第二節(jié)發(fā)病機制

1、,,Hepatic encephalopathy,,肝 性 腦 病,?,能量分泌排泄凝血屏障解毒腎免疫腦,,,肝性腦病,,肝臟— 物質(zhì)代謝中心器官,肝性腦病概念：繼發(fā)于嚴(yán)重肝臟疾病的神經(jīng)精神綜合征,分類：內(nèi)源性門體分流輕微,,一、發(fā)病機制,（一） 氨中毒學(xué)說(ammonia intoxication),1. 主要論點 血氨↑，進(jìn)入腦組織，引起腦的代謝和功能障礙,NH3

2、 NH4+ （氨） （銨離子）,,,pH ?,pH?,血氨形式,,,2. 血氨升高原因 ： (1) 氨產(chǎn)生過多 (2) 氨清除不足,?,?,,,,,,,,,肌肉產(chǎn)氨,,,合成尿素,,通過側(cè)支循環(huán)入血,,,腎臟泌氨,來源,去路,合成谷氨酰胺等,liver,,腸道產(chǎn)氨,血氨,,酮戊二,抑,輔酶,(1)干擾腦的能量代謝?消耗α-酮戊二酸、NADH ；大量消耗ATP

3、,3.氨對腦的毒性作用,,α-酮戊二酸+ NH3,谷氨酸+ NH3,谷氨酰胺,,NADH,ATP,,(2)改變腦內(nèi)神經(jīng)遞質(zhì)的含量： 腦內(nèi)興奮性遞質(zhì)↓，抑制性遞質(zhì)↑,（3）干擾神經(jīng)細(xì)胞膜的離子轉(zhuǎn)運功能，干擾神經(jīng)傳導(dǎo)過程,二、假性神經(jīng)遞質(zhì)學(xué)說,1. 主要論點： 嚴(yán)重肝病時，假遞質(zhì)在腦干網(wǎng)狀結(jié)構(gòu)中堆積，使神經(jīng)沖動的傳遞發(fā)生障礙，引起CNS功能紊亂,,,,,,苯丙aa酪aa,,苯乙胺酪胺,,分解,,多巴,,,,,β-羥化酶,入腦,,入

4、腦,酪aa羥化酶,肝MAO,?,脫羧,2.假遞質(zhì)生成(FNT),,多巴胺,NE,,苯乙醇胺、羥苯乙醇胺↑ （假介質(zhì)）,3.假性神經(jīng)遞質(zhì)的作用,假遞質(zhì)競爭性取代：（1）腦干網(wǎng)狀上行激動系統(tǒng)中NE—— 嗜睡，昏迷（2）錐體外系黑質(zhì)-紋狀體中多巴胺——撲翼樣震顫?,三、血漿氨基酸失衡學(xué)說,1 AAA/BCAA失衡嚴(yán)重肝病時，血漿BCAA/AAA比降低 3 ) →,,?,CNS紊亂,,AAA：aromatic amino acidB

5、CAA:branch chain amino acid,2. 失衡的機制,肝,胰島素↑,胰高血糖素↑,組織攝取、利用BCAA↑,肌肉、肝蛋白分解↑,,AAA↑,糖異生↓,,,,,血氨↑,,,,滅活↓,,,,AAA ↑BCAA?色aa ↑,3. 失衡的后果,,,,血腦屏障,假遞質(zhì)、5-HT形成↑↑,血液,FNT,5-HT,,,?,,?,,,,,,血氨?,,腦能量?,神經(jīng)遞質(zhì)失衡,抑制神經(jīng)細(xì)胞膜,血單胺?,,腦內(nèi)假遞質(zhì)?,胰島素?

6、胰高血糖素? ?,,,,,肝性腦病,肝功?,,滅活?,血BCAA/AAA比?,,*** 色氨酸與腦病?,腦內(nèi)色氨酸?機制（1）色aa分解?（2）白蛋白?游離型?,色氨酸?的后果(1)5-HT生成↑ (2)干擾正常遞質(zhì),色氨酸代謝,色氨酸,,,血色氨酸,,結(jié)合型（+白蛋白）,游離型,,,腦,5-HTP,,5-HT,,5HIAA,吲哚,腸菌,,,,,,,,,GABA-R,BZ-R,BARB-R,Cl-,,,,,,Cl- chan

