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Walls AB, Andersen JV, Waagepetersen HS, Bak LK. Fueling Brain Inhibition: Integrating GABAergic Neurotransmission and Energy Metabolism. Neurochem Res 2025; 50:136. [PMID: 40189668 DOI: 10.1007/s11064-025-04384-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 03/24/2025] [Accepted: 03/24/2025] [Indexed: 04/26/2025]
Abstract
Despite decades of research in brain energy metabolism and to what extent different cell types utilize distinct substrates for their energy metabolism, this topic remains a vibrant area of neuroscience research. In this review, we focus on the substrates utilized by the inhibitory GABAergic neurons, which has been less explored than glutamatergic neurons. First, we discuss how GABAergic neurons may utilize both glucose, lactate, or ketone bodies under different functional conditions, and provide some preliminary data suggesting that unlike glutamatergic neurons, GABAergic neurons work well when substrate supply is restricted to lactate. We end by discussing the role of GABAergic neuron energy metabolism in pathologies where failure of inhibitory function play a central role, namely epilepsy, hepatic encephalopathy, and Alzheimer's disease.
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Affiliation(s)
- Anne B Walls
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
- Capital Region Hospital Pharmacy, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jens V Andersen
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | | | - Lasse K Bak
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark.
- Translational Research Center (TRACE), Copenhagen University Hospital - Rigshospitalet, Glostrup, Denmark.
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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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Sørensen M, Andersen JV, Bjerring PN, Vilstrup H. Hepatic encephalopathy as a result of ammonia-induced increase in GABAergic tone with secondary reduced brain energy metabolism. Metab Brain Dis 2024; 40:19. [PMID: 39560844 PMCID: PMC11576828 DOI: 10.1007/s11011-024-01473-x] [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: 05/23/2024] [Accepted: 09/02/2024] [Indexed: 11/20/2024]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome caused by liver insufficiency and/or portosystemic shunting. HE is mostly episodic and as such reversible. Hyperammonemia clearly plays a key role in the pathophysiology, but the precise detrimental events in the brain leading to HE remain equivocal. Several pathogenic models have been proposed, but few have been linked to clinical studies and observations. Decreased oxygen metabolism is observed in both type A and C HE and in this review, we advocate that this reflects an actual reduced oxygen demand and not a primary cause of HE. As driving force, we propose that the hyperammonemia via astrocytic glutamine synthetase causes an increased γ-aminobutyric acid (GABA) mediated neuro-inhibition which subsequently leads to an overall decreased energy demand of the brain, something that can be enhanced by concomitant neuroinflammation. This also explains the reversibility of the condition.
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Affiliation(s)
- Michael Sørensen
- Department of Internal Medicine, Viborg Regional Hospital, Viborg, Denmark.
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
| | - Jens Velde Andersen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Peter Nissen Bjerring
- Department of Intestinal Failure and Liver Diseases, Rigshospitalet, Copenhagen, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Thomsen KL, Sørensen M, Kjærgaard K, Eriksen PL, Lauridsen MM, Vilstrup H. Cerebral Aspects of Portal Hypertension: Hepatic Encephalopathy. Clin Liver Dis 2024; 28:541-554. [PMID: 38945642 DOI: 10.1016/j.cld.2024.03.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Portal hypertension has cerebral consequences via its causes and complications, namely hepatic encephalopathy (HE), a common and devastating brain disturbance caused by liver insufficiency and portosystemic shunting. The pathogenesis involves hyperammonemia and systemic inflammation. Symptoms are disturbed personality and reduced attention. HE is minimal or grades I to IV (coma). Bouts of HE are episodic and often recurrent. Initial treatment is of events that precipitated the episode and exclusion of nonhepatic causes. Specific anti-HE treatment is lactulose. By recurrence, rifaximin is add-on. Anti-HE treatment is efficacious also for prophylaxis, but emergence of HE marks advanced liver disease and a dismal prognosis.
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Affiliation(s)
- Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, Denmark.
| | - Michael Sørensen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, Denmark; Department of Internal Medicine, Viborg Regional Hospital, Heibergs Allé 5A, 8800 Viborg, Denmark
| | - Kristoffer Kjærgaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, Denmark
| | - Peter Lykke Eriksen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, Denmark
| | - Mette Munk Lauridsen
- Department of Gastroenterology and Hepatology, University Hospital of South Denmark, Finsensgade 35, 6700 Esbjerg, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus N 8200, Denmark
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Sepehrinezhad A, Stolze Larsen F, Ashayeri Ahmadabad R, Shahbazi A, Sahab Negah S. The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review. Cells 2023; 12:cells12070979. [PMID: 37048052 PMCID: PMC10093707 DOI: 10.3390/cells12070979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/20/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
| | - Fin Stolze Larsen
- Department of Gastroenterology and Hepatology, Rigshospitalet, Copenhagen University Hospital, 999017 Copenhagen, Denmark
| | | | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran 1449614535, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9919191778, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran 1449614535, Iran
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Mikkelsen ACD, Thomsen KL, Mookerjee RP, Hadjihambi A. The role of brain inflammation and abnormal brain oxygen homeostasis in the development of hepatic encephalopathy. Metab Brain Dis 2022; 38:1707-1716. [PMID: 36326976 DOI: 10.1007/s11011-022-01105-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/10/2022] [Indexed: 11/06/2022]
Abstract
Hepatic encephalopathy (HE) is a frequent complication of chronic liver disease (CLD) and has a complex pathogenesis. Several preclinical and clinical studies have reported the presence of both peripheral and brain inflammation in CLD and their potential impact in the development of HE. Altered brain vascular density and tone, as well as compromised cerebral and systemic blood flow contributing to the development of brain hypoxia, have also been reported in animal models of HE, while a decrease in cerebral metabolic rate of oxygen and cerebral blood flow has consistently been observed in patients with HE. Whilst significant strides in our understanding have been made over the years, evaluating all these mechanistic elements in vivo and showing causal association with development of HE, have been limited through the practical constraints of experimentation. Nonetheless, improvements in non-invasive assessments of different neurophysiological parameters, coupled with techniques to assess changes in inflammatory and metabolic pathways, will help provide more granular insights on these mechanisms. In this special issue we discuss some of the emerging evidence supporting the hypothesis that brain inflammation and abnormal oxygen homeostasis occur interdependently during CLD and comprise important contributors to the development of HE. This review aims at furnishing evidence for further research in brain inflammation and oxygen homeostasis as additional therapeutic targets and potentially diagnostic markers for HE.
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Affiliation(s)
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- UCL Institute of Liver and Digestive Health, University College London, London, UK
| | - Rajeshwar Prosad Mookerjee
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
- UCL Institute of Liver and Digestive Health, University College London, London, UK
| | - Anna Hadjihambi
- The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, SE5 9NT, UK.
- Faculty of Life Sciences and Medicine, King's College London, London, UK.
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Hadjihambi A, Cudalbu C, Pierzchala K, Simicic D, Donnelly C, Konstantinou C, Davies N, Habtesion A, Gourine AV, Jalan R, Hosford PS. Abnormal brain oxygen homeostasis in an animal model of liver disease. JHEP Rep 2022; 4:100509. [PMID: 35865351 PMCID: PMC9293761 DOI: 10.1016/j.jhepr.2022.100509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 04/23/2022] [Accepted: 05/10/2022] [Indexed: 01/15/2023] Open
Abstract
Background & Aims Increased plasma ammonia concentration and consequent disruption of brain energy metabolism could underpin the pathogenesis of hepatic encephalopathy (HE). Brain energy homeostasis relies on effective maintenance of brain oxygenation, and dysregulation impairs neuronal function leading to cognitive impairment. We hypothesised that HE is associated with reduced brain oxygenation and we explored the potential role of ammonia as an underlying pathophysiological factor. Methods In a rat model of chronic liver disease with minimal HE (mHE; bile duct ligation [BDL]), brain tissue oxygen measurement, and proton magnetic resonance spectroscopy were used to investigate how hyperammonaemia impacts oxygenation and metabolic substrate availability in the central nervous system. Ornithine phenylacetate (OP, OCR-002; Ocera Therapeutics, CA, USA) was used as an experimental treatment to reduce plasma ammonia concentration. Results In BDL animals, glucose, lactate, and tissue oxygen concentration in the cerebral cortex were significantly lower than those in sham-operated controls. OP treatment corrected the hyperammonaemia and restored brain tissue oxygen. Although BDL animals were hypotensive, cortical tissue oxygen concentration was significantly improved by treatments that increased arterial blood pressure. Cerebrovascular reactivity to exogenously applied CO2 was found to be normal in BDL animals. Conclusions These data suggest that hyperammonaemia significantly decreases cortical oxygenation, potentially compromising brain energy metabolism. These findings have potential clinical implications for the treatment of patients with mHE. Lay summary Brain dysfunction is a serious complication of cirrhosis and affects approximately 30% of these patients; however, its treatment continues to be an unmet clinical need. This study shows that oxygen concentration in the brain of an animal model of cirrhosis is markedly reduced. Low arterial blood pressure and increased ammonia (a neurotoxin that accumulates in patients with liver failure) are shown to be the main underlying causes. Experimental correction of these abnormalities restored oxygen concentration in the brain, suggesting potential therapeutic avenues to explore.
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Key Words
- 1H-MRS, proton magnetic resonance spectroscopy
- AIT, Animal Imaging and Technology
- ALT, alanine transaminase
- ATZ, acetazolamide
- Ala, alanine
- Asc, ascorbate
- Asp, aspartate
- BDL, bile duct ligation
- BOLD, blood oxygen level dependent
- BP, blood pressure
- CBF, cerebral blood flow
- CIBM, Center for Biomedical Imaging
- CLD, chronic liver disease
- CMRO2, cerebral metabolic rate of oxygen
- CNS, central nervous system
- Chronic liver disease
- Cr, creatine
- EPFL, Ecole Polytechnique Fédérale de Lausanne
- GABA, γ-aminobutyric acid
- GPC, glycerophosphocholine
- GSH, glutathione
- Glc, glucose
- Gln, glutamine
- Glu, glutamate
- HE, hepatic encephalopathy
- Hyperammonaemia
- Ins, myo-inositol
- Lac, lactate
- MAP, mean arterial pressure
- NAA, N acetylaspartate
- NO, nitric oxide
- OP, ornithine phenylacetate
- Ornithine phenylacetate
- Oxygen
- PCho, phosphocholine
- PCr, phosphocreatine
- PE, phenylephrine
- Phenylephrine
- SPECIAL, spin echo full intensity acquired localised
- TE, echo time
- Tau, taurine
- VOI, volume of interest
- [18F]-FDG PET, [18F]-fluorodeoxyglucose positron emission tomography
- eNOS, endothelial nitric oxide synthase
- fMRI, functional magnetic resonance imaging
- hepatic encephalopathy
- mHE, minimal HE
- pCO2, partial pressure of carbon dioxide
- pO2, partial pressure of oxygen
- tCho, total choline
- tCr, total creatine
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Affiliation(s)
- Anna Hadjihambi
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK
- The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, UK
- Faculty of Life Sciences and Medicine, King’s College London, London, UK
| | - Cristina Cudalbu
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Katarzyna Pierzchala
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Dunja Simicic
- CIBM Center for Biomedical Imaging, Lausanne, Switzerland
- Animal Imaging and Technology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Chris Donnelly
- Institute of Sports Science and Department of Physiology, University of Lausanne, Lausanne, Switzerland
| | - Christos Konstantinou
- The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, UK
- Faculty of Life Sciences and Medicine, King’s College London, London, UK
| | - Nathan Davies
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK
| | - Abeba Habtesion
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK
| | - Alexander V. Gourine
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Rajiv Jalan
- UCL Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, UK
- European Foundation for the Study of Chronic Liver Failure
| | - Patrick S. Hosford
- Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, London, UK
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, UK
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Sørensen M, Walls AB, Dam G, Bak LK, Andersen JV, Ott P, Vilstrup H, Schousboe A. Low cerebral energy metabolism in hepatic encephalopathy reflects low neuronal energy demand. Role of ammonia-induced increased GABAergic tone. Anal Biochem 2022; 654:114766. [PMID: 35654134 DOI: 10.1016/j.ab.2022.114766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 05/11/2022] [Accepted: 05/26/2022] [Indexed: 11/01/2022]
Abstract
Hepatic encephalopathy (HE) is a frequent and devastating but generally reversible neuropsychiatric complication secondary to chronic and acute liver failure. During HE, brain energy metabolism is markedly reduced and it remains unclear whether this is due to external or internal energy supply limitations, or secondary to depressed neuronal cellular functions - and if so, which mechanisms that are in play. The extent of deteriorated cerebral function correlates to blood ammonia levels but the metabolic link to ammonia is not clear. Early studies suggested that high levels of ammonia inhibited key tricarboxylic acid (TCA) cycle enzymes thus limiting mitochondrial energy production and oxygen consumption; however, later studies by us and others showed that this is not the case in vivo. Here, based on a series of translational studies from our group, we advocate the view that the low cerebral energy metabolism of HE is likely to be caused by neuronal metabolic depression due to an elevated GABAergic tone rather than by restricted energy availability. The increased GABAergic tone seems to be secondary to synthesis of large amounts of glutamine in astrocytes for detoxification of ammonia with the glutamine acting as a precursor for elevated neuronal synthesis of vesicular GABA.
