修回日期: 2012-07-30
接受日期: 2012-08-11
在线出版日期: 2012-09-08
肝性脑病(hepatic encephalopathy, HE)是肝功能严重障碍和/或门体分流术后患者发生的以代谢紊乱为基础, 神经、精神症状为主要表现的综合征. 其症状包括意识混乱、定向力障碍、协调能力降低, 甚至昏迷. 其发病机制被认为是高氨血症使脑星形胶质细胞内谷氨酰胺浓度升高、钙离子内流启动氧化应激、破坏线粒体功能, 干扰能量代谢并诱发炎症反应, 破坏血脑屏障使内皮细胞、脑星形胶质细胞对水通透性增加, 引发脑水肿. 炎症反应又反过来升高脑内氨浓度, 增加其中枢神经系统毒性, 而锰是参与上述过程的重要组成成分, 故目前公认为高氨血症和炎症反应的协同作用导致星形胶质细胞肿胀, 进而引起脑水肿导致HE. 本文就HE发病机制的研究进展作一综述.
引文著录: 张玉波. 肝性脑病发病机制的研究进展. 世界华人消化杂志 2012; 20(25): 2358-2363
Revised: July 30, 2012
Accepted: August 11, 2012
Published online: September 8, 2012
Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of both acute and chronic liver diseases. Symptoms of HE can include confusion, disorientation, poor coordination, and even coma. The pathogenesis of HE was thought to involve the increase in blood levels of ammonia, which increases the intracellular levels of glutamine, promotes calcium influx and initiates oxidative stress, destroys the function of mitochondria, disrupts energy metabolism and causes inflammation, destroys blood brain barrier, increases the water permeability of brain endothelial cells and astrocytes, and then induces brain edema. While, inflammation, in turn, raises the ammonia levels in the brain, which is toxic to the central nervous system. Manganese is an important component which participates in the above processes. A general consensus exists that the synergistic effects of excess ammonia and inflammation cause astrocyte swelling and cerebral edema; however, the precise molecular mechanisms that lead to these morphological changes in the brain are unclear. This article will summarize the research progress in understanding the pathogenesis of HE.
- Citation: Zhang YB. Progress in understanding the pathogenesis of hepatic encephalopathy. Shijie Huaren Xiaohua Zazhi 2012; 20(25): 2358-2363
- URL: https://www.wjgnet.com/1009-3079/full/v20/i25/2358.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i25.2358
肝性脑病(hepatic encephalopathy, HE)是肝功能严重障碍和/或门体分流术后患者发生的以代谢紊乱为基础, 神经、精神症状为主要表现的综合征. 患者可出现不同程度的意识、智力、定向力、情感、行为以及精细运动等改变. 根据临床症状的轻重分为症状明显型HE(overt hepatic encephalopathy, OHE)和轻微型HE(minimal hepatic encephalopathy, MHE). OHE可经临床试验检测到神经、精神异常, 而MHE的神经、精神学临床检查则基本正常, 需特异的心理智能测试则可发现异常. 1998年, 第11界世界胃肠大会工作小组将HE分为3种主要类型: A型为急性肝衰竭相关型, 不包括慢性肝病伴发的急性HE; B型为门体分流相关型, 肝活检证实肝组织学正常; C型指在慢性肝病或肝硬化基础上发生的HE. C型又进一步细分为发作性HE、持续性HE和轻微性HE[1].
数十年来氨中毒学说一直被认为是HE的主要发病机制. 但近年来研究发现, HE的发病存在着其他致病因素, 如炎症反应、神经类固醇、氧化应激和锰中毒等. 发现HE患者脑组织有星形胶质细胞肿胀的病理改变. 虽然HE发病的确切分子机制还不清楚, 但普遍认为在氨、炎症反应、氧化应激等因素的共同作用下, 脑星形胶质细胞肿胀, 进而导致脑水肿, 可解释HE的主要临床表现. 现就其发病机制作一综述.
血氨浓度升高作为HE的发病机制早已得到广泛关注. 18世纪初期, Shawcross等[2]在狗体内制造门腔静脉瘘, 致受试狗表现出神经精神改变. 而对狗喂食肉类可加重其症状, 从而将该类症状命名为肉毒性综合征. 在20世纪末, Phillips等详细描述了肝功能不全患者的行为改变. 1991年, Prakash等[3]应用放射性标记的氮, 对重症肝病和MHE患者进行了PET影像学研究中, 找到了血氨增高是肝性脑病发病机制的直接证据.
