Δ4-3-oxosteroid-5β-reductase deficiency: Responses to oral bile acid therapy and long-term outcomes

Abstract

BACKGROUND Disorders 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. AIM To evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA. METHODS Twelve 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. RESULTS Physical 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. CONCLUSION The 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.

Clinical and genetic features of congenital bile acid synthesis defect with a novel mutation in AKR1D1 gene sequencing

“…The c.797G>A (p.Arg266Gln) homozygous mutation in the AKR1D1 gene found in the first two patients in this study has been reported in several studies [7,18] . However, the homozygous mutation c.155T>C (p.Ile52Thr) in the AKR1D1 gene identified in patient 3 was a thoroughly novel variant [19] .…”

“…[17] The c.797G>A (p.Arg266Gln) homozygous mutation in the AKR1D1 gene found in the first two patients in this study has been reported in several studies. [7,18] However, the homozygous mutation c.155T>C (p.Ile52Thr) in the AKR1D1 gene identified in patient 3 was a thoroughly novel variant. [19] Thus, for the first time, we present this rare disease among the Vietnamese population and describe a novel mutation c.155 T>C, Ile to Thr substitution, which we added to the archive of AKR1D1 variants.…”

Bile Acid Synthesis Disorders in Japan: Long-Term Outcome and Chenodeoxycholic Acid Treatment

“…[17,18,24] In Japan, CDCA is used instead of CA for treatment of BASD, since the latter is not available for clinical use in Japan; the same is true for China. [25] We have obtained a reliable therapeutic effect from CDCA, and believe that a low dose of CDCA (5 to 10 mg/kg/day) can obtain sufficient benefit. [10,13] Low doses are particularly important because CDCA is more hepatotoxic than CA.…”

Fat Malabsorption and Ursodeoxycholic Acid Treatment in Children With Reduced Organic Solute Transporter-α (SLC51A) Expression

“…However, administration of cholic acid or chenodeoxycholic acid suppresses endogenous hepatic bile acid synthesis (14,44,45), which is already low in these patients. In contrast, UDCA and its glycine conjugate can act as a farnesoid X‐receptor antagonist in humans (15,45) to stimulate endogenous hepatic bile acid synthesis (45,46), which is predicted to be beneficial for promoting intestinal lipid absorption.…”

“…After a hospital stay of 4.5 months and recovery from rickets, the patient continued with mixed intravenous and partial enteral nutrition (gluten-and cow milk-free, enriched for medium-chain fatty acids). At 2 years of age, UDCA treatment was initiated (20 mg/kg/d), given its safety profile, ability to improve liver function, and potential to promote fat absorption (12)(13)(14)(15). Parenteral nutrition was suspended, she transitioned to full oral nutrition, and solid stools were noted.…”