A L García-Otín1, M Cofán, M Junyent, D Recalde, A Cenarro, M Pocoví, E Ros, F Civeira. 1. Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (I+CS), Po Isabel la Católica, 1-3, 50009 Zaragoza, Spain. algarcia.iacs@aragon.es
Abstract
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-FH ADH more than FH more than controls more than FCH, with mean values (95% confidence interval) in 10(2) 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.
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-FH ADH more than FH more than controls more than FCH, with mean values (95% confidence interval) in 10(2) 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.
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