肝臟病理生理學(xué)

1、Pathophysiology of the Liver肝臟病理生理學(xué)病理生理學(xué)系Dept of Pathophysiology高遠(yuǎn)生 在我國(guó)人民的傳統(tǒng)觀念，肝膽都情感有關(guān)。?素問靈闌秘典論?：肝者，將軍之官，謀慮出焉。膽者，中正之官，決斷出焉。肝與意志相聯(lián)系，膽與勇敢相聯(lián)系，這也是中國(guó)人對(duì)於肝膽作用的心理認(rèn)同 忠肝義膽，肝膽相照，肝腦涂地，披肝瀝膽，全無(wú)心肝，肝腸寸斷，摧心剖肝，龍肝鳳髓，肝膽楚越，好心做了驢肝肺 肝者，將軍之官，謀慮出焉Carbohydrate Metabolism: the glucose buffer function due to storage of large a

2、mounts of glycogen & gluconeogenesis.Lipid Metabolism: oxidation of fatty acids to supply energy, synthesis of large quantities of cholesterol, phospholipids, & most lipoproteins, synthesis of fat from proteins & carbohydrates. Protein: Formation of plasma protein, deamination of amino acids, format

3、ion of urea. Synthesis of bile salts: 80% of cholesterol synthesized in the liver is converted into bile salts.The liverStorage of Vitamines: A (10 months), B12 (1yr), D (3-4 months), E, K, & minerals (iron & copper). Coagulation: fibrinogen, prothrombin, Vit. K required by the liver for formation o

4、f prothrombin , VII. IX, & X.Excretion of bilirubin.Processing of drugs, hormones, & other substances.Phagocytosis: Kupffer Cells, a blood-cleansing function: 99% bacteria is removed.The liver肝實(shí)質(zhì)細(xì)胞和枯否細(xì)胞損傷代謝、分泌、合成、解毒與免疫功能黃疸、出血、繼發(fā)性感染、腎功能障礙、腦病肝功能不全 (Hepatic Insufficiency) 肝功能衰竭 (Hepatic Failure) 是指肝功能不

5、全的晚期階段，臨床主要表現(xiàn)為肝性腦病與腎功能衰竭(肝腎綜合征)。(Manifestation and Pathogenesis of Hepatic Insufficiency)第一節(jié) 肝功能不全的表現(xiàn)及發(fā)生機(jī)制一 、糖代謝 (Carbohydrate Metabolism) 低血糖 (hypoglycemia): (1), 肝糖原儲(chǔ)藏, (2), 肝糖原分解, (3), 胰島素滅活。 高血糖 (hyperglycemia) ：門-體分流肝細(xì)胞從門靜脈攝糖 血糖濃度二 、低白蛋白血癥 (Hypoalbuminemia)白蛋白(albumin)只在肝合成肝硬化白蛋白50%腹水白蛋白40g/L (

6、正常: 20-30g/L), A/G 200ml ：腹水Capillary oncoticpressureCapillary filtration Pressure AldosteroneADHAscitesCirrhosisAlbuminsynthesisHormoneclearancePortal hypertensionLymphproduction 問題：肝功能不全? 肝功能衰竭? 嚴(yán)重肝病常出現(xiàn)腸源性內(nèi)毒素血癥機(jī)制？肝性腹水發(fā)生機(jī)制? 第二節(jié) 肝性腦病(Hepatic Encephalopathy) 繼發(fā)于嚴(yán)重肝病的神經(jīng)精神綜合征。一期：輕微性格行為改變二期：睡眠障礙、行為失常三期：

