肝硬化Cirrhosisofliver.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,肝硬化Cirrhosisofliver,肝硬化Cirrhosisofliver肝硬化CirrhosisofliverDefinitionHepatic encephalopathy(HE)is a syndrome observed in some patients with severe liver disease that is marked by personality changes,intellectual impairment,and a depressed level of consciousness.,肝性脑病是由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神经精神综合征，主要临床表现为行为失常、意识障碍和昏迷。,Definition,Hepatic encephalopathy,(HE)is a syndrome observed in some patients with severe liver disease that is marked by personality changes,intellectual impairment,and a depressed level of consciousness.,肝性脑病,是由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神经精神综合征，主要临床表现为行为失常、意识障碍和昏迷。,Definition,轻微肝性脑病,:,（,Minimal hepatic encephalopathy,MHE),患有肝脏疾病和,/,或门,-,体分流病人出现的一种可检测的认知功能障碍,可通过神经,-,心理和神经生理检查发现,但无法通过详细的病史询问（包括患者家属）和周密的神经学检查确诊,同时需排除其他可以引起认知障碍的疾病,肝性脑病研究历史回顾,:,第,11,届世界胃肠病大会推荐的肝性脑病分类（维也纳，,1998,）,Epidemiology:,1,，失代偿肝硬化患者常发生,HE,，发生率至少为,30,而且随着肝功能损害的加重其发生率增加,2,，我国住院肝硬化患者中，,MHE,的发生率约为,39.9%,。随着肝功能损害的加重其发生率增加，且与病因无明显相关性。,3,，肝硬化伴发,HE,国外发生率,30-45%,，进展期更高,我国,10%-50%,Etiology:,Hepatic cirrhosis,（肝硬化）,Severe hepatitis,（重症肝炎）,Primary hepatic carcinoma,（原发性肝癌）,Severe,biliary duct infection,（严重胆道感染）,Acute fatty liver of pregnancy,（妊娠期急性脂肪肝）,门,-,腔静脉分流术后,Etiology:,Induced Factors,:,Nitrogenous Encephalopathy,N,on-,Nitrogenous,Encephalopathy,Uremia(,尿毒症,)/Azotemia(,氮质血症,),Sedatives,benzodiazepines,（镇静剂，苯二氮卓类）,Gastrointestinal bleeding,（消化道出血）,Barbiturates(,巴比妥类药物,),Dehydration(,脱水,),Hypoxia,hypoglycemia(,低血糖,),Metabolic alkalosis(,代谢性碱中毒,),Hypothyroidism(,甲减,),Hypokalemia(,低钾血症,),Anemia,（贫血）,Constipation(,便秘,),Excessive dietary protein,（饮食蛋白过量）,Infection,（感染）,Tab 1.Clinical Factors that may precipitate hepatic encephalopathy,Pathogenesis:,Ammonia neurotoxicity hypothesis,氨中毒学说,False neurotransmitter hypothesis,假神经递质学说,G,ABA,-aminobutyric acid hypothesis,GABA/BZ,复合体学说,Amino acid imbalance hypothesis,氨基酸失衡学说,Benzodiazepine hypothesis,（苯二氮卓类假说）,Ammonia neurotoxicity hypothesis,The GI tract:,90%(about 4g/d),Kidney,:,谷氨酰胺酶和,H,+,的作用,Muscle:,磷酸腺苷脱胺过程,Sources of ammonia:,Ammonia neurotoxicity hypothesis,结肠内,pH6,，,NH,3,大量弥散入血,;,结肠内,pH6,pH,6,NH,3,+H,+,NH,4,+,Ammonia neurotoxicity hypothesis,Clearance of ammonia:,NH,3,鸟氨酸循环,尿素,（肝）,谷氨酸,谷氨酰胺,NH,4,+,NH,3,NH,3,ATP,-,酮戊二酸,ATP,血浆氨的去路,（肝、脑、肾）,（肾、肠）,（肺）,Ammonia neurotoxicity hypothesis,Clearance of ammonia:,the urea cycle,（尿素循环）,(,鸟氨酸,),(,胍氨酸,),(,尿素,),(,精氨酸,),(,天冬氨酸,),（精氨酸代琥珀酸）,(,氨甲酰磷酸,),Ammonia neurotoxicity hypothesis,Mechanisms of ammonia neurotoxicity:,Produce,Clearance,正常人的血氨生成与清除保持动态的平衡；,正常人空腹静脉血氨,4070g/dl,，,门静脉,200300g/dl,。