics were studied for MHE detection by using Psychometric Hepatic Encephalopathy Score (PHES) and Animal Naming Test (ANT). CT scan was used to quantify the skeletal muscle index (SMI) and muscle attenuation, as a measure of myosteatosis. The risk of falls was evaluated by the Timed Up&Go test (TUG). The occurrence of falls during follow up was also detected. RESULTS 32 patients (64%) had an abnormal TUG (< 14 s). In the group with TUG ≥ 14 s, MHE (72vs31%, p<0.005) and myosteatosis (94vs50%, p = 0.002) were significantly more frequent than in patients with TUG<14 s. At multivariate the variables independently associated to TUG ≥ 14 s were myosteatosis, MHE and chronic beta-blockers use. During a mean follow-up of 25±16.9 months, 12 patients fell; the percentage of falls was significantly higher in patients with TUG ≥ 14 s (50%vs9%, p = 0.001) as well as in patients with myosteatosis (33%vs6%, p = 0.03), but similar in patients with or without MHE (35%vs15%, NS). CONCLUSION In cirrhotic patients both muscle alterations and cognitive impairment, as well as chronic beta-blockers use, are associated to the risk of falls.
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Affiliation(s)
- Silvia Nardelli
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome 00185, Italy.
| | - Stefania Gioia
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome 00185, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome 00185, Italy
| | - Michele Carlin
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome 00185, Italy
| | - Antonio Davide Cioffi
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome 00185, Italy
| | - Manuela Merli
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome 00185, Italy
| | - Alessandra Spagnoli
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Rome 00185, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome 00185, Italy
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25
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Fox R, Stenning K, Slee A, Macnaughtan J, Davies N. Sarcopenia in liver cirrhosis: Prevalence, pathophysiology and therapeutic strategies. Anal Biochem 2022; 647:114581. [PMID: 35134388 DOI: 10.1016/j.ab.2022.114581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 01/31/2022] [Indexed: 11/01/2022]
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26
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Yang C, Zhu X, Liu J, Shi Q, Du H, Chen Y, Huang S, Zhou C, Wang Y, Li T, Bai Y, Xiong B. Development and Validation of Prognostic Models to Estimate the Risk of Overt Hepatic Encephalopathy After TIPS Creation: A Multicenter Study. Clin Transl Gastroenterol 2022; 13:e00461. [PMID: 35093957 PMCID: PMC8963844 DOI: 10.14309/ctg.0000000000000461] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/28/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Overt hepatic encephalopathy (HE) is a major complication of transjugular intrahepatic portosystemic shunt (TIPS). This study aimed to develop and validate prognostic models to identify patients at different risks of overt HE within 3 months after TIPS. METHODS Two cohorts of patients with cirrhosis undergoing TIPS insertion were retrospectively included. In the derivation cohort of 276 patients, 3 models were established in increasing order of complexity: core model (age + Child-Pugh class), sarcopenia model (core model + sarcopenia), and full model (sarcopenia model + post-TIPS portal pressure gradient). All models were internally validated for discrimination and calibration and externally validated in an independent cohort of 182 patients. RESULTS During a 3-month follow-up period, 61 (22.1%) and 33 patients (18.1%) developed overt HE in the derivation and validation cohort, and sarcopenia was associated with increased risk of the outcome. In the derivation cohort, the core model showed a c-statistic of 0.68 (95% confidence interval [CI] 0.61-0.75), and discrimination improved in the sarcopenia model (c-statistic 0.73; 95% CI 0.66-0.80). The full model that extended the core model with inclusion of sarcopenia and post-TIPS portal pressure gradient showed a significant improvement in discriminative ability (0.77; 95% CI 0.71-0.83; P = 0.001). Both sarcopenia and full model yielded comparable performances in the validation cohort. DISCUSSION We developed and externally validated 2 prediction models applied before (sarcopenia model) and after TIPS (full model) to estimate the risk of post-TIPS overt HE. These tools could aid to select appropriate candidates for TIPS and guide postoperative management.
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Affiliation(s)
- Chongtu Yang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Xiaoli Zhu
- Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Qin Shi
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Hang Du
- Department of Interventional Radiology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yang Chen
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Songjiang Huang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Tongqiang Li
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
| | - Bin Xiong
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Key Laboratory of Molecular Imaging, Wuhan, China
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27
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Gioia S, Ridola L, Cristofaro L, Merli M, Faccioli J, Riggio O, Nardelli S. The improvement in body composition including subcutaneous and visceral fat reduces ammonia and hepatic encephalopathy after transjugular intrahepatic portosystemic shunt. Liver Int 2021; 41:2965-2973. [PMID: 34543504 PMCID: PMC9293456 DOI: 10.1111/liv.15060] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/07/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Sarcopenia and myosteatosis have been associated to a poor prognosis of cirrhosis and to a higher incidence of hepatic encephalopathy (HE). The prognostic implications of visceral and subcutaneous adiposity are less known. AIM To evaluate the modifications of visceral and subcutaneous adipose tissue after TIPS and to investigate their relationships with the modification of muscle mass and with the incidence of post-TIPS HE. PATIENTS AND METHODS 35 cirrhotic patients submitted to TIPS were retrospectively studied. The modification of skeletal muscle index (SMI), muscle attenuation (myosteatosis), subcutaneous adipose tissue index (SATI), visceral adipose tissue index (VATI), assessed by CT-scan and plasma ammonia were evaluated before and after a mean follow-up of 19 ± 15 months after TIPS. The number of episodes of overt HE was also recorded. RESULTS During the follow-up, the mean SMI and muscle attenuation increased significantly; SATI significantly increased while VATI significantly decreased, although not uniformly in all patients. By comparing the patients with or without improvement in their nutritional status after TIPS, MELD remained stable while the number of episodes of overt HE was significantly lower in the patients with improved SMI and in the patients with improved SATI. Finally, inverse correlation was observed between the variation of ammonia and SATI (r = -.40; P < .05). CONCLUSION In addition to muscle mass, adipose tissue is modified after TIPS. The improvement of subcutaneous adipose tissue as well as of sarcopenia and myosteatosis is associated to the amelioration of cognitive impairment independently of liver function. The correlation between adipose tissue and ammonia modification may suggest an active role of the adipose tissue in the inter-organ ammonia trafficking.
