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This study gives a review of the results obtained from biochemical investigations of 20 patients in The Netherlands suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis. Diagnosis can best be established by determining the excretion of urinary bile alcohols, in particular 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,23,25-pentol, in urine by means of capillary gas chromatography. Measurement of serum cholestanol levels or serum cholestanol/cholesterol ratios, commonly used for establishing cerebrotendinous xanthomatosis, are not reliable. The effectiveness of the different therapies, i.e. administration of bile acids, can be evaluated by monitoring the urinary excretion of bile alcohols. From such investigations it was concluded that cholic acid especially, but also chenodeoxycholic acid are the therapies of choice for the treatment of cerebrotendinous xanthomatosis. All patients, until now diagnosed in The Netherlands were not discovered before the third or fourth decade of life because the characteristic signs only then become manifest clearly. Unfortunately, because sterol storage is almost irreversible, therapy only results in minor improvements of the patient's condition. Therefore early detection of the presence of cerebrotendinous xanthomatosis is desirable so that treatment can start before extensive storage of sterols is a fact. We developed some laboratory assays with the purpose of early detection. One consists of the detection of cerebrotendinous xanthomatosis carriers by subjecting them to oral cholestyramine administration and monitoring the urinary excretion of the bile alcohol 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol before and after treatment. Secondly, a relatively simple screening test for cerebrotendinous xanthomatosis was developed based on an enzymatic assay of 7 alpha-hydroxylated steroids in urine. After suitable modification this assay in principle allows the screening of large populations for the existence of cerebrotendinous xanthomatosis and thus to detect the disease at an earlier stage of life.

Patients suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis, excrete excessive amounts of 23-hydroxylated bile alcohols, 23-norcholic acid and 23-hydroxycholic acid into urine. In this study the configuration of this excreted 23-hydroxycholic acid was established as (23R)-hydroxycholic acid. Urine samples of two treated patients, receiving chenodeoxycholic acid, were investigated to see whether this administered bile acid was partly converted into 23-hydroxychenodeoxycholic acid. One patient was treated with ursodeoxycholic acid for 1 month and subsequently with chenodeoxycholic acid, and the urinary excretion of both (23R)-hydroxychenodeoxycholic acid and (23R)-hydroxyursodeoxycholic acid were followed. Indeed, all three patients excreted (23R)-hydroxylated chenodeoxycholic acid during oral treatment with chenodeoxycholic acid, and the patient treated with ursodeoxycholic acid excreted (23R)-hydroxylated ursodeoxycholic acid. During treatment with chenodeoxycholic acid the excretion of (23R)-hydroxychenodeoxycholic acid increases at first and later on decreases markedly. These findings suggest increased (23R)-hydroxylase activity in patients suffering from cerebrotendinous xanthomatosis, acting both on endogenously synthesized bile alcohols and on exogenously administered bile acids; during continuation of chenodeoxycholic acid treatment in an effective dose (750 mg/day) this enzyme activity gradually disappears.

