超声在胎儿胆道系统中的应用研究及羊水GGT正常参照值的建立

发布时间：2018-04-22 18:43

本文选题：超声 + 产前诊断　；参考：《山东大学》2014年博士论文

【摘要】：研究背景与研究目的产前超声在胎儿时期能够显示的胆道系统异常主要包括：胆道囊性发育异常(biliary cystic malformation, BCM)、胆囊不显示(non-visualization of gallbladder, NVGB)、旦囊大小异常、胆囊腔内异常回声及胆囊位置异常。多年来国外超声研究的相关文献数量有限,不同研究所得到的结论往往差别也较大。针对东方人群的系统研究鲜见报道。我国已开展胎儿产前诊断工作十余年,在超声筛查和诊断胎儿畸形的工作中,对胎儿胆道系统异常的相关研究一直是薄弱环节。对胎儿胆道系统的超声诊断缺乏规范的研究和标准。 BCM产前异常表现主要为胆管树的囊状扩张。包括囊性胆道闭锁(cystic biliary atresia, CBA)和胆总管囊肿(choledochal cyst, CC,属于先天性胆管扩张症范畴)两大类疾病。因诊断经验的差异,在产前超声检查中,易与肠系膜囊肿、肝囊肿、大胆囊,左位胆囊、十二指肠闭锁,及胎儿右上腹部的其它囊性病变相混淆。囊肿与胆囊相通或与扩张肝管相通,是产前超声判断其胆系来源的决定性征象。而在产前超声检查中,上述超声征象在BCM类疾病中常常显示不清晰。胎儿可导致NVGB的相关因素之中,胆囊收缩是最常见的原因。而临床对于胎儿胆囊收缩的规律、可能持续的时间、发生机制知之甚少。最近胎儿NVGB结合羊水中消化酶检测技术已逐渐应用于临床以辅助胆道闭锁(biliary atresia, BA)等严重疾病的产前诊断,虽然对BA的诊断特异性有限,但到目前为止,尚未发现新的可替代辅助诊断方法。东方人相对来说是BA的高发人群,因此建立国人羊水GGT的正常参考值是必要的。为了进一步了解胎儿胆道系统异常的超声表现及掌握有诊断价值的诊断征象,本论文就以下问题进行了深入探讨。 1.如何评价现有超声征象对BCM类疾病的检出效率,及如何提高BCM的产前检出率。 2.CC和CBA产前超声表现虽然相似,产前超声扫查时应如何鉴别。 3.导致胎儿胆囊NVGB相关因素的深入研究。 4.研究胆囊收缩在NVGB中的发生率及胎儿胆囊收缩的持续时间。 5.为提高BA产前诊断水平,有必要建立我们自己的羊水GGT参考值。第一部分：胎儿囊性胆道发育不良的超声表现及具有诊断价值的超声征象筛选目的：1.从常见BCM相关超声征象中,筛选出对产前诊断BCM具有较高特异度及敏感度的征象及其组合。2.总结胎儿BCM的超声表现及临床结局。方法：1.以2009年5月至2013年11月期间,30例发生于中上及右上腹部囊性病变的胎儿作为研究对象。以产前及产后超声诊断,或手术、尸解病理结果为依据,将病例分为BCM(16例)及非BCM(NBCM,14例)两组。比较产前超声诊断BCM的相关征象在两组中的表达率。这些征象包括：囊肿位于胎儿右上腹部(A)、囊肿上端紧贴肝门下方(B)、囊肿并非胆囊(C)、囊肿内无分隔(D)、囊肿与胆囊相通(E)、囊肿与肝管相通(F)、囊肿下缘止于上腹正中、脊柱前方(G)、囊肿上端接近胆囊颈部(H)。通过诊断试验评价各征象及征象组合的诊断效能。以诊断指数作为参考依据,筛选出最有应用价值的征象及征象组合。2.总结BCM病例的产前超声表现,并总结随访病例的临床结局。结果：1.征象A、D在BCM及NBCM两组间表达无统计学差异；其余征象组间表达差异有统计学意义(P0.05)。2.诊断试验表明：单项征象B、F、G及19个征象组合具有诊断效能。诊断指数1.9000的征象组合为B和H、E或F、E或G、B和D、F或G、E或F或G；后三组达到2.0000。3.共9例BCM随访至出生后,8例为CC,1例为CBA。产前超声共6例表达F征,其中4例出生后伴有阻塞性黄疸。4.CC囊肿出生前后均有不同程度增大,CC病例的胆囊大小形态正常。1例III型CBA囊肿产前超声变化不明显,而生后体积逐渐变小,胎儿胆囊显示不清。结论：1.如果胎儿肝门下方出现囊肿,在排除其为胆囊的可能性的前提下,即可考虑为胆系来源囊肿可能；而如果观察到囊肿与胆囊、肝管相通或囊肿下端逐渐向胎儿上腹中部,脊柱前方走行时可进一步明确其胆系来源可能。2.BCM病例产前超声伴有肝管扩张者,生后有可能出现阻塞性黄疸。3.产前超声表现为BCM合并NVGB或胆囊发育不良,且囊肿在出生后有减小趋势时,应考虑到CBA可能性。第二部分超声在胎儿胆囊异常的应用研究目的：1.研究胎儿胆囊异常的临床意义。2.研究胎儿胆囊收缩的持续时间。方法：1.对2009年1月～2013年12月期间,我科诊出的胎儿胆囊异常者分类,进行超声随访,结合临床及其它辅助检查手段获得病因诊断。2.32例孤立性NVGB的胎儿按固定周期进行密切产前及生后超声随访。总结并分析NVGB初诊至胆囊再度显示之间的时间间期(A-B间期)。结果：1.研究期间共检出胎儿胆囊异常者共347例,在门诊病例中的检出率约0.6%。NVGB308例,占胎儿胆囊异常病例总数的88.8%(308/347);胆囊腔内异常回声27例(其中3例产前超声继NVGB之后出现),占7.8%(27/347)；胆囊位置异常15例,占4.3%(15/347),均无明显性别差异。2.在308例胎儿NVGB中,89.9%超声初诊于晚孕期。27例合并其他超声异常,占NVGB总数的8.8%(27/308)其中12例合并多发异常。