肝干细胞移植在肝病治疗中的应用

背景：目前,肝移植存在供体短缺、手术损伤、手术并发症发生率高以及费用高昂等问题,而肝干细胞移植为终末期肝病的治疗提供了崭新的思路。 目的：介绍肝干细胞的来源与分类、肝干细胞移植治疗终末期肝病的研究现状及面临的问题,并展望了其临床应用前景。 方法：应用计算机检索中国期刊全文数据库(CNKI：1999/2009)和Medline database数据库(1999/2009)相关文献,检索词分别为“肝干细胞,肝脏疾病,移植”和 “hepatic stem cells,liver disease, transplantation”,语言分别设定为中文和英文,共检索到87篇文章,阅读文题和摘要进行筛选,选择具有原创性,论点论据可靠且分析全面的与肝干细胞移植临床应用密切相关的文章,排除重复研究及质量较差的文献,最后纳入30篇进行总结综述。 结果与结论：肝干细胞可分为肝源性和非肝源性。肝源性肝干细胞包括肝卵圆细胞、成熟肝细胞和间充质干细胞等,非肝源性肝干细胞主要来源于胚胎干细胞、骨髓造血干细胞和胰腺干细胞等。目前肝干细胞治疗肝病的研究尚处在初期阶段,从肝干细胞的发现到分离、纯化、全面鉴定、体外培养、定向分化及临床试验等,仍存在许多难题需要研究解决。不过作为一种新兴的种子细胞来源,肝干细胞不但可替换受损组织,而且可刺激受体组织再生以达到自身修复的目的,所以相比现在临床常用的原位肝移植和生物人工肝而言,肝干细胞在治疗各种原因引起的肝脏疾病中都具有十分广阔的前景。     

肝移植后乙肝再感染的因素分析及其防治

肝移植患者由于使用免疫抑制剂以及过多种广谱抗生素,使得肝移植比任何其他腹部手术更易发生感染,国内以肝移植后发生乙肝再感染为主。随着乙型肝炎病毒相关性肝病患者行肝移植后长期存活数目的增加,移植学家们把研究的重点延伸到如何优化肝移植后预防乙型肝炎病毒再感染的治疗方案以降低因乙型肝炎病毒变异导致再感染和减少长期用药、降低治疗费用上来。文章分析了肝移植术后乙肝再感染的因素,介绍了肝移植后用于防治乙肝再感染的药物种类及临床应用,展望了肝移植后药物防治乙肝再感染的新的研究方向。     

自体骨髓间充质干细胞移植治疗终末期肝病39例

目前肝脏移植是治疗终末期肝病的惟一有效手段,但仍存在一些问题,尤其是供体短缺、价格昂贵及免疫排斥反应,自体骨髓间充质干细胞移植可避免以上缺点。 目的：探讨自体骨髓间充质干细胞移植对失代偿期肝硬化和慢性重症患者改善作用。 方法：纳入纳入终末期肝病患者39例,肝炎肝硬化失代偿期患者32例,慢性重肝衰竭患者7例。分离其自体骨髓间充质干细胞,行肝动脉插管自体干细胞移植治疗。移植后1,2,4,8周进行生化检测,并观察其移植后临床症状改善情况及术后不良反应。根据实验室检查结果和临床,分别计算出CTP和终末期肝病模型评分,观察各个时间段分值的变化。 结果与结论：移植后1,2,4,8周,37例(93%)患者丙氨酸转氛酶逐渐降低,白蛋白、胆碱脂酶活力、胆固醇、凝血酶原活动度均升高(P < 0.01)。患者临床症状有明显改善:移植后8周内腹水减轻32例(80%),食欲改善34例(85%),乏力好转37例(93%),腹胀减轻34例(85%)。CTP-B级和CTP-C级评分、终末期肝病模型评分均降低。所有移植患者中未发现严重不良反应及并发症。提示,自体骨髓间充质干细胞移植作为治疗慢性肝衰竭的一种新的安全有效的治疗措施。     

