Bile Acids and Cholestatic Liver Disease 3: Inborn Errors of Bile Acid Synthesis

Abstract

Inborn errors of bile acid synthesis are rare genetic disorders that can present as neonatal cholestasis and fat-soluble vitamin deficiency. Though rare, these diseases account for some patients with cholestasis of unknown etiology. Seven known defects of bile acid synthesis occur in children. These defects may be categorized as deficiencies in activity of enzymes catalyzing reactions affecting the steroid nucleus or the side chain. Defects in reactions involving the steroid nucleus include cholesterol 7α-hydroxylase deficiency, 3β-hydroxysteroid-Δ5-C27-steroid dehydrogenase/isomerase deficiency, Δ4-3-oxosteroid 5β-reductase deficiency, and oxysterol 7α-hydroxylase deficiency. Defects in reactions involving side-chain modification are sterol 27-hydroxylase deficiency, α-methyl-CoA racemase deficiency, disorders of peroxisomal β-oxidation, bile acid-CoA: amino acid N-acyltransferase deficiency, and bile acid-CoA ligase deficiency. Cholesterol 7α-hydroxylase deficiency and disorders of peroxisomal β-oxidation are not considered here, since cholesterol 7α-hydroxylase deficiency is not known to occur in children and disorders of peroxisomal β-oxidation represent disease of peroxisomes. When identified early, many patients with inborn errors of bile acid synthesis have a favorable clinical response to oral primary bile acid therapy. These inborn errors characteristically result in elevated serum bilirubin and aminotransferase concentrations but produce no abnormalities of serum γ-glutamyltransferase or of total bile acid concentrations detectable by enzymatic methods. Screening for inborn errors of bile acid synthesis using fast atom bombardment ionization mass spectrometry, gas chromatography-mass spectroscopy, and liquid chromatography-electrospray ionization tandem mass spectrometry is useful. Genetic analysis is available for a definitive diagnosis. Disorders of bile acid synthesis account for some 2–3% of screened cases of cholestatic liver disease in infants and children.