肝硬化患者血清腹水清蛋白梯度与肝性脑病的关系

目的探讨肝硬化失代偿期患者血清腹水清蛋白梯度（SAAG）与肝性脑病的关系。方法 120例肝硬化失代偿期腹水并发肝性脑病患者,其中,Ⅰ级肝性脑病（A组）41例;Ⅱ级肝性脑病（B组）43例;Ⅲ～Ⅳ级肝性脑病（C组）36例。在腹腔穿刺抽液的当日早晨空腹采血测定血清总蛋白、清蛋白;腹水总蛋白、清蛋白。SAAG=血清清蛋清-腹水清蛋白。如果血清球蛋白〈30g/L或〉50g/L,用公式校正SAAG。结果 120例血清腹水清蛋白梯度（SAAG）均≥11g/L,符合门脉高压性腹水。A组SAAG为（12.70±0.45）g/L;B组SAAG为（16.62±1.70）g/L;C组SAAG为（22.96±2.46）g/L。B组与A组比较P〈0.01;C组与B组比较P〈0.01;C组与A组比较P〈0.01,差异有统计学意义。结论血清腹水清蛋白梯度对判断肝性脑病的程度及预后具有临床价值。     

Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

BACKGROUND AND PURPOSE

Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT_1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide.

EXPERIMENTAL APPROACH

Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure.

KEY RESULTS

Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment.

CONCLUSIONS AND IMPLICATIONS

Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain.     

Pharmacotherapy of hepatic encephalopathy in cirrhosis

Importance of the field: Hepatic encephalopathy (HE) is a major complication encountered in nearly half of the patients with liver cirrhosis.

Areas covered in this review: A review of the safety and efficacy of current therapies for HE that seek to pre-empt ammonia production and/or to increase its elimination, reducing inflammation, blocking benzodiazepine-like compound production, and supporting systemic hemodynamics.

What the reader will gain: Insight into some recent advances in the management of HE that could modify our therapeutic approach to end-stage liver disease. Cirrhotic individuals during an overt HE episode require careful management, focusing on precipitant factors as well as metabolic and hemodynamic derangements.

Take home message: Intestinal ammoniagenesis requires flora modification by antibiotics, prebiotics and probiotics; glutaminase inhibition as well as antibiotics to pre-empt systemic inflammation. Hemodynamic/fluid support is essential. Nutritional support is crucial and hypoproteinemic diets should be avoided. Blocking benzodiazepine-like compounds by the use of flumazenil could be useful in patients with severe, benzodiazepine-induced HE. Long-term rifaximin is well tolerated, does not promote resistance and could decrease overt HE bouts in patients with previous episodes of overt HE. Lactulose is better than no treatment in improving quality of life in patients with minimal HE; it also acts as secondary prophylaxis following overt HE.     

Neurochemical studies of hepatic encephalopathy

Despite intensive research, the neurochemical basis of hepatic encephalopathy (HE) has not been defined. Theories that are currently favoured to explain the cerebral dysfunction that accompanies acute or chronic hepatic failure include: (1) ammonia acting as the putative neurotoxin; (2) perturbed monoamine neutrotransmission as a result of altered plasmo amino acid metabolism; (3) an imbalance between excitatory amino acid neurotransmission, mediated by glutamate, and inhibitory amino acid neurotransmission, mediated by γ-aminobutyric acid (GABA); and (4) increased cerebral concentrations of an endogenous benzodiazepine-like substance. Studies of amino acid neurotransmitter receptors in HE have yielded conflicting results. The majority of studies in different animal models of acute and chronic HE and in patients have reported that brain GABA receptor density and affinity are unchanged. There have been fewer studies of excitatory amino acid receptors and these have also yielded conflicting results. However, the majority suggest that components of the glutamate receptor system are perturbed in HE. Further investigation is required to determine the significance of these findings to the pathogenesis of HE.     

