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研究生:倪衍玄
研究生(外文):Ni, Yen-Hsuan
論文名稱:兒童C型肝炎病毒感染的臨床與分子研究
論文名稱(外文):Clinical and Molecular Studies of Hepatitis C Virus Infection in Children
指導教授:張美惠, 陳培哲
指導教授(外文):Chang Mei-Hwei, Chen Pei-Jer
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:1997
畢業學年度:85
語文別:中文
論文頁數:161
中文關鍵詞:兒童病毒準種性
外文關鍵詞:C 型肝炎Hepatitis CChildrenQuasispecies
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論文總結 本文寫作研究的目的,即在於探討兒童C型肝炎病毒感染之後
的自然史,包括臨床的觀察與分子病毒學的互相配合與印證,即利用分子生
物學的技術來支持或檢驗各種臨床的事實與證據。 首先我們以反轉
錄-聚合 連鎖反應的技術來證明母子之間周產期的傳染確實存在,而且依
台灣的特性,了解在只感染C型肝炎但未感染愛滋病毒的孕婦,他們把C型肝
炎傳給下一代的機會大約是18%(即17個母親中有3人傳給子女), 而這三名
感染C型肝炎的嬰兒,有二人走慢性持續感染的路,有一人可以廓清其血中
的HCV RNA,而且Anti-HCV 也完全消失。 這兩名慢性感染的嬰兒我們
取他們與他們母親的血清作長期追蹤與抽血,並將其C型肝炎病毒之高變異
區選殖作成一圖書館,由圖書館中任意選取8株作核 酸序列分析,我們了
解初生嬰兒感染時其病毒群之準種性是較為均質的,而隨時間進展,漸漸演
化複雜,他們與母親的病毒在演化上的距離亦漸行漸遠, 表示即使一開始
甚相關的病毒,在不同宿主因免疫力的不同會有不同速度的演化。 接
著我們討論另一危險族群開心手術兒童的輸血後C型肝炎, 由前瞻性研究
我們推算感染率約在5.2%(2/38),而血庫所作的篩檢是十分有效的,可以幾
乎把輸血後C型肝炎降到消失。 同時這些輸血後C型肝炎作基因分類可以
大略了解台灣地區C型肝炎的基因型仍以Type 1b為主流。 最後是有關
地中海型貧血兒童的輸血後肝炎研究,我們發現,C型肝炎確是造成肝傷害
之一大重要因子,而由分子生物學的研究,我們知道在追蹤4年內,HCV RNA
的效價變化在二個對數值內,又證實了台灣地區C型肝炎基因型的主流確
是1b, HCV的高變異區演化率在未有急性發作情況下,約為1.2-1.7X10-2/
site/年。 以4位(3位實驗組 ,一位對照組)血液疾患有C型肝炎且作了
骨髓移植者作其高變異區之核 酸序列分析,以研究準種性演化,發現在宿
主免疫力尚可時,準種性較複雜,而當宿主免疫力變弱時,便會有一株病毒
變作主要的角色,對比於嬰兒的情況, 年紀越小準種性越單純,似乎也是暗
示免疫系統尚未完成熟發達下, 準種性的均質性類似這種免疫不全的情
況,一旦宿主通過這段免疫抑制期,他們的準種性又會漸漸變複雜,如同嬰
兒長大之後,他們的免疫系統較成熟,準種性也隨之複雜。 結論是免疫系
統可能在準種性演化上扮演十分重要的角色。
原發性兒童C型肝炎感染演成慢性的比率大約是60%,即我們所查到有10名
初感染C型肝炎的兒童有6名變成慢性。而他們急性感染的臨床特徵亦各不
相同,有人可以有明顯的黃疸及IgM抗體出現,有人則毫無症狀,IgM抗體亦
無法測得。 這種種不同的臨床病程目前仍無法以任何方法或因子來預測,
有待未來更多臨床的觀察。

The aim of this dissertation is to explore the natural history
of hepatitis Cinfection in children, including the clinical and
virological features. We try to correlate the virological
characteristics of childhood HCV infectionwiththeir clinical
course.First of all, by reverse transcription-polymerase
chainreaction, we verified existence of mother-to-infant HCV
transmission. Even though the mothers wereinfected with HCV and
without HIV, this route still existed and the incidenceis about
18% (3 cases among 17 pregnancies). Of these three babies, two
ofthem ran a chronic persistent infection coursewhile the other
one could clear viremiaand anti-HCV.The next high risk group of
HCV-infectedchildren was those received open-heartsurgery. They
were tranfused a large amount of blood during the surgery
thustook a great chance of HCV infection. By a prospective
study, we know the incidence of HCV contraction in this group
was 5.2% (2 in 38 cases). The anti-HCV screening in blood bank
confers a lot of benefit in excluding HCV donors: no newly
infected cases was found after the initiation of screening. One
of the two cases ran a chronic persistent course and the other
one was a case of acute hepatitis whose anti-HCV and HCV RNA
disappeared within 6 months. Besides,we started the genotyping
in those with chronic HCV infection and learned that type 1b is
the prevailing type for the childhood post-transfusion hepatitis
C in Taiwan. Thalassemic children were frequently transfused
and were one of the high risk group of childhood HCVinfection.
We found the liver damage, either biochemically or
