王君化， 蔣 謙， 孫靜鋒， 周國志

1. 西安市第四醫(yī)院消化內(nèi)科，陜西 西安 710004；2. 南京醫(yī)科大學(xué)附屬逸夫醫(yī)院腫瘤中心

其他論著

體質(zhì)量指數(shù)與食管賁門腺癌發(fā)病風(fēng)險(xiǎn)相關(guān)性Meta分析

王君化1， 蔣 謙2， 孫靜鋒2， 周國志2

1. 西安市第四醫(yī)院消化內(nèi)科，陜西 西安 710004；2. 南京醫(yī)科大學(xué)附屬逸夫醫(yī)院腫瘤中心

目的 分析不同體質(zhì)量指數(shù)(BMI)與食管賁門腺癌發(fā)病風(fēng)險(xiǎn)相關(guān)性。方法 通過Medline、PubMed、Embase、WOS檢索至2015年相關(guān)文獻(xiàn)，統(tǒng)計(jì)分析BMI與食管、賁門腺癌的發(fā)病關(guān)系。結(jié)果 22項(xiàng)研究入選病例數(shù)共1 307 549例，其中試驗(yàn)組7 718例，對照組1 299 831例。BMI 25～30 kg/m2，賁門、食管腺癌發(fā)病總風(fēng)險(xiǎn)RR=1.56，95%CI：1.46～1.68(P=0.000)；食管腺癌RR=1.82，95%CI：1.57～2.11(P=0.00)；賁門腺癌RR=3.47，95%CI：1.93～6.25(P=0.000)；賁門、食管同時(shí)癌變RR=1.47，95%CI：1.35～1.59(P=0.000)。BMI≥30 kg/m2，賁門、食管腺癌發(fā)病相對風(fēng)險(xiǎn)RR=2.19，95%CI：1.96～2.45(P=0.000)；賁門及食管同時(shí)發(fā)生癌變相對風(fēng)險(xiǎn)RR=2.11，95%CI：1.86～2.39(P=0.000)；賁門腺癌發(fā)生風(fēng)險(xiǎn)RR=2.58，95%CI：1.24～5.35(P=0.011)；食管腺癌發(fā)生風(fēng)險(xiǎn)RR=2.49，95%CI：1.95～3.17(P=0.000)。結(jié)論 BMI>25 kg/m2時(shí)，賁門、食管腺癌發(fā)病率明顯升高。

體質(zhì)量指數(shù)；食管腺癌；賁門腺癌；Meta分析；肥胖；超重

近幾年，胃癌和食管癌發(fā)病率上升，特別是發(fā)達(dá)國家中食管與賁門交界處的癌發(fā)病率上升明顯[1]。2007年Holmes等[2]報(bào)道食管、賁門腺癌同高體質(zhì)量指數(shù)(body mass index，BMI)存在密切關(guān)系，超重人群中食管和賁門腺癌患病人群增加超過40%?？刂品逝?、降低BMI能預(yù)防及減少賁門及食管腺癌的發(fā)病率。BMI能增加賁門、食管腺癌發(fā)病風(fēng)險(xiǎn)循證醫(yī)學(xué)證據(jù)不足[3]。本文通過研究BMI和食管、賁門腺癌關(guān)系，為食管、賁門腺癌一級預(yù)防提供客觀依據(jù)。

1 資料和方法

1.1 檢索策略 以‘body mass index’ or ‘BMI’ or ‘obesity’ and combinations of ‘esophageal neoplasms’ or ‘stomach neoplasms’ and ‘a(chǎn)denocarcinoma’作為檢索詞，采取自由詞同關(guān)鍵詞相結(jié)合方式通過Medline、PubMed、Embase、WOS檢索至2015年相關(guān)文獻(xiàn)，中文研究資料真實(shí)性欠佳，為了保證本研究質(zhì)量，本次不予納入。

1.2 納入標(biāo)準(zhǔn) (1)所有資料類型均為隊(duì)列研究或前瞻對照研究；(2)研究對象BMI和食管、賁門腺癌之間的風(fēng)險(xiǎn)聯(lián)系；(3)具有暴露結(jié)果指標(biāo)如RR、OR、95%CI、P值等。

1.3 排除標(biāo)準(zhǔn) (1)回顧性研究；(2)重復(fù)報(bào)道；(3)資料中沒有涉及RR及95%CI；(4)同一研究多篇文獻(xiàn)的取最近一次文獻(xiàn)，排除其他文獻(xiàn)。

