1、 山東大學齊魯醫(yī)院閻明(peptic ulcer)消化性潰瘍思考題主訴：50歲，左上腹隱痛半月，有時燒心、反酸，不愿吃飯。 作何檢查？考慮何診斷？如果為十二指腸球部潰瘍，請制定醫(yī)療方案？思考題誰了誘發(fā)PU W （who）發(fā)生了什么病理改變 W（ what）哪些臨床表現(xiàn) W （which）并發(fā)癥 C （complication）檢查的選擇 O（option）處理 M （management） WWW.COM表面缺損，粘膜層斷裂； 缺損達或超過粘膜肌層；同時其下有炎性基底。 何謂潰瘍Definition何謂消化性潰瘍自身消化autodigestion胃酸胃蛋白酶發(fā)生部位食管、胃十二指腸等組織學深度

2、粘膜肌層主要病因HP,NSAIDsIn USA about 500,000 new cases per year and 4 million recurrencesCommonly occur in male than in femaleDU: M/F about 4.4-6.8:1GU: M/F about 3.6-4.7:1DUGUDU/GU about 1.5-5.6:1 in ChinaUlcers can occur in any ageDU most between the ages of 30 and 55GU more common between the ages of 55

3、 and 70 Epidemics 多粘膜屏障mucosal barrier粘液屏障mucus barrier前列腺素prostaglandin PG細胞更新cell renewing粘膜血流mucosa circulation表皮生長因子EGF胃酸-胃蛋白酶gastric acid-pepsinHp感染 HP藥物drugs煙酒smoking-alcohol膽鹽胰酶cholate-Pancreatin 保護因素Defensive factors 損傷因素Aggressive factorsEtiology 失衡NormalIncreased Attack HyperacidityWeak de

4、fense Helicobacter pylori* drugs , Stress, smokingEtiology of PUDH pylori is a spiral shaped bacterium that is found in the gastric mucus layer or adherent to the epithelial lining of the stomach. H pylori causes more than 90% of duodenal ulcers and more than 80% of gastric ulcers 50% of world popul

5、ation is infected and is the cause of:Duodenal/gastric ulcers and Malt lymphoma(粘膜相關(guān)淋巴樣組織淋巴瘤)Helicobacter pyloriHelicobacter pylori菌體的一端可伸出26條帶鞘的鞭毛。在分裂時，兩端均可見鞭毛。鞭毛長約為菌體11.5倍。粗約為30nm。鞭毛的頂端有時可見一球狀物，實為鞘的延伸物。每一鞭毛根部均可見一個圓球狀根基伸入菌體頂端細胞壁內(nèi)側(cè)。在其內(nèi)側(cè)尚有一電子密度降低區(qū)域。鞭毛在運動中起推進器作用，在定居過程中起拋錨作用 Helecobacter pyloriH. Pylor

6、i organisms- silver st.Toludine Bluestain（甲苯蘭染色）HP 的發(fā)現(xiàn)史HP實際上早就被人注意過。1893年在狗中，1896年在大鼠和貓中已有人報告在其胃中偶然見到螺形菌。本世紀初在潰瘍性胃癌病人胃內(nèi)容物中曾找到同樣的細菌。其他報告也證實了這一些發(fā)現(xiàn)。也注意到健康人中未發(fā)現(xiàn)這些細菌。經(jīng)過30年的努力，在散載的報告中，良性消化性潰瘍病人胃中發(fā)現(xiàn)了這些細菌。1938年Doenges在一份綜合性尸解研究報告中提出胃中螺形菌的流行率達43，但是并未檢查出這一細菌與不同的胃部疾病之間的關(guān)系。HP的發(fā)現(xiàn)史 關(guān)于這些細菌在人胃疾病中可能的作用一直存在著爭論。有些研究者提

7、出人們在活檢標本中所見到的這種細菌是經(jīng)口吞服的污染物。這一假說1959年由于當時的一位有影響的學者palmer發(fā)表了1000例胃活檢標本大量組織學研究的報告而占了優(yōu)勢。 1975年Steer和Colin-Jones報告了胃潰瘍病人中胃粘液層下的胃粘膜上發(fā)現(xiàn)了細菌，重新引起了人們對胃細菌在消化性潰瘍致病機制中作用的興趣，這提示細菌可能降低胃粘膜的抵抗力，因此易感于潰瘍。Steer等企圖分離這一細菌。結(jié)果生長的是綠膿桿菌。后來仔細審閱文章中的圖片提示在粘膜中所見的是一種與綠膿桿菌無關(guān)的螺形菌?，F(xiàn)在看來這些作者分離到的綠膿性桿菌可能是來自內(nèi)窺鏡的污染菌，而圖片中所見的才是現(xiàn)在大家感興趣的Hp。HP的

