摘要：急性肝衰竭的特点在神经病理学上是细胞毒性脑水肿，在生物化学上是脑内的氨及其解毒产物谷氨酰胺的升高。在星形胶质细胞中合成增多的谷氨酰胺的渗透作用通常被认为是与脑水肿以及急性肝衰竭的并发症（脑内的解毒产物引起颅内高压，脑疝）密切相关。然而很多论文应用多核的(1)h-，(13)c-nmr光谱学证明，在急性肝衰竭时谷氨酰胺的浓度及谷氨酸盐的合成速率与肝性脑病的分期及脑水肿均无关。现在提出另一种机制，在急性肝衰竭中星形胶质细胞新合成的谷氨酸盐是对谷氨酸盐具有高亲和力的转运体SNAT5下调的结果。在急性肝衰竭时，细胞水肿/脑水肿可能由于谷氨酰胺从细胞内转运出细胞外减少并非是由于合成增加所致。而且，谷氨酰胺从星形胶质细胞转运至谷氨酸能神经末梢（在谷氨酸能神经末梢谷氨酸盐为谷氨酸盐转运工具的直接前体）的减少，导致兴奋性传导的降低和过度的神经抑制，这正是急性肝衰竭时肝性脑病的特点。 尽管现在人们重新认为在急性肝衰竭时动脉血氨可以作为颅内压升高和脑疝形成的一个预测指标，然而，矛盾的是，至今为止一些降低肠道内氨的物质对阻止氨对脑的影响的价值是有限的。无论在试验中还是急性肝衰竭患者中，略微降低体温可阻止脑水肿和颅内高血压的发生，而且降低体温对颅内谷氨酸盐合成所产生的独立影响也证表了这一点。然而低体温是否能够恢复ALF中SNAT5的表达水平，这一点还有待进一步研究。颅内谷氨酸盐抑制剂，如methionine sulfoximine，己被推荐用于ALF中脑水肿的预防，但是由于其潜在的不良反应，其适用性受到了一定的限制。
吉林大学第一医院肝胆胰内科 刘素英 摘译
本文首次发表于[Neurochem Int. 2012 Feb 21]
Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: Role of glutamine redefined
Abstract：
Acute liver failure (ALF) is characterized neuropathologically by cytotoxic brain edema and biochemically by increased brain ammonia and its detoxification product, glutamine. The osmotic actions of increased glutamine synthesis in astrocytes are considered to be causally related to brain edema and its complications (intracranial hypertension, brain herniation) in ALF.However studies using multinuclear (1)H- and (13)C-NMR spectroscopy demonstrate that neither brain glutamine concentrations per se nor brain glutamine synthesis rates correlate with encephalopathy grade or the presence of brain edema in ALF. An alternative mechanism is now proposed whereby the newly synthesized glutamine is trapped within the astrocyte as a consequence of down-regulation of its high affinity glutamine transporter SNAT5 in ALF. Restricted transfer out of the cell rather than increased synthesis within the cell could potentially explain the cell swelling/brain edema in ALF. Moreover, the restricted transfer of glutamine from the astrocyte to the adjacent glutamatergic nerve terminal (where glutamine serves as immediate precursor for the releasable/transmitter pool of glutamate) could result in decreased excitatory transmission and excessive neuroinhibition that is characteristic of encephalopathy in ALF. Paradoxically, in spite of renewed interest in arterial ammonia as a predictor of raised intracranial pressure and brain herniation in ALF, ammonia-lowering agents aimed at reduction of ammonia production in the gut have so far been shown to be of limited value in the prevention of these cerebral consequences . Mild hypothermia, shown to prevent brain edema and intracranial hypertension in both experimental and human ALF, does so independent of effects on brain glutamine synthesis; whether or not hypothermia restores expression levels of SNAT5 in ALF awaits further studies.While inhibitors of brain glutamine synthesis such as methionine sulfoximine, have been proposed for the prevention of brain edema in ALF, potential adverse effects have so far limited their applicability.
