本文選題：功能性消化不良　切入點(diǎn)：流行病學(xué)　出處：《蘇州大學(xué)》2012年博士論文　論文類型：學(xué)位論文

【摘要】：研究背景 隨著醫(yī)學(xué)模式由單一的生物模式向生物—心理—社會模式的轉(zhuǎn)變，功能性胃腸病(functional gastrointestinal disorders,FGIDs)越來越受到人們的重視，功能性消化不良（functional dyspepsia，F(xiàn)D）是最常見的功能性胃腸病之一，是一組以反復(fù)發(fā)作的餐后飽脹、早飽、厭食、噯氣、惡心、嘔吐、上腹痛、上腹燒灼感或反酸為主要表現(xiàn)而經(jīng)各項檢查排除器質(zhì)性、系統(tǒng)性或代謝性疾病的一組常見臨床癥候群。其解剖定位為胃及十二指腸。羅馬委員會根據(jù)主要癥狀的不同將FD分為餐后不適綜合征（postprandial distress syndrome, PDS）和上腹痛綜合征（epigastric painsyndrome, EPS）兩個亞型，越來越多的證據(jù)表明FD存在不同的亞型，其臨床表現(xiàn)和發(fā)病機(jī)制不盡相同，建議對不同亞型進(jìn)行獨(dú)立評估和治療。 功能性消化不良在全球范圍內(nèi)發(fā)病十分普遍，國外文獻(xiàn)報道，普通人群中FD患病率約26～34%，而國內(nèi)尚缺乏較系統(tǒng)的兒童FD流行病學(xué)調(diào)查。迄今為止，其病因及病理生理機(jī)制尚不清楚，近年來研究發(fā)現(xiàn)幽門螺桿菌(Helicobacter pylori，Hp)、胃腸激素、炎癥細(xì)胞等在FD的發(fā)病中起重要作用。 目的 本課題研究目的：了解蘇州市兒童FD的患病率及相關(guān)因素，調(diào)查FD兒童的Hp感染率；研究胃腸激素Ghrelin、Leptin及PYY在兒童FD發(fā)病機(jī)制中的作用；探討嗜酸性粒細(xì)胞及趨化因子Eotaxin和RANTES與兒童FD臨床癥狀的相關(guān)性。為臨床兒童功能性消化不良病理生理機(jī)制的進(jìn)一步闡明和臨床開發(fā)治療FD的新型靶藥提供理論依據(jù)。 方法 1.流行病學(xué)調(diào)查： 2010年10～12月對蘇州市滄浪區(qū)22所小學(xué)12923名小學(xué)生進(jìn)行橫斷面調(diào)查，其中男生7265名，女生5658名，年齡6～13歲。FD診斷符合羅馬Ⅲ標(biāo)準(zhǔn)，并將FD分為PDS和EPS兩個亞型，采用問卷調(diào)查和體格檢查的方法調(diào)查兒童FD的患病率及相關(guān)因素，比較不同年齡、不同性別之間FD的患病率是否存在差異,診斷為FD的患兒，進(jìn)行13C呼氣試驗(yàn)檢查Hp感染。 2. ELISA檢測血漿中Ghrelin、Leptin及PYY水平： 124例FD患兒（男71例，女53例，年齡7～12歲）和27例健康兒童（男15例，女12例，年齡7～12歲）納入本項研究。FD組根據(jù)主要癥狀和是否伴Hp感染分為PDS組61例，EPS組63例； Hp+和Hp-各62例。入選兒童均在上午8～10時采集清晨空腹靜脈血2ml,注入含有EDTA和抑肽酶的試管中，充分混勻離心后收集血漿，-70℃低溫冰箱凍存。標(biāo)本收齊后用ELISA方法檢測血漿中Ghrelin、Leptin及PYY水平，并比較各組結(jié)果是否存在差異。 3.RT-PCR法檢測胃黏膜Ghrelin、Leptin及PYY的mRNA表達(dá)： 43例FD患兒（Hp陽性20例，Hp陰性23例）納入本研究，在上午8～10時行常規(guī)胃鏡檢查，于胃竇部取粘膜兩塊，一塊做快速尿素酶試驗(yàn)檢測Hp感染，另一塊放入EP管后，于-70℃低溫冰箱凍存，待標(biāo)本集齊后,RT-PCR法檢測Ghrelin、Leptin及PYY的mRNA表達(dá),并比較Hp+組和Hp-組的結(jié)果是否有差異。 4.HE染色和免疫組化： 71例FD患兒，Hp+23例，Hp-48例（包括EPS25例、PDS23例），21例健康兒童為對照組。取胃竇粘膜固定、切片、HE染色后選取5個清晰的不同高倍視野，400倍光鏡下統(tǒng)計嗜酸性粒細(xì)胞的數(shù)量并求和。采用免疫組化方法檢測胃粘膜中趨化因子Eotaxin和RANTES的表達(dá)，每張切片隨機(jī)選取3個有代表性的視野，400倍光鏡下測量并計算每張切片免疫組化陽性染色的平均灰度值，并比較各組之間的結(jié)果。 結(jié)果 1.流行病學(xué)調(diào)查結(jié)果：(1)調(diào)查12923例兒童，診斷FD1034例，其中EPS646例，PDS388例，蘇州市兒童FD總的患病率為8%。其中EPS為5%，PDS為3%。(2) FD兒童1034例經(jīng)13C呼氣試驗(yàn)檢查，診斷Hp陽性282例，Hp的感染率為27.3%。(3) PDS患病率的相關(guān)因素:年齡越小，父母文化程度越低，齲齒越多，體型偏瘦，患病率越高。(4) EPS患病率的相關(guān)因素:女性，齲齒越多，父親文化程度越高，體型消瘦或超重,患病率越高。 2.