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Affiliation(s)
- Michael Sørensen
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Denmark; Department of Internal Medicine, Viborg Regional Hospital, Denmark.
| | - Anne Byriel Walls
- Department of Drug Design & Pharmacology, University of Copenhagen, Denmark
| | - Gitte Dam
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Denmark
| | - Lasse Kristoffer Bak
- Department of Drug Design & Pharmacology, University of Copenhagen, Denmark; Department of Clinical Biochemistry, Copenhagen University Hospital, Rigshospitalet, Denmark
| | | | - Peter Ott
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology & Gastroenterology, Aarhus University Hospital, Denmark
| | - Arne Schousboe
- Department of Drug Design & Pharmacology, University of Copenhagen, Denmark
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Sepehrinezhad A, Shahbazi A, Sahab Negah S, Joghataei MT, Larsen FS. Drug-induced-acute liver failure: A critical appraisal of the thioacetamide model for the study of hepatic encephalopathy. Toxicol Rep 2021; 8:962-970. [PMID: 34026559 PMCID: PMC8122178 DOI: 10.1016/j.toxrep.2021.04.011] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/17/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) following acute and chronic liver failure is defined as a complex of neuropsychiatric abnormalities, such as discrete personal changes, sleep disorder, forgetfulness, confusion, and decreasing the level of consciousness to coma. The use and design of suitable animal models that represent clinical features and pathological changes of HE are valuable to map the molecular mechanisms that result in HE. Among different types of animal models, thioacetamide (TAA) has been used extensively for the induction of acute liver injury and HE. This agent is not directly hepatotoxic but its metabolites induce liver injury through the induction of oxidative stress and produce systemic inflammation similar to that seen in acute HE patients. In this short review article, we shortly review the most important pathological findings in animal models of acute HE following the administration of TAA.
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Key Words
- ALT, alanine aminotransferase
- AQP4, aquaporin 4 water channel
- AST, aspartate aminotransferase
- Acute liver failure
- Animal model
- B7, B7 molecules (CD80+CD86)
- BBB, blood-brain barrier
- CBF, cerebral blood flow
- CCL2, chemokine ligand 2
- CNS, central nervous system
- CTLA4, Cytotoxic T-lymphocyte-associated Protein 4
- CYP2E1, Cytochrome P450 family 2 subfamily E member 1
- GFAP, glial fibrillary acidic protein
- HE, hepatic encephalopathy
- Hepatic encephalopathy
- IL-6, interleukin 6
- IL-β, interleukin 1 β
- Iba1, ionized calcium-binding adaptor molecule 1
- JNK, c-Jun N-terminal kinase
- NAC, N-acetylcysteine
- NF-κB, nuclear factor κB
- OA, L-ornithine-l-aspartate
- ROS, reactive oxygen species
- TAA, thioacetamide
- TASO, thioacetamide sulfoxide
- TASO2, thioacetamide sulfdioxide
- TLR-2, toll-like receptor 2
- TLR-4, toll-like receptor 4
- TNFα, tumor necrosis factor α
- Thioacetamide
- Toxicity pathway
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Affiliation(s)
- Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sajad Sahab Negah
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Taghi Joghataei
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Fin Stolze Larsen
- Department of Hepatology CA-3163, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark
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Low Serum 25-Hydroxy Vitamin D (25-OHD) and Hepatic Encephalopathy in HCV-Related Liver Cirrhosis. Int J Hepatol 2021; 2021:6669527. [PMID: 33628512 PMCID: PMC7896845 DOI: 10.1155/2021/6669527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 01/19/2021] [Accepted: 01/29/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Patients with liver cirrhosis experience a large variety of metabolic disorders associated with more hepatic decompensation. Hepatic encephalopathy (HE) is a significant complication in liver cirrhosis patients, presenting a wide spectrum of neuropsychological symptoms. A deficiency of 25-hydroxy vitamin D (25-OHD) in the general population is associated with a loss of cognitive function, dementia, and Alzheimer's disease. Aim of the Study. Our study aims to check the relationship between low serum 25-OHD and HE in patients with HCV-related liver cirrhosis and assess its link with patient mortality. Patients and Methods. This study was observationally carried out on 100 patients with HCV-related liver cirrhosis. The patients were divided into 2 groups: Group A-included 50 HCV-related cirrhotic patients with HE, and Group B-included 50 HCV-related cirrhotic patients without HE. Assessment of disease severity using the end-stage liver disease (MELD) model and Child Turcotte Pugh (CTP) scores were done, and 25-OHD levels were measured. Comparison of vitamin D levels in different etiologies and different CTP categories was made using one-way ANOVA. Pearson's correlation between the level of vitamin D and other biomarkers was applied. RESULTS There was a statistically significant Vitamin D level difference between the two groups. A lower level of vitamin D was observed in the HE group where the severe deficiency was 16%, while it was 6% in the other group and the moderate deficiency was 24% in HE group as compared to 10% in the other group. The insufficient vitamin D level represented 46% of the non-HE group while none of the HE group falls in this category. Vitamin D level was statistically higher in Grade 1 HE than in Grade 2 which is higher than in Grades 3 to 4. Vitamin D level was also significantly higher in those who improved from HE as compared to those who died. CONCLUSION The lower levels of 25-OHD were associated with the higher incidence of HE in cirrhotic HCV patients. The worsening vitamin D deficiency was associated with increased severity of the liver disease, so vitamin D may be considered a prognostic factor for the severity of liver cirrhosis and high mortality rate in HE patients.
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Rose CF, Amodio P, Bajaj JS, Dhiman RK, Montagnese S, Taylor-Robinson SD, Vilstrup H, Jalan R. Hepatic encephalopathy: Novel insights into classification, pathophysiology and therapy. J Hepatol 2020; 73:1526-1547. [PMID: 33097308 DOI: 10.1016/j.jhep.2020.07.013] [Citation(s) in RCA: 266] [Impact Index Per Article: 53.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 07/01/2020] [Accepted: 07/03/2020] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed.
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Affiliation(s)
- Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montreal, Canada.
| | - Piero Amodio
- Department of Medicine, University of Padova, Padova, Italy
| | - Jasmohan S Bajaj
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia, USA
| | - Radha Krishan Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Simon D Taylor-Robinson
- Department of Surgery and Cancer, St. Mary's Hospital Campus, Imperial College London, London, United Kingdom
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Denmark
| | - Rajiv Jalan
- Liver Failure Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, United Kingdom; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain.
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12
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Shurubor YI, Cooper AJL, Krasnikov AB, Isakova EP, Deryabina YI, Beal MF, Krasnikov BF. Changes of Coenzyme A and Acetyl-Coenzyme A Concentrations in Rats after a Single-Dose Intraperitoneal Injection of Hepatotoxic Thioacetamide Are Not Consistent with Rapid Recovery. Int J Mol Sci 2020; 21:E8918. [PMID: 33255464 PMCID: PMC7727790 DOI: 10.3390/ijms21238918] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022] Open
Abstract
Small biomolecules, such as coenzyme A (CoA) and acetyl coenzyme A (acetyl-CoA), play vital roles in the regulation of cellular energy metabolism. In this paper, we evaluated the delayed effect of the potent hepatotoxin thioacetamide (TAA) on the concentrations of CoA and acetyl-CoA in plasma and in different rat tissues. Administration of TAA negatively affects liver function and leads to the development of hepatic encephalopathy (HE). In our experiments, rats were administered a single intraperitoneal injection of TAA at doses of 200, 400, or 600 mg/kg. Plasma, liver, kidney, and brain samples were collected six days after the TAA administration, a period that has been suggested to allow for restoration of liver function. The concentrations of CoA and acetyl-CoA in the group of rats exposed to different doses of TAA were compared to those observed in healthy rats. The results obtained indicate that even a single administration of TAA to rats is sufficient to alter the physiological balance of CoA and acetyl-CoA in the plasma and tissues of rats for an extended period of time. The initial concentrations of CoA and acetyl-CoA were not restored even after the completion of the liver regeneration process.
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Affiliation(s)
- Yevgeniya I. Shurubor
- Center for Strategic Planning and Management of Medical and Biological Health Risks, Federal Medical-Biological Agency of The Russian Federation, 119121 Moscow, Russia;
| | - Arthur J. L. Cooper
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
| | | | - Elena P. Isakova
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia; (E.P.I.); (Y.I.D.)
| | - Yulia I. Deryabina
- Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia; (E.P.I.); (Y.I.D.)
| | - M. Flint Beal
- Department of Neurology, The Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10021, USA;
| | - Boris F. Krasnikov
- Center for Strategic Planning and Management of Medical and Biological Health Risks, Federal Medical-Biological Agency of The Russian Federation, 119121 Moscow, Russia;
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
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13
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Caracuel L, Sastre E, Callejo M, Rodrigues-Díez R, García-Redondo AB, Prieto I, Nieto C, Salaices M, Aller MÁ, Arias J, Blanco-Rivero J. Hepatic Encephalopathy-Associated Cerebral Vasculopathy in Acute-on-Chronic Liver Failure: Alterations on Endothelial Factor Release and Influence on Cerebrovascular Function. Front Physiol 2020; 11:593371. [PMID: 33329042 PMCID: PMC7716775 DOI: 10.3389/fphys.2020.593371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 10/23/2020] [Indexed: 11/23/2022] Open
Abstract
The acute-on-chronic liver failure (ACLF) is a syndrome characterized by liver decompensation, hepatic encephalopathy (HE) and high mortality. We aimed to determine the mechanisms implicated in the development of HE-associated cerebral vasculopathy in a microsurgical liver cholestasis (MHC) model of ACLF. Microsurgical liver cholestasis was induced by ligating and extracting the common bile duct and four bile ducts. Sham-operated and MHC rats were maintained for eight postoperative weeks Bradykinin-induced vasodilation was greater in middle cerebral arteries from MHC rats. Both Nω-Nitro-L-arginine methyl ester and indomethacin diminished bradykinin-induced vasodilation largely in arteries from MHC rats. Nitrite and prostaglandin (PG) F1α releases were increased, whereas thromboxane (TX) B2 was not modified in arteries from MHC. Expressions of endothelial nitric oxide synthase (eNOS), inducible NOS, and cyclooxygenase (COX) 2 were augmented, and neuronal NOS (nNOS), COX-1, PGI2 synthase, and TXA2S were unmodified. Phosphorylation was augmented for eNOS and unmodified for nNOS. Altogether, these endothelial alterations might collaborate to increase brain blood flow in HE.
