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·短篇論著·

血清同型半胱氨酸水平在胃癌和癌前疾病中作用的臨床研究*

產(chǎn)松苗1孫為豪2朱小兵1歐希龍3#

上海梅山醫(yī)院消化科1(210039)南京醫(yī)科大學(xué)第一附屬醫(yī)院老年醫(yī)學(xué)科2東南大學(xué)附屬中大醫(yī)院消化科3

背景：近年研究發(fā)現(xiàn)同型半胱氨酸(Hcy)水平增高能增加胃癌的發(fā)病風(fēng)險(xiǎn)，但其在胃癌癌前疾病中的作用未見(jiàn)相關(guān)研究。目的：探討血清Hcy、葉酸和維生素B12在胃癌及其癌前疾病中的作用。方法：選取經(jīng)胃鏡和病理檢查確診的86名正常對(duì)照者、46例萎縮性胃炎、46例胃潰瘍、31例胃息肉、52例胃癌患者，檢測(cè)血清Hcy、葉酸和維生素B12水平，分析其與胃癌臨床病理特征的關(guān)系。結(jié)果：與對(duì)照組相比，萎縮性胃炎組和胃癌組血清Hcy水平顯著增高(P<0.05)；胃潰瘍組、胃息肉組和胃癌組葉酸和維生素B12水平顯著降低(P<0.05)。胃癌組血清Hcy水平與腫瘤浸潤(rùn)深度、TNM分期和淋巴結(jié)轉(zhuǎn)移呈正相關(guān)(P<0.05)，而葉酸和維生素B12與胃癌臨床病理特征無(wú)明顯相關(guān)性。結(jié)論：萎縮性胃炎、胃癌的Hcy水平增高，胃潰瘍、胃息肉和胃癌的葉酸和維生素B12水平降低。高Hcy水平參與了胃癌的浸潤(rùn)和轉(zhuǎn)移，對(duì)高Hcy、低葉酸和維生素B12水平者進(jìn)行干預(yù)可能是防治胃癌及其癌前疾病的一種有效策略。

關(guān)鍵詞同型半胱氨酸；葉酸；維生素B12；胃腫瘤；癌前疾病

Clinical Study on Role of Serum Homocysteine Level in Gastric Cancer and Precancerous Diseases

CHANSongmiao1,SUNWeihao2,ZHUXiaobing1,OUXilong3.

1DepartmentofGastroenterology,ShanghaiMeishanHospital,Nanjing(210039);2DepartmentofGeriatrics,theFirstAffiliatedHospitalwithNanjingMedicalUniversity,Nanjing;3DepartmentofGastroenterology,theAffiliatedZhongdaHospitalofClinicalMedicalCollegeofSoutheastUniversity,Nanjing

Correspondence to: OU Xilong, Email: ouxilong@126.com

Background: Recent studies have showed that high homocysteine (Hcy) level can increase the risk of gastric cancer, but no related studies have been reported on role of Hcy in gastric precancerous diseases. Aims: To investigate the role of serum Hcy, folic acid and vitamin B12in patients with gastric cancer and precancerous diseases. Methods: Eighty-six normal controls, 46 atrophic gastritis, 46 gastric ulcer, 31 gastric polyp, 52 gastric cancer patients diagnosed by gastroscopy and pathology were enrolled. Serum levels of Hcy, folic acid and vitamin B12were determined, and their correlations with clinicopathological features in gastric cancer were analyzed. Results: Compared with normal controls, serum Hcy level in patients with atrophic gastritis and gastric cancer was significantly increased (P<0.05); serum folic acid and vitamin B12levels in patients with gastric ulcer, gastric polyp and gastric cancer were significantly decreased (P<0.05). Serum Hcy level in patients with gastric cancer was positively correlated with depth of tumor infiltration, TNM staging and lymph node metastasis (P<0.05), however, serum folic acid and vitamin B12levels had no correlation with clinicopathological features. Conclusions: Hcy level is increased in chronic atrophic gastritis, gastric cancer; levels of folic acid and vitamin B12are decreased in gastric ulcer, gastric polyp and gastric cancer. High level of Hcy is involved in infiltration and metastasis of gastric cancer. Intervention in patients with high level of Hcy, low levels of folic acid and vitamin B12might be an effective strategy for the prevention and treatment of gastric cancer and precancerous diseases.

