肝胆疾病的生物化学诊断-Biochemistry-Diagnosis-of-Liver-and-Ga.ppt

第八章第八章肝胆疾病的生物化学诊断肝胆疾病的生物化学诊断Biochemistry Diagnosis of Liver Biochemistry Diagnosis of Liver and Gallbladderand Gallbladder1下腔静脉左肝静脉 肝动脉肝门静脉 总胆管 胆囊2 第一节第一节第一节第一节 肝脏的解剖结构特点及其肝脏的解剖结构特点及其肝脏的解剖结构特点及其肝脏的解剖结构特点及其 生物化学功能生物化学功能生物化学功能生物化学功能 Anatomic and PhysiologyAnatomic and PhysiologyAnatomic and PhysiologyAnatomic and Physiology一、解剖结构特点一、解剖结构特点一、解剖结构特点一、解剖结构特点Anatomic structure characteristicAnatomic structure characteristicAnatomic structure characteristicAnatomic structure characteristicq门静脉（门静脉（hepatic portal hepatic portal vein)vein)：获得消化道吸收而来的获得消化道吸收而来的营养物营养物pApproximately 75%of the blood supply comes from the portal veinpDrains the GI tract and is rich in nutrientsq肝动脉肝动脉(hepatic artery)hepatic artery)：获得充足的氧气和代谢物获得充足的氧气和代谢物pRemainder of blood supply enters by hepatic artery pRich in oxygen双重血液供应双重血液供应double blood supplydouble blood supply：3q肝静脉肝静脉(hepatic vein)hepatic vein)：体循环体循环(systemic circulation)systemic circulation)-肾肾(kidney)-kidney)-尿尿uriauria输出通路输出通路 q胆道系统胆道系统(biliarybiliary tract tract)：肠道肠道(intestinal tract)intestinal tract)-粪便粪便(faecesfaeces)4qCell surface have a lot of Cell surface have a lot of microvillimicrovilli(微绒毛微绒毛)增大了与血窦增大了与血窦(sinusoid)sinusoid)的接触面，有利于物质转运的接触面，有利于物质转运qCell membrane have relatively high permeabilityCell membrane have relatively high permeability 为肝细胞内外的物质交换提供了通道；为肝细胞内外的物质交换提供了通道；qAbundance mitochondria in cellAbundance mitochondria in cell 为肝细胞代谢提供能量为肝细胞代谢提供能量qCell have abundance rough surfaced endoplasmicCell have abundance rough surfaced endoplasmic reticulumreticulum、smooth surfaced endoplasmicsmooth surfaced endoplasmic reticulum reticulum andand Golgi Golgi complex complex 为各种蛋白质和酶的合成、药物和毒物等的生物转化以为各种蛋白质和酶的合成、药物和毒物等的生物转化以及物质的分泌排泄提供了场所及物质的分泌排泄提供了场所qCell have abundance enzyme Cell have abundance enzyme 物质代谢和加工物质代谢和加工形态结构形态结构(morphological structure)化学组成化学组成(chemical composition)6MetabolismMetabolism Carbohydrate,Fat&Protein Carbohydrate,Fat&Protein二、肝脏生物化学功能二、肝脏生物化学功能Liver Functions:Liver Functions:SecretorySecretory bile-Bile acids,salts&pigments bile-Bile acids,salts&pigmentsExcretoryExcretory Bilirubin BilirubinSynthesisSynthesis Albumin,coagulation factors Albumin,coagulation factorsStorageStorage Vitamins,carbohydrates etc.Vitamins,carbohydrates etc.DetoxificationDetoxification toxins,ammonia,etc.toxins,ammonia,etc.7 三、肝细胞损伤时的代谢改变三、肝细胞损伤时的代谢改变Metabolic change of hepatocellular injuryMetabolic change of hepatocellular injury (一一)、物质代谢障碍、物质代谢障碍 (Dysfunction