Altered bile acid metabolism has been claimed to play a role in the etiology of benign recurrent intrahepatic cholestasis (BRIC). Therefore, we studied bile acid metabolism in detail in 10 patients with this syndrome. Pool sizes of both primary bile acids were estimated simultaneously, using deuterated cholic acid and chenodeoxycholic acid. The pool sizes of cholic acid and chenodeoxycholic acid, expressed in micromoles per kilogram body weight, were significantly contracted in BRIC patients during a cholestasis-free period: 8.0 +/- 4.2 and 11.7 +/- 4.7, respectively, versus 24.1 +/- 11.7 and 22.9 +/- 7.8 in controls. Fractional turnover rates (per day) for cholic acid and chenodeoxycholic acid were increased: 0.70 +/- 0.29 and 0.58 +/- 0.27, respectively, versus 0.29 +/- 0.12 and 0.23 +/- 0.10 in controls. Bile acid pool composition expressed as percentages in BRIC patients was cholic acid 34 +/- 17, chenodeoxycholic acid 38 +/- 9, deoxycholic acid 27 +/- 18, and lithocholic acid 1 +/- 1, with a glycine to taurine conjugation ratio of 6.7 +/- 4.9. Corresponding values for 32 controls were cholic acid 57 +/- 13, chenodeoxycholic acid 29 +/- 9, deoxycholic acid 14 +/- 9, and lithocholic acid less than 1, with a glycine to taurine conjugation ratio of 2.4 +/- 1.3. Fecal bile acid loss, in micromoles per kilogram body weight per day, was 11.2 +/- 9.0 in BRIC patients compared with 2.8 +/- 1.4 in controls. The serum 7 alpha-hydroxycholesterol level (nanomoles per liter) was significantly increased in BRIC patients: 326 +/- 179 versus 171 +/- 90 in controls. These results suggest that in BRIC patients spillover of bile acids into the colon occurs, which leads to increased fecal bile acid loss and a reduced bile acid pool size. Increased serum 7 alpha-hydroxycholesterol is probably indicative of an accelerated bile acid synthesis rate due to increased activity of cholesterol 7 alpha-hydroxylase, the enzyme catalyzing the first step in the major pathway of bile acid synthesis. The results of our study suggest that in BRIC patients a contracted bile acid pool increases the susceptibility of the liver for cholestatic agents.

Patients suffering from cerebrotendinous xanthomatosis, an inborn error of metabolism in bile acid synthesis, were given oral treatment with chenodeoxycholic acid, ursodeoxycholic acid, cholic acid and taurocholic acid. The effectiveness of the different therapies was evaluated by measuring the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol, which should decrease, when the administered bile acid is able to suppress endogenous bile acid synthesis. From the results it is concluded that chenodeoxycholic acid and cholic acid activate the bile acid negative feedback mechanism, contrary to ursodeoxycholic acid and taurine conjugated cholic acid. Either cholic acid or chenodeoxycholic acid are the therapies of choice for the treatment of cerebrotendinous xanthomatosis. For various reasons the use of cholic acid is especially recommended.

To assess the effect of bile acid sequestrant therapy on bile acid precursors in plasma, we determined hydroxycholesterols in serum from patients with primary hypercholesterolaemia. Compared with a group of 5 male and 12 female patients without any lipid-lowering drug therapy, which has normal to slightly elevated 7 alpha-hydroxycholesterol, normal 7 beta-hydroxycholesterol and high normal to elevated 26-hydroxycholesterol levels, a group of 5 male and 9 female patients, using colestipol had higher 7 alpha-hydroxycholesterol without overlap, and higher 7 beta-hydroxycholesterol levels, but similar levels of 26-hydroxycholesterol. In the latter group, the ratio between 7 alpha-hydroxycholesterol and total cholesterol in serum was also higher without overlap. Both groups did not differ for age, body weight, body mass index and serum lipid levels. In the group of patients without lipid-lowering drug therapy, 7 alpha-hydroxycholesterol correlated positively with total and low-densitylipoprotein cholesterol, 7 beta-hydroxycholesterol negatively with body weight and body mass index, and 26-hydroxycholesterol positively with body weight. In both groups, 7 alpha-hydroxycholesterol correlated positively with 7 beta-hydroxycholesterol. These results suggest that (1) bile acid sequestrants enhance bile acid synthesis via the 7 alpha-hydroxylation but not via the 26-hydroxylation pathway, (2) serum 7 alpha-hydroxycholesterol level and the ratio between this hydroxycholesterol and total cholesterol in serum might be suitable parameters to check intake of bile acid sequestrants irrespective of dose, and (3) 7 beta-hydroxycholesterol is unlikely to be the result of cholesterol auto-oxidation in vitro.