8、發(fā)現(xiàn)史1979年,Warren在1例無潰瘍性消化不良患者的胃部活檢標本中觀察到螺旋菌(spiralbacteria)。通過顯微鏡,Warren觀察到嚴重的胃組織炎癥以及胃黏膜上的微生物。在接下來的2年中,Warren在很多標本中都觀察到這種細菌,這些標本常常和胃炎有關(guān)。在1981年,Marshall開始幫助Warren研究觀察到的細菌。Warren和Marshall觀察到和彎曲桿類菌屬類似的胃部螺旋菌。在1982年4月,這種螺旋狀的生物被第一次培養(yǎng)出來, 1983年命名為幽門彎曲菌(campylobacterpyloridis)。1987年,更名為幽門彎曲桿菌(campylobacterpyl

9、ori),但是RNA分析和其他研究顯示這種細菌不屬于彎曲桿菌屬,于1989年被再次更名為幽門螺桿菌(helicobacterpylori)。 Barry MarshallRobin Warren 1997年9月2日，沃倫（ warren右）和馬歇爾（marshall）在澳大利亞珀斯市1979年，沃倫首次注意到幽門螺桿菌，但因與當時醫(yī)學界的教條不符合，他的發(fā)現(xiàn)沒有受到重視。而馬歇爾“適時”地出現(xiàn)在沃倫的身邊。他們二人合作，最終于1982年確認了幽門螺桿菌的存在及其在胃炎、胃潰瘍和十二指腸潰瘍等疾病中扮演的角色。 HP的發(fā)現(xiàn)史 Marshall博士描述他喝下一杯含有HP飲料后的情形： “剛喝下去沒

10、怎樣，但我也同時開始進行自己發(fā)明的驗定法。到第三天，全身冒冷汗，進食時胃部很困難。然后從第四天開始到第七天，吃的都吐出來，精神壞透。到第八天，吐出來都是水，但沒有了唾液，口臭出現(xiàn)，胃酸破壞情況嚴重，我真正投降了，立刻接受急療，大約兩周后，主要癥狀消失，大約一個月后，我已經(jīng)能從自己那套驗定法里證實自己體內(nèi)再無病菌感染，我終于證實了潰瘍是病菌感染的疾病?！?The high percent of in peptic ulcer90%-100% in DU while 80%-90% in GU15%-20% patients with HP will develop ulcerEradicatio

11、n of HP can hasten the healing rate and decrease the recurrence rateRefractory ulcer難治性潰瘍can heal after HP eradicationthe recurrence rate:5 % per year after eradication, while 50%-70% with conventional therapy HP infection change the balance between the invasive factors with defensive factorsH pylor

12、i (HP) infection-臨床資料Mode of ActionPasses through mucous lining in stomachAttaches to gastric epithelial cells and entersSurvives gastric acidity by production of urease Vacuolating cytotoxin A(Vac A) 空泡毒素A Cytotoxin-assocated gene A(Cag A)細胞毒相關(guān)基因ACauses destruction of gastric mucosaHp可能的致病因子及炎癥反應致病

13、因子可能的作用定居及毒性因子螺旋形菌體結(jié)構(gòu)有利通過胃粘液層鞭毛加速穿透粘液層粘液素酶降解糖蛋白、有利Hp穿透粘液層尿素酶降解尿素，既有利Hp生存，又對上皮細胞有毒粘附素使Hp定居胃上皮細胞表面蛋白酶降解粘液層，破壞上皮細胞膜脂酶和磷脂酶A消化粘液層，破壞上皮細胞膜過氧化氫酶在胃粘膜上起抗氧化作用，保護Hp自身空泡毒素VacA破壞上皮細胞，使胞內(nèi)物質(zhì)溢出CagA蛋白質(zhì)作用未明胃酸分泌物抑制因子有利急性炎癥發(fā)生脂多糖能抑制上皮細胞膜基質(zhì)的合成炎癥反應粘液層完整性破壞中性粒細胞的激活單核細胞與巨噬細胞的激活白三烯B4（ITB4）的繼發(fā)性增加，增強炎癥白細胞移動抑制因子的作用磷脂酶的降解物的趨化和改變