同种异体骨髓间充质干细胞移植治疗急性肝功能衰竭

背景：对于急性肝功能衰竭的临床治疗,目前尚缺乏特效手段。骨髓间充质干细胞在特定环境下可分化为具有部分肝功能的类肝样细胞,从而参与肝功能的修复和重构,为急性肝功能衰竭的治疗提供了新的手段。 目的：评价同种异体骨髓间充质干细胞移植治疗大鼠急性肝功能衰竭的疗效,为其临床应用提供理论依据。 方法：采用全骨髓培养法培养并纯化其骨髓间充质干细胞。30只健康SD大鼠随机均分为3组：正常对照组：不予任何处理;肝衰竭组和移植组：用腹腔注射四氯化碳石蜡油溶液的方法复制鼠急性肝功能衰竭模型后24 h分别经其尾静脉注射生理盐水和等量骨髓间充质干细胞。在移植后第1,2,3,7天抽血检测其肝功能,并取肝脏行病理学检查。 结果与结论：急性肝功能衰竭鼠经骨髓间充质干细胞移植治疗后生存率为70%,与肝衰竭组大鼠存活率20%相比差异有显著性意义(P < 0.05);肝功能指标中谷丙转氨酶和谷草转氨酶相比,移植组明显低于肝衰竭组,差异有显著性意义(P < 0.05)。肝脏组织病理学结果显示移植组肝细胞变性及坏死程度以及炎症浸润程度轻于肝衰竭组。因此,经尾静脉移植骨髓间充质干细胞能提高急性肝功能衰竭大鼠的生存率、改善肝功能及减轻肝脏坏死程度,对大鼠急性肝功能衰竭有一定的治疗作用。     

干细胞移植治疗肝病的研究现状☆

学术背景：常规的内科保肝治疗效果不佳，原位肝移植仍然是治疗终末期肝病最有效的措施，但肝源缺乏、费用昂贵、移植排斥反应及长期应用免疫抑制剂引起并发症等成为限制其广泛应用的主要原因。干细胞移植有利于受损肝组织修复，能够代偿部分肝功能，已成为治疗肝病的一种新方法。 目的：介绍干细胞移植治疗肝病的研究现状。 检索策略：由该论文的研究人员应用计算机检索 Pubmed 2002-01/2007-12的相关文献，检索词“transplantation of stem cell，liver disease，hepatic disease”，并限定文献语种为“English”。同时计算机检索中国知识资源总库CNKI 2002-01/2007-12的相关文献，检索词“干细胞移植，肝病”，并限定文献语种为中文。共检索到125篇文献，对资料进行初审，纳入标准：①文章内容与干细胞移植应用于肝病的治疗相关。②同一领域选择近期发表或在权威杂志上发表的文章。排除标准：重复研究或Meta分析类文章。 文献评价：文献的来源主要是通过对干细胞移植治疗肝病方面内容进行汇总分析，其中36篇相关度较高，对完全符合标准的30篇作为参考文献进行综述。进一步查找全文，2篇为综述，其余均为临床或基础实验研究。 资料综合：①干细胞移植动物实验：采用不同方法建立肝损伤动物模型，对成模动物以不同途径进行不同种类的干细胞移植实验，移植后行肝脏组织学检查及检测转氨酶和白蛋白等肝功能指标，结果显示干细胞移植能够改善肝功能，修复肝脏组织结构，减轻肝脏损伤。②干细胞移植用于临床治疗：多项通过干细胞移植治疗终末期肝病和难治性肝病患者的研究表明，干细胞移植后患者症状缓解，肝功能和凝血功能明显好转，治疗时间缩短，改善预后，且无严重并发症出现。③干细胞移植相关并发症及其应用评价：行干细胞移植治疗肝病患者的临床研究，未经合理的多中心、大样本、随机对照实验设计，其治疗效果不确切，至今仍存在不同观点，且移植后可出现病毒感染及肝静脉梗阻等并发症，以及干细胞的致瘤性，均限制了其应用。 结论：尽管目前多项干细胞移植用于治疗肝病患者的临床研究均已取得一些疗效，但有报道认为其对肝损伤无明显改善，且产生相关并发症，同时仍存在一定问题。因此需要合理设计，并进行随机对照来确证以往研究结果的可靠性，使其成为治疗肝病的一个安全有效措施，从而排除质疑，推进其临床应用。     

