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Natural history of liver disease in a large international cohort of children with Alagille syndrome : Results from the GALA study

ContributorsVandriel, Shannon Morcid; Li, Li-Ting; She, Huiyuorcid; Wang, Jian-She; Gilbert, Melissa A; Jankowska, Irena; Czubkowski, Piotr; Gliwicz-Miedzińska, Dorota; Gonzales, Emmanuel Morcid; Jacquemin, Emmanuel; Bouligand, Jérôme; Spinner, Nancy B; Loomes, Kathleen M; Piccoli, David A; D'Antiga, Lorenzoorcid; Nicastro, Emanuele; Sokal, Étienneorcid; Demaret, Tanguyorcid; Ebel, Noelle H; Feinstein, Jeffrey Aorcid; Fawaz, Rima; Nastasio, Silviaorcid; Lacaille, Florence; Debray, Dominique; Arnell, Henrik; Fischler, Björn; Siew, Susan; Stormon, Michael; Karpen, Saul J; Romero, Rene; Kim, Kyung Mo; Baek, Woo Yim; Hardikar, Winita; Shankar, Sahana; Roberts, Amin Jorcid; Evans, Helen Morcid; Jensen, M Kyle; Kavan, Marianne; Sundaram, Shikha S; Chaidez, Alexander; Karthikeyan, Palaniswamy; Sanchez, Maria Camila; Cavalieri, Maria Lorena; Verkade, Henkjan Jorcid; Lee, Way Seahorcid; Squires, James Eorcid; Hajinicolaou, Christina; Lertudomphonwanit, Chatmanee; Fischer, Ryan Torcid; Larson-Nath, Catherine; Mozer-Glassberg, Yael; Arikan, Cigdem; Lin, Henry C; Bernabeu, Jesus Quintero; Alam, Seemaorcid; Kelly, Deirdre A; Carvalho, Elisa; Ferreira, Cristina Targa; Indolfi, Giuseppe; Quiros-Tejeira, Ruben E; Bulut, Pinar; Calvo, Pier Luigi; Önal, Zerrin; Valentino, Pamela Lorcid; Desai, Dev M; Eshun, John; Rogalidou, Maria; Dezsőfi, Antal; Wiecek, Sabina; Nebbia, Gabriella; Pinto, Raquel Borges; Wolters, Victorien M; Tamara, María Legarda; Zizzo, Andréanne Norcid; Garcia, Jennifer; Schwarz, Kathleen; Beretta, Marisa; Sandahl, Thomas Damgaardorcid; Jimenez-Rivera, Carolina; Kerkar, Nanda; Brecelj, Jernej; Mujawar, Quaisorcid; Rock, Nathalie; Busoms, Cristina Molera; Karnsakul, Wikrom; Lurz, Eberhard; Santos-Silva, Ermelindaorcid; Blondet, Niviann; Bujanda, Luis; Shah, Uzma; Thompson, Richard J; Hansen, Bettina E; Kamath, Binita M; Global ALagille Alliance (GALA) Study Group
Published inHepatology, vol. 77, no. 2, p. 512-529
Publication date2023-02-01
First online date2022-10-13
Abstract

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 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.

eng
Keywords
  • Humans
  • Child
  • Male
  • Female
  • Alagille Syndrome / epidemiology
  • Retrospective Studies
  • Cholestasis
  • Hypertension, Portal / etiology
Citation (ISO format)
VANDRIEL, Shannon M et al. Natural history of liver disease in a large international cohort of children with Alagille syndrome : Results from the GALA study. In: Hepatology, 2023, vol. 77, n° 2, p. 512–529. doi: 10.1002/hep.32761
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ISSN of the journal0270-9139
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