血漿中Ghrelin水平：FD組低于對照組，PDS組低于EPS組，Hp+組低于Hp-組，差異均有統(tǒng)計學(xué)意義(P＜0.001）；血漿Leptin水平：FD組高于對照組，PDS組高于EPS組，Hp+組高于Hp-組，差異均有統(tǒng)計學(xué)意義(P＜0.001)；血漿中PYY水平：FD組高于對照組，差異有統(tǒng)計學(xué)意義(P＜0.001)，PDS組與EPS組，Hp+組與Hp-組比較，差異無統(tǒng)計學(xué)意義。 3.胃粘膜中， Hp+組ghrelin mRNA水平顯著低于Hp-組，Hp+組leptinmRNA水平顯著高于Hp-組的表達(dá)，差異均有統(tǒng)計學(xué)意義(P＜0.01)， PYY在兒童胃粘膜中幾乎未見表達(dá)。 4.胃粘膜嗜酸性粒細(xì)胞計數(shù)、Eotaxin和RANTES表達(dá)水平在Hp+和EPS/Hp-組明顯高于PDS/Hp-組和對照組，差異均有統(tǒng)計學(xué)意義(P＜0.001)。趨化因子Eotaxin主要分布在胃黏膜的上皮細(xì)胞和腺體上皮細(xì)胞的胞漿內(nèi)，而炎癥細(xì)胞內(nèi)未見分布。RANTES在胃黏膜主要分布于胃粘膜上皮細(xì)胞、腺體細(xì)胞、淋巴細(xì)胞的細(xì)胞漿和細(xì)胞核內(nèi)，Eotaxin和RANTES表達(dá)水平與嗜酸性粒細(xì)胞數(shù)量呈正相關(guān) 結(jié)論 1.FD是蘇州地區(qū)兒童的常見病，主要亞型是EPS。兒童FD發(fā)病的危險因素有女性、年齡小、父母文化程度、Hp感染、齲齒、BMI降低。 2Ghrelin、Leptin及PYY三種胃腸激素參與了兒童功能性消化不良的發(fā)病機(jī)制,Ghrelin和Leptin在餐后不適（PDS）亞型中變化更加明顯，推測PDS早飽、厭食等癥狀與Ghrelin和Leptin有更加直接的關(guān)系，Ghrelin可能成為治療PDS的新型靶藥。 3.嗜酸性粒細(xì)胞及趨化因子eotaxin和RANTES主要參與了兒童功能性消化不良上腹痛（EPS）的發(fā)病和疾病進(jìn)展，為臨床研發(fā)治療EPS的新型藥物提供了實(shí)驗(yàn)依據(jù)。
[Abstract]:Research background
With the medical model from a single biological model to bio psycho social model, functional gastrointestinal disease (functional gastrointestinal, disorders, FGIDs) has attracted more and more attention, functional dyspepsia (functional dyspepsia FD) is one of the most common functional gastrointestinal disorders, is a recurrent meal after the fullness, early satiety, belching, nausea, anorexia, vomiting, epigastric pain, epigastric burning sensation or acid reflux is the main and the performance of the examination to exclude organic system, or a group of metabolic diseases common clinical syndrome. The anatomic location for the stomach and duodenum. The Rome committee will be divided into FD postprandial distress syndrome according to the main symptoms of the different (postprandial distress syndrome, PDS) and epigastric pain syndrome (epigastric, painsyndrome, EPS) two subtypes, there is growing evidence that FD has its different subtypes. The clinical manifestations and pathogenesis are different. It is suggested that different subtypes should be evaluated and treated independently.