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Affiliation(s)
- Laura Caracuel
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
| | - Esther Sastre
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
| | - María Callejo
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Raquel Rodrigues-Díez
- Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
- Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain
| | - Ana B. García-Redondo
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain
| | - Isabel Prieto
- Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
- Departamento de Cirugía General y Digestiva, Hospital Universitario la Paz, Madrid, Spain
| | - Carlos Nieto
- Departamento de Cirugía Cardiaca, Hospital Universitario la Paz, Madrid, Spain
| | - Mercedes Salaices
- Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
- Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain
| | - Ma Ángeles Aller
- Cátedra de Cirugía, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Jaime Arias
- Cátedra de Cirugía, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain
| | - Javier Blanco-Rivero
- Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
- Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares, Madrid, Spain
- *Correspondence: Javier Blanco-Rivero,
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14
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Impaired brain function improved by L-carnitine in patients with cirrhosis: evaluation using near-infrared spectroscopy. Sci Rep 2020; 10:13566. [PMID: 32782294 PMCID: PMC7419306 DOI: 10.1038/s41598-020-70585-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023] Open
Abstract
To evaluate the effects of l-carnitine on impaired brain function in patients with liver cirrhosis. We conducted a retrospective cohort study that included sequential 80 liver cirrhosis patients with impaired brain function evaluated using near-infrared spectroscopy (NIRS). Among them, l-carnitine was administered to 48 patients. The NIRS data and blood ammonia level at baseline and after 8 weeks of treatment were compared between patients administered with l-carnitine (l-carnitine group) and those who were not (control group). The NIRS data at baseline were similar between the l-carnitine and control groups (0.04 ± 0.04 vs. 0.04 ± 0.05 mMmm, p = n.s), whereas those in the l-carnitine group (n = 48) were significantly better than that of the control group at 8 weeks of treatment (n = 32) (0.103 ± 0.081 vs. 0.040 ± 0.048 mMmm, p < 0.001). In the l-carnitine group, 35.4% (17/48) of patients had hyperammonemia. The NIRS data of the l-carnitine group at 8 weeks of treatment were significantly improved than that of the control group, irrespective of baseline ammonia levels (0.11 ± 0.09 vs. 0.04 ± 0.05 mMmm, p = 0.005, and 0.10 ± 0.06 vs. 0.02 ± 0.03 mMmm, p = 0.003, for normal baseline ammonia and elevated ammonia levels, respectively). In the multivariate analysis, l-carnitine administration (odds ratio [OR] 3.51, 95% confidence interval [CI] 1.23–9.99, p = 0.019) and baseline NIRS data of ≤ 0.07 mMmm (OR 5.21, 95% CI 1.69–16.0, p = 0.0041) were found as independent significant factors. l-carnitine improves impaired brain function in patients with liver cirrhosis.
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15
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Kerbert AJC, Jalan R. Recent advances in understanding and managing hepatic encephalopathy in chronic liver disease. F1000Res 2020; 9. [PMID: 32399191 PMCID: PMC7194462 DOI: 10.12688/f1000research.22183.1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic encephalopathy (HE) is a common, severe complication of advanced chronic liver disease (CLD) and has a devastating impact on the patient’s quality of life and prognosis. The neurotoxin ammonia and the presence of systemic and neurological inflammation are considered the key drivers of this neuropsychiatric syndrome. Treatment options available in routine clinical practice are limited, and the development of novel therapies is hampered owing to the complexity and heterogeneity of HE. This review article aims to outline the current understanding of the pathomechanisms of HE and the recent advances in the identification and development of novel therapeutic targets.
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Affiliation(s)
- Annarein J C Kerbert
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
| | - Rajiv Jalan
- Institute for Liver and Digestive Health, University College London, Royal Free Campus, Rowland Hill Street, London, NW3 2PF, UK
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16
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Guazzelli PA, Cittolin-Santos GF, Meira-Martins LA, Grings M, Nonose Y, Lazzarotto GS, Nogara D, da Silva JS, Fontella FU, Wajner M, Leipnitz G, Souza DO, de Assis AM. Acute Liver Failure Induces Glial Reactivity, Oxidative Stress and Impairs Brain Energy Metabolism in Rats. Front Mol Neurosci 2020; 12:327. [PMID: 31998076 PMCID: PMC6968792 DOI: 10.3389/fnmol.2019.00327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 12/18/2019] [Indexed: 01/02/2023] Open
Abstract
Acute liver failure (ALF) implies a severe and rapid liver dysfunction that leads to impaired liver metabolism and hepatic encephalopathy (HE). Recent studies have suggested that several brain alterations such as astrocytic dysfunction and energy metabolism impairment may synergistically interact, playing a role in the development of HE. The purpose of the present study is to investigate early alterations in redox status, energy metabolism and astrocytic reactivity of rats submitted to ALF. Adult male Wistar rats were submitted either to subtotal hepatectomy (92% of liver mass) or sham operation to induce ALF. Twenty-four hours after the surgery, animals with ALF presented higher plasmatic levels of ammonia, lactate, ALT and AST and lower levels of glucose than the animals in the sham group. Animals with ALF presented several astrocytic morphological alterations indicating astrocytic reactivity. The ALF group also presented higher mitochondrial oxygen consumption, higher enzymatic activity and higher ATP levels in the brain (frontoparietal cortex). Moreover, ALF induced an increase in glutamate oxidation concomitant with a decrease in glucose and lactate oxidation. The increase in brain energy metabolism caused by astrocytic reactivity resulted in augmented levels of reactive oxygen species (ROS) and Poly [ADP-ribose] polymerase 1 (PARP1) and a decreased activity of the enzymes superoxide dismutase and glutathione peroxidase (GSH-Px). These findings suggest that in the early stages of ALF the brain presents a hypermetabolic state, oxidative stress and astrocytic reactivity, which could be in part sustained by an increase in mitochondrial oxidation of glutamate.
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Affiliation(s)
- Pedro Arend Guazzelli
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Giordano Fabricio Cittolin-Santos
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Leo Anderson Meira-Martins
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Mateus Grings
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Yasmine Nonose
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Gabriel S Lazzarotto
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Daniela Nogara
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Jussemara S da Silva
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Fernanda U Fontella
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Moacir Wajner
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Guilhian Leipnitz
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Diogo O Souza
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil
| | - Adriano Martimbianco de Assis
- Post-graduate Program in Biological Sciences: Biochemistry, ICBS, Universidade Federal do Rio Grande do Sul-UFRGS, Porto Alegre, Brazil.,Post-graduate Program in Health and Behavior, Health Sciences Centre, Universidade Católica de Pelotas-UCPel, Pelotas, Brazil
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17
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Ponziani FR, Funaro B, Lupascu A, Ainora ME, Garcovich M, Caracciolo G, Quadarella A, Nesci A, Riccardi L, Gasbarrini A, Pompili M, Zocco MA. Minimal Hepatic Encephalopathy is Associated with Increased Cerebral Vascular Resistance. A Transcranial Doppler Ultrasound Study. Sci Rep 2019; 9:15373. [PMID: 31653939 PMCID: PMC6814853 DOI: 10.1038/s41598-019-51867-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 10/09/2019] [Indexed: 12/13/2022] Open
Abstract
Minimal hepatic encephalopathy (MHE) is a subclinical complication of liver cirrhosis with a relevant social impact. Thus, there is urgent need to implement easy to use diagnostic tools for the early identification of affected patients. The aim of this study was to investigate cerebral blood flow, systemic hemodynamics as well as endothelial function of cirrhotic patients with MHE, and to verify their change after treatment with rifaximin. Fifty cirrhotic patients with or without MHE and an equal number of healthy controls underwent transcranial Doppler ultrasound (TCD), abdominal Doppler ultrasound (US), and measurement of flow mediated dilation (FMD). In cirrhotic patients diagnosed with MHE receiving rifaximin, the tests were repeated at the end of treatment. Middle (MCA) and posterior (PCA) cerebral artery resistive (RI) and pulsatility (PI) indices were higher in cirrhotic patients than controls, as well as renal and splenic artery RI. Conversely, FMD was reduced. MCA-RI and PI were even higher in cirrhotic patients with MHE compared to those without; a MCA-RI cut-off of 0.65 showed an accuracy of 74% in discriminating the presence of MHE, with 65% sensitivity and 76% specificity. Rifaximin treatment showed no efficacy in the modulation of cerebral vascular flow. In conclusion, cirrhotic patients with MHE have significantly increased cerebral vascular resistances that are not improved by rifaximin treatment. MCA-RI measurement has a good accuracy for the diagnosis of MHE and can be useful for the early identification of this harmful complication of liver cirrhosis.
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Affiliation(s)
- Francesca Romana Ponziani
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy.
| | - Barbara Funaro
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Andrea Lupascu
- Internal Medicine, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Maria Elena Ainora
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Matteo Garcovich
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Gianluigi Caracciolo
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Alessandro Quadarella
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Nesci
- Internal Medicine, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Laura Riccardi
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Maurizio Pompili
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Maria Assunta Zocco
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
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18
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Yousif MM, Sadek AMEM, Farrag HA, Selim FO, Hamed EF, Salama RI. Associated vitamin D deficiency is a risk factor for the complication of HCV-related liver cirrhosis including hepatic encephalopathy and spontaneous bacterial peritonitis. Intern Emerg Med 2019; 14:753-761. [PMID: 30706253 DOI: 10.1007/s11739-019-02042-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 01/19/2019] [Indexed: 02/07/2023]
Abstract
The influence of vitamin D, 25-hydroxyvitamin D (25(OH)D), deficiency on hepatitis C virus (HCV)-related cirrhosis had been poorly elucidated especially in patients with hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP). We aimed to investigate the association between vitamin D deficiency and the risk of SBP or HE, including the mortality rate. Serum 25(OH)D levels were prospectively determined in 135 patients. Of them, 45 patients had complications with HE and 45 patients had complications with SBP; 45 cirrhotic patients without complication served as the control group. Vitamin D deficiency was defined as 25(OH)D levels < 20 ng/ml. Receiver operating characteristic (ROC) and Kaplan-Meier method with log-rank test were used in our statistical analysis. Predictors of survival were determined using Cox regression analysis. Serum 25(OH)D levels were significantly (P < 0.05) lower in the HE and SBP groups than in the control group (6.81 ± 2.75, 7.15 ± 2.10, 16.28 ± 6.60, respectively). Moreover, serum 25(OH)D levels were significantly lower in the high HE grade than in the low grade (P < 0.001). Regarding the SBP group, classic SBP was associated with lower 25(OH)D levels compared to other types (P < 0.001). ROC curve revealed that lower 25(OH)D levels less than 7.1 ng/ml and 6.6 ng/ml could predict the mortality in SBP and HE patients, respectively, with high sensitivity and specificity. Serum 25(OH)D levels < 5 ng/ml were associated with significant higher mortality rate (HR = 2.76, P = 0.001). Lower 25(OH)D levels were associated with HE and SBP in cirrhotic patients. In addition, it may be considered a prognostic parameter for the severity of liver cirrhosis.