血氨有两种主要来源: 一是来源于结肠内肠道菌群, 如革兰阴性厌氧菌、肠杆菌、变形菌、梭菌属等, 细菌尿素酶分解尿素为氨和二氧化碳. 由于肝硬化患者肠壁水肿, 蠕动功能减退使细菌增多, 其分解代谢的氨增多; 二是来源于小肠的肠上皮细胞, 肠上皮细胞通过肠内谷氨酰胺酶分解谷氨酰胺, 产生氨及谷氨酸[4]. 其证据来自西班牙学者的研究: 他们发现肝硬化患者尤其是MHE患者体内编码谷氨酰胺酶的基因上调[5]. 发现导致谷氨酰胺酶活性增加的基因增强子区域存在特定变异, 使肝硬化患者发生OHE的几率增加[6].
哺乳动物体内氨代谢途径主要有3种: (1)经肝代谢, 源于肠道的氨由内脏静脉网进入肝脏, 经过鸟氨酸循环代谢为无毒且具有水溶性的尿素, 由肾排出. 而肝功能受损时, 血氨经鸟氨酸循环代谢减少; 门体分流时, 血氨绕过肝脏代谢, 经血脑屏障入脑; (2)经肾脏代谢, 氨以尿素或铵离子(NH4+)形式经尿排出体外, 该途径受pH值影响较大, 肝硬化易发生碱中毒, 使铵离子转化为气态氨增多, 后者易通过血脑屏障, 从而加重HE. 此外, 肝硬化患者常因腹泻、过度利尿, 发生肾灌注不足, 肾小球滤过率下降, 肾脏排氨能力减弱. 而单纯的盐水输注即可改善患者的肾脏排氨[7]; (3)经骨骼肌细胞代谢, 肌细胞内谷氨酰胺合成酶将氨合成为谷氨酰胺, 肝硬化患者多存在肌肉萎缩, 使谷氨酰胺合成障碍, 影响氨的代谢[8].
目前认为氨造成脑毒性的机制为: 一是氨通过血脑屏障进入颅内, 星形胶质细胞是脑内唯一能代谢氨的细胞[9], 其内质网内的谷氨酰胺合成酶, 催化等摩尔的谷氨酸和氨合成谷氨酰胺, 致使星形胶质细胞内生成的谷氨酰胺明显升高. 谷氨酰胺具有胶体渗透性, 可吸引水分子进入细胞内引起细胞肿胀、脑水肿及颅内高压. 在动物实验中, 给予谷氨酰胺合成酶抑制剂甲硫氨酸亚矾胺可预防星形胶质细胞肿胀[10,11]. 体外试验使星形胶质细胞突然暴露于高浓度氨(基本类同于急性肝衰竭和A型HE患者脑内氨浓度)中, 将导致谷氨酸的大量释放[12,13]. 由于后者属兴奋性神经递质, 临床上A型HE患者则出现易激惹, 混乱、癫痫样发作和昏迷等症状. C型HE的特征性临床表现是轻度脑水肿和神经抑制状态[14,15]. 星形胶质细胞在高浓度氨中暴露时间延长, 将导致一系列变化: (1)细胞内渗透性物质如肌醇和牛磺酸释放增多, 可部分代偿星形胶质细胞的肿胀[16]. 这种内环境的稳态机制, 可导致细胞内肌醇储备减少, 使HE突然恶化[17]; (2)突触后板的谷氨酰胺受体活性降低, 星形胶质细胞膜上的谷氨酰胺载体失活[18], 随着时间延长, 这些细胞转化成阿尔茨海默Ⅱ型星形胶质细胞[19]; 二是研究表明, 氨可使星形胶质细胞钙离子内流增加, 直接启动氧化及硝基化应激, 导致线粒体功能障碍, 并通过开放线粒体通透性转换孔导致能量丢失. 他还可诱导RNA发生氧化作用, 激活细胞丝裂原活化蛋白激酶及NF-κB, 导致炎症反应、损害细胞内信号通路, 发生神经系统功能障碍[20]; 三是氨的直接毒性作用还包括: 导致抑制性与兴奋性神经递质比例失调, 终使抑制性神经递质含量增加; 干扰脑细胞能量代谢; 改变基因表达, 使维持大脑正常功能的蛋白发生异常改变; 损害颅内血流的自动调节功能[21].
