臺灣博碩士論文加值系統

膽道閉鎖（Biliary Atresia）是小兒外科領域中最令人困惑的一個疾病。在臨床上的表現為新生兒黃膽，直接型膽紅素升高，解灰白便，肝臟外膽管閉鎖。在1957年以前大家對此疾病仍是束手無策，直到日本外科醫師葛西氏（Kasai）發明葛西氏手術將肝外閉鎖之膽管切除到肝門處（Liver hilum），再以空腸套在肝門處以期待膽汁的排出，才開始有治療的一個希望。這四十年來由於對於此疾病之病因的探討研究，在病因學以及預後因子的了解有一些進步。在病因的研究上，有許多種假說，包括先天性肝內膽管發育畸型 （Congenital ductal plate malformation），病毒感染，自體免疫系統功能失調，肝動脈畸型等等，但是莫衷一是。在預後因子的研究上，包括接受手術的年齡，接受手術時肝臟肝門處膽管直徑大小及肝臟纖維化程度，肝臟細胞以及肝內膽管上皮細胞的炎性介質抗原的表現與否等等。在我們的研究中，我們希望能更進一步探討膽道閉鎖的病因以及預後因子。
大部份對於膽道閉鎖的研究都是著重於肝外膽管（Extrahepatic bile duct），少部份探討肝內膽管（Intrahepatic bile duct, ductule），很少有探討到膽小管（Bile canaliculus）的層次。我們了解肝臟細胞是一具有極性的上皮細胞，含有血管竇，基底側和膽小管三種功能團。利用抗人類肝細胞中膽小管功能團的單株抗體（9B2），以人類肝癌細胞株為模式發現分化良好的肝癌細胞株如：HepG2，HuH-7等可以在肝細胞之間形成膽小管的構造，但是在分化不良的細胞株如：HA22T/VGH，SK-HEP-1則無法形成。我們的研究假設人類胎兒肝臟中膽小管的發育應該是漸漸成熟，而不成熟的情況可能在某些膽道閉鎖的病患可以發現。而呈現不成熟膽小管發育的膽道閉鎖病患其致病原因可能含有先天性的問題，而非只有後天的問題。其他，膽小管發育成熟的膽道閉鎖可能是後天問題為主。
我們利用9B2單株抗體藉著免疫組織化學染色以及流式細胞計數法 (Flow cytometry) 在人類胎兒，早產兒，足月新生兒及兒童肝臟切片的檢驗，發現膽小管在足月新生兒的發育已漸趨完整，而32週大的早產兒仍發育較差，20週大的胎兒發育極不成熟。另外比較總膽管囊腫病患的膽小管抗原表現，可以發現阻塞性黃疸可以使9B2抗原表現增強。而在我們所研究的膽道閉鎖病患，有一部份的9B2抗原表現相當強，比足月新生兒高得多，有一部份病患的9B2抗原表現和足月新生兒強度相當，甚至有一小部份病患的9B2抗原表現強度與32週大的早產兒相近。有趣的是9B2抗原表現愈強的病患接受葛西氏手術失敗機率愈高。由這些結果我們認為做葛西氏手術前的9B2表現強弱可以預測肝外膽管阻塞的嚴重程度以及時間長短，除此之外表現9B2強度低於足月新生兒的病例其病因可能合併有先天性發育的問題。
此外，由於免疫功能失調可能是膽道閉鎖病因之一，而許多報告曾指出Fas-Fas ligand系統所造成的細胞計劃性死亡 (Apoptosis) 可以在許多肝臟疾病扮演肝細胞壞死的角色，而在動物實驗上也發現將肝外膽管紮住引起阻塞性黃疸可以誘發由Fas-Fas ligand系統所引起的肝細胞Apoptosis。所以我們將膽道閉鎖病患的肝臟切片作關於Fas，Fas ligand表現的研究。發現Fas ligand蛋白質以及訊息核醣核酸 (mRNA) 可以表現在某一部份的膽道閉鎖病患的肝內膽管上皮細胞，而這些病患的肝內膽管上皮細胞（Intrahepatic bile duct epithelium）有Apoptosis的現象，而且這些病患的浸潤淋巴球（Infiltrating lymphocytes）呈現Apoptosis的量也高於其他病患。更有趣的是這些肝內膽管上皮細胞有Fas ligand蛋白質及mRNA表現者，其手術預後在統計上，有顯著的高失敗率。此結果讓我們推論肝內膽管上皮細胞可能分泌Fas ligand來攻擊浸潤淋巴球而卻造成Autocrine或Paracrine suicide而破壞肝內膽管而使得手術後仍使肝內膽管持續破壞，Fas/Fas ligand系統可能不是起始病因，但可以反應免疫系統功能失調在膽道閉鎖病因中扮演一個相當重要的角色。比較9B2的表現可以發現那一小部份9B2表現強度與早產兒相近者，其肝內膽管上皮細胞都沒有表現FAS ligand蛋白質及mRNA，也沒有Apoptosis的情況。
從我們的研究中，我們認為膽道閉鎖可能合併多種病因，先天發育及後天免疫功能失調都可能為其中的原因之一。9B2抗原的表現強度和肝內膽管上皮是否分泌Fas ligand都可以作為術後成功與否的預後因子。

