同型半胱氨酸的代謝機制及其與臨床疾病的關系

　　摘    要：　同型半胱氨酸(homocysteine,Hcy)產生于必需氨基酸甲硫氨酸向半胱氨酸轉化的過程,并通過甲基化作用參與脫氧核糖核酸(DNA)代謝。近年來諸多研究表明,血Hcy水平與多種疾病有直接或間接關系,如動脈硬化、心血管疾病、高血壓、神經系統疾病、糖尿病、惡性腫瘤、妊娠期疾病、眼部疾病和骨質疏松等。人體血漿中Hcy的正常范圍是5～15μmol/L,>15μmol/L為高Hcy血癥(hyper homocysteine,HHcy)�；�因突變,葉酸、維生素B6、B12缺乏導致的營養不良及高甲硫氨酸的飲食模式均是Hcy升高的常見原因。研究證實,亞甲基四氫葉酸還原酶(methylenetetrahydrofolate reductase,MTHFR)C677T基因多態性與血漿Hcy水平升高的易感性相關。而中國人群中MTHFR 677TT基因型表達顯著高于其他種族。血清Hcy水平升高的致病機理可能為:促進炎癥和血管鈣化;脂質過氧化和抗氧化過程受損;刺激活性氧的產生,誘導氧化應激和血管功能障礙;內皮細胞毒性及功能障礙;抑制神經遞質釋放等。其他致病機制仍有待進一步研究。Hcy水平在預測疾病風險、控制疾病并發癥、影響疾病轉歸中有重要價值。中國人口總體HHcy患病率較高,且地域差異顯著。隨著年齡增大,患病率也隨之升高。Hcy水平監測有利于疾病的早發現、早診斷及嚴重并發癥的早預防。結合最新文獻報道,文章探討Hcy致病機制及其與疾病的關系,為Hcy的臨床應用提供參考。

　　關鍵詞 :     同型半胱氨酸;高同型半胱氨酸血癥;臨床價值;研究進展;

　　Abstract：　Homocysteine(Hcy) is produced in the process of essential amino acid methionine to cysteine conversion, and participates in DNA metabolism through methylation. In recent years, many studies have shown that serum Hcy levels were directly or indirectly related to various diseases, such as arteriosclerosis, cardiovascular disease, hypertension, neurological disease, diabetes, cancer, pregnancy disease, eye disease and osteoporosis. The normal range of Hcy in human plasma is 5-15 μmol/L, and >15 μmol/L is hyper homocysteine(HHcy). Gene mutations, malnutrition caused by folic acid, vitamin B6, and B12 deficiency, and a high-methionine diet are common causes of elevated Hcy. Studies have confirmed that the methylenetetrahydrofolate reductase(MTHFR) C677 T gene polymorphism is associated with the susceptibility to elevated plasma Hcy levels, and the expression of the MTHFR 677 TT genotype in the Chinese population is significantly higher than that of other races. The pathogenic mechanism of increased serum Hcy levels may be: promotion of inflammation and vascular calcification, impaired lipid peroxidation and antioxidant processes, stimulation of the production of reactive oxygen species, induction of oxidative stress and vascular dysfunction, endothelial cell toxicity and dysfunction, inhibit the release of neurotransmitters, and so on. Other pathogenic mechanisms still need to be further studied. The level of Hcy is important for the risk prediction of the disease, the controlling of the disease complications and the prognosis of the disease. The overall prevalence of HHcy in Chinese population is high, and the regional differences are significant. With the increase of age, the prevalence also increases. Monitoring of Hcy is conducive to early detection and diagnosis of diseases and prevention of serious complications. To provide reference for the clinical application of Hcy, this study comprehensively explores the relationship between Hcy and disease and its pathogenic mechanism on the basis of the latest literatures.

