Oral cholic acid for hereditary defects of primary bile acid synthesis: a safe and effective long-term therapy.
OBJECTIVE
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 3beta-hydroxy-Delta(5)-C(27)-steroid oxidoreductase (3beta-HSD) (n = 13) or Delta(4)-3-oxosteroid 5beta-reductase (Delta(4)-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 3beta-HSD and Delta(4)-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 3beta-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.
Gonzales
Emmanuel
E
Pediatric Hepatology Unit, Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris, Paris, France.
Gerhardt
Marie F
MF
Fabre
Monique
M
Setchell
Kenneth D R
KD
Davit-Spraul
Anne
A
Vincent
Isabelle
I
Heubi
James E
JE
Bernard
Olivier
O
Jacquemin
Emmanuel
E
D015096:3-Hydroxysteroid Dehydrogenases / Q000172:deficiency*; D000284:Administration, Oral; D000293:Adolescent; D001647:Bile Acids and Salts / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D002756:Cholagogues and Choleretics / Q000008:administration & dosage* / Q000009:adverse effects; D019826:Cholic Acid / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D004334:Drug Administration Schedule; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007223:Infant; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010088:Oxidoreductases / Q000172:deficiency*; D011446:Prospective Studies; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013997:Time Factors; D016896:Treatment Outcome
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D010088:Oxidoreductases; D015096:3-Hydroxysteroid Dehydrogenases; C066485:3 beta-hydroxy-delta 5-C(27)-steroid dehydrogenase; C051860:cholestenone 5 beta-reductase; D019826:Cholic Acid