血清标志物β-痕迹蛋白（BTP）在预测妊娠高血压疾病的应用研究

发布时间：2018-07-18 16:05

【摘要】：研究背景:妊娠高血压疾病是妊娠期最为常见的并发症之一,是孕妇、胎儿和新生儿的发病率和死亡率的主要原因,而该疾病的治疗取决于很多因素,包括血压水平、孕龄、症状的存在和相关的危险因素。除了蛋白尿,妊娠高血压的孕妇还有很高罹患心血管疾病以及死亡的风险。相比正常孕妇,妊娠期高血压具有更高的胎盘早剥、心脑血管意外、器官衰竭和弥散性血管内凝血风险。而这些妊娠高血压母亲的胎儿则具有更高相关病症的发病风险,例如胎儿宫内发育迟缓,早产和胎儿宫内死亡。早期诊断、密切的产前监测以及及时的干预治疗是处理妊娠期引发的高血压的关键。目前,经济、可重复、值得信赖的临床检测预测方法仍十分欠缺。妊娠高血压疾病会发生胰岛素抵抗、交感神经异常兴奋以及过度的系统性炎症等一系列综合征。性激素结合球蛋白(SHBG)对高胰岛素血症、胰岛素抵抗均有着密切关系,雄激素可增强血管对血管活性物质的反应性,降低前列环素水平并增加血栓素的产生,直接增加血小板凝集诱导微血栓形成,此外,炎症在妊娠高血压疾病中发病过程中起重要作用,因为妊娠高血压疾病孕妇胎盘中慢性血管炎的症状显著增加。已有研究表明血清睾酮、性激素结合球蛋白(SHBG)、超敏C反应蛋白(hs-CRP)的水平与妊娠期高血压发生可能相关,本课题的目的即是要从妊娠高血压疾病患者体内的特殊表现找到评估妊娠高血压疾病的高危因素和更有效的潜在标志物分子。β-痕迹蛋白是一种前列腺素D2合成酶,属于脂质运载蛋白家族成员,其蛋白分子量很小,仅有23-29 kDa。最近对于β-痕迹蛋白的研究主要集中在其作为血清肌酸酐的替代标志物用来评价肾功能,以及心血管疾病的新的标志物。β-痕迹蛋白已被发现是比血清肌酸酐更加灵敏的用于监测肾功能损伤的标志物。β-痕迹蛋白可以作为糖尿病引发的肾功能异常的理想标志物。研究表明β-痕迹蛋白与许多生物学过程有关,包括炎症反应、心绞痛、动脉粥样化形成、血管舒缩性反应以及系统性动脉高压,具有抗炎症、抗血栓形成、抗细胞凋亡、抗动脉粥样硬化等心血管保护作用,可显著聚集在人冠状动脉粥样硬化性狭窄的病变的纤维斑块中,有多个研究报道,血清β-痕迹蛋白的水平在长期冠心病患者中是显著升高的,并且血清β-痕迹蛋白的升高程度与其受损血管的数量、年龄、高血压的情况密切相关。高水平的β-痕迹蛋白的能够预测心房纤维性颤动接受抗凝治疗的病人的不良的心血管事件、死亡率以及主要出血的发生,也可能用来反应心血管疾病的发病进程。Hirawa等人比较了正常人和高血压患者的β-痕迹蛋白的水平,发现在高血压病人体内β-痕迹蛋白的水平显著高于正常对照组,说明β-痕迹蛋白在高血压中发挥着重要的作用,然而,循环中的β-痕迹蛋白水平与妊娠高血压之间的关系目前仍是未知。本研究着眼于检测正常妊娠孕妇以及患有妊娠高血压的孕妇体内的血清β-痕迹蛋白的水平,探寻血清β-痕迹蛋白的水平与妊娠高血压之间的联系。据我们所知,这是首个揭示血清β-痕迹蛋白的水平与妊娠高血压之间关联的研究。研究目的:通过对比正常孕妇组和患有妊娠高血压疾病组(简称妊娠高血压组)的年龄、孕前BMI、妊娠史、血压、体重、左心室射血分数(LVEF)、尿蛋白,检测血清睾酮、性激素结合球蛋白(SHBG)、超敏C反应蛋白(hs-CRP)和β-痕迹蛋白(BTP)的水平,调查研究孕妇发生妊娠期高血压的高危因素及血清睾酮、性激素结合球蛋白(SHBG)、超敏C反应蛋白(hs-CRP)的水平与妊娠期高血压的发生是否具有相关性。探究正常孕妇和妊娠高血压的孕妇在不同孕期的血清中β-痕迹蛋白(BTP)的水平变化情况,比较两组孕妇血清BTP水平有无差异性,并通过ROC分析,评估血清β-痕迹蛋白(BTP)的水平与妊娠期高血压发生是否具有相关性,能否反应该疾病的严重程度,能否作为新的更有效的预测妊娠高血压疾病的标志物以及对妊娠高血压疾病的诊断识别能力。研究对象及方法:选取2014年在齐鲁医院和淄博市中心医院产检分娩的1206名孕妇,从中选择孕龄以及孕妇年龄匹配的57名正常妊娠的孕妇,设为正常对照组(血压140/90 mmHg,且孕期无蛋白尿);46名患有妊娠高血压疾病的孕妇,设为妊娠高血压组(妊娠高血压疾病是指在怀孕前20周无高血压症状,而在怀孕20周之后两次以上血压测量显示,收缩压≥140 mmHg或者舒张压≥90 mmHg,且测量间隔至少4小时,伴有先兆子痫或者无蛋白尿症)。46名妊娠高血压孕妇按有无蛋白尿分为单纯高血压组和子痫前期组,按左心室射血分数60%为界分为LVEF60%组和LVET≥60%组。所有的孕妇都是单胎妊娠,两组孕龄和胎龄匹配。排除标准主要包括:妊娠高血压组可能还伴随患有其他疾病如第二种类型的高血压,冠状动脉心脏病,肾脏疾病,或者是糖尿病等。首先收集整理所有孕妇的各项临床指标,如产妇平均年龄(岁)、孕前身高质量指数BMI(kg/m2)、贫血(n,%)、种族(n,%)、PIH家族史(n,%)、自然流产史(3)(n,%)、妊娠次数(3)(n,%)等,并且比较分析了收缩压(毫米汞柱)、舒张压(毫米汞柱)、出生时胎龄(天数)、分娩方式(n,%,正常阴道分娩或计划CS)以及胎盘重量(g),新生儿性别(n,%)与出生体重(g)等数据。妊娠高血压组孕妇于终止妊娠行超声心动图监测左心室射血分数(LVEF)。采集所有孕妇不同怀孕阶段孕早期(1-12周)、孕中期(13-27周)、孕晚期(28-40周)的血液样品备用,4℃,7000 rpm离心10分钟后-80℃保存备用。孕期各阶段均检测尿蛋白。采用酶联免疫测定分析法测定血清SHBG浓度,免疫发光法测定睾酮和超敏C反应蛋白水平,血清β-痕迹蛋白的水平采用酶联免疫吸附(ELISA)试剂盒进行检测。收集两组孕妇尿蛋白、hs-CRP(mg/1)(孕中期、孕晚期)、睾酮(孕中期、孕晚期)、SHBG(nmol/l)(孕中期、孕晚期)和BTP(孕早期、孕中期、孕晚期)等实验数据,ELISA检测结果采用非参数检验法。潜在风险评估通过绘制ROC曲线进行分析。研究结果:(1)与孕龄及产妇年龄相符的正常对照组孕妇相比,患有妊娠高血压的孕妇具有更高的孕前身高质量指数(BMI)(p0.05)、更高的贫血发病率(p0.001),以及明显的妊娠高血压家族遗传史(p0.001);在出生时胎龄相同的前提下,对于其他参数如分娩方式,胎盘重量和出生体重等,妊娠高血压组孕妇与正常健康对照组孕妇之间没有明显差异;(2)通过对比分析两组孕妇中晚期血清睾酮、性激素结合球蛋白(SHBG)、C反应蛋白(hs-CRP)的水平提示在妊娠期高血压组和正常妊娠组差异无统计学意义;(3)在正常妊娠孕妇的各阶段血清β-痕迹蛋白的水平之间无明显差异,而患有妊娠高血压的孕妇其血清β-痕迹蛋白的水平随着不同的怀孕阶段呈现逐渐上升的趋势,但是妊娠高血压的孕妇在孕中期和孕晚期的血清β-痕迹蛋白的水平相比并没有显著性差异;(4)与正常孕妇相比,患有妊娠高血压的孕妇,其血清β-痕迹蛋白的水平在孕中期和孕晚期时显著高于正常对照组孕妇(p0.05),而在孕早期两组间血清β-痕迹蛋白的水平之间的差异并不明显;(5)妊娠晚期子痫前期组血清β—痕迹蛋白的水平较单纯高血压组升高,差异具有统计学意义;妊娠高血压组左心室射血分数LVET60%的孕妇血清中BTP的水平明显高于LVET≥60%的孕妇;(6)通过ROC分析评估血清β-痕迹蛋白的水平用于预测妊娠高血压疾病的潜在价值,结果显示使用血清BTP量321.3ng/mL作为截断值,对妊娠高血压疾病的预测灵敏度可达91.3%,特异性可达89.5%。研究结论:1、孕妇有妊娠期高血压病家族遗传史、孕前身高质量指数偏高、孕期贫血者应纳入本次妊娠高血压发生的高危监测人群。2、本研究未发现妊娠中晚期血清睾酮、性激素结合球蛋白(SHBG)、C反应蛋白(hs-CRP)的水平与妊娠期高血压发生具有相关性,因此该指标不能作为预测妊娠高血压疾病的标志物。3、高水平的血清β-痕迹蛋白与妊娠高血压的发生具有相关性,可以用来反映妊娠高血压疾病的疾病进程,此外,血清β-痕迹蛋白也可作为妊娠高血压累及肾脏或心脏功能的预测指标,与其它研究发现B-痕迹蛋白可以作为心肾功能异常的标志物结论一致,可以用来反应妊娠期高血压孕妇的疾病严重程度。4、通过ROC分析显示β-痕迹蛋白的水平用于预测妊娠高血压疾病具有较高的灵敏度和特异性,因此,血清β-痕迹蛋白的水平有望成为妊娠高血压疾病的新型诊断标志物,在具有高危因素的孕妇中进行检测可提高预测灵敏度,用于妊娠高血压疾病的预测。