7、昏 睡、嚴(yán)重精 神 錯(cuò) 亂四期：神志喪失，昏迷 一、病因和分類 (Etiology and Classification)(一)病因: 嚴(yán)重肝臟疾患,肝臟不能處理毒性代謝產(chǎn)物門-體分流,毒性產(chǎn)物繞過肝臟毒性代謝產(chǎn)物(二)分類:內(nèi)源性肝性腦病:急性嚴(yán)重肝細(xì)胞壞死毒性代謝產(chǎn)物入血細(xì)胞毒性腦水腫顱內(nèi)高壓(爆發(fā)性肝功能衰竭) 外源性肝性腦病:慢性肝病如肝硬化門-體分流 (門-體型肝性腦病 )二、發(fā)病機(jī)制(Mechanisms) 氨中毒學(xué)說(shuō) 假性神經(jīng)遞質(zhì)學(xué)說(shuō) 血漿氨基酸失衡學(xué)說(shuō) -氨基丁酸學(xué)說(shuō)肝性腦病患者80%有血氨慢性肝病患者口服含氮物質(zhì)后血氨降氨治療可以緩解病情(一) 氨中毒學(xué)說(shuō): 證據(jù) (Theo

8、ry of Ammonia Intoxication: The evidence)血氨 肝功能障礙肝性腦病氨生成 氨清除 氨中毒學(xué)說(shuō): 機(jī)制 (Theory of Ammonia Intoxication: The mechanisms)正常人血氨的來(lái)源與去路氨基酸 氧化酶NH3NH4+ H+OH-糞 NH3鳥AA 循環(huán)尿素尿素腺苷酸NH3鳥氨酸循環(huán) (Ornithine Cycle)精氨酸Arginine瓜氨酸Citrulline鳥氨酸OrnithineUreaNH3NH3+CO2+3ATP血氨升高原因 (Causes of Bloood Ammonia Elevation)正常:血氨：主要

9、來(lái)自腸道含氮物質(zhì)分解肝性腦病患者:氨生成過多: 腸黏膜淤血、水腫，菌群活潑，上消化道出血產(chǎn)氨; 腸內(nèi)pH, NH4+ NH3, NH3 易入血；合并腎功能障礙血尿素 彌散至腸道的尿素 腸內(nèi)細(xì)菌尿素酶作用下轉(zhuǎn)為氨; 肌肉腺苷酸分解產(chǎn)氨血氨升高原因 (Causes of Bloood Ammonia Elevation)氨去除缺乏：正常:氨鳥氨酸循環(huán)經(jīng)腎排出2 NH3urea3 ATP鳥氨酸循環(huán)障礙: ATP, 酶受損門-體分流使腸內(nèi)氨不經(jīng)鳥氨酸循環(huán)肝性腦病患者:肝臟氨對(duì)腦組織的毒性作用 (Intoxication Effect of Ammonia on Brain Tissue) 干擾腦的能量

10、代謝：氨+-酮戊二酸谷氨酸：-酮戊二酸，NADH，ATP； 高濃度的氨可抑制丙酮酸脫羧酶系的活性乙酰輔酶A生成減少。 影響腦神經(jīng)遞質(zhì)間的平衡 (腦內(nèi)興奮性神經(jīng)遞質(zhì)：去甲腎上腺素、多巴胺、乙酰膽堿、谷氨酸等;抑制性神經(jīng)遞質(zhì)：谷氨酰胺、5-羥色胺、-氨基丁酸等)。氨興奮性遞質(zhì)(乙酰膽堿谷氨酸) 抑制性遞質(zhì)(谷氨酸+氨谷氨酰胺,谷氨酸經(jīng)谷氨酸脫羧酶催化脫羧 -氨基丁酸氨). (3) 氨對(duì)神經(jīng)細(xì)胞膜的抑制作用： 干擾神經(jīng)細(xì)胞膜上Na+、K+-ATP酶活性； 與K+競(jìng)爭(zhēng)，影響K+在神經(jīng)細(xì)胞膜內(nèi)外的正常分布。(二) 假性神經(jīng)遞質(zhì)學(xué)說(shuō) (Theory of False Neurotransmitter) 苯

