J Clin Invest 1988 Dec;82(6):2148-57

Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twin
with neonatal hepatitis. A new inborn error in bile acid synthesis

Setchell KD, Suchy FJ, Welsh MB, Zimmer-Nechemias L, Heubi J, Balistreri WF
Mass Spectrometry Laboratory, Children's Hospital Medical Center, Cincinnati,
Ohio 45229.

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