Liver Failure Group Institute for Liver and Digestive Health, Division of Medicine, UCL Medical School, Royal Free Hospital, Rowland Hill Street, NW3 2PF London, UK; Centre for Cardiovascular and Metabolic Neuroscience, Neuroscience, Physiology and Pharmacology, University College London, WC1E 6BT London, UK.
UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, WC1E 6BT London, UK.
J Hepatol. 2019 Jan;70(1):40-49. doi: 10.1016/j.jhep.2018.08.021. Epub 2018 Sep 8.
BACKGROUND & AIMS: Neuronal function is exquisitely sensitive to alterations in the extracellular environment. In patients with hepatic encephalopathy (HE), accumulation of metabolic waste products and noxious substances in the interstitial fluid of the brain is thought to result from liver disease and may contribute to neuronal dysfunction and cognitive impairment. This study was designed to test the hypothesis that the accumulation of these substances, such as bile acids, may result from reduced clearance from the brain.
In a rat model of chronic liver disease with minimal HE (the bile duct ligation [BDL] model), we used emerging dynamic contrast-enhanced MRI and mass-spectroscopy techniques to assess the efficacy of the glymphatic system, which facilitates clearance of solutes from the brain. Immunofluorescence of aquaporin-4 (AQP4) and behavioural experiments were also performed.
We identified discrete brain regions (olfactory bulb, prefrontal cortex and hippocampus) of altered glymphatic clearance in BDL rats, which aligned with cognitive/behavioural deficits. Reduced AQP4 expression was observed in the olfactory bulb and prefrontal cortex in HE, which could contribute to the pathophysiological mechanisms underlying the impairment in glymphatic function in BDL rats.
This study provides the first experimental evidence of impaired glymphatic flow in HE, potentially mediated by decreased AQP4 expression in the affected regions.
The 'glymphatic system' is a newly discovered brain-wide pathway that facilitates clearance of various substances that accumulate in the brain due to its activity. This study evaluated whether the function of this system is altered in a model of brain dysfunction that occurs in cirrhosis. For the first time, we identified that the clearance of substances from the brain in cirrhosis is reduced because this clearance system is defective. This study proposes a new mechanism of brain dysfunction in patients with cirrhosis and provides new targets for therapy.
神经元功能对外界环境的变化极其敏感。在肝性脑病（HE）患者中，认为脑间质液中代谢废物和有害物质的积累是由肝脏疾病引起的，可能导致神经元功能障碍和认知障碍。本研究旨在验证这样一个假设，即这些物质（如胆汁酸）的积累可能是由于大脑清除能力降低所致。
在一种具有最小 HE 的慢性肝病大鼠模型（胆管结扎[BDL]模型）中，我们使用新兴的动态对比增强 MRI 和质谱技术来评估糖质系统的疗效，该系统有助于溶质从大脑中清除。还进行了水通道蛋白-4（AQP4）的免疫荧光和行为学实验。
我们在 BDL 大鼠中发现了糖质清除作用改变的离散脑区（嗅球、前额叶皮层和海马体），这与认知/行为缺陷一致。在 HE 中观察到嗅球和前额叶皮层 AQP4 表达减少，这可能导致 BDL 大鼠糖质功能障碍的病理生理机制。
这项研究提供了 HE 中糖质流受损的首个实验证据，这可能是受影响区域中 AQP4 表达降低所致。
糖质系统是一种新发现的大脑广泛途径，可促进由于其活动而在大脑中积累的各种物质的清除。本研究评估了该系统在发生肝硬化的大脑功能障碍模型中是否发生改变。我们首次发现，由于该清除系统有缺陷，肝硬化患者大脑中物质的清除减少。这项研究提出了肝硬化患者大脑功能障碍的新机制，并为治疗提供了新的靶点。
