0 引言

食管癌是常見的上消化道惡性腫瘤之一,其發(fā)病率及死亡率分別居世界惡性腫瘤的第8位及第6位

.在西方國家,食管腺癌(esophageal adenocarcinoma,EAC)已替代食管鱗癌成為最常見的食管癌病理類型

,近年來,其發(fā)病率在中國也呈上升趨勢

.Barrett食管(Barrett’s esophagus,BE)是指食管與胃黏膜交界處的連接線(齒狀線,又稱Z線)1 cm以上的食管下段的正常復(fù)層鱗狀上皮被化生的單層柱狀上皮所取代的一種病理現(xiàn)象

.BE是目前唯一已知的EAC的癌前病變

,有報道顯示

,80%的EAC與BE密切相關(guān),BE患者罹患EAC的風(fēng)險是正常人群的30-40倍

.因此,識別和了解BE發(fā)生發(fā)展的相關(guān)危險因素對其早期診治及降低EAC的發(fā)病率具有重要意義.本文通過全面概述BE發(fā)生發(fā)展的相關(guān)危險因素的臨床研究證據(jù),為BE的臨床防治提供更多有價值的科學(xué)依據(jù).

1 臨床相關(guān)危險因素

1.1 胃食管反流病和反流癥狀 胃食管反流病(gastroesophageal reflux disease,GERD)是指胃十二指腸內(nèi)容物反流至食管引起的相關(guān)癥狀和(或)并發(fā)癥的疾病,是公認(rèn)發(fā)生BE最主要的危險因素

.一項基于愛爾蘭人群的病例對照研究證實,GERD與發(fā)生BE顯著相關(guān)(OR=12.0,95%CI=7.64-18.70)

.然而,并非所有的GERD患者均會出現(xiàn)反酸、胃灼熱等反流癥狀

.為此,多項研究也進一步探討了反流癥狀與發(fā)生BE之間的關(guān)系,它們發(fā)現(xiàn),反流癥狀的發(fā)作頻率和嚴(yán)重程度與BE的發(fā)生風(fēng)險呈正相關(guān)

.一項納入了26項研究的薈萃分析發(fā)現(xiàn),反流癥狀與短段BE的發(fā)生風(fēng)險無關(guān)(OR=1.15,95%CI=0.76-1.73),但與長段BE的發(fā)生風(fēng)險顯著相關(guān)(OR=4.92,95%CI=2.01-12.00),反流癥狀似乎只能作為長段BE的可靠預(yù)測指標(biāo)

.持續(xù)的胃酸反流可誘導(dǎo)食管鱗狀上皮改變發(fā)育轉(zhuǎn)錄因子的表達模式,使其逐步轉(zhuǎn)化為柱狀上皮和腸上皮,最終發(fā)展為BE

.除胃酸反流外,膽汁反流在BE的發(fā)生發(fā)展中也可能起著重要作用.由膽汁酸誘導(dǎo)的食管組織氧化應(yīng)激和DNA損傷可激活BE細(xì)胞的抗凋亡通路并增加炎性反應(yīng),從而促進BE的發(fā)生發(fā)展

.當(dāng)前指南認(rèn)為,長期GERD病史和(或)＞5年的反流癥狀是BE的危險因素

.

1.2 食管裂孔疝 食管裂孔疝(hiatal hernia,HH)是指除食管以外的任何腹腔組織結(jié)構(gòu)通過擴大的食管裂孔進入胸腔形成的疝

.BE患者中HH的發(fā)病率高達96%

.一項橫斷面研究發(fā)現(xiàn),BE患者HH的患病率顯著高于非BE患者(79.8%

52.8%,

＜0.01);并且HH是BE的獨立危險因素(OR=3.04,95%CI=1.77-5.23,

＜0.01)

.一項納入了13項研究的薈萃分析也證實,HH顯著增加了BE的發(fā)生風(fēng)險(OR=2.74,95%CI=1.58-4.75)

.這可能是因為HH可降低食管下括約肌(transient lower esophageal sphincter,LES)壓力,從而加重胃酸和膽汁反流,最終增加BE的發(fā)生風(fēng)險.

