Fig. 9.1
Simplified scheme of the two major pathways for the synthesis of bile acids from cholesterol and for their recycling. The “neutral” pathway starts with conversion of cholesterol to 7α-hydroxycholesterol, while the “acidic” pathway begins with formation of 27-hydroxycholesterol. Numbered bars indicate blockades imposed by enzymatic defects. (1) cholesterol 7α-hydroxylase; (2) 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase; (3) Δ4-3-oxosteroid 5β-reductase; (4) sterol 27-hydroxylase; (5) α-methylacyl CoA racemase; (6) proteins involved in peroxisomal biogenesis and β-oxidation; (7) bile acid-CoA: amino acid N-acyl transferase; (8) bacterial deconjugation in the gut; (9) bile acid-CoA ligase; (10) oxysterol 7α-hydroxylase; (11) sterol 12α-hydroxylase. Known enzyme defects are depicted by solid bars across the arrows (Adapted from [1])
9.2 Clinical Features and Diagnosis of Inborn Errors of Bile Acid Synthesis [3]
Although inborn errors of bile acid synthesis (IEBAS) show cholestasis, serum total bile acid (TBA) concentrations are normal when measured by enzymatic methods. Serum γ-glutamyltransferase (GGT) concentrations also are normal. Even though the patient shows obstructive jaundice, pruritus is absent. Histopathologic findings associated with defects involving reactions affecting the steroid nucleus vary with patient age and rate of disease progression. Specimens from infants with impaired steroid nucleus modification show giant cell hepatitis, canalicular bile plugs, hepatocyte bile stasis, and portal tract inflammation, with variable severity of fibrosis. Generally, urinary screening for IEBAS uses fast atom bombardment ionization mass spectrometry (FAB-MS) in the USA and Europe and gas chromatography-mass spectroscopy (GC-MS) or liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in Japan [4] (Table 9.1). Genetic analysis is available for definitive diagnosis [5].
Table 9.1
Bile acid analysis of the urine using GC/MS in three patients with inborn errors of bile acid synthesis
Patient | HSD3B7 deficiency (F, 22years) | SRD5B1 deficiency (M, 6 months) | CYP7B1 deficiency (F, 6 months) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Treatment | Before | After 3 years | Before | After 4 years | Before | After 1 month | ||||||
mmol/molCre (%) | mmol/molCre (%) | mmol/molCre (%) | mmol/molCre (%) | mmol/molCre (%) | mmol/molCre (%) | |||||||
Total bile acids | 115.4 | 0.8 | 125.9 | 6.2 | 109.5 | 11.4 | ||||||
Usual bile acids | 2.2 | (9.8) | 0.2 | (30.2) | 1.2 | (1.0) | 0.5 | (8.7) | 4.9 | (9.7) | 2.7 | (92.9) |
UDCA | 93.0 | – | 0.1 | – | 0.0 | – | 0.0 | – | 59.2 | – | 8.5 | – |
3-Oxo-Δ4-bile acids | 0.0 | (0.0) | 0.0 | (0.0) | 123.9 | (98.4) | 5.4 | (87.0) | 2.0 | (3.9) | 0.0 | (1.4) |
Monohydroxy-Δ5-bile acids | 0.0 | (0.0) | 0.1 | (11.1) | 0.0 | (0.0) | 0.1 | (1.3) | 41.7 | (82.9) | 0.0 | (0.0) |
Dihydroxy-Δ5-bile acids | 5.0 | (22.5) | 0.1 | (12.7) | 0.0 | (0.0) | 0.0 | (0.3) | 0.2 | (0.3) | 0.0 | (0.0) |
Trihydroxy-Δ5-bile acids | 15.2 | (67.7) | 0.3 | (44.4) | 0.0 | (0.0) | 0.0 | (0.0) | 0.0 | (0.0) | 0.0 | (0.0) |
Others | 0.0 | (0.0) | 0.0 | (1.6) | 0.8 | (0.6) | 0.2 | (2.7) | 1.6 | (3.1) | 0.2 | (5.8) |
9.3 Inborn Errors of Bile Acid Synthesis [3]
9.3.1 Defects Involving Reactions Affecting the Steroid Nucleus
9.3.1.1 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase/Isomerase (3βHSD, HSD3B7) Deficiency [6]
3βHSD deficiency, the most common bile acid synthetic defect, is caused by mutation in the HSD3B7 gene on chromosome 16p. The inheritance pattern is autosomal recessive. The major bile acids present in serum and excreted as sulfate esters in the urine are Δ5-3β,7α-dihydroxy-5-cholenoic and Δ5-3β,7α,12α-trihydroxy-5-cholenoic acids. About 50 patients with this disorder have been reported. Even adults with this disease have been reported reflecting its relatively mild nature. Some treated patients with this disease have had normal children [7]. Orally administered primary bile acids (CA and/or CDCA) represent an effective treatment that may normalize and growth and development. However, ursodeoxycholic acid (UDCA) is not effective. Bile acid profiles in serum and urine after bile acid therapy show a marked decrease in amounts of unusual bile acids but no decrease in their percentages.
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