Hadjihambi Anna, Cudalbu Cristina, Pierzchala Katarzyna, Simicic Dunja, Donnelly Chris, Konstantinou Christos, Davies Nathan, Habtesion Abeba, Gourine Alexander V, Jalan Rajiv, Hosford Patrick S
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.
JHEP Rep. 2022 May 24;4(8):100509. doi: 10.1016/j.jhepr.2022.100509. eCollection 2022 Aug.
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.
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.
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 CO was found to be normal in BDL animals.
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.
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.
血浆氨浓度升高及随之而来的脑能量代谢紊乱可能是肝性脑病（HE）发病机制的基础。脑能量稳态依赖于脑氧合的有效维持，而调节异常会损害神经元功能，导致认知障碍。我们推测HE与脑氧合降低有关，并探讨了氨作为潜在病理生理因素的作用。
在轻度HE（mHE；胆管结扎[BDL]）的慢性肝病大鼠模型中，采用脑组织氧测量和质子磁共振波谱技术，研究高氨血症如何影响中枢神经系统的氧合和代谢底物可用性。使用苯乙酸鸟氨酸（OP，OCR - 002；美国加利福尼亚州Ocera Therapeutics公司）作为实验性治疗手段来降低血浆氨浓度。
在BDL动物中，大脑皮质中的葡萄糖、乳酸和组织氧浓度显著低于假手术对照组。OP治疗纠正了高氨血症并恢复了脑组织氧含量。尽管BDL动物存在低血压，但通过提高动脉血压的治疗，皮质组织氧浓度得到了显著改善。发现BDL动物对外源性应用CO的脑血管反应性正常。
这些数据表明，高氨血症显著降低皮质氧合，可能损害脑能量代谢。这些发现对mHE患者的治疗具有潜在的临床意义。
脑功能障碍是肝硬化的严重并发症，约30%的肝硬化患者受其影响；然而，其治疗仍是未满足的临床需求。本研究表明，肝硬化动物模型脑中的氧浓度明显降低。低动脉血压和氨（一种在肝衰竭患者体内蓄积的神经毒素）增加被证明是主要潜在原因。对这些异常进行实验性纠正可恢复脑中的氧浓度，提示了潜在的治疗途径有待探索。
