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
. 2023 Dec 7;18(1):383.
doi: 10.1186/s13023-023-02984-z.

∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid

Antoine Gardin  1 , Mathias Ruiz  2 , Jan Beime  3 , Mara Cananzi  4 , Margarete Rathert  5 , Barbara Rohmer  2 , Enke Grabhorn  3 , Marion Almes  1 , Veena Logarajah  6 , Luis Peña-Quintana  7 , Thomas Casswall  8 , Amaria Darmellah-Remil  1 , Ana Reyes-Domínguez  7 , Emna Barkaoui  9 , Loreto Hierro  10 , Carolina Baquero-Montoya  11 , Ulrich Baumann  5 , Björn Fischler  8 , Emmanuel Gonzales  1 , Anne Davit-Spraul  12 , Sophie Laplanche  13 , Emmanuel Jacquemin  14
Affiliations

∆4-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid

Antoine Gardin et al. Orphanet J Rare Dis. .

Abstract

Background: Oral cholic acid therapy is an effective therapy in children with primary bile acid synthesis deficiencies. Most reported patients with this treatment have 3β-hydroxy-Δ5-C27-steroid oxidoreductase deficiency. The aim of the study was the evaluation of cholic acid therapy in a cohort of patients with the rarer Δ4-3-oxosteroid 5β-reductase (Δ4-3-oxo-R) deficiency.

Methods: Sixteen patients with Δ4-3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed.

Results: First symptoms were reported early in life (median 2 months of age), with 14 and 3 patients having cholestatic jaundice and severe bleeding respectively. Fifteen patients received ursodeoxycholic acid before diagnosis, with partial improvement in 8 patients. Four patients had liver failure at the time of cholic acid initiation. All 16 patients received cholic acid from a median age of 8.1 months (range 3.1-159) and serum liver tests normalized in all within 6-12 months of treatment. After a median cholic acid therapy of 4.5 years (range 1.1-24), all patients were alive with their native liver. Median daily cholic acid dose at last follow-up was 8.3 mg/kg of body weight. All patients, but one, had normal physical examination and all had normal serum liver tests. Fibrosis, evaluated using liver biopsy (n = 4) or liver elastography (n = 9), had stabilized or improved. Cholic acid therapy enabled a 12-fold decrease of 3-oxo-∆4 derivatives in urine. Patients had normal growth and quality of life. The treatment was well tolerated without serious adverse events and signs of hepatotoxicity.

Conclusions: Oral cholic acid therapy is a safe and effective treatment for patients with Δ4-3-oxo-R deficiency.

Keywords: AKR1D1; Bile acid; Genetic cholestasis.

PubMed Disclaimer

Conflict of interest statement

EJ is consultant for Vivet Therapeutics and Laboratoire CTRS. EG is consultant for Vivet Therapeutics, Laboratoire CTRS, Albireo, Mirum.

Figures

Fig. 1
Fig. 1
Evolution of 3-oxo-∆4 derivatives in urine of patients before (n = 6) and after (n = 13) cholic acid treatment. Data are presented as median ± interquartile range, with a logarithmic scale. Of note, among the 13 patients with quantification of 3-oxo-∆4 derivatives at last follow-up, six also had quantification at baseline. Statistical analysis was performed using non-parametric two-tailed Mann–Whitney test. CA = cholic acid
See this image and copyright information in PMC

References

    1. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003;72:137–174. doi: 10.1146/annurev.biochem.72.121801.161712. - DOI - PubMed
    1. Setchell KDR. Disorders of bile acid synthesis and metabolism. In: Suchy FJ, Sokol RJ, Balistreri WF, editors. Liver disease in children. 4. Cambridge: Cambridge University Press; 2014. pp. 567–586.
    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. Cheng JB, Jacquemin E, Gerhardt M, Nazer H, Cresteil D, Heubi JE, et al. Molecular genetics of 3β-Hydroxy-Δ5-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. 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