　　Keyword：　Homocysteine; Hyperhomocysteinemia; Clinical value; Research progress;

　　同型半胱氨酸(homocysteine,Hcy)是必需氨基酸甲硫氨酸向半胱氨酸轉化過程中產生的含硫氨基酸。Hcy通過甲基化作用參與脫氧核糖核酸(DNA)代謝。Hcy與多種疾病的發生和發展有直接或間接關系。根據最新的文獻報道,現對相關內容展開綜述。

　　1 、同型半胱氨酸的代謝機制與預測價值

　　1.1、 同型半胱氨酸的代謝機制

　　Hcy是甲硫氨酸和半胱氨酸代謝過程的中間產物。甲硫氨酸在甲硫氨酸合酶還原酶作用下生成S-腺苷甲硫氨酸,經甲基轉移酶作用生成S-腺苷同型半胱氨酸,再水解為Hcy和腺苷。Hcy在體內的代謝途徑有:再甲基化途徑、轉硫途徑、直接釋放到細胞外基質。任一代謝途徑異常均會使血漿Hcy濃度升高。人體血漿中Hcy的正常范圍是5～15 μmol/L,>15 μmol/L為高同型半胱氨酸血癥(hyper homocysteine,HHcy)[1]。中國人口總體HHcy患病率達39.7%[2]。隨著年齡增大,患病率升高,在>60歲的老年男性中HHcy患病率達46.23%[3]。

　　1.2 、同型半胱氨酸對疾病的預測價值

　　在顱內動脈粥樣硬化患者中,HHcy聯合斑塊增強可提高缺血性卒中的鑒別診斷[4]。Hcy結合三葉因子3和膽堿酯酶活性指標可作為判斷帕金森病和血管性帕金森病患者認知功能障礙的早期病理生理指標[5]。癌胚抗原結合胸水中的Hcy可提高診斷惡性胸腔積液的能力[6]。Hcy可作為疾病診斷與預后的輔助生物學指標。

　　2、 同型半胱氨酸與臨床常見疾病的關系

　　2.1、 同型半胱氨酸與心血管疾病

　　Hcy升高在心血管疾病(cardiovascular disease, CVD)人群中普遍存在。中國東北農村的橫斷面研究報道,45.08%的高血壓患者合并HHcy[7]。藏族居民中,平均每增加1個lnHcy(Hcy水平的對數轉換),收縮壓增加3.78 mm Hg(1 mm Hg=0.133 kPa),舒張壓增加3.02 mm Hg[8]。高血壓伴Hcy≥10 μmol/L定義為H型高血壓[9,10]。血漿Hcy低水平者血壓變異性小,可預防高血壓相關心血管事件[11]。高血壓患者服用降壓藥的同時補充葉酸,可顯著降低血壓水平(收縮壓降低7.85 mm Hg;舒張壓降低6.77 mm Hg),同時使CVD事件風險降低12.9%[12],中風風險降低15.0%[13]。補充葉酸降低血清Hcy水平在高血壓、CVD的一級和二級預防是有效的[14]。

　　2.2 、同型半胱氨酸與惡性腫瘤

　　研究報道Hcy主要與消化系統(結直腸部、胃部)、呼吸系統(肺部)、生殖系統(卵巢、前列腺)的惡性腫瘤及相關癌前病變有關[15]。晚期惡性腫瘤患者血漿Hcy急劇升高,可能因腫瘤細胞增長過程爭奪了葉酸,導致Hcy代謝障礙。Meta分析[16]發現Hcy每升高5 μmol/L,消化道腫瘤發生幾率增加7%。DNA低甲基化是癌前病變和惡性腫瘤發生的重要原因[15],而同型半胱氨酸-蛋氨酸循環是維持細胞內甲基化平衡的代謝調節系統。但也有研究未觀察到Hcy與惡性腫瘤(乳腺癌)的相關性[17]。Hcy水平異常對惡性腫瘤的影響可能受到其他因素(如治療過程用藥)的干擾:胃癌患者化療后Hcy水平相對升高,差異具有統計學意義[18]。

　　2.3、 同型半胱氨酸與2型糖尿病

　　Hcy與2型糖尿病(type 2 diabetes mellitus,T2DM)顯著相關。Hcy在氧化還原反應中產生活性氧可降低胰島素分泌細胞活力,減弱葡萄糖激酶磷酸化反應和胰島素分泌反應,并引起細胞凋亡[19]。血漿Hcy每升高5 μmol/L,T2DM患病風險可增加1.29倍[20]。糖尿病患者中,Hcy水平升高是糖尿病微血管并發癥的標志[21],發生率可達到73.3%[22]。攜帶亞甲基四氫葉酸還原酶(methylenetetrahydrofolate reductase,MTHFR) 677TT基因的T2DM患者的血漿Hcy明顯高于其他基因型。而在中國人群中MTHFR 677TT基因型表達顯著高于其他種族[23,24]。糖尿病患者Hcy水平的隨訪監測可能有助于及早發現微血管并發癥。

