NIH conference. The gamma-aminobutyric acid A (GABAA) receptor complex and hepatic encephalopathy. Some recent advances

Increased neural inhibition appears to be an important component of the syndrome of hepatic encephalopathy. The pathways subserved by the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex are the principal inhibitory systems in the mammalian brain. Hyperpolarization of neural membranes is accomplished by an increase in transmembrane chloride flux through a GABA-gated chloride channel in the complex. The opening of the chloride channel is induced by the binding of GABA to its receptors, and it is potentiated by barbiturates or benzodiazepines that act at distinct recognition sites on the complex. Involvement of the GABA neurotransmitter system in hepatic encephalopathy is suggested by several findings in animal models of fulminant hepatic failure. For example, hepatic encephalopathy resembles encephalopathies induced by drugs (including benzodiazepines) that potentiate GABAergic neurotransmission. In addition, neurons from animals with hepatic encephalopathy show increased sensitivity to benzodiazepine and GABA receptor agonists. Moreover, these neurons are excited by benzodiazepine receptor antagonists at concentrations that do not affect control neurons. Also, elevated levels of a substance that inhibits radioligand binding to benzodiazepine receptors have been found in cerebrospinal fluid from animals with hepatic encephalopathy. Furthermore, manifestations of hepatic encephalopathy can be ameliorated by benzodiazepine receptor antagonists. The relevance of these findings to hepatic encephalopathy in human beings is supported by clinical observations showing that a benzodiazepine receptor antagonist can lessen the degree of hepatic encephalopathy. These findings suggest that an endogenous substance with benzodiazepine-like properties contributes to the neuropsychiatric manifestations of hepatic encephalopathy by augmenting GABAergic neurotransmission.     

Chronic hepatitis C virus infection and neurological and psychiatric disorders:An overview

Hepatitis C virus(HCV)infection is considered a systemic disease because of involvement of other organs and tissues concomitantly with liver disease.Among the extrahepatic manifestations,neuropsychiatric disorders have been reported in up to 50%of chronic HCV infected patients.Both the central and peripheral nervous system may be involved with a wide variety of clinical manifestations.Main HCV-associated neurological conditions include cerebrovascular events,encephalopathy,myelitis,encephalomyelitis,and cognitive impairment,whereas“brain fog”,depression,anxiety,and fatigue are at the top of the list of psychiatric disorders.Moreover,HCV infection is known to cause both motor and sensory peripheral neuropathy in the context of mixed cryoglobulinemia,and has also been recently recognized as an independent risk factor for stroke.These extrahepatic manifestations are independent of severity of the underlying chronic liver disease and hepatic encephalopathy.The brain is a suitable site for HCV replication,where the virus may directly exert neurotoxicity;other mechanisms proposed to explain the pathogenesis of neuropsychiatric disorders in chronic HCV infection include derangement of metabolic pathways of infected cells,alterations in neurotransmitter circuits,autoimmune disorders,and cerebral or systemic inflammation.A pathogenic role for HCV is also suggested by improvement of neurological and psychiatric symptoms in patients achieving a sustained virologic response following interferon treatment;however,further ad hoc trials are needed to fully assess the impact of HCV infection and specific antiviral treatments on associated neuropsychiatric disorders.     

Management of hepatic encephalopathy in patients with cirrhosis

The term hepatic encephalopathy encompasses a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction. Distinct syndromes are identified in acute liver failure and cirrhosis. Rapid deterioration in consciousness level and increased intracranial pressure that may result in brain herniation and death are a feature of acute liver failure whereas manifestations of hepatic encephalopathy in cirrhosis include psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, coma. In patients with acute-on-chronic liver failure the pathophysiology remains undefined. Ammonia has been considered central to its pathogenesis. In the brain, the astrocyte is the main site for ammonia detoxification, during the conversion of glutamate to glutamine. An increased ammonia level raises the amount of glutamine within astrocytes, causing an osmotic imbalance resulting in cell swelling and ultimately brain oedema. Recent studies suggest that inflammation and it modulators may play a synergistic role with ammonia in the pathogenesis of hepatic encephalopathy. Therapy of hepatic encephalopathy is directed primarily at reducing ammonia generation and increasing its detoxification. The currently accepted regimens to treat hepatic encephalopathy such as lactulose and protein restricted diets need further clinical trials and therefore placebo controlled clinical trials in hepatic encephalopathy are justified. In liver failure, ammonia metabolism involves multiple organs and therefore ammonia reduction will require simultaneous targeting of these organs. The present review describes the pathophysiological basis of hepatic encephalopathy and evaluates the available therapies.     

