郭薇薇，陳 玲，繆 鑫，朱曉娟，劉 政

南京醫(yī)科大學(xué)第二附屬醫(yī)院消化醫(yī)學(xué)中心，江蘇 南京 210011

論著·胃相關(guān)疾病

幽門螺桿菌對胃食管反流病影響的Meta分析

郭薇薇，陳 玲，繆 鑫，朱曉娟，劉 政

南京醫(yī)科大學(xué)第二附屬醫(yī)院消化醫(yī)學(xué)中心，江蘇 南京 210011

目的探討根除幽門螺桿菌(Helicobacter pylori,H.pylori)對胃食管反流病(gastroesophageal reflux disease, GERD)的影響。方法檢索PubMed、Web of Science和Cochrane圖書館關(guān)于H.pylori與GERD相關(guān)性的文獻(xiàn)。采用Revman 5.2和Stata 12.0軟件分析繪制森林圖，采用Begg’s和Egger’s檢驗(yàn)檢測發(fā)表偏倚，并進(jìn)行結(jié)果分析。結(jié)果16項(xiàng)研究符合納入標(biāo)準(zhǔn)。Meta分析提示，根除H.pylori有可能促進(jìn)GERD的發(fā)展(RR=1.44，95%CI：1.03～2.01)。尤其在亞洲人群中，H.pylori可能為GERD的一個(gè)重要保護(hù)性因素(RR=4.53，95%CI：1.66～12.36)。隨訪時(shí)間延長，這一趨勢越明顯，隨訪時(shí)間>1年根除H.pylori可能誘發(fā)GERD或加重GERD癥狀(RR=1.84，95%CI：1.01～3.34)。Egger’s和Begg’s檢驗(yàn)檢測發(fā)表偏倚顯示，無發(fā)表偏倚(P>0.05)。結(jié)論根除H.pylori后可能會(huì)導(dǎo)致GERD的發(fā)生、發(fā)展，尤其在亞洲國家，且隨訪時(shí)間越長這一趨勢越明顯。

幽門螺桿菌；胃食管反流?。籑eta分析

胃食管反流病(gastroesophageal reflux disease，GERD)是由多種因素導(dǎo)致的胃內(nèi)容物反流至食管而引起的反流、燒心及口腔、咽喉部、肺部癥狀[1]。GERD是上消化道最常見的疾病之一，在歐洲及美國的發(fā)病率分別為23.7%和28.8%，而在亞洲發(fā)病率稍低，但逐年升高[2-3]。其發(fā)病機(jī)制尚不明確，多種病因參與食管抗反流和清除機(jī)制。早在20世紀(jì)中期，有文獻(xiàn)[4]報(bào)道，根除幽門螺桿菌(Helicobacter pylori，H.pylori)后可以促進(jìn)GERD的發(fā)展，說明H.pylori是GERD的一種保護(hù)性因素。同樣也有多項(xiàng)研究[5]表明，H.pylori感染與Barrett’s食管(Barrett’s esophagus，BE)及食管腺癌的發(fā)生呈負(fù)相關(guān)。但也有研究[6]表明，根除H.pylori后并沒有加重GERD的臨床癥狀。因此，關(guān)于H.pylori是GERD的保護(hù)因素還是危險(xiǎn)因素仍有爭議。本文旨在通過Meta分析的方法評估根除與未根除H.pylori對GERD的影響。

1 材料與方法

1.1文獻(xiàn)檢索計(jì)算機(jī)檢索PubMed、Wed of Science及Cochrane圖書館數(shù)據(jù)庫中2000年1月-2015年2月的英文文獻(xiàn)，檢索關(guān)鍵詞包括Helicobacter pylori/H.pylori、gastroesophageal reflux/esophagitis、Barrett’s esophagus、GERD/GORD。

1.2文獻(xiàn)納入及排除標(biāo)準(zhǔn)所有納入的研究對象需經(jīng)消化內(nèi)鏡活檢診斷，進(jìn)行洛杉磯分級。納入標(biāo)準(zhǔn)：(1)試驗(yàn)組需詳細(xì)描述H.pylori的根治方法，對照組使用安慰劑或質(zhì)子泵抑制劑(proton pump inhibitor，PPI)；(2)改良Jadad評分[7]≥3分；(3)研究中注明H.pylori的檢測方法；(4)文獻(xiàn)中包括納入人群的一般數(shù)據(jù)，如H.pylori的根除率、隨訪時(shí)間及失訪率。排除標(biāo)準(zhǔn)：(1)研究對象為動(dòng)物，語種為非英語類；(2)研究人群年齡<18周歲；(3)未提供可計(jì)算相關(guān)預(yù)測值的原始數(shù)據(jù)；(4)病例報(bào)道、案例分析、綜述及Meta分析。

1.3數(shù)據(jù)收集及提取由2名研究者獨(dú)立進(jìn)行文獻(xiàn)搜索、數(shù)據(jù)提取及文獻(xiàn)質(zhì)量評估，如遇到意見不一致與第三研究者討論決定。數(shù)據(jù)提取包括文獻(xiàn)第一作者姓名、發(fā)表年限、設(shè)計(jì)類型、國家及詳細(xì)信息(樣本量、隨訪時(shí)間、H.pylori檢查方法、Jadad評分)。