肝性脑病的药物治疗

肝性脑病系指由肝功能严重失调或障碍所致，以代谢紊乱为主要特征的中枢神经系统功能失调综合征。有肝功能失调或障碍的患者，出现神经、精神症状，在排除其他大脑疾病后，即可诊断为肝性脑病。美国胃肠病学院实践资料委员会的《肝性脑病实践指导》提出，肝性脑病的防治应该在正确的诊断和分期分级的前提下，采用综合的防治方案。目前认为，对肝性脑病的治疗主要以预防和药物治疗为主，其中药物治疗包括营养支持，降低肠道氮质负荷，脱氨药物、支链氦基酸、影响神经传导药物以及纳络酮等药物的综合应用等。     

Emerging drugs for hepatic encephalopathy

Background: Hepatic encephalopathy (HE) is a severe complication of cirrhosis, seriously affecting the patients' quality of life. The classical approach aimed at reducing the production of gut-derived toxins, such as ammonia, is under debate as, at the moment, the information obtained from the clinical trials does not support any specific treatment for HE. Objectives: i) To discuss present therapeutic strategies and possible future developments; ii) to identify areas of medical needs and iii) to suggest the ideal design and methodology for randomized controlled trials (RCTs) in HE. Methods: Current approaches were obtained from already available RCTs or from experimental animal studies. Those approaches developed from studies on HE pathophysiology were considered as working hypotheses for future therapies.Results/conclusion: Our competence in testing old and new treatment modalities by RCTs with appropriate clinically relevant end points should urgently be improved. The patients at risk of HE are identifiable, and studies specifically aimed at establishing whether HE may be prevented or not are needed. As far as new treatment modalities are concerned, RCTs on the modulators of the intestinal bacterial flora and on the molecular adsorbent recirculating system are already available, but further studies are needed to confirm these promising approaches.     

门冬氨酸鸟氨酸联合精氨酸治疗肝硬化肝性脑病的临床研究

目的观察门冬氨酸鸟氨酸(瑞甘)联合精氨酸治疗肝硬化并发肝性脑病的临床疗效。方法将84例肝硬化并发肝性脑病的患者随机分为治疗组和对照组。治疗组采用精氨酸加门冬氨酸鸟氨酸(瑞甘),对照组仅用精氨酸治疗,药物均用7d,两组其他基础治疗相同,治疗前后测定血氨含量、TBIL,并观察肝性脑病转归的影响、临床有效率。结果门冬氨酸鸟氨酸(瑞甘)联合精氨酸治疗肝硬化并发肝性脑病对降低血氨、TBIL和肝性脑病评分改善等明显优于单用精氨酸(P<0.05),临床显效率及总有效率高于对照组,两组间差异有统计学意义(P<0.05)。结论门冬氨酸鸟氨酸(瑞甘)联合精氨酸治疗肝硬化并发肝性脑病疗效确切,效果优于单用精氨酸,且无不良反应发生率增加,有较好临床推广价值。     

pathogenesis and treatment of chronic hepatic encephalopathy

The various treatment strategies for hepatic encephalopathy are compared in the light of the available body of scientific work on the pathogenesis of the syndrome. Data on animal models of hepatic encephalopathy and in vitro studies on brain slices are discussed. Difficulties in extrapolating the results obtained to the human situation are highlighted, while results of human positron emission tomography and magnetic resonance spectroscopy studies are outlined on the background of the potential weaknesses of these non-invasive techniques.     

低钠血症与肝性脑病的关系

目的　利尿是肝硬变腹水的主要治疗措施 ,但并非病因治疗 ,需要研究。方法　收集我院肝硬变腹水住院病人病历 680份 ,逐份分析。结果　入院前即因使用利尿剂 ,3 8 4 %病人出现低血Na+,治疗后 68.2 %上升 ,平均下降 8.4～ 9.4mmol/L ,血Na+含量平均降至 12 1.3～ 12 4 .9mmol/L ;临床显示肝昏迷者 76.6%血Na+均在 13 0mmol/L以内 ;而未使用利尿剂者 ,血Na+均在正常范围内 ,而且低血Na+与肝昏迷的出现有一定关系。结论　利尿剂治疗中引起的低血Na+可导致脑水肿出现脑功能障碍 ,值得重视。三原则两辅助治疗措施可以避免这一缺点。     