氨代谢障碍并不能独立解释HE的所有神经改变[22]. 研究表明, 高氨血症联合炎症反应或其他神经毒性分子可诱发HE. Toll样受体4(toll-like receptor 4, TLR-4)可识别革兰氏阴性菌, 而肝硬化患者TLR-4结构发生多态性改变, 产生炎症反应, 使中性粒细胞过度激活, 释放多种炎症因子, 增加HE的发生率[23]. Shawcross等[24]给患有全身炎症反应综合征(systemic inflammatory response syndrome, SIRS)的肝硬化患者口服氨基酸溶液诱导出高氨血症, 使这些患者的心理测试结果加重. 一旦患者的SIRS或感染得到及时控制(如应用亚低温处理或布洛芬、吲哚美辛治疗), 炎症反应标记物如肿瘤坏死因子(tumor necrosis factor, TNF)和白细胞介素(interleukin, IL)-1、血氨的水平将恢复正常, 患者的心理测试结果也不会因被诱导高氨血症而加重. 另一组大样本的研究, 通过检测肝硬化患者血氨以及炎症反应标记物水平, 得到了与Shawcross研究类似的结论, 均提示炎症反应和炎症因子在HE发病机制中发挥重要作用. MHE的发生及严重程度与血氨水平及肝病严重程度无相关性, 但MHE患者血清中炎症反应标记物(如C反应蛋白、白细胞计数、IL-6)水平却明显高于无HE的患者[25].
研究表明, 星形胶质细胞和小神经胶质细胞在受到炎症刺激时释放炎症因子如IL-1、IL-6时, TNF的水平也同样升高. 而TNF、IL-1β都能损害脑血管内皮细胞, 影响血脑屏障神经胶质细胞面的完整性[26]. 体外研究表明, TNF和IL-6能提高离体脑组织内皮细胞对水的通透性, TNF可促进血氨弥散进入星形胶质细胞, 进一步加重星形胶质细胞的肿胀. 在对急性肝衰竭的研究中发现, 使TNF-α或IL-1受体基因缺失, 可抑制炎症反应, 延迟HE的发生, 减轻脑水肿[27].
炎症反应激活小神经胶质细胞, 使转位蛋白(又称为边缘型苯二氮卓类受体)表达上调, 从而导致线粒体内神经类固醇合成增多[28]. 已证明神经类固醇参与HE的发病机制[29]. 神经类固醇可在中枢或外周神经系统合成, 原料来自胆固醇或类固醇前体(由性腺和肾上腺产生的类固醇激素的代谢物). 脑内的神经类固醇主要在星形胶质细胞的线粒体内质网合成[30]. 神经胶质细胞线粒体膜上的转位蛋白可调控神经类固醇的合成[31,32]. 肝衰竭患者体内增多的氨和锰, 使转位蛋白表达增加, 促进神经类固醇的合成. 尸检发现肝硬化患者脑内转位蛋白表达增加[33]. Cagnin等[28]应用特异转位蛋白配体对患有MHE患者PET成像, 发现转位蛋白的密度也是增加的. 神经类固醇参与HE发病的机制可能为: (1)改变神经递质信号传递, 神经类固醇是γ-氨基丁酸受体的正性变构调节剂, 可以增加氯离子细胞内流, 增强γ-氨基丁酸能的作用, 使神经元γ-氨基丁酸的突触后膜抑制功能增强, 脑干网状结构唤醒机制被打破, 产生中枢抑制效应, 产生C型HE的临床表现, 如神志改变和昏迷等; (2)改变基因表达, 神经类固醇使星形胶质细胞内胶质纤维酸性蛋白, 胞内葡萄糖、谷氨酸、甘氨酸的载体, 单胺氧化酶、一氧化氮合成酶等发生改变[34]. 但具体分子机制和信号途径有待进一步明确.
