溃疡性结肠炎的研究进展课件.pptx

1、Introduction Introduction n IBDIBD是一是一种种病因病因尚尚不十分不十分清清楚的慢性非特楚的慢性非特异异性性肠肠道炎症，包括道炎症，包括UCUC和和CDCD 。n 其其发发病率呈逐年上升病率呈逐年上升趋势趋势，且多，且多为青壮为青壮年年发发病，病，临临床表床表现复杂现复杂，并发并发症症严严重，重，肠肠外表外表现现多多样样，严严重影重影响个响个人生活人生活质质量和社量和社会会生生产产力。力。n 此外，因其有癌此外，因其有癌变变的的风险风险，备备受广大受广大医医生的重生的重视视。n 近年来在国内外近年来在国内外IBDIBD基础与临床研究高潮迭起，基础研究的成果直接指

2、向临基础与临床研究高潮迭起，基础研究的成果直接指向临床治疗，取得了划时代的进展。床治疗，取得了划时代的进展。n 探讨和摸索适合国人的治疗方案以降低重症探讨和摸索适合国人的治疗方案以降低重症UCUC的并发症和死亡率显得十分的并发症和死亡率显得十分重要。重要。EpidemiolgyEpidemiolgyn The incidence of UC ranged from 1.0 to 2.0 per 100 000 person years.The prevalence of UC has ranged from 4.0 to 44.3 per 100 000.n In a recent study

3、,the speculated prevalence was 11.6/100 000 in China.n Compared to time trends in the West,there appears to be a time lag phenomenon involving incidence and and prevalence of IBD with regard to the Asian experience.n Ouyang Q,Tandon R,Goh KL et al.Management consensus of inflammatory bowel disease f

4、or the Asia-Pacific region.J Gastroenterol.Hepatol.2006;21:177282.n Lennrd-Jones JE.Incidence of infammatory bowel disease across Europe:is there a difference between north and south?.Gut 1996;39:690-697.Etiology and PathogenesisEtiology and Pathogenesisn 目前对IBD病因和发病机制的认识可概括为：n 环境因素作用于遗传易感者，在肠道菌群丛的参

5、与下，启动了肠道免疫系统及非免疫系统，最终导致免疫反应和炎症过程。n 可能是由于抗原的持续刺激或（及）免疫调节紊乱，这种免疫炎症反应表现为过度亢进或难于自限。n Baumgart DC,Carding SR.Inflammatory bowel disease:cause and immunobiology.Lancet 2007;369:16271640.n Brown SJ，Mayer IThe immune response in inflammatory bowel diseaseAm J Gastroenterol，2007，102：20582069n Bernstein CN，Sh

6、anahan FDisorders of a modern lifestylel reconciling the epidemiology of inflammatory bowel diseasesGut，2008，57：1185-1191Family historyFamily historyn Kitahora et al.found a strong familial occurrence in UC among Japanese patients.In a Korean study,a similar familial aggregation was also reported.n

7、Kitahora T,Utsunomiya T,Yokota A.Epidemiological study of ulcerative colitis in Japan:incidence and familial occurrence.The Epidemiology Group of the Research Committee of Inflammatory Bowel Disease in Japan.J.Gastroenterol.1995;30(Suppl.8):58.n Park ER,Yang SK,Myung SJ et al.Familial occurrence of

8、ulcerative colitis in Korea.Korean J.Gastroenterol.2000;36:7704.R Risk factorsisk factorsn Objective To screen the risk factors of inflammatory bowel disease(IBD)by case investigationn Methords 72 determined IBD patients and 72 paired healthy subjects were surveyed with an organized inventory compri

9、sing of relevant items to IBDCOX regression method was used to screen the statistically significant risk factors for IBDn Results COX regression indicated the statistical significance in stressmilk and fried food over the other postulated risk factorsfor IBDn Conclusion Stress，milk and fried food ar