MR and 1H MR spectroscopy of the brain in patients with liver cirrhosis and early stages of hepatic encephalopathy

BACKGROUND/AIMS: Hepatic encephalopathy is a serious problem in patients with liver cirrhosis and precise pathophysiological mechanisms responsible for encephalopathy are not fully understood. Magnetic resonance imaging and magnetic resonance spectroscopy can be used to detect specific morphological and metabolic abnormalities in the brain even in patients with early stages of hepatic encephalopathy. METHODOLOGY: Twenty patients with liver cirrhosis and 14 patients with grade I-II hepatic encephalopathy were studied with magnetic resonance and proton magnetic resonance spectroscopy. Localized magnetic resonance spectra were acquired in the parietal gray/white matter regions and basal ganglia. Control group consisted of 20 healthy volunteers. RESULTS: Frequency and degree of brain atrophy and bilateral signal hyperintensities in globus pallidus were similar in groups with liver cirrhosis and with encephalopathy. Decreased myoinositol, choline and increased glutamine levels were noted in both groups whereas N-acetylaspartate levels were unchanged. The statistically significant differences between cirrhotic and encephalopathic groups were observed only in myoinositol/creatine ratio in basal ganglia. There were no significant differences in metabolic concentrations between parietal and basal ganglia regions. CONCLUSIONS: Metabolic brain alterations occur earlier than clinical evidence of hepatic encephalopathy but there is no correlation between presence of symptoms encephalopathy and magnetic resonance and magnetic resonance spectroscopy findings.     

Clinical Significance of Basal Ganglia Alterations at Brain MRI and 1H MRS in Cirrhosis and Role in the Pathogenesis of Hepatic Encephalopathy

In hepatic encephalopathy, a progressive and diffuse impairment in brain function is associated with gradual alterations that can be detected by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (¹H MRS). In some patients, a variety of movement disorders suggestive of extrapyramidal impairment points toward basal ganglia (BG) alterations. Accordingly, (i) hyperintensities at MRI predominant in the pallidum, an important region of BG involved in the motor control, (ii) redistribution of cerebral blood flow from cortical areas to BG structures observed using positron emission tomography studies, and (iii) the preferential pallidal location of Alzheimer astrocytosis, all support this hypothesis. In most clinical studies, little if any correlations have been found between cerebral hyperintensities and neurological manifestations. The application of a test designed to evaluate patients with Parkinson's disease (where extrapyramidal signs are typical) showed significant clinical correlations both with pallidal hyperintensity and with choline/creatine ratio at ¹H MRS in BG structures. Because of complex neuronal connections between BG and many cortical areas, BG dysfunction may influence the neurocognitive manifestations of hepatic encephalopathy. Similarities between chronic Mn intoxication and cirrhosis suggest common pathophysiological mechanisms including altered dopaminergic neurotransmission, although information in chronic liver failure is limited. Clinical observations are presented regarding the evolution of parkinsonian signs in various situations.     

Gastrointestinal and hepatic manifestations of mitochondrial disorders

Inherited defects of oxidative phosphorylation lead to heterogeneous, often multisystem, mitochondrial diseases. This review highlights those mitochondrial syndromes with prominent gastrointestinal and hepatic symptoms, categorised according to underlying disease mechanism. Mitochondrial encephalopathies with major gastrointestinal involvement include mitochondrial neurogastrointestinal encephalopathy and ethylmalonic encephalopathy, which are each associated with highly specific clinical and metabolic profiles. Mitochondrial hepatopathies are most frequently caused by defects of mitochondrial DNA maintenance and expression. Although mitochondrial disorders are notorious for extreme clinical, biochemical and genetic heterogeneity, there are some pathognomonic clinical and metabolic clues that suggest a specific diagnosis, and these are highlighted. An approach to diagnosis of these complex disorders is presented, together with a genetic classification, including mitochondrial DNA disorders and nuclear-encoded defects of mitochondrial DNA maintenance and translation, OXPHOS complex assembly and mitochondrial membrane lipids. Finally, supportive and experimental therapeutic options for these currently incurable diseases are reviewed, including liver transplantation, allogeneic haematopoietic stem cell transplantation and gene therapy.     

