Liver disease in infancy caused by oxysterol 7 α-hydroxylase deficiency: successful treatment with chenodeoxycholic acid.

Dongling Dai, Philippa B. Mills, Emma Footitt, Paul Gissen, Patricia McClean, Jens Stahlschmidt, Isabelle Coupry, Julie Lavie, Fanny Mochel, Cyril Goizet, Tatsuki Mizuochi, Akihiko Kimura, Hiroshi Nittono, Karin Schwarz, Peter J. Crick, Yuqin Wang, William J. Griffiths, Peter T. Clayton
J Inherit Metab Dis. 2014-03-22; 37(5): 851-861
DOI: 10.1007/s10545-014-9695-6

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1. J Inherit Metab Dis. 2014 Sep;37(5):851-61.

Liver disease in infancy caused by oxysterol 7 α-hydroxylase deficiency:
successful treatment with chenodeoxycholic acid.

Dai D, Mills PB, Footitt E, Gissen P, McClean P, Stahlschmidt J, Coupry I, Lavie
J, Mochel F, Goizet C, Mizuochi T, Kimura A, Nittono H, Schwarz K, Crick PJ, Wang
Y, Griffiths WJ, Clayton PT.

A child of consanguineous parents of Pakistani origin developed jaundice at 5
weeks and then, at 3 months, irritability, a prolonged prothrombin time, a low
albumin, and episodes of hypoglycaemia. Investigation showed an elevated alanine
aminotransferase with a normal γ-glutamyl-transpeptidase. Analysis of urine by
electrospray ionisation tandem mass spectrometry (ESI-MS/MS) showed that the
major peaks were m/z 480 (taurine-conjugated 3β-hydroxy-5-cholenoic acid) and m/z
453 (sulphated 3β-hydroxy-5-cholenoic acid). Analysis of plasma by gas
chromatography-mass spectrometry (GC-MS) showed increased concentrations of
3β-hydroxy-5-cholenoic acid, 3β-hydroxy-5-cholestenoic acid and
27-hydroxycholesterol, indicating oxysterol 7 α-hydroxylase deficiency. The
patient was homozygous for a mutation (c.1249C>T) in CYP7B1 that alters a highly
conserved residue in oxysterol 7 α-hydroxylase (p.R417C) – previously reported in
a family with hereditary spastic paraplegia type 5. On treatment with
ursodeoxycholic acid (UDCA), his condition was worsening, but on chenodeoxycholic
acid (CDCA), 15 mg/kg/d, he improved rapidly. A biopsy (after 2 weeks on CDCA),
showed a giant cell hepatitis, an evolving micronodular cirrhosis, and steatosis.
The improvement in liver function on CDCA was associated with a drop in the
plasma concentrations and urinary excretions of the 3β-hydroxy-Δ5 bile acids
which are considered hepatotoxic. At age 5 years (on CDCA, 6 mg/kg/d), he was
thriving with normal liver function. Neurological development was normal apart
from a tendency to trip. Examination revealed pes cavus but no upper motor neuron
signs. The findings in this case suggest that CDCA can reduce the activity of
cholesterol 27-hydroxylase – the first step in the acidic pathway for bile acid

DOI: 10.1007/s10545-014-9695-6
PMID: 24658845 [Indexed for MEDLINE]

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