目的 分析血清髓鞘碱性蛋白(MBP)、胶质纤维酸性蛋白(GFAP)水平与新生儿缺氧缺血性脑病(HIE)脑损伤严重程度的关系。方法 回顾分析2018-02—2019-10平顶山市第一人民医院121例HIE患儿的临床资料,根据脑损伤严重程度分为轻中度组和重度组。比较轻中度组与重度组血清MBP与GFAP水平,分析可能影响HIE病情的相关因素,Logistic回归分析明确导致HIE损伤程度的危险因素。采用Spearman相关系数分析患儿血清MBP、GFAP水平与HIE临床分度的关系。结果 重度组血清MBP、GFAP水平高于轻中度组(P<0.05)。单因素分析显示重度组产程异常和羊水污染占比高于轻中度组(P<0.05)。Logistic回归分析显示产程异常、羊水污染、MBP、GFAP是导致HIE的危险因素(P<0.05)。Spearman相关性分析显示HIE患儿血清MBP、GFAP水平与HIE临床分度呈正相关(r=0.816、0.835,P<0.001)。结论 血清MBP、GFAP水平可反映HIE患儿脑损伤严重程度,且其是影响HIE病情的危险因素,两者表达水平与HIE患儿脑损伤严重程度呈正相关。
血清MBP GFAP水平与新生儿缺氧缺血性脑病脑损伤程度的关系研究
张军建 张矿召 武振江
平顶山市第一人民医院,河南 平顶山 467000
基金项目:河南省医学科技攻关计划项目(编号:2018020623)
作者简介:张军建,Email:jian_730@tom.com
【摘要】 目的 分析血清髓鞘碱性蛋白(MBP)、胶质纤维酸性蛋白(GFAP)水平与新生儿缺氧缺血性脑病(HIE)脑损伤严重程度的关系。方法 回顾分析2018-02—2019-10平顶山市第一人民医院121例HIE患儿的临床资料,根据脑损伤严重程度分为轻中度组和重度组。比较轻中度组与重度组血清MBP与GFAP水平,分析可能影响HIE病情的相关因素,Logistic回归分析明确导致HIE损伤程度的危险因素。采用Spearman相关系数分析患儿血清MBP、GFAP水平与HIE临床分度的关系。结果 重度组血清MBP、GFAP水平高于轻中度组(P<0.05)。单因素分析显示重度组产程异常和羊水污染占比高于轻中度组(P<0.05)。Logistic回归分析显示产程异常、羊水污染、MBP、GFAP是导致HIE的危险因素(P<0.05)。Spearman相关性分析显示HIE患儿血清MBP、GFAP水平与HIE临床分度呈正相关(r=0.816、0.835,P<0.001)。结论 血清MBP、GFAP水平可反映HIE患儿脑损伤严重程度,且其是影响HIE病情的危险因素,两者表达水平与HIE患儿脑损伤严重程度呈正相关。
【关键词】 新生儿;缺氧缺血性脑病;髓鞘碱性蛋白;胶质纤维酸性蛋白;脑损伤;血清
【中图分类号】 R722.1 【文献标识码】 A 【文章编号】 1673-5110(2020)22-1986-06 DOI:10.12083/SYSJ.2021.02.005
Study on the relationship between serum MBP and GFAP levels and the severity of brain damage in neonates with hypoxic ischemic encephalopathy
ZHANG Junjian,ZHANG Kuangzhao,WU Zhenjiang
The First People's Hospital of Pingdingshan,Pingdingshan 467000,China
【Abstract】 Objective To analyze the relationship between the levels of serum myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) and the severity of neonatal ischemic hypoxic encephalopathy (HIE) brain injury.Methods The clinical data of 121 children with HIE admitted to the Department of Neonatology in the First People's Hospital of Pingdingshan from February 2018 to October 2019 were reviewed.According to the severity of HIE brain injury,they were divided into mild to moderate group and severe group.Compared the levels of serum MBP and GFAP between HIE mild-moderate group and severe group,single factor analysis may affect the related factors of HIE disease,logistic regression analysis clarified the risk factors leading to HIE severe brain injury.Spearman correlation coefficient method was used to calculate serum MBP,The correlation coefficient between GFAP level and HIE clinical scale.Results The levels of serum MBP and GFAP in severe HIE group were higher than mild to moderate group (P<0.05).According to univariate analysis,the proportion of abnormal labor and amniotic fluid pollution in the severe HIE group was higher than that in the mild to moderate group (P<0.05).Logistic regression analysis of abnormal labor,amniotic fluid pollution,MBP,GFAP are the risk factors of severe HIE (P<0.05).Spearman correlation analysis showed that serum MBP and GFAP levels in children with HIE were positively correlated with the clinical scale of HIE (r=0.816,0.835,P<0.001).Conclusion Serum MBP and GFAP levels can reflect the severity of brain injury in children with HIE,and are risk factors affecting the condition of HIE.The expression levels of the two are positively correlated with the severity of brain injury in children with HIE.