of substance metabolism)(Dysfunction of substance metabolism)8Fasting-plasma Fasting-plasma glucose(FPG)glucose(FPG)decreased decreased 空腹血糖降低空腹血糖降低 v糖原合成障碍糖原合成障碍 glycogenesisglycogenesis disorder disorderv糖原贮存减少糖原贮存减少 glycogen storage decreasedglycogen storage decreasedPostchallenge plasma Postchallenge plasma glucose(PPG)glucose(PPG)increased increased 餐后血糖增高餐后血糖增高 肝病肝病(disease of the liver)10严重肝病严重肝病(serious disease of the liver)糖有氧氧化糖有氧氧化(aerobic oxidation)三羧酸循环三羧酸循环(tricarboxylic acid cycle)血中丙酮酸血中丙酮酸(pyruvic acid)(pyruvic acid)肝病肝病(disease of the liver)磷酸戊糖途径磷酸戊糖途径(phosphopentose pathway)(phosphopentose pathway)糖酵解途径糖酵解途径(glycolytic pathway)(glycolytic pathway)糖耐糖曲线（糖耐糖曲线（OGTTOGTT）异常）异常呈低平型、高峰型、高坡型呈低平型、高峰型、高坡型 11pAmmonia(potential toxin)is Ammonia(potential toxin)is byproduct of byproduct of gluconeogenesisgluconeogenesis(糖糖异生）异生）pLiver converts ammonia into ureaLiver converts ammonia into ureapAlso removes ammonia produced by Also removes ammonia produced by intestinal bacteria from portal bloodintestinal bacteria from portal bloodpUrea is excreted in urineUrea is excreted in urineAmmonia ConversionAmmonia Conversion13 转氨基转氨基(transamination)(transamination)脱氨基脱氨基(deamination)(deamination)脱羧基脱羧基(decarboxylase)(decarboxylase)支链氨基酸支链氨基酸/芳香族氨基酸比值芳香族氨基酸比值 (Branched-chain amino acid/Aromatic amino acid)(Branched-chain amino acid/Aromatic amino acid)：（BCAA/AAA)BCAA/AAA)肝细胞内转氨酶肝细胞内转氨酶(transaminase)(transaminase)含量高：含量高：ALT ALTBranched-chain：Extrahepatic metabolism(Leu、Ile、Val）Aromatic：Liver metabolism（Trp、Tyr、Phe）支支/芳芳=3-3.5/1（2 2）.氨基酸代谢氨基酸代谢(amino acid metabolism)(amino acid metabolism)：15.解除氨毒：解除氨毒：氨氨(ammonia)(ammonia)尿素尿素(urea)(urea)肾排肾排vblood ammonia(blood ammonia(血氨血氨)vBCAA/AAA(BCAA/AAA(支支/芳芳)vamineamine（胺）胺）肝性脑病肝性脑病hepatic encephalopathyhepatic encephalopathy(HE)(HE)16.消化、吸收消化、吸收(digest and absorb):(digest and absorb):胆固醇胆固醇(cholesterol)(cholesterol)胆汁酸胆汁酸(bile acid)(bile acid)“脂肪泻脂肪泻”Steatorrhea”Steatorrhea.合成、运输合成、运输(synthesize and transport)(synthesize and transport)：qSynthesize Synthesize：TGTG、ChEChE/Ch/Ch、PLPL、LCAT LCAT、acetone body(acetone body(酮体酮体)qTransportTransport：VLDLVLDL、HDLHDL18分解分解(decompose)(decompose)：TGTG、FAFAfat oxygenolysis decreaseExcess fat accumulate in hepatic cells fatty liver(当肝内脂类含量超过肝重的当肝内脂类含量超过肝重的5%5%时，称为脂时，称为脂肪肝脂肪肝肪肝脂肪肝)脂肪肝肝脏脂肪肝肝脏19 二、凝血与纤维蛋白溶解障碍二、凝血与纤维蛋白溶解障碍(Dysfunction of coagulation(Dysfunction of coagulation and fibrinolysis)and fibrinolysis)三、免疫功能障碍三、免疫功能障碍 (Dysfunction of immunity)(Dysfunction of