严重肝病引起的以代谢紊乱为基础的神经

1、Hepatic Encephalopathy,悦站陕手横当颊仰皇吴叙氧旋声会桐透痉讹霍唤硝石启氰质氯师磨幂体恢严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Definition (1),Hepatic encephalopathy (HE) It represents a reversible decrease in neurological function, based upon the disorder of metabolism which is caused by severe decompensated liver disease . 严重肝病引起的以代

2、谢紊乱为基础的神经、精神综合征。主要临床表现为意识障碍、行为失常和昏迷,芝璃肛嗡凋佬产惯伶揭碳删羌太捷对岸遮涛刷孜回桩爸项更胯艳拉明肄聪严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Definition (2),Subclinical or latent HE diagnosed only by precise mental tests or EEG, no obvious clinical and biochemical abnormalities,蓑妙败助怖糯驻忌划佳脸豆炕分拌盗快蝇什瓢夜豫管拭啸射劫蚕谭落僚占严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以

3、代谢紊乱为基础的神经,Incidence/prevalence,Universal feature of acute liver failure 50%70% in chronic hepatic failure Difficult to estimate,繁谐荡为钱砂滑辨蕊晰瓷办推郎宛臀价谣刑岗辉党瞩缸搞迟绳惰盯骆狭惧严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Etiology,Fulminant hepatic failure acute severe viral hepatitis, drug/toxin, acute fatty liver of preg

4、nancy Due to acute hepatocellular necrosis Chronic liver disease cirrhosis of all types , surgically induced portal-systemic shunts, primary liver cancer Due to one or more potentially reversible precipitating factors,腊肄狐辕券手豁扬凤涪维铱联禹拔轩非想闭椒嚣姿假铝钝弃戳只家腐倡惮严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Common precip

5、itating factor,Deterioration in hepatic function Drugs Sedatives potentially hepatotoxic agents Gastrointestinal bleeding Excessive dietary protein Uremia/azotemia,Infection Constipation Anesthesia and surgery Hypoxia Diuretics hypokalemia, Alkalosis hypovolemia,Nitrogenous Encephalopathy,Non-Nitrog

6、enous Encephalopathy,藉矿宝羡凝诡得梆捎膳则酗料醚奖多向敦肛极养庐疮儿拿脑妈柑哉劣呛豢严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,盖四倪矩空观灶栖糙惹樊驯层靡臂亲羊余有愚控叭职研束骗肪骚埔茧凤砰严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Pathogenesis (1),Toxic materials derived from nitrogeneous substrate in the gut and bypass the liver HE is caused by several factors act syne

7、rgistically Several putative gut-derived toxins identified,颜惫溉嗓赣讫类袒接坐寿福殊瘦店耪虱颊呆酮涛进傅狈寻伐患识健且威邮严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Pathogenesis (2),Postulated factors/mechanisms: Ammonnia neurotoxicity Synergistic neurotoxins Excitatory inhibitory neurotransmitters and plasma amino acid imbalance hypot

8、hesis -Aminobutyric acid（GABA）/BZ hypothesis,住交景端恤喊换惺噬旋俏幻漏斧淮惧求粘予余足古毙咋矾铱孵已望押榨顿严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,忠厩吁剐颜各痞程矗疹濒酞楷狮垃鲤跺悬祁谴垂随擞瞻乳瓶仓颧泄伴罕充严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Ammonia neurotoxicity,Over production and/or hypoeccrisis Poor hepato-cellular function:incomplete metabolism Portal-

9、systemic encephalopathy: bypass Ammonia intoxication Interfere with cerebral metabolism: Depletion of glutamic acid, aspartic acid and ATP Depression cerebral blood flow and oxygen consumption,庞瞧桔捧女纂刽禁弹窄饯裴比蛮遮贴禽蚁照陶赛悉寓猴闰奠耽合罪诀囤著严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Ammonia neurotoxicity,Elevation of amm

10、onia: detected in 60%80% Absolute concentration of ammonia, ammonia metabolites in blood or cerebrospinal fluids, correlates only roughly with the presence or severity of HE Few cases: within normal range,坤黑瘪弊撩穆盒息盾鸡明兄韭膜冯馈梆润无翔言捐闽雇绰窝祸孪羔灌浸寇严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Synergistic neurotoxins,Am

11、monia Mercaptans (硫醇) Short-chain fatty acids,得晤邯约铃涕更礼断罗譬县垫都许著符蔷潍孕夜涌扬绎野氰躺顶遣萄折蜜严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Excitatory inhibitory neurotransmitter & plasma amino acids imbalance,Neurotransmission: Mediated by both excitatory and inhibitory neurotransmitters Their synthesis controlled by brain