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Affiliation(s)
- Stefania Gioia
- Department of Translational and Precision Medicine‘Sapienza' University of RomeRomeItaly
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine‘Sapienza' University of RomeRomeItaly
| | - Ludovica Cristofaro
- Department of Translational and Precision Medicine‘Sapienza' University of RomeRomeItaly
| | - Manuela Merli
- Department of Translational and Precision Medicine‘Sapienza' University of RomeRomeItaly
| | - Jessica Faccioli
- Department of Translational and Precision Medicine‘Sapienza' University of RomeRomeItaly
| | - Oliviero Riggio
- Department of Translational and Precision Medicine‘Sapienza' University of RomeRomeItaly
| | - Silvia Nardelli
- Department of Translational and Precision Medicine‘Sapienza' University of RomeRomeItaly
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28
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Yang C, Liu J, Shi Q, Huang S, Zhou C, Wang Y, Li T, Chen Y, Xiong B. Effect of splenectomy on the outcomes in patients with cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Gastroenterol Hepatol 2021; 36:2893-2902. [PMID: 33973270 PMCID: PMC8518516 DOI: 10.1111/jgh.15543] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 04/28/2021] [Accepted: 05/08/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIM Patients indicated to transjugular intrahepatic portosystemic shunt (TIPS) placement may have splenectomy history due to thrombocytopenia. This study aimed to evaluate the effect of prior splenectomy on TIPS procedure and post-TIPS outcomes. METHODS We conducted a longitudinal analysis based on a cohort of 284 patients with cirrhosis submitted to TIPS; 74 patients had splenectomy history (splenectomy group) and 210 did not (non-splenectomy group). Cox proportional hazards models were used to evaluate the association between splenectomy and outcomes after TIPS. The primary outcome was shunt dysfunction. Secondary outcomes included all-cause mortality, clinical recurrence of bleeding or ascites, and overt hepatic encephalopathy (OHE). RESULTS During a median follow-up of 16.2 months, the splenectomy group had significantly lower rates of postoperative shunt patency (85.5% vs 95.6% at 1 year and 75.2% vs 86.5% at 2 years; adjusted hazard ratio [HR] 2.53; 95% confidence interval [CI] 1.21-5.12; P = 0.01) and higher risk of OHE (adjusted HR 1.82; 95% CI 1.03-3.54; P = 0.04). But the risk of mortality (adjusted HR 0.87; 95% CI 0.41-1.87; P = 0.73) and recurrent bleeding or ascites (adjusted HR 1.17; 95% CI 0.53-2.35; P = 0.77) showed no statistical difference. Multivariate analysis confirmed splenectomy history and endoscopic therapy as independent predictors of shunt dysfunction. Besides, pre-TIPS splenectomy increased the difficulty of TIPS procedure by complicating portal vein puncture. CONCLUSIONS For patients with cirrhosis submitted to TIPS, prior splenectomy complicated TIPS procedure and increased the risk of shunt dysfunction and OHE after TIPS, but was not significantly associated with the occurrence of mortality and recurrent bleeding or ascites.
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Affiliation(s)
- Chongtu Yang
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
| | - Qin Shi
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
| | - Songjiang Huang
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
| | - Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
| | - Tongqiang Li
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
| | - Yang Chen
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
| | - Bin Xiong
- Department of Radiology, Union Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina,Hubei Province Key Laboratory of Molecular ImagingWuhanChina
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Kolchina AN, Yatsyshina EE, Malysheva LV, Ledentsova EE, Lidyaeva EE, Khaletskaya OV. Diagnostics of Inherited Metabolic Diseases in Newborns with the Hyperammonemia Syndrome at the Onset of Disease (Pilot Study). Sovrem Tekhnologii Med 2021; 13:59-64. [PMID: 34513067 PMCID: PMC8353695 DOI: 10.17691/stm2021.13.1.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Indexed: 11/23/2022] Open
Abstract
The aim of the study was to develop a diagnostic model that allows with a high degree of probability predicting the development of inherited metabolic disease (IMD) in newborns with the hyperammonemia syndrome at the onset of disease and determine the adequate management tactics for such patients.
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Affiliation(s)
- A N Kolchina
- PhD Student, Department of Hospital Pediatrics, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - E E Yatsyshina
- Associate Professor, Department of Hospital Pediatrics, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
| | - L V Malysheva
- Head of the Clinical Diagnostic Laboratory, Children's City Clinical Hospital No.1, 76 Prospect Gagarina, Nizhny Novgorod, 603081, Russia
| | - E E Ledentsova
- Physician of Clinical Laboratory Diagnostics, Children's City Clinical Hospital No.1, 76 Prospect Gagarina, Nizhny Novgorod, 603081, Russia
| | - E E Lidyaeva
- Anesthesiologist-Resuscitator, Resuscitation and Intensive Care Unit, Children's City Clinical Hospital No.1, 76 Prospect Gagarina, Nizhny Novgorod, 603081, Russia
| | - O V Khaletskaya
- Professor, Head of the Department of Hospital Pediatrics, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Square, Nizhny Novgorod, 603005, Russia
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30
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Smedberg M, Helleberg J, Norberg Å, Tjäder I, Rooyackers O, Wernerman J. Plasma glutamine status at intensive care unit admission: an independent risk factor for mortality in critical illness. Crit Care 2021; 25:240. [PMID: 34233720 PMCID: PMC8265095 DOI: 10.1186/s13054-021-03640-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/11/2021] [Indexed: 12/01/2022] Open
Abstract
Background A plasma glutamine concentration outside the normal range at Intensive Care Unit (ICU) admission has been reported to be associated with an increased mortality rate. Whereas hypoglutaminemia has been frequently reported, the number of patients with hyperglutaminemia has so far been quite few. Therefore, the association between hyperglutaminemia and mortality outcomes was studied in a prospective, observational study. Patients and methods Consecutive admissions to a mixed general ICU were eligible. Exclusion criteria were < 18 years of age, readmissions, no informed consent, or a ‘do not resuscitate’ order at admission. A blood sample was saved within one hour from admission to be analysed by high-pressure liquid chromatography for glutamine concentration. Conventional risk scoring (Simplified Acute Physiology Score and Sequential Organ Failure Assessment) at admission, and mortality outcomes were recorded for all included patients. Results Out of 269 included patients, 26 were hyperglutaminemic (≥ 930 µmol/L) at admission. The six-month mortality rate for this subgroup was 46%, compared to 18% for patients with a plasma glutamine concentration < 930 µmol/L (P = 0.002). A regression analysis showed that hyperglutaminemia was an independent mortality predictor that added prediction value to conventional admission risk scoring and age. Conclusion Hyperglutaminemia in critical illness at ICU admission was an independent mortality predictor, often but not always, associated with an acute liver condition. The mechanism behind a plasma glutamine concentration outside normal range, as well as the prognostic value of repeated measurements of plasma glutamine during ICU stay, remains to be investigated. Supplementary Information The online version contains supplementary material available at 10.1186/s13054-021-03640-3.