【Key words】 Neonatal hypoxic ischemic encephalopathy;Myelin basic protein;Glial fibrillary acidic protein;Brain injury;Serum
新生儿缺氧缺血性脑病(hypoxic-ischemic encephalopathy,HIE)是指围生期窒息导致的新生儿脑缺氧缺血性损害,可导致新生儿颅内出血、多器官功能损伤、智力障碍、运动障碍、继发性癫痫等,严重者导致患儿死亡[1-2]。HIE临床症状以意识状态改变、肌张力变化和惊厥为主要表现,是判断脑病严重程度和后遗症的主要指标[3]。HIE严重影响新生儿神经系统发育,早期诊断与科学检测脑细胞损伤的严重程度在临床上具有重要意义[4-5]。髓鞘碱性蛋白(myelin base protein,MBP)位于中枢神经系统髓鞘浆膜面,主要作用是维持髓鞘结构与功能的稳定,MBP含量可以反映髓鞘损伤情况[6]。血清胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)是星形胶质细胞分化和反应性标记物,其作用主要是维持星形胶质细胞的形态和功能,有研究表明GFAP水平的增高一定程度上反映了脑损伤的程度,是一种较敏感的脑损伤指标[7-8]。因此,本研究探讨血清MBP、GFAP水平与HIE患儿脑损伤的关系,旨在为HIE临床诊断提供指导。
1 资料和方法
1.1 临床资料 回顾分析2018-02—2019-10平顶山市第一人民医院121例HIE患儿的临床资料,其中男67例,女54例;年龄1~4(2.10±0.32)周。纳入标准:(1)符合HIE新生儿诊断标准;(2)无严重心、肝、肾等器官器质性疾病;(3)患儿均在本院出生。排除标准:(1)伴感染性疾病;(2)先天性心脏病患儿;(3)中枢系统畸形患儿;(4)伴呼吸系统疾病患儿。本研究获院伦理委员会批准。
1.2 方法
1.2.1 血清MBP、GFAP水平检测方法:新生儿出生24 h后取静脉血2 mL,血液标本置于抗凝管中,室温下3 000 r/min离心15 min(离心半径10 cm),取血清置于—80 ℃保存待测,采用双抗体夹心酶联免疫法测定血清MBP水平,酶联免疫吸附法检测GFAP水平,测量3次求平均值。MBP试剂盒购自上海科顺生物科技有限公司,GFAP试剂盒购自上海博谷生物科技有限公司。
1.2.2 分组方法:根据新生儿缺氧缺血性脑病诊断依据和临床分度[9]:①存在产前高危因素,胎动减少,胎心率减慢,羊水Ⅲ度胎粪污染等病史;②Apgar评分1 min≤3分,5 min≤6分;③存在意识、肌张力改变、反射改变、惊厥等中枢神经系统症状体征;④颅脑CT或B超的影像学改变。将本组HIE患儿分为轻中度组89例和重度组32例。
1.2.3 收集相关资料:统计可能影响HIE病情的危险因素,包括患儿性别、出生时胎龄、是否多胎、出生体质量、妊娠期高血压、母体贫血、产程异常、胎盘异常、胎膜早破、脐带异常、羊水污染、母体高龄(>35岁)、产前发热、自然分娩、产前使用催产素、定期产检等。
1.2.4 Logistic回归分析法赋值:将发生HIE作为因变量Y(发生=1,未发生=0),患儿性别(男=1,女=0)、是否多胎(是=1,否=0)、妊娠期高血压(是=1,否=0)、母体贫血(是=1,否=0)、产程异常(是=1,否=0)、胎盘异常(是=1,否=0)、胎膜早破(是=1,否=0)、脐带异常(是=1,否=0)、羊水污染(是=1,否=0)、母体高龄(是=1,否=0)、产前发热(是=1,否=0)、自然分娩(是=1,否=0)、产前使用催产素(是=1,否=0)、定期产检(是=1,否=0)为二分类变量,出生时胎龄、出生体质量、MBP、GFAP为连续变量,以上各因素均为自变量,实施Logistic回归分析。
1.3 统计学分析 应用SPSS 24.0软件处理数据,计量资料用均数±标准差(x±s)表示,样本间比较用t检验;计数资料用n(%)表示,组间比较采用χ2检验;采用Logistic回归模型进行多因素分析,筛选危险系数。采用Spearman相关系数分析HIE患儿血清MBP、GFAP水平与HIE临床分度的相关性。P<0.05为差异有统计学意义。
2 结果
2.1 2组患儿血清MBP、GFAP水平比较 重度组血清MBP、GFAP水平高于轻中度组(P<0.05)。见表1。
表1 2组血清MBP、GFAP水平比较 (x±s)