大量研究证明, 氨可以诱导氧化应激, 将分离的小鼠星形胶质细胞暴露于高浓度氨中培养, 可引起细胞外谷氨酸盐浓度升高, 谷氨酸盐激活N-甲基-D天冬氨酸受体, 生成大量活性氮族(reactive nitrogen species, RNS)和活性氧族(reactive oxygen species, ROS), 发生氧化应激损伤, 加重HE[35,36]. 2006年Albrecht[37]等提出"特洛伊木马"假说用来解释谷氨酰胺对星形胶质细胞的毒性作用, 认为高氨环境中的星形胶质细胞内, 产生过多的谷氨酰胺进入线粒体基质内, 被磷酸化激活的谷氨酰胺酶分解出高浓度氨, 诱导线粒体活性氧产生, 并认为这一过程产生的ROS和RNS是通过钙依赖途径调节的. 除此之外, ROS还参与细胞内蛋白的酪氨酸残基硝化, 从而影响底物的跨星形胶质细胞运输, 选择性地降低血脑屏障渗透性, 最终导致星形胶质细胞肿胀及脑水肿[10]. 另一方面, 氧化应激也可加重氨中毒, 首先氧化应激会导致蛋白质硝化, 其中谷氨酸合成酶的硝化会导致氨与谷氨酸盐结合发生障碍, 引起脑中氨浓度升高; 其次, 研究发现氧化应激可导致线粒体通透性转换的直接结果使线粒体内膜电位消失, 引起线粒体基质肿胀, ATP能量合成障碍, 也可加重氨中毒. 以上提示氨中毒与氧化应激相互影响的密切关系引起脑星状胶质细胞的病理损害是HE发生的重要环节[38].
锰是中枢神经系统内谷氨酰胺合成酶、线粒体超氧化物歧化酶、丙酮酸羧化酶的重要组成成分. 人体内锰主要来源于食物, 由胃肠道吸收, 经胆汁排泄. 肝硬化患者常有胆汁淤积, 锰经胆道排泄减慢, 导致血锰水平升高. 锰作为神经毒素, 主要影响苍白球、黑质区域, 其机制可能是导致线粒体代谢紊乱及氧化应激以及与铁稳态失衡、炎症、谷氨酸及多巴胺代谢障碍有关. 锰是谷氨酰胺合成酶的重要成分, 而80%的锰沉积于星形胶质细胞的线粒体内[39]. 可使星形胶质细胞转变成Ⅱ型阿尔茨海默细胞, 产生氧化和亚硝基化应激, 通过开放线粒体通透性转换孔道(mitochondrial permeability transition, MPT), 损害线粒体功能, 从而使星形胶质细胞肿胀, 诱发脑水肿. 但给予抗氧化剂如维生素E或MPT抑制剂如环孢素A可大大阻滞星形胶质细胞的肿胀[40]. 锰还可兴奋星形胶质细胞上的转位蛋白, 促进神经类固醇的合成, 增强γ-氨基丁酸能的作用[41]. 用MRI技术科以检测到肝硬化患者和广泛门腔静脉分流术后小鼠脑基底节区锰的沉积[42-44], 肝功能复常后锰沉积会逐渐消失[45]. 锰优先沉积于大脑基底节还可解释HE患者出现的帕金森样症状等[46].
研究发现对肝硬化患者使用苯二氮卓类药物、其肠道细菌产生的内源性苯二氮卓类物质、细菌代谢色氨酸的副产物吲哚及羟吲哚等均有镇静作用, 与HE的抑制状态有关[47,48]. 肝硬化患者和C型HE动物模型中乙胆碱酯酶活性增强, 使乙酰胆碱减少50%-60%, 可引发HE, 该因素与高氨血症无关[49]. 这一机制对研制乙酰胆碱酯酶抑制剂, 治疗HE发挥重大作用[50].
HE的发病机制除氨中毒引起脑星形胶质细胞肿胀外, 近年来研究证明炎症反应、神经类固醇、氧化或硝基化应激以及锰中毒等因素也参与HE发病. 在众多因素的协同作用下, 导致星形胶质细胞发生肿胀, 使胶质细胞与神经元之间的神经递质传递障碍, 引发HE的神经、精神症状. 提示今后在临床治疗HE过程中, 除降低血氨外, 其他减轻炎症反应、抗氧化应激等措施也是重要的治疗方法, 今后随着对HE发病分子机制的研究和阐明, 会开发出更有效的诊断与治疗方法.
