台灣大學附設醫院胎兒、新生兒與兒童先天性心臟病的病理解剖案例之回溯性探討

Abstract

背景與論述重點 本論文收錄台大醫院二十年來解剖之新生兒與兒童先天性心臟病之系列案例，進行病因病理的回顧性研究，針對不同類型的先天性結構性心臟異常作統計與分析，並就其作系統性的文獻回顧，並針對先天性心臟病案例的心肌切片做特定蛋白的免疫組織染色。 材料和方法 本研究收錄了自1998年至2024年在台灣大學附設醫院解剖的七十五例胎兒、新生兒與兒童先天性心臟病的解剖個案，將所有的案例解剖報告或臨床報告中記載有先天性心臟病的診斷進行紀錄，並把案例的死亡原因進行統整。同時，將這些解剖案例的心肌細胞切片(心室肌肉切片)作鏡檢觀察，並挑特並先天性心臟病案例進行YAP-1蛋白免疫組織抗體染色，與對照組作比較。 結果與討論 七十五例兒童先天性心臟病死亡的解剖個案中，其中女性有34例(45.3%)，男性41例(54.6%)。解剖年紀統計，未出生的胎兒有15例(20%)，出生後的新生兒有22例(29.3%)，嬰兒(infant)有32例(42.6%)，一歲以上的幼童(child)有6例(8%)。主要診斷為複雜性先天性心臟病的有54例(72%)，單純性先天性心臟病共有8例(10.6%)，染色體異常合併先天性心臟病有8例(10.6%)，其它先天性心臟病診斷有5例(6.6%)。複雜性先天性心臟病佔比最多的為異位綜合症 (heterotoxy syndrome)(n=14, 18.6%)，其次為左心發育不全症候群(Hypoplastic left heart syndrome )(n=12, 16%)，排名第三為大動脈轉位 (Transposition of great aorta)(n=10, 13.3%)。死亡原因與機轉中，15例的胎兒先天性心臟病案例都是接受中止姙娠(termination)而進行引產手術，出生後的新生兒、嬰兒或兒童案例中，敗血性休克有29例，心因性休克有30例，神經性休克有1例。正常對照組的心肌切片中，所有的案例(n=17)YAP-1蛋白均呈現細胞核保留染色的表現(preserved nuclear expression)，並且依胎兒、新生兒與兒童不同的年紀，YAP-1蛋白的免疫染色在核染色的表現範圍與強度會隨年紀增長而減弱。左心發育不全症候群的案例中(n=11)，有72.7%(8/11)的案例的心肌切片YAP-1蛋白免疫染色呈現喪失表現(p值=0.00022)；右心發育不全症候群(n=2)與大動脈轉位(n=7)的案例，也都呈現統計上具意義的喪失表現，核染色喪失的比例分別是100% (2/2, p值= 0.0095)與71.4% (5/7, p值=0.0014)。相對來說，異位綜合症(n=7)案例的YAP-1蛋白免疫染色則是只有28.6%(2/7, p值= 0.0877)呈現核喪失染色，其餘均為保留染色(preserved nuclear expression)。 結論 本研究收錄了台大醫院近二十年，七十五例的胎兒、新生兒、兒童的先天性心臟病解剖案例，其中持續性動脈導管是出現頻率最高的先天性心臟異常，且多數收錄的死亡案例為複雜性先天性心臟病。解剖案例的死亡的原因主要為與先天性心臟結果異常相關的心因性休克，或是感染性相關的敗血性休克。除了異位綜合症之外，左心發育不全症候群、右心發育不全症候群與大動脈轉位的死亡案例之心肌切片之YAP1免疫組織染色呈現具統計上意義的喪失表現。

Background This thesis includes a series of congenital heart disease cases in neonates and children collected from autopsies performed over the past twenty years at National Taiwan University Hospital. It conducts a retrospective study on the etiology and pathology of these cases, provides statistical analysis of different types of congenital structural cardiac anomalies, and includes a systematic review of the related literature. In addition, immunohistochemical staining for specific proteins related to congenital heart disease is performed.

Material and method This study included 75 autopsy cases of fetuses, neonates, and children with congenital heart disease (CHD) conducted at National Taiwan University Hospital between 1998 and 2024. Diagnoses of CHD documented in autopsy or clinical reports were systematically recorded, and the causes of death for each case were reviewed and categorized. In addition, myocardial tissue sections (ventricular myocardium) from these autopsy cases were examined microscopically. Selected cases with congenital heart disease were further analyzed by immunohistochemical staining for YAP1 protein and compared with a control group.

Result and discussion Among the 75 pediatric autopsy cases of congenital heart disease (CHD), 34 were female (45.3%) and 41 were male (54.6%). Based on age at autopsy, there were 15 fetal cases (20%), 22 neonatal cases (29.3%), 32 infant cases (42.6%), and 6 cases in children over one year old (8%). Regarding the primary diagnosis, 54 cases (72%) involved complex congenital heart disease, 8 cases (10.6%) involved simple congenital heart disease, 8 cases (10.6%) were associated with chromosomal abnormalities and CHD, and 5 cases (6.6%) were categorized under other types of congenital heart disease. Among the complex CHD cases, the most common diagnosis was heterotaxy syndrome (n=14, 18.6%), followed by hypoplastic left heart syndrome (HLHS) (n=12, 16%), and transposition of the great arteries (TGA) (n=10, 13.3%). As for the causes and mechanisms of death, all 15 fetal CHD cases underwent termination of pregnancy via induced labor. Among neonates, infants, and children, septic shock was reported in 29 cases, cardiogenic shock in 30 cases, and neurogenic shock in 1 case. In the control group, all myocardial tissue sections (n=17) showed preserved nuclear expression of YAP1 protein. Notably, the extent and intensity of nuclear YAP1 immunostaining tended to decrease with increasing age from fetus to child. In the HLHS group (n=11), 72.7% (8/11) of cases demonstrated loss of nuclear YAP1 expression (p = 0.00022). Similarly, significant loss of nuclear expression was observed in right heart hypoplasia cases (n=2, 100%, p = 0.0095) and TGA cases (n=7, 71.4%, 5/7, p = 0.0014). In contrast, among heterotaxy syndrome cases (n=7), only 28.6% (2/7) showed loss of nuclear YAP1 staining (p = 0.0877), while the remaining cases retained preserved nuclear expression.

Conclusion This study included 75 autopsy cases of fetuses, neonates, and children with congenital heart disease (CHD) collected over the past two decades at National Taiwan University Hospital. Among these cases, patent ductus arteriosus (PDA) was the most frequently observed congenital cardiac anomaly, and the majority of deaths were associated with complex congenital heart disease. The primary causes of death in these autopsy cases were cardiogenic shock related to the underlying cardiac malformations, and septic shock due to infection. Except for heterotaxy syndrome, cases of hypoplastic left heart syndrome, right heart hypoplasia, and transposition of the great arteries demonstrated a statistically significant loss of YAP1 expression