董偉華　唐　文

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代謝綜合征與結(jié)直腸腺瘤的關(guān)系

董偉華唐文

結(jié)直腸癌(CRC)是世界上常見的惡性腫瘤之一。近年來(lái)，大量流行病學(xué)研究證實(shí)代謝綜合征(MS)及其組分與CRC的發(fā)病有關(guān)，而大部分CRC來(lái)源于結(jié)直腸腺瘤(CRA)。近年來(lái)國(guó)外大量研究表明MS及其組分是CRA發(fā)病的危險(xiǎn)因素，目前國(guó)內(nèi)這方面的研究還較少。此文就MS及其組分與CRA發(fā)病的關(guān)系作一綜述。

代謝綜合征；肥胖； 血脂紊亂；結(jié)直腸腺瘤；結(jié)直腸癌

結(jié)直腸腺瘤(CRA)是起源于結(jié)直腸黏膜上皮的、突出于腸道黏膜的贅生物，屬于結(jié)直腸癌(CRC)的癌前病變。代謝綜合征(MS)是一組以多種代謝異常聚集的病理狀態(tài)和臨床癥候群，主要包括中心性肥胖、高血糖、血脂異常等組分。近年來(lái)大量研究證實(shí)MS是CRC的危險(xiǎn)因素[1-5]。研究表明，大部分CRC是通過CRA發(fā)展而來(lái)的，因此，明確CRA發(fā)生的危險(xiǎn)因素，對(duì)于預(yù)防CRC有重要的意義?；谝陨侠碚撝С?，近年來(lái)眾多學(xué)者致力于MS及其組分與CRA之間關(guān)系的研究。眾多國(guó)外研究表明，MS及其組分亦是CRA的危險(xiǎn)因素[2,6-13]。

1　肥胖與CRA的相關(guān)性

肥胖是MS重要的組成部分，近年來(lái)有很多關(guān)于肥胖與CRA發(fā)病相關(guān)性的研究。在這些臨床研究中，應(yīng)用較多的定義肥胖的指標(biāo)有體質(zhì)量指數(shù)(BMI)、腰圍、腰圍-臀圍比等。其中BMI的應(yīng)用較多，可以簡(jiǎn)單代表肥胖程度，而腰圍的優(yōu)點(diǎn)是能反映腹型肥胖的情況。Wang等[11]和Lee等[14]提出相對(duì)高水平的BMI與CRA的發(fā)生有關(guān)。隨后Stein等[15]研究證實(shí)肥胖是CRA的危險(xiǎn)因素，且無(wú)種族差異。近年來(lái)Kim等[9]的研究得出了相似結(jié)論，認(rèn)為BMI>25 kg/m2以及男性腰圍>90 cm、女性腰圍>80 cm是CRA的高危因素，尤其是進(jìn)展性腺瘤和多發(fā)腺瘤的高危因素。Yun等[16]的研究提出肥胖的個(gè)體，即使代謝正常，依然是患CRA的高危人群。但有學(xué)者提出BMI僅能反映整體脂肪分布情況，腰圍則在一定程度上反映內(nèi)臟脂肪沉積的情況，他們通過臨床研究證實(shí)，較粗的腰圍確實(shí)是CRA的高危因素[7,10,17-18]。另外，有學(xué)者提出肥胖既然是CRA的高危因素，肥胖人群在腺瘤摘除后理論上也更容易復(fù)發(fā)。隨后有大量臨床研究證實(shí)了這一觀點(diǎn)[19-23]，更加確定了肥胖尤其是腹型肥胖是腺瘤的高危因素。

2　血脂紊亂與CRA的相關(guān)性

近年來(lái)國(guó)內(nèi)外眾多研究發(fā)現(xiàn)，血脂紊亂與CRA的發(fā)生有關(guān)。其中研究較多的是有關(guān)三酰甘油(TG)、總膽固醇(TC)、低密度脂蛋白(LDL-C)、高密度脂蛋白膽固醇(HDL-C)與CRA之間的關(guān)系。雖然有關(guān)TG與CRA之間關(guān)系的研究采用的截點(diǎn)值不同，但大部分認(rèn)為相對(duì)高水平的TG是CRA的高危因素[7,9,24-28]。另有多項(xiàng)研究一致認(rèn)為相對(duì)高水平的TC能導(dǎo)致患CRA的風(fēng)險(xiǎn)增加[8,28-29]。此外，LDL-C與CRA之間關(guān)系的研究報(bào)道較少，Bayerdorffer等[30]和Jung等[31]認(rèn)為相對(duì)高水平的LDL-C是CRA的高危因素。HDL-C被認(rèn)為是“有益膽固醇”，但目前關(guān)于HDL-C與CRA之間關(guān)系的研究所得出的結(jié)論并不一致。有研究認(rèn)為HDL-C的水平與CRA的風(fēng)險(xiǎn)呈負(fù)相關(guān)，但也有報(bào)道認(rèn)為兩者無(wú)關(guān)，還有報(bào)道認(rèn)為是呈正相關(guān)[7,30,32-33]。這可能與研究的設(shè)計(jì)、樣本量大小等有關(guān)，需要進(jìn)一步、更深入的研究進(jìn)行證實(shí)。