10、e the potential risk factors for IBDn Kaichun Wu et al.Investigation on the risk factors of inflammatory bowel disease：A paired study of 72 cases.Chin J Gastroenterol Hepatol.2006,15(2):161-162Protective factorsProtective factorsn A study from Japan found a protective effect of smoking for UC.Nam et

11、 al.found that appendectomy was protective against UC in their group of Korean patients.n A case-control study of ulcerative colitis in relation to dietary and other factors in Japan.The Epidemiology Group of the Research Committee of Inflammatory Bowel Disease in Japan.J Gastroenterol.1995;30(Suppl

12、.8):912.n Nam SW,Yang SK,Jung HY et al.Appendectomy and the risk of developing ulcerative colitis:results after control of smoking factor.Korean J.Gastroenterol.1998;32:5560.n Vleggaar FP,Lutgens MW,Claessen MM.Review article:the relevance of surveillance endoscopy in long-lasting inflammatory bowel

13、 disease.Aliment.Pharmacol.Ther.2007;26(Suppl.2):4752.Serological markersSerological markersn The two most widely studied serological markers in inflammatory bowel disease in recent years have been p-ANCA and ASCA.The clinical utility of p-ANCA or ASCA testing in the diagnosis of inflammatory bowel

14、disease,in patients with non-specific gastrointestinal symptoms,is limited because of the varying seroprevalence of these antibodies in patients with inflammatory bowel disease and the inadequate sensitivity of the assays.n Lawrance IC,Murray K,Hall A,Sung JJ,Leong R.A prospective comparative study

15、of ASCA and pANCA in Chinese and Caucasian IBD patients.Am.J.Gastroenterol.2004;99:218694n Reese GE,Constantinides VA,Simillis C et al.Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease.Am J Gastroenter

16、ol.2006(Oct);101(10):241022.n Bossuyt XSerologic markers in inflammatofy bowel diseaseC1in Chem 2006：52：171一181探讨和摸索适合国人的治疗方案以降低重症UC的并发症和死亡率显得十分重要。此外，因其有癌变的风险，备受广大医生的重视。2007;26(Suppl.方法 收集UC患者30例和健康对照者30名的血清标本，双向凝胶电泳(2-DE)分离等量混合血清的蛋白质，运用图像分析软件进行比较和分析，识别差异表达蛋白质。2):4752.In a recent study,the speculate

17、d prevalence was 11.Conclusion Stress，milk and fried food are the potential risk factors for IBD经质谱分析发现触珠蛋白，热休克转录因子2，受体酪氨酸激酶、醛脱氢酶、载脂蛋白c一、中心粒旁物质l在UC患者中表达水平升高，角蛋白1，细丝蛋白A结合蛋白1、肌球蛋白3在UC患者中表达水平降低。方法：对临床确诊的32例IBD患者（UC 27例，CD 5 例)在疾病的不同时期，用免疫放射比浊法测定尿中白蛋白，并结合临床 Harvey 和 Bradshaw 指数进行综合分析，选取25例健康人为正常对照。Judd

18、TA，Day AS，Lemberg DA，et a1Update of fecal markers of inflammation in inflammatory bowel diseaseJ Gastroenterol Hepat012011，26：14931499IntroductionChin J Gastroenterol Hepatol.巨细胞病毒(CMV)属疱疹病毒科B属双链DNA病毒，近年随着IBD与CMV研究的深入，发现CMV在IBD的发生和疾病进展中起一定作用，且对IBD的临床诊治亦有一定指导价值。患者尿中白蛋白明显高于正常人（活动期 Po05)。初步筛选出UC患者与健康对照

19、者存在明显差异的39个蛋白点，选择其中9个点。经质谱分析发现触珠蛋白，热休克转录因子2，受体酪氨酸激酶、醛脱氢酶、载脂蛋白c一、中心粒旁物质l在UC患者中表达水平升高，角蛋白1，细丝蛋白A结合蛋白1、肌球蛋白3在UC患者中表达水平降低。n 结论 采用蛋白质组学2-DE和质谱技术，筛选并鉴定出与UC相关的9个血清蛋白质，为提供新的UC生物学行为研究分子标志物奠定基础。n 缪应雷，等.溃疡性结肠炎血清差异蛋白的筛选研究.中华消化杂志.2010,30(12):898-901.菌群失菌群失调调n IBD患者肠遭细菌存在菌群失调，正常细菌数量减少，而致病菌、条件致病菌数量明显增多。n Duchmann等