[Abstract]:Background: pregnancy induced hypertension is one of the most common complications of pregnancy. It is the main cause of the incidence and mortality of pregnant women, fetus and newborn, and the treatment of the disease depends on many factors, including blood pressure, gestational age, symptoms and related risk factors. Besides proteinuria and pregnant women, pregnant women also have high blood pressure. There is a high risk of cardiovascular disease and death. Compared to normal pregnant women, pregnancy induced hypertension has higher placental abruption, cardio cerebrovascular accident, organ failure, and diffuse intravascular coagulation risk. Intrauterine and fetal death. Early diagnosis, close antenatal monitoring and timely intervention are the key to the treatment of hypertension induced by pregnancy. Currently, the economy, repeatability, reliable clinical detection and prediction methods are still very short. Sex hormone binding globulin (SHBG) has a close relationship with hyperinsulinemia and insulin resistance. Androgen can enhance the responsiveness of blood vessels to vasoactive substances, reduce the level of prostacyclin and increase the production of thromboxane, directly add platelet agglutination to induce microthrombus formation, in addition, inflammation. There is an important role in the pathogenesis of pregnancy induced hypertension because the symptoms of chronic vasculitis in placenta are significantly increased in pregnant women with pregnancy induced hypertension. The level of serum testosterone, sex hormone binding globulin (SHBG) and hypersensitivity C reactive protein (hs-CRP) may be related to the occurrence of hypertension in pregnancy. The high risk factors of pregnancy induced hypertension and a more effective potential marker are found from the special manifestations of the patients with pregnancy induced hypertension. Beta trace protein is a prostaglandin D2 synthetase, a member of the lipid carrying protein family, whose protein molecular weight is very small. Only 23-29 kDa. has recently been studied for beta trace protein. It is mainly focused on the marker of serum creatinine as an alternative marker for the evaluation of renal function and a new marker of cardiovascular disease. Beta trace protein has been found to be a more sensitive marker for monitoring renal impairment than serum creatinine. Beta trace protein can be an ideal sign of renal dysfunction caused by glycuria. Research shows that beta trace protein is related to many biological processes, including inflammatory reaction, angina, atheromatous formation, vasoconstrictive reaction and systemic arterial pressure, with anti inflammation, antithrombotic formation, anti apoptosis, anti atherosclerosis and other cardiovascular protective effects, which can be significantly aggregated in human coronary atherosclerosis. Many studies have reported that the level of serum beta