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Affiliation(s)
- Monkez Moteih Yousif
- Internal Medicine Department, Faculty of Medicine, Zagazig University Hospitals, Zagazig, Sharkia, 44519, Egypt
| | | | - Hesham Ahmad Farrag
- Internal Medicine Department, Faculty of Medicine, Zagazig University Hospitals, Zagazig, Sharkia, 44519, Egypt
| | - Fayrouz Othman Selim
- Internal Medicine Department, Faculty of Medicine, Zagazig University Hospitals, Zagazig, Sharkia, 44519, Egypt
| | - Emad Fawzi Hamed
- Internal Medicine Department, Faculty of Medicine, Zagazig University Hospitals, Zagazig, Sharkia, 44519, Egypt
| | - Rasha Ibrahim Salama
- Tropical Medicine Department, Faculty of Medicine, Zagazig University Hospitals, Zagazig, Egypt
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19
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TLR5 silencing reduced hyperammonaemia-induced liver injury by inhibiting oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals. Chem Biol Interact 2018; 299:102-110. [PMID: 30508503 DOI: 10.1016/j.cbi.2018.11.026] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 11/20/2018] [Accepted: 11/29/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver injury is a serious threat for human health and life. Toll-like receptor 5 (TLR5) has reported to be a vital mediator in flagellin or tetrachloride (CCl4)-induced liver injury. However, the roles and etiology of TLR5 in hyperammonaemia (HA)-induced liver injury are poor defined. METHODS HA rats were generated by intragastric administration using ammonium chloride solution. Liver status was assessed by haematoxylin and eosin (H&E) staining and measuring serum levels of liver injury markers. Immunohistochemistry (IHC) assay was used to visualize protein expression in tissues. Apoptotic index in tissues was determined by TUNEL assay. RT-qPCR assay was employed to test mRNA expression. Oxidative stress responses was assessed by detecting levels of reactive oxygen species (ROS) and related indicators. NF-κB activity was examined by TransAM NF-κB colorimetric kit. RESULTS TLR5 was highly expressed in liver tissues of HA rats. TLR5 knockdown ameliorated HA-induced liver injury by inhibiting liver cell apoptosis. TLR5 depletion inhibited HA-induced pro-inflammatory cytokine expression in liver tissues, but had no effect on the infiltration of T and macrophage cells into liver tissues. TLR5 silencing impaired HA-induced oxidative stress responses in hepatocytes, but not in hepatic stellate cells (HSCs). TLR5 downregulation inhibited HA-induced activation on TLR5/NF-κB and TLR5/MAPK signaling pathways. CONCLUSION TLR5 silencing reduced HA-induced liver injury by inhibiting hepatocyte apoptosis, oxidative stress and inflammation responses via inactivating NF-κB and MAPK signals, deepening our understanding on the molecular mechanism of HA-induced liver injury and providing a potential therapeutic target for alleviating liver injury.
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20
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Zielonka M, Breuer M, Okun JG, Carl M, Hoffmann GF, Kölker S. Pharmacologic rescue of hyperammonemia-induced toxicity in zebrafish by inhibition of ornithine aminotransferase. PLoS One 2018; 13:e0203707. [PMID: 30199544 PMCID: PMC6130883 DOI: 10.1371/journal.pone.0203707] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 08/24/2018] [Indexed: 12/30/2022] Open
Abstract
Hyperammonemia is the common biochemical hallmark of urea cycle disorders, activating neurotoxic pathways. If untreated, affected individuals have a high risk of irreversible brain damage and mortality. Here we show that acute hyperammonemia strongly enhances transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death in ammoniotelic zebrafish larvae via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Intriguingly, specific and irreversible inhibition of ornithine aminotransferase (OAT) by 5-fluoromethylornithine rescues zebrafish from lethal concentrations of ammonium acetate and corrects hyperammonemia-induced biochemical alterations. Thus, OAT inhibition is a promising and effective therapeutic approach for preventing neurotoxicity and mortality in acute hyperammonemia.
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Affiliation(s)
- Matthias Zielonka
- University Hospital Heidelberg, Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
- Heidelberg Research Center for Molecular Medicine (HRCMM), Heidelberg, Germany
- * E-mail:
| | - Maximilian Breuer
- University Hospital Heidelberg, Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Jürgen Günther Okun
- University Hospital Heidelberg, Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Matthias Carl
- Heidelberg University, Medical Faculty Mannheim, Department of Cell and Molecular Biology, Mannheim, Germany
- University of Trento, Center for Integrative Biology (CIBIO), Laboratory of Translational Neurogenetics, Trento, Italy
| | - Georg Friedrich Hoffmann
- University Hospital Heidelberg, Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
| | - Stefan Kölker
- University Hospital Heidelberg, Center for Child and Adolescent Medicine, Division for Pediatric Neurology and Metabolic Medicine, Heidelberg, Germany
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Bjerring PN, Gluud LL, Larsen FS. Cerebral Blood Flow and Metabolism in Hepatic Encephalopathy-A Meta-Analysis. J Clin Exp Hepatol 2018; 8:286-293. [PMID: 30302046 PMCID: PMC6175738 DOI: 10.1016/j.jceh.2018.06.002] [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: 02/22/2018] [Accepted: 06/11/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatic Encephalopathy (HE) is associated with abnormalities in brain metabolism of glucose, oxygen and amino acids. In patients with acute liver failure, cortical lactate to pyruvate ratio is increased, which is indicative of a compromised cerebral oxidative metabolism. In this meta-analysis we have reviewed the published data on cerebral blood flow and metabolic rates from clinical studies of patients with HE. We found that hepatic encephalopathy was associated with reduced cerebral metabolic rate of oxygen, glucose, and blood flow. One exemption was in HE type B (shunt/by-pass) were a tendency towards increased cerebral blood flow was seen. We speculate that HE is associated with a disturbed metabolism-cytopathic hypoxia-and that type specific differences of brain metabolism is due to differences in pathogenesis of HE.
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Key Words
- ALF, Acute Liver Failure
- CBF, Cerebral Blood Flow
- CMR, Cerebral Metabolic Rate
- HE, Hepatic Encephalopathy
- ICH, Intracranial Hypertension
- MHE, Minimal Hepatic Encephalopathy
- MRI, Magnetic Resonance Imaging
- OHE, Overt Hepatic Encephalopathy
- PCS, Portocaval Shunt
- cerebral blood flow
- cerebral metabolism
- hepatic encephalopathy
- liver failure
- pcMRI, Phase-Contrast MRI
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Affiliation(s)
- Peter N. Bjerring
- Department of Hepatology, Rigshospitalet, Copenhagen, Denmark
- The Gastro Unit, Medical Division, Hvidovre Hospital, Hvidovre, Denmark
- Address for correspondence: Peter N. Bjerring, Department of Hepatology, Rigshospitalet, Copenhagen, Denmark.
| | - Lise L. Gluud
- The Gastro Unit, Medical Division, Hvidovre Hospital, Hvidovre, Denmark
| | - Fin S. Larsen
- Department of Hepatology, Rigshospitalet, Copenhagen, Denmark
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22
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Disrupted metabolic and functional connectivity patterns of the posterior cingulate cortex in cirrhotic patients. Neuroreport 2018; 29:993-1000. [DOI: 10.1097/wnr.0000000000001063] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Bjerring PN, Bjerrum EJ, Larsen FS. Impaired cerebral microcirculation induced by ammonium chloride in rats is due to cortical adenosine release. J Hepatol 2018; 68:1137-1143. [PMID: 29452205 DOI: 10.1016/j.jhep.2018.01.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 01/28/2018] [Accepted: 01/30/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Liver failure results in hyperammonaemia, impaired regulation of cerebral microcirculation, encephalopathy, and death. However, the key mediator that alters cerebral microcirculation remains unidentified. In this study we show that topically applied ammonium significantly increases periarteriolar adenosine tone on the brain surface of healthy rats and is associated with a disturbed microcirculation. METHODS Cranial windows were prepared in anaesthetized Wistar rats. The flow velocities were measured by speckle contrast imaging and compared before and after 30 min of exposure to 10 mM ammonium chloride applied on the brain surface. These flow velocities were compared with those for control groups exposed to artificial cerebrospinal fluid or ammonium plus an adenosine receptor antagonist. A flow preservation curve was obtained by analysis of flow responses to a haemorrhagic hypotensive challenge and during stepwise exsanguination. The periarteriolar adenosine concentration was measured with enzymatic biosensors inserted in the cortex. RESULTS After ammonium exposure the arteriolar flow velocity increased by a median (interquartile range) of 21.7% (23.4%) vs. 7.2% (10.2%) in controls (n = 10 and n = 6, respectively, p <0.05), and the arteriolar surface area increased. There was a profound rise in the periarteriolar adenosine concentration. During the hypotensive challenge the flow decreased by 27.8% (14.9%) vs. 9.2% (14.9%) in controls (p <0.05). The lower limit of flow preservation remained unaffected, 27.7 (3.9) mmHg vs. 27.6 (6.4) mmHg, whereas the autoregulatory index increased, 0.29 (0.33) flow units per millimetre of mercury vs. 0.03 (0.21) flow units per millimetre of mercury (p <0.05). When ammonium exposure was combined with topical application of an adenosine receptor antagonist, the autoregulatory index was normalized. CONCLUSIONS Vasodilation of the cerebral microcirculation during exposure to ammonium chloride is associated with an increase in the adenosine tone. Application of a specific adenosine receptor antagonist restores the regulation of the microcirculation. This indicates that adenosine could be a key mediator of the brain dysfunction seen during hyperammonaemia and is a potential therapeutic target. LAY SUMMARY In patients with liver failure, disturbances in brain function are caused in part by ammonium toxicity. In our project we studied how ammonia, through adenosine release, affects the blood flow in the brain of rats. In our experimental model we demonstrated that the detrimental effect of ammonia on blood flow regulation was counteracted by blocking the adenosine receptors in the brain. With this observation we identified a novel potential treatment target. If we can confirm our findings in a future clinical study, this might help patients with liver failure and the severe condition called hepatic encephalopathy.
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Affiliation(s)
- Peter Nissen Bjerring
- Department of Hepatology, Rigshospitalet, Copenhagen, Denmark; The Gastro Unit, Medical Section, Hvidovre Hospital, Hvidovre, Denmark.
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24
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Weiss N, Dam G, Rose CF. Ammonia: This is not the end but rather the end of the beginning. J Hepatol 2018; 68:1110-1113. [PMID: 29626494 DOI: 10.1016/j.jhep.2018.03.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 03/29/2018] [Accepted: 03/29/2018] [Indexed: 01/16/2023]
Affiliation(s)
- Nicolas Weiss
- Sorbonne Université, Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM, Centre de Recherche Saint-Antoine, Assistance Publique - Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière Charles Foix, Département de Neurologie, Unité de réanimation neurologique, Paris, France
| | - Gitte Dam
- Department of Medicine V (Hepatology and Gastroenterology), Aarhus, Denmark
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, Montréal, Québec, Canada.