肝移植围手术期110例中10例死亡原因分析

目的：回顾性分析110例成人肝移植病例的临床资料,以期筛选出影响肝移植围手术期死亡率的危险因素。 方法：选择2005-01/2007-12在解放军总医院第二附属医院器官移植中心完成肝移植的资料完整、符合统计学要求的受者110例,均为经典式同种异体原位肝移植,尸体供肝。其中移植后存活﹤30 d的10例患者列入围手术期死亡组,移植后存活≥30 d的100例患者列入生存组。对影响两组患者移植后转归的因素进行比较分析,并对差异显著的影响因素进行Logistic回归分析。 结果：单因素分析结果显示,死亡组受者的终末期肝病模型评分、凝血酶原国际标准化比值、移植术中出血量及输血量均高于生存组(P < 0.01）,凝血酶原活动度低于生存组(P < 0.05）。Logistic回归分析表明,移植前终末期肝病模型评分、凝血酶原活动度是肝移植围手术期死亡率的独立危险因素。 结论：移植前终末期肝病模型高评分、凝血酶原活动度低是导致肝移植患者围手术期死亡的主要原因,改善移植前受者的危重病情及凝血功能障碍能够降低肝移植围手术期的死亡率。     

肝移植围手术期中的人工肝支持

人工肝脏支持系统是以血液净化为基础的体外循环系统, 包括血液透析、血液滤过、血液灌流、血浆置换等方法。临床应用非生物型人工肝脏尤其是血浆置换技术, 能有效地解决高胆红素血症、内毒素血症、毒性物质积蓄与氨基酸代谢障碍及水、电解质、酸碱失衡等问题, 改善患者内环境, 促进肝细胞再生, 纠正肝性脑病、降低重型肝炎的病死率, 使患者能渡过危险的肝功能衰竭难关而获得生存。通过人工肝治疗, 不仅可明显改善肝衰竭患者的全身情况, 为手术降低风险, 为寻找供肝争得保贵的时间, 而且能有效地改善肝移植术后早期患者的生理紊乱状况, 帮助渡过排斥反应期, 有利于移植肝功能的恢复。因此, 人工肝可成为肝移植的桥梁。文章从人工肝脏支持系统的功能出发, 分析其特点, 探讨其应用于人体原位肝移植围手术期的方法及其发展方向。     

肝移植后肺外细菌感染：同一机构9年52例分析

背景：既往文献主要针对肝移植后肺部感染进行研究,而肺外感染研究较少。 目的：探讨肝移植后肺外细菌感染的危险因素,提出预防移植后肺外细菌感染方案和治疗策略。 方法：回顾性分析52例肝移植后发生肺外细菌感染的肝移植患者病历资料,归纳可能的危险因素,总结其发病特点、常见病原菌及治疗方案。 结果与结论：356例肝移植患者共发生肺外细菌感染52例,其中切口感染36例,腹腔感染13例,胆道感染6例,同时发生两个部位感染3例。培养出病原菌37例,其中单一病原菌感染32例,混合细菌感染5例。未发生因肺外细菌感染死亡病例。病原菌主要包括：铜绿假单胞菌、大肠埃希菌、金黄色葡萄球菌、粪肠球菌、屎肠球菌等。其相关危险因素主要包括：移植过程中出血量超过10 000 mL、移植后胆道并发症、再移植、重度腹水、暴发性肝衰竭肝移植等。对于肝移植细菌感染的控制,预防重于治疗,感染发生后,需尽可能去除引起感染的病因,合理应用药物治疗。     