中药提取物水苏糖对临床／亚临床肝性脑病的预防作用

目的：探讨中药提取物水苏糖对临床／亚临床肝性脑病（HE／SHE）的预防作用。方法：乳果糖组,水苏糖组和葡萄糖对照组新西兰家兔各8只,实验前行体感诱发电位（SEP）,脑干听觉诱发电位（BAEP）和动脉血氨检查。于0．24h分别耳缘静脉注射硫代乙酰胺（TAA）,并在实验开始时3组分别灌胃乳果糖、水苏糖和葡萄糖（剂量均为1．33g.kg^-1)作为HE／SHE的预防性用药,待出现肝衰竭后重复检测SEP,BAEP及动脉血氨。结果：水苏糖组,乳果糖组家兔SEP,BAEP各波潜伏期较对照组明显缩短（P＜0．01）,动脉血氨水平明显下降（P＜0．01）,水苏糖组和乳果糖组各波潜伏期和乳果糖组各波潜伏期和动脉血氨无差异（P＜0．05）,结论：水苏糖对临床,亚临床肝性脑病有预防作用。     

cGMP signaling pathway in hepatic encephalopathy neuroinflammation and cognition

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that results from liver failure and is characterized by a wide range of symptoms such as alteration in the sleep-waking cycle, neuromuscular coordination, mood, and cognition. The deregulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) signaling pathway is thought to play an important role in the etiology and progression of neurodegenerative diseases, and several studies pointed that the cGMP signaling is impaired in patients with HE and experimental models of chronic hyperammonemia. This review aimed to briefly present the current knowledge of the cGMP signaling pathways in neuroinflammation, neurogenesis, and memory in hepatic encephalopathy and its potential therapeutic role.     

大鼠急性与慢性肝衰竭肝性脑病模型对照研究

目的制备SD大鼠的急、慢性肝衰竭(ALF、CLF)和肝性脑病(HE)动物模型。方法SD大鼠100只,随机分为5组:正常对照组为Ⅰ号组,ALFⅡ、Ⅲ号组,CLF组Ⅳ、Ⅴ号组,每组20只。分别用5%硫代乙酰胺(TAA)500m g/kg和3%TAA300m g/kg灌胃,制作ALF组和CLF组肝性脑病动物模型。检测肝生化指标、血氨及肝脏和脑组织组织学对照分析。结果应用5%TAA 500m g/kg灌胃法建立的大鼠ALF及CLF实验模型,肝功能TB IL与3%TAA 300m g/kg组比较差异有非常显著性(P<0.01)。脑和肝脏组织病理学检查前者较后者更符合肝衰竭HE表现。死亡率和死亡时间两者相仿。结论5%TAA 500m g/kg两次灌胃法制作大鼠肝衰竭方法简便易行,且更符合研究要求。     

肝性脑病的药物治疗

肝性脑病是各种急、慢性肝病的常见并发病。本文概述乳果糖、乳梨醇、氟马西尼等药物对肝性脑病的治疗作用。     

Endocannabinoids in neuroimmunology and stress

Two topics are presented in this review. In the first section, we review data regarding the effects of the endocannabinoids (eCBs) and cannabinoid receptors on neuroimmune function. The function of eCBs in the interaction between the immune system and the central nervous system (CNS) is of particular interest, since the CNS itself is a rich source of eCBs while being exquisitely sensitive to inflammation. There are several sites at which cannabinoids can influence neuroinflammation. Microglial cells express both CB receptors and make eCBs. Activation of CB receptors on these cells seems to promote migration and proliferation but to reduce activation to macrophages. In several neurodegenerative diseases, up-regulation of microglial CB2 receptors have been observed. It is our hypothesis that microglial CB receptor activity is anti-inflammatory and could be exploited to manipulate neuroinflammatory processes with a minimum of unwanted effects. The second topic discussed suggests that the eCB/CB1 receptor pair is involved in the responses of animals to acute, repeated and variable stress. The roles of this pair are complex and dependent upon previous stress, among other things. Dysfunctional responding to stress is a component of several human neuropsychiatric disorders, including anxiety and panic disorders, post-traumatic stress disorders, premenstrual dysphoria and quite possibly, drug abuse. While it is too early to say with certainty, it is very possible that either inhibition or potentiation of endocannabinoid signaling will be an efficacious novel therapeutic approach to more than one human psychiatric disease.     

