硫代乙酰胺诱导大鼠急性肝性脑病模型建立的用药时间研究

目的通过硫代乙酰胺（TAA,300mg·kg^-1·d^-1）不同用药时间诱导A型肝性脑病,比较大鼠的行为学、生物化学以及组织学改变,探讨造模最适时间。方法将大鼠分为A、B、C、D四组,其中A组为正常对照组;B、C、Di组用TAA（300mg·kg^-1·d^-1）分别连续灌胃2d、3d、4d,A组用相等量生理盐水灌胃4d。比较各组大鼠行为学变化、脑功能评分、AHE的诱导率和致死率,并分析各组给药结束24h后血氨、ALT、AST、TBIL的差异。结果C、D组比B组大鼠脑功能评分高,差异有统计学意义（P〈0．0083）;C、D组比B组诱导率高（P〈0．0083）,而D组比B、C组的大鼠致死率高,差异有统计学意义（P〈0．0083）;C、D组血氨及ALT、AST、TBIL肝功能指标比B组高,差异有统计学意义（P〈0．0083）;C、D组TAA用药后肝组织学观察炎症浸润、坏死、纤维化等损害最明显。结论300mg·kg^-1·d^-1的TAA连续灌胃3d,行为学改变显著．致死率较低．血氨较高．肝功能损害明显．为TAA诱导大鼠急性肝性脑病适宜时间。     

肝性脑病

症状性脑病源于多种病因,涉及各系统疾病,所以鉴别诊断就显得格外重要。只有确定诊断后“对症下药”,才能取得理想的疗效。本笔谈注重实用,望能对大家有所启迪。     

丁酸钠对肝性脑病大鼠血氨浓度的影响初探

目的：观察不同浓度丁酸钠对肝性脑病（HE）大鼠血氨浓度的影响以及对HE的防治效果。方法采用腹腔注射硫代乙酰胺（TAA）诱导急性肝性脑病模型。饲喂两周后造模两天,观察大鼠一般情况,并进行神经反射评级,血浆TBil、DBil、AST、ALT、血氨和肠道pH值等指标的测定。结果丁酸钠各组HE大鼠TBil、DBil、ALT、AST均有所下降,其中丁酸钠A组的肠道pH值较模型组差异有统计学意义（P ＜0.05）,丁酸钠A、B两组的血氨浓度较模型组明显降低（P均＜0.001）。丁酸钠处理可改善大鼠的神经反射,降低大鼠肝性脑病的分期。结论丁酸钠通过酸化肠道,降低HE大鼠的血氨浓度,进而改善HE大鼠所表现出来的精神症状。     

亚临床型肝性脑病

亚临床型肝性脑病贾林李瑜元所谓亚临床型肝性脑病（ｓｕｂｃｌｉｎｉｃａｌｈｅｐａｔｉｃｅｎ－ｃｅｐｈａｌｏｐａｔｈｙ，ＳＨＥ）是指某些肝硬化患者（无论病因如何），其临床表现、常规的精神和神经功能检查正常，但有智力检测和脑诱发电位异常［１］。其最初是作为...     

肝性脑病的防治

肝性脑病的防治山东医科大学附属医院（２５００１２）赵宪，郭建强肝性脑病为肝脏疾病的主要死因之一，临床上主要采取综合治疗。１消除诱因急性病毒性、药物性或中毒性重症肝炎引起的急性或亚急性肝性脑病多无明显锈因，而因肝硬化和门脉高压症行门体分流术的患者，术后...     

肝性脑病的治疗近况

肝性脑病可由严重肝病或门一体分流(Portalsystemic encephalopath y,PSE)引起。其发病机理为:血脑屏障的结构与功能发生改变,以氨为主的多种毒性物质在血内沉积,氨基酸失平衡、假性神经递质及γ-氨基丁酸受体兴奋等。它常是由多个因素联合作用所致,治疗上应采用针对性的综合性措施,方能提高治疗成功率,降低病死率. 一、治疗原则氨对大脑有潜在毒性,它在肝内通过尿素合成而被解毒。严重肝病时尿素合成率明显减低,氨稳定性的维持由肝脏转向其它器官、组织,如肾及骨骼肌.在那里,氨被转化为谷氨酰胺及丙氨酸。晚期肝硬化患者有肌肉消瘦,肌肉对氨的摄取减少,同时蛋白质分解代谢旺盛,特别在伴有感染时.氨基酸     

硝酸甘油治疗肝性脑病的临床观察

目前肝性脑病的治疗是以减少和消除氨、拮抗假性神经递质等综合基础疗法为主。笔者根据肝硬化肝性脑病的发病机理,应用血管扩张药治疗20例,特总结如下。 1 资料与方法 1.1 一般资料 全部病例均为1992～1995年度住院患者,均经详细采集病史,系统体检,检测肝功能,用ELISA法检测乙肝病毒有关血清学指标,B超或     

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。     

Evidence against a role for endotoxin in the hepatic encephalopathy of rats with thioacetamide-induced fulminant hepatic failure

