發(fā)布時間：2018-05-29 10:55

  本文選題：克羅恩病 + 蒙特利爾分型�。� 參考：《南方醫(yī)科大學(xué)》2014年碩士論文

【摘要】：背景和目的克羅恩病(Crohn's Disease, CD)是炎癥性腸病(Inflammatory Bowel Disease, IBD)的一個主要亞型,是一種慢性復(fù)發(fā)性、炎性肉芽腫性疾病,病變呈節(jié)段性分布,可累及全消化道,以回腸末端和鄰近結(jié)腸多見。CD在歐美國家是常見病,其年發(fā)病率約為6-15/10萬,患病率約為50-200/10萬。新近一項亞洲-太平洋地區(qū)多中心合作的流行病學(xué)調(diào)查表明,2011年4月1日至2012年3月31日,亞洲地區(qū)的CD年發(fā)病率平均為0.54/10萬,CD在亞洲地區(qū)平均發(fā)病率仍然遠低于西方歐美國家,但近20年來的流行病學(xué)研究顯示,CD在亞洲地區(qū)的發(fā)病率呈上升趨勢。 克羅恩病的病因復(fù)雜,發(fā)病機制至今尚不清楚。近年的觀點認(rèn)為,CD的發(fā)生與基因遺傳、環(huán)境因素和免疫因素均有關(guān)系,攜帶遺傳易感基因的宿主在環(huán)境因素參與下,免疫功能紊亂,最終導(dǎo)致疾病發(fā)生。西方的大規(guī)模的流行病學(xué)發(fā)現(xiàn)CD患者的家族陽性率高達13.4%-18.0%,并且CD患者的一級親屬患CD的危險比普通人群高6-10倍。日本、韓國、中國香港報道的CD家族陽性率為1.51-2.80%,明顯要低于西方國家的報道。同時,歐美國家的分子遺傳學(xué)研究發(fā)現(xiàn)16號染色體上的NOD2/CARD15基因與白種人的克羅恩病發(fā)病明顯相關(guān),然而在亞洲人群中并未發(fā)現(xiàn)這一現(xiàn)象,這也說明亞洲人群CD發(fā)病同西方白色人種存在著基因遺傳學(xué)的差異。 除了遺傳背景不一樣,亞洲人群CD的臨床特征和疾病的自然病程可能與西方白種人也有差異。而2005年世界胃腸病大會上提出的蒙特利爾分型為我們提供了一種可用于比較不同人群之間CD特征的標(biāo)準(zhǔn)。同時,由于CD患者在整個病程中手術(shù)率非常高,有研究表明,有高達70-90%的CD患者在疾病發(fā)展進程中因為發(fā)生腸梗阻、瘺管形成、腹腔膿腫、消化道大出血等嚴(yán)重并發(fā)癥而需要手術(shù)治療。手術(shù)治療僅僅是為了控制癥狀、恢復(fù)腸道功能,而并不能治愈本病。同時約有一半CD患者需要再次手術(shù)治療。這種需要反復(fù)手術(shù)的病程嚴(yán)重危害患者的身心健康。 目前關(guān)于預(yù)測CD首次手術(shù)危險因素的研究較少,NOD2/CARD15陽性、診斷年齡、累及上消化道、狹窄型、穿透型、腸外表現(xiàn)、肛周病變、吸煙行為被認(rèn)為是CD患者的手術(shù)危險因素,但在各個獨立的研究中的結(jié)果并不一致。目前我國關(guān)于CD的研究多數(shù)為臨床病例報道,關(guān)于CD的臨床特征、蒙特利爾分型和手術(shù)的危險因素的研究報道仍然較少。但是,明確CD患者的手術(shù)風(fēng)險因素具有極其重要的臨床意義。研究克羅恩病的疾病發(fā)展規(guī)律,確定CD手術(shù)率增高的危險因素,可以為臨床上篩選出可能需要手術(shù)的高風(fēng)險CD患者,并針對高危因素積極進行干預(yù),以期降低CD患者的手術(shù)率,從而使患者從治療中獲得更大的益處。 正是基于以上考慮,我們設(shè)計了本次華南地區(qū)單中心的回顧性歷史隊列研究,旨在了解CD的臨床特征、蒙特利爾分型和疾病進程中的首次腸切除手術(shù)率,探討導(dǎo)致CD患者手術(shù)率增高的危險因素,為臨床上制定更有益于患者的治療方案提供客觀依據(jù),同時也為將來多中心合作的前瞻性研究提供可以參考的數(shù)據(jù)。 方法回顧性分析2003年1月1日-2012年12月31日在南方醫(yī)科大學(xué)第一附屬醫(yī)院南方醫(yī)院住院且既往無腸切除手術(shù)史的確診為CD的連續(xù)性病例,收集患者的一般人口學(xué)資料、臨床表現(xiàn)、實驗室檢查資料、影像學(xué)資料、內(nèi)鏡資料、病理資料、內(nèi)科用藥情況、手術(shù)情況,并對在我院住院期間未手術(shù)的CD患者進行電話隨訪。將疾病發(fā)生的時間點視為研究起點,首次腸切除手術(shù)或未手術(shù)的患者末次隨訪的時間點視為研究終點,研究起點到研究終點的時間間隔視為疾病病程,評估CD患者的首次腸切除手術(shù)率。應(yīng)用Kaplan-Meier法估算年累積手術(shù)率,以log-rank檢驗各個臨床變量是否均一,最后應(yīng)用COX比例風(fēng)險回歸模型分析引起CD患者手術(shù)率升高的獨立的危險因素,以相對危險度HR和95%的可信區(qū)間來衡量危險的大小,p0.05認(rèn)為具有統(tǒng)計學(xué)差異。 結(jié)果 1.共有315例CD患者納入本次研究,男女性別比為2.6：1(228/87),91.9%的患者來自于華南地區(qū)。中位診斷年齡(32歲,9-69歲)比中位發(fā)病年齡(28歲,8-63歲)要晚4年。22例(7.0%)患者既往有闌尾切除史,30例(9.5%)患者有吸煙習(xí)慣且吸煙者均為男性,2例(0.6%)患者發(fā)現(xiàn)有克羅恩病陽性家族史。腹痛(87.6%)、腹瀉(65.4%)、體重減輕(54.0%)是CD患者最常見的三大臨床癥狀。 2.