兒童之肝內膽汁滯留及BSEP基因分析

BSEP 及FIC1 基因異常近年來被發 現是進行性家族性肝內膽汁滯留的致病原 因，這些基因的變異在亞洲兒童並未被報 告過，本研究的目的在於釐清BSEP 及FIC1 基因在本地兒童慢性膽汁滯留的角色。 方法及結果：在1980 至1999 年，301 名肝 內膽汁滯留病童中，共有52 名慢性膽汁滯 留，其中31 名不明原因，其中四名經膽汁 酸診斷為先天性膽汁酸合成缺陷，另外27 名，在其中篩選出18 名GGT 值低下者，13 名進行BSEP 及FIC1 之基因變異分析。發 現在13 名病人中明顯的分為兩種表現型， 第一組病人（五名）組織學只有膽汁滯留 的變化，第二組病人（八名）組織學有明 顯的巨細胞變化，在七名病人之基因分析 中，第一組之四名均有FIC1 基因突變，第 二組之三名中，兩名有BSEP 之突變，且這 些突變均與西方國家之報告相異。並且發 現AFP 之值與基因變異有相關性。 結論：BSEP 及FIC1 變異，以及膽酸合成缺 陷，是本地兒童慢性肝內膽汁滯留重要的 原因，結合GGT 及AFP 及組織學診斷，對 於早期診斷這些基因變異有很大的幫助。Background/Aim: Genetic defects of FIC1 and BSEP have recently been found to cause progressive familial intrahepatic cholestasis (PFIC). Mutations in both genes have not been reported in Asian children, and the roles of these genetic disorders in non-familial infantile cholestasis are unclear. This study is to elucidate the role of FIC1 and BSEP mutations in children with infantile onset chronic cholestasis in Taiwan. Methods and Results: We examed 301 children admitted for intrahepatic cholestasis during 1980 to 1999 in Taiwan. Fifty-two had chronic intrahepatic cholestasis, including 18 with Alagille syndrome, 2 with neonatal Dubin-Johnson syndrome, 1 with tyrosinemia, and 31 of unknown etiology. These 31 patients were sub-grouped according to g-glutamyltranspeptidase (GGT) levels: low GGT (18 cases), high GGT (8 cases), and unknown GGT levels (5 cases). Inborn errors of bile acid synthesis were identified in four patients by serum bile acid analysis. In the low GGT patients, two distinct phenotypes could be defined: group 1 (5 patients) was characterized by bland cholestasis and group 2 (8 patients) by giant cell transformations. Group 2 patients were associated with higher transaminase levels, α -fetoprotein levels, and early mortality (p=0.02). Reverse transcription-polymerase chain reaction and cDNA sequencing were performed in 7 infants with low GGT levels for mutation analyses of FIC1 and BSEP genes. FIC1 mutations were found in all 4 patients in group 1 but none in the 3 patients in group 2. Whereas BSEP mutations were found in 2 of the 3 patients in group 2. The FIC1 mutations comprised of two deletions and three missense mutations. The BSEP mutations included two missense mutations and 1 deletion. All the mutations were novel. Conclusion: FIC1, BSEP mutations and inborn errors of bile acid synthesis are important etiologies in infants with nonfamilial chronic intrahepatic cholestasis in Taiwan. Combination of serum GGT, AFP levels and histology is useful in differentiating patients of FIC1 from BSEP 2 mutation, and the phenotype strongly correlated with genetic diagnosis and prognosis