immunity)20四、维生素代谢四、维生素代谢(vitamin metabolism)(vitamin metabolism)1 1、吸收、吸收(absorption(absorption）：）：胆汁酸（胆汁酸（bile acidbile acid）-脂溶性维生素（脂溶性维生素（fat-soluble fat-soluble vitaminvitamin）2 2、转化（、转化（transformtransform）：）：synthesize coenzymesynthesize coenzyme P Provitamin A rovitamin A vitamine A vitamine A vitamin D3 25-OH-D3 vitamin D3 25-OH-D321五、激素的灭活作用五、激素的灭活作用（inactivation of hormoneinactivation of hormone）：）：steroid hormone steroid hormone（类固醇激素）（类固醇激素）Protein hormoneProtein hormone（蛋白质类激素）（蛋白质类激素）Catecholamine hormoneCatecholamine hormone（儿茶酚胺类激素）（儿茶酚胺类激素）许多激素在其发挥调节作用之后，主要在肝许多激素在其发挥调节作用之后，主要在肝脏内被分解转化，从而降低或失去活性，这脏内被分解转化，从而降低或失去活性，这称之为激素的灭活作用。称之为激素的灭活作用。22 第二节肝脏的生物转化作用第二节肝脏的生物转化作用 Biotransformation Biotransformation 一、生物转化（一、生物转化（biotransformation)biotransformation)24 第二节肝脏的生物转化作用第二节肝脏的生物转化作用 Biotransformation reactionBiotransformation reaction 一、生物转化（一、生物转化（biotransformation)biotransformation)外源性非营养物质外源性非营养物质Exogenous non-nutrientExogenous non-nutrient(药物药物drugdrug、毒物、毒物Toxin Toxin、致癌物致癌物Carcinogens)Carcinogens)内源性非营养物质内源性非营养物质Endogenous non-nutrientEndogenous non-nutrient 激素激素(hormone),NH(hormone),NH3 3,神经神经递质递质(neurotransmitter),(neurotransmitter),Bilirubin,Bilirubin,胺类胺类(amine)(amine)肝肝尿、胆汁尿、胆汁排出排出25第一相反应第一相反应(Phase I)(Phase I)：氧化氧化(oxidation)(oxidation)还原还原(reduction)(reduction)水解水解(hydrolysis)(hydrolysis)增加极性增加极性(increasing polarity(increasing polarity）二、反应类型二、反应类型(type)(type)26 ReductionReduction:azo-and nitro-,carbonyl,disulfide,:azo-and nitro-,carbonyl,disulfide,sulfoxide,quinone,dihydropyrimidinesulfoxide,quinone,dihydropyrimidine还原反应：主要有硝基还原酶和偶氮还原酶所催化还原反应：主要有硝基还原酶和偶氮还原酶所催化的两类反应。的两类反应。28 HydrolysisHydrolysis:functional group such as carboxylic:functional group such as carboxylic acid ester,amide,thioester,acid anhydrideacid ester,amide,thioester,acid anhydride水解反应：肝细胞微粒体和胞液中含有各种水解酶类，水解反应：肝细胞微粒体和胞液中含有各种水解酶类，可将酯类、糖苷类化合物水解，以减低或消除其生物可将酯类、糖苷类化合物水解，以减低或消除其生物学活性。学活性。29三、生物转化的特点三、生物转化的特点Feature of biotransformationFeature of biotransformation 1.1.连续性连续性continuitycontinuity一种物质的生物转化常需进行几种化学反应一种物质的生物转化常需进行几种化学反应乙酰水杨酸acetyl salicylic acid 水解hydrolysis 羟化hydroxylation结合combine 312.2.多样性多样性multiplicitymultiplicity同一类物质的可因结构的差异而经历不同同一类物质的可因结构的差异而经历不同类型的生物转化反应，甚至同一物质经不类型的生物转化反应，甚至同一物质经不同的生物转化途径而产生不同的转化产物。同的生物转化途径而产生不同的转化产物。苯甲酸+甘氨酸苯乙酸+谷氨酰胺马尿酸苯乙酰谷氨酰胺323.3.解毒致毒双重性解毒致毒双重性detoxifcation/detoxifcation/carcinogencarcinogen 一种物质经生物转化后，其毒性可能减弱一种物质经生物转化后，其毒性可能减弱（解毒），也可能增强（致毒）。（解毒），也可能增强（致毒）。