病理学论文
摘 要： 同型半胱氨酸(homocysteine,Hcy)产生于必需氨基酸甲硫氨酸向半胱氨酸转化的过程,并通过甲基化作用参与脱氧核糖核酸(DNA)代谢。近年来诸多研究表明,血Hcy水平与多种疾病有直接或间接关系,如动脉硬化、心血管疾病、高血压、神经系统疾病、糖尿病、恶性肿瘤、妊娠期疾病、眼部疾病和骨质疏松等。人体血浆中Hcy的正常范围是5～15μmol/L,>15μmol/L为高Hcy血症(hyper homocysteine,HHcy)。基因突变,叶酸、维生素B6、B12缺乏导致的营养不良及高甲硫氨酸的饮食模式均是Hcy升高的常见原因。研究证实,亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR)C677T基因多态性与血浆Hcy水平升高的易感性相关。而中国人群中MTHFR 677TT基因型表达显着高于其他种族。血清Hcy水平升高的致病机理可能为:促进炎症和血管钙化;脂质过氧化和抗氧化过程受损;刺激活性氧的产生,诱导氧化应激和血管功能障碍;内皮细胞毒性及功能障碍;抑制神经递质释放等。其他致病机制仍有待进一步研究。Hcy水平在预测疾病风险、控制疾病并发症、影响疾病转归中有重要价值。中国人口总体HHcy患病率较高,且地域差异显着。随着年龄增大,患病率也随之升高。Hcy水平监测有利于疾病的早发现、早诊断及严重并发症的早预防。结合最新文献报道,文章探讨Hcy致病机制及其与疾病的关系,为Hcy的临床应用提供参考。
关键词 : 同型半胱氨酸;高同型半胱氨酸血症;临床价值;研究进展;
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转化过程中产生的含硫氨基酸。Hcy通过甲基化作用参与脱氧核糖核酸(DNA)代谢。Hcy与多种疾病的发生和发展有直接或间接关系。根据最新的文献报道,现对相关内容展开综述。
1 、同型半胱氨酸的代谢机制与预测价值
1.1、 同型半胱氨酸的代谢机制
Hcy是甲硫氨酸和半胱氨酸代谢过程的中间产物。甲硫氨酸在甲硫氨酸合酶还原酶作用下生成S-腺苷甲硫氨酸,经甲基转移酶作用生成S-腺苷同型半胱氨酸,再水解为Hcy和腺苷。Hcy在体内的代谢途径有:再甲基化途径、转硫途径、直接释放到细胞外基质。任一代谢途径异常均会使血浆Hcy浓度升高。人体血浆中Hcy的正常范围是5～15 μmol/L,>15 μmol/L为高同型半胱氨酸血症(hyper homocysteine,HHcy)[1]。中国人口总体HHcy患病率达39.7%[2]。随着年龄增大,患病率升高,在>60岁的老年男性中HHcy患病率达46.23%[3]。
1.2 、同型半胱氨酸对疾病的预测价值
在颅内动脉粥样硬化患者中,HHcy联合斑块增强可提高缺血性卒中的鉴别诊断[4]。Hcy结合三叶因子3和胆碱酯酶活性指标可作为判断帕金森病和血管性帕金森病患者认知功能障碍的早期病理生理指标[5]。癌胚抗原结合胸水中的Hcy可提高诊断恶性胸腔积液的能力[6]。Hcy可作为疾病诊断与预后的辅助生物学指标。
2、 同型半胱氨酸与临床常见疾病的关系
2.1、 同型半胱氨酸与心血管疾病
Hcy升高在心血管疾病(cardiovascular disease, CVD)人群中普遍存在。中国东北农村的横断面研究报道,45.08%的高血压患者合并HHcy[7]。藏族居民中,平均每增加1个lnHcy(Hcy水平的对数转换),收缩压增加3.78 mm Hg(1 mm Hg=0.133 kPa),舒张压增加3.02 mm Hg[8]。高血压伴Hcy≥10 μmol/L定义为H型高血压[9,10]。血浆Hcy低水平者血压变异性小,可预防高血压相关心血管事件[11]。高血压患者服用降压药的同时补充叶酸,可显着降低血压水平(收缩压降低7.85 mm Hg;舒张压降低6.77 mm Hg),同时使CVD事件风险降低12.9%[12],中风风险降低15.0%[13]。补充叶酸降低血清Hcy水平在高血压、CVD的一级和二级预防是有效的[14]。
2.2 、同型半胱氨酸与恶性肿瘤
研究报道Hcy主要与消化系统(结直肠部、胃部)、呼吸系统(肺部)、生殖系统(卵巢、前列腺)的恶性肿瘤及相关癌前病变有关[15]。晚期恶性肿瘤患者血浆Hcy急剧升高,可能因肿瘤细胞增长过程争夺了叶酸,导致Hcy代谢障碍。Meta分析[16]发现Hcy每升高5 μmol/L,消化道肿瘤发生几率增加7%。DNA低甲基化是癌前病变和恶性肿瘤发生的重要原因[15],而同型半胱氨酸-蛋氨酸循环是维持细胞内甲基化平衡的代谢调节系统。但也有研究未观察到Hcy与恶性肿瘤(乳腺癌)的相关性[17]。Hcy水平异常对恶性肿瘤的影响可能受到其他因素(如治疗过程用药)的干扰:胃癌患者化疗后Hcy水平相对升高,差异具有统计学意义[18]。