Table 1 Comparison of serum MBP and GFAP levels between HIE mild-moderate group and severe group (x±s)
组别 |
n |
MBP(μg/L) |
GFAP(ng/L) |
轻中度组 |
89 |
1.78±0.24 |
92.75±11.67 |
重度组 |
32 |
3.86±0.40 |
198.91±19.47 |
t值 |
|
34.761 |
36.468 |
P值 |
|
<0.001 |
<0.001 |
2.2 HIE病情的可能影响因素 2组患儿性别、出生时胎龄、多胎、出生体质量、妊娠期高血压、母体贫血、胎盘异常、胎膜早破、脐带异常、母亲高龄、产前发热、自然分娩、产前使用催产素、定期产检比较差异无统计学意义(P>0.05);重度组产程异常和羊水污染占比高于轻中度组(P<0.05)。见表2。
2.3 影响HIE重度脑损伤的危险因素Logistic回归分析 经Logistic回归分析,产程异常、羊水污染、MBP、GFAP均是HIE重度脑损伤的危险因素(P<0.05)。见表3。
2.4 血清MBP、GFAP水平与病情程度的相关性 经Spearman相关性分析,HIE患者血清MBP、GFAP水平与HIE临床分度呈正相关(r=0.816、0.835,P<0.001)。
表2 2组HIE病情的可能影响因素比较
Table 2 Comparison of the possible influencing factors of HIE in the two groups
可能影响因素 |
轻中度组(n=89) |
重度组(n=32) |
t/χ2值 |
P值 |
性别(男) |
32(35.96) |
12(37.50) |
0.024 |
0.876 |
出生时胎龄/(周,x±s) |
2.30±0.24 |
2.27±0.31 |
0.56 |
0.577 |
多胎[n(%)] |
2(2.25) |
1(3.13) |
1.936 |
0.055 |
出生体质量(kg) |
2.62±0.32 |
2.57±0.30 |
0.764 |
0.446 |
妊娠期高血压[n(%)] |
12(13.48) |
4(12.50) |
0.02 |
0.888 |
母体贫血[n(%)] |
8(8.99) |
3(9.38) |
0.004 |
0.948 |
产程异常[n(%)] |
3(3.37) |
6(18.75) |
8.086 |
0.004 |
胎盘异常[n(%)] |
3(3.37) |
1(3.13) |
0.004 |
0.947 |
胎膜早破[n(%)] |
6(6.74) |
2(6.25) |
0.009 |
0.924 |
脐带异常[n(%)] |
10(11.24) |
4(12.50) |
0.037 |
0.848 |
羊水污染[n(%)] |
2(2.25) |
6(18.75) |
10.382 |
0.001 |
母体高龄[n(%)] |
10(11.24) |
5(15.63) |
0.418 |
0.518 |
产前发热[n(%)] |
9(10.11) |
4(12.50) |
0.14 |
0.708 |
自然分娩[n(%)] |
80(89.89) |
28(87.50) |
0.14 |
0.708 |
产前使用催产素[n(%)] |
19(21.35) |
7(21.88) |
0.004 |
0.95 |
定期产检[n(%)] |
85(95.51) |
30(93.75) |
0.154 |
0.695 |
表3 影响HIE脑损伤的危险因素Logistic回归分析
Table 3 Logistic regression analysis of risk factors affecting severe brain injury in HIE
变量 |
β值 |
SE |
Wald χ2 |
P值 |
OR值 |
95% CI |
产程异常 |
0.812 |
0.315 |
6.645 |
0.004 |
2.252 |
1.776~2.729 |
羊水污染 |
0.848 |
0.271 |
9.792 |
0.001 |
2.335 |
1.874~2.796 |
MBP |
0.912 |
0.306 |