1.4 資料收集 初次檢索：通過檢索并仔細(xì)閱讀全文，共有22篇國外文獻(xiàn)納入研究。再次檢索：根據(jù)以上檢索所得到文獻(xiàn)的參考文獻(xiàn)進(jìn)行擴(kuò)大檢索，未發(fā)現(xiàn)新的符合條件的文獻(xiàn)。

1.5 統(tǒng)計(jì)學(xué)分析 采用Stata 11.0統(tǒng)計(jì)軟件進(jìn)行分析，取得BMI同賁門、食管腺癌相對風(fēng)險(xiǎn)及95%CI，進(jìn)行分層分析各研究之間異質(zhì)性差異判定用χ2檢驗(yàn)，用統(tǒng)計(jì)量Q表示，其中P<0.05表示納入資料存在異質(zhì)性，使用隨機(jī)效應(yīng)模型，反之表示資料不存在異質(zhì)性用固定效應(yīng)模型。分析結(jié)果用RR值和95%CI表示，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 最終納入的文獻(xiàn)為22篇[4-25]。所有評分均為>3分的高質(zhì)量文獻(xiàn)，入選病例共1 307 549例，其中試驗(yàn)組7 718例，對照組1 299 831例；詳細(xì)的文獻(xiàn)特征及數(shù)據(jù)如表1所示。

表1 納入研究的資料特征Tab 1 Characteristics of included studies

2.2 Meta分析結(jié)果 BMI 25～30 kg/m2:賁門、食管腺癌發(fā)病相對風(fēng)險(xiǎn)分析中I2=65.7%，采用固定效用模型，賁門、食管腺癌發(fā)病相對風(fēng)險(xiǎn)RR=1.56，95%CI：1.46～1.68，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)。(1)部位分層：食管癌變發(fā)生風(fēng)險(xiǎn)I2=57.7%，采用固定效用模型相對風(fēng)險(xiǎn)RR=1.82，95%CI：1.57～2.11，差異有統(tǒng)計(jì)學(xué)意義(P=0.00)；賁門癌變發(fā)生風(fēng)險(xiǎn)I2=18.9%，采用隨機(jī)效用模型RR=3.47，95%CI：1.93～6.25，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)；賁門、食管同時(shí)癌變發(fā)生風(fēng)險(xiǎn)I2=64.5%，采用固定效用模型RR=1.47，95%CI：1.35～1.59，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)(見圖1)；(2)地域分層：美洲發(fā)生風(fēng)險(xiǎn)I2=28.6%，采用隨機(jī)效用模型相對風(fēng)險(xiǎn)RR=1.53，95%CI：1.36～1.72，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)；亞洲發(fā)生風(fēng)險(xiǎn)I2=50.4%，采用隨機(jī)效用模型RR=3.93，95%CI：1.97～7.81，差異有統(tǒng)計(jì)學(xué)意義(P=0.00)；歐洲發(fā)生風(fēng)險(xiǎn)I2=71.0%，采用隨機(jī)效用模型RR=1.65，95%CI：1.49～1.82，差異有統(tǒng)計(jì)學(xué)意義(P=0.00)；大洋洲發(fā)生風(fēng)險(xiǎn)I2=14.7%，采用隨機(jī)效用模型RR=1.14，95%CI：0.90～1.43，差異無統(tǒng)計(jì)學(xué)意義(P=0.284)(見圖2)；(3)性別分層:男性發(fā)生風(fēng)險(xiǎn)I2=82.4%，采用隨機(jī)效用模型相對風(fēng)險(xiǎn)RR=1.75，95%CI：1.54～2.00，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)；女性發(fā)生風(fēng)險(xiǎn)I2=0，采用隨機(jī)效用模型RR=1.64，95%CI：1.30～2.07，差異有統(tǒng)計(jì)學(xué)意義(P=0.00)；未分男女研究發(fā)生風(fēng)險(xiǎn)I2=58.7%，采用固定效用模型RR=1.47，95%CI：1.34～1.61，差異有統(tǒng)計(jì)學(xué)意義(P=0.00)(見圖3)。BMI≥30 kg/m2賁門、食管腺癌發(fā)病相對風(fēng)險(xiǎn)分析中I2=53.6%，采用隨機(jī)效用模型，發(fā)病相對風(fēng)險(xiǎn)RR=2.19，95%CI：1.96～2.45，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)。(1)部位分層：賁門及食管同時(shí)發(fā)生癌變分析I2=73.0%，采用固定效用模型，發(fā)病相對風(fēng)險(xiǎn)RR=2.11，95%CI：1.86～2.39，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)；賁門癌變發(fā)生風(fēng)險(xiǎn)I2=0，采用隨機(jī)效用模型RR=2.58，95%CI：1.24～5.35，差異有統(tǒng)計(jì)學(xué)意義(P=0.011)；食管癌變發(fā)生風(fēng)險(xiǎn)I2=0，采用固定效用模型RR=2.49，95%CI：1.95～3.17，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)(見圖4)；(2)地域分層:歐洲發(fā)生風(fēng)險(xiǎn)I2=66.5%，采用隨機(jī)效用模型相對風(fēng)險(xiǎn)RR=2.36，95%CI：2.01～2.76，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)；大洋洲發(fā)生風(fēng)險(xiǎn)I2=18.3%，采用隨機(jī)效用模型RR=2.11，95%CI：1.64～2.71，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)；美洲發(fā)生風(fēng)險(xiǎn)I2=0，采用隨機(jī)效用模型RR=2.00，95%CI：1.64～2.44，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)(見圖5)；(3)性別分層:男性發(fā)生風(fēng)險(xiǎn)I2=72.3%，采用隨機(jī)效用模型相對風(fēng)險(xiǎn)RR=2.07，95%CI：1.58～2.72，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)；女性發(fā)生風(fēng)險(xiǎn)I2=0，采用隨機(jī)效用模型RR=2.30，95%CI：1.62～3.25，差異有統(tǒng)計(jì)學(xué)意義(P=0.00)；未分男女研究發(fā)生風(fēng)險(xiǎn)I2=63.1%，采用固定效用模型RR=2.20，95%CI：1.94～2.51，差異有統(tǒng)計(jì)學(xué)意義(P=0.006)(見圖6)。

