张建磊等
【摘要】 目的:探讨血清同型半胱氨酸水平(Hcy)与多发性硬化(MS)的关系。方法:检测41例MS患者(MS组)和42例正常对照者(NC组)血清中Hcy浓度、叶酸及维生素B12浓度,并将结果进行比较分析。结果:MS组和NC组血清中Hcy浓度分别为(25.82±1.724)μmol/L、(13.60±1.517)μmol/L。MS组的Hcy浓度明显高于NC组,差异有统计学意义(P<0.01),而两组的叶酸、维生素B12浓度比较差异均无统计学意义(P>0.05)。结论:MS患者血清Hcy水平升高,同型半胱氨酸可能在多发性硬化病理过程中起作用。
【关键词】 多发性硬化; 同型半胱氨酸; 叶酸; 维生素B12
【Abstract】 Objective:To investigate the relationship between the serum level of homocysteine(Hcy) and multiple sclerosis(MS).Method:The concentration of Hcy,folic acid and vitamin B12 in serum in 41 MS patients(MS group) and 42 normal controls(NC group) were detected,and the results were compared and analyzed.Result:The mean concentrations of Hcy in MS group and NC group were (25.82±1.724)μmol/L,(13.60±1.517)μmol/L respectively.The mean concentration of Hcy in the MS group was significantly higher than the NC group,the difference was statistically significant(P<0.01),while there were no statistically significant differences in folic acid and vitamin B12 between the two groups (P>0.05).Conclusion:The level of Hcy is higher in MS patients,homocysteine may play a role in the pathological process of multiple sclerosis.
【Key words】 Multiple sclerosis; Homocysteine; Folic acid; Vitamin B12
First-authors address:Huaihe Hospital of Henan University,Kaifeng 475000,China
doi:10.3969/j.issn.1674-4985.2014.18.018
多发性硬化(multiple sclerosis,MS)是一种病理特点为中枢神经系统炎性脱髓鞘的自身免疫性疾病,该病的发病机制同病原体感染、自身免疫反应、遗传因素和外部环境作用等因素有关。同型半胱氨酸(homocysteine,Hcy)是一种氨基酸,具有神经毒性,维生素B12、叶酸能促进Hcy的代谢。如果饮食中叶酸、维生素B12摄入不足、甲基化障碍,则Hcy无法代谢生成蛋氨酸,就有可能导致Hcy在血清中蓄积。已有研究资料显示,多种神经系统疾病和血清同型半胱氨酸的升高有关,如脑血管病、阿尔茨海默病、帕金森病等[1-5]。脑白质病变与Hcy的关系亦有研究证实[6]。目前有的研究表明,高Hcy血症与MS具有相关性,但也有一些研究得出不同结论[7]。本研究拟通过比较MS患者与正常对照组的血清Hcy与维生素B12、叶酸的浓度,进一步探讨其内在联系,现报告如下。
1 资料与方法
1.1 一般资料 选取2011年1月-2013年12月在本院神经内科住院的41例MS患者作为多发性硬化组(MS组),其中男14例,女27例,所有患者均符合McDonald的多发性硬化诊断标准[4]:(1)≥2次发作+≥2个病灶。(2)≥2次发作+1处病灶+a、b、c附加之一(a、MRI证实空间病灶的弥散性;b、有与MS一致的2个或2 个以上的病灶,加上脑脊液的阳性证据;c、等待提示另一病变的又一次临床发作)。(3)1次发作+≥2个病灶+a、b附加之一(a、MRI证实时间的弥散性;b、有第2次临床发作)。(4)1次发作+1个病灶+a、b、c附加之一(a、MRI上病灶空间的弥散性;b、≥2个与MS一致的MRI病灶+脑脊液阳性证据+MRI时间上的弥散性;c、有第2次临床发作)。入选的MS患者在3个月内未曾服用维生素B12以及叶酸,平均年龄(36.47±8.60)岁,病程3.5~74个月,平均(27.5±12.55)个月。另外选取42例健康志愿者作为正常对照组(NC组),其中男16例,女26例,无吸烟、酗酒等不良嗜好,平均年龄(37.82±10.31)岁。两组研究对象的年龄、性别等一般资料比较差异均无统计学意义(P>0.05),具有可比性。
