Journal of Inherited Metabolic Disease

, Volume 37, Issue 5, pp 851–861

Liver disease in infancy caused by oxysterol 7α-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
Case Report

DOI: 10.1007/s10545-014-9695-6

Cite this article as:
Dai, D., Mills, P.B., Footitt, E. et al. J Inherit Metab Dis (2014) 37: 851. doi:10.1007/s10545-014-9695-6

Abstract

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 7α-hydroxylase deficiency. The patient was homozygous for a mutation (c.1249C>T) in CYP7B1 that alters a highly conserved residue in oxysterol 7α-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 synthesis.

Supplementary material

10545_2014_9695_MOESM1_ESM.docx (178 kb)
Fig. 1(DOCX 178 kb)
10545_2014_9695_MOESM2_ESM.docx (130 kb)
Fig. 2(DOCX 129 kb)
10545_2014_9695_MOESM3_ESM.docx (35 kb)
Table 1(DOCX 34 kb)

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Dongling Dai
    • 1
    • 2
  • Philippa B. Mills
    • 1
  • Emma Footitt
    • 1
  • Paul Gissen
    • 1
  • Patricia McClean
    • 3
  • Jens Stahlschmidt
    • 3
  • Isabelle Coupry
    • 4
  • Julie Lavie
    • 4
  • Fanny Mochel
    • 5
  • Cyril Goizet
    • 4
    • 6
  • Tatsuki Mizuochi
    • 7
  • Akihiko Kimura
    • 7
  • Hiroshi Nittono
    • 8
  • Karin Schwarz
    • 9
  • Peter J. Crick
    • 10
  • Yuqin Wang
    • 10
  • William J. Griffiths
    • 10
  • Peter T. Clayton
    • 1
  1. 1.Clinical and Molecular Genetics UnitUCL Institute of Child HealthLondonUK
  2. 2.Department of GastroenterologyShenzhen Children’s HospitalShenzhenChina
  3. 3.Children’s Liver Unit and Department of HistopathologyLeeds Teaching Hospitals NHS TrustLeedsUK
  4. 4.Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576 2ème étage Ecole de Sage-FemmesHôpital PellegrinBordeaux CedexFrance
  5. 5.Inserm UMR S975/Department of Genetics/University Pierre et Marie Curie, Hôpital de La SalpêtrièreParisFrance
  6. 6.CHU Bordeaux, Service de Génétique MédicaleBordeauxFrance
  7. 7.Department of Pediatrics and Child HealthKurume University School of MedicineKurumeJapan
  8. 8.Junshin Clinic Bile Acid InstituteTokyoJapan
  9. 9.Neonatal UnitCRHHalifaxUK
  10. 10.Institute of Mass Spectrometry, College of MedicineSwansea UniversitySwanseaUK