肝性脑病(HE)严重危害人类健康, 其病理基础为脑水肿, 氨中毒学说仍是主要发病机制之一, 但具体发病机制目前仍不明确, 随着研究的进展, 又增加了炎症反应等学说.
庄林, 主任医师, 昆明市第三人民医院肝病科; 范小玲, 主任医师, 北京地坛医院综合科
目前主要认为高氨血症与炎症反应、神经类固醇、氧化或硝基化应激协同作用导致脑星形胶质细胞肿胀, 进而发生脑水肿.
近年来不断有关于HE的体内外实验研究, 如血氨在脑内的代谢途径、炎症反应因子的参与等, 从分子水平、信号通路结合大体标本、影像学等方面探讨HE的发病机制.
本文从高氨血症、炎症反应、神经类固醇、氧化或硝基化应激、锰等方面, 综述HE发病机制的研究进展.
通过本文可较系统的了解HE的发病机制, 有利于开发新的治疗手段.
该综述较全面地总结了近年来HE的发生机制, 内容相对较新、概括较全面, 对临床有一定的指导意义.
编辑:张姗姗 电编:鲁亚静
| 1. | Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy--definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35:716-721. [PubMed] [DOI] |
| 2. | Shawcross DL, Olde Damink SW, Butterworth RF, Jalan R. Ammonia and hepatic encephalopathy: the more things change, the more they remain the same. Metab Brain Dis. 2005;20:169-179. [PubMed] [DOI] |
| 3. | Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol. 2010;7:515-525. [PubMed] [DOI] |
| 4. | Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol (N Y). 2011;7:222-233. [PubMed] |
| 5. | Romero-Gómez M, Ramos-Guerrero R, Grande L, de Terán LC, Corpas R, Camacho I, Bautista JD. Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy. J Hepatol. 2004;41:49-54. [PubMed] [DOI] |
| 6. | Romero-Gómez M, Jover M, Del Campo JA, Royo JL, Hoyas E, Galán JJ, Montoliu C, Baccaro E, Guevara M, Córdoba J. Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study. Ann Intern Med. 2010;153:281-288. [PubMed] |
| 7. | Jalan R, Kapoor D. Enhanced renal ammonia excretion following volume expansion in patients with well compensated cirrhosis of the liver. Gut. 2003;52:1041-1045. [PubMed] [DOI] |
| 8. | Olde Damink SW, Jalan R, Redhead DN, Hayes PC, Deutz NE, Soeters PB. Interorgan ammonia and amino acid metabolism in metabolically stable patients with cirrhosis and a TIPSS. Hepatology. 2002;36:1163-1171. [PubMed] [DOI] |
| 9. | Cooper AJ, Plum F. Biochemistry and physiology of brain ammonia. Physiol Rev. 1987;67:440-519. [PubMed] |
| 10. | Häussinger D, Schliess F. Pathogenetic mechanisms of hepatic encephalopathy. Gut. 2008;57:1156-1165. [PubMed] [DOI] |
| 11. | Tanigami H, Rebel A, Martin LJ, Chen TY, Brusilow SW, Traystman RJ, Koehler RC. Effect of glutamine synthetase inhibition on astrocyte swelling and altered astroglial protein expression during hyperammonemia in rats. Neuroscience. 2005;131:437-449. [PubMed] [DOI] |
| 12. | Rose C, Kresse W, Kettenmann H. Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes, an effect of pH. J Biol Chem. 2005;280:20937-20944. [PubMed] [DOI] |
| 13. | Rose C. Effect of ammonia on astrocytic glutamate uptake/release mechanisms. J Neurochem. 2006;97 Suppl 1:11-15. [PubMed] [DOI] |
| 14. | Häussinger D. Low grade cerebral edema and the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology. 2006;43:1187-1190. [PubMed] [DOI] |
| 15. | Rovira A, Alonso J, Córdoba J. MR imaging findings in hepatic encephalopathy. AJNR Am J Neuroradiol. 2008;29:1612-1621. [PubMed] [DOI] |
| 16. | Córdoba J, Sanpedro F, Alonso J, Rovira A. 1H magnetic resonance in the study of hepatic encephalopathy in humans. Metab Brain Dis. 2002;17:415-429. [PubMed] [DOI] |
| 17. | Shawcross DL, Balata S, Olde Damink SW, Hayes PC, Wardlaw J, Marshall I, Deutz NE, Williams R, Jalan R. Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia. Am J Physiol Gastrointest Liver Physiol. 2004;287:G503-G509. [PubMed] [DOI] |