3，4-苯并芘33 药物或毒物：抑制作用，诱导作用药物或毒物：抑制作用，诱导作用 Drugs or poison Drugs or poison Drugs or poison Drugs or poison：inhibitor or inducer inhibitor or inducer inhibitor or inducer inhibitor or inducer 年龄，性别，种族年龄，性别，种族 Age,Sex.Race Age,Sex.Race Age,Sex.Race Age,Sex.Race 病理病理 Condition of liver and kidney Condition of liver and kidney Condition of liver and kidney Condition of liver and kidneyphysiological significancesphysiological significances.detoxication.detoxication.detoxication.detoxication.the products are less toxic or carcinogen.the products are less toxic or carcinogen.the products are less toxic or carcinogen.the products are less toxic or carcinogen四、四、Factors influenceFactors influence(影响因素）影响因素）34第三节第三节 胆红素与胆汁酸代谢及其异常胆红素与胆汁酸代谢及其异常一、胆红素代谢及其异常一、胆红素代谢及其异常metadolism of bilirubin and abnormitymetadolism of bilirubin and abnormity35（一）胆红素代谢（一）胆红素代谢bilirubin metabolismbilirubin metabolismp生成生成 formationformationp运输运输 transportationtransportationp肝内代谢肝内代谢 liver liver metabolismetabolisp肝外代谢肝外代谢 extrahepaticextrahepatic metabolism metabolism p排泄排泄 excreteexcrete361 1、胆红素的生成胆红素的生成血红素（血红素（heme)heme)胆红素（胆红素（bilirubin)bilirubin)37Extravascular Pathway for RBC Destruction(Liver,Bone marrow,&Spleen)HemoglobinGlobinAmino acidsAmino acid poolHemeHemeBilirubinBilirubinFeFe2+2+ExcretedExcretedPhagocytosis&Lysis(1)(1)血红素（血红素（heme)heme)38血红素加氧酶系血红素加氧酶系血红素加氧酶系血红素加氧酶系 heme oxygenaseFeFeFeFe2+2+2+2+NADPH+HNADPH+HNADPH+HNADPH+H+NADPNADPNADPNADP+胆绿素还原酶胆绿素还原酶胆绿素还原酶胆绿素还原酶biliverdin reductase(2)(2)胆红素（胆红素（bilirubin)bilirubin)血红素血红素 hemeheme胆绿素胆绿素biliverdin胆红素胆红素bilirubinbilirubingreenred-orange3940-次甲基桥键次甲基桥键次甲基桥键次甲基桥键 41l血红素血红素 4 4个次甲基碳桥个次甲基碳桥 红色红色l胆绿素胆绿素 3 3个次甲基碳桥个次甲基碳桥 蓝色蓝色l胆红素胆红素 2 2个次甲基碳桥个次甲基碳桥 黄色黄色l胆素胆素 1 1个次甲基碳桥个次甲基碳桥 棕褐色棕褐色l胆素原胆素原 0 0个次甲基碳桥个次甲基碳桥 无色无色Methine-carbon bondMethine-carbon bond42Hydrophilic groups lipotropy（亲脂）Hydrophobicity bilirubin through the cells into the bloodintracelular432 2、胆红素在血液中的转运胆红素在血液中的转运bilirubin bilirubin in the blood transfer in the blood transfer 意义意义(signification)(signification)：（1 1）in favor of transportin favor of transport（2 2）restrict bilirubin into cellrestrict bilirubin into cell胆红素胆红素-清蛋白清蛋白bilirubin-albuminbilirubin-albumin间接胆红素间接胆红素 indirect bilirubin indirect bilirubin 未结合胆红素未结合胆红素 unconjugated bilirubin unconjugated bilirubin 游离胆红素游离胆红素 free bilirubinfree bilirubin443 3、胆红素在肝细胞内的代谢、胆红素在肝细胞内的代谢bilirubin bilirubin in hepatic cells metabolizein hepatic cells metabolizeq摄取摄取(upuptake)take)q转化转化(transform)transform)q排泄排泄(excrete)excrete)(1)(1)摄取摄取(up(uptake)take)胆红素胆红素-Y-Y蛋白蛋白胆红素胆红素-Z-Z蛋白蛋白清蛋白清蛋白45（2 