王冰雪 李文靜 肖劍礴 徐峰
(1. 鄭州大學(xué)第一附屬醫(yī)院 消化內(nèi)科 河南 鄭州 450052; 2. 鄭州大學(xué)第四附屬醫(yī)院 牙周病科 河南 鄭州 450044)
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維生素D與炎癥性腸病研究進(jìn)展
王冰雪1李文靜1肖劍礴2徐峰1
(1. 鄭州大學(xué)第一附屬醫(yī)院 消化內(nèi)科河南 鄭州450052; 2. 鄭州大學(xué)第四附屬醫(yī)院 牙周病科河南 鄭州450044)
炎癥性腸??;潰瘍性結(jié)腸炎;克羅恩??;維生素D
炎癥性腸病(inflammatory bowel disease,IBD)是腸道慢性非特異性炎癥性疾病,主要包括潰瘍性結(jié)腸炎(ulcerative colitis,UC)和克羅恩病(Crohn’s disease,CD)。目前認(rèn)為其病因與免疫因素、遺傳、環(huán)境及飲食因素有關(guān)。IBD的發(fā)病率存在地域及種族差異,歐洲、北美洲、亞洲的UC最高發(fā)病率分別為24.3/10萬、19.2/10萬、6.3/10萬,CD最高發(fā)病率分別為12.7/10萬、20.2/10萬、5.0/10萬[1]。近20 a來IBD在我國(guó)的發(fā)病率明顯增加,UC的患病率約為11.6/10萬[1],CD患病率為1.4/10萬[2]。IBD的治療方法主要有5-氨基水楊酸制劑、激素、免疫抑制劑、生物制劑、手術(shù)治療等。近年研究發(fā)現(xiàn)維生素D (vitamin D,VitD)對(duì)抗感染和調(diào)節(jié)免疫具有廣泛作用,補(bǔ)充VitD治療免疫相關(guān)性疾病已經(jīng)成為目前研究的熱點(diǎn)。本文就VitD與IBD發(fā)病的關(guān)系及治療意義作一綜述。
1.1VitD的來源及代謝VitD在身體內(nèi)的儲(chǔ)存形式包括VitD2和VitD3,經(jīng)皮膚的光照合成的VitD3是人體VitD最主要的來源[3],占90%左右。一小部分的VitD來自飲食,即Vit D2,如蛋黃、牛肉肝、魚肝油等。所以VitD的水平主要取決于日照時(shí)間及額外補(bǔ)充量。由于25-(OH)D3在血中的穩(wěn)定性,通常用其來反應(yīng)患者的Vit D水平。維生素的活化是其發(fā)揮作用的基礎(chǔ),25-(OH)D3在腎臟中被25-羥維生素D-lα-羥化酶轉(zhuǎn)化為1,25-(OH)2D3才具有生物學(xué)作用,1,25-(OH)2D3通過與靶組織維生素D受體(vitamin D receptor,VDR)相結(jié)合發(fā)揮作用?,F(xiàn)己證實(shí)VDR有廣泛的組織學(xué)基礎(chǔ),不僅存在于小腸、腎臟、骨豁、甲狀旁腺中,還存在于胰腺、垂體、肌肉、脾臟、骨豁、大腸及皮膚等組織中,人的單核細(xì)胞、激活的T細(xì)胞、B細(xì)胞和多種腫瘤細(xì)胞也含有VDR。
1.2VitD與免疫VitD的免疫相關(guān)性直到80年代才被發(fā)現(xiàn),研究表明,VitD可能與很多自身免疫性疾病的發(fā)生、發(fā)展或嚴(yán)重性有關(guān),如風(fēng)濕性關(guān)節(jié)炎、多發(fā)性硬化癥、哮喘、系統(tǒng)性紅斑狼瘡和炎癥性腸病等[4-9]。VitD在免疫反應(yīng)中的作用主要有:①參與保持上皮細(xì)胞的完整性;②參與固有免疫,VitD誘導(dǎo)產(chǎn)生抗菌酶,通過被巨噬細(xì)胞吞噬殺滅入侵細(xì)菌;③維持免疫耐受,減少細(xì)胞因子的產(chǎn)生,例如腫瘤壞死因子[10-12]。T細(xì)胞介導(dǎo)的免疫應(yīng)答也受1,25-(OH)2D3的調(diào)節(jié),VitD缺乏影響T細(xì)胞介導(dǎo)的免疫反應(yīng),T細(xì)胞過度產(chǎn)生炎癥介質(zhì),如IL-17、TNF-α、IFN-γ等[13]。
