Background and Aim: Alagille syndrome (ALGS) is an inherited multisystem disorder typically manifesting as cholestasis, and potentially leading to end‐stage liver disease and death. The aim of the study was to perform the first systematic review of the epidemiology, natural history, and burden of ALGS with a focus on the liver component.Methods: Electronic databases and proceedings from key congresses were searched in accordance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) 2009 guidelines. This analysis included publications reporting epidemiology, natural history, economic burden or health‐related quality of life (HRQoL) outcomes in patients with ALGS.Results: Of 525 screened publications, 20 met the inclusion criteria. Liver‐related features included cholestasis (87%–100% of patients), jaundice (66%–85%), and cirrhosis (44%–95%). Between 15% and 47% of patients underwent liver transplantation and 4% to 14% received partial biliary diversion. Pruritus affected the majority of patients (59%–88%, of whom up to 45% had severe pruritus) and manifested during the first 10 years of life. Children with ALGS had significantly impaired HRQoL compared with healthy controls and those with other diseases. Itching was the symptom that most affected children with ALGS. No study assessed the economic burden of ALGS.Conclusions: Our findings consolidate information on the clinical course of ALGS, and highlight gaps in knowledge, most notably the absence of any research on the economic consequences of the disease. Further research is needed to establish the incidence of genetically confirmed ALGS. Disease‐specific tools are also needed to improve the measurement of symptoms, such as itching, and better understand the impact of ALGS on HRQoL.

Alagille syndrome (ALGS) is a multisystem disorder that manifests as childhood cholestasis. Reports of liver transplantation (LT) for patients with ALGS have come largely from single centers, which have reported survival rates of 57% to 79%. The aim of this study was to determine LT outcomes for patients with ALGS. We performed a retrospective analysis of the Studies of Pediatric Liver Transplantation database, which contains information about 3153 pediatric LT recipients. Data were available for 91 patients with ALGS and for 236 age-matched patients with biliary atresia (BA). The frequency of complex cardiac anomalies was lower in the LT group with ALGS versus published ALGS series (5% versus 13%). The pretransplant glomerular filtration rate (GFR) was <90 mL/minute/1.73 m² in 18% of the LT patients with ALGS and in 5% of the LT patients with BA (P < 0.001). The height deficit at listing was worse for the ALGS patients (66%) versus the BA patients (22%). The 1-year patient survival rates were 87% for the ALGS patients and 96% for the BA patients (P = 0.002). The deaths in the ALGS group mostly occurred within the first 30 days. No pretransplant factors associated with death were identified in the ALGS group. A survival analysis revealed that biliary (P = 0.02), vascular (P < 0.001), central nervous system (CNS; P < 0.001), and renal complications (P < 0.001) after LT were associated with death in the ALGS group. Renal insufficiency in the ALGS patients worsened after LT, and at 1 year, GFR was <90 mL/minute/1.73 m² in 22% of the LT patients with ALGS but in only 8% of the patients with BA (P = 0.0014). More LT pediatric patients with ALGS either were currently receiving special education (50% versus 30% for BA patients, P = 0.02) or had received special education in the past (60% versus 36%, P = 0.01). Vascular, CNS, and renal complications were increased in the ALGS patients after LT, and this reflected multisystem involvement. Although the 1-year survival rate was modestly lower for the ALGS patients versus the BA patients, the clustering of deaths within the first 30 days is notable and warrants increased vigilance and further investigation. Liver Transpl, 2012. © 2012 AASLD.

Background and Aims: 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. Approach and Results: 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 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). Conclusions: 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 syndrome (ALGS) is an autosomal dominant multisystem disorder with cholestasis as a defining clinical feature. We sought to characterize hepatic outcomes in a molecularly defined cohort of children with ALGS‐related cholestasis. Two hundred and ninety‐three participants with ALGS with native liver were enrolled. Participants entered the study at different ages and data were collected retrospectively prior to enrollment, and prospectively during the study course. Genetic analysis in 206 revealed JAGGED1 mutations in 91% and NOTCH2 mutations in 4%. Growth was impaired with mean height and weight z‐scores of <−1.0 at all ages. Regression analysis revealed that every 10 mg/dL increase in total bilirubin was associated with a decrease in height z‐score by 0.10 (P = 0.03) and weight z‐score by 0.15 (P = 0.007). Total bilirubin was higher for younger participants (P = 0.03) with a median of 6.9 mg/dL for those less than 1 year old compared with a median of 1.3 mg/dL for participants 13 years or older. The median gamma glutamyl transferase also dropped from 612 to 268 in the same age groups. After adjusting for age, there was substantial within‐individual variation of alanine aminotransferase. By 20 years of age, 40% of participants had developed definite portal hypertension. Estimated liver transplant–free survival at the age of 18.5 years was 24%. Conclusions: This is the largest multicenter natural history study of cholestasis in ALGS, demonstrating a previously underappreciated burden of liver disease with early profound cholestasis, a second wave of portal hypertension later in childhood, and less than 25% of patients reaching young adulthood with their native liver. These findings will promote optimization of ALGS management and development of clinically relevant endpoints for future therapeutic trials.