trace protein in patients with chronic coronary artery disease is significantly increased in patients with chronic coronary artery disease, and the level of serum beta trace protein is closely related to the number of damaged vessels, age, and hypertension. The high level of beta trace protein can predict atrial fibrillation The adverse cardiovascular events, mortality, and major bleeding of patients receiving anticoagulant therapy may also be used to respond to the progression of cardiovascular disease,.Hirawa et al. Compared the level of beta trace protein in normal and hypertensive patients, and found that the level of beta trace protein in high blood pressure patients is significantly higher than that in high blood pressure patients. The normal control group shows that beta trace protein plays an important role in hypertension. However, the relationship between the level of circulating beta trace protein and pregnancy induced hypertension is still unknown. This study aims to detect the level of serum beta trace protein in normal pregnant women and pregnant women with pregnancy induced hypertension and to explore the serum levels. The relationship between the level of beta trace protein and pregnancy induced hypertension. To our knowledge, this is the first study to reveal the association between serum level of beta trace protein and pregnancy induced hypertension. Objective: To compare the age of normal pregnant women with pregnancy induced hypertension (gestation hypertension group), prepregnancy BMI, pregnancy history, blood pressure, Weight, left ventricular ejection fraction (LVEF), urine protein, serum testosterone, sex hormone binding globulin (SHBG), hypersensitive C reactive protein (hs-CRP) and beta trace protein (BTP) were investigated to investigate the high risk factors of pregnancy induced hypertension in pregnant women and the level of serum testosterone, sex hormone binding globulin (SHBG) and hypersensitive C reactive protein (hs-CRP). Whether there is a correlation between the occurrence of pregnancy induced hypertension and the level of serum beta trace protein (BTP) in the serum of normal pregnant women and pregnant women during pregnancy at different stages of pregnancy, the level of serum BTP in the two groups of pregnant women was compared, and the level of serum beta trace protein (BTP) and pregnancy induced hypertension were evaluated by ROC analysis. Whether it is relevant, can the severity of the disease be counter to the severity of the disease, can be used as a new and more effective marker for predicting pregnancy induced hypertension and the ability to diagnose and identify pregnancy induced hypertension. Research objects and methods: select 1206 pregnant women who were born in Qilu Hospital and Zibo Central hospital in 2014 and choose pregnancy from them. 57 pregnant women of normal pregnancy age and pregnant age matched the normal control group (blood pressure 140/90 mmHg, and no proteinuria during pregnancy); 46 pregnant women with pregnancy induced hypertension were set up as pregnancy hypertension group (gestational hypertension disease was a symptom of no high blood pressure at 20 weeks before pregnancy, and the blood pressure was measured over two times after 