星形胶质细胞与肝性脑病

肝性脑病(HE)是由肝功能障碍引起的,以代谢紊乱为主要特征的中枢神经系统功能失调综合征.目前认为,HE患者脑组织中神经胶质细胞,尤其是星形胶质细胞的肿胀是HE发病机制的关键环节.此文就近年来关于星形胶质细胞与HE发病机制的研究进展作一综述.     

肝性脑病发病机制的研究进展

肝性脑病(HE)是一种由急、慢性肝功能障碍或门体分流异常所引起,基于代谢紊乱的轻、重程度不等的神经精神异常综合征,是各种终末期肝病的常见并发症和死亡原因之一。其临床表现可从性格改变、行为异常到意识障碍、昏迷。HE发病机制复杂,经典的氨中毒学说、神经递质改变已被普遍接受,近年提出的炎症反应、肠道菌群、星形胶质细胞早衰、脑血流改变、半通道功能障碍、胆汁酸等学说也日益受到重视。本文就HE发病机制的研究进展作一综述。     

高氨血症在肝性脑病发生中的地位

正肝性脑病(HE)是由于肝脏疾病和(或)门体分流引起的广泛神经系统或神经精神系统疾病表现。高血氨以及全身炎性反应对HE病理发生的主要作用已逐渐显现,然而相关的下游级联反应机制尚未明确~([1])。至今报道的HE病理发生机制可以概括为:谷氨酸能和γ-氨基丁酸能神经传导改变、线粒体功能异常、能量障碍、乳酸盐平衡失调、血脑屏障通透性增加、脑水肿/星形胶质细胞肿胀,以及毒性物质蓄积,如锰、胆汁酸、吲     

星形胶质细胞与肝性脑病

肝性脑病（HE）是由肝功能障碍引起的,以代谢紊乱为主要特征的中枢神经系统功能失调综合征。目前认为,HE患者脑组织中神经胶质细胞,尤其是星形胶质细胞的肿胀是HE发病机制的关键环节。此文就近年来关于星形胶质细胞与HE发病机制的研究进展作一综述。     

周细胞在脑小血管病发病机制中的作用

周细胞位于脑毛细血管内皮细胞、星形胶质细胞和神经元之间,具有维持血脑屏障完整性、调节脑血流量等多种功能。周细胞丢失可导致脑微循环功能障碍和血脑屏障破坏等病理过程,并与多种疾病有关,但目前其与脑小血管病的相关性研究较少。文章主要对周细胞在脑小血管病发病机制中的作用进行了综述。     

肝性脑病的治疗／肝性脑病治疗的临床研究

肝性脑病（HE）是在各种急慢性及终末期肝病的基础上出现的、以代谢混乱为主要特征的一系列神经精神紊乱综合征。其发病机制尚未明了，但已知山各种因素参与，包括氨、GABA受体上调、脑水肿及炎症介质反应等。其临床表现可从轻度的心理脑智能降低，到明显的精神神经症状和深度昏迷。HE的治疗原则主要基于现有对发病机制的了解和临床经验，氨中毒学说仍然在发病机制中占主要地位，因而其治疗亦主要以减少产氨的细菌及加速氨的排泄。     

U0126及地塞米松对氨培养SD乳鼠脑星形胶质细胞AQP4表达的影响

目的观察氨培养的脑星形胶质细胞水通道蛋白4(AQP4)的表达,地塞米松及丝裂原活化蛋白激酶(MAPKs)信号转导通路抑制剂U0126对其表达的影响。方法分离、培养SD大鼠脑星形胶质细胞,分为氨培养组、氨培养+U0126组、氨培养+地塞米松组和正常对照组,采用免疫组织化学及逆转录聚合酶链式反应检测AQP4在蛋白和基因水平的表达和变化。结果氨可致培养的星形胶质细胞AQP4蛋白和AQP4 mRNA的表达增加。U0126和地塞米松均可使氨培养星形胶质细胞AQP4 mRNA和AQP4蛋白的表达减少。结论氨可致AQP4表达增加,U0126和地塞米松有细胞保护作用,可有效保护脑星形胶质细胞。     

肝性脑病的诊断和治疗

肝性脑病(hepatic encephalopathy，HE)是由肝功能严重失调或障碍、以代谢紊乱为主要特征的中枢神经系统功能失调综合征。肝性脑病的发病机制比较复杂．但氨中毒学说依然处于中心地位。并且随着研究的不断发展，该学说的内容也在不断更新，包括氨干扰脑的能量代谢、对神经递质的影响及对星形胶质细胞的影响等。     

