https://pubmed.ncbi.nlm.nih.gov/36036223/ Alagille syndrome

Hepatology. 2022 Aug 29.
doi: 10.1002/hep.32761. Online ahead of print.

Natural History of Liver Disease in a Large International Cohort of Children with Alagille syndrome: Results from The GALA Study

Shannon M Vandriel 1, Li-Ting Li 2, Huiyu She 2, Jian-She Wang 2, Melissa A Gilbert 3, Irena Jankowska 4, Piotr Czubkowski 4, Dorota Gliwicz-Miedzińska 4, Emmanuel M Gonzales 5, Emmanuel Jacquemin 5, Jérôme Bouligand 6, Nancy B Spinner 3, Kathleen M Loomes, David A Piccoli, Lorenzo D'Antiga 7, Emanuele Nicastro 7, Étienne Sokal 8, Tanguy Demaret 8, Noelle H Ebel 9, Jeffrey A Feinstein 10, Rima Fawaz 11, Silvia Nastasio 12, Florence Lacaille 13, Dominique Debray 14, Henrik Arnell 15, Björn Fischler 16, Susan Siew 17, Michael Stormon 17, Saul J Karpen 18, Rene Romero 18, Kyung Mo Kim 19, Woo Yim Baek 19, Winita Hardikar 20, Sahana Shankar 21, Amin J Roberts 22, Helen M Evans 22, M Kyle Jensen 23, Marianne Kavan 23, Shikha S Sundaram 24, Alexander Chaidez 24, Palaniswamy Karthikeyan 25, Maria Camila Sanchez 26, Maria Lorena Cavalieri 26, Henkjan J Verkade 27, Way Seah Lee 28, James E Squires 29, Christina Hajinicolaou 30, Chatmanee Lertudomphonwanit 31, Ryan T Fischer 32, Catherine Larson-Nath 33, Yael Mozer-Glassberg 34, Cigdem Arikan 35, Henry C Lin 36, Jesus Quintero Bernabeu 37, Seema Alam 38, Deirdre Kelly 39, Elisa Carvalho 40, Cristina Targa Ferreira 41, Giuseppe Indolfi 42, Ruben E Quiros-Tejeira 43, Pinar Bulut 44, Pier Luigi Calvo 45, Zerrin Önal 46, Pamela L Valentino 11, Dev M Desai 47, John Eshun 48, Maria Rogalidou 49, Antal Dezsőfi 50, Sabina Wiecek 51, Gabriella Nebbia 52, Raquel Borges Pinto 53, Victorien M Wolters 54, María Legarda Tamara 55, Andréanne N Zizzo 56, Jennifer Garcia 57, Kathleen Schwarz 58, Marisa Beretta 59, Thomas Damgaard Sandahl 60, Carolina Jimenez-Rivera 61, Nanda Kerkar 62, Jernej Brecelj 63, Quais Mujawar 64, Nathalie Rock 65, Cristina Molera Busoms 66, Wikrom Karnsakul 67, Eberhard Lurz 68, Ermelinda Santos-Silva 69, Niviann Blondet 70, Luis Bujanda 71, Uzma Shah 72, Richard J Thompson 73, Bettina E Hansen 74 75, Binita M Kamath 1, Global ALagille Alliance (GALA) Study Group
Affiliations expand
PMID: 36036223

DOI: 10.1002/hep.32761
Abstract
Background: 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.

Methods: Multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born Jan-1997 - Aug-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.

Results: 1433 children (57% male) from 67 centers in 29 countries were included. 10 and 18-years NLS rates were 54.4% and 40.3%. By 10 and 18-years, 51.5% and 66.0% of ALGS children 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% 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).

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 novel therapies.