,Ammonia neurotoxicity hypothesis,Mechanisms of ammonia neurotoxicity:,Produce,Clearance,血氨生成过多：,外源性和内生性,血氨清除过少,Ammonia neurotoxicity hypothesis,Mechanisms of ammonia neurotoxicity:,Neurotoxic effects of ammonia:,Alter the transit of amino acids,water,and electrolytes across the neuronal membrane.,Inhibit the generation of both excitatory and inhibitory postsynaptic potentials.,氨对脑组织的毒性作用,:,抑制丙酮酸脱氢酶乙酰辅酶,A,减少 影响三羧酸循环；,氨的清除需要消耗,-,酮戊二酸、,ATP,等物质影响能量代谢；,直接作用于神经膜 突触后抑制。,Ammonia neurotoxicity hypothesis,Factors of influence ammonia neurotoxicity:,Excessive dietary protein,（饮食中蛋白过量）,Hypoxia&Dehydration,（缺氧或脱水）,GI hemorrhage,（消化道出血）,Constipation,（便秘）,Infection,（感染）,Hypoglycemia,（低血糖）,False neurotransmitter hypothesis,兴奋性神经递质,抑制性神经递质,去甲肾上腺素,鱆胺,乙酰胆碱,苯乙醇胺,门冬氨酸,多巴胺,-,氨基丁酸,谷氨酸,表,2.,两大类神经递质,False neurotransmitter hypothesis,酪氨酸,苯丙氨酸,酪胺,苯乙胺,苯乙醇胺,鱆 胺,BBB,肠道,肝脏,脑,假神经递质,抑制性神经递质的生成过程示意图,Gamma-aminobutyric acid hypothesis,GABA/BZ,复合体学说,GABA is a neuroinhibitory substance produced in the GI tract.,GABA,是一种胃肠道分泌的抑制性神经递质,GABA,体循环,血脑屏障 脑脊液,突触后,GABA,受体,神经抑制作用,.,Amino acid imbalance hypothesis,芳香族氨基酸如,色氨酸,、苯丙氨酸和酪氨酸增多；,支链氨基酸如缬氨酸、亮氨酸及异亮氨酸减少；,肝脏对胰岛素的灭活作用降低，促进支链氨基酸进入肌肉组织的作用，而致血浆含量降低。,Pathogenesis,:summary,Mechanism,Hypothesis,Ammonia neurotoxicity hypothesis,Ammonia and mercaptans produced by the action of intestinal bacteria on urea and protein are elevated in blood and brain as a result of defective hepatic clearance and lead to impaired neural function through cytotoxicity,cell swelling,and depletion of glutamate,False neurotransmitter hypothesis,Increases in the ratio of plasma aromatic amino acids to branched-chain amino acids increase brain levels of aromatic amino acid precursors of false neurotransmitters,GABA,-aminobutyric acid hypothesis,Defective hepatic clearance of GABA produced by intestinal bacteria,increased neuronal GABA synthesis,and increased production of benzodiazepine receptor agonists leads to neuronal inhibition through stimulation of the GABA receptor complex in postsynaptic membranes,Tab 3.Pathogenesis of hepatic encephalopathy,Pathology:,急性肝性脑病：脑组织常无特异性改变；,慢性肝性脑病：可出现大脑和小脑及皮质下组织的原浆性星形细胞肥大和增多。,临床表现,临床表现因原有肝病的性质、肝细胞损伤的轻重缓急以及诱因的不同，差异很大。,临床表现,意识障碍：神志恍惚，情绪低沉；,讲话缓慢，口齿不清；,定向力和理解力减退；,木僵、嗜睡；昏迷。,临床表现,运动异常：扑翼样震颤,(asterixis),步履不稳,共济失调,临床表现,肝功能严重受损的表现：,黄疸、出血倾向、肝臭等。