老年人海绵状脑病一例报告及文献复习

目的：探讨老年期发病的海绵状脑病的临床特点并分析误诊原因。方法：报告1例79例老年海绵状脑病的临床病理诊断过程。并复习国内报道的经病理学证实的8例60岁以上老年海绵状脑病患者的持征及脑电图、MRI资料。结果：老年人海绵状脑病急性发病者病程短,但都有进行性痴呆、肌阵挛及各种不自主运动发作。6例脑电图有典型的周期性三相波,1例MRI发现双侧基底节区T2高信号。3例初诊为脑血管病,1例为单疱性脑炎。病理上有典型的空泡和海绵状改变。结论：急性发病的老年人海绵状脑病容易误诊为脑血管病,但根据患者典型的临床表现,结论动态脑电图特征,必要时脑活检,可尽早诊断,减少医源性传播。     

肝性脑病的病因和防治探讨

肝性脑病至今仍以血液检查所见的生化代谢异常来解释，因不能圆满解释全面情况，需进一步探讨。不加选择收集70例肝硬化死亡者脑组织，分别作HE和免疫组化检查，观察病理改变和HBsAg、HBcAg表达。在70例脑组织标本中免疫组化染色HBsAg、HBcAg阳性者计30例，阳性率42.3%，临床上有肝性脑病表现者阳性率明显高于无表现者，脑组织病理改变较明显者，阳性率亦明显高于较轻者。肝硬化脑组织内出现HBsAg和HBcAg表达，而且阳性率与脑组织病理改变和是否出现临床表现密切有关。提示HBV侵及脑组织，导致病理形态改变可能是肝性脑病的病理基础，生化代谢异常可能仅是肝衰的表现。     

肝性脑病脑组织乙型肝炎病毒标志物免疫组化染色观察

目的 肝性脑病至今仍以血液检查所见的生化代谢异常来解释,因不能圆满解释全面情况,需进一步探讨。方法 不加选择收集70例肝硬变死亡者脑组织,分别作HE和免疫组化检查,观察病理改变和HBsAg、HBeAg表达。结果 在70例脑组织标本内免疫组化染色HBsAg、HBeAg阳性者计30例,阳性率42.3％,临床上有肝性脑病表现者阳性率明显高于无表现者,脑组织病理改变较明显者,阳性率亦明显高于较轻者。结论 肝硬变脑组织内出现HBsAg和HBeAg表达,而且阳性率与脑组织病理改变和是否出现临床表现密切相关,提示HBV侵及脑组织,导致病理形态改变可能是肝性脑病的病理基础,生化代谢异常可能仅是肝衰的表现。     

肝硬化患者稀释性低钠血症的研究现状与展望

稀释性低钠血症（DH）是肝硬化腹水患者常发生的一个并发症,并与难以控制的腹水、肝性脑病（HE）、自发性细菌性腹膜炎（SBP）及肝肾综合征（HRS）密切相关。肝硬化患者DH,轻者可表现为疲乏无力、肌张力低,重者可出现低钠性脑病,表现为认知、运动功能障碍,严重者可出现抽搐或昏迷。肝移植前存在DH的患者,其移植后的并发症和病死率明显增加。治疗上限制水摄入、输入白蛋白以纠正DH,严重低钠血症,静脉补充高张钠。几种非肽V2受体拮抗剂有望在肝硬化患者DH的治疗上发挥一定的作用。     

Hepatic encephalopathy: a review

Hepatic encephalopathy (HE) is a complication that presents in as many as 28% of patients with cirrhosis, and reported up to ten years after the diagnosis of cirrhosis. Commonly, it is observed in patients with severe hepatic failure and is characterized by neuropsychiatric manifestations that can range in severity from a mild alteration in mental state to a coma; additionally, some neuromuscular symptoms can be observed. This complication of either acute or chronic hepatic disease is the result of a diminished hepatic reservoir and inability to detoxify some toxins that originate in the bowel. Today, the role of astrocytes, specifically the Alzheimer type II cells, is known to be very important in the pathogenesis of the hepatic encephalopathy, and will be reviewed later. In conclusion, the objectives of this review are: To understand the pathogenesis of hepatic encephalopathy, To recognize the precipitating factors, as well as preventive measures for the development of the hepatic encephalopathy, To describe the new classification of hepatic encephalopathy and its clinical implications, To recognize the clinical manifestations and stages of the disease, To understand the main diagnostic tests used to detect the hepatic encephalopathy, To describe the main therapeutic treatments of hepatic encephalopathy.     