2）转化）转化(transform)(transform)胆红素胆红素(bilirubin)(bilirubin)B-UGTB-UGT胆红素葡萄糖醛酸酯胆红素葡萄糖醛酸酯UDPGAUDPGAUDPGAUDPGAUDPUDPUDPUDPB-UGT:B-UGT:胆红素尿苷二磷酸胆红素尿苷二磷酸-葡萄糖葡萄糖醛酸基转移酶醛酸基转移酶 bilirubin bilirubin UDP-UDP-glucuronosyltransferaseglucuronosyltransferaseUDPGAUDPGAUDPGAUDPGA：尿苷二磷酸尿苷二磷酸-葡糖糖醛酸葡糖糖醛酸uridine diphosphate uridine diphosphate glucurnic acid glucurnic acid 直接胆红素直接胆红素 direct bilirubin direct bilirubin 结合胆红素结合胆红素 conjugated bilirubinconjugated bilirubin46（主要）（主要）（主要）（主要）（次要）（次要）（次要）（次要）474849（3 3）排泄）排泄(excrete)(excrete)结合胆红素结合胆红素conjugated bilirubinconjugated bilirubin阴离子载体阴离子载体 (Anion carrier)(Anion carrier)胆汁胆汁(bile)(bile)（毛细胆管（毛细胆管bile capillarybile capillary）胆汁胆汁(bile)(bile)（肠道（肠道intestinal tractintestinal tract）50514 4、胆红素在肠管中的变化及其肠肝循环、胆红素在肠管中的变化及其肠肝循环 metabolism of bilirubin in intestine and metabolism of bilirubin in intestine and metabolism of bilirubin in intestine and metabolism of bilirubin in intestine and bilinogen enterohepatic circulationbilinogen enterohepatic circulationbilinogen enterohepatic circulationbilinogen enterohepatic circulation结合胆红素结合胆红素肠道细菌（水解肠道细菌（水解）肠道细菌（还原肠道细菌（还原）胆色素原族胆色素原族中胆素原中胆素原mesobilirubinogenmesobilirubinogen粪胆素原粪胆素原stercobilinogenstercobilinogen尿胆素原尿胆素原urobilinogenurobilinogen未结合胆红素葡萄糖醛酸基glucuronic acid52 胆色素原族胆色素原族中胆素原中胆素原mesobilirubinogenmesobilirubinogen粪胆素原粪胆素原stercobilinogenstercobilinogen尿胆素原尿胆素原urobilinogenurobilinogen 胆素胆素bilinbilin中胆素中胆素mesobilirubinmesobilirubin粪胆素粪胆素stercobilinstercobilin尿胆素尿胆素urobilinurobilin80-90%80-90%OO粪便粪便faeces10-20%10-20%10-20%10-20%肠黏膜重吸收肠黏膜重吸收 portal veinportal vein门门静脉静脉 portal veinportal vein肝肝liverliver 肾肾kidneykidney（尿胆素原（尿胆素原）2-5%2-5%2-5%2-5%OO 尿胆素尿胆素尿尿urineurineurineurinebrown color of fecesyellow color of urine535455 肠道中有少量肠道中有少量肠道中有少量肠道中有少量(10%-20%)(10%-20%)(10%-20%)(10%-20%)的胆素原可被肠粘的胆素原可被肠粘的胆素原可被肠粘的胆素原可被肠粘膜细胞重吸收，经门静脉入肝，其中大部分膜细胞重吸收，经门静脉入肝，其中大部分膜细胞重吸收，经门静脉入肝，其中大部分膜细胞重吸收，经门静脉入肝，其中大部分(95%)(95%)(95%)(95%)再随胆汁排入肠道，形成胆素原循环。再随胆汁排入肠道，形成胆素原循环。再随胆汁排入肠道，形成胆素原循环。再随胆汁排入肠道，形成胆素原循环。胆素原肠肝循环的概念胆素原肠肝循环的概念(concept of bilinogen enterohepatic(concept of bilinogen enterohepatic circulation)circulation)In intestine(10%-20%)of bilinogenbilinogen-intestinal cells could be reabsorbed,by hepatic portal vein into liver,most of them(95%)and then with the bile into the intestine,form bilinogenbilinogen circulationcirculation56v尿胆红素尿胆红素(urine urine bilirubinbilirubin)v尿尿胆素原胆素原(urobilinogenurobilinogen)v尿尿胆素胆素(urobilinurobilin)尿三胆概念（尿三胆概念（concept)concept)：57NORMAL BILIRUBIN NORMAL BILIRUBIN METABOLISMMETABOLISM Uptake of bilirubin by the