Key wordsHomocysteine;Folic Acid;Vitamin B 12;Stomach Neoplasms;Precancerous Diseases

同型半胱氨酸(Hcy)是蛋氨酸分解代謝的重要中間產(chǎn)物。由于Hcy具有細(xì)胞毒性、神經(jīng)毒性和基因毒性，可造成細(xì)胞增殖性改變，如鱗狀上皮增生、上皮異型增生等。近年Hcy在惡性腫瘤發(fā)病機(jī)制中的作用已引起關(guān)注[1-2]。有研究發(fā)現(xiàn)食管癌、肝癌、乳腺癌患者血清Hcy水平升高[3-4]，高Hcy水平能增加胃癌的發(fā)病風(fēng)險(xiǎn)[5]，但Hcy在胃癌前疾病中的表達(dá)情況目前缺乏相關(guān)研究。本研究通過(guò)檢測(cè)萎縮性胃炎、胃潰瘍、胃息肉和胃癌患者血清Hcy、葉酸和維生素B12水平，旨在探討Hcy在胃癌發(fā)病中的可能作用，為臨床補(bǔ)充葉酸和維生素B12防治胃癌和癌前疾病提供理論依據(jù)。

對(duì)象與方法

一、研究對(duì)象

選取2011年1月—2013年12月至上海梅山醫(yī)院行胃鏡檢查的門診和住院患者261例，診斷由組織病理學(xué)明確。其中男154例，女107例，年齡17~85歲，平均(56.48±12.30)歲。所有研究對(duì)象在入選前一周內(nèi)無(wú)特殊用藥史(包括質(zhì)子泵抑制劑、H2受體拮抗劑等)；近期均無(wú)腎功能衰竭、甲狀腺功能減退、嚴(yán)重貧血、嚴(yán)重硬皮病等可致Hcy水平升高的疾??；未服用過(guò)抗癲癇藥、利尿藥等可致Hcy水平升高的藥物。

二、研究方法

1. 分組：根據(jù)組織病理學(xué)檢查結(jié)果將受檢者分為5組：①對(duì)照組：胃黏膜正?；蚴据p度非萎縮性胃炎。共86例，其中男47例，女39例；年齡17~63歲，平均(53.72±15.08)歲；②萎縮性胃炎組：46例，其中男22例，女24例；年齡 32~85歲，平均(58.48±10.78)歲；③胃潰瘍組：46例，其中男38例，女8例；年齡18~79歲，平均(55.98±17.28)歲；④胃息肉組：31例，其中男9例，女22例；年齡30~77歲，平均(54.90±18.30)歲；⑤胃癌組：52例，其中男38例，女14例；年齡36~75歲，平均(59.78±13.67)歲；根據(jù)國(guó)際抗癌聯(lián)盟(UICC)美國(guó)抗癌聯(lián)合會(huì)(AJCC)的TNM分期標(biāo)準(zhǔn)[6]分為Ⅰ、Ⅱ、Ⅲ、Ⅳ期；根據(jù)癌腫浸潤(rùn)胃壁的深度分早期胃癌和進(jìn)展期胃癌；根據(jù)腫瘤病變部位分胃竇部癌、胃體部癌和賁門部癌；根據(jù)淋巴結(jié)轉(zhuǎn)移分為有轉(zhuǎn)移組和無(wú)轉(zhuǎn)移組；根據(jù)分化程度分為高分化、中分化和低分化組。

2.檢測(cè)方法：受檢者禁食8 h后采集血液標(biāo)本，2 000×g離心10 min，貯存于-70 ℃冰箱中待測(cè)。采用免疫比濁法測(cè)定血清Hcy水平(Beckman DXC800全自動(dòng)生化分析儀)，采用電化學(xué)發(fā)光法檢測(cè)血清葉酸、維生素B12水平(電化學(xué)發(fā)光羅氏E601)。

三、統(tǒng)計(jì)學(xué)分析

結(jié)果

一、血清Hcy、葉酸和維生素B12水平

與對(duì)照組相比，萎縮性胃炎組和胃癌組血清Hcy水平顯著增高(P<0.05)，胃潰瘍組和胃息肉組無(wú)明顯差異；胃潰瘍組、胃息肉組和胃癌組葉酸和維生素B12水平顯著降低(P<0.05)，而萎縮性胃炎組無(wú)明顯差異(表1)。

二、各指標(biāo)與胃癌臨床病理特征的關(guān)系

胃癌組血清Hcy水平與腫瘤浸潤(rùn)深度[早期和進(jìn)展期分別為(13.39±3.49)μmol/L和(22.92±10.97)μmol/L，P=0.001]、TNM分期[Ⅰ+Ⅱ期和Ⅲ+Ⅳ期分別為(13.45±3.39)μmol/L和(23.17±11.03)μmol/L，P=0.001]和淋巴結(jié)轉(zhuǎn)移[有轉(zhuǎn)移和無(wú)轉(zhuǎn)移分別為(22.67±10.73)μmol/L和(12.73±3.20)μmol/L，P=0.001]呈正相關(guān)(P<0.05)，而葉酸和維生素B12與胃癌臨床病理特征(性別、年齡、浸潤(rùn)深度、腫瘤部位、TNM分期、病理類型、分化程度、淋巴結(jié)轉(zhuǎn)移)均無(wú)明顯相關(guān)性(P>0.05)。

±s)