Alcohol use disorders and the brain

A diagnosis of alcohol use disorder is associated with a higher risk of dementia, but a dose–response relationship between alcohol intake consumption and cognitive impairment remains unclear. Alcohol is associated with a range of effects on the central nervous system at different doses and acts on a number of receptors. Acute disorders include Wernicke's encephalopathy (WE), traumatic brain injury, blackouts, seizures, stroke and hepatic encephalopathy. The most common manifestations of chronic alcohol consumption are Korsakoff's syndrome (KS) and alcohol‐related dementia (ARD). There is limited evidence for benefit from memantine in the treatment of ARD, but stronger evidence for the use of high‐dose parenteral thiamine in the progression of neuropsychiatric symptoms for WE. Accumulating evidence exists for pharmacological treatment in the prevention of hepatic encephalopathy. Rehabilitation of people with ARD may take several years, and requires an approach that addresses physical and psychosocial factors.     

Encéphalopathies métaboliques

Metabolic encephalopathies (ME) are a common cause of admission to emergency rooms, to hospitalization wards or to intensive care units. They could account for 10 to 20% of causes of comatose states in ICU and could be associated to a poor outcome especially in older patients. Nevertheless, they are often reversible and are associated with a favorable outcome when diagnosed and rapidly treated. They correspond to an altered brain functioning secondary to the deficiency of a substance that is mandatory for the normal brain functioning or to the accumulation of a substance that can be either endogenous or exogenous. It preferably occurs in co-morbid patients, complicating its diagnosis and its management. Altered brain functioning, going from mild neuropsychological impairment to coma, movement disorders especially myoclonus and the absence of any obvious differential diagnosis are highly suggestive of the diagnosis. Whereas some biological samplings and brain MRI are essential to rule out differential diagnosis, some others, such as electroencephalogram, may be able to propose important clues in favor of the diagnosis. Once simple symptomatic measures are introduced, the treatment consists mainly in the correction of the cause. Specific treatment options are only seldom available for ME; this is the case for hepatic encephalopathy and some drug-induced encephalopathies. We will successively describe in this review the main pathophysiological mechanisms, the main causes, favoring circumstances of ME, the differential diagnosis to rule out and the etiological work-up for the diagnosis. Finally, a diagnostic and therapeutic strategy for the care of patients with ME will be proposed.     

Hepatic encephalopathy: lack of changes of gamma-aminobutyric acid content in plasma and cerebrospinal fluid

The aim of the study was to verify the role of gamma-aminobutyric acid in the pathogenesis of hepatic encephalopathy occurring in cirrhotic patients by attempting to correlate plasma and cerebrospinal fluid content of authentic gamma-aminobutyric acid with the neurological manifestations of hepatic encephalopathy. For this purpose, plasma and cerebrospinal fluid gamma-aminobutyric acid levels were measured by means of mass fragmentography in 17 cirrhotic patients with hepatic encephalopathy and in 6 cirrhotics without neurological symptoms. Moreover, in all patients, a second sample was obtained during the clinical course of hepatic encephalopathy. The mean plasma and cerebrospinal fluid gamma-aminobutyric acid levels were not different in patients with or without hepatic encephalopathy and did not change during the evolution of the neurological symptoms. The lack of changes in the gamma-aminobutyric acid content in plasma and cerebrospinal fluid during hepatic encephalopathy is in contrast with the hypothesized importance of increased entry into the brain of gamma-aminobutyric acid in the pathogenesis of hepatic encephalopathy.     

