1. Volume 137, Issue 4, Pages 1310-1320.e3 (October 2009)
Oral Cholic Acid for Hereditary Defects of Primary Bile Acid Synthesis: A Safe and Effective Long-term Therapy 
Emmanuel Gonzales, Marie F. Gerhardt, Monique Fabre, Kenneth D.R. Setchell, Anne Davit–Spraul, Isabelle Vincent, James E. Heubi, Olivier Bernard, Emmanuel Jacquemin 
Gastroenterology 
Volume 137, Issue 4, Pages e3 (October 2009)
DOI: /j.gastro
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2. Figure 1
Primary bile acids synthesis pathway, regulation, and consequences of 3β-HSD and Δ4-3-oxo-R deficiencies. (A) Primary bile acids down-regulate their own biosynthesis via activation of farnesoid X receptor, which represses transcription of the CYP7A1 gene encoding cholesterol 7α-hydroxylase, the rate-limiting enzyme of bile acid synthesis. (B) In 3β-HSD or Δ4-3-oxo-R deficiency, absence of primary bile acids leads to cholestasis and unregulated accumulation of toxic bile acid precursors (3β-hydroxylated-Δ5 [3βOH-Δ5] or 3-oxo-Δ4 bile acids). The rationale for CA therapy is improvement of bile flow and fat absorption and restoration of a physiologic feedback inhibition on bile acid synthesis, lowering the production of toxic bile acid precursors.
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3. Figure 2
Effect with oral CA therapy on serum liver function test results, serum vitamin E concentration, and steatorrhea in 15 children with 3β-HSD and Δ4-3-oxo-R deficiencies. (A) Total bilirubin level (normal, <17 μmol/L), ALT level (normal, <40 IU/L), γ-glutamyltransferase level (GGT; normal, <30 IU/L), and prothrombin time (normal, >70%). (A) *P < .05, UDCA vs at CA; #P < .0001, at CA vs CA 5 years. (B) Total bile acids level (normal, <10 μmol/L), vitamin E level (normal, 5.5–11.8 mg/L), and steatorrhea (normal, <2.5 g/24 h). Means ± SEM are presented. (B) *P < .005, before any bile acid therapy vs CA 5 years.
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4. Figure 3
Effect of oral CA therapy on total urinary bile acids and on (A) 3β-hydroxylated-Δ5 bile acids in 13 children with 3β-HSD deficiency or (B) Δ4-3-oxo-bile acids in 2 children with Δ4-3-oxo-R deficiency. (A) Total urinary bile acids represent the sum of 3β-hydroxylated-Δ5 (3βOH-Δ5) and physiologic bile acids. 3βOH-Δ5 derivatives were assayed by measuring the concentration of 3β,7α-dihydroxy-5-cholenoic acid (mean values ± SEM). *Evaluation performed in 5 patients with UDCA and before CA therapy. £P < .05, initial vs UDCA; #P < .005, initial vs CA 5 years; §P < .005, initial vs CA last visit. (B) Total urinary bile acids represent the sum of Δ4-3-oxo bile acids and physiologic bile acids. 3-oxo-Δ4 bile acids were assayed by measuring the concentration of 7α-hydroxy-3-oxo-Δ4-cholenoic acids and 7α,12α-dihydroxy-3-oxo-Δ4-cholenoic acids (mean values). *Evaluation performed with UDCA and before CA therapy was started; °CA therapy was associated with UDCA during the first 14 months of treatment.
Gastroenterology  , e3DOI: ( /j.gastro )
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5. Figure 4
Initial liver biopsy specimens and the effect of oral CA therapy in children with 3β-HSD and Δ4-3-oxo-R deficiencies. (A and B) Patient 4 with 3β-HSD deficiency. (A) Liver histology at onset of CA therapy. (B) Liver histology after 7 years of CA therapy. Note the decrease of fibrosis score from F4 to F3/F2. (C and D) Patient 14 with Δ4-3-oxo-R deficiency. (C) Liver histology after 14 months of combined UDCA plus CA therapy. (D) Liver histology after 5.5 years of CA therapy. Note the decrease of fibrosis score from F4 to F4/F3. Sirius red stain; original magnification 30×. See Supplementary Table 2 for fibrosis scores.
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6. Figure 5
Effect of oral CA therapy on liver pathology in 14 children with 3β-HSD and Δ4-3-oxo-R deficiencies. Fibrosis and activity scored according to METAVIR (mean values ± SD). Liver biopsies were performed before CA therapy and after a mean duration of CA therapy of 6.1 years (range, 5.1–11.5 years). Detailed data from each patient are provided in Supplementary Table 2. *P < .005, before CA therapy vs with long-term CA therapy.
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7. Supplementary Figure 1
GC-MS analysis of urinary bile acids before and with cholic acid therapy in children with 3β-hydroxy-Δ5-C27-steroid oxidoreductase and Δ4-3-oxosteroid 5β-reductase deficiencies. (A) Normal subject. (B and C) Patient 9 (3β-HSD deficiency). (B) Before cholic acid (CA) therapy, note peaks U1 and U2 corresponding to the specific metabolites (3β-hydroxylated-Δ5 bile acids) identified in this deficiency. (C) With CA therapy, note the reduction of U1 peak and the disappearance of U2 peak. (D and E) Patient 15 (Δ4-3-oxo-R deficiency). (D) Before CA therapy, note peaks 2 and 3 corresponding to the specific metabolites (Δ4-3-oxo bile acids) identified in this deficiency. Note also peak 1 corresponding to allo-bile acids. (E) With CA therapy, note the reduction of peaks 2 and 3. With CA therapy, peak 1 corresponds to the sum of allo-bile acids + DC. 5αCho: 5α-cholestane; C: cholate; CDC: chenodeoxycholate; DC: deoxycholate; U1: 3β,7α-dihydroxycholenoic acid; U2: 3β,7α,12α-trihydroxycholenoic acid. 1: Allo-bile acids (5α-H), 2: 7α-hydroxy-3oxo-4-cholenoic acid, 3: 7α,12α-dihydroxy-3oxo-4-cholenoic acid.
Gastroenterology  , e3DOI: ( /j.gastro )
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