Two Inborn Errors of Bile Acid Biosynthesis: The Need for Recognition and Treatment by Primary Bile Acid Replacement

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Elsewhere in this issue, Jahnel et al (1) report the results of a web-based survey of academic pediatric departments asking whether 2 inborn errors of bile acid synthesis had been recognized. The survey also asked how infants with these enzyme deficiencies were treated. The 2 enzyme defects were the second and third steps in bile acid formation from cholesterol in the major pathway for bile acid synthesis.
The majority of pediatric centers responded to the questionnaire, and of those responding, about half had never made such a diagnosis in their practice. In most infants who were identified as having either of the enzymatic defects, treatment was the oral administration of primary bile acids—cholic acid or chenodeoxycholic acid. The survey established the extreme rarity of these 2 defects in Europe. The first defect, absence of the dehydrogenase/isomerase enzyme, was 8 times more prevalent than the second defect, absence of the reductase.
Bile acid synthesis is complex and is synonymous with cholesterol degradation. Cholesterol is insoluble, and rests comfortably in cell membranes between phospholipid molecules where it increases membrane stability. Bile acids, in contrast, are highly water-soluble and solubilize cell membranes in the form of mixed micelles in intestinal content (2). Thus, cholesterol and bile acids are diametrically opposed in their functions.
Multiple enzymatic steps are involved in the complex pathway by which the cholesterol molecule is converted to a bile acid molecule in the human hepatocyte (3). The steroid nucleus must be altered from the Δ5 structure of cholesterol to that of a fully saturated product. The isooctane side chain of cholesterol must be converted to the isopentanoic acid side chain of C24 bile acids. In the major pathway of bile acid biosynthesis (called the “neutral” pathway), changes to the nucleus are completed before changes to the side chain occur. In the minor pathway, termed the “acidic” pathway, bile acid synthesis begins with side chain oxidation. The defects described by Jahnel et al are in the major (“neutral”) pathway. Excellent reviews of bile acid synthesis and its defects are available (4,5).
The initial and rate-limiting step in the biosynthesis of bile acids from cholesterol is hydroxylation at C-7 (the 7th carbon atom in the steroid nucleus) by cholesterol 7α-hydroxylase (CYP7A1), a microsomal enzyme. The phenotype of cholesterol 7α-hydroxylase deficiency in man is astonishingly unremarkable, possibly because of the nontoxicity of cholesterol as well as the compensatory increase in bile acid formation via the acidic pathway (6). In contrast, the enzyme defects queried by Jahnel et al are fatal, unless treated by bile acid replacement.
The first concern of Jahnel et al was a deficiency in 3β-dehydrogenase/isomerase, the second step in bile acid biosynthesis. This enzyme (HSD3B7) catalyzes the simultaneous oxidation of the 3β-hydroxy group to a 3-oxo group and shifting of the Δ5 double bond to a Δ4 position. This intermediate is also termed C4, and its serum concentration correlates greatly with the rate of bile acid biosynthesis for unknown reasons (7,8). When a deficiency of the dehydrogenase/isomerase occurs, side chain oxidation nonetheless proceeds normally in the peroxisomes, resulting in the formation of C24 bile acids whose steroid nucleus is identical to that of cholesterol. Such compounds may undergo hydroxylation at C-12. These monohydroxy- or dihydroxy acidic intermediates in bile acid synthesis may be sulfated and/or conjugated with glycine or taurine, giving rise to a group of C24 cholenoic acids whose concentrations in urine can be quantified by tandem mass spectrometry (9).
Presumably, these cholenoic acids are poor substrates for the canalicular bile salt export pump, and accumulate in the hepatocyte.
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