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25
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Zheng G, Lu H, Yu W, Luo S, Liu Y, Liu W, Liu H, Wu L, Zheng L, Kong X, Zhang LJ, Lu GM. Severity-specific alterations in CBF, OEF and CMRO2 in cirrhotic patients with hepatic encephalopathy. Eur Radiol 2017; 27:4699-4709. [PMID: 28523351 DOI: 10.1007/s00330-017-4809-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 02/21/2017] [Accepted: 03/13/2017] [Indexed: 01/02/2023]
Abstract
OBJECTIVES To assess how the severity of hepatic encephalopathy (HE) affects perfusion and metabolic changes in cirrhotic patients and the association between severity and liver disease and anemia. METHODS The study groups comprised 31 healthy subjects and 33 cirrhotic patients who underwent MR examinations, and blood and neuropsychological tests. Of the cirrhotic patients, 14 were unaffected, and 11 had covert HE (CHE) and 8 overt HE (OHE). Global cerebral blood flow (CBF), oxygen extraction fraction (OEF), and metabolic rate of oxygen (CMRO2) were noninvasively measured by phase-contrast and T2-relaxation-under-spin-tagging MRI. Correlations were performed between MR measurements, hematocrits, ammonia levels, Child-Pugh scores and neuropsychological test scores. RESULTS Compared with the values in healthy subjects, CBF was higher in unaffected patients, the same in CHE patients and lower in OHE patients, OEF was higher in all patients, and CMRO2 was the same in unaffected and CHE patients and lower in OHE patients. Hematocrit was negatively correlated with CBF and OEF, but not with CMRO2. Ammonia level was negatively correlated with CBF and CMRO2, and Child-Pugh score was negatively correlated with CMRO2. CONCLUSIONS The severity-associated alterations in cirrhotic patients indicate that homeostasis of oxygen delivery and oxidative metabolism in HE is regulated by multiple mechanisms. These physiological alterations appeared to be associated with the degree of anemia, ammonia level, and liver function. KEY POINTS • CBF, OEF and CMRO2 did not change monotonically with HE progression. • Anemia possibly contributed to CBF and OEF changes in cirrhotic patients. • Liver dysfunction mainly contributed to changes in CMRO2 in cirrhotic patients.
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Affiliation(s)
- Gang Zheng
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
- College of Civil Aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, 210016, China
| | - Hanzhang Lu
- The Russell H. Morgan Department of Radiology & Radiological Science, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Wenkui Yu
- Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Song Luo
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
| | - Ya Liu
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
- College of Civil Aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, 210016, China
| | - Wei Liu
- Siemens Shenzhen Magnetic Resonance Ltd., Shenzhen, Guangdong, China
| | - Hui Liu
- Siemens MR NEA Collaboration, Siemens Ltd., China, Shanghai, China
| | - Long Wu
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
| | - Lijuan Zheng
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
| | - Xiang Kong
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
| | - Long Jiang Zhang
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
| | - Guang Ming Lu
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China
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26
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Dasarathy S, Mookerjee RP, Rackayova V, Rangroo Thrane V, Vairappan B, Ott P, Rose CF. Ammonia toxicity: from head to toe? Metab Brain Dis 2017; 32:529-538. [PMID: 28012068 PMCID: PMC8839071 DOI: 10.1007/s11011-016-9938-3] [Citation(s) in RCA: 153] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 11/30/2016] [Indexed: 12/14/2022]
Abstract
Ammonia is diffused and transported across all plasma membranes. This entails that hyperammonemia leads to an increase in ammonia in all organs and tissues. It is known that the toxic ramifications of ammonia primarily touch the brain and cause neurological impairment. However, the deleterious effects of ammonia are not specific to the brain, as the direct effect of increased ammonia (change in pH, membrane potential, metabolism) can occur in any type of cell. Therefore, in the setting of chronic liver disease where multi-organ dysfunction is common, the role of ammonia, only as neurotoxin, is challenged. This review provides insights and evidence that increased ammonia can disturb many organ and cell types and hence lead to dysfunction.
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Affiliation(s)
- Srinivasan Dasarathy
- Department of Gastroenterology, Hepatology and Pathobiology, Cleveland Clinic, Cleveland, OH, USA
| | - Rajeshwar P Mookerjee
- Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, London, UK
| | - Veronika Rackayova
- Laboratory of Functional and Metabolic Imaging, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Vinita Rangroo Thrane
- Department of Ophthalmology, Haukeland University Hospital, 5021, Bergen, Norway
- Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY, USA
| | - Balasubramaniyan Vairappan
- Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Dhanvantri Nagar, Pondicherry, India
| | - Peter Ott
- Department of Medicine V (Hepatology and Gastroenterology), Aarhus, Denmark
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Department of Medicine, Université de Montréal, Montréal, Québec, Canada.
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27
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Rackayova V, Braissant O, McLin VA, Berset C, Lanz B, Cudalbu C. 1H and 31P magnetic resonance spectroscopy in a rat model of chronic hepatic encephalopathy: in vivo longitudinal measurements of brain energy metabolism. Metab Brain Dis 2016; 31:1303-1314. [PMID: 26253240 DOI: 10.1007/s11011-015-9715-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 07/26/2015] [Indexed: 12/21/2022]
Abstract
Chronic liver disease (CLD) leads to a spectrum of neuropsychiatric disorders named hepatic encephalopathy (HE). Even though brain energy metabolism is believed to be altered in chronic HE, few studies have explored energy metabolism in CLD-induced HE, and their findings were inconsistent. The aim of this study was to characterize for the first time in vivo and longitudinally brain metabolic changes in a rat model of CLD-induced HE with a focus on energy metabolism, using the methodological advantages of high field proton and phosphorus Magnetic Resonance Spectroscopy (1H- and 31P-MRS). Wistar rats were bile duct ligated (BDL) and studied before BDL and at post-operative weeks 4 and 8. Glutamine increased linearly over time (+146 %) together with plasma ammonium (+159 %). As a compensatory effect, other brain osmolytes decreased: myo-inositol (-36 %), followed by total choline and creatine. A decrease in the neurotransmitters glutamate (-17 %) and aspartate (-28 %) was measured only at week 8, while no significant changes were observed for lactate and phosphocreatine. Among the other energy metabolites measured by 31P-MRS, we observed a non-significant decrease in ATP together with a significant decrease in ADP (-28 %), but only at week 8 after ligation. Finally, brain glutamine showed the strongest correlations with changes in other brain metabolites, indicating its importance in type C HE. In conclusion, mild alterations in some metabolites involved in energy metabolism were observed but only at the end stage of the disease when edema and neurological changes are already present. Therefore, our data indicate that impaired energy metabolism is not one of the major causes of early HE symptoms in the established model of type C HE.
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Affiliation(s)
- Veronika Rackayova
- Laboratory of Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Olivier Braissant
- Service of Biomedicine, University Hospital of Lausanne, Lausanne, Switzerland
| | - Valérie A McLin
- Swiss Center for Liver Disease in Children, Department of Pediatrics, University Hospitals Geneva, Geneva, Switzerland
| | - Corina Berset
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Bernard Lanz
- Laboratory of Functional and Metabolic Imaging (LIFMET), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
| | - Cristina Cudalbu
- Centre d'Imagerie Biomedicale (CIBM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
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28
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Multifactorial Effects on Different Types of Brain Cells Contribute to Ammonia Toxicity. Neurochem Res 2016; 42:721-736. [PMID: 27286679 DOI: 10.1007/s11064-016-1966-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 05/20/2016] [Accepted: 05/24/2016] [Indexed: 12/12/2022]
Abstract
Effects of ammonia on astrocytes play a major role in hepatic encephalopathy, acute liver failure and other diseases caused by increased arterial ammonia concentrations (e.g., inborn errors of metabolism, drug or mushroom poisoning). There is a direct correlation between arterial ammonia concentration, brain ammonia level and disease severity. However, the pathophysiology of hyperammonemic diseases is disputed. One long recognized factor is that increased brain ammonia triggers its own detoxification by glutamine formation from glutamate. This is an astrocytic process due to the selective expression of the glutamine synthetase in astrocytes. A possible deleterious effect of the resulting increase in glutamine concentration has repeatedly been discussed and is supported by improvement of some pathologic effects by GS inhibition. However, this procedure also inhibits a large part of astrocytic energy metabolism and may prevent astrocytes from responding to pathogenic factors. A decrease of the already low glutamate concentration in astrocytes due to increased synthesis of glutamine inhibits the malate-aspartate shuttle and energy metabolism. A more recently described pathogenic factor is the resemblance between NH4+ and K+ in their effects on the Na+,K+-ATPase and the Na+,K+, 2 Cl- and water transporter NKCC1. Stimulation of the Na+,K+-ATPase driven NKCC1 in both astrocytes and endothelial cells is essential for the development of brain edema. Na+,K+-ATPase stimulation also activates production of endogenous ouabains. This leads to oxidative and nitrosative damage and sensitizes NKCC1. Administration of ouabain antagonists may accordingly have therapeutic potential in hyperammonemic diseases.
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29
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Chen HJ, Zheng G, Wichmann JL, Schoepf UJ, Lu GM, Zhang LJ. The brain following transjugular intrahepatic portosystemic shunt: the perspective from neuroimaging. Metab Brain Dis 2015; 30:1331-41. [PMID: 26404041 DOI: 10.1007/s11011-015-9735-4] [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: 05/20/2015] [Accepted: 09/17/2015] [Indexed: 11/25/2022]
Abstract
Hepatic encephalopathy (HE) is a common complication after implantation of a transjugular intrahepatic portosystemic shunt (TIPS). Neuroimaging offers a variety of techniques for non-invasive evaluation of alterations in metabolism, as well as structural and functional changes of the brain in patients after TIPS implantation. In this article, we review the epidemiology and pathophysiology of post-TIPS HE. The potential of neuroimaging including positron emission tomography and multimodality magnetic resonance imaging to investigate the pathophysiology of post-TIPS HE is presented. We also give a perspective on the role of neuroimaging in this field.
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Affiliation(s)
- Hui Juan Chen
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210002, Jiangsu Province, China
| | - Gang Zheng
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210002, Jiangsu Province, China
- College of Civil Aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, 210016, China
| | - Julian L Wichmann
- Department of Radiology and Radiological Science, Medical University of South Carolina, Ashley River Tower, MSC 226, 25 Courtenay Dr, Charleston, SC, 29401, USA
- Department of Diagnostic and Interventional Radiology, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany
| | - U Joseph Schoepf
- Department of Radiology and Radiological Science, Medical University of South Carolina, Ashley River Tower, MSC 226, 25 Courtenay Dr, Charleston, SC, 29401, USA
| | - Guang Ming Lu
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210002, Jiangsu Province, China
| | - Long Jiang Zhang
- Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, No. 305 Zhongshan East Road, Nanjing, 210002, Jiangsu Province, China.
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30
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Abstract
Hepatic encephalopathy (HE) is defined by an altered mental status in the setting of portosystemic shunting, with or without cirrhosis. The basis of HE is probably multi-factorial, but increased ammonia delivery to the brain is thought to play a pivotal role. Medical therapies have typically focused on reducing blood ammonia concentrations. These measures are moderately effective, but further improvements will require identification of new therapeutic targets. Two medications, lactulose and rifaximin, are currently approved for the treatment of HE in the USA - new compounds are available off-label, and are in clinical trials. The presence of HE is associated with a higher risk of death in cirrhotic patients. Liver transplantation typically cures HE, but HE does not increase the MELD score, and therefore does not contribute to the likelihood of liver transplantation.