　　2.4 、同型半胱氨酸與妊娠期疾病

　　妊娠期血容量增加,血液相對稀釋、腎小球濾過增加。同時,胎兒對甲硫氨酸需求增多。因此,正常妊娠時Hcy水平是降低的。妊娠期HHcy可能導致早期流產、胎兒神經管缺陷、先兆子癇、胎兒宮內發育遲緩等。33%的早期流產是因為妊娠期伴HHcy[25]。薈萃分析顯示,基因型MTHFR C677T和MTHFR A1298C的妊娠者早期流產風險顯著升高。妊娠期患先兆子癇婦女的Hcy水平顯著高于正常婦女[26]。在篩檢試驗中引入Hcy測量,可顯著提高先兆子癇預測模型敏感性[27]。高濃度Hcy可使女性患嚴重先兆子癇的風險增加1.12倍[28]。HHcy對內皮細胞的毒性引起細胞功能障礙、微血栓形成、胎盤灌注受阻和氧化應激反應,可導致胎兒循環衰竭,引發胎兒生長受限[29]。

　　2.5、 同型半胱氨酸與慢性腎病

　　腎臟是Hcy代謝的主要部位。Hcy代謝途徑紊亂可引起腎功能損害。腎功能不全將導致Hcy積累,引發慢性腎功能衰竭。HHcy與估計腎小球濾過率(estimated glomerular filtration rate,eGFR)的降低獨立相關[30]。85%以上的慢性腎病患者存在HHcy[31]。微量白蛋白尿是腎功能損害的強有力預測指標。而HHcy是微量白蛋白尿的獨立危險因素[32]。臨床上腎功能損害患者及時監測血漿Hcy水平對遠期嚴重并發癥的預測有重要意義。

　　2.6 、同型半胱氨酸與骨質疏松癥

　　Hcy可影響骨骼系統的骨膠原交聯、降低骨密度、刺激破骨細胞形成并增加其活性、促進成骨細胞凋亡,增加骨吸收,引起骨質疏松甚至骨折。老年男性患者髖關節骨密度與 Hcy水平呈負相關[33]。Hcy升高是骨質疏松癥的獨立危險因素[34]。HHcy與骨折風險增加顯著相關[35]。老年人應常規監測血Hcy水平,發現HHcy應及早干預,可能有利于預防骨質疏松及脆性骨折的發生[36]。

　　2.7 、同型半胱氨酸與眼部疾病

　　糖尿病視網膜病變及老年性黃斑變性均與Hcy有關。糖尿病視網膜病變是糖尿病患者普遍存在且最嚴重的微血管并發癥之一,70%的糖尿病患者會發生視網膜病變,表現為視力低下和失明。薈萃分析[37]顯示,Hcy升高可增加糖尿病視網膜病變風險。因HHcy可導致氧化應激和血管功能障礙,使其與滲出性老年性黃斑變性發病顯著相關[38]。

　　3 、同型半胱氨酸的防治

　　要降低Hcy升高對疾病的影響,主要從一級和二級預防入手。薈萃分析明確表示葉酸、維生素B6(Vitamin B6,Vit B6)、維生素B12(Vitamin B12,Vit B12)、可降低卒中風險[39]。為降低卒中風險,應進行Vit B12缺乏癥及HHcy檢測[40]、配合飲食健康教育、選擇甲基鈷胺素進行治療[41]。補充Vit B12、Vit B6的好處可能歸因于預防無癥狀的腦血管疾病[42]。目前尚無足夠的實驗證據表明補充葉酸降低Hcy可預防T2DM的進展[43]。Hcy對于疾病的具體預防效果仍需要進一步研究證明。

　　4、 總結與展望

　　綜上,Hcy水平在預測疾病風險、延緩疾病并發癥上有重要價值。CVD、T2DM、慢性腎病、惡性腫瘤及其并發癥的治療給社會和醫療系統帶來巨大經濟負擔。對35～84歲美國HHcy患者進行葉酸補充,推斷可在15年內節省社會成本效益超過110億美元[44]�？刂艸cy水平的前提是進行人群篩查,我國MTHFR 677TT變異者較多,對人群Hcy水平進行動態監測有益于疾病早防早診,未來將Hcy納入常規檢測項目勢在必行。

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