We describe a metabolic defect in bile acid synthesis involving a deficiency in 7alpha-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7alpha-hydroxylase enzyme, active in the acidic pathway for bile acid synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary bile acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic acids, and an absence of primary bile acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic synthesis to be 3beta-hydroxy-5-cholenoic and 3beta-hydroxy-5-cholestenoic acids, which accounted for 96% of the total serum bile acids. Levels of 27-hydroxycholesterol were > 4,500 times normal. The biochemical findings were consistent with a deficiency in 7alpha-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy bile acids. Hepatic microsomal oxysterol 7alpha-hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon. The truncated protein was inactive when expressed in 293 cells. These findings indicate the quantitative importance of the acidic pathway in early life in humans and define a further inborn error in bile acid synthesis as a metabolic cause of severe cholestatic liver disease.
K D Setchell, M Schwarz, N C O'Connell, E G Lund, D L Davis, R Lathe, H R Thompson, R Weslie Tyson, R J Sokol, D W Russell
Title and authors | Publication | Year |
---|---|---|
Biomarkers, metabonomics, and drug development: can inborn errors of metabolism help in understanding drug toxicity?
S Vangala, A Tonelli |
The AAPS Journal | 2007 |
Alterations in xenobiotic metabolism in the long-lived Little mice
D Amador-Noguez, A Dean, W Huang, K Setchell, D Moore, G Darlington |
Aging Cell | 2007 |
Review article: the function and regulation of proteins involved in bile salt biosynthesis and transport
A Pellicoro, KN Faber |
Alimentary Pharmacology & Therapeutics | 2007 |
Review article: the function and regulation of proteins involved in bile salt biosynthesis and transport: REVIEW: BILE SALT BIOSYNTHESIS AND TRANSPORT
A Pellicoro, KN Faber |
Alimentary Pharmacology & Therapeutics | 2007 |
Colestasis neonatales
E Gonzales, E Jacquemin |
EMC - Pediatría | 2007 |
Lysosomal unesterified cholesterol content correlates with liver cell death in murine Niemann-Pick type C disease
EP Beltroy, B Liu, JM Dietschy, SD Turley |
Journal of lipid research | 2007 |
Metabolomics and Metabolite Profiling: Past Heroes and Future Developments
WJ Griffiths, K Karu, M Hornshaw, G Woffendin, Y Wang |
European journal of mass spectrometry (Chichester, England) | 2007 |
Bile Acids: Biological Actions and Clinical Relevance
D Keppler, U Leuschner, M Trauner, U Beuers, A Stiehl, G Paumgartner |
2007 |