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Affiliation(s)
- Norman L Sussman
- Baylor College of Medicine and Baylor-St. Luke's Medical Center, Division of Abdominal Transplantation, 6620 Main Street #1425, Houston, TX 77030, USA.
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31
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Basu PP, Shah NJ. Clinical and Neurologic Manifestation of Minimal Hepatic Encephalopathy and Overt Hepatic Encephalopathy. Clin Liver Dis 2015. [PMID: 26195201 DOI: 10.1016/j.cld.2015.05.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatic encephalopathy (HE) shows a wide spectrum of neuropsychiatric manifestations. A combined effort with neuropsychological and psychometric evaluation has to be performed to recognize the syndrome, whereas minimal HE (MHE) is largely under-recognized. Subtle symptoms of MHE can only be diagnosed through specialized neuropsychiatric testing. Early diagnosis and treatment may drastically improve the quality of life for many cirrhotic patients. Further research to gain better insight into the pathophysiology and diagnostic accuracy of HE will help determine future management strategies.
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Affiliation(s)
- P Patrick Basu
- Department of Medicine, Columbia University College of Physicians and Surgeons, 622 West 168 Street, New York, NY 10032, USA; Department of Medicine, King's County Hospital Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
| | - Niraj James Shah
- Department of Medicine, James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, 130 West Kingsbridge Road, New York, NY 10468, USA.
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32
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Abstract
In patients with cirrhosis and portal hypertension, it is largely the frequency and severity of complications relating to the diseased liver, degree of portal hypertension and hemodynamic derangement that determine the prognosis. It can be considered as a multiple organ failure that apart from the liver involves the heart, lungs, kidneys, the immune systems and other organ systems. Progressive fibrosis of the liver and subsequent metabolic impairment leads to a systemic and splanchnic arteriolar vasodilatation. With the progression of the disease development of portal hypertension leads to formation of esophageal varices and ascites. The circulation becomes hyperdynamic with cardiac, pulmonary as well as renal consequences for dysfunction and reduced survival. Infections and a changed cardiac function known as cirrhotic cardiomyopathy may be involved in further aggravation of other complications such as renal failure precipitating the hepatorenal syndrome. Patients with end-stage liver disease and related complications as for example the hepatopulmonary syndrome can only radically be treated by liver transplantation.
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Affiliation(s)
- Søren Møller
- Department of Clinical Physiology and Nuclear Medicine 239, Faculty of Health Sciences, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, University of Copenhagen , Hvidovre , Denmark
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Macías-Rodríguez RU, Duarte-Rojo A, Cantú-Brito C, Sauerbruch T, Ruiz-Margáin A, Trebicka J, Green-Gómez M, Díaz Ramírez JB, Sierra Beltrán M, Uribe-Esquivel M, Torre A. Cerebral haemodynamics in cirrhotic patients with hepatic encephalopathy. Liver Int 2015; 35:344-352. [PMID: 24690075 DOI: 10.1111/liv.12557] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Accepted: 03/27/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Factors other than elevated levels of ammonia may be implicated in hepatic encephalopathy (HE) pathophysiology, including abnormal cerebral haemodynamics. Transcranial Doppler ultrasonography (TCD) evaluates cerebrovascular structural integrity and reactivity, through pulsatility index (PI) and breath-holding index (BHI) respectively. The aim of this study was to evaluate cerebral haemodynamics by TCD in patients with compensated and decompensated cirrhosis, and patients with and without HE. METHODS We studied 90 subjects by TCD measuring PI and BHI in the middle cerebral artery: 30 with cirrhosis and no HE, 30 with cirrhosis and low-grade HE and 30 healthy subjects. Critical flicker frequency, psychometric hepatic encephalopathy score and West-Haven criteria were performed to assess MHE and HE respectively. RESULTS Pulsatility index increased in decompensated cirrhotics (Child ≥ 7) when compared with compensated cirrhotics and healthy subjects [median (IQR) 1.07 (0.95-1.21) vs 0.90 (0.83-1.05) vs 0.87 (0.78-0.96); P < 0.001]. A reverse relationship was observed for BHI among the three groups [0.82 (0.45-1.11) vs 1.20 (0.82-1.52) vs 1.28 (1.06-1.68); P < 0.001]. Similar findings were observed in decompensation [model for end-stage liver disease (MELD) score ≥14]. Patients with HE showed higher PI and lower BHI [1.05 (1.00-1.16) and 0.89 (0.59-1.15)], when compared with patients without HE [0.96 (0.83-1.13) and 1.00 (0.60-1.53)] or controls [0.87 (0.78-0.96) and 1.28 (1.06-1.68)] (P < 0.001 for PI, and P = 0.007 for BHI). In multivariate regression models, only PI predicted HE, but it was outperformed by MELD-sodium and tumour necrosis factor-alpha. CONCLUSIONS These results indicate that cerebral haemodynamics are altered in patients with cirrhosis, in relation to severity of disease and HE. Findings on impaired PI and BHI suggest that structural vascular damage and loss of vascular autoregulation are implicated in the pathophysiology of HE.
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Affiliation(s)
- Ricardo U Macías-Rodríguez
- Liver Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", México D.F, Tlalpan, México
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Ott P, Vilstrup H. Cerebral effects of ammonia in liver disease: current hypotheses. Metab Brain Dis 2014; 29:901-11. [PMID: 24488230 DOI: 10.1007/s11011-014-9494-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2013] [Accepted: 01/21/2014] [Indexed: 12/15/2022]
Abstract
Hyperammonemia is necessary for development of the cerebral complications to liver disease including hepatic encephalopathy and cerebral edema but the mechanisms are unclear. Ammonia is taken up by the brain in proportion to its arterial concentration. The flux into the brain is most likely by both diffusion of NH3 and mediated transport of NH4 (+) . Astrocytic detoxification of ammonia involves formation of glutamine at concentrations high enough to produce cellular edema, but compensatory mechanisms reduce this effect. Glutamine can be taken up by astrocytic mitochondria and initiate the mitochondrial permeability transition but the clinical relevance is uncertain. Elevated astrocytic glutamine interferes with neurotransmission. Thus, animal studies show enhanced glutamatergic neurotransmission via the NMDA receptor which may be related to the acute cerebral complications to liver failure, while impairment of the NMDA activated glutamate-NO-cGMP pathway could relate to the behavioural changes seen in hepatic encephalopathy. Elevated glutamine also increases GABA-ergic tone, an effect which is aggravated by mitochondrial production of neurosteroids; this may relate to decreased neurotransmission and precipitation of encephalopathy by GABA targeting drugs. Hyperammonemia may compromise cerebral energy metabolism as elevated cerebral lactate is generally reported. Hypoxia is unlikely since cerebral oxygen:glucose utilisation and lactate:pyruvate ratio are both normal in clinical studies. Ammonia inhibits α-ketoglutaratedehydrogenase in isolated mitochondria, but the clinical relevance is dubious due to the observed normal cerebral oxygen:glucose utilization. Recent studies suggest that ammonia stimulates glycolysis in excess of TCA cycle activity, a hypothesis that may warrant further testing, in being in accordance with the limited clinical observations.
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Affiliation(s)
- Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, 8000C, Aarhus, Denmark,
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Schousboe A, Waagepetersen HS, Leke R, Bak LK. Effects of hyperammonemia on brain energy metabolism: controversial findings in vivo and in vitro. Metab Brain Dis 2014; 29:913-7. [PMID: 24577633 DOI: 10.1007/s11011-014-9513-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Accepted: 02/14/2014] [Indexed: 12/21/2022]
Abstract
The literature related to the effects of elevated plasma ammonia levels on brain energy metabolism is abundant, but heterogeneous in terms of the conclusions. Thus, some studies claim that ammonia has a direct, inhibitory effect on energy metabolism whereas others find no such correlation. In this review, we discuss both recent and older literature related to this controversial topic. We find that it has been consistently reported that hepatic encephalopathy and concomitant hyperammonemia lead to reduced cerebral oxygen consumption. However, this may not be directly linked to an effect of ammonia but related to the fact that hepatic encephalopathy is always associated with reduced brain activity, a condition clearly characterized by a decreased CMRO2. Whether this may be related to changes in GABAergic function remains to be elucidated.
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Affiliation(s)
- Arne Schousboe
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen Ø, Denmark
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Dennis CV, Sheahan PJ, Graeber MB, Sheedy DL, Kril JJ, Sutherland GT. Microglial proliferation in the brain of chronic alcoholics with hepatic encephalopathy. Metab Brain Dis 2014; 29:1027-39. [PMID: 24346482 PMCID: PMC4063896 DOI: 10.1007/s11011-013-9469-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 12/04/2013] [Indexed: 12/11/2022]
Abstract
Hepatic encephalopathy (HE) is a common complication of chronic alcoholism and patients show neurological symptoms ranging from mild cognitive dysfunction to coma and death. The HE brain is characterized by glial changes, including microglial activation, but the exact pathogenesis of HE is poorly understood. During a study investigating cell proliferation in the subventricular zone of chronic alcoholics, a single case with widespread proliferation throughout their adjacent grey and white matter was noted. This case also had concomitant HE raising the possibility that glial proliferation might be a pathological feature of the disease. In order to explore this possibility fixed postmortem human brain tissue from chronic alcoholics with cirrhosis and HE (n = 9), alcoholics without HE (n = 4) and controls (n = 4) were examined using immunohistochemistry and cytokine assays. In total, 4/9 HE cases had PCNA- and a second proliferative marker, Ki-67-positive cells throughout their brain and these cells co-stained with the microglial marker, Iba1. These cases were termed 'proliferative HE' (pHE). The microglia in pHEs displayed an activated morphology with hypertrophied cell bodies and short, thickened processes. In contrast, the microglia in white matter regions of the non-proliferative HE cases were less activated and appeared dystrophic. pHEs were also characterized by higher interleukin-6 levels and a slightly higher neuronal density . These findings suggest that microglial proliferation may form part of an early neuroprotective response in HE that ultimately fails to halt the course of the disease because underlying etiological factors such as high cerebral ammonia and systemic inflammation remain.
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Affiliation(s)
- Claude V Dennis
- Discipline of Pathology, Sydney Medical School, Camperdown, NSW, 2050, Australia
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Abstract
Human adults produce around 1000 mmol of ammonia daily. Some is reutilized in biosynthesis. The remainder is waste and neurotoxic. Eventually most is excreted in urine as urea, together with ammonia used as a buffer. In extrahepatic tissues, ammonia is incorporated into nontoxic glutamine and released into blood. Large amounts are metabolized by the kidneys and small intestine. In the intestine, this yields ammonia, which is sequestered in portal blood and transported to the liver for ureagenesis, and citrulline, which is converted to arginine by the kidneys. The amazing developments in NMR imaging and spectroscopy and molecular biology have confirmed concepts derived from early studies in animals and cell cultures. The processes involved are exquisitely tuned. When they are faulty, ammonia accumulates. Severe acute hyperammonemia causes a rapidly progressive, often fatal, encephalopathy with brain edema. Chronic milder hyperammonemia causes a neuropsychiatric illness. Survivors of severe neonatal hyperammonemia have structural brain damage. Proposed explanations for brain edema are an increase in astrocyte osmolality, generally attributed to glutamine accumulation, and cytotoxic oxidative/nitrosative damage. However, ammonia neurotoxicity is multifactorial, with disturbances also in neurotransmitters, energy production, anaplerosis, cerebral blood flow, potassium, and sodium. Around 90% of hyperammonemic patients have liver disease. Inherited defects are rare. They are being recognized increasingly in adults. Deficiencies of urea cycle enzymes, citrin, and pyruvate carboxylase demonstrate the roles of isolated pathways in ammonia metabolism. Phenylbutyrate is used routinely to treat inherited urea cycle disorders, and its use for hepatic encephalopathy is under investigation.