20 weeks of pregnancy. " The results showed that the systolic pressure was more than 140 mmHg or the diastolic pressure was more than 90 mmHg, and the measurement interval was at least 4 hours, accompanied by preeclampsia or no proteinuria. The pregnant women of.46 pregnant hypertension were divided into simple hypertension group and preeclampsia group according to non albuminuria. The left ventricular ejection fraction was divided into group LVEF60% and LVET more than 60% groups according to the left ventricular ejection fraction 60%. All pregnant women were Single pregnancy, two groups of gestational age and gestational age matching. The exclusion criteria include: pregnancy induced hypertension may also accompany other diseases such as second types of hypertension, coronary heart disease, kidney disease, or diabetes. First, collect all the clinical indicators of all pregnant women, such as the average age of the pregnant women (age), and the height and quality before pregnancy. Volume index BMI (kg/m2), race (n,%), PIH family history (n,%), natural abortion history (3) (n,%), pregnancy times (3) (n,%) and so on, and compared and analyzed systolic pressure (millimeter mercury column), diastolic pressure (millimeter mercury column), birth gestational age (days), birth mode (n,%, normal vaginal delivery or CS), and placental weight (g), neonatal sex (n,%) and out of birth. Maternal weight (g) and other data. Pregnant women in pregnancy induced hypertension were monitored by echocardiography to monitor left ventricular ejection fraction (LVEF). All pregnant women were collected at different stages of pregnancy (1-12 weeks), mid trimester (13-27 weeks), late pregnancy (28-40 weeks) of blood samples, 4, 7000 RPM centrifugation and -80 C after 10 minutes. All stages of pregnancy were examined. The serum concentration of SHBG was measured by enzyme immunoassay. The level of testosterone and hypersensitive C reaction protein was measured by immunoluminescence. The level of serum beta trace protein was detected by enzyme linked immunosorbent assay (ELISA) kit. Two groups of pregnant women's urine protein, hs-CRP (mg/1) (mid trimester, late trimester), testosterone (mid trimester, late trimester), S were collected, S HBG (nmol/l) (mid trimester, late trimester of pregnancy) and BTP (early pregnancy, mid trimester, late pregnancy) and other experimental data, the results of the ELISA test were tested by non parametric test. The potential risk assessment was analyzed by plotting the ROC curve. (1) pregnant women with pregnancy induced hypertension were higher than the pregnant women in the normal control group that was in line with the age of pregnancy and the maternal age. The preconception height mass index (BMI) (P0.05), the higher anemia incidence (p0.001), and the family hereditary history of pregnancy induced hypertension (p0.001); under the premise of the same gestational age at birth, for other parameters such as delivery mode, placental weight, and birth weight, pregnant women with pregnancy and normal health control group have no obvious difference between pregnant women and pregnant women. (2) the level of serum testosterone, SHBG, and C reactive protein (hs-CRP) in the two groups of pregnant women