Cholesterol oversynthesis markers define familial combined hyperlipidemia versus other genetic hypercholesterolemias independently of body weight.

Primary hypercholesterolemia of genetic origin, negative for mutations in LDLR, APOB, PCSK9 and APOE genes (non-FH GH), and familial combined hyperlipidemia (FCHL) are polygenic genetic diseases that occur with hypercholesterolemia, and both share a very high cardiovascular risk. In order to better characterize the metabolic abnormalities associated with these primary hypercholesterolemias, we used noncholesterol sterols, as markers of cholesterol metabolism, to determine their potential differences. Hepatic cholesterol synthesis markers (desmosterol and lanosterol) and intestinal cholesterol absorption markers (sitosterol and campesterol) were determined in non-FH GH (n=200), FCHL (n=100) and genetically defined heterozygous familial hypercholesterolemia subjects (FH) (n=100) and in normolipidemic controls (n=100). FCHL subjects had lower cholesterol absorption and higher cholesterol synthesis than non-FH GH, FH and controls (P<.001). When noncholesterol sterols were adjusted by body mass index (BMI), FCHL subjects had higher cholesterol synthesis than non-FG GH, FH and controls (P<.001). An increase in BMI was accompanied by increased cholesterol synthesis and decreased cholesterol absorption in non-FH GH, FH and controls. However, this association between BMI and cholesterol synthesis was not observed in FCHL. Non-high-density-lipoprotein cholesterol showed a positive correlation with cholesterol synthesis markers similar to that of BMI in non-FH GH, FH and normolipemic controls, but there was no correlation in FCHL. These results suggest that FCHL and non-FH GH have different mechanisms of production. Cholesterol synthesis and absorption are dependent of BMI in non-FH GH, but cholesterol synthesis is increased as a pathogenic mechanism in FCHL independently of age, gender, APOE and BMI.