The association between hypercholesterolemia and sitosterolemia, and report of a sitosterolemia kindred

Abstract

Sitosterolemia is associated with increases in intestinal sterol absorption, low-density lipoprotein cholesterol (LDL-C), and cardiovascular disease risk. We examined the relationship between hypercholesterolemia and sitosterolemia in a large population and report a new sitosterolemia case. Plasma sterol concentrations were measured by gas chromatography/mass spectrometry, and LDL-C by direct assay. Of 207,926 subjects tested, 4.3% had LDL-C ≥190mg/dL. Plasma β-sitosterol concentrations ≥8.0mg/L (99th percentile) were found in 4.3% of these subjects vs 0.72% with LDL-C <130mg/dL. Among all subjects, 0.050% had β-sitosterol levels ≥15.0mg/L, consistent with sitosterolemia, while among those with LDL-C ≥190mg/dL, 0.334% had this rare disorder. A 13-year-old boy with the highest LDL-C (679mg/dL) of all subjects had planar xanthomas and a β-sitosterol level of 53.5mg/L (normal <3.3mg/L). He was a compound heterozygote for 2 ABCG8 mutations (p.N409D and an intron 11+2T>A splice site mutation). On a low-cholesterol and plant-sterol diet, his LDL-C decreased to 485mg/dL (-29%) and β-sitosterol to 44.6mg/L (-27%). On atorvastatin 20mg/d, his LDL-C decreased to 299mg/dL (-38%). With added ezetimibe 10mg/d, his LDL-C normalized to 60mg/dL (-80% further decrease); and his β-sitosterol decreased to 14.1mg/L (-68% further decrease). Our data indicate that about 4% of subjects with LDL-C concentrations ≥190mg/dL have plasma β-sitosterol concentrations above the 99th percentile and about 0.3% have concentrations consistent with sitosterolemia. Therefore, this diagnosis should be considered in such patients.