Abstract
孤独症谱系障碍(ASD)目前病因和发病机制尚不清楚。近年来的研究发现ASD患儿普遍存在维生素D的缺乏, 维生素D与ASD的关系逐渐引起人们的关注。该文对ASD患儿外周血维生素D水平的检测结果、维生素D水平低下的可能原因及其与ASD病因的可能关系、补充维生素D对ASD的疗效等研究进展作一综述。
Keywords: 孤独症谱系障碍, 维生素D, 病因, 治疗
Abstract
The etiology and pathogenic mechanism of autism spectrum disorders(ASD) are still unclear.The relationship between vitamin D and ASD has drawn attention in recent years due to common vitamin D deficiency in children with ASD.This article reviews the peripheral blood levels of vitamin D in children with ASD, the possible reasons for hypovitamin D and its possible roles in the etiology of ASD and the efficacy of vitamin D supplementation in ASD.
Keywords: Autism spectrum disorders, Vitamin D, Etiology, Treatment
孤独症谱系障碍(autism spectrum disorders, ASD)是一组儿童早期起病，以社会交往、交流障碍和重复刻板行为、兴趣狭窄为特征的神经心理发育障碍性疾病[1-3]。目前本病病因和发病机制不明，多认为是遗传因素和环境因素相互作用所致[4-6]。近年来，人们发现维生素D除了调节钙磷代谢外，在胎儿期及出生后早期脑发育中也发挥着重要作用[7-9]。而且，维生素D可能参与了ASD的发病过程[10]。本文就近年来维生素D在ASD中的作用的研究进展作一综述。
1. 维生素D及ASD简介
美国医生Kanner于1943年在世界上最先报道了11例ASD患儿，这些患儿存在着社会交往、交流及行为、兴趣方面的异常[11]。以往ASD被认为是罕见病，但近30年来，本病的患病率快速增高，2014年美国疾病控制与预防中心的监测数据发现，儿童ASD患病率达到14.7/1 000，即相当于68例儿童中有1例儿童患ASD[12]。本病已经引起国际社会的广泛关注。
维生素D是引起儿童时期佝偻病的主要病因，既往曾认为维生素D主要作用为调节钙磷代谢而影响骨骼的生长和发育[13-15]。目前研究已经发现脑组织内广泛存在维生素D合成的关键酶1α羟化酶，且存在维生素D受体，并且维生素D在脑发育过程中起着重要作用[16-20]。大鼠孕期严重维生素D缺乏可引起脑体积增大、脑室扩大等病理改变，影响神经元分化、轴突联系和多巴胺系统的发育[21-24]。Cannell[25]的流行病学调查结果表明，美国人群中维生素D水平逐年降低，ASD患病率逐年升高，并且在空气污染及城市地区、高海拔地区患病率高，结合维生素D对脑发育的影响，在2008年首次提出了维生素D缺乏可能导致ASD发病的病因学假说。
2. ASD患儿及ASD大鼠外周血中维生素D水平
自Cannel提出维生素D缺乏可能导致ASD的假说后，越来越多的人开始研究ASD患儿血清中维生素D水平的改变。自2010年至今，国内外共有12篇检测ASD患儿和健康对照儿童血清维生素D水平的文章[26-37]。其中有9篇文章的结果表明ASD患儿外周血中维生素D水平低于健康对照儿童[26-34]。Fernell等[34]对58个ASD患儿及其健康同胞用出生时代谢筛查的纸血片进行了维生素D含量的检测，结果表明ASD患儿组外周血中25(OH)D水平明显低于健康对照儿童(24.0±19.6 nM vs 31.9±27.7 nM，P = 0.013)。这一结果表明，与健康同胞相比，ASD患儿在出生前就已经存在着维生素D水平的降低。
