SLUGGISH SITOSTEROL TURNOVER AND HEPATIC-FAILURE TO EXCRETE SITOSTEROL INTO BILE CAUSE EXPANSION OF BODY POOL OF SITOSTEROL IN PATIENTS WITH SITOSTEROLEMIA AND XANTHOMATOSIS

Sitosterolemia and xanthomatosis are characterized by the development of tendon and tuberous xanthomas at an early age and premature atherosclerosis despite normal plasma cholesterol concentrations. The reason(s) for the xanthoma formation and premature atherosclerosis are not clearly understood. The accumulation of sitosterol in the tissues of these patients could be due to increased uptake of low density lipoprotein (LDL) via LDL receptors because of an expanded sitosterol pool caused by sluggish turnover and decreased excretion of sitosterol into bile and feces coupled with the hyperabsorption of sitosterol. We have studied sitosterol and cholesterol turnovers, the biliary and fecal excretion of neutral and acidic steroids, and the response of plasma sterol (sitosterol and cholesterol) levels to either a sterol-free formula or low plant sterol diet in three patients. The average half-life of the first exponential (t(A)1/2) for sitosterol was 9.2 +/- 3.3 (mean +/- SD) days, which was more than twice that in normal humans. The second exponential (t(B)1/2) was 156 +/- 108 days, which was nearly 10 times longer than that for normal humans. The average cholesterol production rate in pool A was 0.87 g/day, whic is about 40% of that in normal humans. Cholesterol synthesis measured by the sterol balance technique was also found to be about 70% lower than that for normal humans. In two patients fed a sterol-free formula diet, by 25 days their plasma sitosterol and cholesterol levels had decreased by 42% and 36%, respectively. However, in one patient plasma sitosterol and cholesterol concentrations remained unchanged while on the low plant sterol-mixed food diet. The sitosterol to cholesterol ratio in bile (0.05) was extremely low compared with that found in plasma (0.14), indicating low excretion of sitosterol into the bile. Thus, patients with sitosterolemia have a slow turnover of sitosterol, low excretion of sitosterol into the duodenal bile and feces, and low cholesterol synthesis. These metabolic defects have implications in the formation of xanthomas and the development of premature atherosclerosis in these patients.