Outcomes of Childhood Cholestasis in Alagille Syndrome: Results of a Multicenter Observational Study

• Type of Material: Article
• Authors: Binita M. Kamath, University of Toronto; Wen Ye, University of Michigan; Nathan P. Goodrich, University of Michigan; Kathleen M. Loomes, University of Pennsylvania; Rene Romero, Emory University; James E. Heubi, Cincinnati Children's Hospital Medical Center; Daniel H. Leung, Texas Children's Hospital; Nancy B. Spinner, University of Pennsylvania; David A. Piccoli, University of Pennsylvania; Estella M. Alonso, Northwestern University; Stephen L. Guthery, University of Utah; Sual J. Karpen, Emory University; Cara L. Mack, University of Colorado; Jean P. Molleston, Indiana University; Karen F. Murray, University of Washington; Philip Rosenthal, University of California San Francisco; James E. Squires, UPMC Childrens Hospital Pittsburgh; Jeffrey Teckman, St Louis University; Kasper S. Wang, Childrens Hospital Los Angeles; Richard Thompson, Kings College London; John C. Magee, University of Michigan; Ronald J. Sokol, University of Colorado
• Language: English
• Date: 2020-01-22
• Publisher: JOHN WILEY & SONS LTD
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/hep4.1468
• Title of Journal or Parent Work: HEPATOLOGY COMMUNICATIONS
• Volume: 4
• Issue: 3
• Start Page: 387
• End Page: 398
• Grant/Funding Information: Supported by the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award (Grant/Award Nos. UL1 RR025014, UL1 TR000423, UL1 TR000454, UL1 TR001108, UL1 TR001425, UL1 TR001857, UL1 TR001872, UL1 TR001878, UL1 TR002535, and UL1TR00130); the National Institute of Diabetes, Digestive and Kidney Diseases (Grant/Award Nos. DK 62436 [Ann & Robert H. Lurie Children’s Hospital], DK 62445, DK 62453 [University of Colorado, Denver], DK 62456 [The University of Michigan], DK 62466 [Children’s Hospital of Pittsburgh], DK 62470 [Children’s Healthcare of Atlanta], DK 62481 [The Children’s Hospital of Philadelphia], DK 62497 [Cincinnati Children’s Hospital Medical, DK 62500 [UCSF Children’s Hospital], DK 84536 [Riley Hospital for Children], DK 84538 [Children’s Hospital Los Angeles], DK 84575 [Seattle Children’s Hospital], DK103135 [The Hospital for Sick Children], DK103140 [University of Utah], and DK103149 [Texas Children’s Hospital]).
• Keywords: BILE; CHILDREN; Science & Technology; GROWTH; JAGGED1; Gastroenterology & Hepatology; LIVER-TRANSPLANTATION; Life Sciences & Biomedicine; MUTATIONS; NONPARAMETRIC-ESTIMATION
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

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.