histologically,are much more severe in those infected with HCV
than those without HCV infection.Five of the thalassemic
children were infected during our study period and threeof them
ran a chronic persistent infection course. We checked the
clinical manifestations at the acute stage and found they varied
in the outcome. Some of them had jaundice with detectable anti-
HCV IgM while some got a subclinicalinfection without signal of
anti-HCV IgM. We could not deduce any factors which can predict
the prognosis. By competitive PCR technique, we know the HCV
RNA titer fluctuated within 10-100 fold during two-year-long
follow-up period. We also reconfirm the main genotype of HCV in
Taiwan area was type 1b,followed by type 2a and 2b, while type
1a almost nonexistent. The variation rate of HCV HVR inone
thalassemic child was estimated to be 0.012-0.017/site/year.
Overall, the chronicity of childhood HCV infection was 60%. The
clinicalcourse varied and it seems that these young patients ran
a subclinical course of infection. The two infants who were
infected with HCV through mother-to-infant routes were
longitudinally followed for three years. We cloned theirand
corresponding mothers' HVR of seral HCV cDNA. Eight clones were
randomlyselected from each case's plasmid library for nucleotide
sequencing. We learnthat the nucleotide diversity of the
newborn baby (at the age of three months)were small, that is,
they had a relatively homogeneous quasispecies of
viralpopulations. It became more and more heterogeneous when
time increased as reflected by the increased value off
nucleotide diversity. The quasispecies ofthe infants also
evolved more and more distant from their corresponding mothersas
time increased. The infants' viruses came from their mother,
half of thegenetic materials of their immunity also from their
mothers, but the evolutionof HCV quasispecies did not parallel
in terms of mutation rate and phylogeneticdirection. Perhaps
this is due to the young age of the infants,, which made their
immunity not as mature as their mothers. The following study to
show thequasispecies evolution in four hematological patients
enlighted some more information in this aspect. Three of four
patients underwent bone marrow transplantation (BMT) while the
other one who did not served as a control.The quasispecies was
relatively heterogeneous before BMT when the hosts werestill
immunocompetent. As the host's immunity declined, there emerged
one dominant strain. When the immunity grandually recovered,
the nucleotide diversity also increased. Both studies (mother-
infant pairs and thalassemic children) of quasispecies evolution
implicated that the host immune status plays an important role
in the evolution of HCV quasispecies. When the hostimmune
status is competent, like the adult mothers and the grown-up and
thepatients before BMT, their HCV quasispecies are heterogeneous
(a high nucleotide diversity). On the other hand, when the
immune status was suppressed, like the very young infants and
the immunocompromised hosts undergoing BMT, there would be one
dominant strain of HCV and lower downthleotide diversity.

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