肝性脑病的病因及治疗进展

肝性脑病是严重肝病引起的,以代谢紊乱为基础的中枢神经系统功能失调的综合征,根据临床症状的轻重分为症状明显型肝性脑病和轻微型肝性脑病。本文中,作者就肝性脑病在病因及治疗的应用进展方面作了一个综述。     

Selective cyclooxygenase inhibition improves hepatic encephalopathy in fulminant hepatic failure of rat

Prostaglandin plays an important role in the pathogenesis of hepatic encephalopathy. This study investigated the therapeutic effects of selective cyclooxygenase (COX) inhibitor on hepatic encephalopathy in thioacetamide-induced fulminant hepatic failure (FHF) rats. The selective COX-1 inhibitor (SC-560), COX-2 inhibitor (NS-398) or distilled water (control) was administered in the normal and FHF rats. The mortality rates were calculated and severity of hepatic encephalopathy was evaluated using Opto-Varimex activity sensors. Besides, the levels of blood ammonia, 6-keto-prostaglandin-F(1α) (PGF(1α), active metabolite of prostacyclin), tumor necrosis factor α (TNF-α) and liver biochemistry tests were measured. The hepatic mRNA expressions of nitric oxide synthase and COX were determined, and the liver histopathological changes were examined. The liver biochemistries and motor activities were similar among COX-1, COX-2 treated and control groups. SC-560 treatment improved the survival of FHF rats (mortality rates: SC-560 group 0%, control 33%; P=0.037). Besides, SC-560 treatment improved hepatic encephalopathy and decrease plasma levels of PGF(1α), but did not change TNF-α levels. There were no significant differences in liver biochemistry and ammonia levels except that the aspartate aminotransferase levels were lower in the NS-398 treated group. Both hepatic COX-1 and COX-2 mRNA expressions were attenuated after SC-560 treatment. The decreased COX-2 and increased constitutive nitric oxide synthase mRNA expressions were found after NS-398 treatment. Besides, the histopathology of liver got improved after selective COX inhibition. In conclusion, COX-1 inhibition by SC-560 decreases the mortalities and improves motor activities, suggesting COX-1, rather than COX-2, plays a major role in hepatic encephalopathy of FHF rats.     

Clinical trial: oral zinc in hepatic encephalopathy

Aliment Pharmacol Ther 2010; 32: 1080–1090

Summary

Background Hepatic encephalopathy has a negative effect on patient health‐related quality of life (HRQOL). Zinc supplementation has been effective with regard to altered nitrogen metabolism. Aim To investigate the effectiveness of oral zinc supplementation on hepatic encephalopathy and HRQOL. Methods Seventy‐nine cirrhotic patients with hepatic encephalopathy were randomized to receive 225 mg of polaprezinc in addition to standard therapies of a protein‐restricted diet including branched‐chain amino acid and lactulose, or to continue only standard therapies for 6 months. The change of HRQOL by Short Form‐36, hepatic encephalopathy grade, laboratory parameters, and neuropsychological (NP) tests were compared at baseline and at 6 months. We also evaluated via multivariate analysis whether zinc supplementation and clinical variables correlated with the changes in physical component scale (PCS) and mental component scale (MCS) between the two visits. Results Zinc supplementation significantly improved the PCS (P = 0.04), but not the MCS (P = 0.95). Zinc supplementation significantly decreased hepatic encephalopathy grade and blood ammonia levels (P = 0.03 and P = 0.01), and improved Child‐Pugh score and NP tests compared with standard therapy (P = 0.04 and P = 0.02). In multivariate analysis, zinc supplementation was significantly associated with improvement in PCS (P = 0.03), whereas it was not significantly associated with change in MCS (P = 0.98). Conclusion Zinc supplementation is effective in hepatic encephalopathy and consequently improves patients HRQOL.