,临床表现,根据意识障碍程度、神经系统,表现和脑电图改变分四期：,前驱期,昏迷前期,昏睡期,昏迷期,分期,主要神经精神表现,神经系体征,脑电图,前驱期,轻度性格改变、,举止反常,多无扑翼震颤,无明显异常，,波的频率可减少,昏迷前期,精神错乱、,意识模糊,常出现扑翼震颤、腱反射亢进、肌张力增高、锥体束征（一）,常出现异常的慢波,（,波）,昏睡期,昏睡,可引出扑翼需震颤,明显异常的,波和,三相慢波,昏迷期,昏睡、,昏迷,深昏迷时不能引出扑翼震颤、反射消失,出现,波,表,4-1.,慢性肝性脑病的分期,Clinical Grading,Grade,Consciousness,Intellectual function,Behavior/,personality,Neuromuscular signs,0,Normal,Normal,Normal,Normal,I,Lack of awareness/,Sleep disorder,Shortened,attention span,Euphoria,anxiety,Impaired handwriting,tremor,II,Drowsiness,Disorientation,for time or place,Inappropriate behavior,Asterixis,ataxia,hyporeflexia,III,Somnolence,Gross disorientation,Massive personality,change,Hyperreflexia,rigidity,Babinski sign,IV,Coma,No response,Table 4-2.Grading of hepatic encephalopathy,Clinical Grading,实验室检查,血氨水平上升,血液氨基酸组分分析,特殊检查,脑电图,诱发电位,心理测验,脑电图,High-amplitude low-frequency waves,（高幅低频波）,Triphasic waves(,三相波,),wave,(8-13 times/s),wave,(4-7 times/s).,wave,(1-5 times/s).,EEG of a 69 yrs old patient with hepatic encephalopathy,showing triphasic waves,（三相波）,.,Evoked Potential,视觉诱发电位,(VEP),听觉诱发电位,(AFP),体感诱发电位,(SEP),Facility Psychometric tests,（心理测验）,Number-connection test,（数字连接测验）,Writing,drawing,et al.,（写作、绘画等）,诊断,病史,:,急,/,慢性肝病,诱发因素,:,感染,出血,症状与体征,:,精神症状,扑翼样震颤,其他并发症,实验室检查,:,肝功能,血氨水平,异常脑电图,鉴别诊断,Other causes of mental disorder&coma:,Intracranial lesions,：,各种颅内占位；,Infections:,脑炎、脑膜炎、脑脓肿等；,Metabolic encephalopathy:,低血糖、电解质紊乱等；,Toxic encephalopathy due to alcohol:,急性酒精中毒,戒断综合症,Wernicke,脑病等；,Toxic encephalopathy due to drugs:,镇静催眠药等,;,肝性脑病的诊断及评估流程,治疗原则,:,纠正促发因素,控制血氨,对症治疗,其他,Treatment,(1),Assess vital signs,（评估重要生命体征）,Evaluate for GI bleeding,（评估胃肠道出血）,Eliminate sedatives or similar drugs,（停止镇静剂及类似物）,Screening for hypoxia,hypoglycemia,anemia,hypokalemia,other metabolic/endocrine factors,（寻找缺氧、低血糖、贫血及其他代谢,/,内分泌因素）,去除诱因,:,Treatment,(2),减少吸收,:,Low-protein diets(,低蛋白饮食,),Cathartics or enemas(,导泄,/,灌肠,),Lactulose(,乳果糖,),Oral nonabsorbable antibiotics(,抗生素,),降低血氨,:,Treatment,(2),增加血氨清除,Ammonia-lowering drugs,：谷氨酸钾、谷氨酸钠、精氨酸、鸟氨酸、门冬氨酸、乙酰谷氨酰胺,Compound Amino Acid,：以支链氨基酸为主,GABA/BZ receptor antagonist:,氟马西尼,Ammonia-lowering therapy,最新药物治疗,:,1,，,拉克替醇,可改善肝硬化患者的,HE,，提高患者的生活质量，疗效与乳果糖相当。推荐的初始剂量为,0.6 g/kg,，分,3,次于就餐时服用。以每日排软便次为标准来增减本品的服用剂量,2,，,利福昔明,被美国,FDA,批准用于治疗,HE/MHE,，还可有效维持,HE,的长期缓解并可预防复发。提高肝硬化患者智力测验结果，改善,MHE,。我国批准剂量为,400mg/,次，每,8,小时,1,次,Treatment,(3),维持水、电解质、酸碱平衡,保护脑细胞,防止脑水肿,保持呼吸道畅通,对症治疗,Treatment,(4),糖皮质激素,腹膜透析,血液透析,人工肝,肝移植和干细胞移植,其他方法,Treatment,(5),高压氧,益生菌,中医药,其他方法,:,药物治疗MHE-国外meta分析,Dhiman RK,Indian J Gastroenterol 2009,28:516,治疗总结,:,肠道,:,减少毒素的生成和吸收,肝脏,:,改善肝功能和增加毒素清除,.,血脑屏障,:,预防毒素渗透入血脑屏障,.,大脑,:,纠正异常神经元活性,预后,:,依赖于肝脏损害程度及疾病的诱发因素,爆发性肝炎的患者预后最差,:80%,死亡率,思考题,:,肝性脑病的发病机制？,肝性脑病的治疗进展？,谢谢！,