Familial giant cell hepatitis with low bile acid concentrations and increased urinary excretion of specific bile alcohols: a new inborn error of bile acid synthesis?
A 9-wk-old infant with familial giant cell hepatitis and severe intrahepatic cholestasis had low plasma concentrations of chenodeoxycholic acid and cholic acid and elevated plasma concentrations of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 zeta-tetrol, and 5 beta-cholest-24-ene-3 alpha,7 alpha,12 alpha-triol. Analysis of the urine by fast atom bombardment mass spectrometry and by gas chromatography-mass spectrometry after treatment with Helix pomatia glucuronidase/sulfatase showed that the major cholanoids in urine were the glucuronides of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24S,25-pentol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol, and 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24 zeta-tetrol. These results are consistent with an inborn error of the 25-hydroxylase pathway for bile acid synthesis, specifically one of the enzymes responsible for conversion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,24S,25-pentol to cholic acid and acetone. Treatment with chenodeoxycholic acid was tried on two occasions. On the first it appeared to precipitate a rise in bilirubin, on the second the liver function tests improved and the improvement was maintained when the treatment was modified to a combination of chenodeoxycholic acid and cholic acid and finally, cholic acid alone. Despite the normalization of liver function tests, a liver biopsy at 1.25 y showed an active cirrhosis. Nonetheless, the child is thriving at the age of 3.5 y, whereas an affected sibling died at 13 mo.
Clayton
P T
PT
Metabolic Disease Unit, Institute of Child Health, London, United Kingdom.
Casteels
M
M
Mieli-Vergani
G
G
Lawson
A M
AM
D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002635:Chenodeoxycholic Acid / Q000097:blood; D002777:Cholestanols / Q000652:urine*; D002779:Cholestasis / Q000235:genetics; D019826:Cholic Acid; D002793:Cholic Acids / Q000097:blood; D005500:Follow-Up Studies; D015726:Giant Cells; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D008661:Metabolism, Inborn Errors / Q000209:etiology* / Q000235:genetics; D015394:Molecular Structure
D001647:Bile Acids and Salts; D002777:Cholestanols; D002793:Cholic Acids; D002635:Chenodeoxycholic Acid; D019826:Cholic Acid