早產兒肝內 膽汁滯留之藥物治療及分子機轉

Abstract

全靜脈營養引肝內膽汁滯留(PNALD) 是長期使用全靜脈營養(TPN)的重要併發 症，主要的危險因子包括早產及低出生體 重，肝臟功能尚未成熟可能是重要的致病 原因。許多藥物曾被嘗試用來治療及預防 PNALD 但仍未有確定結論。UDCA 是一種親 水性的膽酸，已被廣泛用在兒童及成人的 肝臟疾病。在豬的PNALD 模式，UDCA 可以 促進膽汁流量並降低血清及肝臟的膽紅素 濃度。膽汁傳送蛋白BSEP 是一種新近發現 基因，它是肝細胞主要的膽汁傳送蛋白， BSEP 在PNALD 的角色仍然不明瞭，我們認 為PNALD 的機轉可能與BSEP 的功能不佳有 關。 研究結果：在本研究的臨床部份中， 總共有35 名罹患PNALD 早產兒納入研究： 22 名PNALD 病人以UDCA 30 mg/kg/d 治療， 13 名是控制組PNALD 病人，並未以UDCA 治療。血清膽紅素含量在治療組有95% (21/22) 降低，但在控制組只有46% (6/13) 降低。治療組治療後與治療前的膽紅素變 化為-5.4 + 5.6 mg/dl，而控制組變化為1.7+ 6.5 mg/dl，在ALT 方面治療組平均變化為 -25 + 58 U/L，控制組為34 + 17 U/L，另外 我們以RT-PCR 測量BSEP 的表現，在PNALD 的病人有2/5 呈現陽性，而在另一組膽汁 滯留(膽道閉鎖)病人有6/7 呈陽性。免疫 染色分析發現在PNALD 的病人膽小管的 BSEP 呈現微弱的陽性反應，並有一些BSEP 染色在細胞質內並未正確的位於膽小管 上。 我們的研究顯示UDCA 可有效的降低早 產兒PNALD 的膽紅素及ALT 值，而PNALD 病人之BSEP 表現量較低，在細胞的表現位 置也有異常現象，因此PNALD 的機轉可能 與BSEP 的異常表現有相關性。

Total parenteral nutrition associated liver disease (PNALD) is a major and potentially lethal complication in patients receiving long-term parenteral nutrition therapy. The key predisposing factors for the development of PNALD are prematurity and low birth weight. Immaturity of hepatic function appears to be important in the pathogenesis of PNALD in premature infants. A number of pharmacologic agents have been proposed for the prevention and treatment of PNALD but no conclusive results have been documented for their beneficial effects. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid and has been widely used in various cholestatic liver diseases in adult and in children. UDCA improves bile flow and reduces serum and liver bilirubin concentrations in piglets with PNALD. Bile salt export pump (BSEP), an ATP-dependent bile acid exporter has recently been cloned and proved to be the major canalicular bile salt transporter. The role of BSEP in PNALD has not been reported. In this report we investigate the effect of UDCA treatment in premature patients with PNALD and test the expression of BSEP in their liver samples. Results: A total of 35 premature patients with TPN related cholestasis were recruited.Twenty-two of them were treated with UDCA 30 mg/kg/d and 13 patients in the control group were not treated. The total bilirubin levels decreased in 95% (21/22) treated 46% (6/13) control patients. The mean change of bilirubin was -5.4 + 5.6 mg/dl in the treatment group and 1.7+ 6.5 mg/dl in the control group. The mean changes of alanine aminotransferase (ALT) levels were -25 + 58 U/L in the treatment group and 34 + 17 U/L in the control group. Expression of Bile salt export pump (BSEP) was tested by using RT-PCR. Two of the five premature patients of TPN liver disease and 6/7 patients of biliary atresia were tested positive for BSEP. Immunofluorescent staining showed weak canalicular staining and some cytoplasmic staining. The results showed that UDCA treatment was effective in decreasing the bilirubin levels and ALT levels in premature patients with PNALD. Liver from patients with PNALD liver disease had lower expression levels of BSEP than biliary atresia. The mechanism of TPN cholestasis may be related to abnormal BSEP expression and bile salt excretion function.