隨著旅游業(yè)在嘉絨地區(qū)的開展，以當(dāng)?shù)靥厣幕癁橹黝}的旅游項目陸續(xù)開發(fā)上市，越來越多的游客開始進入嘉絨藏區(qū)觀光體驗。根據(jù)甘孜州丹巴文化旅游局的數(shù)據(jù)顯示從2004年到2017年，丹巴的游客總數(shù)、綜合收入以及人均消費都是呈現(xiàn)出逐年增長的態(tài)勢。到2017年丹巴縣的游客總?cè)藬?shù)已超過90萬，旅游收入超過9億，人均消費達到1000元，但仔細(xì)研究便可發(fā)現(xiàn)游客消費的主要項目來源于住宿和門票收入，由當(dāng)?shù)貍鹘y(tǒng)文化商業(yè)化的旅游文化產(chǎn)品消費寥寥無幾。在實際的調(diào)查中筆者也發(fā)現(xiàn)當(dāng)?shù)貗D聯(lián)曾經(jīng)將以嘉絨藏繡為主題的皮具制品作為支持幫扶的產(chǎn)品之一，但由于設(shè)計、做工等原因未能得到游客認(rèn)可，銷售狀況較差。

1.3 中心性肥胖 根據(jù)脂肪分布部位,肥胖可分為全身性肥胖和中心性肥胖.中心性肥胖是指以腹部或內(nèi)臟脂肪積聚為主引起的肥胖,比全身性肥胖對健康的危害更大,是多種慢性病的重要危險因素

.研究表明

,中心性肥胖是發(fā)生BE的獨立預(yù)測因素.兩項病例對照研究比較了有無BE患者的脂肪分布、脂肪含量和體脂百分比,以探討肥胖類型與BE的關(guān)系;結(jié)果顯示,腰圍、腰臀比等中心性肥胖指標(biāo)與BE的患病風(fēng)險呈正相關(guān),而體重指數(shù)(body mass index,BMI)、脂肪含量、體脂百分比等全身性肥胖指標(biāo)與BE的患病風(fēng)險無關(guān)

.此外,Nelsen等

發(fā)現(xiàn)內(nèi)臟脂肪(OR=4.88,95%CI=1.04-22.85,

＜0.01)和胃食管交界處脂肪(OR=5.97,95%CI=1.28-27.74,

＜0.01)堆積也會增加BE的患病風(fēng)險,且不受BMI的影響.多項薈萃分析也證實,通過腰圍、腰臀比和(或)內(nèi)臟脂肪組織面積鑒定的中心性肥胖可獨立預(yù)測BE的發(fā)生風(fēng)險

.這是由于中心性肥胖可以導(dǎo)致腹內(nèi)壓力增加并機械地破壞胃食管交界處屏障的完整性,從而促進胃酸和膽汁反流,進而加重反流性食管炎并誘導(dǎo)食管鱗狀上皮化生,最終導(dǎo)致BE形成

.另一方面,中心性肥胖患者內(nèi)臟脂肪組織代謝活躍,促進了白細(xì)胞介素-6(interleukin-6,IL-6)、白細(xì)胞介素-1β(interleukin-1β,IL-1β)、腫瘤壞死因子-α(tumor necrosis factor-α,TNF-α)等炎性細(xì)胞因子和脂聯(lián)素(adiponectin,APN)、游離脂肪酸(free fatty acid,FFA)、瘦素(leptin,LEP)等脂肪因子的釋放,這些生物活性物質(zhì)通過遠(yuǎn)距分泌和旁分泌的方式發(fā)揮全身慢性炎癥作用,獨立或協(xié)同地促進BE的發(fā)生發(fā)展

.

1.4 阻塞性睡眠呼吸暫停綜合征 阻塞性睡眠呼吸暫停綜合征(obstructive sleep apnea syndrome,OSAS)是指睡眠期間氣道部分或完全阻塞,導(dǎo)致以間歇性缺氧和低通氣為主要臨床表現(xiàn)的一種潛在致死性綜合征

.OSAS患者睡眠時常因呼吸道阻塞導(dǎo)致吸氣時胸腔負(fù)壓和食管內(nèi)負(fù)壓增高,且呼吸暫停后連續(xù)吸氣會引起胸腔和LES壓力降低,從而加重胃食管反流并誘發(fā)BE

.此外,OSAS患者多肥胖

;相較于健康人群,肥胖人群的腹內(nèi)壓力顯著更高,因此更容易引起胃食管返流,最終導(dǎo)致BE的發(fā)生

.最近,Hadi等

的研究結(jié)果顯示,BE患者OSAS的患病率顯著高于非BE患者(90.7%

72.4%,

＜0.01).當(dāng)校正GERD和BMI后,OSAS仍顯著增加了BE的發(fā)生風(fēng)險(OR=3.26,95%CI=1.72-6.85,

＜0.01),且隨著OSAS的程度加重,BE的發(fā)生風(fēng)險隨之上升,這可能與缺氧誘導(dǎo)的全身慢性炎癥反應(yīng)有關(guān),而不完全依賴于胃食管反流和肥胖

.

