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

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.

SUBMITTER: Kamath BM

PROVIDER: S-EPMC7049675 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Kamath Binita M BM Ye Wen W Goodrich Nathan P NP Loomes Kathleen M KM Romero Rene R Heubi James E JE Leung Daniel H DH Spinner Nancy B NB Piccoli David A DA Alonso Estella M EM Guthery Stephen L SL Karpen Saul J SJ Mack Cara L CL Molleston Jean P JP Murray Karen F KF Rosenthal Philip P Squires James E JE Teckman Jeffrey J Wang Kasper S KS Thompson Richard R Magee John C JC Sokol Ronald J RJ

Hepatology communications 20200122 3

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 ...[more]

PMID: 33313463

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Project description:BackgroundChildhood cancer survivors are at high risk of developing adverse late health effects. Poor nutritional intake may contribute to this risk, but information about dietary intake is limited.ObjectiveThis study will assess childhood cancer survivors' dietary intake and compare two dietary assessment tools: a self-reported food frequency questionnaire, and dietary measurements from urine spot samples.MethodsIn a substudy of the Swiss Childhood Cancer Survivor Study (SCCSS), SCCSS-Nutrition, we assessed childhood cancer survivors' dietary intake via a validated food frequency questionnaire. We sent a urine spot collection kit to a subset of 212 childhood cancer survivors from the French-speaking region of Switzerland to analyze urinary sodium, potassium, urea, urate, creatinine, and phosphate content. We will compare the food frequency questionnaire results with the urine spot analyses to quantify childhood cancer survivors' intake of various nutrients. We collected data between March 2016 and March 2018.ResultsWe contacted 1599 childhood cancer survivors, of whom 919 (57.47%) returned a food frequency questionnaire. We excluded 11 childhood cancer survivors who were pregnant or were breastfeeding, 35 with missing dietary data, and 71 who had unreliable food frequency questionnaire data, resulting in 802 childhood cancer survivors available for food frequency questionnaire analyses. To a subset of 212 childhood cancer survivors in French-speaking Switzerland we sent a urine spot collection kit, and 111 (52.4%) returned a urine sample. We expect to have the results from analyses of these samples in mid-2019.ConclusionsThe SCCSS-Nutrition study has collected in-depth dietary data that will allow us to assess dietary intake and quality and compare two dietary assessment tools. This study will contribute to the knowledge of nutrition among childhood cancer survivors and is a step toward surveillance guidelines and targeted nutritional recommendations for childhood cancer survivors in Switzerland.Trial registrationClinicalTrials.gov NCT03297034; https://clinicaltrials.gov/ct2/show/NCT03297034.International registered report identifier (irrid)DERR1-10.2196/14427.

Dataset Information

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

Publications

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

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