PATHOGENESIS OF HEPATIC COMA

拟议中的研究集中在氨作为神经学疾病的主要原因。 急性和慢性肝病引起的并发症。我们的假设 是病变的肝脏不能将氨从循环中排出 引起中枢神经递质(乙酰胆碱、谷氨酸、GABA)异常 降低的等价物的功能、能量代谢和细胞内转运 通过苹果酸-天冬氨酸穿梭从细胞质到线粒体。它更远了 提出，随着时间的推移，高氨血症会导致蛋白质周转受到抑制 在脑内，血脑屏障功能异常与脑出血的发生发展 大脑对氨、缺氧和其他叠加因素的敏感性增加 代谢压力。氨对这些重要神经化学物质的干扰 过程被认为是导致典型的神经病理图像的原因 慢性肝性脑病。为了检验这些假设，我们选择了一个 多方面的方法：1)检查大脑摄取和代谢 门腔分流术大鼠和病人体内13N-氨和13N-氨基酸的变化 有肝病；2)判断急性和慢性的影响 有或没有叠加缺氧或氨负荷的高氨血症 脑血流，氧化能量偶联，碳水化合物代谢，以及 乙酰胆碱周转；3)阐明α-酮戊二酸和乙酰胆碱的作用 与实验性肝昏迷症状有关的其他α-酮酸； 和4)评估慢性门体分流的影响和 高氨血症对脑内蛋白质合成和降解速度的影响 血脑屏障对氨基酸和其他物质的渗透性。它 预计这些调查将澄清 氨会引起神经毒性，并将提出更有效的方法来预防 这种毒性作用于肝病患者。

The proposed research focuses upon ammonia as a prime cause of the neurological complications arising from both acute and chronic liver desease. Our hypothesis is that failure of the diseased liver to remove ammonia from the circulation causes CNS abnormalities of neurotransmitter (acetylcholine, glutamate, GABA) function, energy metabolism, and intracellular transport of reduced equivalents from cytoplasm to mitochondrion via the malate-aspartate shuttle. It is further proposed that, with time, hyperammonemia leads to inhibition of protein turnover in brain, abnormalities of blood-brain barrier function, and the development of an increased cerebral "sensitivity" to ammonia, hypoxia, and other superimposed metabolic stresses. Interference by ammonia with these vital neurochemical processes is believed to give rise to the typical neuropathological picture of chronic hepatic encephalopathy. To test these hypotheses, we have chosen a multifaceted approach: 1) To examine the cerebral uptake and metabolism of 13N-ammonia and 13N-amino acids in rats with portacaval shunts and in patients with liver disease; 2) To determine the effect of acute and chronic hyperammonemia, with and without superimposed hypoxia or ammonia loading, upon cerebral blood flow, oxidative energy coupling, carbohydrate metabolism, and acetylcholine turnover; 3) To clarify the role of alpha-ketoglutaramate and of other alpha-keto acids in relation to the symptoms of experimental hepatic coma; and 4) To assess the effects of chronic portal-systemic shunting and hyperammonemia on the rates of protein synthesis and degradation in brain and on the permeability of the blood-brain barrier to amino acids and other agents. It is anticipated that these investigations will clarify the mechanisms by which ammonia causes neurotoxicity and will suggest more effective methods to prevent this toxicity in patients with liver disease.