Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Oct 29;13(1):190.
doi: 10.1186/s13023-018-0920-5.

Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood

Emmanuel Gonzales  1   2   3   4 , Lorenza Matarazzo  5 , Stéphanie Franchi-Abella  2   6 , Alain Dabadie  7 , Joseph Cohen  1 , Dalila Habes  1 , Sophie Hillaire  8 , Catherine Guettier  2   9 , Anne-Marie Taburet  10 , Anne Myara  11 , Emmanuel Jacquemin  12   13   14
Affiliations

Cholic acid for primary bile acid synthesis defects: a life-saving therapy allowing a favorable outcome in adulthood

Emmanuel Gonzales et al. Orphanet J Rare Dis. .

Abstract

Background: Oral cholic acid (CA) replacement has been shown to be an effective therapy in children with primary bile acid synthesis defects, which are rare and severe genetic liver diseases. To date there has been no report of the effects of this therapy in children reaching adulthood. The aim of the study was to evaluate the long-term effectiveness and safety of CA therapy.

Methods: Fifteen patients with either 3β-hydroxy-Δ5-C27-steroid oxidoreductase (3β-HSD) (n = 13) or Δ4-3-oxosteroid 5β-reductase (Δ4-3-oxo-R) (n = 2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed prospectively.

Results: The median age at last follow-up and the median time of follow-up with treatment were 24.3 years (range: 15.3-37.2) and 21.4 years (range: 14.6-24.1), respectively. At last evaluation, physical examination findings and blood laboratory test results were normal in all patients. Liver sonograms were normal in most patients. Mean daily CA dose was 6.9 mg/kg of body weight. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites remained low or traces in amount with CA therapy. Liver fibrosis scored in liver biopsies or assessed by elastography in 14 patients, after 10 to 24 years with CA therapy, showed a marked improvement with disappearance of cirrhosis (median score < F1; range: F0-F2). CA was well tolerated in all patients, including five women having 10 uneventful pregnancies during treatment.

Conclusions: Oral CA therapy is a safe and effective long-term treatment of 3β-HSD and Δ4-3-oxo-R deficiencies and allows affected children to reach adulthood in good health condition without the need for a liver transplantation.

Keywords: AKR1D1; Bile acid; Genetic cholestasis; HSD3B7.

PubMed Disclaimer

Conflict of interest statement

Ethics approval and consent to participate

The study complied with the Declaration of Helsinki. For the treatment period from 1993 to August 2007, the study was approved by the Ethics Committee of Bicêtre Hospital (Comité de Protection des Personnes, Hôpital Bicêtre, Le Kremlin-Bicêtre, France) and written informed consent was obtained from parents prior to enrollment, as previously reported [14]. Since August 2007 to September 2013, patients benefited from a “Autorisation Temporaire d’Utilisation” delivered for each patient by the “Agence Nationale de Sécurité du Médicament et des Produits de Santé (France)”. Thereafter, the European Commission granted a marketing authorisation valid throughout the European Union for Orphacol on September 2013 [21]. Therefore, for the 10 year period from August 2007 to 2017 which represents the basis of the study, consent to participate was not needed.

Consent for publication

Not applicable.

Competing interests

EJ consulted for laboratory CTRS (France). EG received support for travel from CTRS, Alexion, Spindler Mayoli, Albireo. The other authors reported no conflict of interest.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Effect of long-term oral CA therapy on liver fibrosis in 15 children with 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency (n = 13) or Δ4–3-oxosteroid 5β-reductase deficiency (n = 2). Fibrosis scores were assessed according to Metavir in liver biopsy specimens or as described in the patients and methods section in cases of assessment using non-invasive methods. See Table 2 for the details of fibrosis scores. Data are presented as mean +/− SD values. When in a patient 2 values of fibrosis score were recorded during the same time period, only the most recent score was considered to calculate the mean +/− SD values
Fig. 2
Fig. 2
Initial liver biopsy specimens and the effect of long-term oral CA therapy in patient 10 with 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency. a Liver histology at onset of CA therapy. b Liver histology after 11.5 years of CA therapy. See Table 2 for fibrosis scores
Fig. 3
Fig. 3
Evolution during long-term CA therapy of liver pathology in patient 15 (a and b) and patient 14(c and d) with Δ4–3-oxosteroid 5β-reductase deficiency. a Liver histology after 5.5 years of combined UDCA plus CA therapy. b Liver histology after 16 years of combined UDCA plus CA therapy. c Liver histology after 5.5 years of CA therapy. d Liver histology after 16 years of CA therapy. See Table 2 for fibrosis scores
See this image and copyright information in PMC

References

    1. Clayton PT, Leonard JV, Lawson AM, Setchell KD, Andersson S, Egestad B, et al. Familial giant cell hepatitis associated with synthesis of 3 beta, 7 alpha-dihydroxy-and 3 beta,7 alpha, 12 alpha-trihydroxy-5-cholenoic acids. J Clin Invest. 1987;79:1031–1038. doi: 10.1172/JCI112915. - DOI - PMC - PubMed
    1. Setchell KD, Suchy FJ, Welsh MB, Zimmer-Nechemias L, Heubi J, Balistreri WF. Delta 4-3-oxosteroid 5 beta-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis. J Clin Invest. 1988;82:2148–2157. doi: 10.1172/JCI113837. - DOI - PMC - PubMed
    1. Schwarz M, Wright AC, Davis DL, Nazer H, Björkhem I, Russell DW. The bile acid synthetic gene 3beta-hydroxy-Delta(5)-C(27)-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis. J Clin Invest. 2000;106:1175–1184. doi: 10.1172/JCI10902. - DOI - PMC - PubMed
    1. Cheng JB, Jacquemin E, Gerhardt M, Nazer H, Cresteil D, Heubi JE, et al. Molecular genetics of 3beta-hydroxy-Delta5-C27-steroid oxidoreductase deficiency in 16 patients with loss of bile acid synthesis and liver disease. J Clin Endocrinol Metab. 2003;88:1833–1841. doi: 10.1210/jc.2002-021580. - DOI - PubMed
    1. Lemonde HA, Custard EJ, Bouquet J, Duran M, Overmars H, Scambler PJ, et al. Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003;52:1494–1499. doi: 10.1136/gut.52.10.1494. - DOI - PMC - PubMed

Publication types

Substances

Supplementary concepts

LinkOut - more resources