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


Gastroenterology. 2013;144(5):945-955. 

In This Article

Abstract and Introduction


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.


Hepatic bile acid conjugation with the amino acids glycine and taurine represents the final step in primary bile acid synthesis in humans.[1] The liver has a high capacity for conjugation, and as a result negligible amounts of unconjugated bile acids (<2%) typically appear in bile under normal or cholestatic conditions.[2] Conjugation significantly alters the physicochemical characteristics of an unconjugated bile acid by increasing the molecular size (Figure 1) and lowering the pKa, thus enhancing aqueous solubility at the pH of the proximal intestine and preventing nonionic passive absorption.[3] Conjugation thus promotes a high intraluminal bile acid concentration and therefore efficient solubilization of lipids with low aqueous solubility such as saturated fatty acids and fat-soluble vitamins. Two enzymes catalyze the reactions leading to bile acid amidation. A CoA thioester is first formed by the rate-limiting bile acid-CoA ligase enzyme (BACL; encoded by SLC27A5),[4,5] and then glycine or taurine is coupled to the carboxyl group of the bile acid in a reaction catalyzed by cytosolic bile acid-CoA:amino acid N-acyltransferase (BAAT; encoded by BAAT).[6]

Figure 1.

Space-filling models showing the influence of bile acid conjugation with glycine and taurine on the size of the molecule, its physicochemical properties, and its physiological features.

In 1997, we first described in a preliminary report a defect in bile acid amidation in a 14-year-old boy with fat malabsorption and fat-soluble vitamin deficiency.[7] This child presented in the first 3 months of life with conjugated hyperbilirubinemia, elevated serum transaminase levels, and a normal γ-glutamyl transpeptidase (GGT) level. Two other patients, a 5-year-old Saudi Arabian boy and his 8-year-old sister, the products of a consanguineous marriage, were later identified with the same bile acid defect. Remarkably, the boy had undergone a portoenterostomy for a diagnosis of "extrahepatic biliary hypoplasia," whereas his sister was reportedly asymptomatic. We have now identified a bile acid conjugation defect in 10 patients with clinical histories of normal or mildly elevated liver chemistry values but a severe fat-soluble vitamin deficiency, often resulting in coagulopathy and rickets. The main feature, fat-soluble vitamin deficiency, occurs because of reduced biliary secretion of conjugated bile acids and an inability to form mixed micelles because of rapid passive absorption of unconjugated cholic acid in the proximal small intestine. The recognition that genetic defects in bile acid synthesis are associated with unexplained fat-soluble vitamin deficiency warrants a concerted effort to explore this patient population for these disorders. This report describes the clinical, biochemical, and molecular features of defective bile acid conjugation in the largest cohort of patients thus far reported.