骨髓间充质干细胞在肝衰竭中的应用

背景：近年来诸多研究已经报道了骨髓间充质干细胞在肝脏病理条件下能够分化为具部分功能的类肝细胞且可修复受损肝脏。 目的：总结和分析骨髓间充质干细胞的生物学特性及其在肝衰竭中的研究与应用。 方法：应用计算机检索CNKI和PubMed数据库中1997-01/2009-12关于“骨髓间充质干细胞在肝衰竭中的研究与应用”的文章,以“骨髓间充质干细胞,肝衰竭”或“肝干细胞,肝脏疾病” 为检索词进行检索。选择文章内容与骨髓间充质干细胞治疗肝衰竭相关,同一领域文献则选择近期发表或发表在权威杂志文章。初检得到中英文共371篇文献,根据纳入标准选择31篇文章进行综述。 结果与结论：骨髓间充质干细胞是成体干细胞的一种,其具有高度自我更新能力和多向分化潜能,用于肝衰竭治疗的作用机理主要是转分化和细胞融合。随着研究不断得深入,骨髓间充质干细胞移植已逐渐开展应用至肝衰竭治疗中,但其研究有待进一步完善。     

亲属成人间活体肝移植1例临床分析

背景：活体肝移植的开展扩大了供体来源,有效缓解了供肝匮乏的局面,且活体供肝冷缺血时间短、质量好;若供、受者为亲属,可能具有免疫相容的优势。 目的：总结1例亲属成人间活体肝移植的临床体会,探讨成人间活体肝移植治疗终末期肝病的手术方式及移植效果。 方法：乙型肝炎后肝硬化(失代偿期)并门脉高压症患者1例,女性,年龄54岁,拟行肝移植手术。供者为患者外甥,23岁,既往身体健康。经术前评估后,切取供者右半肝并原位移植给受者。术后常规给予免疫抑制、防治感染、护肝、支持等治疗。 结果与结论：术后供者生命体征平稳,手术历时4 h,失血约150 mL,术后第5天肝功能基本恢复正常,术后10 d行上腹部CT平扫加增强提示符合活体肝移植供体右半肝切除术后改变。术后受者生命体征平稳,手术历时7 h,失血约500 mL,彩超检查移植肝血管通畅,血供良好;生化指标逐渐恢复至正常范围,提示移植肝功能情况良好。术后供、受者无严重并发症发生,均健康存活,门诊随访肝功能正常。结果说明成人间活体肝移植为术前周密的准备工作,选择最佳的移植手术时机以及手术的成功创造了最佳条件,是在尸体供肝短缺的情况下治疗终末期肝病的理想方法。 关键词：肝移植;活体;成人;终末期肝病;器官;亲属     

Progressive neuronal degeneration of childhood with liver disease (Alpers-Huttenlocher syndrome): a personal review

Thirty-two autopsied cases of progressive neuronal degeneration of childhood with liver disease are reviewed. The typical clinical course is intractable seizures and liver failure following a period of developmental delay and failure to thrive in early infancy, but some children first present with seizures. Characteristic changes on the electroencephalogram, loss of visual-evoked potentials, occipital atrophy on computed tomographic scan, and particular changes on liver biopsy may assist diagnosis. Most patients succumb in less than 3 years, but some have a protracted survival into their teens, and very rarely they may present in early adulthood. Liver pathology comprises fatty change, hepatocyte loss, bile duct proliferation, fibrosis, and often cirrhosis. Gradual progression can be followed in sequential biopsies. Macroscopically, the cerebral cortex is variably involved, but usually there is patchy thinning and discoloration, with a striking predilection for the striate cortex. Microscopic changes include spongiosis, neuronal loss, and astrocytosis, which progresses down through the cortical layers. All areas may be affected but the calcarine cortex is usually most affected. Etiology is still obscure, though mitochondrial and slow viral disorders have been postulated.     