3　糖尿病與CRA的相關(guān)性

糖尿病是MS的重要組成部分。大量研究認(rèn)為糖尿病是CRA的危險(xiǎn)因素[31,34-35]。其中大部分關(guān)于糖尿病與CRA之間關(guān)系的研究，采取的是空腹血糖(FBG)、糖化血紅蛋白(HbAlc)、血胰島素水平等客觀的實(shí)驗(yàn)室指標(biāo)。研究發(fā)現(xiàn)，相對(duì)高水平的FBG[13,31,36]、HbAlc[13,37-38]、胰島素抵抗[13,18,39]是CRA的高危因素。早在2004年，Keku等[36]就發(fā)現(xiàn)高水平的血胰島素、血糖是CRA的高危因素。隨后，Ortiz等[18]提出胰島素抵抗是CRA發(fā)生的高危因素。Hsu等[37]和Kim等[38]均認(rèn)為HbAlc是CRA的高危因素。近期，Rampal等[13]報(bào)道高血糖、HbAlc、C-肽均是CRA發(fā)生的高危因素。此外，最近韓國(guó)的另一項(xiàng)大樣本研究證實(shí)血糖和CRA的發(fā)生明顯相關(guān)[31]。

4　MS引起的CRA與解剖部位和性別的關(guān)系

MS及其組分與CRA的發(fā)病是相關(guān)的，近年大量臨床研究支持這一觀點(diǎn)，其中一部分研究進(jìn)行亞組分析發(fā)現(xiàn)男性患者的這一相關(guān)性更強(qiáng)[6-7,12,14]。關(guān)于相關(guān)性在性別方面的差異，具體機(jī)制尚不完全明確，有研究認(rèn)為這與女性的孕酮、雌二醇的保護(hù)作用有關(guān)[7,40]。有研究根據(jù)解剖部位的不同進(jìn)行亞組分析發(fā)現(xiàn)，MS及其組分尤其與右側(cè)結(jié)腸的腺瘤發(fā)生有關(guān)[7,9-10,12,41]。此外，有學(xué)者發(fā)現(xiàn)具有MS癥狀越多的群體，患CRA的風(fēng)險(xiǎn)就越大[7,9]。

5　MS導(dǎo)致CRA風(fēng)險(xiǎn)增加的機(jī)制

MS發(fā)病的主要機(jī)制是內(nèi)臟脂肪沉積，其被認(rèn)為與胰島素抵抗、高胰島素血癥、高血清水平胰島素樣生長(zhǎng)因子-Ⅰ(IGF-Ⅰ)有關(guān)。目前研究認(rèn)為MS通過以下機(jī)制導(dǎo)致CRA發(fā)?。?1)隨著人體脂肪體積增加，為適應(yīng)機(jī)體代謝需要，胰島素分泌增加，導(dǎo)致高胰島素血癥、胰島素抵抗，胰島素本身有很強(qiáng)的促進(jìn)有絲分裂的作用，能直接促進(jìn)體外的細(xì)胞增殖。此外，胰島素可直接活化IGF-Ⅰ。研究證實(shí)胰島素、IGF-Ⅰ通過促進(jìn)細(xì)胞增殖、抗細(xì)胞凋亡途徑促進(jìn)癌變過程[10,42]。有研究認(rèn)為IGF-Ⅰ與受體結(jié)合后，活化酪氨酸激酶受體，通過PI3K/Akt和MAKP/Ras這兩條信號(hào)通路參與細(xì)胞增殖及分化，發(fā)揮致癌作用[43]。(2)近年來(lái)研究發(fā)現(xiàn)，內(nèi)臟脂肪組織具有內(nèi)分泌功能，能分泌一系列炎性因子、蛋白質(zhì)類激素，包括C-反應(yīng)蛋白(CRP)、腫瘤壞死因子、白細(xì)胞介素-6(IL-6)、瘦素等，為癌前病變創(chuàng)造條件[44-45]。瘦素可通過PI3K/Akt/mTOR信號(hào)轉(zhuǎn)導(dǎo)通路促進(jìn)結(jié)腸癌細(xì)胞增殖，并抑制其凋亡[46]。(3)高血糖和血脂紊亂可促進(jìn)活性氧類形成，活性氧類通過調(diào)節(jié)基因表達(dá)、突變、重排的方式損傷DNA，促進(jìn)腫瘤形成[47]。(4)血糖和TG可促進(jìn)膽汁酸形成，且能直接供給腫瘤細(xì)胞能量，而膽汁酸可能促進(jìn)結(jié)直腸上皮增生，促進(jìn)腺瘤形成[48]。

綜上所述，目前研究已基本達(dá)成一致觀點(diǎn)，認(rèn)為MS及其組分是CRA的高危因素。但也有少部分報(bào)道MS與CRA之間無(wú)關(guān)[49]。結(jié)論不一致的原因可能與實(shí)驗(yàn)設(shè)計(jì)、樣本量大小等差異有關(guān)。為了得到更可靠的結(jié)論，還需進(jìn)行大樣本的深入研究。

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(本文編輯：周駿)

215000蘇州大學(xué)附屬第二醫(yī)院消化內(nèi)科

唐文，Email: louisetangwen@163.com

10.3969/j.issn.1673-534X.2016.02.011

2015-08-15)