1.7 幽門螺桿菌感染和幽門螺桿菌根除治療 幽門螺桿菌(

,

)是一種定植于胃黏膜的微需氧革蘭氏陰性菌,1994年世界衛(wèi)生組織將其認(rèn)定為Ⅰ類致癌原

.多數(shù)研究認(rèn)為,

感染,尤其是CagA陽性菌株感染,與BE的發(fā)病風(fēng)險呈負(fù)相關(guān)

.最近,一項薈萃分析也表明,

感染可能是發(fā)生BE的保護因素(OR=0.70,95%CI=0.51-0.96,

＜0.05),并且CagA陽性菌株感染對發(fā)生BE的保護作用更為明顯(OR=0.28,95%CI=0.15-0.54,

＜0.01)

.這可能是因為持續(xù)的

感染通過破壞壁細(xì)胞的功能、升高LES壓力以及減少一過性食管下括約肌松弛(transient lower esophageal sphincter relaxations,TLESR)的頻率及持續(xù)時間,減少了胃酸的分泌和反流,最終降低了BE的發(fā)生風(fēng)險

.目前,僅有一項基于瑞典人群的前瞻性隊列研究探討了

根除治療與BE發(fā)病風(fēng)險的關(guān)系,結(jié)果顯示,

根除治療后,瑞典人群BE的發(fā)病率顯著增加(SIR=3.67,95%CI=3.15-4.25)

,提示

根除治療可能是BE的危險因素.

“不會吧？據(jù)我所知，小區(qū)里所有的防盜門都是同一個品牌，這個品牌的防盜門在全國范圍內(nèi)有著較高的知名度，銷路很不錯，怎么會存在嚴(yán)重的質(zhì)量問題呢？”

1.5 糖尿病 僅少數(shù)研究探討了糖尿病(diabetes mellitus,DM)與BE之間的關(guān)聯(lián),且研究結(jié)果并不一致.一項大型的病例對照研究發(fā)現(xiàn),BE患者的DM患病率顯著高于非BE患者(5.8%

5.3%,

＜0.05);校正BMI、GERD等危險因素后,DM仍顯著增加了BE的發(fā)生風(fēng)險 (OR=1.49,95%CI=1.16-1.91,

＜0.01)

.然而,另一項基于英國人群的病例對照研究發(fā)現(xiàn),DM并不會增加BE的發(fā)病風(fēng)險(OR=1.07,95%CI=0.98-1.18)

.最近一項薈萃分析也發(fā)現(xiàn),DM與BE無關(guān)(OR=0.93,95%CI=0.71-1.20),但顯著增加了EAC的發(fā)生風(fēng)險(OR=1.63,95%CI=1.19-2.22).這些研究結(jié)果提示DM可能不會影響B(tài)E的發(fā)病,但會促進BE進展至EAC

.

2 人口統(tǒng)計學(xué)相關(guān)危險因素

3.2 飲酒 多數(shù)研究未發(fā)現(xiàn)飲酒與BE之間存在直接關(guān)聯(lián)

.然而,最近一項納入了62項觀察性研究的薈萃分析卻表明,飲酒可能是發(fā)生BE的危險因素(RR=1.23,95%CI=1.13-1.34,

＜0.01)

.這可能是由于酒精會導(dǎo)致LES壓力降低并加重反流癥狀,從而引起食管黏膜損傷并誘導(dǎo)BE形成

.

2.3 種族 全球范圍內(nèi),白人種族BE的發(fā)病率最高

.一項納入20412例患者的觀察性研究發(fā)現(xiàn),白人發(fā)生BE的風(fēng)險是黃種人的6倍(OR=6.03,95%CI=3.56-10.22)

;同樣,一項來自美國的大型橫斷面研究表明,白人BE的發(fā)病率是黑人的5倍

.目前尚不清楚種族對BE發(fā)生發(fā)展的作用機制.白人種族肥胖率更高可能是其BE高發(fā)病率的原因

.

2.5 受教育程度 僅少數(shù)研究探討了受教育程度對BE發(fā)病風(fēng)險的影響.Kendall等

發(fā)現(xiàn),受教育程度與BE的發(fā)病風(fēng)險呈負(fù)相關(guān),隨著受教育程度的提高,BE的患病率顯著降低.受教育程度高的患者依從性好,自身接受能力、自我保健意識、認(rèn)知疾病的能力強,有利于控制危險因素

.因此,受教育程度高的人群罹患BE的風(fēng)險較低.