圖1 BMI 25～30 kg/m2時(shí)賁門、食管腺癌相對風(fēng)險(xiǎn)部位分層分析
Fig 1 Site stratification analysis of the relative risk of esophageal and gastric cardia adenocarcinoma when BMI was 25～30 kg/m2

圖2 BMI 25～30 kg/m2時(shí)賁門、食管腺癌相對風(fēng)險(xiǎn)洲際分層分析
Fig 2 Intercontinental stratification analysis of the relative risk of esophageal and gastric cardia adenocarcinoma when BMI was 25～30 kg/m2

圖3 BMI 25～30 kg/m2時(shí)賁門、食管腺癌相對風(fēng)險(xiǎn)性別分層分析
Fig 3 Gender stratification analysis of the relative risk of esophageal and gastric cardia adenocarcinoma when BMI was 25～30 kg/m2

圖4 BMI≥30 kg/m2時(shí)賁門、食管腺癌相對風(fēng)險(xiǎn)部位分層分析
Fig 4 Site stratification analysis of the relative risk of esophageal and gastric cardia adenocarcinoma when BMI was more than 30 kg/m2

圖5 BMI≥30 kg/m2時(shí)賁門、食管腺癌相對風(fēng)險(xiǎn)洲際分層分析
Fig 5 Intercontinental stratification analysis of the relative risk of esophageal and gastric cardia adenocarcinoma when BMI was more than 30 kg/m2

圖6 BMI≥30 kg/m2時(shí)賁門、食管腺癌相對風(fēng)險(xiǎn)性別分層分析
Fig 6 Gender stratification analysis of the relative risk of esophageal and gastric cardia adenocarcinoma when BMI was more than 30 kg/m2

2.3 偏倚識別 漏斗圖顯示基本對稱，Begg’s檢驗(yàn)P=0.058，表示發(fā)表偏倚小，可信度高，分析結(jié)果可靠，客觀性強(qiáng)，統(tǒng)計(jì)學(xué)意義大(見圖7)。

圖7 納入文獻(xiàn)的漏斗圖Fig 7 Funnel plot of included stuides

3 討論

食管、賁門腺癌有多種病因，煙草使用、Barrett’s食管是公認(rèn)的危險(xiǎn)因素，其他因素如飲食、膽囊切除、下食管括約肌松弛、哮喘藥物、阿司匹林、非甾體類抗炎藥物的使用和家族史也可能引起食管、賁門腺癌，另外，肥胖也同食管、賁門腺癌發(fā)病關(guān)系密切。我們通過對文獻(xiàn)的綜合分析，研究BMI同賁門、食管腺癌發(fā)病風(fēng)險(xiǎn)發(fā)現(xiàn)，BMI 25～30 kg/m2時(shí)，賁門、食管交界癌發(fā)生風(fēng)險(xiǎn)升高46%～68%，平均升高57%，BMI≥30 kg/m2時(shí)，食管、賁門腺癌風(fēng)險(xiǎn)增加兩倍。

