Reclassification of Clinical Familial Hypercholesterolemia Diagnoses After Adjustment of LDL-C for Lipoprotein(a) Cholesterol: A Systematic Review and Meta-Analysis

Background/Objectives: Low-density lipoprotein cholesterol (LDL-C) measurements include cholesterol carried by lipoprotein(a) [Lp(a)], which may influence the clinical classification of familial hypercholesterolemia (FH). We aimed to systematically review the available evidence and estimate the pooled proportion of individuals reclassified to a lower FH diagnostic category after correction of LDL-C for estimated Lp(a)-cholesterol. Methods: Embase, PubMed, and Scopus were searched from inception through 9 October 2026. We included observational studies with cross-sectional analyses of adults aged ≥18 years evaluated for suspected FH using the Dutch Lipid Clinic Network (DLCN) criteria before and after LDL-C correction for Lp(a)-cholesterol. Lp(a)-cholesterol was estimated as 30% of Lp(a) mass. The primary endpoint was reclassification to a lower DLCN diagnostic category among participants with possible, probable, or definite FH at baseline. Random-effects models were used to estimate pooled proportions. Risk of bias was assessed using the JBI critical appraisal tool for cross-sectional studies. Results: Four studies comprising 2970 individuals were included. The primary analysis included 2793 participants with possible, probable, or definite FH at baseline. After LDL-C correction for estimated Lp(a)-cholesterol, 19.8% (95% CI, 15.9–24.5) were reclassified to a lower DLCN diagnostic category. Conclusions: Correction of LDL-C for estimated Lp(a)-cholesterol resulted in downward DLCN reclassification in approximately one in five adults with at least possible FH from selected referral populations. The clinical utility of this adjustment, including its consequences for genetic testing and missed FH diagnoses, needs to be investigated.