随访NVGB病例215例,90.7%初诊于晚孕期。3例胎儿NVGB,最终证实病因为先天性胆道发育异常,分别为先天性无胆囊、肝小叶间胆管缺乏及III型囊性胆道闭锁(cystic biliary atresia, CBA),占随访病例的1.4%。3.胎儿胆囊腔内异常回声27例,平均孕周(35.7±2.5)周(范围29～39周)。其中3例(3.7%)合并其他结构异常,其余25例胆囊腔内异常回声均随访至消失,21例(84%)消失于生后1周内。4.胆囊位置异常15例。永久性右脐静脉(Persistent right umbilical vein, PRUV)10例,其中50%合并心脏或血管发育异常。左位胆囊2例,预后良好。内脏反位(Situs viscera inversus, SVI)3例,均引产,1例为21-三体。5.A-B间期(NVGB初诊至胆囊再度显示的时间问期)为3天～71天。28.1%(9/32)病例A-B问期≤7天,46.9%(15/32)病例A-B间期在8天～21天之间,25%(8/32)病例A-B间期21天。产前胆囊再显示者21例。11例胎儿胆囊于产后再显示,显示实现均于生后1周以内。经随访32例由胆囊收缩所致的NVGB胎儿预后良好,A-B间期长短对胎儿预后没有明显影响。结论：1.NVGB是最常见的胎儿胆囊异常表现。2.尽管胎儿生理性胆囊收缩是孕晚期胎儿NVGB最常见原因,但仍有存在胆道系统发育异常(1.4%)及合并多发超声异常(3.9%)的可能,临床不容忽视。3.肝小叶间胆管缺乏可能是胎儿胆囊持续不显示的病因之一,其临床意义有待深入研究。4.胎儿胆囊腔内异常回声均出现于晚孕期之后(尤其是孕32周至足月),均于产前产后自行消失,84%于生后1周内消失,预后良好。5.胎儿胆囊的形态和位置异常可合并多发异常及染色体异常。因此胎儿胆囊的超声观察具有重要临床意义。6.胎儿胆囊的持续收缩多是生理现象,A-B间期的长短对胎儿预后无明显影响,其生理机制有待深入研究。第三部分：妊娠20周～24周正常胎儿羊水GGT酶值测定及价值目的：建立20周～24周胎儿羊水GGT正常值,以作为胆道闭锁产前诊断的参考值。方法：试验采用横断设计。羊水采集自2009年6月～2010年4月期间,符合羊水穿刺指征,需进行胎儿染色体检查的孕妇。同时应满足以下条件：胎儿染色体结果正常,孕妇身体健康,孕妇及配偶无染色体异常,产前超声检查无明显胎儿结构异常(包括羊水量异常),无染色体异常胎儿分娩时,或病因不明的异常孕产史。羊水标本抽取后立即送检染色体核型及GGT的定量分析。计算各孕周羊水GGT测值的x±s、1%-99%可信区间,并对LogGGT值与孕周的相关性进行Pearson检验。结果：研究期间共采集符合标准的孕20周～24周胎儿羊水110例。其中女性胎儿73例。随孕周增长GGT酶值的x、中位数、LogGGT均有随孕周逐渐减低的趋势,LogGGT值与孕周呈负相关。结论：随孕周增长GGT酶值有逐渐减低的趋势；胎儿孕20周-24周羊水GGT正常值的建立有望对进一步关于胆道闭锁的产前诊断及CC与CBA产前的鉴别诊断提供新的辅助诊断参考依据。
[Abstract]:Research background and research purpose
The abnormalities of the biliary tract system that the prenatal ultrasound can display in the fetal period mainly include: biliary cystic malformation (BCM), the gallbladder does not display (non-visualization of gallbladder, NVGB), the size of the sac is abnormal, the abnormal echo of the gallbladder and the abnormal position of the gallbladder.
Over the years, the number of relevant literatures on ultrasound studies abroad is limited, and the conclusions from different research institutes are often different.
In China, the prenatal diagnosis of fetal prenatal diagnosis has been carried out for more than ten years. In the work of screening and diagnosis of fetal malformation, the study of abnormal fetal biliary system has been a weak link. The ultrasonic diagnosis of fetal biliary system is lack of standard research and standard.
