Four patients with
cerebrotendinous xanthomatosis (CTX) and 2 healthy controls received a constant proximal intraduodenal infusion of 1- 13 C-
acetate as a stable-
isotope-labeled marker of
sterol synthesis. One patient was treated with
pravastatin (20 mg twice daily) and another patient with
chenodeoxycholic acid (250 mg tid). Every hour, venous blood and duodenal samples were obtained. Stable-
isotope enrichment of neutral and polar
sterols in serum and bile was assessed by gas chromatography/mass spectrometry. Isotopomer spectral analysis was performed on
cholesterol,
lathosterol, Delta-8-cholesterol, methylsterol, and
lanosterol. Stable-
isotope labeling of
cholestanol,
bile acids, and
bile alcohols was analyzed by assessing the change over time of the ratio of M + 3 to M + 0. Eleven hours after marker infusion, we found up to 50% newly synthesized
lathosterol in serum and up to 80% in bile, with similar results for other
cholesterol precursors. In
cholesterol, stable-
isotope labeling could be demonstrated in all study subjects with a more prominent labeling in bile than in serum. No stable-
isotope labeling was detected in
cholestanol. Only minor stable-
isotope incorporation was detectable in polar
sterols in some subjects.
Therapy with
pravastatin did not have any effect on fractional or absolute synthesis rates or on the concentrations of
cholestanol or
cholesterol precursors compared to untreated patients with CTX. In contrast,
therapy with
chenodeoxycholic acid markedly lowered the concentrations of
cholestanol and
cholesterol precursors, led to a disappearance of
bile alcohols, and reduced absolute synthesis rates of
lathosterol. Isotopomer spectral analysis proved to be a powerful method to assess the endogenous synthesis of
cholesterol precursors in patients with CTX. Higher fractional synthesis in bile than in serum may be due to the size of the pools in bile vs serum.
Cholestanol exhibits no marker uptake and is therefore probably synthesized from preformed
cholesterol. Biliary
cholesterol secretion in patients with CTX is decreased compared to healthy controls.