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

doi:10.1002/hep.32761

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

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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.

Original language	English
Pages (from-to)	512-529
Number of pages	18
Journal	Hepatology
Volume	77
Issue number	2
DOIs	https://doi.org/10.1002/hep.32761
Publication status	Published - 1 Feb 2023

Keywords

Alagille Syndrome/epidemiology
Child
Cholestasis
Female
Humans
Hypertension, Portal/etiology
Male
Retrospective Studies

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@article{2023d378fd3b44258b4b6aad646191d6,

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

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.",

keywords = "Alagille Syndrome/epidemiology, Child, Cholestasis, Female, Humans, Hypertension, Portal/etiology, Male, Retrospective Studies",

author = "Vandriel, {Shannon M.} and Li, {Li Ting} and Huiyu She and Wang, {Jian She} and Gilbert, {Melissa A.} and Irena Jankowska and Piotr Czubkowski and Dorota Gliwicz-Miedzi{\'n}ska and Gonzales, {Emmanuel M.} and Emmanuel Jacquemin and J{\'e}r{\^o}me Bouligand and Spinner, {Nancy B.} and Loomes, {Kathleen M.} and Piccoli, {David A.} and Lorenzo D'Antiga and Emanuele Nicastro and {\'E}tienne Sokal and Tanguy Demaret and Ebel, {Noelle H.} and Feinstein, {Jeffrey A.} and Rima Fawaz and Silvia Nastasio and Florence Lacaille and Dominique Debray and Henrik Arnell and Bj{\"o}rn Fischler and Susan Siew and Michael Stormon and Karpen, {Saul J.} and Rene Romero and Kim, {Kyung Mo} and Baek, {Woo Yim} and Winita Hardikar and Sahana Shankar and Roberts, {Amin J.} and Evans, {Helen M.} and Jensen, {M. Kyle} and Marianne Kavan and Sundaram, {Shikha S.} and Alexander Chaidez and Palaniswamy Karthikeyan and Sanchez, {Maria Camila} and Cavalieri, {Maria Lorena} and Verkade, {Henkjan J.} and Lee, {Way Seah} and Squires, {James E.} and Christina Hajinicolaou and Chatmanee Lertudomphonwanit and Fischer, {Ryan T.} and Wolters, {Victorien M.}",

year = "2023",

month = feb,

day = "1",

doi = "10.1002/hep.32761",

language = "English",

volume = "77",

pages = "512--529",

journal = "Hepatology",

issn = "0270-9139",

publisher = "John Wiley & Sons Inc.",

number = "2",

}

TY - JOUR

T1 - Natural history of liver disease in a large international cohort of children with Alagille syndrome

T2 - Results from the GALA study

AU - Vandriel, Shannon M.

AU - Li, Li Ting

AU - She, Huiyu

AU - Wang, Jian She

AU - Gilbert, Melissa A.

AU - Jankowska, Irena

AU - Czubkowski, Piotr

AU - Gliwicz-Miedzińska, Dorota

AU - Gonzales, Emmanuel M.

AU - Jacquemin, Emmanuel

AU - Bouligand, Jérôme

AU - Spinner, Nancy B.

AU - Loomes, Kathleen M.

AU - Piccoli, David A.

AU - D'Antiga, Lorenzo

AU - Nicastro, Emanuele

AU - Sokal, Étienne

AU - Demaret, Tanguy

AU - Ebel, Noelle H.

AU - Feinstein, Jeffrey A.

AU - Fawaz, Rima

AU - Nastasio, Silvia

AU - Lacaille, Florence

AU - Debray, Dominique

AU - Arnell, Henrik

AU - Fischler, Björn

AU - Siew, Susan

AU - Stormon, Michael

AU - Karpen, Saul J.

AU - Romero, Rene

AU - Kim, Kyung Mo

AU - Baek, Woo Yim

AU - Hardikar, Winita

AU - Shankar, Sahana

AU - Roberts, Amin J.

AU - Evans, Helen M.

AU - Jensen, M. Kyle

AU - Kavan, Marianne

AU - Sundaram, Shikha S.

AU - Chaidez, Alexander

AU - Karthikeyan, Palaniswamy

AU - Sanchez, Maria Camila

AU - Cavalieri, Maria Lorena

AU - Verkade, Henkjan J.

AU - Lee, Way Seah

AU - Squires, James E.

AU - Hajinicolaou, Christina

AU - Lertudomphonwanit, Chatmanee

AU - Fischer, Ryan T.

AU - Wolters, Victorien M.

PY - 2023/2/1

Y1 - 2023/2/1

N2 - 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.

AB - 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.

KW - Alagille Syndrome/epidemiology

KW - Child

KW - Cholestasis

KW - Female

KW - Humans

KW - Hypertension, Portal/etiology

KW - Male

KW - Retrospective Studies

UR - http://www.scopus.com/inward/record.url?scp=85138168945&partnerID=8YFLogxK

U2 - 10.1002/hep.32761

DO - 10.1002/hep.32761

M3 - Article

C2 - 36036223

AN - SCOPUS:85138168945

SN - 0270-9139

VL - 77

SP - 512

EP - 529

JO - Hepatology

JF - Hepatology

IS - 2

ER -

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

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Keywords

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