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Affiliation(s)
- Marie Smedberg
- Department of Anaesthesiology and Intensive Care, CLINTEC, Karolinska Institutet and Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge Stockholm, B31 Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.
| | - Johan Helleberg
- Department of Anaesthesiology and Intensive Care, CLINTEC, Karolinska Institutet and Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge Stockholm, B31 Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden
| | - Åke Norberg
- Department of Anaesthesiology and Intensive Care, CLINTEC, Karolinska Institutet and Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge Stockholm, B31 Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden
| | - Inga Tjäder
- Department of Anaesthesiology and Intensive Care, CLINTEC, Karolinska Institutet and Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge Stockholm, B31 Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden
| | - Olav Rooyackers
- Department of Anaesthesiology and Intensive Care, CLINTEC, Karolinska Institutet and Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge Stockholm, B31 Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden
| | - Jan Wernerman
- Department of Anaesthesiology and Intensive Care, CLINTEC, Karolinska Institutet and Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge Stockholm, B31 Perioperative Medicine and Intensive Care, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden
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Wijarnpreecha K, Werlang M, Panjawatanan P, Kroner PT, Cheungpasitporn W, Lukens FJ, Pungpapong S, Ungprasert P. Association between sarcopenia and hepatic encephalopathy: A systematic review and meta-analysis. Ann Hepatol 2021; 19:245-250. [PMID: 31422030 DOI: 10.1016/j.aohep.2019.06.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 04/24/2019] [Accepted: 06/20/2019] [Indexed: 02/07/2023]
Abstract
Studies have suggested that the presence of sarcopenia in patients with cirrhosis could be a predisposing risk factor for hepatic encephalopathy. This systematic review and meta-analysis were conducted to summarize all available evidence on this relationship. A systematic review was carried out in Medline and EMBASE database through December 2018 to identify studies that recruited patients with cirrhosis from any causes and collected data on the presence of minimal or overt hepatic encephalopathy as well as sarcopenia. All study designs (case-control, cohort and cross-sectional studies) were eligible for the meta-analysis. Odds ratio (OR) and 95% confidence interval (CI) were extracted from the included studies and were pooled together using random-effect, generic inverse variance method of DerSimonian and Laird. Five cross-sectional studies with a total of 1,713 patients met our eligibility criteria and were included into the meta-analysis. We found a significantly higher risk of both mild and overt hepatic encephalopathy among cirrhotic patients with sarcopenia when compared with cirrhotic patients without sarcopenia with the pooled OR of 3.34 (95% CI: 1.68-6.67; I2=37%) and 2.05 (95% CI: 1.28-3.29; I2=61%), respectively. This systematic review and meta-analysis demonstrated a significant association between sarcopenia and hepatic encephalopathy among patients with cirrhosis.
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Affiliation(s)
- Karn Wijarnpreecha
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, NY, USA; Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Monia Werlang
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | | | - Paul T Kroner
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Wisit Cheungpasitporn
- Department of Medicine, Division of Nephrology, University of Mississippi Medical Center, Jackson, MS, USA
| | - Frank J Lukens
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Surakit Pungpapong
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Patompong Ungprasert
- Clinical Epidemiology Unit, Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Wang X, Tseng J, Mak C, Poola N, Vilchez RA. Exposures of Phenylacetic Acid and Phenylacetylglutamine Across Different Subpopulations and Correlation with Adverse Events. Clin Pharmacokinet 2021; 60:1557-1567. [PMID: 34125423 PMCID: PMC8613126 DOI: 10.1007/s40262-021-01047-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/01/2021] [Indexed: 11/05/2022]
Abstract
Background Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the l-ornithine salt of phenylacetate, is under development for hepatic encephalopathy. Objective This analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program. Methods Phenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child–Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis. Results Phenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child–Pugh C than in Child–Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy. Conclusions Dose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-021-01047-5.
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Affiliation(s)
- Xiaofeng Wang
- Clinical Pharmacology and Pharmacometrics, Mallinckrodt Pharmaceuticals, Hampton, NJ, USA
| | - Jack Tseng
- Clinical Development, Mallinckrodt Pharmaceuticals, Hampton, NJ, 08827, USA
| | - Carmen Mak
- Clinical Development, Mallinckrodt Pharmaceuticals, Hampton, NJ, 08827, USA
| | - Nagaraju Poola
- Clinical Pharmacology and Pharmacometrics, Mallinckrodt Pharmaceuticals, Hampton, NJ, USA
| | - Regis A Vilchez
- Clinical Development, Mallinckrodt Pharmaceuticals, Hampton, NJ, 08827, USA.
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Lee DU, Fan GH, Ahern RR, Karagozian R. The effect of malnutrition on the infectious outcomes of hospitalized patients with cirrhosis: analysis of the 2011-2017 hospital data. Eur J Gastroenterol Hepatol 2021; 32:269-278. [PMID: 33252419 DOI: 10.1097/meg.0000000000001991] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND In patients with cirrhosis, there is a clinical concern that the development of protein-calorie malnutrition will affect the immune system and predispose these patients to increased infectious outcomes. AIMS In this study, we evaluate the effects of malnutrition on the infectious outcomes of patients admitted with cirrhosis. MATERIALS AND METHODS This study used the 2011-2017 National Inpatient Sample to identify patients with cirrhosis. These patients were stratified using malnutrition (protein-calorie malnutrition, cachexia, and sarcopenia) and matched using age, gender, and race with 1:1 nearest neighbor matching method. The endpoints included mortality and infectious outcomes. RESULTS After matching, there were 96 842 malnutrition-present cohort and equal number of controls. In univariate analysis, the malnutrition cohort had higher hospital mortality [10.40 vs. 5.04% P < 0.01, odds ratio (OR) 2.18, 95% confidence interval (CI) 2.11-2.26]. In multivariate models, malnutrition was associated with increased mortality [P < 0.01, adjusted odds ratio (aOR) 1.32, 95% CI 1.27-1.37] and infectious outcomes, including sepsis (P < 0.01, aOR 1.94, 95% CI 1.89-2.00), pneumonia (P < 0.01, aOR 1.68, 95% CI 1.63-1.73), UTI (P < 0.01, aOR 1.39, 95% CI 1.35-1.43), cellulitis (P < 0.01, aOR 1.09, 95% CI 1.05-1.13), cholangitis (P < 0.01, aOR 1.39, 95% CI 1.26-1.55), and clostridium difficile (P < 0.01, aOR 2.11, 95% CI 1.92-2.31). CONCLUSION The results of this study indicate that malnutrition is an independent risk factor of hospital mortality and local/systemic infections in patients admitted with cirrhosis.