分子吸附循环系统在肝移植等待期急性肝功能衰竭治疗中的作用☆

学术背景：肝移植是目前治疗肝功能衰竭的有效手段,但此法受到了急性肝功能衰竭发病迅速和供体短缺的限制。 目的：充分认识分子吸附循环系统在肝移植等待期急性肝功能衰竭治疗中的作用。 检索策略：由第一作者应用计算机检索Pubmed数据库及ISI Web of Knowledge数据库1993-01/2007-12有关分子吸附循环系统治疗肝移植等待期急性肝功能衰竭的文献,检索词为“acute liver failure,molecular adsorbent recycling system,artificial liver”,并限定文章语言种类为English。同时检索中国期刊全文数据库1993-01/2007-12有关分子吸附循环系统治疗肝移植等待期急性肝功能衰竭的文献,检索词为“急性肝功能衰竭,分子吸附循环系统,人工肝”,并限定文章语言种类为中文。此外手工检索人工肝相关中文文献。对资料进行初审,纳入标准：细胞因子、肝性脑病、肝肾综合征、生存率等相关研究文献。排除标准：明显不随机、研究目的与课题无关的文献及重复性文献。 文献评价：初检得到467篇文献,阅读鉴定纳入32篇满足全部纳入标准,其中9篇中文,23篇英文;有关分子吸附循环系统治疗急性肝功能衰竭学术背景的文献4篇,有关急性肝功能衰竭定义及治疗的文献5篇,有关分子吸附循环系统的应用及其对急性肝功能衰竭治疗效果的文献23篇。 资料综合：传统人工肝治疗急性肝功能衰竭各有利弊,分子吸附循环系统结合以往人工肝的优点,突破各自的局限性,可同时清除水溶性和脂溶性毒素,清除致病因子,减轻脑水肿,维护血流动力学的稳定,改善肝肾功能,提高生存率。 结论：分子吸附循环系统是治疗肝功能衰竭安全而有效的辅助方法,可帮助急性肝功能衰竭患者顺利渡过肝移植等待期。     

Neuropathy in hepatic disorders: A clinical,electrophysiological and histopathological appraisal

The present study deals with 30 patients with cirrhosis of the liver and 12 patients with infective hepatitis who were studied clinically, neurophysiologically and histopathologically for the presence of neuropathy. Simultaneously, 13 healthy individuals were evaluated as controls. Clinical evidence of neuropathy was found in 63.3% of the patients with hepatic cirrhosis and in 16.6% of the patients with infective hepatitis. In hepatic cirrhosis, the conduction velocities were abnormal in 33.3% and histopathological demyelination was found in 80% of the patients. In infective hepatitis, on the other hand, altered nerve conduction velocities were found in 41.6% and segmental demyelination in 75% of the patients.Our data reveal that peripheral nerve involvement is seen both in chronic and acute liver disorders. The neuropathy in hepatic cirrhosis is unrelated to diabetes, alcoholism or portacaval shunt and may be due to unknown metabolic abnormality or to toxins. In infective hepatitis, the neuropathy may either be due to some acute metabolic derangement or may be purely viral in origin.     

Breaking the myths: new treatment approaches for chronic depression.

BACKGROUND: Chronic depressive disorders are common, accounting for approximately one-third of all cases of depression and posing a major public health problem. In the past, chronic depression has been thought to be treatment-resistant, and evidence suggests that it is currently underdiagnosed, misdiagnosed, and suboptimally treated. OBJECTIVES: To review the subtypes of chronic depression and the evidence-base concerning their optimal treatment and to discuss some key clinical issues and areas of future research. METHODS: We identified key studies and randomized controlled trials (RCTs) by systematically searching electronic databases and hand searching specialist journals and bibliographies. RESULTS: Chronic depressive disorders respond well to standard pharmacologic interventions in the acute and maintenance phases of treatment. Standard psychotherapies alone may not be efficacious for chronic depression (especially dysthymia). Recent evidence suggests that treatment combining psychotherapy and medications may be superior to either treatment alone. CONCLUSIONS: Chronic depressive disorders are amenable to treatment, provided that intervention is both thorough and intensive. Although our knowledge about the optimal treatment of chronic depression has developed rapidly, changes in clinical practice have been slower to evolve. Further research is required to assess the effectiveness of multimodal interventions for chronic depression in more naturalistic settings.     

