Context - Autosomal dominant hypercholesterolemia (ADH) is frequently caused by functional mutations in the LDLR or APOB genes, but 40% of ADH subjects disclose no such molecular defects, possibly pointing to alternative genetic mechanisms.

Objective - 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 - Cross-sectional study of consecutive subjects with primary hyperlipidemia identified during an 18-month period in two lipid clinics.

Study subjects - Fifty-two 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 NonFH ADH. Additionally, 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:cholesterol ratios increased in the order NonFH ADH>FH>controls>FCH, with mean values (95% CI) 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 NonFH ADH.

Conclusions - Increased intestinal cholesterol absorption may partially explain the high cholesterol levels of NonFH 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.