liver is mediated by a carrier protein(receptor)On the smooth ER,bilirubin is conjugated with glucoronic acid,xylose,or ribose Glucoronic acid is the major conjugate-catalyzed by UDP glucuronyl tranferase“Conjugated”bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi Converted to stercobilinogen(urobilinogen)(colorless)by bacteria in the gut Oxidized to stercobilin which is colored Excreted in feces Some stercobilin may be re-adsorbed by the gut and re-excreted by either the liver or kidney Uptake of bilirubin by the liver is mediated by a carrier protein(receptor)On the smooth ER,bilirubin is conjugated with glucoronic acid,xylose,or ribose Glucoronic acid is the major conjugate-catalyzed by UDP glucuronyl tranferase“Conjugated”bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi Converted to stercobilinogen(urobilinogen)(colorless)by bacteria in the gut Oxidized to stercobilin which is colored Excreted in feces Some stercobilin may be re-adsorbed by the gut and re-excreted by either the liver or kidney58胆胆素素原原肠肠肝肝循循环环的的过过程程59（一）正常血清（一）正常血清(normal serum)(normal serum)：总胆红素总胆红素(total bilirubin,TB)(total bilirubin,TB)：极少量结合胆红素极少量结合胆红素conjugated bilirubinconjugated bilirubin（直接胆红素（直接胆红素direct bilirubin,DB direct bilirubin,DB）TBTB：1.71-17.11.71-17.1 mol/Lmol/L DBDB：0.51-3.420.51-3.42 mol/Lmol/L少量未结合胆红素少量未结合胆红素unconjugated bilirubin unconjugated bilirubin（间接胆红素（间接胆红素indirect bilirubin indirect bilirubin）胆红素代谢紊乱与黄疸胆红素代谢紊乱与黄疸Disorder of bilirubin metabolism and jaundiceDisorder of bilirubin metabolism and jaundice60（三）黄疸（三）黄疸(jaundice)jaundice)1 1、概念（、概念（concept)concept)：隐性黄疸隐性黄疸(latent jaundice)：TB：17.1 -34.2mol/L 显性黄疸显性黄疸(clinical jaundice)：TB：34.2mol/L多种疾病引起病人血清总胆红素增高多种疾病引起病人血清总胆红素增高，胆红素进胆红素进入组织，引起皮肤、巩膜等组织黄染。入组织，引起皮肤、巩膜等组织黄染。pA variety of diseases caused by increased serum total bilirubinpBilirubin into tissue cell pYellow discoloration of skin&sclera due to excess serum bilirubin6162Jaundice may result from:Jaundice may result from:qincreased production ofincreased production of bilirubin bilirubin qimpaired metabolism ofimpaired metabolism of bilirubin bilirubin qreduced reduced bilirubinbilirubin excretion excretion qcombination of the abovecombination of the above632 2、黄疸的分类、黄疸的分类(classification)(classification)(1)(1)病变部位病变部位溶血性黄疸溶血性黄疸 （hemolytic jaundicehemolytic jaundice）肝细胞性黄疸肝细胞性黄疸 （hepatocellular jaundicehepatocellular jaundice）阻塞性黄疸阻塞性黄疸 （obstructive jaundiceobstructive jaundice）2 2、病因、病因肝前性肝前性黄疸黄疸 (prehepatic jaundice)prehepatic jaundice)肝性肝性