title: Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency.
abstract: OBJECTIVE
  The final step in bile acid synthesis involves conjugation with glycine and taurine, which promotes a high intraluminal micellar concentration to facilitate lipid absorption. We investigated the clinical, biochemical, molecular, and morphologic features of a genetic defect in bile acid conjugation in 10 pediatric patients with fat-soluble vitamin deficiency, some with growth failure or transient neonatal cholestatic hepatitis.
  
  
  METHODS
  We identified the genetic defect that causes this disorder using mass spectrometry analysis of urine, bile, and serum samples and sequence analysis of the genes encoding bile acid-CoA:amino acid N-acyltransferase (BAAT) and bile acid-CoA ligase (SLC27A5).
  
  
  RESULTS
  Levels of urinary bile acids were increased (432 ± 248 μmol/L) and predominantly excreted in unconjugated forms (79.4% ± 3.9%) and as sulfates and glucuronides. Glycine or taurine conjugates were absent in the urine, bile, and serum. Unconjugated bile acids accounted for 95.7% ± 5.8% of the bile acids in duodenal bile, with cholic acid accounting for 82.4% ± 5.5% of the total. Duodenal bile acid concentrations were 12.1 ± 5.9 mmol/L, which is too low for efficient lipid absorption. The biochemical profile was consistent with defective bile acid amidation. Molecular analysis of BAAT confirmed 4 different homozygous mutations in 8 patients tested.
  
  
  CONCLUSIONS
  Based on a study of 10 pediatric patients, genetic defects that disrupt bile acid amidation cause fat-soluble vitamin deficiency and growth failure, indicating the importance of bile acid conjugation in lipid absorption. Some patients developed liver disease with features of a cholangiopathy. These findings indicate that patients with idiopathic neonatal cholestasis or later onset of unexplained fat-soluble vitamin deficiency should be screened for defects in bile acid conjugation.
authors: Department of Pathology and Laboratory Medicine, Children's Hospital Medical Center, Cincinnati, OH 45229, USA. kenneth.setchell@cchmc.org
authors: Kenneth D R
authors: KD
authors: Setchell
authors: James E
authors: JE
authors: Heubi
authors: Sohela
authors: S
authors: Shah
authors: Joel E
authors: JE
authors: Lavine
authors: David
authors: D
authors: Suskind
authors: Mohammed
authors: M
authors: Al-Edreesi
authors: Carol
authors: C
authors: Potter
authors: David W
authors: DW
authors: Russell
authors: Nancy C
authors: NC
authors: O'Connell
authors: Brian
authors: B
authors: Wolfe
authors: Pinky
authors: P
authors: Jha
authors: Wujuan
authors: W
authors: Zhang
authors: Kevin E
authors: KE
authors: Bove
authors: Alex S
authors: AS
authors: Knisely
authors: Alan F
authors: AF
authors: Hofmann
authors: Philip
authors: P
authors: Rosenthal
authors: Laura N
authors: LN
authors: Bull
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D001361:Avitaminosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001647:Bile Acids and Salts / Q000378:metabolism*; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003066:Coenzyme A Ligases / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007223:Infant; D008099:Liver / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D020125:Mutation, Missense
chemical_list: D001647:Bile Acids and Salts; D050612:Fatty Acid Transport Proteins; C484819:SLC27A5 protein, human; D004247:DNA; D000217:Acyltransferases; C026953:bile acid-CoA amino acid N-acyltransferase; D003066:Coenzyme A Ligases; C070656:bile acid-CoA ligase