1.4統(tǒng)計(jì)學(xué)分析采用Review Manager軟件對各研究中根除H.pylori和僅使用安慰劑或PPI對GERD的累積效應(yīng)量進(jìn)行Meta分析，計(jì)算出累積RR值及95%CI。I2值和P值評價(jià)研究間的異質(zhì)性，若I2<50%或P≥0.1則認(rèn)為組間異質(zhì)性小，采用固定效應(yīng)模型進(jìn)行合并效應(yīng)量估計(jì)；否則采用隨機(jī)效應(yīng)模型，并探討異質(zhì)性來源，進(jìn)行分層分析。采用Stata 12.0軟件，用Begg’s檢驗(yàn)[8]和Egger’s檢驗(yàn)[9]檢測發(fā)表偏倚，若P≥0.05，則說明無發(fā)表偏倚。P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

2 結(jié)果

2.1文獻(xiàn)檢索結(jié)果及納入研究信息共檢出相關(guān)文獻(xiàn)381篇，通過閱讀文題和摘要后根據(jù)納入及排除標(biāo)準(zhǔn)，進(jìn)一步閱讀全文后最終納入16篇隨機(jī)對照研究，基本特征見表1。

表1 納入隨機(jī)對照研究的基本特征

注：O：奧美拉唑；A：阿莫西林；L：雷貝拉唑；C：克拉霉素；P：泮托拉唑；T：替硝唑；R：雷尼替?。籑：甲硝唑。

2.2隨機(jī)對照研究中評估根除H.pylori對GERD的影響根據(jù)納入及排除標(biāo)準(zhǔn)，共納入16篇文獻(xiàn)，其中12篇來自歐美國家，4篇來自亞洲國家。由于存在異質(zhì)性(I2=68%)，采用隨機(jī)對照模型，RR值為1.44(95%CI：1.03～2.01,P=0.03)。結(jié)果分析顯示，根除H.pylori后可能增加GERD的發(fā)病率及加重GERD癥狀，但關(guān)聯(lián)強(qiáng)度較弱。

根據(jù)不同地域分成歐美組及亞洲組進(jìn)行亞型分析，歐美組其RR值為1.06(95%CI：0.88～1.29，P=0.53)，可見根除H.pylori后對GERD的發(fā)生及發(fā)展無明顯相關(guān)性。來自亞洲的4項(xiàng)研究結(jié)果分析顯示，RR值為4.53(95%CI：1.66～12.36,P=0.003)，根除H.pylori后明顯增加了GERD的發(fā)病率及癥狀(見圖1)。

根據(jù)隨訪時(shí)間長短進(jìn)行分層分析，9篇隨訪時(shí)間≤1年，另7篇隨訪時(shí)間>1年。隨訪時(shí)間≤1年的RR值為1.15(95%CI：0.77～1.73,P=0.50)，提示隨訪時(shí)間≤1年根除H.pylori對GERD無影響(P>0.05)。隨訪時(shí)間>1年的RR值為1.84(95%CI：1.01～3.34，P=0.05)，提示隨訪時(shí)間>1年根除H.pylori更能體現(xiàn)可誘發(fā)GERD或加重GERD癥狀(見圖2)。

圖1 H.pylori根除組與非根除組GERD比較森林圖Fig 1 Forest plot showed the different incidence of GERD between the H.pylori eradication and no eradication group

圖2 根據(jù)隨訪時(shí)間不同，根除H.pylori對GERD影響的森林圖Fig 2 Forest plot showed the different incidence of GERD in the different follow-up times

2.3發(fā)表偏倚分析對全部納入研究的文獻(xiàn)進(jìn)行發(fā)表偏倚分析，通過Stata軟件，用Begg’s檢驗(yàn)和Egger’s檢驗(yàn)定量判定是否存在發(fā)表偏倚。Begg’s檢驗(yàn)和Egger’s檢驗(yàn)P值均>0.05，提示無發(fā)表偏倚(見表2)。

表2 納入研究的Begg’s值和Egger’s值

注：*:在Begg’s檢驗(yàn)和Egger’s檢驗(yàn)中，P>0.05，無發(fā)表偏倚。

2.4敏感性分析H.pylori感染對GERD總效應(yīng)的敏感性分析中，逐一剔除各項(xiàng)研究，各合并效應(yīng)量與總效應(yīng)量95%CI基本相同，提示本Meta分析研究結(jié)果較穩(wěn)定。

