A new inborn error in bile acid synthesis, manifest in identical infant twins as severe intrahepatic cholestasis, is described involving the A4-3-oxosteroid 5,#-reductase catalyzed conversion of the key intermediates, 7a-hydroxy4-cholesten-3-one and 7a,12a-dihydroxy4-cholesten-3-one for chenodeoxycholic and cholic acid synthesis, to the respective 3a-hydroxy-5#(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 7a-hydroxy-3-oxo-4-cholenoic and 7a,12a-dihydroxy-3-oxo4-cholenoic acids (75-92% of total).Fasting serum bile acid concentrations were > 37 Amol/liter; chenodeoxycholic acid was the major bile acid, but significant amounts of allo(5a-H)-bile acids (-30%) were present. Biliary bile acid concentration was < 2 ,mol/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 A4-3-oxo-C27 intermediates into the corresponding 3a-hydroxy-50(H)-structures, a reaction that is catalyzed by a A4-3-oxosteroid-5j0 reductase enzyme. This defect resulted in markedly reduced primary bile acid synthesis and concomitant accumulation of A4-3-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 A4-3-oxosteroid 5a-reductase catalyzing the conversion of the A4-3-oxosteroid intermediates to the respective 3a-hydroxy5a(H)-structures.

No abstract