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), 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)

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.

Conflict of interest statement

Conflicts of Interest: D.H.L. reports grant/research support from Abbvie, Gilead, and CF Foundation; he also serves on advisory panels for Merck and Gilead. B.M.K. is a consultant for Mirum, Albireo and Audentes; she has unrestricted educational grants from Mirum and Albireo. V.L.N. is a consultant for Albireo. P.R. reports grants from Gilead, Merck, BMS, AbbVie, Travere Therapeutics, Albireo, and Mirum, Arrowhead; and serving as a consultant for Gilead, Mirum, Albireo, Audentes, and Vertex. R.J.S. reports consulting for Albireo, Mirum/Shire, and Retrophin (all <$10,000 per year). K.M.L. reports consulting for Albireo, Mirum and Retrophin (now known as Travere Therapeutics). The remaining authors report no conflicts of interest. The study sponsors did not have a role in study design; collection, analysis, and interpretation of data; writing of the report; or the decision to submit the paper for publication.

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.

Figures

FIGURE 1
FIGURE 1
Distribution of IQ scores by disease group. Distribution of Full Scale and subdomain IQ scores are binned by z score and compared to expected percentages from the normal distribution using chi-square tests. IQ = intelligent quotient.
FIGURE 2
FIGURE 2
Univariate predictors of continuous FSIQ. Linear regression adjusted for parental education was performed, stratified by disease. Variables associated with FSIQ at P < 0.05 (unadjusted) in at least one disease group are shown. P values adjusted for multiple comparisons are also included for reference. FSIQ = Full Scale Intelligent Quotient.

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