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The major bile acids produced in the liver are the taurine and
glycine conjugates (amidates) of chenodeoxycholic acid (CDCA) and
cholic acid (CA). Secretion of these conjugated bile acids into
the canaliculi by the bile salt export pump fuels bile flow out
of the liver. They are powerful detergents. This property is important
in keeping cholesterol in solution in bile, and it is also essential for
the digestion and absorption of fats and fat-soluble vitamins. The conversion
of cholesterol to bile acids and the secretion of cholesterol into
bile represent the major routes for elimination of excess cholesterol
from the body. Thus, individuals with disorders of bile acid synthesis
can present with liver disease due to impaired bile secretion (cholestasis),
with gallstones, steatorrhea, symptoms of fat-soluble vitamin malabsorption,
and buildup of cholesterol in tissues (causing neurological impairment,
atherosclerosis, and xanthomata).
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The conversion of cholesterol to bile acids requires modifications
to the sterol nucleus and to the sterol side chain.1 The
major pathway for bile acid synthesis in adults (the “neutral” pathway)
starts with conversion of cholesterol to 7α-hydroxycholesterol.
A second pathway (the “acidic” pathway) starts
with the conversion of cholesterol to 27-hydroxycholesterol, and
the early steps can take place outside the liver. The neutral and
acidic pathways share several enzymes; thus, inborn errors can disrupt
both routes for the synthesis of bile acids. A simplified version
of the major bile acid synthesis pathways is shown in Figure
165-1.
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The modifications to the cholesterol side chain involve 27-hydroxylation,
further oxidation to a C27 bile acid, alteration of the stereochemistry
of the C27 bile acid CoA ester (racemization), and then β-oxidation
in the peroxisomes to produce a C24 bile acid CoA ester that is
conjugated with glycine or taurine.
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Disorders of bile acid synthesis that affect transformation of
the cholesterol nucleus produce hepatobiliary disease; those that
affect the oxidation of the cholesterol side chain often also cause
extrahepatic (particularly neurological) disease. This is probably
because the early steps of the acidic pathway for bile acid synthesis
play an important role ...