Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Crit Care Med. 2011 Nov;39(11):2550-3. doi: 10.1097/CCM.0b013e31822572fd.
Hyperammonemia is a major contributing factor to the encephalopathy associated with liver disease. It is now generally accepted that hyperammonemia leads to toxic levels of glutamine in astrocytes. However, the mechanism by which excessive glutamine is toxic to astrocytes is controversial. Nevertheless, there is strong evidence that glutamine-induced osmotic swelling, especially in acute liver failure, is a contributing factor: the osmotic gliopathy theory. The object of the current communication is to present evidence for the osmotic gliopathy theory in a hyperammonemic patient who overdosed on acetaminophen.
Case report.
Johns Hopkins Hospital.
A 22-yr-old woman who, 36 hrs before admission, ingested 15 g acetaminophen was admitted to the Johns Hopkins Hospital. She was treated with N-acetylcysteine. Physical examination was unremarkable; her mental status was within normal limits and remained so until approximately 72 hrs after ingestion when she became confused, irritable, and agitated.
She was intubated, ventilated, and placed on lactulose. Shortly thereafter, she was noncommunicative, unresponsive to painful stimuli, and exhibited decerebrate posturing. A clinical diagnosis of cerebral edema and increased intracranial pressure was made. She improved very slowly until 180 hrs after ingestion when she moved all extremities. She woke up shortly thereafter.
Despite the fact that hyperammonemia is a major contributing factor to the encephalopathy observed in acute liver failure, the patient's plasma ammonia peaked when she exhibited no obvious neurologic deficit. Thereafter, her plasma ammonia decreased precipitously in parallel with a worsening neurologic status. She was deeply encephalopathic during a period when her liver function and plasma ammonia had normalized. Plasma glutamine levels in this patient were high but began to normalize several hours after plasma ammonia had returned to normal. The patient only started to recover as her plasma glutamine began to return to normal.
We suggest that the biochemical data are consistent with the osmotic gliopathy theory--high plasma ammonia leads to high plasma glutamine--an indicator of excess glutamine in astrocytes (the site of brain glutamine synthesis). This excess glutamine leads to osmotic stress in these cells. The lag in recovery of brain function presumably reflects time taken for the astrocyte glutamine concentration to return to normal. We hypothesize that an inhibitor of brain glutamine synthesis may be an effective treatment modality for acute liver failure.
血氨升高是肝性脑病的主要致病因素。目前普遍认为，血氨升高会导致星形胶质细胞中谷氨酰胺毒性水平升高。然而，过量谷氨酰胺对星形胶质细胞有毒性的机制仍存在争议。尽管如此，仍有强有力的证据表明，谷氨酰胺诱导的渗透压肿胀，特别是在急性肝衰竭中，是一个致病因素：渗透压性神经病变理论。本通讯的目的是在一名过量服用对乙酰氨基酚的高氨血症患者中为渗透压性神经病变理论提供证据。
病例报告。
约翰霍普金斯医院。
一名 22 岁女性，入院前 36 小时摄入 15 克对乙酰氨基酚，被收入约翰霍普金斯医院。她接受了 N-乙酰半胱氨酸治疗。体格检查无明显异常；她的精神状态正常，直到摄入后约 72 小时，她变得混乱、易怒和激动。
她被插管、通气并使用乳果糖。此后不久，她无法交流，对疼痛刺激无反应，并表现出去脑强直姿势。临床诊断为脑水肿和颅内压增高。她恢复得非常缓慢，直到摄入后 180 小时，她才移动四肢。此后不久，她醒了过来。
尽管血氨升高是急性肝衰竭患者观察到的脑病的主要致病因素，但患者的血浆氨在出现明显神经功能缺陷之前达到峰值。此后，她的血浆氨急剧下降，与神经状态恶化同步。当她的肝功能和血浆氨恢复正常时，她的脑病非常严重。该患者的血浆谷氨酰胺水平较高，但在血浆氨恢复正常数小时后开始恢复正常。患者仅在血浆谷氨酰胺开始恢复正常时才开始恢复。
我们认为生化数据与渗透压性神经病变理论一致——高血浆氨导致高血浆谷氨酰胺——这是星形胶质细胞中过量谷氨酰胺的指标（脑内谷氨酰胺合成部位）。这种过量的谷氨酰胺导致这些细胞中的渗透压应激。脑功能恢复的延迟可能反映了星形胶质细胞谷氨酰胺浓度恢复正常所需的时间。我们假设脑内谷氨酰胺合成抑制剂可能是急性肝衰竭的有效治疗方法。