丙戊酸(valproate acid, VPA)是临床经常应用的抗癫癎药物[38-40]。临床研究表明，母孕期应用VPA是儿童罹患ASD的危险因素[41-43]。对子宫内VPA暴露子鼠的行为学、神经解剖学和分子生物学的研究均表明，母鼠孕12.5 d腹腔注射VPA 600 mg/kg所致子鼠的改变与ASD表现一致，可作为ASD的动物模型[44-45]。新近Selim等[46]对VPA所致ASD大鼠出生时和生后21 d两个时点外周血中25(OH)D水平进行检测的结果表明，ASD大鼠从出生时至生后21 d存在持续性的维生素D的缺乏，此结果与ASD儿童外周血中结果一致。VPA能够引起活性维生素D分解代谢关键酶CYP24增多，从而引起活性维生素D减少，而这可能与子鼠ASD的发病相关[47]。
根据以上ASD患儿及VPA所致的ASD模型大鼠外周血25(OH)D检测结果，推测ASD患儿可能存在着先天性的维生素D缺乏，并且其出生后维生素D缺乏持续存在。
3. ASD患儿维生素D水平低下的原因及与ASD病因的关系
研究发现ASD患儿自出生至儿童期持续存在着维生素D水平的降低，提示维生素D缺乏可能是ASD的病因。导致ASD患儿维生素D缺乏的原因可能与环境和(或)遗传有关。美国的CHARGE(Childhood Autism Risks from Genetics and the Environment)研究对ASD与维生素D代谢途径中常见的功能性的基因多态性进行了研究[48]。该病例对照研究中纳入474例2~5岁的ASD患儿和281例正常儿童。对其中384个ASD患儿家庭和234个正常儿童家庭的父母-子女同胞进行了常见的、功能性的DNA多态性检测，如维生素D代谢相关基因BsmI、TaqI、Cdx2、FokI、GC(rs4588)、CYP27B1(rs4646536)和CYP2R1(rs10741657)，结果表明：存在GC CYP2R1 AA基因型的儿童患ASD的风险低，维生素D受体TaqI CC纯合子基因型父亲的子代患ASD风险显著增加。这项研究表明维生素D代谢相关基因异常可能引起维生素D缺乏，且在ASD发病中起一定作用。
迄今研究确定的可能增加ASD风险的环境因素有9项，其中居民城市化、高纬度地区、高降雨地区和空气_污染这4个因素都降低了紫外线的辐射量而增加了维生素D缺乏的风险[49]。另有研究证明，瑞典的索马里移民后代出现ASD的几率增高，这是因为黑色人种需要大约5~10倍的光照时间才能产生和其他人种等量的维生素D，当黑色人种迁移到高纬度地区时，紫外线的辐射量有限，影响了皮肤合成内源性维生素D，大大增加了维生素D不足的风险[50-51]。以上均提示维生素D缺乏可能是ASD的影响因素。因此，遗传性和(或)发育早期维生素D缺乏可能是引起ASD的危险因素。
4. 补充维生素D治疗ASD的疗效及机制
4.1. 补充维生素D对ASD的疗效分析
丙酸(propoinic acid, PPA)是肠道内细菌的代谢终产物，曾被用作食物防腐剂。研究发现，丙酸导致大鼠中枢神经系统改变并出现孤独症样行为，可作为ASD的动物模型[52]。Alfawaz等[53]进行了维生素D对PPA导致的大鼠的神经毒性是否有预防或治疗作用的研究。该研究将大鼠分为4组：正常对照组只接受磷酸缓冲盐水；PPA对照组口服PPA 250 mg/(kg·d)，共3 d；维生素D预防组采用1 000 IU/(kg·d)两周后，口服PPA 250 mg/ (kg·d)，共3 d；维生素D治疗组口服PPA 250 mg/(kg·d)，3 d后，给予维生素D治疗2周。对血浆中的维生素D和钙、脑组织的5-羟色胺(serotonin, 5-HT)、谷胱甘肽硫转移酶活性(glutathione-s-transferase activity, GST)、γ-干扰素(interferon gamma, IFN-γ)进行了检测。并对大鼠脑组织DNA双螺旋断裂情况进行了研究。结果表明，维生素D预防组和治疗组中维生素D水平均明显高于PPA对照组。维生素D有一定的预防和治疗PPA所引起的脑内5-HT降低、GST降低、IFN-γ增高和DNA双螺旋裂解现象，并且维生素D的预防作用优于治疗作用。
我们研究组在2015年首先报道了1例合并维生素D缺乏的ASD患儿，应用维生素D后孤独症症状明显改善[54]。新近Saad等[33]的研究进一步验证了维生素D治疗对ASD的效果。他们对83例维生素D水平不足或缺乏的ASD患儿采用维生素D补充治疗3个月的患儿进行了评估，发现80.72%(67/83)的患儿临床症状得到了改善。这两个研究均表明维生素D治疗能够改善ASD的临床症状。