Symptomatic myoclonus

A huge number of neurological disorders are associated with myoclonus. This paper describes these disorders whose diagnosis partly relies on the presence of myoclonus. The diagnostic approach is related to certain clinical features of myoclonus, which, after their integration in the clinical context, help orientate towards diagnosis. Myoclonus is frequent during dementia. Although its presence is well-known to take part in the diagnosis of Creutzfeldt-Jakob disease (CJD), myoclonus can also be present to a significant degree in Alzheimer's disease and Lewy body dementia (LBD), which raises a diagnostic issue. Both its clinical and electrophysiological features may help differential diagnosis, given that myoclonus with fast-evolving dementia and focal neurological signs should favor the diagnosis of CJD. Myoclonus in a context of progressive ataxia suggests one clinical form of the Ramsay-Hunt syndrome (progressive myoclonic ataxia, PMA), whose most frequent causes are: coeliac disease, mitochondriopathies, some spino-cerebellar degenerations, and some late metabolic disorders. In addition to ataxia and myoclonus, the presence of opsoclonus directs diagnosis toward the opsoclonus-myoclonus syndrome (OMS), whose origin, in adult, is idiopathic or paraneoplastic. Palatal tremor (myoclonus) with ataxia may represent either a sporadic pattern, which often reflects the evolution of degenerative or lesional disorders, or a familial pattern in some degenerative affections or metabolic diseases. Of more recent knowledge is the association of progressive ataxia, myoclonus, and renal failure, which corresponds to a recessive autosomic disease. In a context of encephalopathy, myoclonus is frequent in metabolic or hydro-electrolytic disorders, and in brain anoxia. One should distinguish these various forms of myoclonus which may occur in the acute post-anoxic phase, from those occurring as sequels at a later stage, i.e. the Lance and Adams syndrome whose clinical aspects are also multiple. Myoclonus is less frequent during toxic or drug exposures. Irrespective of its acute or insidious onset, Hashimoto's encephalopathy is accompanied by myoclonus and tremor. Myoclonus may also be present during encephalic and/or spinal infectious disorders. Myoclonus with focal neurological signs may be observed in thalamic lesions, responsible for unilateral asterixis or unilateral myoclonus superimposed on dystonic posture. Segmental spinal myoclonus or propriospinal myoclonus may be associated with several spinal-cord disorders. Myoclonus associated with peripheral nerve lesions is exceptional or even questionable for some of these.     

Triheptanoin--a medium chain triglyceride with odd chain fatty acids: a new anaplerotic anticonvulsant treatment?

The triglyceride of heptanoate (C7 fatty acid), triheptanoin, is a tasteless oil used to treat rare metabolic disorders in USA and France. Heptanoate is metabolized by β-oxidation to provide propionyl-CoA, which after carboxylation can produce succinyl-CoA, resulting in anaplerosis - the refilling of the tricarboxylic acid cycle. Heptanoate is also metabolized by the liver to the C5 ketones, β-ketopentanoate and/or β-hydroxypentanoate, which are released into the blood and thought to enter the brain via monocarboxylate transporters. Oral triheptanoin has recently been discovered to be reproducibly anticonvulsant in acute and chronic mouse seizures models. However, current knowledge on alterations of brain metabolism after triheptanoin administration and anaplerosis via propionyl-CoA carboxylation in the brain is limited. This review outlines triheptanoin's unique anticonvulsant profile and its clinical potential for the treatment of medically refractory epilepsy. Anaplerosis as a therapeutic approach for the treatment of epilepsy is discussed. More research is needed to elucidate the anticonvulsant mechanism of triheptanoin and to reveal its clinical potential for the treatment of epilepsy and other disorders of the brain.     

