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Multicenter Study
. 2023 Feb 1;77(2):512-529.
doi: 10.1002/hep.32761. Epub 2022 Oct 13.

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  7 , David A Piccoli  7 , Lorenzo D'Antiga  8 , Emanuele Nicastro  8 , Étienne Sokal  9 , Tanguy Demaret  9 , Noelle H Ebel  10 , Jeffrey A Feinstein  11 , Rima Fawaz  12 , Silvia Nastasio  13 , Florence Lacaille  14 , Dominique Debray  15 , Henrik Arnell  16   17 , Björn Fischler  16   18 , Susan Siew  19 , Michael Stormon  19 , Saul J Karpen  20 , Rene Romero  20 , Kyung Mo Kim  21 , Woo Yim Baek  21 , Winita Hardikar  22 , Sahana Shankar  23 , Amin J Roberts  24 , Helen M Evans  24 , M Kyle Jensen  25 , Marianne Kavan  25 , Shikha S Sundaram  26 , Alexander Chaidez  26 , Palaniswamy Karthikeyan  27 , Maria Camila Sanchez  28 , Maria Lorena Cavalieri  28 , Henkjan J Verkade  29 , Way Seah Lee  30 , James E Squires  31 , Christina Hajinicolaou  32 , Chatmanee Lertudomphonwanit  33 , Ryan T Fischer  34 , Catherine Larson-Nath  35 , Yael Mozer-Glassberg  36 , Cigdem Arikan  37 , Henry C Lin  38 , Jesus Quintero Bernabeu  39 , Seema Alam  40 , Deirdre A Kelly  41 , Elisa Carvalho  42 , Cristina Targa Ferreira  43 , Giuseppe Indolfi  44 , Ruben E Quiros-Tejeira  45 , Pinar Bulut  46 , Pier Luigi Calvo  47 , Zerrin Önal  48 , Pamela L Valentino  12 , Dev M Desai  49 , John Eshun  50 , Maria Rogalidou  51 , Antal Dezsőfi  52 , Sabina Wiecek  53 , Gabriella Nebbia  54 , Raquel Borges Pinto  55 , Victorien M Wolters  56 , María Legarda Tamara  57 , Andréanne N Zizzo  58 , Jennifer Garcia  59 , Kathleen Schwarz  60 , Marisa Beretta  61 , Thomas Damgaard Sandahl  62 , Carolina Jimenez-Rivera  63 , Nanda Kerkar  64 , Jernej Brecelj  65 , Quais Mujawar  66 , Nathalie Rock  67 , Cristina Molera Busoms  68 , Wikrom Karnsakul  69 , Eberhard Lurz  70 , Ermelinda Santos-Silva  71 , Niviann Blondet  72 , Luis Bujanda  73 , Uzma Shah  74 , Richard J Thompson  75 , Bettina E Hansen  76   77 , Binita M Kamath  1 ; Global ALagille Alliance (GALA) Study Group
Affiliations
Multicenter Study

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

Shannon M Vandriel et al. Hepatology. .

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.

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Conflict of interest statement

Binita M. Kamath consults for and received grants from Mirum and Albireo. She consults for Audentes Therapeutics and Third Rock Ventures. Bettina E. Hansen consults for Mirum, Albireo, Chemomab, Calliditas, Intercept and Cyma Bay. She received grants from Mirum, Albireo, Intercept and Cyma Bay. Deirdre A. Kelly consults for, advises, and received grants from Mirum and Albireo. Emmanuel M. Gonzales consults for Albireo, CTRS, Mirum, and Vivet. Henrik Arnell consults for Albireo and Baxter. Henry C. Lin advises Albireo. Emmanuel Jacquemin consults for Laboratoire CTRS France and Vivet Therapeutics France. Kathleen Schwarz consults for and received grants from Gilead. She consults for Mirum. She received grants from Albireo. Kathleen M. Loomes consults for and received grants from Albireo and Mirum. She consults for Travere Therapeutics. Lorenzo D'Antiga consults for Albireo and Mirum. M. Kyle Jensen consults for Albireo and Guidepoint Global. Nanda Kerkar advises Albireo and Mirum. Emanuele Nicastro advises and received grants from Mirum Pharmaceuticals. Noelle H. Ebel consults for Mirum Pharmaceuticals. Rene Romero consults for Albireo and Mirum. He received grants from Gilead. Richard J. Thompson owns stock in, consults for, and advises Generation Bio and Rectify. He consults for, advises, and is on the speakers' bureau for Albireo and Mirum. Rima Fawaz consults for Mirum. She advises Albireo. Ryan T. Fischer is on the speakers' bureau for Albireo and Mirum. Saul J. Karpen consults for Albireo, Intercept, and Mirum. Nancy B. Spinner consults for Mirum and Travere. Wikrom Karnsakul consults for and received grants from Albireo and Gilead. He consults for Mirum.