Characteristics of Minimal Hepatic Encephalopathy

The term minimal hepatic encephalopathy refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy. Use of this term emphasizes the fact that the entity of hepatic encephalopathy is a single syndrome with quantitatively distinct features relating to severity. The absence of clinical evidence of hepatic encephalopathy is key to the diagnosis and can only be determined by a detailed assessment of the patients' history and a comprehensive neurological assessment of consciousness, cognitive, and motor function. The neuropsychological features of minimal hepatic encephalopathy point to a disorder of executive functioning, particularly selective attention and psychomotor speed, but other abnormalities may be observed. Alterations in electrophysiological variables have been described; endogenous evoked potentials are, in principle, more likely to reflect the presence of minimal hepatic encephalopathy, since they reflect cognitive phenomena rather than mere stimulus conduction but the specificity of the changes observed is unclear at present. Changes have also been described in the execution of diadochokinetic movements and in the capacity to discriminate flickering light, both of which may have diagnostic potential. The changes observed in cerebral blood flow and metabolism in SPET, PET, and 1H and 31P MRS studies reflect the pathogenic process that underlies the condition rather than providing diagnostic information. Similarly, the morphological brain abnormalities identified in this population, including mild brain oedema, hyperintensity of the globus pallidus and other subcortical nuclei observed in cerebral MR studies, and the central and cortical atrophy observed in neural imaging studies, are unlikely to have diagnostic utility. The presence of minimal hepatic encephalopathy is not without clinical consequence; it has a detrimental effect on health-related quality of life, the ability to perform complex tasks such as driving, and on outcome.     

Encephalopathy and liver transplantation

Liver transplantation (LT) candidates experience frequently episodic or persistent hepatic encephalopathy. In addition, these patients can exhibit neurological comorbidities that contribute to cognitive impairment in the pre-transplant period. Assessment of the respective contribution of hepatic encephalopathy or comorbidities in the cognitive manifestations is critical to estimate the neurological benefits of restoring liver function. Magnetic resonance imaging and spectroscopy are useful to assess the impact of liver failure or comorbidities. This assessment is critical to decide liver transplant in difficult cases. In the early postoperative period, LT is commonly complicated by a confusional syndrome. The possible role of persisting hepatic encephalopathy in its development has not been clearly established. The origin is usually considered multifactorial and relates to complications following LT, such as infections, rejection, primary liver dysfunction, immunosuppressors, etc.… The diagnosis and treatment is based in the recognition of comorbidities and optimal care of metabolic disturbances. Several studies have demonstrated recovery of cognitive function after LT in patients that have exhibited hepatic encephalopathy. However, some deficits may persist specifically among patients with persistent HE. Other factors present before LT that contribute to a worse neuropsychological outcome after LT are diabetes mellitus and alcohol consumption. Long-term after LT, cognitive function may worsen in relation to vascular risk factors.     

Hepatic encephalopathy

Hepatic encephalopathy is a severe complication of cirrhosis that is related to the effects of ammonia. Analysis of interorgan ammonia trafficking has identified an important role of skeletal muscle in ammonia removal and has highlighted the importance of the nutritional status. Ammonia causes neurotransmitter abnormalities and induces injury to astrocytes that is partially mediated by oxidative stress. These disturbances lead to astrocyte swelling and brain edema, which appear to be involved in the pathogenesis of neurological manifestations. Inflammatory mediators worsen brain disturbances. New methods for assessing hepatic encephalopathy include clinical scales, neuropsychological tests, imaging of portal-systemic circulation, and magnetic resonance of the brain. Reappraisal of current therapy indicates the need for performing placebo-controlled trials and the lack of evidence for administering diets with restricted protein content. Liver transplant should be considered in selected patients with hepatic encephalopathy. Future prospects include new drugs that decrease plasma ammonia, measures to reduce brain edema, and liver-support devices.     

The Central Opioid System in Liver Disease and Its Complications

The best known example of an interaction between the liver and the brain is hepatic encephalopathy. In the 90s a central nervous system origin of the pruritis of cholestatic liver disease and more recently of fatigue of liver disease has been suggested. Hence, three important manifestations of liver disease may be of central origin. Evidence is accumulating that the central opioid system is involved in the development of these manifestations. This short review summarizes current knowledge on the role of the opioid system in development of these liver disease manifestations.     

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.     

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自身免疫性脑炎是一组可能由某些自身抗体、活性细胞或者相关因子与中枢神经系统神经元表面的蛋白等相互作用而导致的疾病。该组疾病中各个疾病典型的临床表现分别与目前已知的某个特异性抗体相对应,病情通常与抗体水平相关,少数病例可能与某些潜在的肿瘤有关。目前已知的自身免疫性脑炎常见的有边缘叶脑炎(lim-bic encephalitis,LE)、莫万综合征(movan’s syndrome,MOS)、桥本脑病(Hashimoto’s encephalitis)以及抗NMDA受体脑炎等,广义的讲还包括免疫相关疾病的脑炎表现。疾病分类复杂,诊断主要依靠临床表现和有关特异性检查(免疫标记物、影像)等做出,本文将对目前这一组疾病的诊断和鉴别做一总结。