Abstract：
Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS.
This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001).
In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.
This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001).
In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.
摘要：
背景：Alagille综合征（ALGS）是一种多系统疾病，以胆汁淤积为特征。现有的结果数据主要来自三级中心，缺乏现实世界的数据。这项研究旨在阐明肝病的自然史在当代,国际,ALGS儿童队列。
方法：对临床和/或遗传证实的ALGS诊断儿童的多中心回顾性研究，出生于1997年1月-2019年8月。评估天然肝存活率(NLS)和无事件存活率。建立Cox模型以鉴定临床上明显的门脉高压（CEPH）和NLS的早期生化预测因子。
结果：纳入了来自29个国家67个中心的1433名儿童（57%为男性）。10年和18年NLS率分别为54.4%和40.3%。到10年和18年，51.5%和66.0%的ALGS儿童经历了≥1次不良肝脏相关事件(CEPH，移植或死亡)。与<5.0mg/dL相比，中位总胆红素（TB）水平在5.0和<10.0mg/dL之间的儿童（>6个月和≤12个月）增加了4.1倍（95％CI1.6-10.8），而≥10.0mg/dL的儿童增加了8.0倍（95％CI3.4-18.4）。在≥5.0和<10.0mg/dL和>10.0mg/dL之间的中位TB水平与4.8（95％CI2.4-9.7）和15.6（95％CI8.7-28.2）相对于<5.0mg/dL的移植风险增加相关。相对于≥5.0mg/dL，中值TB<5.0mg/dL与更高的NLS率相关，79％的人成年后肝脏天然（p<0.001）。
结论：在这个大型的ALGS国际队列中，只有40.3%的儿童以其天然肝脏达到成年。6至12月龄之间的TB<5.0mg/dL与更好的肝脏结局相关。这些阈值为临床医生提供了客观工具，以协助临床决策和评估新疗法。
方法：对临床和/或遗传证实的ALGS诊断儿童的多中心回顾性研究，出生于1997年1月-2019年8月。评估天然肝存活率(NLS)和无事件存活率。建立Cox模型以鉴定临床上明显的门脉高压（CEPH）和NLS的早期生化预测因子。
结果：纳入了来自29个国家67个中心的1433名儿童（57%为男性）。10年和18年NLS率分别为54.4%和40.3%。到10年和18年，51.5%和66.0%的ALGS儿童经历了≥1次不良肝脏相关事件(CEPH，移植或死亡)。与<5.0mg/dL相比，中位总胆红素（TB）水平在5.0和<10.0mg/dL之间的儿童（>6个月和≤12个月）增加了4.1倍（95％CI1.6-10.8），而≥10.0mg/dL的儿童增加了8.0倍（95％CI3.4-18.4）。在≥5.0和<10.0mg/dL和>10.0mg/dL之间的中位TB水平与4.8（95％CI2.4-9.7）和15.6（95％CI8.7-28.2）相对于<5.0mg/dL的移植风险增加相关。相对于≥5.0mg/dL，中值TB<5.0mg/dL与更高的NLS率相关，79％的人成年后肝脏天然（p<0.001）。
结论：在这个大型的ALGS国际队列中，只有40.3%的儿童以其天然肝脏达到成年。6至12月龄之间的TB<5.0mg/dL与更好的肝脏结局相关。这些阈值为临床医生提供了客观工具，以协助临床决策和评估新疗法。
