Increased intestinal cholesterol absorption in autosomal dominant Hypercholesterolemia and no mutations in the low-density lipoprotein receptor or apolipoprotein B genes

Context: Autosomal dominant hypercholesterolemia (ADH) is frequently caused by functional mutations in the low-density lipoprotein receptor ( LDLR) or apolipoprotein B-100 ( APOB) genes, but approximately 40% of ADH subjects disclose no such molecular defects, possibly pointing to alternative genetic mechanisms. Objective: Our objective was to test the hypothesis that increased intestinal cholesterol absorption might play a role in the lipid abnormalities of subjects with ADH without identified genetic defects. Design and Setting: This is a cross-sectional study of consecutive subjects with primary hyperlipidemia identified during an 18-month period in two lipid clinics. Study Subjects: A total of 52 subjects with a clinical diagnosis of ADH were examined for molecular defects in LDLR and APOB. No APOB defects were found. Functional LDLR mutations occurred in 31 (60%) subjects, who received a diagnosis of familial hypercholesterolemia (FH). Those for whom no mutations could be identified were labeled as non-FH ADH. In addition, 38 subjects with familial combined hyperlipidemia (FCH) and 45 normolipidemic control subjects were studied. Interventions: Interventions were diagnostic. Main Outcome Measures: Serum noncholesterol sterols were used as markers for the efficiency of intestinal cholesterol absorption. Results: Adjusted campesterol to cholesterol ratios increased in the order non-FHADH more than FH more than controls more than FCH, with mean values ( 95% confidence interval) in 102 mmol/mol cholesterol of 505 (424-600), 397 (345-458), 335 (294-382), and 284 ( 247 328), respectively. Thus, cholesterol absorption was lowest in FCH and highest in non-FH ADH. Conclusions: Increased intestinal cholesterol absorption may partially explain the high cholesterol levels of non-FH ADH subjects. Serum noncholesterol sterols are a useful tool for the differential diagnosis of genetic hypercholesterolemias, especially FCH and ADH unrelated to LDLR or APOB defects.