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

Authors

  • Dongling Dai
    • Clinical and Molecular Genetics UnitUCL Institute of Child Health
    • Department of GastroenterologyShenzhen Children’s Hospital
  • Philippa B. Mills
    • Clinical and Molecular Genetics UnitUCL Institute of Child Health
  • Emma Footitt
    • Clinical and Molecular Genetics UnitUCL Institute of Child Health
  • Paul Gissen
    • Clinical and Molecular Genetics UnitUCL Institute of Child Health
  • Patricia McClean
    • Children’s Liver Unit and Department of HistopathologyLeeds Teaching Hospitals NHS Trust
  • Jens Stahlschmidt
    • Children’s Liver Unit and Department of HistopathologyLeeds Teaching Hospitals NHS Trust
  • Isabelle Coupry
    • Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576 2ème étage Ecole de Sage-FemmesHôpital Pellegrin
  • Julie Lavie
    • Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576 2ème étage Ecole de Sage-FemmesHôpital Pellegrin
  • Fanny Mochel
    • Inserm UMR S975/Department of Genetics/University Pierre et Marie Curie, Hôpital de La Salpêtrière
  • Cyril Goizet
    • Laboratoire Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576 2ème étage Ecole de Sage-FemmesHôpital Pellegrin
    • CHU Bordeaux, Service de Génétique Médicale
  • Tatsuki Mizuochi
    • Department of Pediatrics and Child HealthKurume University School of Medicine
  • Akihiko Kimura
    • Department of Pediatrics and Child HealthKurume University School of Medicine
  • Hiroshi Nittono
    • Junshin Clinic Bile Acid Institute
  • Karin Schwarz
    • Neonatal UnitCRH
  • Peter J. Crick
    • Institute of Mass Spectrometry, College of MedicineSwansea University
  • Yuqin Wang
    • Institute of Mass Spectrometry, College of MedicineSwansea University
  • William J. Griffiths
    • Institute of Mass Spectrometry, College of MedicineSwansea University
    • Clinical and Molecular Genetics UnitUCL Institute of Child Health
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