BACKGROUND AND AIMS: Endotoxin has been proposed to participate in the development of hepatic encephalopathy. However, there is no published data concerning the effects of endotoxin neutralization on the degree of hepatic encephalopathy. The present study investigated the effect of chronic intraperitoneal injection of polymyxin B, a neutralizing antagonist of endotoxin, on hepatic encephalopathy in rats with thioacetamide (TAA)-induced fulminant hepatic failure. METHODS: Male Sprague-Dawley rats weighing 300-350 g were used. Fulminant hepatic failure was induced by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Two series of rats were designed to compare the effects of low dose (0.1 mg) or high dose (0.2 mg) intraperitoneal polymyxin B administration versus normal saline (NS) on hepatic encephalopathy. The injection was twice daily started from 2 days prior to TAA administration and lasted for 5 days. Severity of encephalopathy was assessed by the counts of motor activity in an Opto-Varimex animal activity meter. Plasma levels of endotoxin and tumor necrosis factor-alpha (an index of liver injury) were measured by Limulus assay and the ELISA method, respectively. RESULTS: Neutralization of endotoxin by either low dose or high dose polymyxin B administration did not significantly alleviate the degree of hepatic encephalopathy, as represented by the counts of motor activities (P > 0.05). Plasma levels of endotoxin and tumor necrosis factor-alpha were comparable between rats treated with polymyxin B or NS (P > 0.05). CONCLUSION: Our findings do not support the notion that endotoxin plays a major role in the pathogenesis of hepatic encephalopathy in rats with TAA-induced fulminant hepatic failure.     

Hepatic stimulator substance activity in animal model of fulminant hepatic failure and encephalopathy

Hepatic stimulator substance (HSS) is a known liver-specific but species-nonspecific growth factor. In the present study we examined the activity of the endogenously produced HSS in an established experimental model of fulminant hepatic failure (FHF) and encephalopathy, induced by repeated injections of thioacetamide (TAA). FHF was induced by three consecutive intraperitoneal injections of TAA (400 mg/kg body weight) in rats, at time intervals of 24 hr. The animals were killed at 0, 6, 12, or 18 hr following the last injection of TAA. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of liver thymidine kinase (EC 2.7.1.21), and the assessment of mitotic index in hepatocytes were used to estimate liver regeneration. HSS extract obtained from the livers of TAA-treated rats, sacrificed at the above-mentioned time points was tested for its activity. Increased HSS activity was noted in all TAA-treated animals, presenting a peak at 12 hr following the third TAA dose, suggesting active participation of this growth factor in hepatocyte replication in this animal model of FHF and encephalopathy. It may also be suggested that up-regulation of HSS activity could be used in future as a therapeutic approach in FHF.     

Detrimental effects of nitric oxide inhibition on hepatic encephalopathy in rats with thioacetamide-induced fulminant hepatic failure: role of nitric oxide synthase isoforms

BACKGROUND: Hepatic encephalopathy is a complex neuropsychiatric syndrome. A previous study showed that chronic nitric oxide (NO) inhibition aggravated the severity of encephalopathy in thioacetamide (TAA)-treated rats. The present study investigated the relative contribution of NO synthase (NOS) isoforms on the severity of hepatic encephalopathy in TAA-treated rats. METHOD: Fulminant hepatic failure was induced in male Sprague-Dawley rats by intraperitoneal injection of TAA (350 mg/kg/day) for 3 days. Rats were divided into three groups to receive N(omega)-nitro-L-arginine methyl ester (L-NAME, a non-selective NOS inhibitor, 25 mg/kg/day in tap water), L-canavanine (an inducible NOS inhibitor, 100 mg/kg/day via intraperitoneal injection) or normal saline (N/S) from 2 days prior to TAA administration and lasting for 5 days. Severity of encephalopathy was assessed by the counts of motor activity. Plasma levels of tumor necrosis factor-alpha (TNF- alpha) were determined by enzyme-linked immunosorbent assay (ELISA), and total bilirubin, alanine aminotransferase (ALT) and creatinine were determined by colorimetric assay. RESULTS: Compared with L-canavanine or N/S-treated rats (0% and 4%, respectively), the mortality rate was significantly higher in rats receiving L-NAME administration (29%, P < 0.005). Inhibition of NO created detrimental effects on the counts of motor activities (P < 0.05). Rats treated with L-NAME had significantly higher plasma levels of total bilirubin, ALT, creatinine and TNF- alpha as compared with rats treated with L-canavanine or N/S (P < 0.01). CONCLUSION: Chronic L-NAME administration, but not L-canavanine, had detrimental effects on the severity of hepatic damage and motor activities in TAA-treated rats. These results suggest that constitutive NOS activities play a major protective role in rats with fulminant hepatic failure.     

