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 |
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Comprehensive Physiology
BJ Wilkins, M Pack |
Comprehensive Physiology | 2013 |
Comprehensive Physiology
BJ Wilkins, M Pack |
Comprehensive Physiology | 2013 |
Comprehensive Physiology
BJ Wilkins, M Pack |
Comprehensive Physiology | 2013 |
Comprehensive Physiology
BJ Wilkins, M Pack |
Comprehensive Physiology | 2013 |
Macrophage PPAR gamma Co-activator-1 alpha participates in repressing foam cell formation and atherosclerosis in response to conjugated linoleic acid
C McCarthy, NT Lieggi, D Barry, D Mooney, M Gaetano, WG James, S McClelland, MC Barry, L Escoubet-Lozach, AC Li, CK Glass, DJ Fitzgerald, O Belton |
EMBO Molecular Medicine | 2013 |
Human cytochromes P450 in health and disease
DW Nebert, K Wikvall, WL Miller |
Philosophical Transactions of the Royal Society B: Biological Sciences | 2013 |
Cytochromes p450: roles in diseases
IA Pikuleva, MR Waterman |
The Journal of biological chemistry | 2013 |
Treatment of mouse liver slices with cholestatic hepatotoxicants results in down-regulation of Fxr and its target genes
E Szalowska, G Stoopen, MJ Groot, PJ Hendriksen, AA Peijnenburg |
BMC Medical Genomics | 2013 |
Sulphatation does not appear to be a protective mechanism to prevent oxysterol accumulation in humans and mice
J Acimovic, A Lövgren-Sandblom, M Olin, Z Ali, M Heverin, R Schüle, L Schöls, B Fischler, P Fickert, M Trauner, I Björkhem |
PloS one | 2013 |
A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns
AE DeBarber, J Luo, M Star-Weinstock, S Purkayastha, MT Geraghty, J Chiang, LS Merkens, AS Pappu, RD Steiner |
Journal of lipid research | 2013 |
Sulphatation Does Not Appear to Be a Protective Mechanism to Prevent Oxysterol Accumulation in Humans and Mice
J Acimovic, A Lövgren-Sandblom, M Olin, Z Ali, M Heverin, R Schüle, L Schöls, B Fischler, P Fickert, M Trauner, I Björkhem, JM Lobaccaro |
PloS one | 2013 |
The hepatic bile acid transporters Ntcp and Mrp2 are downregulated in experimental necrotizing enterocolitis
NJ Cherrington, TE Estrada, HA Frisk, MJ Canet, RN Hardwick, B Dvorak, K Lux, MD Halpern |
AJP Gastrointestinal and Liver Physiology | 2013 |
The effect of 5 intravenous lipid emulsions on plasma phytosterols in preterm infants receiving parenteral nutrition: a randomized clinical trial
S Savini, R DAscenzo, C Biagetti, G Serpentini, A Pompilio, A Bartoli, PE Cogo, VP Carnielli |
The American journal of clinical nutrition | 2013 |
Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases
N Blau, M Duran, KM Gibson, CD Vici |
2013 |