The abnormal prenatal manifestation of BCM is the cystic dilatation of the bile duct tree. The two major diseases include cystic biliary atresia (cystic biliary atresia, CBA) and choledochal cyst (choledochal cyst, CC, and congenital cholangiectasis). Due to the difference of diagnostic experience, the mesenteric cyst, hepatic cyst, large gallbladder, and left position in the prenatal hyper acoustic examination Gallbladder, duodenal atresia, and other cystic lesions in the right upper abdomen of the fetus are confused. The cyst is interlinked with the gallbladder or interlinked with the dilated hepatic duct. It is a decisive sign of the source of the biliary system by prenatal ultrasound. In the prenatal ultrasound, the above ultrasound signs are often not clear in the BCM disease.
The most common cause of the cholecystokinin is that the fetus can lead to NVGB, and there is little knowledge about the mechanism of the fetal gallbladder contraction, the possible duration and the mechanism of the gall bladder contraction.
Recently, fetal NVGB combined with amniotic fluid (amniotic fluid) digestive enzyme detection technology has been applied to clinical diagnosis of severe diseases such as biliary atresia (biliary atresia, BA) and other serious diseases. Although the diagnosis of BA is limited, up to now, no new alternative diagnostic methods have been found. The Oriental is a relatively high risk population of BA. It is necessary to establish the normal reference value of Chinese amniotic fluid GGT.
In order to further understand the ultrasonographic manifestations of fetal biliary tract system abnormalities and grasp the diagnostic signs of diagnostic value, the following issues were discussed in depth.
1. how to evaluate the detection efficiency of the existing ultrasonic signs for BCM diseases and how to improve the detection rate of BCM.
Prenatal sonographic findings of 2.CC and CBA are similar. How to identify prenatal ultrasound scanning?
3. in-depth study of NVGB related factors in fetal gallbladder.
4. to study the incidence of gallbladder contraction in NVGB and the duration of fetal gallbladder contraction.
5. in order to improve the level of prenatal diagnosis of BA, it is necessary to establish our own GGT reference value for amniotic fluid.
Part I: ultrasonographic features and diagnostic value of fetal cystic dysplasia of bile.
