Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency

Kenneth D R Setchell, James E. Heubi, Sohela Shah, Joel E. Lavine, David Suskind, Mohammed Al-Edreesi, Carol Potter, David W. Russell, Nancy C. O'Connell, Brian Wolfe, Pinky Jha, Wujuan Zhang, Kevin E. Bove, Alex S. Knisely, Alan F. Hofmann, Philip Rosenthal, Laura N. Bull

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background & Aims: 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.

Original languageEnglish (US)
JournalGastroenterology
Volume144
Issue number5
DOIs
StatePublished - May 2013

Fingerprint

Avitaminosis
Bile Acids and Salts
Fats
Bile
Taurine
Lipids
Glycine
Urine
Pediatrics
Cholic Acid
Cholestasis
Glucuronides
Growth
Serum
Hepatitis
Sulfates
Sequence Analysis
Liver Diseases
Mass Spectrometry

Keywords

  • Chronic Liver Disease
  • Hepatic
  • Inherited
  • Nutrient

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Setchell, K. D. R., Heubi, J. E., Shah, S., Lavine, J. E., Suskind, D., Al-Edreesi, M., ... Bull, L. N. (2013). Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology, 144(5). https://doi.org/10.1053/j.gastro.2013.02.004

Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. / Setchell, Kenneth D R; Heubi, James E.; Shah, Sohela; Lavine, Joel E.; Suskind, David; Al-Edreesi, Mohammed; Potter, Carol; Russell, David W.; O'Connell, Nancy C.; Wolfe, Brian; Jha, Pinky; Zhang, Wujuan; Bove, Kevin E.; Knisely, Alex S.; Hofmann, Alan F.; Rosenthal, Philip; Bull, Laura N.

In: Gastroenterology, Vol. 144, No. 5, 05.2013.

Research output: Contribution to journalArticle

Setchell, KDR, Heubi, JE, Shah, S, Lavine, JE, Suskind, D, Al-Edreesi, M, Potter, C, Russell, DW, O'Connell, NC, Wolfe, B, Jha, P, Zhang, W, Bove, KE, Knisely, AS, Hofmann, AF, Rosenthal, P & Bull, LN 2013, 'Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency', Gastroenterology, vol. 144, no. 5. https://doi.org/10.1053/j.gastro.2013.02.004
Setchell KDR, Heubi JE, Shah S, Lavine JE, Suskind D, Al-Edreesi M et al. Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology. 2013 May;144(5). https://doi.org/10.1053/j.gastro.2013.02.004
Setchell, Kenneth D R ; Heubi, James E. ; Shah, Sohela ; Lavine, Joel E. ; Suskind, David ; Al-Edreesi, Mohammed ; Potter, Carol ; Russell, David W. ; O'Connell, Nancy C. ; Wolfe, Brian ; Jha, Pinky ; Zhang, Wujuan ; Bove, Kevin E. ; Knisely, Alex S. ; Hofmann, Alan F. ; Rosenthal, Philip ; Bull, Laura N. / Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. In: Gastroenterology. 2013 ; Vol. 144, No. 5.
@article{c54ea565feb64c69b73b48cdd5c17371,
title = "Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency",
abstract = "Background & Aims: 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.",
keywords = "Chronic Liver Disease, Hepatic, Inherited, Nutrient",
author = "Setchell, {Kenneth D R} and Heubi, {James E.} and Sohela Shah and Lavine, {Joel E.} and David Suskind and Mohammed Al-Edreesi and Carol Potter and Russell, {David W.} and O'Connell, {Nancy C.} and Brian Wolfe and Pinky Jha and Wujuan Zhang and Bove, {Kevin E.} and Knisely, {Alex S.} and Hofmann, {Alan F.} and Philip Rosenthal and Bull, {Laura N.}",
year = "2013",
month = "5",
doi = "10.1053/j.gastro.2013.02.004",
language = "English (US)",
volume = "144",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "5",

}

TY - JOUR

T1 - Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency

AU - Setchell, Kenneth D R

AU - Heubi, James E.

AU - Shah, Sohela

AU - Lavine, Joel E.

AU - Suskind, David

AU - Al-Edreesi, Mohammed

AU - Potter, Carol

AU - Russell, David W.

AU - O'Connell, Nancy C.

AU - Wolfe, Brian

AU - Jha, Pinky

AU - Zhang, Wujuan

AU - Bove, Kevin E.

AU - Knisely, Alex S.

AU - Hofmann, Alan F.

AU - Rosenthal, Philip

AU - Bull, Laura N.

PY - 2013/5

Y1 - 2013/5

N2 - Background & Aims: 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.

AB - Background & Aims: 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.

KW - Chronic Liver Disease

KW - Hepatic

KW - Inherited

KW - Nutrient

UR - http://www.scopus.com/inward/record.url?scp=84876496656&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876496656&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2013.02.004

DO - 10.1053/j.gastro.2013.02.004

M3 - Article

C2 - 23415802

AN - SCOPUS:84876496656

VL - 144

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 5

ER -