根據(jù)蒙特利爾分型,診斷年齡主要為A2型(17-40歲,66.0%)；疾病部位主要為回腸型(L1,50.5%),其次為回結(jié)腸型(L3,34.9%),結(jié)腸型(L2,14.6%)相對較少,有4.8%的患者累及上消化道(L4)；疾病行為主要為非狹窄非穿透型(B1,56.2%),其次為狹窄型(B2,36.5%),穿透型(B3,7.3%)較少,有18.1%的患者發(fā)現(xiàn)有肛周病變(P)。 3.納入本次研究的CD患者的中位病程為4年(1-20年),整個疾病進程中,共有91例(28.9%)CD患者行手術(shù)治療,其中14.3%的CD患者需要急診手術(shù),手術(shù)切除部位以“小腸(48.4%)”和“小腸+結(jié)腸(46.2%)”為主,單純切除結(jié)腸(5.5%)的病例較少。CD患者首次手術(shù)原因有：腸梗阻(52例,57.14%)、腸道大出血(11例,12.09%)、腸穿孔(6例,6.59)、瘺管形成(6例,6.59)、回盲部包塊(6例,6.59)、腸道巨大潰瘍,內(nèi)科藥物治療無效(6例,6.59)和其他(4例,4.40%)。 4.單變量分析 CD患者自發(fā)病起1年、2年、5年、10年、20年的累積手術(shù)率分別為12%、17%、26%、46%、82%。運用Kaplan-Meier法對各個臨床分類變量進行分析,計算各自的5年累積手術(shù)率,以log-rank檢驗各個臨床分類變量對累積手術(shù)率的影響是否具有統(tǒng)計學(xué)差異。單變量分析發(fā)現(xiàn)： (1)下列臨床變量對CD患者首次腸切除的累積手術(shù)率的影響無統(tǒng)計學(xué)差異(均有p0.05)：診斷年齡分組(5年累及手術(shù)率：A1為40.0%,A2位30.1%,A3為36.7%,p=0.852)、累及上消化道(5年累及手術(shù)率：未累及上消化道為32.8%,累及上消化道為28.6%,p=0.813)、闌尾手術(shù)史(5年累及手術(shù)率：無闌尾手術(shù)史為33.3%,有闌尾切除史為25.0%,p=0.499)、腸外表現(xiàn)(5年累及手術(shù)率：無腸外表現(xiàn)為32.5%,有腸外表現(xiàn)為33.3%,p=0.740)； (2)下列臨床變量與CD患者首次腸道手術(shù)率升高有關(guān)：性別(5年累積手術(shù)率：男性為34.3%,女性為28.0%,p=0.040)、病變部位(5年累積手術(shù)率：L1回腸型為37.5%,L2結(jié)腸型為12.0%,L3回結(jié)腸型為32.8%,p=0.015)、疾病行為(5年累積手術(shù)率：B1非狹窄非穿透型為12.3%,B2狹窄型為49.5%,B3穿透型為38.1%,p0.001)、吸煙(5年累積手術(shù)率：吸煙者為61.9%,不吸煙者為29.1%,p=0.002)。 (3)下列臨床變量與首次腸切除手術(shù)率降低有關(guān)：肛周病變(5年累積手術(shù)率：有肛周病變者為10.7%,無肛周病變者36.4%,p=0.022)。此外,使用任何一種抗克羅恩病藥物治療的CD患者的累積手術(shù)率均顯著低于未用藥患者(p0.05)：氨基水楊酸類(5年累積手術(shù)率：未使用組為68.4%,使用組為17.6%,P0.001)、糖皮質(zhì)激素(5年累積手術(shù)率：未使用組為50.5%,使用組為13.8%,P0.001,)、免疫抑制劑(5年累積手術(shù)率：未使用組為39.0%,使用組為2.9%,P0.001,)、生物制劑(5年累積手術(shù)率：未使用組為35.3%,使用組為13.0%,P=0.003)。 4.多變量分析 進一步應(yīng)用Cox比例風(fēng)險回歸模型(Cox proportional hazards regression model),將所有的臨床變量代入同一個多變量分析模型,應(yīng)用Wald檢驗各個臨床變量有無統(tǒng)計學(xué)差異。在這個Cox多變量模型中,狹窄型(HR：4.803；95%CI：2.466-9.352；P0.001)、穿透型(HR：13.197；95%CI：5.938-29.330；P0.001)、吸煙(HR:1.932;95%CI:1.031-3.619;P=0.041)與首次腸切除手術(shù)率升高顯著相關(guān),而肛周病變與(HR:0.027;95%CI:0.193-0.889; P=0.024)和使用氨基水楊酸類制劑(HR:0.277;95%CI:0.162-0.474;P0.001)與首次腸切除手術(shù)率降低顯著相關(guān)。 結(jié)論 本次華南地區(qū)單中心的隊列研究發(fā)現(xiàn),克羅恩病患者以男性多見,蒙特利爾分型中診斷年齡以A2型(17～40歲)為主,病變部位主要為L1型(回腸型),其次為L3型(回結(jié)腸型),疾病行為主要為B1型(非狹窄非穿透型)。在疾病發(fā)展進程中,克羅恩病患者的累積手術(shù)率逐年增高,狹窄型、穿透型和吸煙行為為首次腸切除手術(shù)的獨立危險因素,肛周病變和氨基水楊酸制劑的使用則有可能降低CD患者首次腸切除手術(shù)的風(fēng)險。
[Abstract]:Background and Objective Crohn ' s Disease ( CD ) is a major subtype of inflammatory bowel disease ( IBD ) . It is a chronic recurrent and inflammatory granulomas disease . The incidence of CD in Asia is still much lower than that of western European countries .