8.883 |
<0.001 |
2.489 |
1.656~3.323 |
GFAP |
1.046 |
0.387 |
7.305 |
<0.001 |
2.846 |
1.547~4.145 |
3 讨论
随着现代医学的发展,新生儿HIE的发病率不断降低,但是新生儿脑损伤的早期诊断至今没有突破性进展,所以新生儿窒息引发的脑水肿、脑性瘫痪、智能低下等后遗症的发生率不断上升[10]。新生儿脑部耗氧量占自身总耗氧量的一半以上,脑部代谢水平最高,因此任何缺血缺氧情况都会导致新生儿窒息、代谢异常以及脑组织损伤[11-13]。HIE的发生可对患儿造成终身影响,并对其家庭造成严重负担。因此,分析血清MBP、GFAP水平与HIE新生儿脑损伤严重程度的关系,以采取最佳治疗手段改善患儿预后至关重要。
MBP主要分布于中枢神经系统髓鞘,在髓鞘结构和功能稳定方面有重要作用。正常情况下血清MBP含量较低,中枢神经系统遭到损害时MBP含量迅速上升。GFAP是中枢神经系统表达蛋白,脑部缺血缺氧导致GFAP含量升高,诱导细胞开始分裂,产生新的星形胶质细胞,星形胶质细胞不断分裂引起中枢系统神经细胞损伤,阻止HIE新生儿神经系统的功能恢复[14-15]。本研究HIE重度组血清MBP、GFAP水平高于轻中度组,表明血清MBP、GFAP水平与HIE进展密切相关。有研究表明脑外伤患者中MBP含量越高,其脑损伤程度越严重[16-19]。另有研究发现,重度窒息患儿血清MBP水平明显上升,轻度窒息患儿血清MBP水平上升低于重度窒息患儿,所以血清MBP水平升高可能是判断HIE新生儿脑损伤的指标[20-22]。研究发现人脑受到损伤时GFAP合成速度加快,血清GFAP含量升高,且GFAP参与HIE早期病理机制及后期脑组织修复过程[23-26]。研究发现新生儿HIE病情越严重,血清GFAP水平越高,因此GFAP水平可以反映脑损伤严重程度[27-30]。以上研究结果与本研究中HIE重度组患者血清MBP、GFAP水平升高结果一致,说明MBP、GFAP水平与脑损伤程度有关。本研究Logistic回归分析显示产程异常、羊水污染、MBP、GFAP均是HIE重度脑损伤的危险因素,提示除产程异常、羊水污染外,MBP、GFAP亦可导致HIE脑损伤的发生。第二产程出现延迟,很大程度上会引起胎儿宫内窘迫,从而导致部分新生儿出现HIE。羊水污染会降低羊水的含氧量,导致胎儿在母体内出现缺氧,引起HIE。研究表明脑损伤患者脑脊液MBP含量升高,与脑损伤程度有关,MBP可作为判断中枢神经系统破坏程度的指标[31-35]。研究表明,与健康新生儿相比,HIE新生儿GFAP水平显著升高,而且GFAP与新生儿神经行为评分呈负相关,因此检测血清GFAP水平能够判断HIE患儿的病情程度及预测预后[36-42]。此外,本研究经Spearman相关性分析发现HIE患者血清MBP、GFAP水平与HIE临床分度呈正相关,进一步提示MBP、GFAP与HIE病情严重程度具有相关性,可作为早期预测新生儿脑损伤程度的理想指标。
血清MBP、GFAP水平是影响HIE脑损伤严重程度的独立因素,与HIE临床分度呈正相关,可通过检测血清MBP、GFAP水平对脑损伤程度进行预判,而更深层次的病理机制有待于进一步研究。
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(收稿2020-08-04)
本文责编:夏保军
本文引用信息:张军建,张矿召,武振江.血清MBP GFAP水平与新生儿缺氧缺血性脑病脑损伤程度的关系研究[J].中国实用神经疾病杂志,2020,23(22):1986-1991.DOI:10.12083/SYSJ.2021.02.005
Reference information:ZHANG Junjian,ZHANG Kuangzhao,WU Zhenjiang.Study on the relationship between serum MBP and GFAP levels and the severity of brain damage in neonates with hypoxic ischemic encephalopathy[J].Chinese Journal of Practical Nervous Diseases,2020,23(22):1986-1991.DOI:10.12083/SYSJ.2021.02.005