Retrospective Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 21, 2019; 25(7): 859-869
Published online Feb 21, 2019. doi: 10.3748/wjg.v25.i7.859
Δ4-3-oxosteroid-5β-reductase deficiency: Responses to oral bile acid therapy and long-term outcomes
Mei-Hong Zhang, Kenneth DR Setchell, Jing Zhao, Jing-Yu Gong, Yi Lu, Jian-She Wang
Mei-Hong Zhang, Jing-Yu Gong, Department of Pediatrics, Jinshan Hospital, Fudan University, Shanghai 201508, China
Kenneth DR Setchell, Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, United States
Jing Zhao, Yi Lu, Jian-She Wang, The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, Shanghai 201102, China
Jing Zhao, Yi Lu, Jian-She Wang, Department of Pediatrics, Shanghai Medical College of Fudan University, Shanghai 201102, China
Author contributions: Zhang MH, Setchell KD, and Zhao J contributed equally to preparation and revision of the manuscript; Gong JY and Lu Y contributed to collection of the clinical data; Setchell KD performed mass spectrometry analysis of patient samples; Wang JS contributed to the paper design, drafting, and revision; all authors contributed to the patient management and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81570468 and No. 81741056; and Jinshan Science and Technology Commission, No. 2014-3-07.
Institutional review board statement: This study was approved by the institutional review board of Children’s Hospital of Fudan University.
Informed consent statement: Informed consent was obtained from each patient.
Conflict-of-interest statement: Setchell KD is a consultant to Retrophin San Diego, United States, and holds a minor equity in Asklepion Pharmaceuticals. The other authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jian-She Wang, MD, PhD, Professor, The Center for Pediatric Liver Diseases, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102, China. jshwang@shmu.edu.cn
Telephone: +86-21-64931171 Fax: +86-21-64931901
Received: October 22, 2018
Peer-review started: October 22, 2018
First decision: December 12, 2018
Revised: January 11, 2019
Accepted: January 18, 2019
Article in press: January 18, 2019
Published online: February 21, 2019
Processing time: 123 Days and 19.8 Hours
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.

Keywords: Δ4-3-oxosteroid-5β-reductase deficiency; Mass spectrometry; Bile acid synthesis disorder; Chenodeoxycholic acid; Ursodeoxycholic acid

Core tip: Δ4-3-oxosteroid 5β-reductase (AKR1D1) deficiency presents as particularly severe and rapidly progressive cholestasis. Treatment with oral primary bile acid has been shown to be effective in normalizing liver function, circumventing the only alternative treatment of liver transplantation. The primary bile acid cholic acid is an approved drug for treating this genetic defect but is not available in China and many other countries. Here we report on the use of the alternative primary bile acid, chenodeoxycholic acid, in the largest cohort of patients with AKR1D1 deficiency studied to date, showing beneficial effects in a personalized regimen approach.