Lack of therapeutic effects of gabexate mesilate on the hepatic encephalopathy in rats with acute and chronic hepatic failure

Background and Aim: Inflammation plays a pivotal role in liver injury. Gabexate mesilate (GM, a protease inhibitor) inhibits inflammation by blocking various serine proteases. This study examined the effects of GM on hepatic encephalopathy in rats with acute and chronic liver failure. Methods: Acute and chronic liver failure (cirrhosis) were induced by intraperitoneal TAA administration (350 mg/kg/day for 3 days) and common bile duct ligation, respectively, in male Sprague‐Dawley rats. Rats were randomized to receive either GM (50 mg/10 mL/kg) or saline intraperitoneally for 5 days. Severity of encephalopathy was assessed by the Opto‐Varimex animal activity meter and hemodynamic parameters, mean arterial pressure and portal pressure, were measured (only in chronic liver failure rats). Plasma levels of liver biochemistry, ammonia, nitrate/nitrite, interleukins (IL) and tumor necrosis factor (TNF)‐α were determined. Results: In rats with acute liver failure, GM treatment significantly decreased the plasma levels of alanine aminotransferase (P = 0.02), but no significant difference of motor activity, plasma levels of ammonia, IL‐1β, IL‐6, IL‐10 and TNF‐α or survival was found. In chronic liver failure rats, GM significantly lowered the plasma TNF‐α levels (P = 0.04). However, there was no significant difference of motor activity, other biochemical tests or survival found. GM‐treated chronic liver failure rats had higher portal pressure (P = 0.04) but similar mean arterial pressure in comparison with saline‐treated rats. Conclusions: Chronic GM treatment does not have a major effect on hepatic encephalopathy in rats with TAA‐induced acute liver failure and rats with chronic liver failure induced by common bile duct ligation.     

门冬氨酸鸟氨酸治疗显性和轻微型肝性脑病

检索2000年至2010年期间在国内外发表的有关门冬氨酸鸟氨酸治疗显性肝性脑病（HE）和轻微型肝性脑病（MHE）的文献,并进行分析综述。结果显示,门冬氨酸鸟氨酸的治疗机制是直接降低血氨,疗效可靠,无明显不良反应,其对显性HE的疗效已得到公认,对MHE的疗效也在国内外研究中得到初步证实。     

单胺类神经递质在大鼠急性肝性脑病发生中的作用

目的:阐明单胺类神经递质在大鼠急性肝性脑病发生中的作用。方法:采用硫代乙酰胺所致大鼠(n=10)急性肝功能衰竭模型,测定血浆及脑组织中单胺类神经递质与血浆内毒素含量,并与正常组(n=5)进行比较。结果:在肝性脑病进入Ⅲ-Ⅳ期时,脑组织中仅5-羟色胺含量明显升高(5 139±48.0比394.7±43.8ng/g),血浆5-羟色胺升高幅度是脑组织中的两倍并伴严重内毒素血症。结论:5-羟色胺可能是肝性脑病时昏迷的因素,脑组织中升高的5-羟色胺部分源于血浆。     

Minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is the mildest form of spectrum of hepatic encephalopathy (HE). Patients with MHE have no recognizable clinical symptoms of HE but have mild cognitive and psychomotor deficits. The prevalence of MHE is high in patients with cirrhosis of liver and varies between 30% and 84%; it is higher in patients with poor liver function. The diagnostic criteria for MHE have not been standardized but rest on careful patient history and physical examination, normal mental status examination, demonstration of abnormalities in cognition and/or neurophysiological function, and exclusion of concomitant neurological disorders. MHE is associated with impaired health-related quality of life, predicts the development of overt HE and is associated with poor survival. Hence, screening all patients with cirrhosis for MHE using psychometric tests, and treatment of those patients diagnosed to have MHE has been recommended. Ammonia plays a key role in the pathogenesis of MHE, which is thought to be similar to that of overt HE. Thus, ammonia-lowering agents such as lactulose and probiotics have been tried. These agents have been shown to improve cognitive and psychometric deficits, and have good safety profile. Future studies will better define the role of other drugs, such as rifaximin, acetyl L-carnitine and L-ornithine L-aspartate.     

Subcortical somatosensory evoked potentials in patients with hepatic encephalopathy caused by severe acute hepatitis

We studied the median nerve stimulated somatosensory evoked potentials (SEP) of 23 patients with hepatic encephalopathy (HE) resulting from severe acute hepatitis and 22 healthy volunteers. Ten patients who improved and survived more than 60 days were classified as Group 1 and the remaining 13 patients who died shortly after the SEP studies were classified as Group 2. The mean N9-N13 interpeak latencies (IPL) were not different among control and two patient groups. The mean N13-N20 IPL of Group 2 was significantly prolonged when compared with normal controls (P < 0.001) and Group 1 (P < 0.001). Five of the six patients with abnormal N13-N20 IPL died of hepatic failure within 24 h after SEP testing. The occurrence of abnormal subcortical conduction together with cortical dysfunction suggested that brain damage in terminal hepatic encephalopathy was diffuse. The presentation of abnormal prolongation of N13–N20 IPL of SEP during the course of severe acute hepatitis indicated a poor prognosis. Peripheral somatosensory conduction is unaffected even in terminal HE.