*與對(duì)照組比較，P<0.05

討論

體內(nèi)Hcy在蛋氨酸合成酶作用下，以葉酸和維生素B12為輔助因子，可發(fā)生甲基化，再合成蛋氨酸。一旦機(jī)體內(nèi)缺乏葉酸和維生素B12，可導(dǎo)致蛋氨酸循環(huán)受阻，造成Hcy水平升高。本研究發(fā)現(xiàn)，與對(duì)照組相比，萎縮性胃炎組患者血清Hcy水平顯著增高。胃體萎縮性胃炎與自身免疫有關(guān)，患者體內(nèi)可檢出抗壁細(xì)胞抗體和內(nèi)因子抗體，多灶性萎縮性胃炎亦有免疫因素參與，但胃竇萎縮性胃炎與免疫因素的相關(guān)性不明顯。胃體和多灶性萎縮性胃炎患者由于自身免疫因素導(dǎo)致胃酸和內(nèi)因子缺乏，限制了維生素B12的吸收，從而導(dǎo)致蛋氨酸循環(huán)受阻，造成Hcy水平升高。有研究[7-8]采用多因素Logistic回歸分析表明，萎縮性胃炎與高同型半胱氨酸血癥顯著相關(guān)，并加速了萎縮性胃炎向胃癌的病變進(jìn)展。有研究[9]發(fā)現(xiàn)，慢性萎縮性胃炎和MTHFR 677TT基因型是Hcy水平升高的顯著影響因素。

本研究發(fā)現(xiàn)，胃癌組患者血清Hcy水平較對(duì)照組顯著增高；與王莉娜等[5]的研究結(jié)果相似。胃癌患者Hcy水平升高的原因可能為：①消化和吸收功能不良，從而導(dǎo)致葉酸攝入不足，絕對(duì)含量下降，影響蛋氨酸循環(huán)，造成Hcy在血液中堆積；②由于腫瘤細(xì)胞分裂增殖加速，需更多的葉酸和維生素B12作為輔酶參與核酸形成，從而造成體內(nèi)葉酸和維生素B12含量相對(duì)不足，客觀上減慢了蛋氨酸循環(huán)速度。本研究還發(fā)現(xiàn)Hcy與胃癌浸潤(rùn)深度、TNM分期和淋巴結(jié)轉(zhuǎn)移呈正相關(guān)。而胃潰瘍組、胃息肉組和胃癌組葉酸和維生素B12水平顯著降低。血清Hcy水平增高、葉酸含量下降的致癌機(jī)制除造成細(xì)胞增殖性改變、影響調(diào)節(jié)基因和腫瘤抑制基因的表達(dá)外，葉酸缺乏還可導(dǎo)致CD8+T細(xì)胞增殖明顯降低，可能導(dǎo)致機(jī)體清除腫瘤細(xì)胞的能力下降[10]。此外，葉酸代謝酶如還原葉酸載體(RFC)基因多態(tài)性、MTHFR的遺傳變異可致Hcy高表達(dá)，使胃癌的發(fā)生風(fēng)險(xiǎn)增加[11-12]。Yoo等[13]發(fā)現(xiàn)葉酸代謝基因MTRR rs1801394位點(diǎn)單核苷酸多態(tài)性亦與胃癌風(fēng)險(xiǎn)相關(guān)。本研究發(fā)現(xiàn)，胃癌組Hcy水平高于胃潰瘍組，但差異無(wú)統(tǒng)計(jì)學(xué)意義，與Sakuta等[14]的研究結(jié)果相似。目前尚未發(fā)現(xiàn)Hcy、葉酸和維生素B12在胃息肉中的研究。

胃腸道惡性腫瘤切除術(shù)后患者的血Hcy水平升高，葉酸和維生素B12水平降低，給予葉酸和維生素B12治療后Hcy水平明顯降低[15]，且補(bǔ)充葉酸和維生素B12水平能明顯延長(zhǎng)MTHFR 677TT陽(yáng)性患者的術(shù)后生存期[16]。口服維生素B12是全胃切除的胃癌患者的一種替代治療方法[17]。本研究發(fā)現(xiàn)萎縮性胃炎、胃癌的Hcy水平增高，胃潰瘍、胃息肉和胃癌的葉酸和維生素B12水平降低。高Hcy水平參與了胃癌的浸潤(rùn)和轉(zhuǎn)移，對(duì)高Hcy、低葉酸和維生素B12水平的患者進(jìn)行干預(yù)可能是防治胃癌及其癌前疾病的一種有效策略。但研究結(jié)論尚需行進(jìn)一步探索。

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(2015-04-29修改；2015-05-14修回)

*基金項(xiàng)目：南京市衛(wèi)生局課題項(xiàng)目(編號(hào)：YKK11209)；南京市衛(wèi)生青年人才基金(編號(hào)：QRX11132)

DOI:10.3969/j.issn.1008-7125.2016.01.010

#本文通信作者，Email: ouxilong@126.com