Objective: 1. to screen out the signs of high specificity and sensitivity for prenatal diagnosis of BCM and the combination of.2. to summarize the ultrasonic manifestations and clinical outcomes of fetal BCM from the common BCM related ultrasonographic signs.
Methods: 1. from May 2009 to November 2013, 30 fetuses born in the upper and right upper abdominal cystic lesions were studied. The cases were divided into BCM (16 cases) and two groups of non BCM (NBCM, 14 cases) with prenatal and postpartum ultrasound diagnosis, or surgery, and the pathological results were obtained. The correlation of prenatal ultrasonography in the diagnosis of BCM was compared in the two groups. These signs include: the cyst is located in the right upper abdomen of the fetus (A), the upper end of the cyst is close to the hepatic portal (B), the cyst is not the gallbladder (C), the cyst is separated from the gallbladder (D), the cyst and the gallbladder are interlinked (E), the cyst and the liver Guan Xiangtong (F), the lower margin of the cyst in the upper abdomen (G), and the upper end of the cyst near the neck of the gallbladder (H). Through diagnostic test evaluation The diagnostic efficiency of the various signs and the combination of signs. The diagnostic index was used as the reference basis to screen out the most valuable signs and signs combination.2. to summarize the prenatal ultrasound manifestations of BCM cases, and to sum up the clinical outcome of the follow-up cases.
Results: there was no statistical difference between the 1. signs of A and D in the two groups of BCM and NBCM; the difference between the other signs was statistically significant (P0.05).2. diagnostic test showed that the single sign of B, F, G and 19 signs had diagnostic efficiency. The combination of the diagnostic index 1.9000 was B and H. 0000.3. 9 cases were followed up to postnatal, 8 cases CC, 1 cases of CBA. prenatal ultrasound and 6 cases of F, of which 4 cases were born with obstructive jaundice.4.CC cyst at birth and before and after birth. The size of the gallbladder in CC case is normal.1 case of III type CBA cyst prenatal ultrasound alteration is not obvious, and the postnatal volume gradually smaller, fetal gallbladder. The display is not clear.
Conclusion: 1. if there is a cyst beneath the hilum of the fetal liver, it is possible to consider the possibility of biliary cyst in the precondition of removing the gallbladder, and if the cyst is connected to the gallbladder, the hepatic duct or the lower end of the cyst to the upper middle of the fetus, the possible.2.BCM case of the biliary tract may be further clarified. Prenatal ultrasound with hepatic duct dilatation may occur after birth of obstructive jaundice with.3. prenatal ultrasound in BCM with NVGB or gallbladder dysplasia, and the possibility of CBA should be considered when the cyst has a decreasing trend after birth.
The second part is the application of ultrasound in fetal gallbladder abnormality.
Objective: 1. to study the clinical significance of fetal gallbladder abnormality..2. study the duration of fetal gallbladder contraction.
Methods: 1. from January 2009 to December 2013, the group of fetal gallbladder abnormalities diagnosed by our department were classified, followed up with ultrasound, combined with clinical and other auxiliary examinations to obtain the etiological diagnosis of.2.32 cases of isolated NVGB. The close prenatal and postnatal ultrasound visits were carried out according to the fixed period of the fetus. The first diagnosis of NVGB to the gallbladder re display was summarized and analyzed. Time interval (A-B interval) between them.