20、 发现。正常人对其体内肠道菌群及抗原物质耐受，而IBD患者肠黏膜免疫细胞对失调的肠道菌群及抗原物质失去了耐受。这一发现证实了IBD患者肠道菌群及抗原物质能诱导肠黏膜异常免疫反应。n Frank等 发现IBD患者肠道菌群中拟杆菌、厚壁菌类减少，而变形杆菌及放线菌等增多。由于在肠道内，拟杆菌、厚壁菌是主要的裂解食物纤维产生丁酸盐和其他短链脂肪酸的细菌，这些细菌数量减少，导致维持肠上皮细胞生长和代谢的丁酸盐和其他短链脂肪酸等营养物质减少。同时。溃疡性结肠炎患者肠道内产硫化氢的细菌增多，硫化氢具有抑制丁酸盐和其他短链脂肪酸等营养物质生存及直接影响肠上皮细胞新陈代谢的功能。n 上述细菌菌群失调导致肠上皮

21、细胞营养缺乏，影响了肠黏膜屏障功能。n Duchmann R。Kaiser I，Hermann E，et a1Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease(IBD)Clin Exp Immunol，1995102：448455n Frank DN，St Amand AL，Feldman RA，et a1Molecularphylogenetic characterization of microbial community imbalan

22、ces in human inflammatory bowel diseasesProc Natl Acad Sci USA，2007，104：1378013785巨细胞病毒巨细胞病毒(CMV)(CMV)n 巨细胞病毒(CMV)属疱疹病毒科B属双链DNA病毒，近年随着IBD与CMV研究的深入，发现CMV在IBD的发生和疾病进展中起一定作用，且对IBD的临床诊治亦有一定指导价值。n Pfau 等发现CMV更易感染肉芽组织生长细胞CMV对炎症的趋向性使IBD患者感染CMV的风险增加。结肠活检组织的炎症和溃疡部位可见CMV包涵体,且研究发现生长旺盛的细胞如肉芽组织或溃疡深部更易发现CMV感染推测CM

23、V可通过单核细胞到达炎症黏膜并可在黏膜内增殖且对炎症黏膜具有特殊亲和力。n CMV急性感染可显著提高血清和肠道自然杀伤细胞、白细胞介素(IL)6、TNF-a、IFN1水平提示CMV感染可改变黏膜免疫提高宿主对炎症的易感性n CMV感染可激活原癌基因、激酶、转录因子致肿瘤发生。可能是IBD患者结直肠癌发病率较高的原因之一例。n Matsuoka K,1wao Y，Mori T，et a1Cytomegalovirus is frequently reactivated and disappears without antiviral agents in ulcerative colitis pa

24、tientsAm J Gastroenterol，2007，102：331-337难辨梭状芽孢杆菌难辨梭状芽孢杆菌 （Clostridium difficile Clostridium difficile）n 目的 通过对炎症性肠病(IBD)患者粪便中难辨梭状芽孢杆菌(Cd)的检测,了解IBD患者中该菌的感染情况及其与IBD的关系.n 方法 收集2009年12月至2011年1月上海交通大学医学院附属瑞金医院消化科确诊的IBD患者130例,包括溃疡性结肠炎(UC)患者60例及克罗恩病(CD)患者70例.同时收集肠易激综合征(IBS)患者及无肠道疾患的健康人群各60例为对照.通过聚合酶链反应(PC

