肝膽疾病的生物化學(xué)診斷 Biochemistry Diagnosis of Liver and Gallbladder

1、第八章肝膽疾病的生物化學(xué)診斷Biochemistry Diagnosis of Liver and Gallbladder1下腔靜脈左肝靜脈 肝動(dòng)脈肝門靜脈 總膽管 膽囊2 第一節(jié) 肝臟的解剖結(jié)構(gòu)特點(diǎn)及其 生物化學(xué)功能 Anatomic and Physiology一、解剖結(jié)構(gòu)特點(diǎn)Anatomic structure characteristic門靜脈hepatic portal vein)： 獲得消化道吸收而來的營養(yǎng)物Approximately 75% of the blood supply comes from the portal veinDrains the GI tract and

2、is rich in nutrients肝動(dòng)脈(hepatic artery)： 獲得充足的氧氣和代謝物Remainder of blood supply enters by hepatic artery Rich in oxygen雙重血液供給double blood supply：3肝靜脈(hepatic vein)： 體循環(huán)(systemic circulation) -腎(kidney)- 尿uria輸出通路 膽道系統(tǒng)(biliary tract )： 腸道(intestinal tract)-糞便(faeces)45Cell surface have a lot of microvi

3、lli(微絨毛) 增大了與血竇(sinusoid)的接觸面，有利于物質(zhì)轉(zhuǎn)運(yùn)Cell membrane have relatively high permeability 為肝細(xì)胞內(nèi)外的物質(zhì)交換提供了通道；Abundance mitochondria in cell 為肝細(xì)胞代謝提供能量Cell have abundance rough surfaced endoplasmic reticulum、smooth surfaced endoplasmic reticulum and Golgi complex 為各種蛋白質(zhì)和酶的合成、藥物和毒物等的生物轉(zhuǎn)化以及物質(zhì)的分泌排泄提供了場(chǎng)所Cell ha

4、ve abundance enzyme 物質(zhì)代謝和加工形態(tài)結(jié)構(gòu)(morphological structure) 化學(xué)組成(chemical composition)6Metabolism Carbohydrate, Fat & Protein二、肝臟生物化學(xué)功能Liver Functions:Secretory bile-Bile acids, salts & pigmentsExcretory BilirubinSynthesis Albumin, coagulation factorsStorage Vitamins, carbohydrates etc.Detoxification t

5、oxins, ammonia, etc.7 三、肝細(xì)胞損傷時(shí)的代謝改變Metabolic change of hepatocellular injury (一)、物質(zhì)代謝障礙 (Dysfunction of substance metabolism) 81、糖代謝 (Glucose metabolism) Important role in metabolism of glucose and regulation of blood glucoseConverts glucose to glycogen (storage) Breaks down glycogen into glucose (e

6、nergy)glucose is synthesized through gluconeogenesis (amino acids or lactate) 9Fasting-plasma glucose(FPG) decreased 空腹血糖降低 糖原合成障礙 glycogenesis disorder糖原貯存減少 glycogen storage decreasedPostchallenge plasma glucose(PPG) increased 餐后血糖增高 肝病(disease of the liver)10嚴(yán)重肝病(serious disease of the liver)糖有氧氧

7、化(aerobic oxidation)三羧酸循環(huán)(tricarboxylic acid cycle)血中丙酮酸(pyruvic acid ) 肝病(disease of the liver)磷酸戊糖途徑(phosphopentose pathway) 糖酵解途徑(glycolytic pathway) 糖耐糖曲線OGTT異常呈低平型、頂峰型、高坡型 11Synthesizes all plasma proteins except gamma globulinAlbumin (osmotic pressure)Alpha and beta globulinsBlood clotting fac

8、torsSpecific transport proteinsProthrombin: liver needs vitamin K2、 蛋白質(zhì)代謝(Protein metabolism)12Ammonia (potential toxin) is byproduct of gluconeogenesis(糖異生Liver converts ammonia into ureaAlso removes ammonia produced by intestinal bacteria from portal bloodUrea is excreted in urineAmmonia Conversio

9、n13 白蛋白(albumin)減少，球蛋白(globulin) 增加， 兩者比值 (A/G) 小于1，提示有慢性肝實(shí)質(zhì)性損害(chronic hepatic parenchymatous injure) 1.蛋白質(zhì)的合成(synthesis protein)：coagulation factor 凝血障礙(coagulation disorder)plasma protein albumin 低白蛋白血癥(hypoalbuminemia)14 轉(zhuǎn)氨基(transamination) 脫氨基(deamination) 脫羧基(decarboxylase) 支鏈氨基酸/芳香族氨基酸比值 (Bra