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Affiliation(s)
- Valerie Walker
- Department of Clinical Biochemistry, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom.
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Iversen P, Mouridsen K, Hansen MB, Jensen SB, Sørensen M, Bak LK, Waagepetersen HS, Schousboe A, Ott P, Vilstrup H, Keiding S, Gjedde A. Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: a PET study with [(11)C]acetate in humans. Front Neurosci 2014; 8:353. [PMID: 25404890 PMCID: PMC4217371 DOI: 10.3389/fnins.2014.00353] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Accepted: 10/14/2014] [Indexed: 12/31/2022] Open
Abstract
In patients with impaired liver function and hepatic encephalopathy (HE), consistent elevations of blood ammonia concentration suggest a crucial role in the pathogenesis of HE. Ammonia and acetate are metabolized in brain both primarily in astrocytes. Here, we used dynamic [(11)C]acetate PET of the brain to measure the contribution of astrocytes to the previously observed reduction of brain oxidative metabolism in patients with liver cirrhosis and HE, compared to patients with cirrhosis without HE, and to healthy subjects. We used a new kinetic model to estimate uptake from blood to astrocytes and astrocyte metabolism of [(11)C]acetate. No significant differences of the rate constant of oxidation of [(11)C]acetate (k 3) were found among the three groups of subjects. The net metabolic clearance of [(11)C]acetate from blood was lower in the group of patients with cirrhosis and HE than in the group of healthy subjects (P < 0.05), which we interpret to be an effect of reduced cerebral blood flow rather than a reflection of low [(11)C]acetate metabolism. We conclude that the characteristic decline of whole-brain oxidative metabolism in patients with cirrhosis with HE is not due to malfunction of oxidative metabolism in astrocytes. Thus, the observed decline of brain oxidative metabolism implicates changes of neurons and their energy turnover in patients with HE.
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Affiliation(s)
- Peter Iversen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital Aarhus, Denmark
| | - Kim Mouridsen
- Center of Functionally Integrative Neuroscience, Aarhus University Aarhus, Denmark
| | - Mikkel B Hansen
- Center of Functionally Integrative Neuroscience, Aarhus University Aarhus, Denmark
| | - Svend B Jensen
- Department of Nuclear Medicine, Aalborg University Hospital Aalborg, Denmark ; Department of Chemistry and Biochemistry, Aalborg University Aalborg, Denmark
| | - Michael Sørensen
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital Aarhus, Denmark ; Department of Hepatology and Gastroenterology, Aarhus University Hospital Aarhus, Denmark
| | - Lasse K Bak
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark
| | - Helle S Waagepetersen
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark
| | - Arne Schousboe
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark
| | - Peter Ott
- Department of Hepatology and Gastroenterology, Aarhus University Hospital Aarhus, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital Aarhus, Denmark
| | - Susanne Keiding
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital Aarhus, Denmark ; Department of Hepatology and Gastroenterology, Aarhus University Hospital Aarhus, Denmark ; Brain Research and Integrative Neuroscience Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark
| | - Albert Gjedde
- Department of Nuclear Medicine and PET Centre, Aarhus University Hospital Aarhus, Denmark ; Center of Functionally Integrative Neuroscience, Aarhus University Aarhus, Denmark ; Brain Research and Integrative Neuroscience Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark
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Díaz-Herrero MM, del Campo JA, Carbonero-Aguilar P, Vega-Pérez JM, Iglesias-Guerra F, Periñán I, Miñano FJ, Bautista J, Romero-Gómez M. THDP17 decreases ammonia production through glutaminase inhibition. A new drug for hepatic encephalopathy therapy. PLoS One 2014; 9:e109787. [PMID: 25329718 PMCID: PMC4201470 DOI: 10.1371/journal.pone.0109787] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 09/03/2014] [Indexed: 11/29/2022] Open
Abstract
Ammonia production is implicated in the pathogenesis of hepatic encephalopathy (HE), being intestinal glutaminase activity the main source for ammonia. Management of ammonia formation can be effective in HE treatment by lowering intestinal ammonia production. The use of glutaminase inhibitors represents one way to achieve this goal. In this work, we have performed a search for specific inhibitors that could decrease glutaminase activity by screening two different groups of compounds: i) a group integrated by a diverse, highly pure small molecule compounds derived from thiourea ranging from 200 to 800 Daltons; and ii) a group integrated by commonly use compounds in the treatment of HE. Results shown that THDP-17 (10 µM), a thiourea derivate product, could inhibit the intestinal glutaminase activity (57.4±6.7%). Inhibitory effect was tissue dependent, ranging from 40±5.5% to 80±7.8% in an uncompetitive manner, showing Vmax and Km values of 384.62 µmol min−1, 13.62 mM with THDP-17 10 µM, respectively. This compound also decreased the glutaminase activity in Caco-2 cell cultures, showing a reduction of ammonia and glutamate production, compared to control cultures. Therefore, the THDP-17 compound could be a good candidate for HE management, by lowering ammonia production.
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Affiliation(s)
- M. Mar Díaz-Herrero
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
| | - José A. del Campo
- Unidad de Gestión Clínica de Enfermedades Digestivas & Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Universitario de Valme, Sevilla, Spain
| | - Pilar Carbonero-Aguilar
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
| | - José M. Vega-Pérez
- Departamento de Química Orgánica y Química Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
| | - Fernando Iglesias-Guerra
- Departamento de Química Orgánica y Química Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
| | - Ignacio Periñán
- Departamento de Química Orgánica y Química Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
| | - Francisco J. Miñano
- Unidad de Farmacología Experimental y Clínica (UFEC), Hospital Universitario de Valme, Universidad de Sevilla, Sevilla, Spain
| | - Juan Bautista
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Sevilla, Spain
- * E-mail: (JDB); (MRG)
| | - Manuel Romero-Gómez
- Unidad de Gestión Clínica de Enfermedades Digestivas & Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Universitario de Valme, Sevilla, Spain
- * E-mail: (JDB); (MRG)
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Pathophysiology, diagnosis, and management of hepatic encephalopathy. Inflammopharmacology 2014; 22:319-26. [DOI: 10.1007/s10787-014-0217-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 09/19/2014] [Indexed: 12/23/2022]
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Hepatic Encephalopathy: From the Pathogenesis to the New Treatments. ISRN HEPATOLOGY 2014; 2014:236268. [PMID: 27335836 PMCID: PMC4890879 DOI: 10.1155/2014/236268] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 01/28/2014] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy is a frequent and serious complication of liver cirrhosis; the pathophysiology of this complication is not fully understood although great efforts have been made during the last years. There are few prospective studies on the epidemiology of this complication; however, it is known that it confers with high short-term mortality. Hepatic encephalopathy has been classified into different groups depending on the degree of hepatic dysfunction, the presence of portal-systemic shunts, and the number of episodes. Due to the large clinical spectra of overt EH and the complexity of cirrhotic patients, it is very difficult to perform quality clinical trials for assessing the efficacy of the treatments proposed. The physiopathology, clinical manifestation, and the treatment of HE is a challenge because of the multiple factors that converge and coexist in an episode of overt HE.
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Merola J, Chaudhary N, Qian M, Jow A, Barboza K, Charles H, Teperman L, Sigal S. Hyponatremia: A Risk Factor for Early Overt Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt Creation. J Clin Med 2014; 3:359-72. [PMID: 26237379 PMCID: PMC4449686 DOI: 10.3390/jcm3020359] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Revised: 03/04/2014] [Accepted: 03/07/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatic encephalopathy (HE) is a frequent complication in cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). Hyponatremia (HN) is a known contributing risk factor for the development of HE. Predictive factors, especially the effect of HN, for the development of overt HE within one week of TIPS placement were assessed. A single-center, retrospective chart review of 71 patients with cirrhosis who underwent TIPS creation from 2006–2011 for non-variceal bleeding indications was conducted. Baseline clinical and laboratory characteristics were collected. Factors associated with overt HE within one week were identified, and a multivariate model was constructed. Seventy one patients who underwent 81 TIPS procedures were evaluated. Fifteen patients developed overt HE within one week. Factors predictive of overt HE within one week included pre-TIPS Na, total bilirubin and Model for End-stage Liver Disease (MELD)-Na. The odds ratio for developing HE with pre-TIPS Na <135 mEq/L was 8.6. Among patients with pre-TIPS Na <125 mEq/L, 125–129.9 mEq/L, 130–134.9 mEq/L and ≥135 mEq/L, the incidence of HE within one week was 37.5%, 25%, 25% and 3.4%, respectively. Lower pre-TIPS Na, higher total bilirubin and higher MELD-Na values were associated with the development of overt HE post-TIPS within one week. TIPS in hyponatremic patients should be undertaken with caution.
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Affiliation(s)
- Jonathan Merola
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
| | - Noami Chaudhary
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
| | - Meng Qian
- Department of Biostatistics, New York University School of Medicine, New York, NY 10016, USA.
| | - Alexander Jow
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
| | - Katherine Barboza
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
| | - Hearns Charles
- Department of Radiology, New York University School of Medicine, New York, NY 10016, USA.
| | - Lewis Teperman
- Department of Surgery, New York University School of Medicine, New York, NY 10016, USA.
| | - Samuel Sigal
- Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA.
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Effect of glutamine synthetase inhibition on brain and interorgan ammonia metabolism in bile duct ligated rats. J Cereb Blood Flow Metab 2014; 34:460-6. [PMID: 24346692 PMCID: PMC3948122 DOI: 10.1038/jcbfm.2013.218] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 10/28/2013] [Accepted: 11/04/2013] [Indexed: 01/03/2023]
Abstract
Ammonia has a key role in the development of hepatic encephalopathy (HE). In the brain, glutamine synthetase (GS) rapidly converts blood-borne ammonia into glutamine which in high concentrations may cause mitochondrial dysfunction and osmolytic brain edema. In astrocyte-neuron cocultures and brains of healthy rats, inhibition of GS by methionine sulfoximine (MSO) reduced glutamine synthesis and increased alanine synthesis. Here, we investigate effects of MSO on brain and interorgan ammonia metabolism in sham and bile duct ligated (BDL) rats. Concentrations of glutamine, glutamate, alanine, and aspartate and incorporation of (15)NH(4)(+) into these amino acids in brain, liver, muscle, kidney, and plasma were similar in sham and BDL rats treated with saline. Methionine sulfoximine reduced glutamine concentrations in liver, kidney, and plasma but not in brain and muscle; MSO reduced incorporation of (15)NH(4)(+) into glutamine in all tissues. It did not affect alanine concentrations in any of the tissues but plasma alanine concentration increased; incorporation of (15)NH(4)(+) into alanine was increased in brain in sham and BDL rats and in kidney in sham rats. It inhibited GS in all tissues examined but only in brain was an increased incorporation of (15)N-ammonia into alanine observed. Liver and kidney were important for metabolizing blood-borne ammonia.