25、R)和Cd毒素快速测试试剂盒(CDTK)方法对粪便样本中毒素A、毒素B基因进行检测,采用SPSS软件进行统计分析.n 结果 纳入研究的130例IBD患者中,Cd感染者16例(12.3),其中UC 10例(16.7),CD 6例(8.6)；对照组中未发现Cd感染者(x2=15.779,P=0.000).处于活动期的IBD患者Cd感染率显著高于非活动期患者(x2=10.092,P=0.001).结肠型CD患者的感染率为4/14,显著高于其他类型的CD患者(x2=13.125,P=0.001).轻度UC患者Cd感染率为4.5、中度为14.3、重度为6/17(x2=6.667,P=0.037)；轻度C

26、D患者的Cd感染率为0、中度为4.2、重度为5/16,感染率随疾病严重程度的上升而增高(x2=13.907,P=0.000).使用广谱抗生素的患者与未使用者其Cd感染率差异无统计学意义(x2=1.414,p=0.378);免疫抑制剂与广谱抗生素同时使用者和单用广谱抗生素者Cd感染率差异亦无统计学意义(x2=0.330,P=0.962).n 结论 IBD患者中存在着一定的Cd感染率,尤其是处于疾病活动期的患者,感染率随IBD疾病严重程度的上升而增高.n 袁耀宗，等.难辨梭状芽孢杆菌与炎症性肠病关系的初步研究难辨梭状芽孢杆菌与炎症性肠病关系的初步研究.中华消化杂志.2012，32(4)：88-89

27、.尿白蛋白尿白蛋白n 目的：探讨炎症性肠病患者尿中白蛋白的临床意义。n 方法：对临床确诊的32例IBD患者（UC 27例，CD 5 例)在疾病的不同时期，用免疫放射比浊法测定尿中白蛋白，并结合临床 Harvey 和 Bradshaw 指数进行综合分析，选取25例健康人为正常对照。n 结果：患者尿白蛋白活动期比缓解期明显增高（0.002），Harvey 和 Bradshaw 指数呈正相关（活动期 r=0.76,P0.001；静止期 r=0.73,P0.001）。患者尿中白蛋白明显高于正常人（活动期 P0.001,缓解期,P0.005）。n 结论：患者尿中白蛋白可作为判断患者疾病活动情况的指标。n

28、 邓长生.炎症性肠病患者尿白蛋白的临床意义.武汉大学学报.2002，23(1)：88-89.FeFecal markerscal markersn Calprotectin(FCP),a heterocomplex of S100A8 and S100A9,is a calcium-binding protein with antimicrobial protective properties derived predominately from neutrophils,and to a lesser extent,from monocytes and reactive macrophages

29、.It constitutes approximately 5%of the total protein and up to 60%of the cytosolic protein in human neutrophils.As such,the fecal calprotectin concentration is proportional to the influx of neutrophils into the intestinal tract,a hallmark of active IBD.n Lactoferrin is an iron-binding glycoprotein i

30、dentified in the secretions overlying most mucosal surfaces that interact directly with external pathogens,including saliva,tears,vaginal secretions,feces,synovial fluid,and mammalian breast milk.It is a major component of the secondary granules of polymorphonuclear neutrophils and is shown to be a

31、primary factor in the acute inflammatory response.In the intestinal lumen,fecal lactoferrin levels quickly increase with the influx of neutrophils during inflammation.n Sugi and colleagues investigated lactoferrin,polymorphonuclear neutrophil(PMN)elastase,and lysozyme together with myeloperoxidase i

32、n fecal material and whole-gut lavage fluid from IBD patients.n Langhorst J,Elsenbruch S,Mueller T et al.Comparison of 4 neutrophil-derived proteins in feces as indicators of disease activity in ulcerative colitis.Inflamm.Bowel Dis.2005;11:108591.FeFecal markerscal markersJudd TA，Day AS，Lemberg DA，e

