The effect of adjusting LDL-cholesterol for Lp(a)-cholesterol on the diagnosis of familial hypercholesterolaemia

Background: Familial hypercholesterolaemia (FH) diagnostic tools help prioritise patients for ge-netic testing and include LDL-C estimates commonly calculated using the Friedewald equation. How-ever, cholesterol contributions from lipoprotein(a) (Lp(a)) can overestimate 'true' LDL-C, leading to potentially inappropriate clinical FH diagnosis.Objective: To assess how adjusting LDL-C for Lp(a)-cholesterol affects FH diagnoses using Simon Broome (SB) and Dutch Lipid Clinic Network (DLCN) criteria.Methods: Adults referred to a tertiary lipid clinic in London, UK were included if they had un-dergone FH genetic testing based on SB or DLCN criteria. LDL-C was adjusted for Lp(a)-cholesterol using estimated cholesterol contents of 17.3%, 30% and 45%, and the effects of these adjustments on reclassification to 'unlikely' FH and diagnostic accuracy were determined.Results: Depending on the estimated cholesterol content applied, LDL-C adjustment reclassified 8-23% and 6-17% of patients to 'unlikely' FH using SB and DLCN criteria, respectively. The highest reclassification rates were observed following 45% adjustment in mutation-negative patients with higher Lp(a) levels. This led to an improvement in diagnostic accuracy (46% to 57% with SB, and 32% to 44% with DLCN following 45% adjustment) through increased specificity. However all adjustment factors led to erroneous reclassification of mutation-positive patients to 'unlikely' FH. Conclusion: LDL-C adjustment for Lp(a)-cholesterol improves the accuracy of clinical FH diagnostic tools. Adopting this approach would reduce unnecessary genetic testing but also incorrectly reclassify mutation-positive patients. Health economic analysis is needed to balance the risks of over-and under -diagnosis before LDL-C adjustments for Lp(a) can be recommended.(c) 2023 National Lipid Association. Published by Elsevier Inc. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Automated summary

Adjusting LDL-C for Lp(a)-cholesterol improves the accuracy of FH diagnostic tools but may lead to misclassification of mutation-positive patients. Health economic analysis is required to balance the risks of over- and under-diagnosis.