Lipoprotein(a) Adjustment Enhances the Diagnosis of Familial Hypercholesterolaemia

Abstract

Aim: To investigate the impact of an LDL-cholesterol level adjusted for lipoprotein(a) [Lp(a)] mass in the diagnosis of familial hypercholesterolaemia (FH) by the Dutch Lipid Clinic Network Criteria (DLCNC). Methods: A cross-sectional adult cohort of 768 index patients with and without genetically confirmed FH were studied. The DLCNC score was generated with and without adjusting the pre-treatment LDL-cholesterol level for the cholesterol content of the Lp(a) particle concentration. Patients were reclassified according to the DLCNC categories (Definite/Probable/Possible/Unlikely FH). Receiver operator characteristic (ROC) curves were generated for the adjusted and unadjusted scores in predicting an FH pathogenic mutation. ROC area-under-the-curves (AUC) were compared using an equality test. Results: After adjusting for Lp(a)-cholesterol concentration, 126 patients (16.4%) were reclassified on the DLCNC scale: Definite to Probable FH (n = 29), Probable to Possible FH (n = 59), Possible to Unlikely FH (n = 38). Of these, 113 (89.7%) did not have a pathogenic mutation for FH. The AUC for the ROC for the DLCNC score in predicting FH mutations was significantly improved after adjusting LDL-cholesterol for the cholesterol content of Lp(a) [0.8415 vs. 0.8276, p = 0.003]. Conclusions: Adjusting LDL-cholesterol in the DLCNC for Lp(a)-cholesterol concentration concentrations down-classifies the phenotypic diagnosis of FH and significantly enhances the prediction of a pathogenic mutation in the LDL receptor pathway.