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  • 3β-Hydroxysteroid-Δ5-oxidoreductase/isomerase deficiency is a very rare cholestatic disease characterized by jaundice, hepatomegaly, pale stools, and dark urine. No normal bile acids are present in plasma. Sulfated 3β,7α-dihydroxy- and 3β,7α,12α-trihydroxy-5-cholenoic acids are excreted in urine and bile. Untreated the disease may lead to early development of liver cirrhosis. Treatment with chenodeoxycholic acid inhibits the rate-limiting enzyme in bile acid biosynthesis, the cholesterol 7α-hydroxylase, and diminishes the production of toxic metabolites from cholesterol.

  • 3-Oxo-Δ4-steroid 5β-reductase deficiency is also a very rare cholestatic disease with symptoms similar to those above. Bile, serum, and urine contain 7α-hydroxylated bile acids with a 3-oxo-Δ4-structure. These patients also respond favorably to bile acid therapy.

  • 27-Hydroxylase deficiency (cerebrotendinous xanthomatosis (CTX)) is a rare familial sterol storage disease with accumulation of cholestanol and cholesterol in most tissues, and in particular in xanthomas, bile, and brain. Clinically, this disorder is characterized by dementia, spinal cord paresis, cerebellar ataxia, tuberous and tendon xanthomas, early atherosclerosis, and cataracts.

    More than 20 different mutations have been defined in the sterol 27-hydroxylase gene of CTX patients. The defect leads to a block in bile acid biosynthesis, with accumulation of substrates for the mitochondrial 27-hydroxylase such as 5β-cholestane-3α,7α,12α-triol and 7α-hydroxy-4-cholestene-3-one. The former metabolite is metabolized into 5β-cholestane-3α,7α,12α,25-tetrol, 5β-cholestane-3α,7α,12α,23-tetrol, and 5β-cholestane-3α,7α,12α,24,25-pentol.

    These bile alcohols are excreted in gram amounts in bile and feces. At least part of the excess cholestanol in patients with CTX is formed from the accumulated 7α-hydroxy-4-cholesten-3-one. The reason for the accumulation of cholesterol in tissues is not known with certainty. In general, the levels of cholesterol in serum are normal, whereas the levels of cholestanol are markedly increased.

    Patients with CTX should be treated with chenodeoxycholic acid which reduces the 7α-hydroxylation of cholesterol, thereby reducing the formation of cholestanol and the excretion of bile alcohols in feces and urine.

  • In addition to the above defects in bile acid synthesis, one fatal case with a defined mutation in the gene coding for the oxysterol 7α-hydroxylase has been reported. A patient with a unique inborn error in bile acid conjugation involving a deficiency in amidation has also been described.

  • Phytosterolemia (sitosterolemia) is a rare inherited sterol storage disease characterized by tendon and tuberous xanthomas and by a strong predisposition to premature coronary atherosclerosis. Some patients may develop hemolytic syndromes. Increased amounts of phytosterols (plant sterols), such as sitosterol and campesterol and their 5α-stanols, are found in blood, plasma, erythrocytes, and different tissues, in particular in the xanthomas and arteries of affected patients. Increased serum cholesterol and cholestanol have also been found in many patients.

    The basic biochemical defect in this autosomal recessive disease has not been defined. Increased intestinal absorption of phytosterols and shellfish sterols has been observed in some cases. Evidence has also been presented for decreased biliary and fecal excretion of cholesterol, phytosterols, and shellfish sterols.

    Patients with phytosterolemia should be treated with diets low in plant and shellfish sterols. In addition, they should be given cholestyramine, ...

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