showed no significant difference between the pregnancy induced hypertension group and the normal pregnancy group; (3) there was no significant difference between the levels of serum beta trace protein in the normal pregnant women and the pregnancy induced pregnancy. The level of serum beta trace protein in pregnant women with pregnancy induced hypertension increased gradually with different pregnancy stages, but there was no significant difference in the level of serum beta trace protein in the middle pregnancy and late trimester of pregnancy. (4) the serum beta mark of pregnant women with pregnancy induced hypertension compared with normal pregnant women. The level of trace protein in the middle and late pregnancy was significantly higher than that of the normal control group (P0.05), but there was no significant difference between the levels of serum beta trace protein between the two groups in the early pregnancy. (5) the level of serum beta trace protein in the pre eclampsia group was higher than that of the Dan Chungao blood pressure group, and the difference was statistically significant. The level of BTP in the serum of pregnant women with left ventricular ejection fraction LVET60% was significantly higher than that of pregnant women with LVET more than 60%. (6) the potential value of serum beta trace protein was assessed by ROC analysis to predict the potential value of pregnancy induced hypertension. The results showed that the use of serum BTP 321.3ng/mL as a truncated value and the predictive sensitivity for pregnancy induced hypertension Up to 91.3%, the specificity can reach the 89.5%. research conclusion: 1, pregnant women have the family history of pregnancy induced hypertension, the height mass index is high before pregnancy, the pregnant anemia should be included in the high risk monitoring group of the pregnancy hypertension,.2. This study did not find the middle and late pregnancy serum testosterone, sex hormone binding globulin (SHBG), C reactive protein (hs-CRP). The level is associated with the occurrence of pregnancy induced hypertension, so the index can not be used as a marker for predicting pregnancy induced hypertension. The high level of serum beta trace protein is associated with the occurrence of pregnancy induced hypertension, which can be used to reflect the progression of pregnancy induced hypertension. In addition, serum beta trace protein can also be used as a pregnancy.3. The predictors of hypertension involving the function of the kidney or heart are consistent with the conclusion that B- trace protein can be used as a marker of abnormal heart and kidney function. It can be used to respond to the severity of.4 in pregnant women with pregnancy induced hypertension. The level of beta trace protein can be used to predict high blood pressure in pregnancy by ROC analysis. It is sensitive and specific, so the level of serum beta trace protein is expected to be a new diagnostic marker for pregnancy induced hypertension. Detection in pregnant women with high risk factors can improve the predictive sensitivity and be used to predict pregnancy induced hypertension.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R714.246

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