| 18. | Butterworth RF. Pathophysiology of hepatic encephalopathy: The concept of synergism. Hepatol Res. 2008;38:S116-S121. [PubMed] [DOI] |
| 19. | Gregorios JB, Mozes LW, Norenberg MD. Morphologic effects of ammonia on primary astrocyte cultures. II. Electron microscopic studies. J Neuropathol Exp Neurol. 1985;44:404-414. [PubMed] [DOI] |
| 20. | Norenberg MD, Rama Rao KV, Jayakumar AR. Signaling factors in the mechanism of ammonia neurotoxicity. Metab Brain Dis. 2009;24:103-117. [PubMed] [DOI] |
| 21. | Seyan AS, Hughes RD, Shawcross DL. Changing face of hepatic encephalopathy: role of inflammation and oxidative stress. World J Gastroenterol. 2010;16:3347-3357. [PubMed] [DOI] |
| 22. | Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation. Cell Mol Life Sci. 2005;62:2295-2304. [PubMed] [DOI] |
| 23. | Guarner-Argente C, Sánchez E, Vidal S, Román E, Concepción M, Poca M, Sánchez D, Juárez C, Soriano G, Guarner C. Toll-like receptor 4 D299G polymorphism and the incidence of infections in cirrhotic patients. Aliment Pharmacol Ther. 2010;31:1192-1199. [PubMed] [DOI] |
| 24. | Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol. 2004;40:247-254. [PubMed] [DOI] |
| 25. | Shawcross DL, Wright G, Olde Damink SW, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis. 2007;22:125-138. [PubMed] [DOI] |
| 26. | Didier N, Romero IA, Créminon C, Wijkhuisen A, Grassi J, Mabondzo A. Secretion of interleukin-1beta by astrocytes mediates endothelin-1 and tumour necrosis factor-alpha effects on human brain microvascular endothelial cell permeability. J Neurochem. 2003;86:246-254. [PubMed] [DOI] |
| 27. | Bémeur C, Qu H, Desjardins P, Butterworth RF. IL-1 or TNF receptor gene deletion delays onset of encephalopathy and attenuates brain edema in experimental acute liver failure. Neurochem Int. 2010;56:213-215. [PubMed] [DOI] |
| 28. | Cagnin A, Taylor-Robinson SD, Forton DM, Banati RB. In vivo imaging of cerebral "peripheral benzodiazepine binding sites" in patients with hepatic encephalopathy. Gut. 2006;55:547-553. [PubMed] [DOI] |
| 29. | Ahboucha S, Butterworth RF. The neurosteroid system: implication in the pathophysiology of hepatic encephalopathy. Neurochem Int. 2008;52:575-587. [PubMed] [DOI] |
| 30. | Baulieu EE. Neurosteroids: a novel function of the brain. Psychoneuroendocrinology. 1998;23:963-987. [PubMed] [DOI] |
| 31. | Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci. 2006;27:402-409. [PubMed] [DOI] |
| 32. | Papadopoulos V, Lecanu L, Brown RC, Han Z, Yao ZX. Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders. Neuroscience. 2006;138:749-756. [PubMed] [DOI] |
| 33. | Bélanger M, Desjardins P, Chatauret N, Rose C, Butterworth RF. Mild hypothermia prevents brain edema and attenuates up-regulation of the astrocytic benzodiazepine receptor in experimental acute liver failure. J Hepatol. 2005;42:694-699. [PubMed] [DOI] |
| 34. | Ahboucha S, Coyne L, Hirakawa R, Butterworth RF, Halliwell RF. An interaction between benzodiazepines and neuroactive steroids at GABA A receptors in cultured hippocampal neurons. Neurochem Int. 2006;48:703-707. [PubMed] [DOI] |