1.2 研究方法 被检者早晨空腹抽取静脉血3~5 mL,离心分离血清,-20 ℃冰箱保存待测。检测Hcy的仪器为奥林巴斯AU2700全自动生化分析仪,采用循环酶法检测血清Hcy浓度,检测试剂由四川迈克生物科技股份有限公司提供;血清叶酸、维生素B12的检测运用Beckman Coulter公司的ACESS2化学发光分析仪,采用化学发光免疫分析法检测血清叶酸、维生素B12的浓度,检测试剂由贝克曼库尔特有限公司提供。endprint
1.3 统计学处理 采用SPSS 13.0软件对所得数据进行统计分析,计量资料用(x±s)表示,比较采用t检验,以P<0.05为差异有统计学意义。
2 结果
MS组和NC组血清中Hcy浓度分别为(25.82±1.724)μmol/L、(13.60±1.517)μmol/L。MS组的Hcy浓度明显高于NC组,差异有统计学意义(P<0.01),而两组的叶酸、维生素B12浓度比较差异均无统计学意义(P>0.05),见表1。
3 讨论
多发性硬化(MS)是导致青壮年神经功能障碍的常见病因之一。1868年法国神经病学家Charcot首先提出,病程中神经系统功能障碍间断发展并伴有脑和脊髓白质血管周围炎症细胞浸润。然而其病因和发病机制至今尚未完全清楚,多数学者认为,MS是由细胞和体液免疫共同参与导致的脑和脊髓白质损伤。Khan等[6]研究发现,脑白质病变组血浆Hcy水平较无脑白质病变组的血浆Hcy水平明显升高,并且脑白质病变的严重程度与血浆Hcy水平呈正相关。由于代谢过程中血浆Hcy的巯基可以发生氧化还原反应,产生自由基损伤血管内皮细胞;Hcy还可以使S腺苷聚集在细胞内,造成血管内皮细胞凋亡异常,导致血管内皮功能障碍;血管内皮功能障碍将使一氧化氮分泌减少,血管舒张调节能力降低,脑血管灌注下降,造成脑缺血、脑白质损伤。因此有学者认为,血浆Hcy是脑白质病变的一个独立的危险因素,并且与病变损伤程度密切相关。
国外对多发性硬化与同型半胱氨酸的关系进行研究,结果差异较大。Ramsaransing等[8]和Vrethem等[9]发现MS患者的血清Hcy平均浓度较正常人升高,而Rio等[10]则报道,血清Hcy水平在MS患者和健康人群中无明显差异。对于造成差异的原因,目前尚无权威解释。本研究的结果表明,MS患者血清Hcy平均浓度明显高于正常人,由此认为Hcy可能在MS的病理发展过程起是一定作用的。研究证实,高Hcy血症与脑梗死的发病密切相关[1,4-5]。但Hcy在MS和Hcy在脑梗死病理过程中的作用是否相似?笔者对叶酸、维生素B12进行了测定,结果表明,这两者在MS患者血清中的浓度和正常对照组的差异均无统计学意义,这与Ramsaransing等[8]的研究结果是一致的。叶酸、维生素B12主要是在Hcy的再甲基化代谢过程中发挥作用,因此在心脑血管疾病、糖尿病等患者血清中有高浓度的Hcy以及相应低浓度的叶酸、维生素B12[11]。而Hcy在MS患者血清中的升高机制可能不同于其在心脑血管疾病中。Hcy在MS病程中的可能作用有:(1)Hcy抑制甲基化过程,甲基化过程在控制DNA甲基化以及神经递质、膜磷脂、髓鞘的合成和分解中起重要作用,通过甲基化作用形成的髓鞘碱性蛋白是维护髓鞘和髓鞘再生的重要物质,Hcy可通过抑制此过程造成损伤[12-13];(2)Hcy通过结合NMDA受体,间接增加钙离子内流,发挥其兴奋性神经毒性,损伤神经元DNA,诱导细胞凋亡,而中枢神经系统对细胞外Hcy很敏感,所以轻度的血清Hcy浓度升高就可能导致中枢神经系统损伤[14-15];(3)Hcy能减少载脂蛋白A-I的产生,载脂蛋白A-I可以干扰巨噬细胞和淋巴细胞的相互作用或抑制白细胞介素-lβ发挥抗炎特性,它的生成减少会促进中枢神经系统炎症的发展[16];(4)Hcy通过核因子-kβ途径产生大量细胞因子、促进巨噬细胞活化[15,17-18];(5)Hcy通过诱导激活细胞外信号调节激酶直接损害中枢神经系统的神经元[14-15,18]。
综上所述,本研究提示,多发性硬化与高同型半胱氨酸血症存在相关性,但与血清中叶酸、维生素B12无明显相关性,鉴于目前同型半胱氨酸在MS发病过程中所起机制不明,降低血清同型半胱氨酸水平是否对MS有防治作用目前不明确,需进一步临床和基础实验研究。
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[18] Au-Yeung K K W,Yip J C W,Siow Y L,et al.Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophages.This paper is one of a selection of papers published in this Special Issue,entitled Young Investigators Forum[J].Can J Physiol Pharmacol,2006,84(1):141-147.