急性肝功能衰竭脑水肿机制研究进展

急性肝功能衰竭(ALF)常因发展为多器官功能衰竭而预后凶险,脑水肿是最常见的并发症,颅内压(ICP)增高、脑疝形成是ALF首位死因。ALF脑水肿机制仍未阐明,星形胶质细胞(AS)总体积占脑组织的50％,ALF脑水肿是以AS肿胀为特征的细胞性水肿。研究表明,脑氨代谢造成的细胞能量代谢障碍、神经递质代谢异常、细胞容量调节改变,以及脑血流自主调节削弱参与ALF脑水肿的形成。     

急性肝衰时脑水肿的发生机制

急性肝衰可引起脑水肿,其机制有两个方面:其一为细胞中毒。急性肝衰时,血中某些毒性物质抑制了脑细胞膜上Na~+,K~+-ATP酶活性,使细胞内Na~+外运发生障碍,同时高血氨使细胞内生成大量谷氨酰胺,两者均可使细胞内溶质浓度增加,吸引水向细胞内转移引起细胞中毒性脑水肿。其二为脑毛细血管通透性改变。某些毒性物质可使血-脑屏障功能及结构改变导致血管源性脑水肿。     

Recent insights into the pathogenesis of hepatic encephalopathy and treatments

Hepatic encephalopathy (HE) encompasses a spectrum of neuropsychiatric disorders related to liver failure. The development of HE can have a profound impact on mortality as well as quality of life for patients and carers. Ammonia is central in the disease process contributing to alteration in neurotransmission, oxidative stress, and cerebral edema and astrocyte swelling in acute liver failure. Inflammation in the presence of ammonia coactively worsens HE. Inflammation can result from hyperammonemic responses, endotoxemia, innate immune dysfunction or concurrent infection. This review summarizes the current processes implicated in the pathogenesis of HE, as well as current and potential treatments. Treatments currently focus on reducing inflammation and/or blood ammonia levels and provide varying degrees of success. Optimization of current treatments and initial testing of novel therapies will provide the basis of improvement of care in the near future.     

Pathogenesis of hepatic encephalopathy in acute liver failure

Hepatic encephalopathy (HE) in acute liver injury signifies a serious prognosis. Brain edema and intracranial hypertension are major causes of death in this syndrome. Comparison of HE in acute liver failure (ALF) with that of cirrhosis allows recognition of important differences and similarities. A key role for ammonia in the pathogenesis of both HE and brain edema is now firmly supported by clinical and experimental data. Additional factors, such as infection, products of the necrotic liver, and synergistic toxins, may contribute to an altered mental state. A low plasma osmolarity, high temperature, and both high and low arterial pressure may affect brain water content. A combined derangement of cellular osmolarity coupled with cerebral hyperemia can explain the development of brain edema in ALF. Increasingly, study of the mechanisms responsible for brain swelling provides critical information for understanding the pathogenesis of HE.     

Systemic inflammation and ammonia in hepatic encephalopathy

Infection and inflammation have been associated with the development of delirium for many centuries and there is a rapidly growing evidence base supporting the role of inflammation in exacerbating the neurological manifestations of both acute and chronic liver failure. Inflammation in the context of hepatic encephalopathy (HE) can arise directly within the brain itself resulting in astrocytic, microglial and neuronal dysfunction, impacting on the development of ‘brain failure’. Inflammation may also develop systemically and indirectly influence brain function. Systemic inflammation develops following liver injury, resulting in hyperammonemia and a ‘cytotoxic soup’ of pro-inflammatory mediators which are released into the circulation and modulate the impact of ammonia on the brain. The aim of this review is to summarise the current evidence base supporting the synergistic role of systemic inflammation and hyperammonemia in the pathogenesis of hepatic encephalopathy. Systemic inflammation and ammonia induce neutrophil degranulation and release reactive oxygen species into the peripheral circulation that may ultimately cross the blood brain barrier. Circulating endotoxin arising from the gut (bacterial translocation), superimposed sepsis, and hyperammonemia upregulate the expression of microbial pattern recognition receptors such as Toll-like receptors. The early recognition and management of systemic inflammation may not only facilitate improved outcomes in HE but supports the development of novel therapeutic strategies that reduce circulating endotoxemia and immune cell dysfunction.     