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Affiliation(s)
- David Uihwan Lee
- Division of Gastroenterology, Liver Center, Tufts Medical Center, 800 Washington Street, Boston, Massachusetts, USA
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34
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Laguna de la Vera AL, Welsch C, Pfeilschifter W, Trebicka J. Gut–liver–brain axis in chronic liver disease with a focus on hepatic encephalopathy. THE COMPLEX INTERPLAY BETWEEN GUT-BRAIN, GUT-LIVER, AND LIVER-BRAIN AXES 2021:159-185. [DOI: 10.1016/b978-0-12-821927-0.00004-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Shal B, Khan A, Naveed M, Ali H, Seo EK, Choi H, Khan S. Neuroprotective effect of 25-Methoxyhispidol A against CCl 4-induced behavioral alterations by targeting VEGF/BDNF and caspase-3 in mice. Life Sci 2020; 253:117684. [PMID: 32315728 DOI: 10.1016/j.lfs.2020.117684] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/11/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022]
Abstract
Brain oxidative stress and neuroinflammation have been implicated in various psychiatric disorders. The current study investigated the effect and mechanism of 25-Methoxyhispidol A (25-MHA) against CCl4-induced anxiety and depression. Mice were challenged with CCl4 (1 ml/kg; i.p.) after 30 min of 25-MHA (1, 5 and 10 mg/kg; i.p.) administration. Pretreatment with 25-MHA (10 mg/kg) significantly attenuated the anxiety and depression-like behavior in testing models. The oxidative stress induced by CCl4 was significantly attenuated by pretreatment with 25-MHA. The immunohistochemical (IHC) analysis showed a reduction in kelch-like ECH-associated protein 1 (Keap1) and improvement in expression of nuclear factor erythroid-2-related factor (Nrf-2) and heme oxygenase (HO)-1. In addition, 25-MHA significantly attenuated the CCl4-mediated depletion of antioxidant enzymes in hippocampus (HC) and prefrontal cortex (PFC) region and reduced the expression of toll-like receptor (TLR)-4 and nuclear factor kappa B (NF-κB), along with a decreased production of pro-inflammatory cytokines in HC and PFC region. Pretreatment with 25-MHA also showed an improved expression of neurotrophic factors i.e., brain derived growth factor (BDNF) and vascular endothelial growth factor (VEGF). Furthermore, 25-MHA inhibited malondialdehyde (MDA) and ammonia level in plasma, liver, HC and PFC regions of mice brain. 25-MHA also exhibited anti-apoptotic effect evident from the reduced expression of caspase-3 and decreased hippocampal DNA damage in comet assay. Furthermore, decreased serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and corticosterone level, along with prevention of CCl4-induced alterations in thickness of dentate gyrus and intact hepatic cells morphology, represented by hippocampal and liver histopathology, indicated the neuroprotective effect of 25-MHA.
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Affiliation(s)
- Bushra Shal
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Adnan Khan
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Naveed
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Hussain Ali
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Eun Kyoung Seo
- College of Pharmacy, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul 03760, South Korea
| | - Hyukjae Choi
- College of Pharmacy, Yeungnam University, Gyeongbuk 38541, South Korea
| | - Salman Khan
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
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Schmidt AC, Hebels ER, Weitzel C, Stoessel B, Bao Y, Altmann KH, Leroux JC. Ammonia uptake by transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) polymersomes. SOFT MATTER 2020; 16:2725-2735. [PMID: 32115597 DOI: 10.1039/d0sm00183j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Transmembrane pH gradient poly(isoprene)-block-poly(ethylene glycol) (PI-b-PEG) polymersomes were investigated for their potential use in the detoxification of ammonia, a metabolite that is excessively present in patients suffering from urea cycle disorders and advanced liver diseases, and which causes neurotoxic effects (e.g., hepatic encephalopathy). Polymers varying in PI and PEG block length were synthesized via nitroxide-mediated polymerization and screened for their ability to self-assemble into polymersomes in aqueous media. Ammonia sequestration by the polymersomes was investigated in vitro. While most vesicular systems were able to capture ammonia in simulated intestinal fluids, uptake was lost in partially dehydrated medium mimicking conditions in the colon. Polymeric crosslinking of residual olefinic bonds in the PI block increased polymersome stability, partially preserving the ammonia capture capacity in the simulated colon environment. These more stable vesicular systems hold promise for the chronic oral treatment of hyperammonemia.
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Affiliation(s)
- Aaron C Schmidt
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Erik R Hebels
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Charlotte Weitzel
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Barbara Stoessel
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Yinyin Bao
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Karl-Heinz Altmann
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
| | - Jean-Christophe Leroux
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.
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Abstract
Purpose of Review The burden of malnutrition is high in patients with cirrhosis, especially in those with hepatic encephalopathy (HE). This has a bearing on increased morbidity and mortality. Heightened attention needs to be paid to screen the patients at high nutritional risk both in the outpatient and hospitalized settings. This review summarizes the current evidence for nutritional support in HE patients and compares the recommendations about nutritional requirement as laid out by various organizations. Recent Findings On survey of the literature, there is a consensus on avoiding protein restriction of the diets in HE patients along with uniform recommendations on caloric requirements. An exciting field of manipulating the gut microbiome in nutritional sciences may hold promise as well as there may be a future role for branched chain amino acids in nutritional management of HE patients. Summary Even though the data suggest that nutritional improvement lead to better outcomes including lower readmission rates in cirrhosis, operationalizing these into practice remains a challenge. To achieve this, a multi-disciplinary approach with nutritional education of the frontline care providers, earlier nutritional risk screening of patients, involvement of the nutrition professionals as part of the team and repeated dietary counseling for the patient and caregiver/s is required. Ultimately, this may need more focus, resource allocation and uniform guidelines across all countries to make this a success.
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A serendipitous voyage in the field of nutrition and metabolism in health and disease: a translational adventure. Eur J Clin Nutr 2020; 74:1375-1388. [PMID: 32060384 DOI: 10.1038/s41430-020-0584-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 01/29/2020] [Accepted: 01/31/2020] [Indexed: 11/08/2022]
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Nardelli S, Lattanzi B, Merli M, Farcomeni A, Gioia S, Ridola L, Riggio O. Muscle Alterations Are Associated With Minimal and Overt Hepatic Encephalopathy in Patients With Liver Cirrhosis. Hepatology 2019; 70:1704-1713. [PMID: 31038758 DOI: 10.1002/hep.30692] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 04/25/2019] [Indexed: 12/21/2022]
Abstract
Muscle alterations (myosteatosis and sarcopenia) are frequent in cirrhosis and related to some complications including overt hepatic encephalopathy (HE). The aim of our study was to investigate the relationship between muscle alterations and minimal HE (MHE) and their role in the risk of overt HE. Sixty-four patients with cirrhosis were administered the Psychometric Hepatic Encephalopathy Score and animal naming test to detect MHE. Computed tomography was used to analyze the skeletal muscle index and attenuation. The incidence of the first episode of HE, taking into account the competing risk nature of the data, was estimated. Myosteatosis was observed in 24 patients (37.5%), sarcopenia in 37 (58%), and MHE in 32 (50%). Both myosteatosis (62.5% versus 12.5%, P < 0.001) and sarcopenia (84% versus 31%, P < 0.001) were more frequent in patients with MHE. The variables independently associated with the presence of MHE were sarcopenia, previous overt HE, and myosteatosis. Thirty-one (48%) patients developed overt HE over 16.1 ± 13 months; myosteatosis was detected in 68% and sarcopenia in 84% of them. Sarcopenia and myosteatosis were also independently associated with the development of overt HE. Venous ammonia was significantly higher in patients with sarcopenia (62.6 ± 17.7 versus 41.4 ± 16.1 μg/dL, P < 0.001) and in patients with myosteatosis (65.2 ± 19.2 versus 46.7 ± 17.1 μg/dL, P < 0.001) and inversely correlated to both parameters. Survival was significantly lower in malnourished patients compared to patients without myosteatosis or sarcopenia (P < 0.001). Conclusion: Myosteatosis and sarcopenia, probably by reducing the handling of ammonia in the muscle, are independently associated with MHE and the risk of overt HE in patients with cirrhosis; in malnourished patients, the amelioration of nutritional status may be a goal to decrease both the prevalence of MHE and the incidence of overt HE.