| 35. | Hilgier W, Anderzhanova E, Oja SS, Saransaari P, Albrecht J. Taurine reduces ammonia- and N-methyl-D-aspartate-induced accumulation of cyclic GMP and hydroxyl radicals in microdialysates of the rat striatum. Eur J Pharmacol. 2003;468:21-25. [PubMed] [DOI] |
| 36. | Reinehr R, Görg B, Becker S, Qvartskhava N, Bidmon HJ, Selbach O, Haas HL, Schliess F, Häussinger D. Hypoosmotic swelling and ammonia increase oxidative stress by NADPH oxidase in cultured astrocytes and vital brain slices. Glia. 2007;55:758-771. [PubMed] [DOI] |
| 37. | Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology. 2006;44:788-794. [PubMed] [DOI] |
| 38. | Schliess F, Görg B, Häussinger D. Pathogenetic interplay between osmotic and oxidative stress: the hepatic encephalopathy paradigm. Biol Chem. 2006;387:1363-1370. [PubMed] [DOI] |
| 39. | Gunter KK, Aschner M, Miller LM, Eliseev R, Salter J, Anderson K, Gunter TE. Determining the oxidation states of manganese in NT2 cells and cultured astrocytes. Neurobiol Aging. 2006;27:1816-1826. [PubMed] [DOI] |
| 40. | Rama Rao KV, Reddy PV, Hazell AS, Norenberg MD. Manganese induces cell swelling in cultured astrocytes. Neurotoxicology. 2007;28:807-812. [PubMed] [DOI] |
| 41. | Talwalkar JA, Kamath PS. Influence of recent advances in medical management on clinical outcomes of cirrhosis. Mayo Clin Proc. 2005;80:1501-1508. [PubMed] [DOI] |
| 42. | Mullen KD, Jones EA. Natural benzodiazepines and hepatic encephalopathy. Semin Liver Dis. 1996;16:255-264. [PubMed] [DOI] |
| 43. | Mullen KD, Cole M, Foley JM. Neurological deficits in "awake" cirrhotic patients on hepatic encephalopathy treatment: missed metabolic or metal disorder? Gastroenterology. 1996;111:256-257. [PubMed] [DOI] |
| 44. | Rose C, Butterworth RF, Zayed J, Normandin L, Todd K, Michalak A, Spahr L, Huet PM, Pomier-Layrargues G. Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction. Gastroenterology. 1999;117:640-644. [PubMed] [DOI] |
| 45. | Naegele T, Grodd W, Viebahn R, Seeger U, Klose U, Seitz D, Kaiser S, Mader I, Mayer J, Lauchart W. MR imaging and (1)H spectroscopy of brain metabolites in hepatic encephalopathy: time-course of renormalization after liver transplantation. Radiology. 2000;216:683-691. [PubMed] |
| 46. | Krieger D, Krieger S, Jansen O, Gass P, Theilmann L, Lichtnecker H. Manganese and chronic hepatic encephalopathy. Lancet. 1995;346:270-274. [PubMed] [DOI] |
| 47. | Baraldi M, Avallone R, Corsi L, Venturini I, Baraldi C, Zeneroli ML. Natural endogenous ligands for benzodiazepine receptors in hepatic encephalopathy. Metab Brain Dis. 2009;24:81-93. [PubMed] [DOI] |
| 48. | Riggio O, Mannaioni G, Ridola L, Angeloni S, Merli M, Carlà V, Salvatori FM, Moroni F. Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: a study on the pathophysiology of hepatic encephalopathy. Am J Gastroenterol. 2010;105:1374-1381. [PubMed] [DOI] |
| 49. | Méndez M, Méndez-López M, López L, Aller MA, Arias J, Arias JL. Acetylcholinesterase activity in an experimental rat model of Type C hepatic encephalopathy. Acta Histochem. 2011;113:358-362. [PubMed] [DOI] |
| 50. | Basu P, Shah NJ, Krishnaswamy N, Hampole H, Pacana T, Rayapudi K, Brown Jr. Transdermal rivastigmine for treatment of encephalopathy in liver cirrhosis-a randomized placebo controlled trial (TREC TRIAL). J Hepatology. 2010;52:S67-S68. [DOI] |