Figures

None
Graphical abstract
FIGURE 1
FIGURE 1
Ascertainment of the GALA Study cohort stratified by patients with Alagille syndrome (ALGS) with and without a history of neonatal cholestasis. Abbreviations: GALA, The Global ALagille Alliance (GALA) Study; JAG1, JAGGED1; VUS, variant of uncertain significance.
FIGURE 2
FIGURE 2
Cumulative incidence of native liver survival (NLS) in the presence of competing events (liver transplantation [LT] or risk of death without LT; n = 1184) in children with Alagille syndrome (ALGS) who presented with neonatal cholestasis. At 5, 10, and 18 years, the rate of NLS was 66.8%, 54.4%, and 40.3%.
FIGURE 3
FIGURE 3
Patient and graft survival following isolated liver transplantation (LT) in 345 children with Alagille syndrome (ALGS). Patient and graft survival following LT is calculated from the date of LT until retransplantation, death or the date of last known clinical follow‐up. (A) After LT, 10‐ and 20‐year patient survival rates were 91.0% and 88.0%, respectively. (B) After LT, 10‐ and 20‐year graft survival rates were 86.3% and 83.4%, respectively.
FIGURE 4
FIGURE 4
Time to first adverse liver‐related event in 1184 children with Alagille syndrome (ALGS). A Kaplan–Meier analysis revealed by 5, 10, and 18 years, 36.3%, 51.5%, and 66.0% of children with ALGS will experience at least one adverse liver‐related event, respectively.
FIGURE 5
FIGURE 5
Cumulative incidence of clinically evident portal hypertension in an international cohort of children with Alagille syndrome (ALGS). (A) Ultrasound‐confirmed splenomegaly and PLT <150 × 109/L; (B) ascites requiring treatment with diuretics; (C) gastrointestinal varices requiring intervention; (D) clinically evident portal hypertension. Abbreviation: PLT, platelet count.
FIGURE 6
FIGURE 6
Early biochemical predictors for native liver survival in children with Alagille syndrome (ALGS). (A) Median serum total bilirubin levels between >6 and ≤12 months; (B) Median serum total bilirubin levels from the first 12 months of life; (C) Median serum aspartate aminotransferase (AST) levels between >6 and ≤12 months; (D) Median serum AST levels from the first 12 months of life.
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References

    1. Alagille D, Odièvre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. 1975;86:63–71. - PubMed
    1. Alagille D, Estrada A, Hadchouel M, Gautier M, Odièvre M, Dommergues JP. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J Pediatr. 1987;110:195–200. - PubMed
    1. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29:822–9. - PubMed
    1. Gilbert MA, Bauer RC, Rajagopalan R, Grochowski CM, Chao G, McEldrew D, et al. . Alagille syndrome mutation update: comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification. Hum Mutat. 2019;40:2197–220. - PMC - PubMed
    1. Leonard LD, Chao G, Baker A, Loomes K, Spinner NB. Clinical utility gene card for: Alagille Syndrome (ALGS). Eur J Hum Genet. 2014;22(3). 10.1038/ejhg.2013.140 - DOI - PMC - PubMed

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