膽道閉鎖病童合併長期膽汁鬱積之系統免疫功能的研究及臨床意義

研究背景：慢性阻塞性黃疸的病患在臨床上經常發生各種嚴重的感染性併發症，而膽道閉鎖則是兒童常見的慢性阻塞性黃疸及膽汁鬱積的病因之一，病患於出生後六十天前接受葛西手術，已經被確定能大幅的改善膽汁的排出及病患長期的預後。然而，部分膽道閉鎖的病童於手術後仍然有持續性黃疸的問題存在，甚至合併營養不良，肝硬化，反覆感染甚至慢性肝衰竭等併發症，因此釐清這群病患處於長期膽汁鬱積之下，是否出現系統免疫功能的缺陷是很重要的課題。在一些動物實驗上被發現阻塞性黃疸會造成中性白血球的吞噬功能以及過氧化氫離子分泌功能有明顯的下降。淋巴球的功能包括延遲皮膚敏感性測試，淋巴球分類，血清抗體濃度，血清抗體對疫苗反應以及淋巴球對刺激物反應等在一些動物模式實驗及少數的人體體外試驗中被提及有缺陷的存在。然而，膽道閉鎖的病患處於長期膽汁鬱積之下是否有免疫功缺陷的研究卻很缺乏。研究方法：研究對象：收集在台大醫院小兒科長期追蹤的膽道閉鎖病童共三十名，其膽道閉鎖的診斷由術中膽管攝影(intra-operation cholangiography)確認，病患於受試前至少有兩週以上沒有明顯的感染症狀，而且沒有長期使用免疫抑制劑，未經肝臟移植，並得到病患或家屬的同意，取得同意書。研究的進行：在病患及家屬知情同意後，依收案時血清中直接膽紅素濃度分成兩組，病患的血清中直接膽紅素濃度大於2 mg/dL超過六個月者歸於實驗組，共十二名患者歸於實驗組; 病患的血清中直接膽紅素濃度小於2mg/dL超過六個月者歸為對照組，共有十八名患者為對照組，病患於本研究收案時單次抽血以檢驗血球，血清項目，系統體液性及細胞性免疫功能，並評估病童的營養狀態，病患於收案於本研究後，前瞻性的追蹤六個月以觀察是否併發需要住院治療的嚴重感染併發症。結果: 相較於對照組病患，合併長期鬱積性黃疸的膽道閉鎖病患在刺激物phytohemagglutinin (PHA) mitogen的試驗中顯示有較差的T淋巴球增生功能(p = 0.02)，至於在系統體液免疫功能(humoral immune function)與非特異性細胞免疫功能(non-Specific cellular immune function)的評估上，兩組則無顯著的差異存在(p > 0.05)。在研究的追蹤期間發現，合併長期鬱積性黃疸的膽道閉鎖病患合併有較高的風險會發生需要住院治療的感染併發症(risk ratio = 5.87; p = 0.001)，而血液直接膽紅素的數值與T淋巴球的增生功能有顯著的負相關存在(相關係數R為-0.38，adjusted R square = 11.18%，標準誤為2.40，p值為0.04，Y = 126.85 – 4.96 X)，此外雖然於本實驗中黃疸的實驗組病患有較差的肌肉量指數，但是在多重線性回歸的統計處理下顯示，較差的肌肉營養狀態並非此研究的顯著干擾因子。結論: 合併長期鬱積性黃疸的膽道閉鎖病患相較於沒有黃疸的膽道閉鎖病患而言，有較差的T淋巴球增生功能，而體液免疫功能與非特異性細胞免疫則無明顯的差異，同時合併長期鬱積性黃疸的膽道閉鎖病患有比較高的風險會發生嚴重感染併發症。

關鍵字

膽道閉鎖；體液免疫功能；細胞免疫功能

並列摘要

Biliary atresia (BA) is one of the most common cholestatic liver diseases in early infancy. Early diagnosis with Kasai operation performed before the age of 60 days old is an important prognostic factor. However, about one-third of patients with biliary atresia remain jaundiced even after prompt intervention, and another one-third again become jaundiced after recurrent episodes of ascending cholangitis. To investigate the association between chronic cholestatic jaundice, systemic immunity, and various infectious complications in patients with biliary atresia, we performed a survey of the systemic immune function in 30 children with biliary atresia. Patients were divided into a jaundice group (total serum bilirubin above 2 mg/dL for more than 6 months) and control group (total serum bilirubin below 2 mg/dL for more than 6 months) with comparable age. Patients were tested for serum immunoglobulin and complement levels, mitogen response, interleukin-4, interleukin-5, and interferon-gamma production after phytohemagglutinin stimulation, blood cell and lymphocyte subpopulation counts, phagocytic function, and leukocyte adhesion complex. They were then followed prospectively for 6 months, and severe infectious complications requiring hospitalization were recorded. Compared to jaundice-free patients, T-lymphocyte proliferation function, determined by phytohemagglutinin mitogen test was significantly lower (p = 0.02) in biliary atresia patients with chronic cholestatic jaundice after Kasai operation. There is no obvious difference in the humoral and non-specific cellular immune function between these two groups. During the study period, patients with chronic cholestatic jaundice had a higher risk of severe infectious complications than their jaundice-free counterparts (risk ratio = 5.87; p = 0.001). In conclusion, biliary atresia patients with chronic cholestatic jaundice are associated with impairment of T-lymphocyte proliferation and increased incidence of severe infectious complications.

並列關鍵字

biliary atresia ； humoral immunity ； cellular immunity

參考文獻

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膽道閉鎖病童合併長期膽汁鬱積之系統免疫功能的研究及臨床意義

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