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Jover-Cobos M, Noiret L, Lee K, Sharma V, Habtesion A, Romero-Gomez M, Davies N, Jalan R. Ornithine phenylacetate targets alterations in the expression and activity of glutamine synthase and glutaminase to reduce ammonia levels in bile duct ligated rats. J Hepatol 2014; 60:545-53. [PMID: 24512823 DOI: 10.1016/j.jhep.2013.10.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Revised: 10/07/2013] [Accepted: 10/08/2013] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS In liver failure, ammonia homeostasis is dependent upon the function of the ammonia metabolising enzymes, glutamine synthetase (GS) and glutaminase (GA) but data about their protein expression and activity are lacking. The aims of this study were to determine the protein expression and activity of GS and GA in individual organs in a rat model of chronic liver disease and to test whether the treatment with the ammonia-lowering agent ornithine phenylacetate (OP) modulates their activities. METHODS 49 SD rats were studied 35 days after sham-operation or bile duct ligation (BDL). The BDL group received: L-ornithine (0.6 mg/kg/day), Phenylacetate (0.6 mg/kg/day), OP (0.6 mg/kg/day) or placebo (saline) for 5 days prior to sacrifice. Arterial ammonia, amino acids and liver biochemistry were measured. Expressions of GS and GA were determined by Western-blotting and activities by end-point methods in liver, muscle, gut, kidney, lung, and frontal cortex. RESULTS In BDL rats, hepatic GS enzyme activity was reduced by more than 80% compared to sham rats. Further, in BDL rats GA activity was reduced in liver but increased in the gut, muscle and frontal cortex compared to sham rats. OP treatment resulted in a reduction in hyperammonemia in BDL rats, associated with increased GS activity in the muscle and reduced gut GA activity. CONCLUSIONS In a rat model of chronic liver failure, hyperammonemia is associated with inadequate compensation by liver and muscle GS activity and increased gut GA activity. OP reduces plasma ammonia by increasing GS in the muscle and reducing GA activity in the gut providing additional insights into its mechanism of its action. GS and GA may serve as important future therapeutic targets for hyperammonemia in liver failure.
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Affiliation(s)
- M Jover-Cobos
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom
| | - L Noiret
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom; COMPLEX CoMPLEX, UCL, Gower Street, London WC1E 6BT, United Kingdom
| | - K Lee
- Royal Veterinary College, Hatfield, Hertfordshire AL9 7TA, United Kingdom
| | - V Sharma
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom
| | - A Habtesion
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom
| | - M Romero-Gomez
- CIBEREHD, UCM Digestive Diseases, Valme University Hospital, Seville, Spain
| | - N Davies
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom
| | - R Jalan
- Liver Failure Group, UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College of London (UCL), Pond Street, London, United Kingdom.
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Rockey DC, Vierling JM, Mantry P, Ghabril M, Brown RS, Alexeeva O, Zupanets IA, Grinevich V, Baranovsky A, Dudar L, Fadieienko G, Kharchenko N, Klaryts'ka I, Morozov V, Grewal P, McCashland T, Reddy KG, Reddy KR, Syplyviy V, Bass NM, Dickinson K, Norris C, Coakley D, Mokhtarani M, Scharschmidt BF. Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy. Hepatology 2014; 59:1073-83. [PMID: 23847109 PMCID: PMC4237123 DOI: 10.1002/hep.26611] [Citation(s) in RCA: 119] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Accepted: 06/22/2013] [Indexed: 12/19/2022]
Abstract
UNLABELLED Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P=0.02), time to first event (hazard ratio [HR]=0.56; P<0.05), as well as total events (35 versus 57; P=0.04), and was associated with fewer HE hospitalizations (13 versus 25; P=0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P<0.01), time to first event (HR=0.29; P<0.01), and total events (7 versus 31; P<0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. CONCLUSION GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167).
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Affiliation(s)
| | | | - Parvez Mantry
- Liver Institute at Methodist Dallas Medical CenterDallas, TX
| | | | | | - Olga Alexeeva
- Nizhny Novgorod Regional HospitalNizhny Novgorod, Russia
| | | | | | | | - Larysa Dudar
- O.O. Bogomolets, National Medical UniversityKiev, Ukraine
| | - Galyna Fadieienko
- State Institution “L.T. Malaya Institute of Therapy of NAMS of Ukraine,”Kharkiv, Ukraine
| | - Nataliya Kharchenko
- National Medical Academy of Postgraduate Education; Kiev City Clinical Hospital #8Kiev, Ukraine
| | - Iryna Klaryts'ka
- Crimean Republican Institution “M.O. Semashko Clinical Hospital,”Simferopol, Ukraine
| | | | - Priya Grewal
- Icahn School of Medicine at Mt. SinaiNew York, NY
| | | | | | | | | | - Nathan M Bass
- University of California San FranciscoSan Francisco, CA
| | | | | | - Dion Coakley
- Hyperion Therapeutics, Inc.South San Francisco, CA
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Scott TR, Kronsten VT, Hughes RD, Shawcross DL. Pathophysiology of cerebral oedema in acute liver failure. World J Gastroenterol 2013; 19:9240-9255. [PMID: 24409052 PMCID: PMC3882398 DOI: 10.3748/wjg.v19.i48.9240] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 10/28/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Cerebral oedema is a devastating consequence of acute liver failure (ALF) and may be associated with the development of intracranial hypertension and death. In ALF, some patients may develop cerebral oedema and increased intracranial pressure but progression to life-threatening intracranial hypertension is less frequent than previously described, complicating less than one third of cases who have proceeded to coma since the advent of improved clinical care. The rapid onset of encephalopathy may be dramatic with the development of asterixis, delirium, seizures and coma. Cytotoxic and vasogenic oedema mechanisms have been implicated with a preponderance of experimental data favouring a cytotoxic mechanism. Astrocyte swelling is the most consistent neuropathological finding in humans with ALF and ammonia plays a definitive role in the development of cytotoxic brain oedema. The mechanism(s) by which ammonia induces astrocyte swelling remains unclear but glutamine accumulation within astrocytes has led to the osmolyte hypothesis. Current evidence also supports an alternate ‘Trojan horse’ hypothesis, with glutamine as a carrier of ammonia into mitochondria, where its accumulation results in oxidative stress, energy failure and ultimately astrocyte swelling. Although a complete breakdown of the blood-brain barrier is not evident in human ALF, increased permeation to water and other small molecules such as ammonia has been demonstrated resulting from subtle alterations in the protein composition of paracellular tight junctions. At present, there is no fully efficacious therapy for cerebral oedema other than liver transplantation and this reflects our incomplete knowledge of the precise mechanisms underlying this process which remain largely unknown.
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48
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Zheng G, Zhang LJ, Cao Y, Pan Z, Qi RF, Ni L, Shi D, Fan X, Lu GM. Transjugular intrahepatic portosystemic shunt induced short- and long-term cerebral blood flow variations in cirrhotic patients: an arterial spin labeling MRI study. Metab Brain Dis 2013; 28:463-71. [PMID: 23564221 DOI: 10.1007/s11011-013-9400-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Accepted: 03/10/2013] [Indexed: 01/02/2023]
Abstract
Short- and long-term effects of transjugular intrahepatic portosystemic shunt (TIPS) on cerebral blood flow (CBF) in patients with cirrhosis are still unclear. The purpose of this longitudinal study was to explore CBF alteration patterns in cirrhotic patients after TIPS. Thirteen cirrhotic patients (7 male, 6 female, mean age 50.0 ± 9.3 years) underwent arterial-spin labeling (ASL) MRI 1-9 days (median 1 days) before TIPS. Follow-up MR examinations were performed about 1 week (median 6 days), 3 months (n = 6), 6-9 months (n = 5) and 12-18 months (n = 5) after TIPS. CBF, ammonia level, Child-Pugh score, number connection test type A (NCT-A) and digit symbol test (DST) scores were converted into relative values by dividing by his/her pre-TIPS values, and then, compared via one-way analysis of variance (ANOVA). Correlations between the pre- and post-TIPS changes of relative CBF (rCBF) and the changes of relative ammonia (rAmmonia), Child-Pugh (rChild-Pugh), and NCT-A/DST (rNCT-A/rDST) scores were calculated by crossing subjects. Compared with the pre-TIPS level, the global rCBF slightly increased by 10.9 % about 1 week later, then rapidly decreased by 14.2 % 3 months later, and flatly decreased by 17.2 % in 6-9 months and 18.0 % in 12-18 months following TIPS. The changes of 3-month rDST score were slightly correlated with 3-month rCBF rather than 1-week rCBF, (P < 0.1, FDR-corrected) No difference was found between the pre- and post-TIPS rAmmonia levels, rChild-Pugh and rNCT-A/rDST scores (Post-hoc P > 0.05). CBF measured at different time points after TIPS insertion showed different patterns, indicating varying longitudinal effects of TIPS on CBF. A sharp decline of rCBF was found in the 1 week to 3 months period after insertion, indicating that high event rate of hepatic encephalopathy might relate with the unadaptable CBF in patients undergoing TIPS insertion.
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Affiliation(s)
- Gang Zheng
- College of civil aviation, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, 210016, China
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Dam G, Keiding S, Munk OL, Ott P, Vilstrup H, Bak LK, Waagepetersen HS, Schousboe A, S⊘rensen M. Reply: To PMID 22886493. Hepatology 2013; 58:833-4. [PMID: 23280960 DOI: 10.1002/hep.26149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Accepted: 11/01/2012] [Indexed: 12/07/2022]
Affiliation(s)
- Gitte Dam
- Department of Nuclear Medicine & PET Center; Aarhus University Hospital; Aarhus Denmark
| | - Susanne Keiding
- Department of Nuclear Medicine & PET Center; Aarhus University Hospital; Aarhus Denmark
- Department of Hepato-Gastroenterology; Aarhus University Hospital; Aarhus Denmark
| | - Ole L. Munk
- Department of Nuclear Medicine & PET Center; Aarhus University Hospital; Aarhus Denmark
| | - Peter Ott
- Department of Hepato-Gastroenterology; Aarhus University Hospital; Aarhus Denmark
| | - Hendrik Vilstrup
- Department of Hepato-Gastroenterology; Aarhus University Hospital; Aarhus Denmark
| | - Lasse K. Bak
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - Helle S. Waagepetersen
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - Arne Schousboe
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Copenhagen Denmark
| | - Michael S⊘rensen
- Department of Nuclear Medicine & PET Center; Aarhus University Hospital; Aarhus Denmark
- Department of Hepato-Gastroenterology; Aarhus University Hospital; Aarhus Denmark
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Zheng G, Zhang LJ, Cao Y, Lu GM. Venous blood ammonia can be associated with cerebral blood flow in hepatic encephalopathy. Hepatology 2013; 58:832-3. [PMID: 23172676 DOI: 10.1002/hep.26148] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/14/2012] [Indexed: 12/07/2022]
Affiliation(s)
- Gang Zheng
- Department of Medical Imaging; Jinling Hospital; Clinical School of Medical College; Nanjing University; Nanjing China
- College of Civil Aviation; Nanjing University of Aeronautics and Astronautics; Nanjing China
| | - Long Jiang Zhang
- Department of Medical Imaging; Jinling Hospital; Clinical School of Medical College; Nanjing University; Nanjing China
| | - Yue Cao
- Kreiger School of Arts and Science; Johns Hopkins University; Baltimore MD
| | - Guang Ming Lu
- Department of Medical Imaging; Jinling Hospital; Clinical School of Medical College; Nanjing University; Nanjing China
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