Oral Cholic Acid for Hereditary Defects of Primary Bile Acid Synthesis: A Safe and Effective Long-term Therapy

Background & Aims

Oral bile acid replacement has been shown to be an effective therapy in primary bile acid synthesis defects, but to date there have been no reports of the long-term effects of this therapy. The aim of the study was to evaluate the long-term effectiveness and safety of cholic acid (CA) therapy.

Methods

Fifteen patients with either 3β-hydroxy-Δ⁵-C₂₇-steroid oxidoreductase (3β-HSD) (n = 13) or Δ⁴-3-oxosteroid 5β-reductase (Δ⁴-3-oxo-R) (n = 2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed up prospectively.

Results

CA therapy was started at a median age of 3.9 years (range, 0.3–13.1 years). The median follow-up with treatment was 12.4 years (range, 5.6–15 years). The mean daily dose of CA was initially 13 mg/kg and was 6 mg/kg at last evaluation. During CA therapy, physical examination findings, laboratory test results, and findings on sonography normalized. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites was reduced by 500-fold and 30-fold in 3β-HSD and Δ⁴-3-oxo-R deficiency, respectively, and total urinary bile acid excretion decreased dramatically. Liver biopsies performed in 14 patients after at least 5 years of CA therapy showed marked improvement, especially in patients with the 3β-HSD deficiency. CA was well tolerated with all children developing normally, including 2 women having 4 normal pregnancies during treatment.

Conclusions

Oral CA therapy is a safe and effective long-term treatment of the most common primary bile acid synthesis defects.

Abbreviations used in this paper: 3β-HSD, 3β-hydroxy-Δ⁵-C₂₇-steroid oxidoreductase, Δ⁴-3-oxo-R, Δ⁴-3-oxosteroid 5β-reductase, CA, cholic acid, CDCA, chenodeoxycholic acid, FAB-MS, fast atom bombardment/mass spectrometry, GC-MS, gas chromatography/mass spectrometry, GGT, γ-glutamyltransferase