11、乙醇胺和羥苯乙醇胺等的化學(xué)結(jié)構(gòu)與正常神經(jīng)遞質(zhì)去甲腎上腺素和多巴胺相似，可同樣被神經(jīng)末梢攝取、貯存和釋放但生理效應(yīng)遠(yuǎn)較正常遞質(zhì)為弱，故稱為假性神經(jīng)遞質(zhì)。去甲腎上腺素CHOHCH2NH2 HOHOCHOHCH2NH2 苯乙醇胺CHOHCH2NH2 HO羥苯乙醇胺CH2CH2NH2 HOHO多巴胺假性神經(jīng)遞質(zhì)的產(chǎn)生酪氨酸 多巴 DA NE 神經(jīng)遞質(zhì)的產(chǎn)生：酪胺 苯乙胺 羥苯乙醇胺 苯乙醇胺 酪胺 苯乙胺 Blood 酪氨酸 苯丙氨酸 酪胺 苯乙胺 酪胺 苯乙胺 MAO分解 細(xì)菌 假性神經(jīng)遞質(zhì)在腦內(nèi)堆積，競(jìng)爭(zhēng)取代正常遞質(zhì)被神經(jīng)末梢攝取、貯存和釋放，但信息傳遞功能遠(yuǎn)較正常遞質(zhì)弱，使網(wǎng)狀結(jié)構(gòu)上行沖動(dòng)系統(tǒng)及

12、黑質(zhì)-紋狀體通路等功能失常，導(dǎo)致大腦功能紊亂。假性神經(jīng)遞質(zhì)與肝性腦病(三) 血漿氨基酸失衡學(xué)說(shuō) (Theory of Plasma Amino Acid Imbalance) 血漿氨基酸失衡:芳香族氨基酸 (aromatic aa, AAA), 如苯丙氨酸、酪氨酸、色氨酸 支鏈氨基酸 (branched chain aa, BCAA)如亮氨酸、異亮氨酸、纈氨酸 BCAA/ AAA 由正常33.5變?yōu)?.6 1.2 肝AAA 糖 異生與分解 胰高血糖素/胰島素組織蛋白分解 肌肉和肝臟 釋放AAA 血AAA 胰島素 骨骼肌和脂肪 攝取利用BCAA 血BCAA 肝功能障礙 血漿氨基酸失衡機(jī)制血漿氨基

13、酸失衡與肝性腦病羥苯乙醇胺苯乙醇胺酪氨酸苯丙氨酸脫羧酶 酪氨酸多巴多巴胺NE羥化酶 脫羧酶 _假神經(jīng)遞質(zhì)5-羥色胺 色氨酸 兒茶酚胺神經(jīng)元攝取 羥化酶 AAA與BCAA通過同一載體轉(zhuǎn)運(yùn)入腦， AAA BCAA入腦， AAA入腦。(四) - 氨基丁酸學(xué)說(shuō) (Theory of -Amino Butyric Acid ) - 氨基丁酸 (GABA): 使突軸后神經(jīng)元超極化，產(chǎn)生抑制作用。肝功能障礙血GABA 腸源GABA清除 血腦屏障腦GABA腦GABA受體敏感度 肝性腦病三、肝性腦病的誘發(fā)因素 (Precipitating Factors of Hepatic Encephalopathy) 胃

14、腸道出血: (1), 腸道產(chǎn)氨明顯增多; (2), 體循環(huán)血量缺乏，肝腦缺血損傷; (3), 腦對(duì)毒性物質(zhì)敏感性提高酸堿平衡紊亂：(1), 血氨 刺激中樞呼吸加深加快呼吸性堿中毒; (2) ，肝硬化有腹水患者和肝腎綜合征患者常需利尿治療鉀喪失低血鉀性堿中毒。鎮(zhèn)靜藥、麻醉藥使用不當(dāng): (1), 肝解毒減少，藥物蓄積，中樞抑制增強(qiáng); (2), 毒物使腦對(duì)中樞抑制藥敏感。4.腹腔放液： (1), 大量放腹水腹內(nèi)壓突降，氨和其他毒物胃腸吸收增加，促使昏迷發(fā)生; (2), 大量放腹水大量電解質(zhì)喪失，促使昏迷發(fā)生。感染: (1), 細(xì)菌及其毒素直接損傷肝; (2), 分解代謝加強(qiáng)，產(chǎn)氨增多。氮質(zhì)血癥和外源