The etiology of Crohn ' s disease is complex and the pathogenesis is not clear . In recent years , the incidence of CD is related to genetic , environmental and immune factors . The positive rate of CD in CD patients is 1 . 51 - 2 . 80 % .

In addition to the genetic background , the clinical features of CD in Asian populations and the natural history of disease may differ from those in the West . The Montreal typing presented at the 2005 World Conference on Gastroenterology provides us with a standard that can be used to compare CD characteristics among different populations .

There are few studies on the risk factors of CD first operation , NOD2 / CARD15 positive , diagnosis age , upper gastrointestinal tract , narrow type , penetrating type , extraintestinal manifestation , perianal lesion , smoking behavior are considered to be the surgical risk factors of CD patients . However , the study of CD has very important clinical significance .

Based on the above considerations , we designed a retrospective historical cohort study of a single center in South China to understand the clinical features of the CD , the first bowel resection rate in the Montreal typing and disease progression , the risk factors leading to increased procedural rates in CD patients , an objective basis for the clinical setting of a treatment programme that is more beneficial to the patient , and data that can be referenced for prospective studies in future multi - center cooperation .

Methods A retrospective analysis was made on the continuous cases of CD in the southern hospital of the First Affiliated Hospital of South Medical University from January 1 , 2003 to December 31 , 2012 . The time point of the disease occurrence was considered as the study end point . The time interval between the starting point and the end of the study was considered as the study end point . The time interval between the starting point and the end of the study was regarded as the study end point . The time interval between the starting point and the end of the study was considered as the study end point .

Results

1 . A total of 315 CD patients were enrolled in the study , the sex ratio of male and female was 2.6 : 1 ( 228 / 87 ) , and 91.9 % of the patients were from southern China . The median diagnosis age ( 32 years , 9 - 69 years ) was 4 years later than the median age ( 28 years , 8 - 63 years ) . In 22 cases ( 7.0 % ) , there was a history of Crohn ' s disease . Abdominal pain ( 87.6 % ) , diarrhea ( 65.4 % ) , weight loss ( 54.0 % ) were the most common clinical symptoms in CD patients .