14、細胞膜通透性的作用血小板激活因子促進局部粘膜的損壞65kD熱休克蛋白與胃竇上皮有交叉抗原作用漿細胞分泌的IgA激活酸性粒細胞降解破壞粘膜固有層堿性粒細胞釋放組織胺，與IgE結(jié)合釋放血管活性因子Hp可能的致病因子及炎癥反應Helicobacter Peptic ulcer disease六因素假說胃酸 胃蛋白酶胃化生 十二指腸炎 Hp感染高胃泌素血癥 碳酸氫鹽The hypothesis of HP infection“漏屋頂”假說hypothesis of leaking roof胃粘膜屏障：屋頂胃酸：雨Hp感染:漏屋頂H+泥漿水Chronic NSAID users:10%-20%preva

15、lence of GU and 2%-5% prevalence of DUAspirin is the most ulcergenic NSAIDAssociated with:NSAID type,dosage, course of treatment,age,HP,smoking,etcMechanism:local action and system influence 非甾體類抗炎藥 non-steroid anti-inflammatory drugs;NSAIDsTopical action:NSAIDs(aspirin), damage the gastric mucosa b

16、y a topical irritation of the gastric epithelium when PH2.0systemic inhibition of protective gastric endogenous mucosal prostaglandin synthesisInhibit cyclooxygenase(COX),decrease the internal prostaglandins(PG)Taking PG1 analog(misoprotol米索前列醇) can prvent ulcer occurence Mechanism of NSAIDsMechanis

17、m of Action of NSAIDs: New ConceptCOX-2“Inducible”Prostaglandins PGI2 COX-1“Constitutive”ProstaglandinsMediate pain, inflammation, and feverArachidonic acidCO2HNon-specific NSAIDsGI mucosalProtectionHemostasisCOX-2 NSAIDs ThromboxaneGI MucosaPlatelet血栓素凝血作用花生四烯酸 Gastric acid plays a central role inN

18、SAID- associated gastroduodenal damageAspirinand otherNSAIDsPROTECTIVEFACTORSMucus layerIonic gradient離子梯度Bicarbonate layer碳酸氫鹽層ProstaglandinsSurface epithelialcellsMucosal bloodsupplyH. pyloriPepsinGastricacidAGGRESSIVE FACTORSAspirin andother NSAIDsProstaglandinproductionBicarbonateproductionMucus

19、productionAcidicenvironmentNeutral environmentThe exsistence of acid is the critical factorThe activiation of pepsinogen needs acidThe activity of pepsin rely on acid exsistenceBAO（基礎(chǔ)胃酸排量) and MAO（最大排酸量）:both increase in DU,change little in GUThe mechanism of acid over-excretionThe quantity of parie

20、tal cell increaseThe sensitivity of parietal cell increaseThe negative feedback mechanism負反饋機制defectvagal tone迷走神經(jīng)張力增高Acid and peptide 肥大細胞迷走神經(jīng)興奮G細胞乙酰膽堿組胺胃泌素胃泌素受體乙酰膽堿受體組胺H2受體壁細胞炎癥 胃竇炎 （Hp感染的Du）胃酸與胃蛋白酶分泌機制The acid pump is the final step in gastric acid secretionGastrinHistamineAcetylcholineCa2+HCI AC

21、h (M3)H+K+K+Cl-Cl-HClAcidpump蛋白激酶Ga2+Release of Ca2+ from intracellular storescAMPProteinkinasesRelease of Ca2+ from intracellular storesCa2+ProteinkinasesIts importance meet challengeHP infection:familial clustering phenomenaSome mark of heredity disappear after HP eradication（高胃蛋白酶原血癥、家族性高胃泌素血癥）Pe

22、ople of O type blood tend to have DU :its blood type antigen is a special receptor of HPIn some rare hereditary syndrome,peptic ulcer is part of its clinical featureHeredityAbnormal movement of stomach and duodeumDU:move too fast(solid)acid burden（酸負荷）in the bulb region riseGU:gastric movement distu

23、rbance -胃排空障礙（gastric empty disturbance - gastric antrum retention堿性反流（reverse flow- alk solid injury）加重 HP 感染或 NSAIDs的損傷 Ulcer caused by stress:Cushing ulcer, Curling ulcer：燒傷后發(fā)生的十二指腸潰瘍Psychological factor effect on DU obviouslyMechanism:vagus nerveStress and psychogical factorsSmoking:slower the h

24、ealing rate, promote recurrenceMechanism:acid,pepsin,HCO3, tension of pyloric sphincter ,PG synthesisDiet: Alcohol,strong tea,coffee,etcVirus infection:HSV-1單純皰疹病毒, cytomegalovirus巨細胞病毒Other risky factorsDiseases associated with ulcerdiseases risk of ulcer mechanism chronicchronic pulmonary diseases