肝性脑病临床诊治的进展

肝性脑病（HE）是在各种急慢性及终末期肝病的基础上出现的以代谢紊乱为主要特征的神经、精神、功能失调综合征。目前一致认为,由于氨中毒及感染使星型胶质细胞肿胀及脑水肿,从而导致这些症状的出现。然而,导致脑部形态学改变的细胞学机制尚未明确。我们可以通过多种方法来诊断及评估不同程度的HE。HE的治疗主要是去除诱因,同时根据有效的经验用药来明确诊断。HE的经验用药主要是使用利福昔明及乳果糖以减少肠道内氨的产生与吸收。     

Extracellular brain ammonia levels in association with arterial ammonia,intracranial pressure and the use of albumin dialysis devices in pigs with acute liver failure

In acute liver failure (ALF) hyperammonemia plays a mayor role in the pathogenesis of hepatic encephalopathy (HE) but does not always correlate with the severity of mental deterioration and intracranial pressure (ICP). The aim of our study was to evaluate the association with extracellular brain ammonia, ICP and the therapeutical impact of two albumin dialysis devices. ALF was induced by complete hepatectomy in 13 pigs. All pigs were monitored and treated under intensive care conditions until death. Arterial blood and cerebral microdialysis samples were collected and ICP data recorded. Additionally in 5 pigs, standard albumin dialysis and in 3 animals an albumin dialysis prototype was initiated as a tool. Arterial ammonia increased straight after hepatectomy, while extracellular brain ammonia remained on a moderate level 10 h post ALF initiation. After 16 h the brain ammonia reached arterial ammonia levels before plateauing at 1,200 μM, though the arterial ammonia continued to rise. The ICP correlated with the brain ammonia levels. No impact of the different dialysis therapies on neither blood nor brain ammonia levels was observed. In ALF the extracellular brain ammonia revealed a delayed increase compared to arterial ammonia. It correlated strongly with the ICP and could serve as a sensitive marker for HE development. Albumin dialysis did not affect blood or brain ammonia levels.     

Mild hypothermia modifies ammonia-induced brain edema in rats after portacaval anastomosis

BACKGROUND & AIMS: The pathogenesis of brain edema in fulminant hepatic failure is still unresolved. Mild hypothermia (33 degrees-35 degreesC) can ameliorate brain edema after traumatic brain injury. We evaluated mild hypothermia in a model of ammonia-induced brain edema in which accumulation of brain glutamine has been proposed as a key pathogenic factor. METHODS: After portacaval anastomosis, anesthetized rats were infused with ammonium acetate at 33 degrees, 35 degrees, and 37 degreesC or vehicle at 37 degreesC. Water and glutamine levels in the brain, cardiac output, and regional and cerebral hemodynamics were measured when intracranial pressure increased 3-4-fold (ammonia infusion at 37 degrees) and matched times (other groups). RESULTS: Mild hypothermia reduced ammonia-induced brain swelling and increased intracranial pressure. Brain glutamine level was not decreased by hypothermia. Brain edema was accompanied by a specific increase in cerebral blood flow and oxygen consumption, which were normal in both hypothermic groups. When the ammonia infusion was continued in hypothermic rats, plasma ammonia levels continued to increase and brain swelling eventually developed. CONCLUSIONS: Mild hypothermia delays ammonia-induced brain edema. In this model, an increase in cerebral perfusion is required for brain edema to become manifest. Mild hypothermia could be tested for treatment of intracranial hypertension in fulminant hepatic failure.     

Inflammation:A novel target of current therapies for hepatic encephalopathy in liver cirrhosis

Hepatic encephalopathy(HE) is a severe neuropsychiatric syndrome that most commonly occurs in decompensated liver cirrhosis and incorporates a spectrumof manifestations that ranges from mild cognitive impairment to coma. Although the etiology of HE is not completely understood, it is believed that multiple underlying mechanisms are involved in the pathogenesis of HE, and one of the main factors is thought to be ammonia; however, the ammonia hypothesis in the pathogenesis of HE is incomplete. Recently, it has been increasingly demonstrated that inflammation, including systemic inflammation, neuroinflammation and endotoxemia, acts in concert with ammonia in the pathogenesis of HE in cirrhotic patients. Meanwhile, a good number of studies have found that current therapies for HE, such as lactulose, rifaximin, probiotics and the molecular adsorbent recirculating system, could inhibit different types of inflammation, thereby improving the neuropsychiatric manifestations and preventing the progression of HE in cirrhotic patients. The antiinflammatory effects of these current therapies provide a novel therapeutic approach for cirrhotic patients with HE. The purpose of this review is to describe the inflammatory mechanisms behind the etiology of HE in cirrhosis and discuss the current therapies that target the inflammatory pathogenesis of HE.     