2.3、 同型半胱氨酸与2型糖尿病
Hcy与2型糖尿病(type 2 diabetes mellitus,T2DM)显着相关。Hcy在氧化还原反应中产生活性氧可降低胰岛素分泌细胞活力,减弱葡萄糖激酶磷酸化反应和胰岛素分泌反应,并引起细胞凋亡[19]。血浆Hcy每升高5 μmol/L,T2DM患病风险可增加1.29倍[20]。糖尿病患者中,Hcy水平升高是糖尿病微血管并发症的标志[21],发生率可达到73.3%[22]。携带亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR) 677TT基因的T2DM患者的血浆Hcy明显高于其他基因型。而在中国人群中MTHFR 677TT基因型表达显着高于其他种族[23,24]。糖尿病患者Hcy水平的随访监测可能有助于及早发现微血管并发症。
2.4 、同型半胱氨酸与妊娠期疾病
妊娠期血容量增加,血液相对稀释、肾小球滤过增加。同时,胎儿对甲硫氨酸需求增多。因此,正常妊娠时Hcy水平是降低的。妊娠期HHcy可能导致早期流产、胎儿神经管缺陷、先兆子痫、胎儿宫内发育迟缓等。33%的早期流产是因为妊娠期伴HHcy[25]。荟萃分析显示,基因型MTHFR C677T和MTHFR A1298C的妊娠者早期流产风险显着升高。妊娠期患先兆子痫妇女的Hcy水平显着高于正常妇女[26]。在筛检试验中引入Hcy测量,可显着提高先兆子痫预测模型敏感性[27]。高浓度Hcy可使女性患严重先兆子痫的风险增加1.12倍[28]。HHcy对内皮细胞的毒性引起细胞功能障碍、微血栓形成、胎盘灌注受阻和氧化应激反应,可导致胎儿循环衰竭,引发胎儿生长受限[29]。
2.5、 同型半胱氨酸与慢性肾病
肾脏是Hcy代谢的主要部位。Hcy代谢途径紊乱可引起肾功能损害。肾功能不全将导致Hcy积累,引发慢性肾功能衰竭。HHcy与估计肾小球滤过率(estimated glomerular filtration rate,eGFR)的降低独立相关[30]。85%以上的慢性肾病患者存在HHcy[31]。微量白蛋白尿是肾功能损害的强有力预测指标。而HHcy是微量白蛋白尿的独立危险因素[32]。临床上肾功能损害患者及时监测血浆Hcy水平对远期严重并发症的预测有重要意义。
2.6 、同型半胱氨酸与骨质疏松症
Hcy可影响骨骼系统的骨胶原交联、降低骨密度、刺激破骨细胞形成并增加其活性、促进成骨细胞凋亡,增加骨吸收,引起骨质疏松甚至骨折。老年男性患者髋关节骨密度与 Hcy水平呈负相关[33]。Hcy升高是骨质疏松症的独立危险因素[34]。HHcy与骨折风险增加显着相关[35]。老年人应常规监测血Hcy水平,发现HHcy应及早干预,可能有利于预防骨质疏松及脆性骨折的发生[36]。
2.7 、同型半胱氨酸与眼部疾病
糖尿病视网膜病变及老年性黄斑变性均与Hcy有关。糖尿病视网膜病变是糖尿病患者普遍存在且最严重的微血管并发症之一,70%的糖尿病患者会发生视网膜病变,表现为视力低下和失明。荟萃分析[37]显示,Hcy升高可增加糖尿病视网膜病变风险。因HHcy可导致氧化应激和血管功能障碍,使其与渗出性老年性黄斑变性发病显着相关[38]。
3 、同型半胱氨酸的防治
要降低Hcy升高对疾病的影响,主要从一级和二级预防入手。荟萃分析明确表示叶酸、维生素B6(Vitamin B6,Vit B6)、维生素B12(Vitamin B12,Vit B12)、可降低卒中风险[39]。为降低卒中风险,应进行Vit B12缺乏症及HHcy检测[40]、配合饮食健康教育、选择甲基钴胺素进行治疗[41]。补充Vit B12、Vit B6的好处可能归因于预防无症状的脑血管疾病[42]。目前尚无足够的实验证据表明补充叶酸降低Hcy可预防T2DM的进展[43]。Hcy对于疾病的具体预防效果仍需要进一步研究证明。
4、 总结与展望
综上,Hcy水平在预测疾病风险、延缓疾病并发症上有重要价值。CVD、T2DM、慢性肾病、恶性肿瘤及其并发症的治疗给社会和医疗系统带来巨大经济负担。对35～84岁美国HHcy患者进行叶酸补充,推断可在15年内节省社会成本效益超过110亿美元[44]。控制Hcy水平的前提是进行人群筛查,我国MTHFR 677TT变异者较多,对人群Hcy水平进行动态监测有益于疾病早防早诊,未来将Hcy纳入常规检测项目势在必行。
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