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Affiliation(s)
- Silvia Nardelli
- Department of Clinical Medicine, Centre for the Diagnosis and Treatment of Portal Hypertension, "Sapienza" University of Rome, Rome, Italy
| | - Barbara Lattanzi
- Department of Clinical Medicine, Centre for the Diagnosis and Treatment of Portal Hypertension, "Sapienza" University of Rome, Rome, Italy
| | - Manuela Merli
- Department of Clinical Medicine, Centre for the Diagnosis and Treatment of Portal Hypertension, "Sapienza" University of Rome, Rome, Italy
| | - Alessio Farcomeni
- Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Rome, Italy
| | - Stefania Gioia
- Department of Clinical Medicine, Centre for the Diagnosis and Treatment of Portal Hypertension, "Sapienza" University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Clinical Medicine, Centre for the Diagnosis and Treatment of Portal Hypertension, "Sapienza" University of Rome, Rome, Italy
| | - Oliviero Riggio
- Department of Clinical Medicine, Centre for the Diagnosis and Treatment of Portal Hypertension, "Sapienza" University of Rome, Rome, Italy
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Levitt MD, Levitt DG. Use Of Quantitative Modelling To Elucidate The Roles Of The Liver, Gut, Kidney, And Muscle In Ammonia Homeostasis And How Lactulose And Rifaximin Alter This Homeostasis. Int J Gen Med 2019; 12:367-380. [PMID: 31686894 PMCID: PMC6798813 DOI: 10.2147/ijgm.s218405] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/24/2019] [Indexed: 12/18/2022] Open
Abstract
Humans must eliminate approximately 1M of ammonia per day while maintaining the blood concentration of this potent neurotoxin at a concentration of only about 30 µM. The mechanisms producing such effective ammonia homeostasis are poorly understood by clinicians due to the multiple organs (liver, gut, kidney and muscle) involved in ammonia homeostasis. Based on literature values we present a novel, simplified description of normal and disordered ammonia and the potential mechanisms whereby the drugs used to treat hepatic encephalopathy, lactulose and rifaximin, lower the blood ammonia concentration. Concepts discussed include the following: 1) only about 44 mmol of ammonia/day (4.4% of total production) reaches the peripheral circulation due to the efficient linkage of amino deamination and the urea cycle in hepatic mitochondria; 2) the gut and kidney contribute roughly equally to delivery of this 44 mmol/day to systemic blood; 3) the bulk of gut ammonia production seemingly originates in the small bowel from bacterial deamination of urea by bacteria and mucosal deamination of circulating and ingested glutamine; 4) the apparent production of ammonia in the small bowel markedly exceeds that quantity that enters the portal blood, indicating that ammonia disposal mechanisms in the small bowel play a major role in ammonia homeostasis. With regard to the hyperammonemia of chronic liver disease: 1) shunting of portal blood around the liver, by itself, can account for commonly observed ammonia elevations; 2) severe portal hypertension causes an increased release of ammonia by the kidney; 3) high blood ammonia is associated with an unexplained massive increase in the muscle uptake of ammonia that could play an important role in limiting hyperammonemia; and 4) a major action of lactulose administration may be the enhancement of ammonia uptake by small bowel bacteria, while the mechanism of action of rifaximin is unclear.
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Affiliation(s)
- Michael D Levitt
- Research Service, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA
| | - David G Levitt
- Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA
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Nardelli S, Gioia S, Faccioli J, Riggio O, Ridola L. Sarcopenia and cognitive impairment in liver cirrhosis: A viewpoint on the clinical impact of minimal hepatic encephalopathy. World J Gastroenterol 2019; 25:5257-5265. [PMID: 31558871 PMCID: PMC6761233 DOI: 10.3748/wjg.v25.i35.5257] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/08/2019] [Accepted: 08/24/2019] [Indexed: 02/06/2023] Open
Abstract
Minimal hepatic encephalopathy (MHE) represents the mildest type of hepatic encephalopathy (HE). MHE is considered as a preclinical stage of HE and is part of a wide spectrum of typical neurocognitive alterations characteristic of patients with liver cirrhosis, particularly involving the areas of attention, alertness, response inhibition, and executive functions. MHE can be detected by testing the patients' psychometric performance, attention, working memory, psychomotor speed, and visuospatial ability, as well as by means of electrophysiological and other functional brain measures. MHE is very frequent, affecting from 20% up to 80% of patients tested, depending of the diagnostic tools used. Although subclinical, MHE is considered to be clinically relevant. In fact, MHE has been related to the patients' falls, fitness to drive, and working ability. As a consequence, MHE affects the patients and caregivers lives by altering their quality of life and even their socioeconomic status. Recently sarcopenia, a very common condition in patients with advanced liver disease, has been shown to be strictly related to both minimal and overt HE. Aim of this review is to summarize the most recently published evidences about the emerging relationship between sarcopenia and cognitive impairment in cirrhotic patients and provide suggestions for future research.