Acquired hepatocerebral degeneration

Cirrhosis and its co-morbidities may cause a variety of neurological complications, the most common being bouts of toxic metabolic encephalopathy. A proportion of patients with chronic liver disease develop acquired hepatocerebral degeneration (AHD), a chronic progressive neurological syndrome characterized by parkinsonism, ataxia and other movement disorders. This article reviews the clinical spectrum, pathophysiology, neuroimaging features and differential diagnosis of AHD along with emerging treatment options.     

Neuromuscular disease and respiratory failure

Neurologists should be able to anticipate and recognise the onset of respiratory failure in patients with neuromuscular disorders. Symptoms will differ depending on the speed of onset of the respiratory muscle weakness. Careful monitoring of respiratory function is particularly important in acute disorders such as Guillain-Barré syndrome. Patients with an unrecognised neuromuscular disorder may occasionally present with respiratory failure. Important investigations include vital capacity, mouth pressures, arterial blood gases, chest x ray and sometimes overnight respiratory monitoring. Patients with Guillain-Barré and other acute conditions may require short-term ventilatory support in the intensive care unit. Patients with some chronic disorders, such as motor neuron disease and Duchenne dystrophy, can be successfully treated with non-invasive ventilation, usually in collaboration with a respiratory physician. New-onset weakness of limb and respiratory muscles in the intensive care unit is usually due to critical illness myopathy or critical illness polyneuropathy, and treatment is supportive.     

Astrocyte glutamine synthetase: Importance in hyperammonemic syndromes and potential target for therapy

Many theories have been advanced to explain the encephalopathy associated with chronic liver disease and with the less common acute form. A major factor contributing to hepatic encephalopathy is hyperammonemia resulting from portacaval shunting and/or liver damage. However, an increasing number of causes of hyperammonemic encephalopathy have been discovered that present with the same clinical and laboratory features found in acute liver failure, but without liver failure. Here, we critically review the physiology, pathology, and biochemistry of ammonia (i.e., NH₃ plus NH₄ ⁺) and show how these elements interact to constitute a syndrome that clinicians refer to as hyperammonemic encephalopathy (i.e., acute liver failure, fulminant hepatic failure, chronic liver disease). Included will be a brief history of the status of ammonia and the centrality of the astrocyte in brain nitrogen metabolism. Ammonia is normally detoxified in the liver and extrahepatic tissues by conversion to urea and glutamine, respectively. In the brain, glutamine synthesis is largely confined to astrocytes, and it is generally accepted that in hyperammonemia excess glutamine compromises astrocyte morphology and function. Mechanisms postulated to account for this toxicity will be examined with emphasis on the osmotic effects of excess glutamine (the osmotic gliopathy theory). Because hyperammonemia causes osmotic stress and encephalopathy in patients with normal or abnormal liver function alike, the term “hyperammonemic encephalopathy” can be broadly applied to encephalopathy resulting from liver disease and from various other diseases that produce hyperammonemia. Finally, the possibility that a brain glutamine synthetase inhibitor may be of therapeutic benefit, especially in the acute form of liver disease, is discussed.     

Uremic encephalopathy and other brain disorders associated with renal failure

Kidney failure is one of the leading causes of disability and death and one of the most disabling features of kidney failure and dialysis is encephalopathy. This is probably caused by the accumulation of uremic toxins. Other important causes are related to the underlying disorders that cause kidney failure, particularly hypertension. The clinical manifestations of uremic encephalopathy include mild confusional states to deep coma, often with associated movement disorders, such as asterixis. Most nephrologists consider cognitive impairment to be a major indication for the initiation of renal replacement therapy with dialysis with or without subsequent transplantation. Sleep disorders, including Ekbom's syndrome (restless legs syndrome) are also common in patients with kidney failure. Renal replacement therapies are also associated with particular neurologic complications including acute dialysis encephalopathy and chronic dialysis encephalopathy, formerly known as dialysis dementia. The treatments and prevention of each are discussed.