15、性氮負(fù)荷增加: (1), 肝性腦病多伴腎功能不全，尿素排除血尿素尿素滲入腸腔，在尿素酶作用下產(chǎn)氨血氨；(2), 患者高蛋白飲食腸產(chǎn)氨。三、肝性腦病的誘發(fā)因素 (Precipitating Factors of Hepatic Encephalopathy) II(一), 去除誘因。1, 嚴(yán)格限制蛋白質(zhì)攝入量; 2, 防止食道下端靜脈破裂出血; 3, 慎用鎮(zhèn)靜劑和麻醉劑;4,保持大便通暢。(二), 降低血氨?？诜楣牵?, 乳果糖乳酸鹽 抑制腸內(nèi)細(xì)菌產(chǎn)氨；2, 腸內(nèi)pH: NH3 NH4+, 氨吸收。(三), 促進(jìn)正常神經(jīng)遞質(zhì)功能恢復(fù)。左旋多巴 經(jīng)血腦屏障進(jìn)入CNS，變?yōu)檎嫘赃f質(zhì); 外周轉(zhuǎn)變?yōu)?/p>

16、多巴胺，改善腎功能。 (四), 氨基酸治療補(bǔ)充支鏈氨基酸, 糾正肝性腦病血漿氨基酸失衡四、防治的病理生理根底 (Pathophysiological Base of Prevention and Treatment)問題：肝性腦病病因和分類？肝功能衰竭患者血氨升高機(jī)制？假性神經(jīng)遞質(zhì)？血漿氨基酸失衡與肝性腦病關(guān)系？ 是指肝硬化患者在失代償期所發(fā)生的功能性腎功能衰竭及重癥肝炎所伴隨的急性腎小管壞死。第三節(jié) 、 肝腎綜合征(Hepatorenal Syndrome)一、肝腎綜合征的類型 (Classification of Hepatorenal Syndrome)(一)、肝性功能性腎衰竭: 患者腎

17、臟無(wú)器質(zhì)性病變,但腎血流量明顯減少,腎小球?yàn)V過率降低,而腎小管功能正常(二)、肝性器質(zhì)性腎衰竭: 器質(zhì)性腎衰竭的主要病理變化是腎小管壞死。主要與腸源性內(nèi)毒素血癥和大出血有關(guān)。二、肝性功能性腎衰竭的發(fā)病機(jī)制 (Mechanisms of Hepatic Functional Renal Failure) 多數(shù)肝硬變晚期患者伴有肝性功能性腎衰竭。肝硬變腹水有效循環(huán)血量腎血流量腎素-血管緊張素系統(tǒng)腎血管收縮交感-腎上腺髓質(zhì)系統(tǒng)興奮肝臟腎素滅活肝功能障礙胃腸道出血12二、肝性功能性腎衰竭的發(fā)病機(jī)制 (Mechanisms of Hepatic Functional Renal Failure) 前列腺

18、素合成缺乏：肝硬變有腹水患者如PGE2,PGI2高，腎小球?yàn)V過率正常。前列腺素合成酶抑制劑腎血流量和腎小球?yàn)V過率。內(nèi)毒素血癥：有內(nèi)毒素血癥者，肝腎綜合征患者比例高，不伴有腎功能衰竭者內(nèi)毒素血癥陰性。假性神經(jīng)遞質(zhì)蓄積：假性神經(jīng)遞質(zhì)腎皮質(zhì)血流量問題：肝腎綜合征?VocabularyHepatic Insufficiency 肝功能不全Hepatic Failure 肝功能衰竭 Hypoglycemia 低血糖癥，Hyperglycemia 高血糖癥 Fatty Liver 脂肪肝, Spider nevi 蜘蛛痣, Cirrhosis 肝硬化 Bilirubin 膽紅素，Conjugated bi

19、lirubin 結(jié)合膽紅素Hyperbilirubinemia 高膽紅素血癥Jaundice 黃疸，Nuclear jaundice 核黃疸Intestinal endotoxemia 腸源性內(nèi)毒素血癥 Portal hypertension 門脈高壓癥 Portal-systemic shunt 門-體分流Hepatic ascites 肝性腹水Hepatic encephalopathy 肝性腦病Ammonia intoxication 氨中毒False neurotransmitter 假性神經(jīng)遞質(zhì) -Amino butyric acid 氨基丁酸Hepatorenal syndrome