Functional dyspepsia worldwide disease is very common, foreign literature reports, the prevalence rate of about 26 ~ 34% FD in the general population, and the lack of children's FD epidemiological survey systematically. So far, the etiology and pathophysiology remains unclear, recent studies found that Helicobacter pylori (Helicobacter pylori, Hp), gastrointestinal hormones, inflammatory cells play an important role in the pathogenesis of FD.
objective
This study is to investigate the prevalence rate and related factors of children in Suzhou FD children, investigation of FD infection rate of Hp; Study on gastrointestinal hormones Ghrelin, Leptin and PYY in the pathogenesis of FD in children; to investigate the relationship between eosinophil and chemokine Eotaxin and RANTES in children with FD clinical symptoms. The theoretical basis of new target drugs and further clarify the clinical development for clinical treatment of FD in children with functional dyspepsia pathophysiology.
Method
1. epidemiological survey:
In 2010 10~12 a cross-sectional survey was conducted in 22 primary school in Canglang District of Suzhou City, 12923 students, including 7265 boys and 5658 girls, aged 6~13 years old.FD diagnostic Rome III standard and FD were divided into PDS and EPS two subtypes, the prevalence rate and related factors of questionnaire survey and physical examination method the survey of children FD, different age, different gender differences exist between the FD prevalence rate is, children who were diagnosed FD, 13C breath test for Hp infection.
The levels of Ghrelin, Leptin and PYY in plasma were measured by 2. ELISA.
In 124 FD patients (male 71 cases, female 53 cases, age 7~12 years) and 27 healthy children (male 15 cases, female 12 cases, age 7~12) into the.FD group in this study according to the main symptoms and with Hp infection were divided into PDS group of 61 cases, 63 cases in group EPS; Hp+ and Hp- the 62 cases of children were selected. Fasting venous blood 2ml in the afternoon 8~10 when collecting, injected with EDTA and aprotinin in vitro, and mixing collected after centrifugation of plasma, -70 low temperature refrigerator frozen. After collecting samples by the method of ELISA Ghrelin detection in plasma Leptin and PYY levels, and compare the results whether there are differences.
3.RT-PCR was used to detect the mRNA expression of Ghrelin, Leptin and PYY in gastric mucosa.