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Affiliation(s)
- Silvia Nardelli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Stefania Gioia
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Jessica Faccioli
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Oliviero Riggio
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
| | - Lorenzo Ridola
- Department of Translational and Precision Medicine, “Sapienza” University of Rome, Rome 00185, Italy
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Vairappan B, Sundhar M, Srinivas BH. Resveratrol Restores Neuronal Tight Junction Proteins Through Correction of Ammonia and Inflammation in CCl 4-Induced Cirrhotic Mice. Mol Neurobiol 2019; 56:4718-4729. [PMID: 30377987 DOI: 10.1007/s12035-018-1389-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 10/11/2018] [Indexed: 12/31/2022]
Abstract
Systemic inflammation and ammonia (hyperammonemia) act synergistically in the pathogenesis of hepatic encephalopathy (HE), the neurobehavioral sequelae of advanced liver disease. In cirrhotic patients, we have recently observed elevated levels of circulating neuronal tight junction (TJ) protein, zonula occludens 1 (ZO-1), reflective of a change to blood-brain barrier (BBB) integrity. Moreover, ZO-1 levels positively correlated with hyperammonemia, although any potential relationship remains unclear. Using a carbon tetrachloride (CCl4)-induced mouse model of cirrhosis, we primarily looked to explore the relationship between neuronal TJ protein expression and hyperammonemia. Secondarily, we assessed the potential role of a natural antioxidant, resveratrol, on neuronal TJ protein expression and hyperammonemia. Over 12 weeks, male Swiss mice were randomized (n = 8/group) to either naïve controls or induced cirrhosis, using two doses of intraperitoneal CCl4 (0.5 ml/kg/week). After 12 weeks, naïve and cirrhotic mice were randomized to receive either 2 weeks of par-oral resveratrol (10 mg/kg). Plasma samples were analyzed for ammonia, liver biochemistry (ALT, AST, albumin, and bilirubin), and pro-inflammatory cytokines (TNF-α and IL-1β), and brain tissue for brain water content, TJ protein expression (e.g., ZO-1, claudin 5, and occludin), and tissue oxidative stress and inflammatory markers (NF-κB and iNOS) using western blotting. Compared to naïve mice, cirrhosis significantly increased circulating ammonia, brain water, ALT, AST, TNF-α, IL-1β, 4HNE, NF-κB, and iNOS levels, with a concomitant reduction in all TJ proteins (P < 0.05, respectively). In cirrhotic mice, resveratrol treatment ameliorated these changes significantly (P < 0.05, respectively). Our findings provide evidence for a causal association between hyperammonemia and inflammation in cirrhosis linked to TJ protein alterations, BBB disruption, and HE predilection. Moreover, this is the first report of a potential role for resveratrol as a novel therapeutic approach to managing neurological sequelae complicating cirrhosis.
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Affiliation(s)
- Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Pondicherry, 605 006, India.
| | - M Sundhar
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantari Nagar, Pondicherry, 605 006, India
| | - B H Srinivas
- Department of Pathology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, 605006, India
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Campion D, Giovo I, Ponzo P, Saracco GM, Balzola F, Alessandria C. Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis. World J Hepatol 2019; 11:489-512. [PMID: 31293718 PMCID: PMC6603507 DOI: 10.4254/wjh.v11.i6.489] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/15/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a common and serious neuropsychiatric complication of cirrhosis, acute liver failure, and porto-systemic shunting. HE largely contributes to the morbidity of patients with liver disease, severely affecting the quality of life of both patients and their relatives and being associated with poor prognosis. Its presentation is largely variable, manifesting with a broad spectrum of cognitive abnormalities ranging from subtle cognitive impairment to coma. The pathogenesis of HE is complex and has historically been linked with hyperammonemia. However, in the last years, it has become evident that the interplay of multiple actors, such as intestinal dysbiosis, gut hyperpermeability, and neuroinflammation, is of crucial importance in its genesis. Therefore, HE can be considered a result of a dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by "gut-centric" therapies, such as non-absorbable disaccharides, non-absorbable antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. In this context dietary modifications, by modulating the intestinal milieu, can also provide significant benefit to cirrhotic patients with HE. This review will provide a comprehensive insight into the mechanisms responsible for gut-liver-brain axis dysregulation leading to HE in cirrhosis. Furthermore, it will explore the currently available therapies and the most promising future treatments for the management of patients with HE, with a special focus on the dietary approach.
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Affiliation(s)
- Daniela Campion
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Ilaria Giovo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Paola Ponzo
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Giorgio M Saracco
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Federico Balzola
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy
| | - Carlo Alessandria
- Division of Gastroenterology and Hepatology, Città della Salute e della Scienza di Torino Hospital, University of Turin, 10126 Turin, Italy.
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Gioia S, Merli M, Nardelli S, Lattanzi B, Pitocchi F, Ridola L, Riggio O. The modification of quantity and quality of muscle mass improves the cognitive impairment after TIPS. Liver Int 2019; 39:871-877. [PMID: 30667572 DOI: 10.1111/liv.14050] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 12/17/2018] [Accepted: 01/11/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatic encephalopathy (HE) is the major complication of transjugular intrahepatic portosystemic shunt (TIPS). In cirrhotic patients, a correlation between sarcopenia and HE has been suggested. AIM To evaluate the evolution of the skeletal muscle quantity and quality at CT scan and of the patients' cognitive impairment (both overt and minimal HE) before and after TIPS. PATIENTS AND METHODS Twenty-seven cirrhotic patients submitted to TIPS were studied. The modification of Skeletal Muscle Index (SMI), muscle attenuation, HE and plasma ammonia were evaluated before and after a mean follow-up of 9.8 ± 4 months after TIPS. RESULTS During the follow-up, the mean SMI and muscle attenuation increased significantly, although not uniformly in all patients. Psychometric Hepatic Encephalopathy Score (PHES) and ammonia improved significantly in the patients with amelioration in SMI >10% (n = 16) and not in those without (n = 11) (PHES: -1.6 ± 2 vs -4.8 ± 2.1; P = 0.0005; ammonia: 48.5 ± 28.7 vs 96 ± 31.5 μg/dL; P = 0.0004). Moreover, the prevalence of minimal HE (12.5% vs 73%, P = 0.001) as well as the number of episodes of overt HE during the follow-up were significantly reduced in the patients with improved SMI. Model for end-stage liver disease remained stable or worsened after TIPS and was not significantly different between the groups with or without SMI improvement. CONCLUSION The amelioration of muscle wasting and HE independent of liver function observed after TIPS supports the causal relationship between muscle wasting and HE.
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Affiliation(s)
- Stefania Gioia
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Manuela Merli
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Silvia Nardelli
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Barbara Lattanzi
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Francesca Pitocchi
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Lorenzo Ridola
- Department of Gastroenterology, Sapienza" University of Rome, Latina, Italy
| | - Oliviero Riggio
- Department of Clinical Medicine, "Sapienza" University of Rome, Rome, Italy
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Luo SH, Chu JG, Huang H, Zhao GR, Yao KC. Targeted puncture of left branch of intrahepatic portal vein in transjugular intrahepatic portosystemic shunt to reduce hepatic encephalopathy. World J Gastroenterol 2019; 25:1088-1099. [PMID: 30862997 PMCID: PMC6406189 DOI: 10.3748/wjg.v25.i9.1088] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 01/24/2019] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Transjugular intrahepatic portosystemic shunt (TIPS) is currently used for the treatment of complications of portal hypertension. The incidence of hepatic encephalopathy (HE) remains a problem in TIPS placement. It has been reported that the right branch mainly receives superior mesenteric venous blood while the left branch mainly receives blood from the splenic vein. We hypothesized that targeted puncture of the left portal vein would divert the non-nutritive blood from the splenic vein into the TIPS shunt; therefore, targeted puncture of the left branch of the intrahepatic portal vein during TIPS may reduce the risk of HE.
