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

ABSTRACT: 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. Sixteen patients with Δ4-3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed. 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. Oral cholic acid therapy is a safe and effective treatment for patients with Δ4-3-oxo-R deficiency.

SUBMITTER: Gardin A

PROVIDER: S-EPMC10704681 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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∆<sup>4</sup>-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid.

Gardin Antoine A Ruiz Mathias M Beime Jan J Cananzi Mara M Rathert Margarete M Rohmer Barbara B Grabhorn Enke E Almes Marion M Logarajah Veena V Peña-Quintana Luis L Casswall Thomas T Darmellah-Remil Amaria A Reyes-Domínguez Ana A Barkaoui Emna E Hierro Loreto L Baquero-Montoya Carolina C Baumann Ulrich U Fischler Björn B Gonzales Emmanuel E Davit-Spraul Anne A Laplanche Sophie S Jacquemin Emmanuel E

Orphanet journal of rare diseases 20231207 1

<h4>Background</h4>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-Δ<sup>5</sup>-C<sub>27</sub>-steroid oxidoreductase deficiency. The aim of the study was the evaluation of cholic acid therapy in a cohort of patients with the rarer Δ<sup>4</sup>-3-oxosteroid 5β-reductase (Δ<sup>4</sup>-3-oxo-R) deficiency.<h4>Methods</h4>Sixteen patients with Δ<sup>4</sup>-3-oxo-R deficiency co ...[more]

PMID: 38062451

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Project description:BackgroundDisorders of primary bile acid synthesis may be life-threatening if undiagnosed, or not treated with primary bile acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5β-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral bile acid replacement therapy with chenodeoxycholic acid (CDCA) in patients with this bile acid synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic acid, which is currently unavailable in China.AimTo evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA.MethodsTwelve patients with AKR1D1 deficiency, confirmed by fast atom bombardment ionization-mass spectrometry analysis of urine and by gene sequencing for mutations in AKR1D1, were treated with differing doses of CDCA or ursodeoxycholic acid (UDCA). The clinical and biochemical responses to therapy were monitored over a period ranging 0.5-6.4 years. Dose adjustment, to optimize the therapeutic dose, was based on changes in serum biochemistry parameters, notably liver function tests, and suppression of the urinary levels of atypical hepatotoxic 3-oxo-Δ4-bile acids measured by mass spectrometry.ResultsPhysical examination, serum biochemistry parameters, and sonographic findings improved in all 12 patients during bile acid therapy, except one who underwent liver transplantation. Urine bile acid analysis confirmed a significant reduction in atypical hepatotoxic 3-oxo-Δ4 bile acids concomitant with clinical and biochemical improvements in those patients treated with CDCA. UDCA was ineffective in down-regulating endogenous bile acid synthesis as evidenced from the inability to suppress the urinary excretion of atypical 3-oxo-Δ4-bile acids. The dose of CDCA required for optimal clinical and biochemical responses varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids and improvement in serum biochemistry parameters, and careful titration of the dose was necessary to avoid side effects from CDCA.ConclusionThe primary bile acid CDCA is effective in treating AKR1D1 deficiency but the therapeutic dose requires individualized optimization. UDCA is not recommended for long-term management.

Project description:Steroid hormones, including glucocorticoids and androgens, exert a wide variety of effects in the body across almost all tissues. The steroid A-ring 5β-reductase (AKR1D1) is expressed in human liver and testes, and three splice variants have been identified (AKR1D1-001, AKR1D1-002, AKR1D1-006). Amongst these, AKR1D1-002 is the best described; it modulates steroid hormone availability and catalyses an important step in bile acid biosynthesis. However, specific activity and expression of AKR1D1-001 and AKR1D1-006 are unknown. Expression of AKR1D1 variants were measured in human liver biopsies and hepatoma cell lines by qPCR. Their three-dimensional (3D) structures were predicted using in silico approaches. AKR1D1 variants were overexpressed in HEK293 cells, and successful overexpression confirmed by qPCR and Western blotting. Cells were treated with either cortisol, dexamethasone, prednisolone, testosterone or androstenedione, and steroid hormone clearance was measured by mass spectrometry. Glucocorticoid and androgen receptor activation were determined by luciferase reporter assays. AKR1D1-002 and AKR1D1-001 are expressed in human liver, and only AKR1D1-006 is expressed in human testes. Following overexpression, AKR1D1-001 and AKR1D1-006 protein levels were lower than AKR1D1-002, but significantly increased following treatment with the proteasomal inhibitor, MG-132. AKR1D1-002 efficiently metabolised glucocorticoids and androgens and decreased receptor activation. AKR1D1-001 and AKR1D1-006 poorly metabolised dexamethasone, but neither protein metabolised cortisol, prednisolone, testosterone or androstenedione. We have demonstrated the differential expression and role of AKR1D1 variants in steroid hormone clearance and receptor activation in vitro. AKR1D1-002 is the predominant functional protein in steroidogenic and metabolic tissues. In addition, AKR1D1-001 and AKR1D1-006 may have a limited, steroid-specific role in the regulation of dexamethasone action.

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

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∆<sup>4</sup>-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid.

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

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∆&lt;sup&gt;4&lt;/sup&gt;-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid.

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∆<sup>4</sup>-3-oxo-5β-reductase deficiency: favorable outcome in 16 patients treated with cholic acid.