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

•Lp(a)-associated cholesterol is not accounted for in the Friedwald equation.•Adjusting estimated LDL-C by Lp(a) improves accuracy of FH diagnostic criteria.•However, this approach may lead to patients with an FH mutation being missed. Familial hypercholesterolaemia (FH) diagnostic tools help prioritise patients for genetic testing and include LDL-C estimates commonly calculated using the Friedewald equation. However, cholesterol contributions from lipoprotein(a) (Lp(a)) can overestimate ‘true’ LDL-C, leading to potentially inappropriate clinical FH diagnosis. To assess how adjusting LDL-C for Lp(a)-cholesterol affects FH diagnoses using Simon Broome (SB) and Dutch Lipid Clinic Network (DLCN) criteria. Adults referred to a tertiary lipid clinic in London, UK were included if they had undergone 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. 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. 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.