我們分析體質(zhì)量增加導(dǎo)致食管、賁門腺癌風(fēng)險(xiǎn)上升主要有以下幾方面原因：超重和肥胖能促進(jìn)食管上皮細(xì)胞增生和分化形成Barrent’s食管，繼續(xù)發(fā)展有可能成為食管癌[26]。另外，肥胖本身腹部壓力大，對賁門、食管有擠壓作用，胃酸被擠壓后容易突破食管下括約肌壓力進(jìn)入食管，刺激下段食管黏膜引起食管上皮分化[27]。肥胖患者堆積的脂肪組織過多，過多的脂肪組織增加內(nèi)源性激素的濃度，包括性激素、胰島素和胰島素生長因子1，這些激素能加速細(xì)胞增殖，延緩細(xì)胞凋亡，從而導(dǎo)致細(xì)胞增生凋亡障礙造成組織過度增生[28]。肥胖是世界上一個(gè)公認(rèn)的促炎因子，它通過增加炎癥介質(zhì)的釋放，促進(jìn)腫瘤細(xì)胞的快速生長[29]。肥胖者因腹內(nèi)壓和胸腔內(nèi)壓增加導(dǎo)致食管內(nèi)食物不易通過食管進(jìn)入胃部，食物同食管上皮接觸時(shí)間自然延長，食品中可能致癌的成分可能促進(jìn)食管、賁門部黏膜的增殖及異常分化[30]。

綜上所述，隨著體質(zhì)量增加，食管、賁門腺癌發(fā)病風(fēng)險(xiǎn)大幅度增加，預(yù)防肥胖、控制體質(zhì)量、健康飲食顯得尤為重要。本研究尚有以下不足：(1)納入的文獻(xiàn)數(shù)量少；(2)總病例數(shù)不大,缺乏臨床多中心研究；(3)各個(gè)研究之間存在偏倚。期待更多的研究及更大的樣本量、更廣泛的資料佐證本研究的結(jié)論。

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(責(zé)任編輯：陳香宇)

Meta-analysis of body mass index and esophageal and gastric cardia adenocarcinoma

WANG Junhua1,JIANG Qian2,SUN Jingfeng2,ZHOU Guozhi2

1. Department of Gastroenterology,the Fourth Hospital of Xi’an,Xi’an 710004; 2. Center of the Tumor,Affiliated Yifu Hospital of Nanjing Medical University,China

Objective To evaluate the relationship of body mass index (BMI) with esophageal and gastric cardia adenocarcinoma.Methods Related articls (1990-2015) were searched in Medline,PubMed,Embase,WOS. The qualities of the included studies were evaluated by the Jadad scale.RRand 95%CIwere evaluated by Meta-analysis.Results A total of 22 studies were adopted,and the number of cases was 1 307 549,experimental group had 7 718 cases,control group had 1 299 831 cases. The Meta-analysis showed that: when BMI was 25-30 kg/m2,esophageal or gastric cardia adenocarcinomaRRwas 1.56 (95%CI: 1.46-1.68,P=0.000); esophageal adenocarcinomaRRwas 1.82 (95%CI: 1.57-2.11，P=0.00); gastric cardia adenocarcinomaRRwas 3.47 (95%CI: 1.93-6.25,P=0.000); esophageal and gastric cardia adenocarcinomaRRwas 1.47 (95%CI: 1.35-1.59，P=0.000). BMI was more than 30 kg/m2,esophageal or gastric cardia adenocarcinomaRRwas 2.19 (95%CI: 1.96-2.45,P=0.000); esophageal and gastric cardia adenocarcinomaRRwas 2.11 (95%CI: 1.86-2.39,P=0.000); gastric cardia adenocarcinomaRRwas 2.58 (95%CI: 1.24-5.35,P=0.011); esophageal adenocarcinomaRRwas 2.49 (95%CI: 1.95-3.17,P=0.000). Conclusion The morbidity of esophageal and gastric cardia adenocarcinoma is high when BMI is more than 25 kg/m2.

Body mass index; Esophageal adenocarcinoma; Gastric cardia adenocarcinoma; Meta-analysis; Obesity; Overweight

10.3969/j.issn.1006-5709.2016.04.022

王君化，主治醫(yī)師，研究方向：消化內(nèi)科疾病基礎(chǔ)及臨床。E-mail：7868137586@qq.com

周國志，碩士，主任醫(yī)師，研究方向：腫瘤疾病的基礎(chǔ)及臨床。E-mail：124278956@qq.com

R735

A

1006-5709(2016)04-0439-05

2015-08-03