Adjusting low-density lipoprotein (LDL) cholesterol measurements for lipoprotein(a), or Lp(a), cholesterol concentration improves the diagnostic accuracy of two key tools used to identify familial hypercholesterolemia (FH). These findings underscore that Lp(a) should be measured in all patients suspected of having FH, according to the authors of a study published in Clinical Chemistry.

Determination of LDL cholesterol concentration using the Friedewald equation includes a contribution from the cholesterol content of Lp(a). “This inclusion may influence the LDL cholesterol values by 30%–45% and hence the clinical diagnosis of FH, especially with increased Lp(a). However, this notion has not been previously examined in patients referred to specialist clinics where a definite diagnosis of FH is usually made,” explained the authors.

Their study investigated the potential influence of Lp(a)on FH diagnosis, using two common clinical tools for FH: the Dutch Lipid Clinic Network (DLCN) and Simon Broome (SB) criteria. Enlisting more than 900 adult patients seen at one clinic, the investigators estimated the diagnostic criteria from both models prior to and after adjusting LDL cholesterol concentration for Lp(a) cholesterol. 

The investigators found that adjusting LDL cholesterol for Lp(a) cholesterol reclassified to “unlikely” FH 8.2% and 22.8% of patients defined by DLCN and SB criteria, respectively. Furthermore, as Lp(a) concentrations increased, fewer FH patients fell into DLCN (probable/definite) or SB (possible/definite) criteria. Overall, diagnostic FH reclassification overall was much higher in patients with Lp(a) concentration >1.0g/L. However, when LDL cholesterol concentration exceeded 251 mg/dL the Lp(a) cholesterol adjustment didn’t make a significant difference in the area under the receiver operating characteristic (AUROC) in predicting whether a patient had an FH mutation.

The study also found a link between increased Lp(a) and FH patients with a history of premature coronary artery disease without a causative mutation. This finding “reinforces the notion that this historical information may relate to familial increase in Lp(a) regardless of the presence or absence of an FH mutation,” wrote the investigators. In conclusion, they determined that the adjustment improved the diagnostic accuracy of the two criteria models.

To improve clinical diagnosis of FH, “Lp(a) should be measured in all patients suspected of having FH,” they recommended.

These findings are timely on several fronts, Anne Langsted and Børge G. Nordestgaard wrote in a related editorial. “In many countries national efforts are being made to find and diagnose individuals living with FH. Importantly, both European and U.S. consensus statements now recommend screening all individuals suspected of FH for high Lp(a) concentrations,” they observed. A number of studies and metanalyses have also cited a link between high cardiovascular disease risk and high Lp(a) concentrations.

“Most importantly, studies using a Mendelian randomization design finally convinced most researchers and clinicians that high Lp(a) is a genetic causal risk factor for cardiovascular disease,” noted Langsted and Nordestgaard. What remains unclear, are Lp(a)’s physiological and pathophysiological roles in heart disease, they added.

No effective treatment currently exists to lower Lp(a). However, such drugs are in the clinical trial pipeline. The anticipation is these studies “will show that lowering of Lp(a) in a safe and efficient way will lead to lower risk of cardiovascular disease,” wrote the editorialists.

Read October’s Clinical Chemistry to learn more about Lp(a)’s growing role as a predictor of FH and cardiovascular disease.