25、 smoking=2 multiple ulcersSize:usually the diameter of DU 1.5cm while GU2cm,GU3cmShape:typically round or oval,also irregular or linear form exsitingDepth(different): fleet ulcer only over mucosa muscle layer,while deep penetrate muscle layer to serosa Complications:perforation front wall:acute perf

26、orationperitonitis腹膜炎Back wall:penetrate ulcer穿透性潰瘍 PathologyObserve under microscope:four zonesInflammatory cells zone. Superficial necrotic layer.Granulation tissue zone Collagenous scar layer.Normal StomachGastric UlcerGastric peptic ulcer: Gastric and Duodenal UlcersGastric UlcerGastric UlcerPun

27、ched out ulcer 鳥眼狀潰瘍Clean baseSmall singleRadiating mucosal folds.Benign ulcer.No tumor.Duodenal ulcerPeptic Ulcer Microscopy:Clinical featuresAbdominal pain(discomfort, abdominal fullness, or cramping)Position:typically localized to the epgastriumCharacter:gently,gnawing,dull,aching,hunger-likeRhyt

28、hmicity:GU 1h after meal,DU usually in the nightGastric acid excretionPeriodicity:late autumn or early spring Other:heartburn, belching, loating,dyspepsia nausea, vomiting, anorexia, and weight lossAbdominal painPhysical examinationOfen unremarkable Mild,localized epigastric tenderness Anemia caused

29、 by chronic hemorrhageSilence ulcer:15%-35%Old man or recur from H2-RA treatmentPeptic ulcer in old man:GUDU,untypicalCo-ulcer:5%，Both in stomach and duodenalPyloric channel ulcer:similar to DUPain after meal,vomiting, obstructionUlcer below duodenal bulb:5% of DUPain in the night or reflect to the

30、backRefractory ulcer:standard treatment with H2RA(GU 12w, DU 8w) /PPI (8w) not heal by endoscopy examination；Special type劉文忠.胃腸病學 2011，16（4）：193195H.pylori test:Invasive test:RUT（快速尿素酶試驗）,histology test, PCR,etcNoninvasive test:UBT（尿素呼氣試驗）,serum test,HpSA（糞便HP抗原檢測）Gastric fluid analysis:Acid in GU :

31、 normal or below normalAcid in DU:increaseSerum gastrin determination:above normalLaboratory testHow To Diagnose H pyloriInvasive tests (biopsy through endoscope)Rapid Urease Test (RUT)CultureHistologyPolymerase Chain Reaction (PCR)Non-Invasive testsUrea Breath Tests (UBT) Serological testsStool ant

32、igen testsThe Basis for Urea Breath TestUrea HydrolysisH pylory servival strategy in the acid environment of the stomachUrea is broken down to ammonia and carbon dioxide DiagnosisBarium meal: X-ray contrastDirect manifestation : niche signIndirect: spasm, irritationEndoscopy:better diagnostic accura

33、cyDirect observation,taking photoes,biopsyThree stages:active stage(A:A1,A2); healing stage(H:H1,H2); scar stage(S:S1,S2)DiagnosisEndoscopy對吻A1A1Gastric UlcerH1A2NSAID induced ulcersFunctional dyspepsia(FD):no organic diseases,X-ray and endoscopy distinguishChronic cholecystitis and cholelithiasis:

34、The pain associated with oily meal,fever,jaundice,B ultrasonic and ERCP identifyGastirc cancer:Barium meal, endoscopyZollinger-Ellison syndrome: Carcinoma: Small (D150mmol/h;BAO/MAO60%;gastin500pg/mlDifferencial diagnosisGastric cancer胃癌必須依賴X線和內(nèi)鏡加活檢確診 惡性潰瘍的特點：龕影位于腔內(nèi)形狀不規(guī)則，龕影周圍胃壁強直，黏膜皺襞融合中斷；內(nèi)鏡下底凹凸不平，表

35、面污穢，邊緣呈結(jié)節(jié)狀隆起。 懷疑惡性潰瘍的處理： 加強隨訪、短期復查內(nèi)鏡和活檢，不能依賴于強力抑酸藥物的效果。Benign vs. Malignant Malignant:Antrum location Lesser curvatureLarger size: 2 cmIrregular shape Heaping of MarginsExophytic appearanceuneven clean baseBenign:Greater curvatureGU50-100ml出現(xiàn)黑糞、1000-循環(huán)障礙， 半小時內(nèi) 1500-休克約占各種上消出血病因的50易為NSAID誘發(fā)，NSAID相關(guān)潰瘍

