Division of Gastroenterology, Hepatology and Nutrition , The Hospital for Sick Children and the University of Toronto , Toronto , Canada.
The Center for Pediatric Liver Diseases , Children's Hospital of Fudan University , Shanghai , China.
Hepatology. 2023 Feb 1;77(2):512-529. doi: 10.1002/hep.32761. Epub 2022 Oct 13.
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.
Alagille 综合征（ALGS）是一种多系统疾病，其特征为胆汁淤积。现有的预后数据主要来源于三级中心，缺乏真实世界的数据。本研究旨在阐明当代国际 ALGS 患儿的肝脏疾病自然史。
这是一项多中心回顾性研究，纳入了 1997 年 1 月至 2019 年 8 月期间临床和/或基因确诊的 ALGS 患儿。评估了原发性肝存活率（NLS）和无事件存活率。构建 Cox 模型以确定早期生化指标与临床明显门脉高压（CEPH）和 NLS 的关系。共有来自 29 个国家的 67 个中心的 1433 名患儿（57%为男性）纳入研究。10 年和 18 年 NLS 率分别为 54.4%和 40.3%。10 年和 18 年时，51.5%和 66.0%的 ALGS 患儿经历了≥1 次与肝脏相关的不良事件（CEPH、移植或死亡）。中位总胆红素（TB）水平在 5.0 至 10.0 mg/dl 之间（6 至 12 个月龄）的患儿发生 CEPH 的风险增加 4.1 倍（95%CI，1.6-10.8），而中位 TB 水平≥10.0 mg/dl 的患儿发生 CEPH 的风险增加 8.0 倍（95%CI，3.4-18.4）。TB 水平在 5.0 至 10.0 mg/dl 和>10.0 mg/dl 之间的患儿发生移植的风险分别增加 4.8 倍（95%CI，2.4-9.7）和 15.6 倍（95%CI，8.7-28.2）。TB 水平<5.0 mg/dl 与 NLS 率升高相关，79%的患儿在成年时具有原肝（p<0.001）。
在本项大型国际 ALGS 患儿队列中，仅有 40.3%的患儿成年时具有原肝。6 至 12 个月龄时 TB<5.0 mg/dl 与更好的肝脏结局相关。这些界值为临床医生提供了一种客观的工具，以协助临床决策和评估治疗效果。