A male born to first cousins presented at 12 months with hypocalcemic convulsions, rickets, epistaxis due to vitamin K deficiency, and extremely low serum levels of beta-carotene and vitamin A. Liver function was altered moderately (glutamic-oxaloacetic transaminase, 55 U/L; glutamic-pyruvic transaminase, 37 U/L; lactate dehydrogenase, 255 U/L; alkaline phosphatase, 437 U/L). To correct the deficiencies, 8,000 IU vitamin D/day, 10,000 IU vitamin A/day, and intramuscular administration of vitamin K1 were required. At 9 years, he presented signs of neuromuscular affection, and the serum vitamin E level (measured for the first time) was extremely low. Classic lipid malabsorption syndromes (abetalipoproteinemia, chronic cholestasis, mucoviscidosis, coeliac disease, Whipple's disease) were excluded by appropriate examinations. Composition of duodenal bile acids was characterized by undetectable levels of cholic acid metabolites, and only chenodeoxycholic acid metabolites were present. Serum total bile acid concentration was normal, with an atypical low cholic acid/chenodeoxycholic acid ratio and abnormal presence of 3 beta-OH-delta 5-cholenic acid and 6-OH-bile acids. Urinary bile acid composition was also characterized by elevated 6-OH-bile acids. Known enzymopathies of the bile acid synthetic pathway were excluded (cerebrotendinous xanthomatosis, cerebro-hepato-renal syndrome of Zellweger, coprostanic acidemia). Bile acid pool sizes were determined by using stable isotopes: cholic acid pool size [2.90 (N, 32 +/- 16) microM/kg] and chenodeoxycholic acid pool size [10.8 (N, 32.6 +/- 9.9) microM/kg] were extremely low; fractional turnover rates of both bile acids were in a normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

The urinary bile acid profile, obtained by capillary gas chromatography, of a patient suffering from cerebrotendinous xanthomatosis and treated with ursodeoxycholic acid demonstrated, besides the occurrence of 23-norcholic acid and (23R)-hydroxycholic acid (as a consequence of this disease), six additional unknown bile acids and three known bile acids, viz. ursodeoxycholic acid, hyocholic acid and omega-muricholic acid. The structure of two of the unknown bile acids were elucidated and proven by organic syntheses. These were 23-norursodeoxycholic acid and 3 beta-ursodeoxycholic acid. The structures of three bile acids were tentatively elucidated as being 1 beta-hydroxyursodeoxycholic acid, 21-hydroxyursodeoxycholic acid and 22-hydroxyursodeoxycholic acid, and the possibility that the structure of the remaining bile acid is that of 5-hydroxyursodeoxycholic acid is discussed. Two of these bile acids (1 beta-hydroxyursodeoxycholic acid and 5-hydroxyursodeoxycholic acid) also occurred in urine of a healthy individual during oral ursodeoxycholic acid treatment, whereas 23-norcholic acid, 23-norursodeoxycholic acid, (23R)-hydroxycholic acid, 21-hydroxyursodeoxycholic acid and 22-hydroxyursodeoxycholic acid were only present in urine of the patient suffering from cerebrotendinous xanthomatosis. The metabolism of ursodeoxycholic acid, both in the normal state and in the cerebrotendinous xanthomatosis, is discussed.

Urine samples and serum samples of a patient with cerebrotendinous xanthomatosis (CTX) were investigated by means of capillary gas chromatography, both before and during oral treatment with ursodeoxycholic acid (UDCA), and the results compared with those obtained during chenodeoxycholic acid (CDCA) therapy. The predominantly excreted bile alcohol, 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol and two abnormal bile acids, i.e. 23-norcholic acid and 23-hydroxycholic acid were determined. In addition, the serum cholestanol/cholesterol ratio was determined. Whereas previous experiments demonstrated that the urinary excretion of 5 beta-cholestane-3 alpha,7 alpha,12 alpha,23,25-pentol and the abnormal bile acids decreased within a few weeks during CDCA therapy, the present study shows that their urinary excretions remain essentially the same during UDCA treatment. In contrast to the decrease in the serum cholestanol/cholesterol ratio during CDCA therapy, this ratio remains essentially the same during UDCA therapy. It is therefore concluded that, in contrast to CDCA therapy, UDCA treatment is not effective in the treatment of CTX.