Fat Malabsorption and Ursodeoxycholic Acid Treatment in Children With Reduced Organic Solute Transporter-α (SLC51A) Expression.

• Type of Material: Article
• Authors: Rune Rose Tronstad, Haukeland University Hospital.; Siren Berland, Haukeland University Hospital; Erling Tjora, Haukeland University Hospital; Khadija El Jellas, University of Bergen; Ingvlid Aukrust, Haukeland University Hospital; Kurt Kristensen, Aarhus University Hospital, Aarhus, Denmark.; Dag Tveitnes, Stavanger University Hospital, Stavanger, Norway.; Anders Molven, University of Bergen; Hanns-Ulrich Marschall, University of Gothenburg; Anuradha Rao, Emory University; Paul Dawson, Emory University
• Language: English
• Date: 2022-08
• Publisher: Wolters Kluwer Health, Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022 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.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1097/pg9.0000000000000229
• Title of Journal or Parent Work: JPGN Rep
• Volume: 3
• Issue: 3
• Grant/Funding Information: Drs Rao and Dawson were supported by National Institutes of Health R01 DK047987.; Dr Marschall received research support from Albireo Pharma and Intercept Pharma. Dr Rao received research support from Albireo Pharma.; Dr Dawson received research support from Albireo Pharma. Dr Marschall was supported by Swedish Medical Research Council 2016-01125.
• Keywords: fecal fat; 7α-hydroxy-4-cholesten-3-one; fibroblast growth factor 19; bile acids
• Research Categories: Health Sciences, Pathology

Abstract

OBJECTIVES: A bile acid homeostasis disorder was suspected in 2 siblings and their second cousin who presented in infancy with fat malabsorption, severe fat-soluble vitamin deficiency, rickets, and mild liver involvement. Our aims were to identify the genetic cause, describe the disease, and evaluate the response to ursodeoxycholic acid (UDCA) treatment. METHODS: Whole exome sequencing, immunohistochemistry of duodenal biopsies and candidate variant testing in a cell-based model was performed. Fecal fat excretion, serum bile acids, 7α-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF19) were quantified in both siblings on and off UDCA treatment. RESULTS: A novel homozygous variant of SLC51A, which encodes the bile acid carrier organic solute transporter (OST)-α, was identified in all affected children. OSTα protein expression was readily detected by immunohistochemistry in duodenum of pediatric control subjects but not in the affected siblings. The siblings had low serum levels of bile acids and C4 and high serum levels of FGF19 consistent with repression of hepatic bile acid synthesis. On treatment with UDCA, fecal fat excretion was reduced and serum levels of C4, FGF19, and liver enzymes normalized. CONCLUSIONS: We report an apparent deficiency of OSTα associated with early onset fat malabsorption and mild liver involvement. The clinical presentation partially overlaps previous reports for 3 patients with OSTα or OSTβ deficiency and extends the clinical spectrum associated with loss of SLC51A expression. Our data suggest that repression of hepatic bile acid synthesis contributes to fat malabsorption in OSTα-OSTβ deficiency but can be partly reversed with UDCA treatment.