Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver

Daniel H Leung; Lisa G Sorensen; Wen Ye; Kieran Hawthorne; Vicky L Ng; Kathleen M Loomes; Emily M Fredericks; Estella M Alonso; James E Heubi; Simon P Horslen; Saul J Karpen; Jean P Molleston; Philip Rosenthal; Ronald J Sokol; Robert H Squires; Kasper S Wang; Binita M Kamath; John C Magee; Childhood Liver Disease Research Network (ChiLDReN)

doi:10.1097/MPG.0000000000003337

Neurodevelopmental Outcomes in Children With Inherited Liver Disease and Native Liver

J Pediatr Gastroenterol Nutr. 2022 Jan 1;74(1):96-103. doi: 10.1097/MPG.0000000000003337.

Authors

Daniel H Leung¹, Lisa G Sorensen², Wen Ye³, Kieran Hawthorne⁴, Vicky L Ng⁵, Kathleen M Loomes⁶, Emily M Fredericks⁷, Estella M Alonso⁸, James E Heubi⁹, Simon P Horslen¹⁰, Saul J Karpen¹¹, Jean P Molleston¹², Philip Rosenthal¹³, Ronald J Sokol¹⁴, Robert H Squires¹⁵, Kasper S Wang¹⁶, Binita M Kamath¹⁷, John C Magee¹⁸; Childhood Liver Disease Research Network (ChiLDReN)

Affiliations

¹ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.
² Department of Child & Adolescent Psychiatry, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.
³ Department of Biostatistics, University of Michigan.
⁴ ArborResearch Collaborative for Health, Ann Arbor, MI.
⁵ Transplant and Regenerative Medicine Center, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
⁶ Pediatric Gastroenterology, Children's Hospital of Philadelphia, Philadelphia, PA.
⁷ CS Mott Children's Hospital, University of Michigan Medical School, Ann Arbor, MI.
⁸ Ann and Robert H. Lurie Children's Hospital and Northwestern University, Chicago, IL.
⁹ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
¹⁰ Division of Gastroenterology and Hepatology, Seattle Children's, Seattle, WA.
¹¹ Pediatrics, Emory University, Children's Healthcare Atlanta, Atlanta, GA.
¹² Pediatric Gastroenterology, Hepatology and Nutrition, James Whitcomb Riley Hospital for Children, Indianapolis, IN.
¹³ Pediatrics and Surgery, University of California San Francisco, San Francisco, CA.
¹⁴ Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, CO.
¹⁵ Pediatrics, University of Pittsburgh, Pittsburgh, PA.
¹⁶ Children's Hospital Los Angeles, Los Angeles, CA.
¹⁷ Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
¹⁸ Surgery, University of Michigan School of Medicine, Ann Arbor, MI.

Abstract

Objective: To evaluate neurodevelopmental status among children with inherited cholestatic liver diseases with native liver and variables predictive of impairment.

Methods: Participants with Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), and alpha 1 antitrypsin deficiency (A1AT) enrolled in a longitudinal, multicenter study and completed the Wechsler Preschool and Primary Scale of Intelligence-III or Intelligence Scale for Children-IV. Full Scale Intelligence Quotient (FSIQ) was analyzed continuously and categorically (>100, 85-99, 70-84, <70). Univariate linear regression was performed to study association between FSIQ and risk factors, stratified by disease.

Results: Two hundred and fifteen completed testing (ALGS n = 70, PFIC n = 43, A1AT n = 102); median age was 7.6 years (3.0-16.9). Mean FSIQ in ALGS was lower than A1AT (94 vs 101, P = 0.01). Frequency of FSIQ < 85 (>1 standard deviation [SD] below average) was highest in ALGS (29%) versus 18.6% in PFIC and 12.8% in A1AT, and was greater than expected in ALGS based on normal distribution (29% vs 15.9%, P = 0.003). ALGS scored significantly lower than test norms in almost all Wechsler composites; A1AT scored lower on Working Memory and Processing Speed; PFIC was not different from test norms. Total bilirubin, alkaline phosphatase, albumin, hemoglobin, and parental education were significantly associated with FSIQ.

Conclusions: Patients with ALGS are at increased risk of lower FSIQ, whereas our data suggest A1AT and PFIC are not. A1AT and ALGS appear vulnerable to working memory and processing speed deficits suggestive of attention/executive function impairment. Malnutrition, liver disease severity, and sociodemographic factors appear related to FSIQ deficits, potentially identifying targets for early interventions.

Trial registration: ClinicalTrials.gov NCT00571272.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alagille Syndrome* / complications
Alagille Syndrome* / genetics
Child
Child, Preschool
Cholestasis*
Cholestasis, Intrahepatic*
Humans
Wechsler Scales

Associated data

ClinicalTrials.gov/NCT00571272

Abstract

Publication types

MeSH terms

Associated data

Grants and funding