埃及学者研究发现，口服维生素D3 2 000 U/d可以提高ASD患儿体内维生素D水平，但ASD的症状无改善，研究者认为需要进一步加大维生素D补充剂量以明确是否ASD症状无改善与维生素D补充不足有关[37]。
4.2. 维生素D治疗ASD的可能机制
目前研究结果认为ASD的病因及发病机制可能与以下几方面有关：自身免疫学说、炎症学说、氧化应激学说、神经递质学说、基因突变学说[55-63]。补充维生素D可能通过以下机制对ASD起到治疗作用。
(1) 维生素D与自身免疫的关系：目前已有学者在ASD患儿外周血中发现多种与脑组织相关的自身抗体，而且抗体的水平与ASD严重程度呈正相关[57]。另有研究发现很多自身免疫疾病中存在维生素D缺乏、补充维生素D能减轻自身免疫疾病的临床表现[64-65]。有学者发现补充维生素D能提高体内调节性T细胞比例，从而抑制免疫细胞对自身组织的破坏、改善自身免疫疾病病情[66]。因此，推测维生素D对包括ASD在内自身免疫相关疾病有治疗作用。
(2) 维生素D的抗炎作用：目前研究发现ASD是一种炎症相关疾病[55-56]。而有研究认为维生素D具有免疫调节作用，能够增强保护性免疫反应、减少炎症反应[67]。从而推测维生素D应该具有抗炎作用。
(3) 维生素D与氧化应激：现发现ASD患儿血浆中氧化谷胱甘肽的浓度升高，氧化应激水平增高[58]。有人报道维生素D能够上调谷胱甘肽生成过程中的限速酶γ-谷氨酰转肽酶的表达，从而增加脑内还原型谷胱甘肽的含量，而还原型谷胱甘肽具有清除氧化副产物作用，具有脑保护作用[68]。另有报道，维生素D能够直接上调某些抗氧化剂(如超氧化物歧化酶和硫氧还蛋白还原酶)相关基因[69]。从而认为维生素D能够降低氧化应激水平，起到脑保护作用。
(4) 维生素D与5-HT：脑内5-HT具有促进亲近社会行为和矫正社会情绪的功能[70]。ASD患儿存在5-HT反常现象，即外周血中5-HT水平较正常儿童升高，而脑内5-HT水平较正常儿童降低。研究发现，人类中枢神经系统中存在的5-TH合成酶为色氨酸羟化酶2(TPH2)，而血脑屏障外存在的5-TH合成酶为色氨酸羟化酶1(TPH1)。维生素D具有促进TPH2基因转录而抑制TPH1转录的作用[71]，推测补充维生素D能够使ASD患儿脑内5-HT增高，从而改善ASD的临床症状。
(5) 维生素D与基因突变：目前关于ASD的遗传学研究发现此类患儿存在多种新生突变[62-63]。而这些新生突变只有少数新生突变可能增加患ASD的几率[72]。而维生素D可通过多种机制起到DNA修复和维护功能[73]，目前已发现至少5种维生素D依赖的基因编码DNA修复蛋白为专职DNA突变修复蛋白。8-羟脱氧鸟苷(8-OhdG)是DNA氧化损伤的标记物。在一项试验中发现每天应用维生素D3 800 IU，可使人体内8-OhdG含量降低25%[74]。另外，研究发现维生素D水平低下时，DNA修复酶PARP往往会出现过度反应并且会破坏邻近的DNA[75]。另外一项研究表明每天应用小剂量维生素D3能够上调Bax水平，起到促进凋亡而防止基因突变的作用[76]。因此，推测维生素D缺乏可能引起ASD患儿出现新生基因突变，而目前在ASD患儿中发现的多种新发突变可能为维生素D缺乏所致的结果而非ASD的致病因素。
5. 结语
综上所述，ASD的高发病率已使本病成为迫切需要解决的社会问题，但目前本病的病因不明，多认为是遗传及环境因素综合作用的结果。有关ASD与遗传的研究有较多发现，但不同研究结果遗传改变的一致性差，基因突变的结果显示多为新生突变，且目前的遗传因素和环境因素病因研究结果并不能合理解释ASD的流行病学特点，根据现有各种发病机制进行的临床药物治疗并未取得公认的临床疗效。因此，有必要从新的角度对ASD的病因和发病机制进行探索，为ASD治疗提供新的思路。虽然有部分研究者发现维生素D缺乏的ASD患儿，随着维生素D水平的增加其核心症状有所改善，但维生素D对ASD的治疗效果尚未达成共识，有待于进一步实施大样本、随机双盲试验进行研究。关于维生素D与ASD的病因及发病机制间的研究需要进行大量的、严谨的科学实验来进一步探讨。
Biography
单玲，女，硕士，主治医师
SHAN Ling, Email: shanling19830605@163.com
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