20、 肝腎綜合征50 Ways to Love Your Liver (1-15)1. Avoid taking unnecessary medications (Too many chemicals can harm me). 2. Dont mix medicines without the advice of a doctor. (You could create something poisonous that could damage me badly) 3. Street drugs cause serious damage and scar me permanently.4.Dont

21、 drown me in beer, liquor or wine. (If you drink alcohol, have two or fewer drinks per day) .5. Never mix alcohol with other drugs & medications. 6. Be careful when using aerosol cleaners. I have to detoxify what you breathe in, so when you go on a cleaning binge, make sure the room is well ventilat

22、ed, or wear a mask. 7. Bug sprays, paint sprays and all those other chemical sprays you use can harm me too. Be careful what you breathe. 8. Watch what gets on your skin! (Those insecticides you put on trees and shrubs to kill bugs can get to me right through your skin and destroy some cells.) Remem

23、ber, theyre serious chemicals. Hepatitis B & C - contagious viral infections that cause chronic liver disease9. Use caution and common sense regarding intimate contact (Hepatitis viruses live in body fluids, including blood and seminal fluid). 10. The hepatitis B virus also lives in saliva and, unli

24、ke the AIDS virus, can be transmitted through this fluid with relative ease. If you were stuck with a needle used by a person with AIDS, youd have a one in 2,000 chance of picking up the AIDS virus. But if that person had hepatitis B, your chances of picking up the virus increase to one in four!11.

25、Hepatitis C, spread primarily through direct blood contact, can be transmited through contaminated needles used in tattooing, body piercing, or IV drug injection.12. Untreated, chronic hepatitis B and C can cause cirrhosis and liver cancer and is the most frequent reason for liver transplants. 13. M

26、any infected people do not have symptoms until liver damage occurs, sometimes many years later. 14. Teach your children what a syringe looks like and tell them to leave it alone. 15. Never, ever, touch a discarded syringe or needle. 50 Ways to Love Your Liver (16-27)An insidious DiseaseOver 5 millio

27、n Americans have hepatitis B or C, resulting in an estimated 13,000 to 15,000 deaths annually. Yet many people do not know they are infected until serious liver damage occurs because they have few, if any, symptoms. Whos at greater risk of contracting hepatitis B or C? How do you find out if youre a

28、 carrier? Here are the answers. 16. If you or your family has immigrated from Africa, Southeast Asia, Mediterranean countries, or the Caribbean, where hepatitis B affects up to 15% of the population, you should have a blood test to determine if you are a carrier. Your doctor can arrange this for you

29、. 17. If you received a blood transfusion prior to 1990, you may have hepatitis C. As many as 300,000 people may have been infected in this way before the test for hepatitis C was developed. 18. If anyone in your family or a sexual partner tests positive for the hepatitis B virus, ask your doctor to

30、 test you for the virus. if the test is negative, your doctor will vaccinate you against the virus. A simple series or three vaccinations over six months will protect you against the virus for many years. Who else should be tested for hepatitis B and C?19. Users of intravenous drugs, particularly th

31、ose who share their needles. 20. Men or women who have multiple sexual partners. 21. Health care (including ambulance) workers. 22. Staff of institutions for people with developmental disabilities. 23. Firefighters, police officers, mortuary attendants or daycare workers. If you test positive for he

32、patitis B or C.24. Consult your doctor. He or she will determine whether you have liver disease and if you need referral to a specialist. 25. If you have hepatitis B, have your family tested. Those who have never contracted hepatitis B should be vaccinated. 26. Ask your doctor to screen for liver ca

33、ncer in order detect tumors while they are still small and treatable. 27. If you are a pregnant, hepatitis B-infected mother, you can pass the infection to your infants around the time of birth. More than 90% of this form of transmission can be prevented by vaccination of the baby. 50 Ways to Love Y