10、nched-chain amino acid/Aromatic amino acid)：BCAA/AAA)肝細(xì)胞內(nèi)轉(zhuǎn)氨酶(transaminase)含量高： ALTBranched-chain：Extrahepatic metabolism (Leu、Ile、ValAromatic ： Liver metabolism Trp、Tyr、Phe 2.氨基酸代謝(amino acid metabolism)：15.解除氨毒：氨(ammonia) 尿素(urea) 腎排blood ammonia (血氨) BCAA/AAA(支/芳)amine胺肝性腦病hepatic encephalopathy(H

11、E)16Fatty acids broken down into ketonesProvide source of energy for muscles and other tissues.Occurs when glucose is limited as in starvation or uncontrolled diabetesFatty acids also used for synthesis of cholesterol, lipoproteins and other complex lipids脂質(zhì)代謝(Lipid metabolism)17.消化、吸收(digest and ab

12、sorb) : 膽固醇(cholesterol) 膽汁酸(bile acid) “脂肪瀉 Steatorrhea. 合成、運(yùn)輸(synthesize and transport )：Synthesize ：TG、ChE/Ch、PL、LCAT 、 acetone body(酮體) Transport：VLDL、HDL18分解(decompose)：TG、FAfat oxygenolysis decreaseExcess fat accumulate in hepatic cells fatty liver (當(dāng)肝內(nèi)脂類含量超過肝重的5%時(shí)，稱為脂肪肝脂肪肝)脂肪肝肝臟19 二、凝血與纖維蛋白溶解

13、障礙(Dysfunction of coagulation and fibrinolysis) 三、免疫功能障礙 (Dysfunction of immunity)20四、維生素代謝(vitamin metabolism) 1、吸收(absorption： 膽汁酸bile acid-脂溶性維生素fat-soluble vitamin2、轉(zhuǎn)化transform： synthesize coenzyme Provitamin A vitamine A vitamin D3 25-OH-D321五、激素的滅活作用inactivation of hormone： steroid hormone 類固醇

14、激素Protein hormone蛋白質(zhì)類激素Catecholamine hormone兒茶酚胺類激素許多激素在其發(fā)揮調(diào)節(jié)作用之后，主要在肝臟內(nèi)被分解轉(zhuǎn)化，從而降低或失去活性，這稱之為激素的滅活作用。22皮膚蜘蛛痣 (skin spider) 肝掌 (liver palms)面部色素沉著 ( face pigmentation)肝功能受損：23 第二節(jié)肝臟的生物轉(zhuǎn)化作用 Biotransformation 一、生物轉(zhuǎn)化biotransformation)24 第二節(jié)肝臟的生物轉(zhuǎn)化作用 Biotransformation reaction 一、生物轉(zhuǎn)化biotransformation) 外源性

15、非營養(yǎng)物質(zhì)Exogenous non-nutrient(藥物drug、毒物Toxin 、 致癌物Carcinogens) 內(nèi)源性非營養(yǎng)物質(zhì)Endogenous non-nutrient 激素(hormone), NH3,神經(jīng)遞質(zhì)(neurotransmitter), Bilirubin ,胺類(amine)肝尿、膽汁排出25第一相反響(Phase I)：氧化(oxidation) 復(fù)原(reduction)水解(hydrolysis)增加極性( increasing polarity二、反響類型(type)26Oxidation: alcohol, aldehyde, ketone, mono

16、amine, aromatization, molybdenum, flavin Key oxidation enzyme: cytochrome P450氧化反響：肝細(xì)胞微粒體、線粒體及胞液中均含有參與生物轉(zhuǎn)化的不同氧化酶系，包括單氧酶系、脫氫酶系等。27 Reduction: azo- and nitro-, carbonyl, disulfide, sulfoxide, quinone, dihydropyrimidine復(fù)原反響：主要有硝基復(fù)原酶和偶氮復(fù)原酶所催化的兩類反響。28 Hydrolysis: functional group such as carboxylic acid

17、ester, amide, thioester, acid anhydride水解反響：肝細(xì)胞微粒體和胞液中含有各種水解酶類，可將酯類、糖苷類化合物水解，以減低或消除其生物學(xué)活性。29結(jié)合反響(conjugation reactions) 乙酰CoA，甘氨酸，GSH，進(jìn)一步增加極性，掩蓋有毒基團(tuán)Less toxic ,easy for excretion第二相反響(Phase II) ：30三、生物轉(zhuǎn)化的特點(diǎn)Feature of biotransformation 1.連續(xù)性continuity一種物質(zhì)的生物轉(zhuǎn)化常需進(jìn)行幾種化學(xué)反響乙酰水楊酸acetyl salicylic acid 水解hy

