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
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.
To evaluate the therapeutic responses of patients with AKR1D1 deficiency to oral bile acid therapy, specifically CDCA.
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.
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.
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.
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.