7、nel,Cl- Cl- Cl- Cl-,突觸后膜,超極化,,,,（四） γ-氨基丁酸 (GABA)學(xué)說,,——要點：GABA↑+受體 中樞抑制?,,Cl- -C,,,,,,GABA-D,BZ-D,Steroid-D,Barbital-D,,血漿GABA↑的原因：,（1）肝臟對腸源性GABA代謝↓（2）門-體分流,,GABA的生成代謝,谷氨酸,,GABA,谷氨酸,,,琥珀酸半醛,,琥珀酸,,,,HE早期—谷

8、aa消耗性?HE晚期—GABA蓄積性?,（腸）,~ 脫羧酶,,,（CNS）,~ 轉(zhuǎn)氨酶,（五）當(dāng)前觀點（ 綜合學(xué)說）,主要論點：高血氨與氨基酸失衡互為因果，共同促進(jìn)HE,綜合學(xué)說機制：,高血氨（1）刺激胰高血糖素分泌→胰島素分泌，　加重氨基酸失平衡（2）使腦內(nèi)谷氨酰胺↑；AAA入腦↑（3）增加腦內(nèi)GABA ， 增強GABA能神經(jīng)　傳導(dǎo),二、決定和影響HE發(fā)生的因素,（一）神經(jīng)毒質(zhì)硫醇氨吲哚酚類單胺短鏈脂肪酸?

9、,,腦能量腦細(xì)胞呼吸Na+泵神經(jīng)傳遞突觸毒性,神經(jīng)毒質(zhì)協(xié)同增毒作用,氮的過度負(fù)荷消化道出血高蛋白飲食便秘氮質(zhì)血癥炎癥,酸堿平衡紊亂 某些藥物應(yīng)用不當(dāng) 其他 ?,HE誘因,Hepatic encephalopathy stages,,Grading of symptoms,Stage 1- Mild confusion, decreased attention, irritability, reversed sl

10、eep pattern. flapping tremaStage 2- Drowsiness, personality changes, intermittent disorientation, flapping tremaStage 3- Gross disorientation, marked confusion, slurred speech , flapping tremaStage 4- Frank coma,Lab a

11、bnormalities,Hepatic synthetic and biochemical dysfunctionElectrolyte disturbancesAmmoniaEEG - high-amplitude low-frequency waves and triphasic waves. Evoked potentialsPsychometric testsMagnetic resonance spectrosc

12、opy,Psychometric testing,,,Diagnosis,Hepatic encephalopathy is a diagnosis of exclusionExistence of acute or chronic liver disease, and/or a prior history of HE are clinical elements needed for diagnosis.Pos

13、itive test of liver dysfunction Conscious disturbance ,abnormal behavior, comaNeuromuscular function: Flapping tremorEEG,Differential Diagnosis,Metabolic encephalopathyDiabetes ( hypoglycemia, ketoacidosis)Hypoxia

14、CO2 narcosisElectrolyte imbalances,Toxic encephalopathyAlcoholRecreational drugsInfectionsencephalitisabscessIntra cranial lesionsIntracerebral bleedtumors,Principles of Treatment,Eliminating or correcting preci

15、pitating factorsReducing plasma ammonia and other toxinsCorrecting plasma amino acid imbalance and supplying normal neurotrasmittersImproving hepatocyte functionsLiver transplantation,Treatment,Identification and cor

16、rection of the precipitating factors.Correction of hypokalemiaReduction in ammoniagenic substrates NG lavage in GI bleedingTreatment of constipationLimiting protein intake 40 to 70 g/day,Lactulose and lactitol,,Curr

17、ently mainstay of treatmentCan be given orally, thro NG tube or as a retention enemaDose is 45-90 gms per dayTitrated to achieve 2-3 soft stools per daySide effects include abdominal cramping, diarrhea, and flatulenc

18、e,Oral antibiotics,Rifamixin Therapeutic alternatives if patient cannot tolerate disaccharides Neomycin 3- 6 gms/ day POassd with ototoxicity and nephrotoxicityMetronidazole250 mg BIDNeurotoxicity in cirrhoticsVan

19、comycin,Other treatments,Ornithine-aspartate lower serum ammonia levels through stimulation of the urea cycle and urea formation Probiotics and prebiotics BCAA infusions L-DopaLiver transplantationArtificial suppor