18、drolysis 羥化hydroxylation結(jié)合combine 31multiplicity同一類物質(zhì)的可因結(jié)構(gòu)的差異而經(jīng)歷不同類型的生物轉(zhuǎn)化反響，甚至同一物質(zhì)經(jīng)不同的生物轉(zhuǎn)化途徑而產(chǎn)生不同的轉(zhuǎn)化產(chǎn)物。苯甲酸+甘氨酸苯乙酸+谷氨酰胺馬尿酸苯乙酰谷氨酰胺32detoxifcation/ carcinogen 一種物質(zhì)經(jīng)生物轉(zhuǎn)化后，其毒性可能減弱解毒，也可能增強(qiáng)致毒。3，4-苯并芘33 藥物或毒物：抑制作用，誘導(dǎo)作用 Drugs or poison：inhibitor or inducer 年齡，性別，種族 Age, Sex .Race 病理 Condition of liver and ki

19、dneyphysiological significances.detoxication.the products are less toxic or carcinogen四、 Factors influence (影響因素34第三節(jié) 膽紅素與膽汁酸代謝及其異常一、膽紅素代謝及其異常metadolism of bilirubin and abnormity35一膽紅素代謝bilirubin metabolism生成 formation運(yùn)輸 transportation肝內(nèi)代謝 liver metabolis肝外代謝 extrahepatic metabolism 排泄 excrete361、

20、膽紅素的生成血紅素heme)膽紅素bilirubin)37Extravascular Pathway for RBC Destruction(Liver, Bone marrow, & Spleen)HemoglobinGlobinAmino acidsAmino acid poolHemeBilirubinFe2+ExcretedPhagocytosis & Lysis(1)血紅素heme)38血紅素加氧酶系 heme oxygenaseFe2+NADPH+H+NADP+膽綠素復(fù)原酶biliverdin reductase(2)膽紅素bilirubin)血紅素 heme膽綠素biliverd

21、in膽紅素bilirubingreenred-orange3940-次甲基橋鍵 41血紅素 4個(gè)次甲基碳橋 紅色膽綠素 3個(gè)次甲基碳橋 藍(lán)色膽紅素 2個(gè)次甲基碳橋 黃色膽素 1個(gè)次甲基碳橋 棕褐色膽素原 0個(gè)次甲基碳橋 無色Methine-carbon bond42Hydrophilic groups lipotropy親脂Hydrophobicity bilirubin through the cells into the bloodintracelular432、膽紅素在血液中的轉(zhuǎn)運(yùn)bilirubin in the blood transfer 意義(signification)：1in

22、favor of transport2restrict bilirubin into cell膽紅素-清蛋白bilirubin-albumin間接膽紅素 indirect bilirubin 未結(jié)合膽紅素 unconjugated bilirubin 游離膽紅素 free bilirubin443、膽紅素在肝細(xì)胞內(nèi)的代謝bilirubin in hepatic cells metabolize攝取(uptake)轉(zhuǎn)化(transform)排泄(excrete) (1)攝取(uptake)膽紅素-Y蛋白膽紅素-Z蛋白清蛋白452轉(zhuǎn)化(transform)膽紅素(bilirubin)B-UGT膽紅

23、素葡萄糖醛酸酯UDPGAUDPB-UGT:膽紅素尿苷二磷酸-葡萄糖醛酸基轉(zhuǎn)移酶 bilirubin UDP-glucuronosyltransferaseUDPGA：尿苷二磷酸-葡糖糖醛酸uridine diphosphate glucurnic acid 直接膽紅素 direct bilirubin 結(jié)合膽紅素 conjugated bilirubin46主要次要4748493排泄(excrete)結(jié)合膽紅素conjugated bilirubin陰離子載體 (Anion carrier)膽汁(bile) 毛細(xì)膽管bile capillary 膽汁(bile) 腸道intestinal tr

24、act50514、膽紅素在腸管中的變化及其腸肝循環(huán) metabolism of bilirubin in intestine and bilinogen enterohepatic circulation結(jié)合膽紅素腸道細(xì)菌水解腸道細(xì)菌復(fù)原 膽色素原族中膽素原mesobilirubinogen糞膽素原stercobilinogen尿膽素原urobilinogen未結(jié)合膽紅素葡萄糖醛酸基glucuronic acid52 膽色素原族中膽素原mesobilirubinogen糞膽素原stercobilinogen尿膽素原urobilinogen 膽素bilin中膽素mesobilirubin糞膽素s