33、t a1Update of fecal markers of inflammation in inflammatory bowel diseaseJ Gastroenterol Hepat012011，26：14931499FeFecal markerscal markers感谢您的观看！Introduction Introduction n IBDIBD是一是一种种病因病因尚尚不十分不十分清清楚的慢性非特楚的慢性非特异异性性肠肠道炎症，包括道炎症，包括UCUC和和CDCD 。n 其其发发病率呈逐年上升病率呈逐年上升趋势趋势，且多，且多为青壮为青壮年年发发病，病，临临床表床表现复杂现复杂，并发

34、并发症症严严重，重，肠肠外表外表现现多多样样，严严重影重影响个响个人生活人生活质质量和社量和社会会生生产产力。力。n 此外，因其有癌此外，因其有癌变变的的风险风险，备备受广大受广大医医生的重生的重视视。n 近年来在国内外近年来在国内外IBDIBD基础与临床研究高潮迭起，基础研究的成果直接指向临基础与临床研究高潮迭起，基础研究的成果直接指向临床治疗，取得了划时代的进展。床治疗，取得了划时代的进展。n 探讨和摸索适合国人的治疗方案以降低重症探讨和摸索适合国人的治疗方案以降低重症UCUC的并发症和死亡率显得十分的并发症和死亡率显得十分重要。重要。Family historyFamily histor

35、yn Kitahora et al.found a strong familial occurrence in UC among Japanese patients.In a Korean study,a similar familial aggregation was also reported.n Kitahora T,Utsunomiya T,Yokota A.Epidemiological study of ulcerative colitis in Japan:incidence and familial occurrence.The Epidemiology Group of th

36、e Research Committee of Inflammatory Bowel Disease in Japan.J.Gastroenterol.1995;30(Suppl.8):58.n Park ER,Yang SK,Myung SJ et al.Familial occurrence of ulcerative colitis in Korea.Korean J.Gastroenterol.2000;36:7704.2004;99:218694方法：对临床确诊的32例IBD患者（UC 27例，CD 5 例)在疾病的不同时期，用免疫放射比浊法测定尿中白蛋白，并结合临床 Harvey

37、和 Bradshaw 指数进行综合分析，选取25例健康人为正常对照。Sugi and colleagues investigated lactoferrin,polymorphonuclear neutrophil(PMN)elastase,and lysozyme together with myeloperoxidase in fecal material and whole-gut lavage fluid from IBD patients.The two most widely studied serological markers in inflammatory bowel dis

38、ease in recent years have been p-ANCA and ASCA.方法 收集UC患者30例和健康对照者30名的血清标本，双向凝胶电泳(2-DE)分离等量混合血清的蛋白质，运用图像分析软件进行比较和分析，识别差异表达蛋白质。Introduction0 per 100 000 person years.此外，因其有癌变的风险，备受广大医生的重视。经质谱分析发现触珠蛋白，热休克转录因子2，受体酪氨酸激酶、醛脱氢酶、载脂蛋白c一、中心粒旁物质l在UC患者中表达水平升高，角蛋白1，细丝蛋白A结合蛋白1、肌球蛋白3在UC患者中表达水平降低。Langhorst J,Elsenbr

39、uch S,Mueller T et al.应用基质辅助激光解吸电离飞行时间质谱(MAI，DI-TOF-MS)鉴定部分差异蛋白质点。Review article:the relevance of surveillance endoscopy in long-lasting inflammatory bowel disease.Lactoferrin is an iron-binding glycoprotein identified in the secretions overlying most mucosal surfaces that interact directly with ext

40、ernal pathogens,including saliva,tears,vaginal secretions,feces,synovial fluid,and mammalian breast milk.3),其中UC 10例(16.0 per 100 000 person years.In a recent study,the speculated prevalence was 11.The prevalence of UC has ranged from 4.巨细胞病毒(CMV)属疱疹病毒科B属双链DNA病毒，近年随着IBD与CMV研究的深入，发现CMV在IBD的发生和疾病进展中起一

41、定作用，且对IBD的临床诊治亦有一定指导价值。Kitahora T,Utsunomiya T,Yokota A.Langhorst J,Elsenbruch S,Mueller T et al.Park ER,Yang SK,Myung SJ et al.Inflammatory bowel disease:cause and immunobiology.0 per 100 000 person years.Matsuoka K,1wao Y，Mori T，et a1Cytomegalovirus is frequently reactivated and disappears without

