title: Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis.
abstract: A new inborn error in bile acid synthesis, manifest in identical infant twins as severe intrahepatic cholestasis, is described involving the delta 4-3-oxosteroid 5 beta-reductase catalyzed conversion of the key intermediates, 7 alpha-hydroxy-4-cholesten-3-one and 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one for chenodeoxycholic and cholic acid synthesis, to the respective 3 alpha-hydroxy-5 beta (H) products. This defect was detected by fast atom bombardment ionization-mass spectrometry from an elevated excretion and predominance of taurine conjugated unsaturated hydroxy-oxo-bile acids. Gas chromatography-mass spectrometry confirmed these to be 7 alpha-hydroxy-3-oxo-4-cholenoic and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic acids (75-92% of total). Fasting serum bile acid concentrations were greater than 37 mumol/liter; chenodeoxycholic acid was the major bile acid, but significant amounts of allo(5 alpha-H)-bile acids (approximately 30%) were present. Biliary bile acid concentration was less than 2 mumol/liter and consisted of chenodeoxycholic, allo-chenodeoxycholic, and allo-cholic acids. These biochemical findings, which were identical in both infants, indicate a defect in bile acid synthesis involving the conversion of the delta 4-3-oxo-C27 intermediates into the corresponding 3 alpha-hydroxy-5 beta(H)-structures, a reaction that is catalyzed by a delta 4-3-oxosteroid-5 beta reductase enzyme. This defect resulted in markedly reduced primary bile acid synthesis and concomitant accumulation of delta 4-3-oxo-and allo-bile acids. These findings indicate a pathway in bile acid synthesis whereby side chain oxidation can occur despite incomplete alterations to the steroid nucleus, and lend support for an active delta 4-3-oxosteroid 5 alpha-reductase catalyzing the conversion of the delta 4-3-oxosteroid intermediates to the respective 3 alpha-hydroxy-5 alpha(H)-structures.
authors.affiliation: Mass Spectrometry Laboratory, Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: K D
authors.initials: KD
authors.lastname: Setchell
authors.forename: F J
authors.initials: FJ
authors.lastname: Suchy
authors.forename: M B
authors.initials: MB
authors.lastname: Welsh
authors.forename: L
authors.initials: L
authors.lastname: Zimmer-Nechemias
authors.forename: J
authors.initials: J
authors.lastname: Heubi
authors.forename: W F
authors.initials: WF
authors.lastname: Balistreri
mesh_terms: D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000652:urine; D055598:Chemical Phenomena; D002621:Chemistry; D006525:Hepatitis, Viral, Human / Q000201:enzymology*; D006801:Humans; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000201:enzymology*; D010088:Oxidoreductases / Q000172:deficiency*; D014427:Twins; D014430:Twins, Monozygotic
chemical_list: D001647:Bile Acids and Salts; D010088:Oxidoreductases; C021936:3-oxo-5 beta-steroid delta 4-dehydrogenase