關(guān)系價值指顧客和企業(yè)員工之間的情感或關(guān)系紐帶所帶來的利益[10]。以Hartline、Ferrell[32]和Zeithaml[44]的研究為基礎(chǔ)，本文采用Chan等[10]對關(guān)系價值的測量量表，包含3個題目，如“建立了非常好的關(guān)系”“交往非常愉快”等。

2.4 家族遺傳史 BE可能是具有遺傳傾向的后天性疾病

,BE及其相關(guān)癌癥家族史可增加BE的發(fā)生風(fēng)險.Chak等

發(fā)現(xiàn),約7.3%的BE患者有BE或EAC家族史.目前,幾項全基因組關(guān)聯(lián)研究已確定CRTC1、FOXP1、BARX1、TBX5、GDF7等是BE和EAC的易感基因

.

2.2 年齡 年齡是發(fā)生BE的獨立危險因素.年齡每增加10歲,罹患BE的風(fēng)險將增加1-2倍

.一項來自英國和荷蘭的多中心、回顧性隊列研究比較了不同年齡段人群發(fā)生BE的風(fēng)險;結(jié)果顯示,在40歲-44歲組,英國和荷蘭BE的發(fā)病率分別為16/10

和24/10

;在70歲-74歲組,英國和荷蘭BE的發(fā)病率分別增至85.6/10

和87/10

,BE的發(fā)病率與年齡呈線性相關(guān)

.目前國內(nèi)外多項指南也推薦,年齡＞50歲是發(fā)生BE的獨立預(yù)測因素

.

1.6 代謝綜合征 代謝綜合征(metabolic syndrome,MS)是以胰島素抵抗、中心性肥胖、高脂血癥及高血壓等疾病為主的癥候群

.多項研究顯示,MS是發(fā)生BE的高危因素

.最近,一項納入了14項研究的薈萃分析也證實,MS顯著增加了BE的發(fā)病風(fēng)險(OR=1.35,95%CI=1.15-1.60,

＜0.01)

.此外,一項基于白人男性退伍軍人的病例對照研究表明,MS的嚴(yán)重程度與BE的發(fā)生風(fēng)險呈劑量-反應(yīng)關(guān)系,即BE的發(fā)病風(fēng)險隨著MS成分?jǐn)?shù)量的增加而呈線性增加,且高脂血癥對BE的發(fā)生風(fēng)險影響最大

.除了脂肪因子可發(fā)揮全身慢性炎癥作用外

,MS患者血清中的高甘油三酯水平還會促進膽囊收縮素的分泌,從而延緩胃排空并降低LES壓力

,最終加重胃食管反流并誘導(dǎo)BE形成.此外,胰島素樣生長因子-1(insulin-like growth factor-I,IGF-1)與靶細(xì)胞表面的相應(yīng)受體結(jié)合可調(diào)控食管上皮細(xì)胞的增殖和分化

.因此,繼發(fā)于MS的血清高IGF-1水平可能會進一步增加MS患者發(fā)生BE的風(fēng)險

.

2.6 社會經(jīng)濟地位 一項英國的病例對照研究表明,較高的社會經(jīng)濟地位可能是發(fā)生BE的獨立危險因素(OR=1.58,95%CI=1.15-2.15)

.此外,一項納入了20,975例受試者的回顧性隊列研究也發(fā)現(xiàn),與低社會經(jīng)濟地位人群相比,高社會經(jīng)濟地位人群BE的患病率顯著更高(

＜0.01),且確診為BE時的年齡更小

.這似乎與受教育程度高的人群罹患BE的風(fēng)險更低的結(jié)論相矛盾.然而我們需要澄清的是,高社會經(jīng)濟地位人群常有著高糖高脂的飲食習(xí)慣

,且就醫(yī)條件更好,可能會通過更頻繁的內(nèi)鏡檢查發(fā)現(xiàn)BE的患病情況

.

3 生活方式相關(guān)危險因素

3.1 吸煙 吸煙可能會增加BE的發(fā)生風(fēng)險.BE患者吸煙史的比例顯著高于人群對照組,且BE的發(fā)生風(fēng)險與吸煙包年數(shù)呈正相關(guān)

.Balasubramanian等

進一步指出,吸煙的GERD患者BE的患病率顯著高于無吸煙史的GERD患者(5.2%

17.0%,

＜0.01),吸煙是GERD患者發(fā)生BE的獨立危險因素;隨著戒煙時間的延長,BE的發(fā)生風(fēng)險逐漸降低(

for trend＜0.01).此外,一項隨訪16年的前瞻性隊列研究也發(fā)現(xiàn),吸煙史和吸煙時長均顯著增加了BE的發(fā)生風(fēng)險

.這是由于尼古丁可降低LES壓力并導(dǎo)致頻繁的TLESR,從而促進胃食管反流,最終誘導(dǎo)Barrett上皮生成

.

