Abnormal brain oxygen homeostasis in an animal model of liver disease
Anna Hadjihambi,
Cristina Cudalbu,
Katarzyna Pierzchala,
Dunja Simicic,
Chris Donnelly,
Christos Konstantinou,
Nathan Davies,
Abeba Habtesion,
Alexander V. Gourine,
Rajiv Jalan,
Patrick S. Hosford
Affiliations
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; The Roger Williams Institute of Hepatology London, Foundation for Liver Research, London, UK. Tel.: (+44) 207 255 9852.
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; Corresponding author. Addresses: William Harvey Heart Centre, Barts and The London School of Medicine and Dentistry, London EC1M 6BQ, UK
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.
