Published online Feb 21, 2019. doi: 10.3748/wjg.v25.i7.859
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
The Δ4-3-oxosteroid 5β-reductase (AKR1D1) deficiency is a rare bile acid synthesis disorder. There have been few reports describing the effectiveness of treatment regimens for this rare genetic disease and the long-term outcomes of oral primary bile acid therapy are unclear. This study provides evidence on how these patients should ideally be managed.
Oral cholic acid (CA), one of the two primary bile acids synthesized by the liver, is an approved therapy for the treatment of bile acid synthesis disorders but is not available to many patients. Chenodeoxycholic acid (CDCA), the other primary bile acid, offers an alternative potential therapy but has been contraindicated in a few reported cases of AKR1D1 deficiency due to its more hydrophobic and potentially hepatotoxic effects. However, in the absence of access to CA in China, we evaluated the effectiveness of CDCA in patients with AKR1D1 deficiency and showed that provided that the therapeutic doses is individually optimized, it is an effective treatment for this disorder.
Through retrospective analysis of the clinical and biochemical responses to bile acid therapy with CDCA in patients with AKR1D1 deficiency, our objective was to better understand the disease progression and long-term outcomes of treatment in order to make recommendations regarding its effectiveness and safety.
Twelve patients with confirmed AKR1D1 deficiency, diagnosed by fast atom bombardment ionization-mass spectrometry analysis of the urinary bile acid profile and by gene sequencing of AKR1D1, were treated with oral bile acids. The clinical and biochemical responses to CDCA therapy were retrospectively evaluated and analyzed, including the results on urinary bile acid profiles and serum liver function indices.
Physical examination, biochemistry parameters, and sonographic findings improved in the patients during CDCA therapy, except for one who underwent liver transplantation. The urinary levels of atypical hepatotoxic 3-oxo-Δ4 bile acids were suppressed concomitantly with clinical improvements in those patients treated with CDCA, but not with ursodeoxycholic acid (UDCA). The dose of CDCA varied from 5.5-10 mg/kg per day among patients based on maximum suppression of the atypical bile acids.
CDCA is an effective alternative therapy to CA, provided that the dose is carefully optimized on an individual patient basis to minimize side effects. UDCA does not achieve the therapeutic goal of suppressing the production of atypical hepatotoxic bile acids and is not recommended for long-term treatment.
CDCA is effective in the treatment of the patients with AKR1D1 deficiency. However, CDCA is intrinsically hepatotoxic, and therefore its dose must be optimized to individual patients. Future studies should focus on continued long-term monitoring of these patients to provide more detailed information of the natural history of this rare metabolic liver disease and to determine long-term outcomes of therapy with primary bile acids.