3 討論

早在1989年就已提出一項(xiàng)具有里程碑意義的發(fā)現(xiàn)，即H.pylori與胃十二指腸疾病有關(guān)[26]。已公認(rèn)H.pylori與胃十二指腸潰瘍、胃腺癌及胃黏膜相關(guān)性淋巴瘤有密切關(guān)系。而H.pylori感染與GERD關(guān)系是近年來消化系統(tǒng)疾病的一個(gè)熱點(diǎn)。本研究發(fā)現(xiàn)，根治H.pylori后可能會(huì)影響GERD的發(fā)生、發(fā)展，但其相關(guān)性仍較弱。因此，我們根據(jù)不同地域進(jìn)行了分層分析，發(fā)現(xiàn)亞洲人群在根除H.pylori后可明顯增加GERD的發(fā)病率。

目前關(guān)于H.pylori與GERD關(guān)系的解釋有以下幾種可能：(1)H.pylori作用于壁細(xì)胞使胃酸分泌減少，一旦根除了H.pylori，酸反流就會(huì)增加，進(jìn)而加重GERD癥狀，尤其是在急慢性胃體炎[27]。(2)在炎癥性腸病中，H.pyloriDNA通過下調(diào)干擾素1和白介素-10/12而減輕炎癥刺激的反應(yīng)[28]，那么是不是也有可能作用于食管黏膜？(3)H.pylori可抑制瘦素及胃饑餓素的分泌，研究[29-30]發(fā)現(xiàn)，H.pylori陽性者血清胃饑餓素濃度及胃饑餓素mRNA均降低，同時(shí)分泌胃饑餓素的胃黏膜細(xì)胞數(shù)也下降。Goll等[31]研究發(fā)現(xiàn)，H.pylori感染患者胃黏膜Treg細(xì)胞數(shù)增加，而Treg可分泌瘦素。瘦素和胃饑餓素可間接導(dǎo)致肥胖，肥胖是GERD的一個(gè)獨(dú)立危險(xiǎn)因素[32]。但以上這些可能的解釋均需進(jìn)一步研究。2013年美國GERD診療指南不推薦GERD患者常規(guī)篩查H.pylori，H.pylori感染不作為常規(guī)抗反流治療[33]，并強(qiáng)烈推薦，但證據(jù)等級較弱。

本Meta分析具有以下優(yōu)勢：不僅納入來自不同地域的隨機(jī)對照研究，還在隨機(jī)對照研究根據(jù)不同地域及隨訪時(shí)間進(jìn)行了分層分析。但也存在以下局限性：(1)文章僅限于英文文獻(xiàn)，可能造成選擇偏倚；(2)研究可能會(huì)存在一些已知的或未知的混雜因素，由于納入研究之間的異質(zhì)性較大，還應(yīng)選擇隨機(jī)效應(yīng)模型，并探討異質(zhì)性來源。

綜上所述，根除H.pylori后可能會(huì)導(dǎo)致GERD發(fā)生或癥狀加重，尤其在亞洲國家。而且隨訪時(shí)間越長，趨勢越明顯。但由于納入的亞洲地區(qū)研究的異質(zhì)性較大，本結(jié)果還需進(jìn)一步評估。

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(責(zé)任編輯：馬 軍)

勘誤：發(fā)表于我刊2017年第26卷第9期1071-1074頁，第一作者為田翀的文章《萎縮性胃炎相關(guān)疾病概述》，作者單位修改為：重慶市東南醫(yī)院，特此更正。

AssociationofHelicobacterpyloriongastroesophagealrefluxdiseaseaMeta-analysis

GUO Weiwei, CHEN Ling, MIAO Xin, ZHU Xiaojuan, LIU Zheng

Gastroenterology Medical Center, the Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China

ObjectiveTo investigate the effect of Helicobacter pylori (H.pylori) on gastroesophageal reflux disease (GERD).MethodsThe literatures on the relevance ofH.pyloriand GERD in PubMed, Web of Science, and Cochrane libraries were retrieved. Revman 5.2 and Stata 12.0 software were used to analyze and plot forest plots.Begg’stest andEgger’stest were used to detect publication bias and the results were analyzed.ResultsSixteen articles met the inclusion and exclusion criteria. RCTs showed there was statistical difference in the incidence of GERD after eradication ofH.pylori(RR=1.44, 95%CI: 1.03-2.01). Sub-analysis showed that the risk existed especially in Asia countries (RR=4.53, 95%CI: 1.66-12.36). The eradication ofH.pyloriwas more likely induced the development of GERD after more than one year follow-up (RR=1.84, 95%CI: 1.01-3.34). Publication bias was assessed byEgger’stest andBegg’stests, there was no publication bias (P>0.05).ConclusionH.pylorimay be negatively associated with GERD. The eradication ofH.pylorimay induce the development of GERD. However, in Asia countries, the eradication ofH.pylorimay be an incitive risk factor for GERD.

Helicobacter pylori; Gastroesophageal reflux disease; Meta-analysis

R378;R57

A

1006-5709(2017)10-1133-05

2016-11-15

郭薇薇，碩士研究生。E-mail：guoweiwei011@sina.com

劉政，博士，博士生導(dǎo)師，主任醫(yī)師，研究方向：胃食管反流病的發(fā)病機(jī)制。E-mail：liuzheng117@yeah.net

10.3969/j.issn.1006-5709.2017.10.017