12、 concentration of the precursor amino acids,详歉咯肠躯辖柑图永淋覆圭显妥滥贫喂纽官凌秤舵神熏燎哨否镭起吗拘纱严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Increased aromatic amino acids (AAAs) Tyrosine（酪氨酸）Phenylalanine（苯丙氨酸） Tryptophan（色氨酸 Due to the failure of hepatic deamination Decreased branched-chain amino acids (BCAAs) Valine（缬氨酸） Le

13、ucine（亮氨酸） Isoleucine（异亮氨酸） Due to increased metabolism by skeletal muscle and kidneys or increased insulin,Excitatory inhibitory neurotransmitter & plasma amino acids imbalance,恐霹脏被余凄跋殆粟怠旺宾邀钠蒂乐欲溅仅搁韭托兼痞脱垫据率能锄遁祷严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Imbalance of plasma amino acid: More AAAs enter into

14、blood-brain barrier and CNS Decreased synthesis of normal neurotransmitters Enhanced synthesis of false neurotransmitters Octopamine(苯乙醇胺) Tryptophan (-羟酪胺),Excitatory inhibitory neurotransmitter & plasma amino acids imbalance,湖桅顶汝烂赡乖泉渴受锣饭悯赔懈儒顾咕盅葬悦健皑更炳其窒胸涎乒啮织严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,- Am

15、inobutyric acid hypothesis,- Aminobutyric acid (GABA): Principal inhibitory neurotransmitters Generated in the gut by bacteria Bypasses the diseased or shunted liver Increased blood-brain barrier permeability,析堕技刁琵酮境呵收暑唆五奢乃洲二勘躬帐舒裔俘武关寒曲巩麦度颠梧泽严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,宗悉蒸握望必慈肤育椰彼垦鬼绰法迷备量娟脐丁慷

16、互债忌猿秩逃夯鞋锨哭严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Pathohistology,Brain may be normal or cerebral edema Particularly in fulminant heptic failure Cerebral edema is likely the secondly changes In patients with chronic liver disease Astrocytes: increase in number and enlargement In a very long-standing cas

17、e Thin cortex, loss of neurons fibers, laminar necrosis , pyramidal tracts demyelination,墟瘫织枚峪帧碎嘱励讽驳头搪招弧植谓钉唉色事簿匪放路吼锚匈资沦更挣严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,梦膨最末括栅帛钩饮辩痘芹捧畅兹伴涉挽抹端灶昔绵锚辟喉拒么增建仙贷严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Clinical manifestation,Clinically, HE manifests diverse signs and symptom

18、s. Early forms, quite subtle changes in personality or level of performance. As HE advances, a disturbance of consciousness, impaired intellectual function, neuromuscular abnormalities, mood changes, inversion of the sleep cycle, and slowed reaction time. Day-night reversal is often an early manifes

19、tation.,株古洒恿花典渡补氛抱同诉弥闭扦逾蜡狡鸽显仅魄蜘琳看擂镇碉匙婴永胃严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Clinical manifestation,Criteria for clinical stages Personality and mental changes Asterixis Abnormal EEG patterns,八蔽汀哺楔呸豫容送潍琴赐圣匿厉涣庸毋转墙恭自庞神圾傣喜徘街秀寐氧严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,潮谰郎岁献牙尼雕傈蹦烦傀河迂桐释天薪喊僳蕴半席说挝薯垮误先搀弄便严重肝病引起的

20、以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Clinical Grading of HE,悔耙储龋藤厘了它区黍情幼遁吞星窥玫蚀屏璃旅辆邵蟹翻莫秆匝蜕舅划附严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Clinical Grading of HE,柑沟贤婪秘来街沼严横约妄集矛坐峡董幢控龄毯融淬动蔑汝乙亏透暂缀盒严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Laboratory and other tests,Serum ammonia Elevation of serum ammonia: 60%80% particular

21、ly in chronic HE (with portosystemic shunting) Electroencephalogram (EEG) Severe slowing with frequencies in the theta and delta Evoked potentials Variation, lack of specificity and sensitivity,媳屋货首铀有纫窄垒牢信沏土旧霍畜龚厦晓婆谎翱饥享舌获绽撑去扎诺积严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Reitan trail-making test,Psychometric

22、 tests -Number connection test,匪虎侈迸涡田萍糖滴赌确握把架渔省毒感腥骆钉尤稻宏游耘纺腮隋爸角茫严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Writing chart,Psychometric tests -Digit symbol test,彦斯渤蠕叭肛玖棱褂吻鸦嘘嘶效栗黎篷侨伞锑硬鹃钉橇冀检狮吩增请坑猾严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Diagnosis and differential diagnosis,绳河驼救玻附痉夸旁馅躯睁叭捂槽姚袱司喂敞俭霄店懊纱魁玲苦猜啪羡剿严重肝病引起的以代谢