Biliary atresia (BA) is the most puzzled disease in the field of pediatric surgery. Clinical manifestations are neonatal jaundice, direct hyperbilirubinemia, passage of clay stool and obliteration of extrahepatic bile duct. This disease was incurable until Dr. Kasai, a Japanese surgeon, reported his portoenterostomy in 1957, which was the procedure of excision of extrahepatic fibrotic bile duct to liver hilum and roux-en-y portojejunostomy. During the past four decades, many investigations have been made to figure out the etiologies of BA and the predictors for post-Kasai outcome. There are many hypotheses about the etiology, including congenital ductal plate malformation, viral infection, immunological/inflammatory system disorder and defect in fetal/perinatal circulation. There are also many predictors for post-Kasai outcome, including age at Kasai operation, diameter of bile duct at hilum, severity of liver fibrosis and the presentation of some inflammatory mediators on hepatocytes and intrahepatic bile ductule epithelia. In this study, we try to further study the etiology and clinical predictors of BA.
Most studies on BA focused on the extrahepatic bile duct and intrahepatic bile duct and ductule, very few studies discussed about bile canaliculi, which is the most cephalic part of bile secretory apparatus. The hepatocyte is known as a polarized epithelial cell, composed of sinusoid, basolateral and bile canalicular domains. Previous studies used monoclonal antibodies (9B2), shown to react with the antigens on the bile canalicular domain of human hepatocytes, and the human hepatoma cell lines as in vitro model to study the biliary polarity of human hepatocytes. In Hep G2 and HuH-7, known as well differentiated hepatoma cell lines, the 9B2 antigen could be located on the bile canaliculus structure; whereas in HA22T/VGH and SK-HEP-1, known as poorly differentiated lines, no 9B2 antigen located on the bile canaliculus structure. In this study, we hypothesize the bile canaliculus of human fetal hepatocytes is progressively developed and the under-developed status could be found in some cases of BA. Congenital malformation could be one of the causative factors of BA in the cases with under-development of bile canaliculi while the postnatal insults should be responsible for the cases without under-development of bile canaliculi.
When comparing the expression of 9B2 antigens in the livers of 20-weeks fetuses, premature babies, term neonates and children by means of semiquantitative analysis of immunohistochemistry staining and quantitative analysis of flow cytometry, we find that bile canaliculi are well developed in term neonates, under-developed in premature babies and even less developed in 20 week fetuses. We also find the fact that obstructive jaundice rather than hepatitis will induce 9B2 antigen expression stronger by examining the livers of choledochal cysts and neonatal hepatitis. In the livers of BA patients, some cases have much stronger 9B2 expression than term neonates, some cases have about the same expressive intensity as term neonates but a few cases have the intensity as premature babies. We also find that the more intensive expression of 9B2 antigens, the higher failure rate of Kasai operation. Based on the results, we suggest the intensity of 9B2 expression in the pre-Kasai livers could reflect the severity and duration of extrahepatic obstruction before Kasai operation. In the cases showing premature development of bile canaliculi, congenital malformation may be a causative factor of BA.
The disorder of immunological system had been proposed to be one of the etiologies in BA. Many reports indicated that apoptosis induced by Fas/Fas ligand (FasL) system may play a role on various types of hepatitis and some animal studies indicated ligation of extrahepatic bile duct would cause hepatocytes apoptosis by Fas/FasL system. So, we question whether the Fas/FasL system is involved in the persistent liver damage of BA by examining the expression of FasL proteins and FasL mRNA on the livers of BA patients. We find that positive expression of FasL protein and mRNA is noted on some intrahepatic bile ductule epithelia in some BA patients. In these cases, apoptosis of intrahepatic bile ductule epithelia is noted and larger amount of apoptosis of infiltrating lymphocytes as compared with the cases without expression of FasL on bile ductule epithelia. We also note that the post-Kasai outcome in the cases with positive FasL expression had a significantly higher failure rate. This result suggests intrahepatic bile ductule epithelia could secret FasL to attack the infiltrating lymphocytes and result in apoptotic suicide/fratricide and these leads to persistent destruction of intrahepatic bile ductule after Kasai-operation. Although Fas/
FasL system should not be the initiating cause of BA, it may play a significant role in the pathogenesis of BA. Very interestingly, in the cases of BA with under- development of 9B2, there is neither expression of FasL on intrahepatic bile ductile epithelia nor the phenomenon of apoptosis.
From our study, we conclude that the etiology of BA is multiple and congenital malformation and post-natal disorder of immunological system may play a role in the pathogenesis. Both the expression intensity of 9B2 and FasL on bile ductule epithelia could serve as the prognostic factors of Kasai operation.

封面
中文摘要　　　　　
英文摘要
第一章 概論　　
第二章 材料與方法　　
第三章 肝臟APN表現與膽道閉鎖的關聯
第一節 人類胎兒到新生兒以及兒童其膽小管抗原的表現
第二節 膽道閉鎖病患, 新生兒肝炎病患以及兒童阻塞性黃疸病患的膽小管抗原的表現
第三節 圖及表
第四章 Fas以及Fas ligand系統與膽道閉鎖的關聯
第一節 Fas以及Fas ligand系統所引發的細胞凋亡在膽道閉鎖可能扮演的角色
第二節 預後因子和可能病因
第三節 圖及表
第五章 結語　　　
參考文獻
附錄

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