2 . According to the Montreal classification , the diagnosis age is mainly type A2 ( 17 - 40 years , 66.0 % ) ;
The disease site was mainly ileum type ( L1 , 50.5 % ) , followed by ileocolic ( L3 , 34.9 % ) , colon ( L2 , 14.6 % ) , and the upper digestive tract ( L4 ) was 4.8 % .
The disease behavior was mainly the non - narrow non - penetrating type ( B1 , 56.2 % ) , followed by the narrow ( B2 , 36 . 5 % ) , the penetrating type ( B3 , 7.3 % ) , and 18.1 % of the patients had perianal lesions ( P ) .

3 . The median course of CD patients included in this study was 4 years ( 1 - 20 years ) , and 91 ( 28 . 9 % ) CD patients were treated surgically in the whole disease course . Among them , 14.3 % of CD patients had fewer cases . The first operative reason for CD patients was : intestinal obstruction ( 52 cases , 57.14 % ) , intestinal bleeding ( 6 cases , 6.59 ) , ileocecal ligation ( 6 cases , 6.59 ) , intestinal large ulcer , ineffective internal medicine treatment ( 6 cases , 6.59 ) and other ( 4 cases , 4.40 % ) .

4 . Single variable analysis

The cumulative surgical rates of patients with CD were 12 % , 17 % , 26 % , 46 % and 82 % from 1 year , 2 years , 5 years , 10 years and 20 years , respectively .

( 1 ) The effect of the following clinical variables on the cumulative surgical rate of the first bowel resection of CD patients was not statistically different ( all p < 0.05 ) : the diagnostic age group ( 5years and operation rate : A1 was 40.0 % , A2 was 30.1 % , A3 was 33.7 % , p = 0.852 ) , and the upper gastrointestinal tract ( 5 years of progressive operation rate : not involving the upper gastrointestinal tract was 33.8 % , with appendix resection history of 25.0 % , p = 0.499 ) , and out - of - intestinal manifestations ( 5 years of progressive operation : no intestinal manifestations were 32.5 % , with an external appearance of 33.3 % , p = 0.740 ) ;


( 2 ) The following clinical variables were related to the increase in the first bowel operation rate in patients with CD : sex ( 5 years cumulative surgery rate : 36.3 % for men , 28 . 0 % for women , p = 0 . 040 ) , disease behavior ( cumulative surgical rate in 5 years : 38.8 % for L1 ileum , 12.0 % for L2 colonic type , 38.8 % for L3 ileocolic type , p = 0.015 ) , disease behavior ( 5 year cumulative surgery rate : 61.9 % for smokers and 29 . 1 % for non - smokers , p = 0.002 ) .

( 3 ) The following clinical variables were related to the reduction of the first bowel resection rate : perianal lesions ( 5 - year cumulative surgery rate : 10.7 % for perianal lesions , 36 . 4 % for perianal lesions , p = 0 . 022 ) . In addition , the cumulative surgical rates for CD patients treated with any one of the anti - Crohn ' s disease drugs were significantly lower than those in the untreated patients ( p 0.05 ) : aminosalicylic acid ( 5 - year cumulative surgery rate : 68.4 % in the unused group , 17.6 % in the use group , P0.001 ) , and the immune inhibitor ( 5 - year cumulative surgery rate : 39.0 % in the unused group , P = 0.001 , P = 0.003 ) , and the biological agent ( 5 - year cumulative surgery rate : 35 . 3 % in the unused group , 13.0 % in the use group , P = 0.003 ) .

4 . Multivariate analysis

Cox proportional hazards regression model ( Cox proportional hazards regression model ) was further applied to substitute all clinical variables into the same multivariate analysis model , and Wald was used to test whether there was statistical difference in each clinical variable . In this Cox multivariate model , the stenosis type ( HR : 4.803 ;
95 % CI : 2.466 - 9.352 ;
P0.001 ) , penetrating type ( HR : 13.197 ;
95 % CI : 5.938 - 29.330 ;
P0 . 001 ) , smoking ( HR : 1.932 ; 95 % CI : 1.031 - 3.619 ; P = 0.041 ) was significantly associated with the increase in the first bowel resection rate , while perianal lesions were significantly associated with the reduction in the first bowel resection rate ( HR : 0.027 ; 95 % CI : 0.193 - 0.889 ; P = 0 . 024 ) and the use of aminosalicylic acid preparations ( HR : 0.277 ; 95 % CI : 0.162 - 0.474 ; P0.001 ) .

Conclusion

According to cohort study of single center in South China , patients with Crohn ' s disease were mostly male with age A2 ( 17 - 40 years old ) . The lesion was mainly L1 type ( ileum type ) , followed by L3 type ( ileocolic ) , and the disease behavior was mainly B1 type ( non - narrow non - penetrating type ) . In the course of disease development , the cumulative surgical rate of patients with Crohn ' s disease was increased year by year .
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R574

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本文編號：1950622