Zwingmann Claudia, Butterworth Roger
Neuroscience Research Unit, Hôpital Saint-Luc, 1058 St.-Denis Street, Montreal, Que., Canada H2X 3J4.
Neurochem Int. 2005 Jul;47(1-2):19-30. doi: 10.1016/j.neuint.2005.04.003.
Ammonia is a neurotoxin that is implicated in the pathogenesis of hepatic encephalopathy due to acute and chronic liver failure. However, its relation to neurological damage and brain edema is poorly understood. During the last decades, it has been the prevailing hypothesis that an osmotic disturbance induced by the astrocytic accumulation of glutamine leads to brain edema. However, various findings are at variance with this hypothesis. The present review will discuss: (a) correlation of ammonia with encephalopathy and brain edema in HE; (b) glutamine synthesis and astrocyte swelling; (c) glutamine synthesis and the glutamine-cycle: relation to brain energy metabolism; (d) glutamine synthesis and the glutamate-glutamine cycle and its relation to anaplerotic activity; (e) evidence favouring the "glutamine hypothesis"; (f) evidence contradicting the "glutamine hypothesis"; (g) glutamine synthesis and osmoregulation; (h) glutamine synthesis in chronic liver failure; (i) impaired brain energy metabolism in acute liver failure (ALF) and its relation to astrocytic glutamine synthesis. Taken together, the precise role of glutamine in the development of brain edema in ALF remains unclear. Astrocytic changes due to glutamine accumulation may lead secondarily to effects on brain energy metabolism. However, the relation between impaired energy metabolism and glutamine accumulation has not been well established. It is noteworthy that no single biochemical factor appears to be responsible for the many symptoms of HE. For example, brain glutamine accumulation and low-grade brain edema occur in chronic liver failure (CLF) suggesting common mechanisms are responsible for the neurological dysfunction in CLF and ALF. Recent NMR spectroscopic studies have provided considerably new information in this area. Future NMR studies using the stable isotope 13C may be useful in the study of the dynamics of brain metabolism in patients with ALF so as to better elucidate the precise role of glutamine accumulation and of glutamine-independent components to brain edema in ALF.
氨是一种神经毒素，与急性和慢性肝衰竭所致肝性脑病的发病机制有关。然而，其与神经损伤和脑水肿的关系尚不清楚。在过去几十年里，普遍的假说是星形胶质细胞中谷氨酰胺的积累引起渗透紊乱，进而导致脑水肿。然而，各种研究结果与这一假说并不一致。本综述将讨论：(a) 氨与肝性脑病中脑病和脑水肿的相关性；(b) 谷氨酰胺合成与星形胶质细胞肿胀；(c) 谷氨酰胺合成与谷氨酰胺循环：与脑能量代谢的关系；(d) 谷氨酰胺合成与谷氨酸-谷氨酰胺循环及其与回补反应活性的关系；(e) 支持“谷氨酰胺假说”的证据；(f) 与“谷氨酰胺假说”相矛盾的证据；(g) 谷氨酰胺合成与渗透压调节；(h) 慢性肝衰竭中的谷氨酰胺合成；(i) 急性肝衰竭（ALF）中脑能量代谢受损及其与星形胶质细胞谷氨酰胺合成的关系。综上所述，谷氨酰胺在急性肝衰竭脑水肿发生过程中的具体作用仍不清楚。谷氨酰胺积累引起的星形胶质细胞变化可能继而影响脑能量代谢。然而，能量代谢受损与谷氨酰胺积累之间的关系尚未明确确立。值得注意的是，似乎没有单一的生化因素能解释肝性脑病的众多症状。例如，慢性肝衰竭（CLF）中出现脑谷氨酰胺积累和轻度脑水肿，提示CLF和ALF中的神经功能障碍有共同机制。最近的核磁共振波谱研究在这一领域提供了大量新信息。未来使用稳定同位素13C的核磁共振研究可能有助于研究急性肝衰竭患者脑代谢的动态变化，从而更好地阐明谷氨酰胺积累和谷氨酰胺非依赖性成分在急性肝衰竭脑水肿中的具体作用。