AIM To evaluate the influence of targeted puncture of left branch of portal vein in TIPS on HE.
METHODS A retrospective analysis of 1244 patients with portal-hypertension-related complications of refractory ascites or variceal bleeding who underwent TIPS from January 2000 to January 2013 was performed. Patients were divided into group A (targeting left branch of portal vein, n = 937) and group B (targeting right branch of portal vein, n = 307). TIPS-related HE and clinical outcomes were analyzed.
RESULTS The symptoms of ascites and variceal bleeding disappeared within a short time. By the endpoint of follow-up, recurrent bleeding and ascites did not differ significantly between groups A and B (P = 0.278, P = 0.561, respectively). Incidence of HE differed significantly between groups A and B at 1 mo (14.94% vs 36.80%, χ2 = 4.839, P = 0.028), 3 mo (12.48% vs 34.20%, χ2 = 5.054, P = 0.025), 6 mo (10.03% vs 32.24%, χ2 = 6.560, P = 0.010), 9 mo (9.17% vs 31.27%, χ2 = 5.357, P = 0.021), and 12 mo (8.21% vs 28.01, χ2 = 3.848, P = 0.051). There were no significant differences between groups A and B at 3 years (6.61% vs 7.16%, χ2 = 1.204, P = 0.272) and 5 years (5.01% vs 6.18%, χ2 = 0.072, P = 0.562). The total survival rate did not differ between groups A and B (χ2 = 0.226, P = 0.634, log-rank test).
CONCLUSION Targeted puncture of the left branch of the intrahepatic portal vein during TIPS may reduce the risk of HE but has no direct influence on prognosis of portal-hypertension-related complications.
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Affiliation(s)
- Shi-Hua Luo
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Jian-Guo Chu
- Department of Radiology, Air Force Medical Center of PLA, Beijing 100142, China
| | - He Huang
- Department of Radiology, Air Force Medical Center of PLA, Beijing 100142, China
| | - Guo-Rui Zhao
- Department of Interventional Radiology, Henan Provincial Infectious Disease Hospital, Zhengzhou 450015, Henan Province, China
| | - Ke-Chun Yao
- Department of Ultrasound, Air Force Medical Center of PLA, Beijing 100142, China
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Lattanzi B, D’Ambrosio D, Merli M. Hepatic Encephalopathy and Sarcopenia: Two Faces of the Same Metabolic Alteration. J Clin Exp Hepatol 2019; 9:125-130. [PMID: 30765945 PMCID: PMC6363954 DOI: 10.1016/j.jceh.2018.04.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 04/25/2018] [Indexed: 12/12/2022] Open
Abstract
Sarcopenia is an important burden in liver cirrhosis representing a negative prognostic factor for mortality. Moreover, sarcopenia is an independent predictor of complications in patients with liver cirrhosis, including Hepatic Encephalopathy (HE). An association between sarcopenia and HE in liver cirrhosis has been reported in recent studies, indeed both these complications often affect patients with advanced liver cirrhosis and may exert a synergic effect in deteriorating patients' outcome. Episodes of HE occur more often in patients with muscle depletion. The rationale for these finding is based on the role played by muscle in ammonia detoxification due to the inability of urea synthesis in the cirrhotic liver. Consequently, muscle depletion may have relevant implications in favoring hyperammonemia and HE. At the same time hyperammonemia has been found to impair muscle protein synthesis through myostatin down-regulation. From this point of view, modulation of diet and amelioration of nutritional status and muscle mass can be considered a potential goal to prevent this vicious circle and improve the cognitive impairment in cirrhotic patients.
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Affiliation(s)
| | | | - Manuela Merli
- Department of Clinical Medicine, Gastroenterology, Sapienza University of Rome, Italy
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Dam G, Aamann L, Vistrup H, Gluud LL. The role of Branched Chain Amino Acids in the treatment of hepatic Encephalopathy. J Clin Exp Hepatol 2018; 8:448-451. [PMID: 30568347 PMCID: PMC6286665 DOI: 10.1016/j.jceh.2018.06.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Accepted: 06/11/2018] [Indexed: 12/12/2022] Open
Abstract
The relationship between intake of nutrients and Hepatic Encephalopathy (HE) dates back to the historical roots of experimental hepatology. Branched-Chain Amino Acids (BCAA; Isoleucine, leucine and valine) have attracted particular interest and in 1956 Müting described the amino acid pattern in patients with cirrhosis. The abnormal plasma pattern has been characterized by the ratio between BCAA and aromatic amino acids in plasma, the so called 'Fischer´s ratio'. This ratio has been associated with the grade of HE. Under normal conditions, ammonia detoxification predominantly takes place in the liver. When the liver fails, the homeostasis is altered and muscle tissue becomes the main alternative organ for at least temporary detoxification of ammonia. BCAA are believed to support this muscle ammonia detoxification and the ammonia lowering effect of BCAA has been intensely investigated. In this review the effect of BCAA on muscle ammonia metabolism and the protein sparing and anabolic effects of BCAA are discussed. A Cochrane metaanalysis showed that BCAA had beneficial effects on HE with a number needed to treat of 5 patients (RR 0.73, 95% CI 0.61 to 0.88). The combined evidence suggests that although the pathophysiology is poorly understood, there is evidence to support clinical benefits of BCAA. BCAAs enhance muscle mass and exert anabolic effects via stimulation of protein synthesis. The beneficial long-term effects of BCAA on HE could be related to these effects and not only related to Branched-Chain Amino Acid increased ammonia metabolism.