25、tercobilin尿膽素urobilin80-90%O糞便faeces10-20%腸黏膜重吸收 portal vein門靜脈 portal vein肝liver 腎kidney（尿膽素原）2-5%O 尿膽素尿urinebrown color of fecesyellow color of urine535455 腸道中有少量(10%-20%)的膽素原可被腸粘膜細(xì)胞重吸收，經(jīng)門靜脈入肝，其中大局部(95%)再隨膽汁排入腸道，形成膽素原循環(huán)。膽素原腸肝循環(huán)的概念(concept of bilinogen enterohepatic circulation)In intestine (10% -2

26、0%) of bilinogen -intestinal cells could be reabsorbed ,by hepatic portal vein into liver, most of them (95%) and then with the bile into the intestine, form bilinogen circulation56尿膽紅素(urine bilirubin)尿膽素原(urobilinogen)尿膽素 (urobilin)尿三膽概念concept)：57NORMAL BILIRUBIN METABOLISM Uptake of bilirubin by

27、 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 b

28、iliary 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 c

29、arrier 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 t

30、o 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膽素原腸肝循環(huán)的過程59一正常血清(normal serum)： 總膽紅素(total bilirubin,TB)：極少量結(jié)合膽紅素conjugated bi

31、lirubin直接膽紅素direct bilirubin,DB mol/L mol/L少量未結(jié)合膽紅素unconjugated bilirubin 間接膽紅素indirect bilirubin 膽紅素代謝紊亂與黃疸Disorder of bilirubin metabolism and jaundice60三黃疸(jaundice)1、概念concept)：隱性黃疸(latent jaundice) ： 顯性黃疸(clinical jaundice)：多種疾病引起病人血清總膽紅素增高，膽紅素進(jìn)入組織，引起皮膚、鞏膜等組織黃染。A variety of diseases caused by i

32、ncreased serum total bilirubinBilirubin into tissue cell Yellow discoloration of skin & sclera due to excess serum bilirubin6162Jaundice may result from:increased production of bilirubin impaired metabolism of bilirubin reduced bilirubin excretion combination of the above632、黃疸的分類(classification)(1)

33、病變部位溶血性黃疸 hemolytic jaundice 肝細(xì)胞性黃疸 hepatocellular jaundice阻塞性黃疸 obstructive jaundice2、病因肝前性黃疸 (prehepatic jaundice)肝性黃疸 (hepatic jaundice)肝后性黃疸 (posthepatic jaundice) 3、升高的膽紅素類型高未結(jié)合膽紅素性黃疸高結(jié)合膽紅素黃疸 6465 Over production of Bilirubin (Hemolytic)各種原因引起紅細(xì)胞破壞過多未結(jié)合膽紅素生成過多超過肝細(xì)胞的結(jié)合和排泄能力溶血性黃疸 A variety of cau

34、ses excessive red blood cell damage generate too much unconjugated bilirubinexcess the combination of ability and excretion of liver cells hemolytic jaundice.6667Impaired hepatic function (Hepatitic)肝細(xì)胞對(duì)未結(jié)合膽紅素的攝取、結(jié)合、排泄發(fā)生障礙Hepatocellular dysfunction in handling bilirubin(uptake,combine,excrete)血中未結(jié)合膽

35、紅素或結(jié)合膽紅素升高 unconjugated bilirubin or conjugated bilirubin increased6869 各種原因?qū)е屡判构δ苷系K excretion dysfunction 膽汁返流使血中結(jié)合膽紅素升高 the bile reflux ,conjugated bilirubin in the blood increased 阻塞性O(shè)bstruction to bile flow (Obstructive)Intrahepatic cholestasisExtrahepatic Obstruction (Surgical Jaundice)70直膽71Ty

36、pe of jaundiceBilirubin metabolismPrehepatic (increased plasma unconjugated bilirubin)Degradation of haem from haemoglobin, myoglobin and cytochromes produces bilirubinBilirubin is bound to albumin to make it water soluble and is transported to hepatocytesHepatocellular (increased plasma conjugated and unconjugated bilirubin)Bilirubin is taken up by hepatocytes and conjugated with glucuronic acid to make it water soluble Obstruction (plasma conjugated bilirubin parti