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Increased Intestinal Cholesterol Absorption in Autosomal Dominant Hypercholesterolemia and No Mutations in the Low-Density Lipoprotein Receptor or Apolipoprotein B Genes

Unidad de Lípidos and Laboratorio de Investigación Molecular (A.L.G.-O., D.R., A.C., F.C.), Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud, 50009 Zaragoza, Spain; Unidad de Lípidos (M.C., M.J., E.R.), Servicio de Endocrinología y Nutrición, Institut d’Investigacions Biomediques August Pi i Sunyer, Hospital Clínic, Barcelona and Ciber CB06/03 Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 08036 Barcelona, Spain; and Departamento de Bioquímica (M.P.), Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain

Address all correspondence and requests for reprints to: Angel-Luis García-Otín, Ph.D., Laboratorio de Investigación Molecular, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (I+CS), P° Isabel la Católica, 1-3, 50009 Zaragoza, Spain. E-mail: algarcia.iacs{at}aragon.es.

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 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.