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Affiliation(s)
- Gitte Dam
- Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Aarhus, Denmark
- Address for correspondence: Gitte Dam, Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Aarhus, Denmark.
| | - Luise Aamann
- Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Aarhus, Denmark
| | - Hendrik Vistrup
- Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Aarhus, Denmark
| | - Lise Lotte Gluud
- Department of Gastroenterology, Hvidovre Hospital, Copenhagen University, Hvidovre, Denmark
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Predicting Hepatic Encephalopathy-Related Hospitalizations Using a Composite Assessment of Cognitive Impairment and Frailty in 355 Patients With Cirrhosis. Am J Gastroenterol 2018; 113:1506-1515. [PMID: 30267028 DOI: 10.1038/s41395-018-0243-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Accepted: 07/05/2018] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatic encephalopathy (HE) is the most common potentially modifiable reason for admission in patients with cirrhosis. Cognitive and physical components of frailty have pathophysiologic rationale as risk factors for HE. We aimed to assess the utility of a composite score (MoCA-CFS) developed using the Montreal Cognitive Assessment (MoCA) and the Clinical Frailty Scale (CFS) for predicting HE admissions within 6 months. METHODS Consecutive adult patients with cirrhosis were followed for 6 months or until death/transplant. Patients with overt HE and dementia were excluded. Primary outcome was the prediction of HE-related admissions at 6 months. RESULTS A total of 355 patients were included; mean age 55.9 ± 9.6; 62.5% male; Hepatitis C and alcohol etiology in 64%. Thirty-six percent of patients had cognitive impairment according to the MoCA (≤24) and 14% were frail on the CFS (>4). The MoCA-CFS independently predicted HE hospitalization within 6 months, a MoCA-CFS score of 1 and 2 respectively increasing the odds of hospitalization by 3.3 (95% CI:1.5-7.7) and 5.7 (95% CI:1.9-17.3). HRQoL decreased with increasing MoCA-CFS. Depression and older age were independent predictors of a low MoCA. CONCLUSIONS Cognitive and physical frailty are common in patients with cirrhosis. In addition to being an independent predictor of HE admissions within 6 months, the MoCA-CFS composite score predicts impaired HRQoL and all-cause admissions within 6 months. These data support the predictive value of a "multidimensional" frailty tool for the prediction of adverse clinical outcomes and highlight the potential for a multi-faceted approach to therapy targeting cognitive impairment, physical frailty and depression.
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Chang KV, Chen JD, Wu WT, Huang KC, Lin HY, Han DS. Is sarcopenia associated with hepatic encephalopathy in liver cirrhosis? A systematic review and meta-analysis. J Formos Med Assoc 2018; 118:833-842. [PMID: 30279030 DOI: 10.1016/j.jfma.2018.09.011] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/17/2018] [Accepted: 09/12/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/PURPOSE Hepatic encephalopathy (HE), a major neuropsychiatric complication in advanced liver disease, is associated with poor prognosis. Sarcopenia, characterized by a decline in muscle mass, strength, and physical performance, is prevalent in liver cirrhosis. This study aims to explore whether sarcopenia is associated with HE in cirrhotic patients. METHODS PubMed and EMBASE were searched for relevant cohort and case-control studies investigating the association between sarcopenia and HE up to July 2018. Data of patients' characteristics, definition of low muscle mass, and protocols of grading/diagnosing HE were retrieved. The primary outcome was estimated by a pooled odds ratio (OR) and its 95% confidence interval (CI), using a random effect model. RESULTS The meta-analysis enrolled 6 studies, comprising 1795 patients. Sarcopenia was positively associated with the presence of HE (OR 2.74 with a 95% CI, 1.87 to 4.01). The association was less likely to be influenced by differences in research designs, focused study outcomes, muscle mass measurements, and protocols of grading/diagnosing HE. There was lack of evidence supporting higher serum ammonia levels in patients with sarcopenia. CONCLUSION In patients with liver cirrhosis, there is a significant association between sarcopenia and HE. A greater number of prospective studies are necessary to clarify whether the association remains even after adjusting relevant confounders and to suggest effective prevention of HE in patients with coexisting sarcopenia.
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Affiliation(s)
- Ke-Vin Chang
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jin-De Chen
- Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Department of Gastroenterology, National Taiwan University Hospital, Bei-Hu Branch, Taiwan
| | - Wei-Ting Wu
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taiwan
| | - Kuo-Chin Huang
- Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Department of Family Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Hong-Yi Lin
- Department of Physical Medicine and Rehabilitation, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Der-Sheng Han
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Community and Geriatric Medicine Research Center, National Taiwan University Hospital, Bei-Hu Branch, Taiwan; Department of Physical Medicine and Rehabilitation, National Taiwan University College of Medicine, Taipei, Taiwan; Health Science and Wellness Center, National Taiwan University, Taipei, Taiwan.
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Levitt DG, Levitt MD. A model of blood-ammonia homeostasis based on a quantitative analysis of nitrogen metabolism in the multiple organs involved in the production, catabolism, and excretion of ammonia in humans. Clin Exp Gastroenterol 2018; 11:193-215. [PMID: 29872332 PMCID: PMC5973424 DOI: 10.2147/ceg.s160921] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Increased blood ammonia (NH3) is an important causative factor in hepatic encephalopathy, and clinical treatment of hepatic encephalopathy is focused on lowering NH3. Ammonia is a central element in intraorgan nitrogen (N) transport, and modeling the factors that determine blood-NH3 concentration is complicated by the need to account for a variety of reactions carried out in multiple organs. This review presents a detailed quantitative analysis of the major factors determining blood-NH3 homeostasis – the N metabolism of urea, NH3, and amino acids by the liver, gastrointestinal system, muscle, kidney, and brain – with the ultimate goal of creating a model that allows for prediction of blood-NH3 concentration. Although enormous amounts of NH3 are produced during normal liver amino-acid metabolism, this NH3 is completely captured by the urea cycle and does not contribute to blood NH3. While some systemic NH3 derives from renal and muscle metabolism, the primary site of blood-NH3 production is the gastrointestinal tract, as evidenced by portal vein-NH3 concentrations that are about three times that of systemic blood. Three mechanisms, in order of quantitative importance, release NH3 in the gut: 1) hydrolysis of urea by bacterial urease, 2) bacterial protein deamination, and 3) intestinal mucosal glutamine metabolism. Although the colon is conventionally assumed to be the major site of gut-NH3 production, evidence is reviewed that indicates that the stomach (via Helicobacter pylori metabolism) and small intestine and may be of greater importance. In healthy subjects, most of this gut NH3 is removed by the liver before reaching the systemic circulation. Using a quantitative model, loss of this “first-pass metabolism” due to portal collateral circulation can account for the hyperammonemia observed in chronic liver disease, and there is usually no need to implicate hepatocyte malfunction. In contrast, in acute hepatic necrosis, hyperammonemia results from damaged hepatocytes. Although muscle-NH3 uptake is normally negligible, it can become important in severe hyperammonemia. The NH3-lowering actions of intestinal antibiotics (rifaximin) and lactulose are discussed in detail, with particular emphasis on the seeming lack of importance of the frequently emphasized acidifying action of lactulose in the colon.
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Affiliation(s)
- David G Levitt
- Department of Integrative Biology and Physiology, University of Minnesota
| | - Michael D Levitt
- Research Service, Veterans Affairs Medical Center, Minneapolis, MN, USA
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