42、 antiviral agents in ulcerative colitis patientsAm J Gastroenterol，2007，102：331-337found a strong familial occurrence in UC among Japanese patients.Epidemiological study of ulcerative colitis in Japan:incidence and familial occurrence.Appendectomy and the risk of developing ulcerative colitis:result

43、s after control of smoking factor.3),其中UC 10例(16.Family history难辨梭状芽孢杆菌与炎症性肠病关系的初步研究.2006,15(2):161-162The two most widely studied serological markers in inflammatory bowel disease in recent years have been p-ANCA and ASCA.Introduction这一发现证实了IBD患者肠道菌群及抗原物质能诱导肠黏膜异常免疫反应。IBD是一种病因尚不十分清楚的慢性非特异性肠道炎症，包括UC和

44、CD。Familial occurrence of ulcerative colitis in Korea.J Gastroenterol.目前对IBD病因和发病机制的认识可概括为：In a recent study,the speculated prevalence was 11.Langhorst J,Elsenbruch S,Mueller T et al.Results COX regression indicated the statistical significance in stressmilk and fried food over the other postulated

45、risk factorsfor IBD2004;99:218694方法 收集UC患者30例和健康对照者30名的血清标本，双向凝胶电泳(2-DE)分离等量混合血清的蛋白质，运用图像分析软件进行比较和分析，识别差异表达蛋白质。Judd TA，Day AS，Lemberg DA，et a1Update of fecal markers of inflammation in inflammatory bowel diseaseJ Gastroenterol Hepat012011，26：14931499Methords 72 determined IBD patients and 72 paired

46、healthy subjects were surveyed with an organized inventory comprising of relevant items to IBDCOX regression method was used to screen the statistically significant risk factors for IBDLanghorst J,Elsenbruch S,Mueller T et al.通过聚合酶链反应(PCR)和Cd毒素快速测试试剂盒(CDTK)方法对粪便样本中毒素A、毒素B基因进行检测,采用SPSS软件进行统计分析.Manage

47、ment consensus of inflammatory bowel disease for the Asia-Pacific region.IBD是一种病因尚不十分清楚的慢性非特异性肠道炎症，包括UC和CD。轻度UC患者Cd感染率为4.Gastroenterol.0 per 100 000 person years.Baumgart DC,Carding SR.2006;21:177282.2010,30(12):898-901.Bowel Dis.Bowel Dis.炎症性肠病患者尿白蛋白的临床意义.Methords 72 determined IBD patients and 72

48、paired healthy subjects were surveyed with an organized inventory comprising of relevant items to IBDCOX regression method was used to screen the statistically significant risk factors for IBDfound a strong familial occurrence in UC among Japanese patients.found a strong familial occurrence in UC am

49、ong Japanese patients.In a Korean study,a similar familial aggregation was also reported.Gastroenterol.Fecal markers1995;30(Suppl.IBD患者肠遭细菌存在菌群失调，正常细菌数量减少，而致病菌、条件致病菌数量明显增多。Epidemiological study of ulcerative colitis in Japan:incidence and familial occurrence.其发病率呈逐年上升趋势，且多为青壮年发病，临床表现复杂，并发症严重，肠外表现多样，

50、严重影响个人生活质量和社会生产力。Gut 1996;39:690-697.found a strong familial occurrence in UC among Japanese patients.Ouyang Q,Tandon R,Goh KL et al.IBD患者肠遭细菌存在菌群失调，正常细菌数量减少，而致病菌、条件致病菌数量明显增多。近年来在国内外IBD基础与临床研究高潮迭起，基础研究的成果直接指向临床治疗，取得了划时代的进展。Lawrance IC,Murray K,Hall A,Sung JJ,Leong R.目的：探讨炎症性肠病患者尿中白蛋白的临床意义。Familial o