(收稿日期:2014-03-21) (本文编辑:欧丽)endprint
[8] Ramsaransing G S M,Fokkema M R,Teelken A,et al.Plasma homocysteine levels in multiple sclerosis[J].J Neurol Neurosurg Psychiatry,2006,77(2):189-192.
[9] Vrethem M,Mattsson E,Hebelka H,et al.Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid[J].Multiple Sclerosis,2003,9(3):239-245.
[10] Rio J,Malinow M R,Montalban J,et al.Serum homocysteine levels in multiple sclerosis[J].Arch Neurol,1994,51(12):1181.
[11] Brosnan J T,Jacobs R L,Stead L M,et al.Methylation demand:a key determinant of homocysteine metabolism[J].Acta Biochim Pol,2004,51(2):405-414.
[12] Kim S,Lim I K,Park G H,et al.Biological methylation of myelin basic protein:enzymology and biological significance[J].Int J Biochem Cell Biol,1997,29(5):743-751.
[13] Reynolds E.Vitamin B12,folic acid,and the nervous system[J].Lancet Neurol,2006,5(11):949-960.
[14] Ho P I,Ortiz D,Rogers E,et al.Multiple aspects of homocysteine neurotoxicity:glutamate excitotoxicity,kinase hyperactivation and DNA damage[J].J Neurosci Res,2002,70(5):694-702.
[15] Kruman I I,Culmsee C,Chan S L,et al.Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity[J].J Neurosci,2000,20(18):6920-6926.
[16] Liao D,Tan H,Hui R,et al.Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein AI Protein synthesis and enhancing HDL cholesterol clearance[J].Circ Res,2006,99(6):598-606.
[17] Sengupta S,Wehbe C,Majors A K,et al.Relative roles of albumin and ceruloplasmin in the formation of homocystine,homocysteine-cysteine-mixed disulfide,and cystine in circulation[J].Journal of Biological Chemistry,2001,276(50):46 896-46 904.
[18] Au-Yeung K K W,Yip J C W,Siow Y L,et al.Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophages.This paper is one of a selection of papers published in this Special Issue,entitled Young Investigators Forum[J].Can J Physiol Pharmacol,2006,84(1):141-147.
(收稿日期:2014-03-21) (本文编辑:欧丽)endprint
[8] Ramsaransing G S M,Fokkema M R,Teelken A,et al.Plasma homocysteine levels in multiple sclerosis[J].J Neurol Neurosurg Psychiatry,2006,77(2):189-192.
[9] Vrethem M,Mattsson E,Hebelka H,et al.Increased plasma homocysteine levels without signs of vitamin B12 deficiency in patients with multiple sclerosis assessed by blood and cerebrospinal fluid homocysteine and methylmalonic acid[J].Multiple Sclerosis,2003,9(3):239-245.
[10] Rio J,Malinow M R,Montalban J,et al.Serum homocysteine levels in multiple sclerosis[J].Arch Neurol,1994,51(12):1181.
[11] Brosnan J T,Jacobs R L,Stead L M,et al.Methylation demand:a key determinant of homocysteine metabolism[J].Acta Biochim Pol,2004,51(2):405-414.
[12] Kim S,Lim I K,Park G H,et al.Biological methylation of myelin basic protein:enzymology and biological significance[J].Int J Biochem Cell Biol,1997,29(5):743-751.
[13] Reynolds E.Vitamin B12,folic acid,and the nervous system[J].Lancet Neurol,2006,5(11):949-960.
[14] Ho P I,Ortiz D,Rogers E,et al.Multiple aspects of homocysteine neurotoxicity:glutamate excitotoxicity,kinase hyperactivation and DNA damage[J].J Neurosci Res,2002,70(5):694-702.
[15] Kruman I I,Culmsee C,Chan S L,et al.Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity[J].J Neurosci,2000,20(18):6920-6926.
[16] Liao D,Tan H,Hui R,et al.Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein AI Protein synthesis and enhancing HDL cholesterol clearance[J].Circ Res,2006,99(6):598-606.
[17] Sengupta S,Wehbe C,Majors A K,et al.Relative roles of albumin and ceruloplasmin in the formation of homocystine,homocysteine-cysteine-mixed disulfide,and cystine in circulation[J].Journal of Biological Chemistry,2001,276(50):46 896-46 904.
[18] Au-Yeung K K W,Yip J C W,Siow Y L,et al.Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophages.This paper is one of a selection of papers published in this Special Issue,entitled Young Investigators Forum[J].Can J Physiol Pharmacol,2006,84(1):141-147.
(收稿日期:2014-03-21) (本文编辑:欧丽)endprint