36、可毫無癥狀而突發(fā)出血鑒別：急診內(nèi)鏡2448h1.BleedingAcute bleeding穿孔的三種后果：急性腹膜炎（急性穿孔），前壁，1-5%，腹膜炎體征、氣腹征、肝濁音界消失，出血（10%）穿透性潰瘍（慢性穿孔），后壁，劇烈背痛，節(jié)律消失，頑固而持續(xù)，穿入胰腺淀粉酶增高局限性腹膜炎（亞急性穿孔），臨近后壁或穿孔很小2.PerforationPerforation:功能性幽門梗阻（幽門痙攣）：內(nèi)科治療器質(zhì)性幽門梗阻（瘢痕收縮）：外科手術(shù) 表現(xiàn)：嘔吐、甚或隔夜宿食，吐后癥狀緩解；胃形、蠕動波、震水音、消瘦、營養(yǎng)差清晨胃內(nèi)有振水音、抽胃液量200ml者考慮之，應行胃鏡檢查（X線？?。?.Pyl

37、oric obstrution1%-2%GU,潰瘍邊緣慢性GU病史45歲以上潰瘍頑固不愈巨大潰瘍胃鏡復查、隨訪和活檢4.Gastric carcinomaAim: Eliminate etiology, E Release symptom, R hasten healing, H Prevent from recurrence PTreatment:Life styleDrug therapyStrategy of treatment 消化性潰瘍的治療生活規(guī)律起居有序、調(diào)整心態(tài)勞逸結(jié)合牛奶豆?jié){好處多多、但含鈣較高不宜多飲 濃茶咖啡煙酒藥物、適時適情適可而止傷胃藥物盡量少用1.Life styl

38、eAgents eradicating HPAnti-acid agents (anti-secretory, anti-acid )Mucosal protective agentsPrevention and treatment of NSAID-UlcersTreatment of refractory ulcersPrevention from recurrence2.Drug treatmentPeptic Ulcer DrugsThe ProblemsInfection with H. pyloriIncreased acid secretionInadequate mucosal

39、 defenseSolutions:Antimicrobials (抗生素) Acid secretion inhibtors： H2- histamine blockers； Proton pump inhibtors Mucosa protectant: Prostaglandins; MisoprostolAnti-Ulcer AgentsH+K+Protein KinaseCa+cAMPAch-RHistamine-RPG-R+-PPIPirenzipineRanitidinePGsAntimicrobials-+AC-+PARIETAL CELLIn stomach抗HP藥物抗菌藥物

40、：克拉霉素，阿莫西林，甲硝唑，四環(huán)素, 呋喃唑酮, 左氧氟沙星抑酸藥： 質(zhì)子泵抑制劑：奧美拉唑,蘭索拉唑, 潘托拉唑等 H受體阻斷劑：雷尼替丁，法莫替丁鉍制劑： 枸櫞酸鉍鉀（膠體次枸櫞酸鉍）Treatment of HP三聯(lián)療法（PPI或鉍劑種抗生素） PPI或膠體鉍劑 抗菌藥物 奧美拉唑 40mg/d 克拉霉素500-1000mg/d 蘭索拉唑 60mg/d 阿莫西林1000-2000mg/d 枸櫞酸鉍鉀 甲硝唑800mg/d（膠體次枸櫞酸鉍）480mg/d 呋喃唑酮 200mg/d 選擇一種 選擇兩種 上述劑量分2次口服，療程7天20121.Proton pump inhibitors(P

41、PI):inactivate H+-K+ ATPase irreversibly,action 24hCompared with H2RA,provide longer and durable actionDosage:omeprazole 20mg,lansoprazole 30mg,pantoprazole 40mg,rabeprazole 10mgAdministered 30min before meal Acid-Antisecretory drugs2.H2 receptor antagonist(H2RA): 藥 物 抑酸相對強度 抑酸等效劑量 每日常用劑量西米替丁 1 600800mg 800hs(400 bid) 雷尼替丁 410 150mg 300hs(150 bid)法莫替丁 2050 20mg 40hs(20 bid)尼扎替丁 410 150mg 300hs(150 bid) 幾種常見的H2RA抑酸作用比較Acid-Antisecretory drugs3.Others:堿性抗酸藥：氫氧化鋁等 中和胃酸、保護粘膜，作為加強止痛的輔助治療抗膽堿藥：哌吡氮平，不理想促胃液素受體拮抗劑： 丙谷胺，不理想Acid-Antisecretory drugs1.