Results: 1. a total of 347 cases of fetal gallbladder abnormalities were detected in the 1. study period. In the outpatient cases, the detection rate was about 0.6%.NVGB308 cases, accounting for 88.8% (308/347) of the total number of abnormal gallbladder cases, 27 cases of abnormal echo in the gallbladder (3 cases of prenatal ultrasound after NVGB), 7.8% (27/347), and 15 cases of gallbladder location, accounting for 4.3% (15/347), all of them were all cases (15/347). There were no significant gender differences in 308 cases of fetal NVGB, 89.9% ultrasound first diagnosed in late pregnancy.27 cases combined with other ultrasound abnormalities, accounting for 8.8% (27/308) of the total number of NVGB (27/308) of which 12 cases were associated with multiple abnormalities. 215 cases of NVGB cases were followed up, 90.7% first diagnosed in late pregnancy.3 case fetal NVGB, and finally confirmed that the disease was congenital biliary dysplasia, respectively, congenital absence of congenital biliary tract development. The gallbladder, the hepatic interlobular bile duct deficiency and the type III cystic biliary atresia (cystic biliary atresia, CBA), accounted for 27 cases of abnormal echo echo in the gallbladder of the follow-up cases, the average gestational age (35.7 + 2.5) weeks (29~39 weeks). 3 cases (3.7%) were combined with other structural abnormalities, and the other 25 cases of abnormal echo in the gallbladder were followed up to disappear, 21 cases (84%). There were 15 cases of abnormal.4. gallbladder disposition within 1 weeks after birth. 10 cases of permanent right umbilical vein (Persistent right umbilical vein, PRUV), of which 50% had cardiac or vascular dysplasia. 2 cases of left gallbladder had good prognosis. 3 cases of visceral reverse position (Situs viscera inversus, SVI) were induced, 1 cases were first diagnosed to gallbladder again. .28.1% (9/32) case A-B of 3 days to 71 days was less than 7 days, 46.9% (15/32) A-B interval was 8 to 21 days, 25% (8/32) A-B interval was 21 days. The postnatal gallbladder re display of 21 cases of.11 case of fetal gallbladder was re displayed postpartum, showing that the realization was within 1 weeks after birth. After follow-up, 32 cases of NVGB fetus caused by gallbladder contraction were followed up. The prognosis is good, and the length of A-B interval has no significant effect on the prognosis of the fetus.
Conclusion: 1.NVGB is the most common abnormal manifestation of fetal gallbladder (.2.). Although fetal physiological gallbladder contraction is the most common cause of fetal NVGB in the late pregnancy, there is still a possibility of abnormal development of biliary tract (1.4%) and multiple ultrasound abnormalities (3.9%), which may not be ignored in the clinic, which may not be the continuous undisplay of the fetal gallbladder. One of the causes of the disease is to study the clinical significance of the abnormal echo in the gallbladder of.4. fetus after the late pregnancy (especially in 32 weeks to full term), all of which disappear spontaneously before and after birth and after birth, 84% in 1 weeks after birth. The prognosis is good for the form and position of the gall bladder of the fetus of.5., which may be combined with multiple abnormalities and chromosomal abnormalities. The ultrasonic observation of the gallbladder has important clinical significance. The continuous contraction of the gall bladder in the.6. is a physiological phenomenon. The length of the A-B interval has no obvious influence on the prognosis of the fetus, and its physiological mechanism needs to be further studied.
The third part: determination and value of GGT enzyme value in normal fetuses from 20 weeks to 24 weeks of gestation.
Objective: to establish the normal GGT value of fetal amniotic fluid 20 weeks to 24 weeks, so as to provide reference value for prenatal diagnosis of biliary atresia.
Methods: the transection design was used. The amniotic fluid was collected from June 2009 to April 2010. The pregnant women who were in accordance with the indications of amniotic fluid puncture were required to carry out the fetal chromosome examination. The following conditions should be met: the fetal chromosome results were normal, pregnant women were healthy, pregnant women and spouses had no dyed body abnormalities, and prenatal ultrasound examination had no obvious fetal structural difference. Often (including abnormality of amniotic fluid), no chromosomal abnormal fetal birth, or abnormal pregnancy history of unknown etiology. The karyotype and GGT quantitative analysis of amniotic fluid samples were taken immediately after the extraction of amniotic fluid samples. The X + s, 1%-99% confidence interval of the GGT values of amniotic fluid in each week were calculated, and the correlation between the LogGGT value and the pregnancy week was tested by Pearson test.
Results: during the study, 110 cases of fetal amniotic fluid were collected from 20 weeks to 24 weeks of pregnancy, of which 73 were female. With the growth of GGT enzyme, the median of X, the median, LogGGT decreased gradually with the gestational weeks, and the LogGGT value was negatively correlated with the gestational weeks.
Conclusion: the GGT enzyme value gradually decreases with the growth of gestational weeks, and the establishment of the normal value of amniotic fluid GGT at 20 weeks -24 weeks in fetal pregnancy is expected to provide a new diagnostic reference for the further diagnosis of biliary atresia and the differential diagnosis of CC and CBA prenatal.

【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R714.5;R445.1

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