34、our Liver (28-35)Eat for health28. Eat a well balanced, nutritionally adequate diet. if you enjoy foods from each of the four food groups, you will probably obtain the nutrients you need. 29. Cut down on the amount of deep-fried and fatty foods you and your family consume. Doctors believe that the r

35、isk of gallbladder disorders (including gallstones, a liver-related disease) can be reduced by avoiding high-fat and cholesterol foods. 30. Minimize your consumption of smoked, cured and salted foods. Taste your food before adding salt! Or try alternative seasonings in your cooking such as lemon jui

36、ce, onion, vinegar, garlic, pepper, mustard, cloves, sage or thyme. MEAT, FISH, POULTRY & ALTERNATIVES PROVIDE: protein, vitamin A, iron, vitamin B12, niacin, fiber, thiamin; BREADS AND CEREALS PROVIDE: carbohydrates, niacin, thiamin, iron, riboflavin, fiber; FRUITS AND VEGETABLES PROVIDE: vitamin A

37、, vitamin C, iron, fiber, folacin; MILK AND MILK PRODUCTS PROVIDE:calcium, riboflavin, niacin,folacin, vitamin A, vitamin B12, vitamin D 31. Increase your intake of high-fiber foods such as fresh fruits and vegetables, whole grain breads, rice and cereals. A high-fiber diet is especially helpful in

38、keeping me healthy.32. Rich desserts, snacks and drinks are high in calories because of the amount of sweetening (and often fat) they contain. Why not munch on some fruit instead? 33. Keep your weight close to ideal. Medical researchers have established a direct correlation between obesity and the d

39、evelopment of gallbladder disorders. 34. If you are dieting to lose weight, make sure that you are still getting all the vitamins and minerals your body - and I! - need to function properly 35. A regular exercise routine, two or three days a week, will help keep me healthy, too. TROUBLE SIGNS. 36. Y

40、ellow discoloration of the skin or eyes; 37. Abdominal swelling or severe abdominal pain; 38. Prolonged itching of the skin; 39. Very dark urine or pale stools-, or the passage of bloody or tar-like stools; 40. Chronic fatigue, nausea or loss of appetite.50 Ways to Love Your Liver (41-50)What to do

41、if you have liver disease.41. Follow your doctors advice on food, exercise and other lifestyle guidelines. Learn about liver disease and understand how your diet helps you. Learn what and how much you can eat and drink. 42. Contact the American Liver Foundation for a listing of chapters near you. jo

42、in the chapter -talking to other people who are also affected by liver disease will help. 43. Invite family and close friends to attend chapter meetings or any learning sessions your local chapter may hold. The limitations of transplants.While transplants are not the answer for eliminating liver dis

43、ease (We need to find cures!), transplants are the only hope for survival many liver disease patients have. But there just are not enough organ donors to meet the demand. 44. Consider donating your organs in the event of your death. You can sign the organ donor card on your drivers license if your s

44、tate has such a program or obtain an organ donor card from the American Liver Foundation. Be sure to discuss your wishes with your family and your family doctor. AMERICAN LIVER FOUNDATION (45. Support the American Liver Foundation with a tax-deductible donation. Whatever you can afford to give, $15,

45、 $25, or $50, would be greatly appreciated. 46. Consider leaving a gift to the American Liver Foundation in your will. Contact our national office for a free pamphlet on our planned giving program.47. You may also wish to name the American Liver Foundation as the beneficiary of a life insurance poli

46、cy. Contact our office for more information on this as well. 48. If you can spare just a few hours a week, consider becoming a volunteer for the American Liver Foundation. AND FINALLY.49. See your doctor for a check-up on a regular basis. Remember, prevention is always the best medicine. 50. Take ca

47、re of yourself in everything you do. Be a healthy liver - keep a healthy liver! American Liver FoundationThanks! 謝謝！+-)(*&%$!#ZYXWVUTSRQPONMLKJJIHGFEDCBAzyxwvutsrqponmlkkjihgfedcba9876543210+-)(*&%$!#ZYXWVUTSRQPONMLKJIHGFFEDCBAzyxwvutsrqponmlkjihgffedcba9876543210+-)(*&%$!#ZYXWVUTSRQPONMLKJIHGFEDCBA

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