In 43 FD patients (20 cases were Hp positive and 23 Hp negative cases) were included in this study, in the morning of 8~10 were performed with conventional gastroscopy in the gastric antrum mucosa of two blocks, a rapid urease test to detect Hp infection, another piece in the EP tube, -70 low temperature refrigerator to be frozen specimens collect after the detection of Ghrelin RT-PCR method, the expression of Leptin and PYY mRNA, were compared between Hp+ group and Hp- group the result of whether there is a difference.
4.HE staining and immunohistochemistry:
The 71 FD cases, Hp+23 cases, Hp-48 cases (including EPS25 cases, PDS23 cases), 21 cases of healthy children as control group. The gastric mucosa is fixed, sliced, HE stained to select 5 clear different HPF, 400 times microscope statistics the number of eosinophils and summation. The expression of factor Eotaxin and RANTES method to detect the chemotaxis in gastric mucosa, each slice randomly selected 3 representative field, average gray 400 times under light microscope to measure and calculate each section immunohistochemical staining, and compare the results.
Result
1. epidemiological survey results: (1) the investigation of 12923 cases of children diagnosed FD1034 cases, EPS646 cases, PDS388 cases, Suzhou city children's FD total prevalence rate was 8%. EPS for 5%, PDS for 3%. (2) FD 1034 cases of children by 13C breath test and diagnosis of 282 cases were Hp positive Hp infection rate of 27.3%. (3) PDS related factors of prevalence of parents: the younger, lower educational level, caries more slim, the higher the prevalence (4) related factors of EPS prevalence rate of dental caries: female, more, the higher education level of father, lean or overweight, prevalence rate the higher.
The level of Ghrelin 2. in plasma: FD group than in the control group, PDS group than in EPS group, Hp+ group than in Hp- group, the differences were statistically significant (P < 0.001); plasma Leptin level of FD group was higher than that of control group, PDS group than in EPS group, Hp+ group than in Hp- group, the differences were statistically significant (P < 0.001); the level of plasma PYY in FD group was higher than the control group, the difference was statistically significant (P < 0.001), PDS group and EPS group, Hp+ group and Hp- group, the difference was not statistically significant.
3., in gastric mucosa, the level of ghrelin mRNA in group Hp+ was significantly lower than that in group Hp-, and the level of leptinmRNA in group Hp+ was significantly higher than that in group Hp- (P < 0.01), and PYY was hardly expressed in gastric mucosa of children.
4. gastric mucosal eosinophil count, the expression level of Eotaxin and RANTES in Hp+ and EPS/Hp- group was significantly higher than that of PDS/Hp- group and control group, the differences were statistically significant (P < 0.001). The trend of cytoplasmic Eotaxin gene mainly distributed in gastric mucosa epithelial cells and glandular epithelial cells, and inflammatory cells were not found in distribution.RANTES in the gastric mucosa mainly distributed in gastric mucosal epithelial cells, gland cells, cell cytoplasm and nucleus, the expression level of Eotaxin and RANTES were positively associated with the number of eosinophil
conclusion
1.FD is a common disease of children in Suzhou area. The main subtype is EPS. children. The risk factors for FD are female, younger age, parental education level, Hp infection, dental caries and BMI decrease.
2Ghrelin, Leptin and PYY three kinds of gastrointestinal hormones involved in the pathogenesis of functional dyspepsia in children, Ghrelin and Leptin in the postprandial discomfort (PDS) subtypes in more obvious changes, suggesting that PDS early satiety, anorexia and other symptoms have direct relation with Ghrelin and Leptin, Ghrelin may become a new target of drug therapy PDS.
3. eosinophils and chemokines eotaxin and RANTES are mainly involved in the pathogenesis and disease progression of children with functional dyspepsia and upper abdominal pain (EPS), which provide experimental evidence for clinical research and development of new drugs for EPS.

【學(xué)位授予單位】：蘇州大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R725.7

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