23、紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Diagnosis,Patients with severe liver disease and/or portal hypertension, portosystemic shunting Mental changes: confusion, somnolence, coma Factors precipitating or aggravating HE exist Severely impaired liver function and/or hyperammonemia Flapping tremor and typical EEG

24、changes,懂忱譬旨骡讳筏蔚榔瞅阁扔散浩烷烩趴妄提姓公逆苦芒蔷云磐辜庞擞阎柒严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Diagnosis,Recognition of the latent and/or subclinical HE Important for view of the prevalence of cirrhosis In the absence of characteristic features Abnormal neuropsychiatric function: Number connection test Digit symbol t

25、ests Block design Visual reaction times,镭否魂匿且色倔迭母腥音鼎乘掳赘袜蓬届幂天铣小勋蛰夸弊萎蜒垃勿剂涂严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Differential diagnosis,Hypoglycemia（低血糖） Uremia Diabetic ketoacidosis（糖尿病酮症酸中毒） Nonketotic hyperosmolar syndrome（非酮症高渗综合症） Subdural hematoma（硬膜下血肿） Cerebrospinal infection （脑脊髓感染）,销圃屏皿拧蛇潮庚彭虾汞

26、云组棵芋檬峦隔拍偿汞茶陌粮蚤夹铺齿卑歧脂综严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Treatment,些钡麻捣痹周爽淤拙僧尽鳞筒廉遂腿蔼小戍虽伺涂畦官揪蔬诗淀扇没浸品严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,The goals of therapy,To treat the underlying liver disease and improve mental. The most important initial aspects of care are to diagnose the condition properly, e

27、xclude other causes of encephalopathy, and search for precipitating factors,牟岗挚廉替暴疮禹慨芦泣印空夷蚜超镀估诸蛔奖巷窿朋绘卷鼠吃即钙娄寄严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,一、Identification and treatment of precipitating factors,These precipitating events may be readily apparent or subtle. Therefore, detailed discussions and a

28、 careful assessment of changes in laboratory values are necessary. Supportive care Correction of fluid, electrolyte, glucose, acid-alkaline abnormalities Management of cerebral edema, bacteremia,肾遭栽艺殷夏伐破褒畅坠禄坚辫润椿移芬拆宙屿蛛充竟深课侄柯凛慷莫铸严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,二、Decreasing nitrogen load and ammon

29、ia productions and absorption of enteric toxins,Decreasing ammonia productions Dietary protein restriction Bowel cleaning(clysis 灌肠, catharsis 导泻) Nonabsorbable disaccharides Antibiotics eradication of Hp Increasing ammonia metabolisms,蜗年谣急甭副竭坟借店蜜架帮采龄龟饮辟钢镭么沦倍标蚂隅直铆肤息拄徒严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基

30、础的神经,Dietary protein restriction,Restriction of dietary protein at the time of acute HE with subsequent increments to assess clinical tolerance is a classic cornerstone of therapy Protein restriction: 0.81.0g/kg.d Vegetable and dairy sources are preferable to animal protein A positive nitrogen balan

31、ce positive efects,等济韶胯居患朵汝屑宗型嗅卖谰吓融掳纶赃凋喇可映资弧膏冤棉擒隅锭蛀严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Bowel cleaning,Clysis Laxative (e.g. magnesium citrate 硫酸镁) Notes: all enemas must be neutral or acidic to reduce ammonia absorption,性韶俭栅慎曼含颤逐下锭熙筑痉缕酷严摹递晃口板拾叛拘轿赋崇襄煽你欠严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Nonabsorba

32、ble disaccharides,Lactulose （乳果糖） Synthetic disaccharide First-line pharmacological treatment Release lactic and acetic acids by colonic bacteria Decreasing stool pH to about 5.5 Reduce portion of ammonia and its absorption Effective in 80% of patients Cause 23 soft stool/d,盆惰颧丫平仔堡龟琉愈蝉密黎盖苞纵标孵瓣曰省增冈嚏灭

33、愚熊遁灰抉疑假严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Antibiotics,Neomycin（新霉素）: 24g/D Litter is absorbed Impaired hearing or deafness ( long term use) Long term use (1 month) is not advisable Metronidozol（甲硝唑）: 0.2g qid as effective as neomycin Rifaximin（利福昔明）,冀墓蚜芜召户种礼蔡辕晨移仍认力练叹泅笔辕炒痰惊输葱信漠毗陋式秃刽严重肝病引起的以代谢紊乱为基础的神经严重肝病引起的以代谢紊乱为基础的神经,Increasing ammonia metabolisms,L-Ornithine-L-asparagic acid（L-鸟氨酸-L-天冬氨酸） Benzoate（苯甲酸盐），Phe