1.3VitD對(duì)IBD的影響目前認(rèn)為IBD的發(fā)病是以遺傳易感性為基礎(chǔ),環(huán)境因素參與,黏膜免疫系統(tǒng)發(fā)生的異常免疫應(yīng)答,感染和免疫是IBD發(fā)病的關(guān)鍵[14]。有許多研究證實(shí)VitD缺乏與IBD發(fā)病密切相關(guān),生態(tài)研究表明,IBD的發(fā)病南北緯度有差別,由于紫外線照射減少,IBD在高緯度人群中發(fā)病率更高[15]。Ashwin N等[16]進(jìn)行了一項(xiàng)72 719名婦女(年齡40~73歲)參加的為期22 a的前瞻性隊(duì)列研究,結(jié)果表明高水平血漿25-(OH)D顯著降低CD風(fēng)險(xiǎn)事件,可能降低UC的發(fā)病風(fēng)險(xiǎn)。VitD和IBD的發(fā)病相關(guān)有遺傳學(xué)證據(jù),VDR基因位于12號(hào)染色體,研究表明VDR的單核苷酸多態(tài)性增加CD和UC易感性[17-20]。動(dòng)物實(shí)驗(yàn)支持VitD對(duì)IBD發(fā)病起關(guān)鍵作用。Cantorna等[21]對(duì)IL-10 KO小鼠研究發(fā)現(xiàn),當(dāng)VitD缺乏時(shí),小鼠很快自發(fā)出現(xiàn)便血、消耗等結(jié)腸炎癥狀,伴隨很高的死亡率。給予足量的VitD結(jié)腸炎癥狀緩解,顯示VitD與IBD的發(fā)病相關(guān)。Kong等[22]研究發(fā)現(xiàn),VDR KO小鼠結(jié)腸黏膜顯示嚴(yán)重的潰瘍,傷口愈合不良,提示VDR在黏膜屏障平衡中扮演關(guān)鍵角色,VitD缺乏可能危害黏膜屏障,導(dǎo)致黏膜損傷及發(fā)生IBD的風(fēng)險(xiǎn)加大。由此可見VitD在調(diào)節(jié)腸道菌群,抑制致病菌黏附,維持腸黏膜屏障完整,抑制致病菌入侵及易位,調(diào)整免疫反應(yīng)等結(jié)腸炎發(fā)病的各個(gè)環(huán)節(jié)均發(fā)揮重要作用。
VitD缺乏定義為血漿25-(OH)D水平小于20 ng/ml(50 nmol/L),在IBD患者中VitD缺乏較常見,較多學(xué)者進(jìn)行了相關(guān)研究,探索IBD患者補(bǔ)充VitD治療的方案及治療效果。Pappa等[23]進(jìn)行的臨床試驗(yàn)中,71名5~21歲的VitD缺乏的IBD患者被隨機(jī)分為3組,治療6周,結(jié)果表明每周50 000 IU VitD2和每天2 000 IU VitD3優(yōu)于每天2 000 IU VitD2,然而每周50 000 IU VitD2優(yōu)于每天2 000 IU VitD3。結(jié)果顯示在IBD患者中VitD替代治療顯示出劑量反應(yīng),大劑量的更有效。Jorgensen等[24]進(jìn)行了一項(xiàng)多中心、隨機(jī)、雙盲、安慰劑對(duì)照試驗(yàn),在1 a的研究期間,VitD治療組只有13%的人復(fù)發(fā),對(duì)照組有29%的人復(fù)發(fā) (P=0.06),結(jié)果表明補(bǔ)充VitD治療對(duì)緩解期CD患者有維持緩解的作用。對(duì)于有VitD缺乏風(fēng)險(xiǎn)的患者,內(nèi)分泌實(shí)踐指南協(xié)會(huì)推薦每天至少1 000單位的維持劑量[25],治療已有的VitD缺乏,為了使25-(OH)D大于 30 ng/ml,建議兒童使用VitD2或VitD3每天2 000 IU,治療6周,或每周50 000 IU,治療6周;成人維生素VitD2或VitD3每天6 000 IU,治療8周,或每周50 000 IU,治療8周。
越來越多的研究表明VitD缺乏對(duì)IBD的發(fā)病及病情嚴(yán)重程度有重要影響[26],盡管CD和UC都有共同的特點(diǎn),他們的發(fā)病機(jī)制卻有明顯的差別,大部分研究結(jié)果顯示25-(OH)D在CD的發(fā)病中作用更強(qiáng)[27]。補(bǔ)充VitD治療的臨床試驗(yàn)證實(shí)補(bǔ)充VitD治療有維持緩解和減少?gòu)?fù)發(fā)的作用,但是VitD治療的最佳劑量和方式及目標(biāo)血漿VitD水平仍未有統(tǒng)一結(jié)論,同時(shí)需要更多的前瞻性臨床試驗(yàn)研究來驗(yàn)證VitD對(duì)于高危個(gè)體的預(yù)防發(fā)病作用。盡管越來越多的研究證實(shí)VitD在IBD發(fā)病中有重要作用,但大多數(shù)臨床醫(yī)生并沒有測(cè)定血漿VitD水平的習(xí)慣及進(jìn)行補(bǔ)充VitD治療的意識(shí)。對(duì)于IBD患者應(yīng)常規(guī)監(jiān)測(cè)其VitD水平,對(duì)VitD缺乏的患者應(yīng)進(jìn)行補(bǔ)充VitD治療。
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R 574doi: 10.3969/j.issn.1004-437X.2016.09.024
2015-10-21)