2.1 性別 男性BE的發(fā)病率是女性的1.5-4.0倍

.性激素的差異可能在一定程度上解釋了這一現(xiàn)象.一項基于男性的病例對照研究發(fā)現(xiàn),游離睪酮(OR=5.36,95%CI=2.21-13.03,

＜0.01)和游離雙氫睪酮(OR=4.25,95%CI=1.87-9.66,

＜0.01)可顯著增加BE的發(fā)生風(fēng)險,睪酮可降低LES壓力并增加TLESR的頻率,從而加重胃食管反流

.一項動物實驗也發(fā)現(xiàn),雌激素可通過抑制壁細(xì)胞的功能并減少壁細(xì)胞的數(shù)量,以降低基礎(chǔ)胃酸分泌,從而降低BE的發(fā)生風(fēng)險

.

3.3 飲食習(xí)慣 近期,多項研究探討了飲食習(xí)慣與BE的相關(guān)性.隨著糖類

和脂肪

攝入量的增加以及膳食纖維

和富含膳食抗氧化劑的蔬菜、水果

攝入量的減少,BE的發(fā)生風(fēng)險將逐漸增加.高糖高脂和低膳食纖維飲食通過損傷食管黏膜或影響其它危險因素,如GERD、HH和中心性肥胖,直接或間接地促進BE的發(fā)生發(fā)展

.當(dāng)蔬菜、水果的攝入量過少時,人體便會缺乏某些抗氧化活性成分(維生素C、維生素E、硒、鎂和β-胡蘿卜素)

,從而誘導(dǎo)食管組織氧化應(yīng)激和DNA損傷,進而促進BE細(xì)胞增殖并增加炎性反應(yīng),最終增加BE的發(fā)生風(fēng)險

.

解剖高頻關(guān)鍵詞，可直觀讀懂該領(lǐng)域的研究熱點與重點。標(biāo)準(zhǔn)化處理138篇文獻共得關(guān)鍵詞573個。將高頻數(shù)界定為≥3，獲22個高頻關(guān)鍵詞，其累計占比58.59%，符合知識圖譜規(guī)定的27%，適宜進行數(shù)據(jù)統(tǒng)計分析。22個高頻關(guān)鍵詞見表1。

4 藥物相關(guān)危險因素

僅少數(shù)研究探討了藥物和BE發(fā)病風(fēng)險之間的相關(guān)性.一項基于美國退伍軍人的病例對照研究比較了有無BE患者雙膦酸鹽類藥物的使用情況,結(jié)果發(fā)現(xiàn),BE患者雙膦酸鹽類藥物的使用率顯著高于非BE患者(4.6%

2.5%),且口服雙膦酸鹽類藥物可能是發(fā)生BE的危險因素(OR=2.33,95%CI=1.11-4.88,

＜0.01)

.雙膦酸鹽是破骨細(xì)胞介導(dǎo)的骨質(zhì)吸收的選擇性抑制劑,用于治療和預(yù)防骨質(zhì)疏松癥

.它可通過抑制甲羥戊酸途徑干擾細(xì)胞周期進程,從而影響食管上皮干細(xì)胞的增殖與分化,最終加重胃食管反流引起的食管損傷并誘導(dǎo)Barrett上皮生成

.此外,有研究也發(fā)現(xiàn),非甾體類抗炎藥

和他汀類藥物

的使用可能會降低BE的發(fā)生風(fēng)險.

北京市人大常委會相關(guān)負(fù)責(zé)人表示,條例實施以來,北京市人大常委會每年都確定一個重點難點問題,持續(xù)開展監(jiān)督。聚焦居家養(yǎng)老健康服務(wù)和醫(yī)養(yǎng)結(jié)合工作,是今年北京市人大常委會確定的重點。

5 結(jié)論

作為目前唯一已知的EAC的癌前病變,BE在全球的發(fā)病率不斷升高.因此,掌握BE發(fā)生發(fā)展的危險因素對于EAC的預(yù)防、風(fēng)險分層、早期識別和診治至關(guān)重要.除性別、種族、遺傳等不可變因素外,以GERD、中心性肥胖、吸煙等為主的可變危險因素應(yīng)引起重視(圖1).未來應(yīng)正確引導(dǎo)人們認(rèn)識這些危險因素,提高人群健康意識,保持良好的生活習(xí)慣,從而降低BE和EAC的發(fā)病率.

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