Cholesterol is converted to
cholic acid and
chenodeoxycholic acid by a series of reactions involving modifications to the
steroid nucleus and oxidation of the side chain. These reactions can be affected by a number of
inborn errors of metabolism. When this happens unusual
bile acids or
bile alcohols are synthesized; these can be identified using gas chromatography-mass spectrometry and fast atom bombardment mass spectrometry techniques. Two defects affecting the modifications to the
steroid nucleus have been described; both present with cholestatic
liver disease of neonatal onset. The better characterized of the two--3 beta-hydroxy-delta 5-C27-steroid
dehydrogenase deficiency--leads to excretion of 3 beta-7 alpha-dihydroxy-5-cholenoic
acid and
3 beta,7 alpha,12 alpha-trihydroxy-5-cholenoic acid in the urine. The
liver disease improves dramatically on treatment with
chenodeoxycholic acid. Deficient activity of 3-oxo-delta 4-steroid 5 beta-
reductase is thought to be the cause of familial
liver disease in some infants who excrete 7 alpha-hydroxy-3-oxo-4-cholenoic
acid and 7 alpha,12 alpha-dihydroxy-3-oxo-4-cholenoic
acid in the urine. However, diagnosis of this disorder is problematical; a similar pattern of metabolite excretion can occur as a result of liver damage caused by viruses or inborn errors of pathways unrelated to
bile acid synthesis. Defective side chain oxidation in patients with
cerebrotendinous xanthomatosis (CTX) leads to synthesis of
bile alcohols such as 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25-tetrol and
5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol. Patients with CTX do not have cholestatic
liver disease. Their major problems (neurological disease,
atherosclerosis and xanthomata) are caused by accumulation of
cholestanol and
cholesterol in the tissues.
Bile acid precursors are probably diverted into synthesis of
cholestanol.
Chenodeoxycholic acid suppresses the production of abnormal metabolites from
cholesterol (by inhibition of
cholesterol 7 alpha-hydroxylase) and leads to improvement in the neurological disease. Defective side chain oxidation also occurs in
peroxisomal disorders but this time it leads to accumulation of C27
bile acids such as
3 alpha,7 alpha,12 alpha-trihydroxy-5 beta-cholestanoic acid (trihydroxycoprostanic
acid, THCA). This compound is readily detected in the bile and plasma of patients with defects of peroxisome biogenesis. In patients with defects of a single peroxisomal beta-oxidation
enzyme (the 3-hydroxyacyl-
CoA component of the bifunctional
protein or the thiolase), the major C27
bile acid in bile may be
3 alpha,7 alpha,12 alpha,24-tetrahydroxy-5 beta-cholestanoic acid (
varanic acid).(ABSTRACT TRUNCATED AT 400 WORDS)