Brain metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography

Animal studies and results from 13N-ammonia positron emission tomography (PET) in patients with cirrhosis and minimal hepatic encephalopathy suggest that a disturbed brain ammonia metabolism plays a pivotal role in the pathogenesis of hepatic encephalopathy (HE). We studied brain ammonia kinetics in 8 patients with cirrhosis with an acute episode of clinically overt HE (I-IV), 7 patients with cirrhosis without HE, and 5 healthy subjects, using contemporary dynamic 13N-ammonia PET. Time courses were obtained of 13N-concentrations in cerebral cortex, basal ganglia, and cerebellum (PET-scans) as well as arterial 13N-ammonia, 13N-urea, and 13N-glutamine concentrations (blood samples) after 13N-ammonia injection. Regional 13N-ammonia kinetics was calculated by non-linear fitting of a physiological model of brain ammonia metabolism to the data. Mean permeability-surface area product of 13N-ammonia transfer across blood-brain barrier in cortex, PS(BBB), was 0.21 mL blood/min/mL tissue in patients with HE, 0.31 in patients without HE, and 0.34 in healthy controls; similar differences were seen in basal ganglia and cerebellum. Metabolic trapping of blood 13N-ammonia in the brain showed neither regional, nor patient group differences. Mean net metabolic flux of ammonia from blood into intracellular glutamine in the cortex was 13.4 micromol/min/L tissue in patients with cirrhosis with HE, 7.4 in patients without HE, and 2.6 in healthy controls, significantly correlated to blood ammonia. In conclusion, increased cerebral trapping of ammonia in patients with cirrhosis with acute HE was primarily attributable to increased blood ammonia and to a minor extent to changed ammonia kinetics in the brain.     

Pathophysiology and management of hepatic encephalopathy 2014 update: Ammonia toxicity and hyponatremia

Hyperammonemia is a major factor involved in the pathogenesis of hepatic encephalopathy (HE). Ammonia elicits astrocyte swelling and causes brain edema. In addition, hyponatremia, a condition frequently observed in hepatic cirrhosis, also exacerbates brain edema, potentially becoming a factor that exacerbates HE. Therefore, as a treatment strategy for HE, alleviating ammonia toxicity is essential. In addition to restricting protein intake, synthetic disaccharides such as lactulose and lactitol, probiotics that improve gut flora, and rifaximin, an antibiotic with poor bioavailability, are also administrated. Additionally, branched‐chain amino acids and carnitine have also been administrated. Moreover, we investigated the current trend in the concomitant use of drugs with different mechanisms of action. In Japan, the V2 receptor antagonist tolvaptan can be administrated to hepatic cirrhosis patients with fluid retention. This drug is also useful as a countermeasure for hyponatremia in hepatic cirrhosis, and elucidating its effects in HE patients may therefore become an agenda in the future. These observations indicate that ammonia toxicity, gut flora control and low sodium control are major focuses in HE improvement and long‐term prognosis.     

Factors contributing to the development of overt encephalopathy in liver cirrhosis patients

The aim of this study was to clarify the relationships among psychometric testing results, blood ammonia (NH₃) levels, electrolyte abnormalities, and degree of inflammation, and their associations with the development of overt hepatic encephalopathy (HE) in liver cirrhosis (LC) patients. The relationships between covert HE and blood NH₃, sodium (Na), and C-reactive protein (CRP) were examined in 40 LC patients. The effects of elevated NH₃, hyponatremia, and elevated CRP on the development of overt HE were also investigated. The covert HE group had significantly lower serum Na levels and significantly higher serum CRP levels. During the median observation period of 11 months, 10 patients developed overt HE, and the results of multivariate analysis showed that covert HE and elevated blood NH₃ were factors contributing to the development of overt HE. Electrolyte abnormalities and mild inflammation are involved in the pathogenesis of HE. Abnormal psychometric testing results and hyperammonemia are linked to subsequent development of overt HE.