Higher Lp(a) in children with clinical presentation of FH but no genetic mutation
Lipoprotein(a) levels in children with suspected familial hypercholesterolaemia: a cross-sectional study
Introduction and methods
Familial hypercholesterolemia (FH) is caused by mutations in the genes LDLR, APOB, or PCSK9 that lead to impaired circulatory clearance of LDL-c and, subsequently, very high LDL-c levels from birth onwards . Depending on the diagnostic tool used, the clinical diagnosis of FH in adults relies on (extremely) high LDL-c levels, clinical features of FH (such as tendon xanthomas, arcus cornealis, and a history of premature CVD) and/or affected first-degree relatives.
The preferred method for diagnosing FH in adults and children is genetic testing [2-4]. However, in many children with a clinical presentation of FH, no FH-causing mutation can be identified [5,6], which suggests that other factors may lead to this clinical presentation. As it turns out, a substantial part of the clinical FH diagnoses in adults can be explained by high levels of Lp(a) [7-9]. The reason for this is the LDL-like core of Lp(a), as conventional LDL-c assays measure the cholesterol content of both LDL particles and Lp(a) particles [10-12].
Aim of the study
The authors sought to examine whether high Lp(a) levels can lead to a clinical presentation of FH in children by comparing Lp(a) levels in children with a clinical presentation of FH in whom no mutation was detected with those in children with an FH-causing mutation and their unaffected siblings.
In this cross-sectional study, 2721 children (mean age: 10.1 years; range: 0.7–17.9 ) were included who were referred to the pediatric lipid clinic of the Amsterdam University Medical Centers in Amsterdam, the Netherlands between June 1989 and January 2020 for a tentative diagnosis of FH based on a family history of premature CVD (i.e., any CV event <60 years of age), family members with FH, or high LDL-c levels in the child or its family members. As part of routine care, a lipid profile, including LDL-c and Lp(a) levels, was obtained and DNA analysis to detect FH mutations was performed. For the analyses, log-transformed Lp(a) levels were used.
Children were divided into the following 4 groups:
- 1931 children with definite FH (mutation detected) (71%);
- 290 unaffected siblings/normolipidemic controls with definite non-FH (mutation excluded) (11%);
- 108 children with probable FH (clinical presentation of FH (i.e. LDL-c >5 mmol/L or 4–5 mmol/L with family history of premature CVD); no mutation detected) (4%);
- 392 children with probable non-FH (no clinical presentation of FH; mutation not excluded) (14%).
- In the entire study population, the geometric mean Lp(a) level at first visit was 11.5 mg/dL (95%CI: 11.0–12.1; range: 0.2–171.0). In total, 665 children (24.4%) had Lp(a) levels >30 mg/dL and 331 (12.2%) had Lp(a) levels >50 mg/dL.
- In children with probable FH, the geometric mean Lp(a) level was 15.9 mg/dL (95%CI: 12.3–20.6), which was significantly higher than that in children with definite FH (11.5 mg/dL; 95%CI: 10.9–12.1; P=0.017) and those with definite non-FH (9.8 mg/dL; 95%CI: 8.4–11.3; P=0.002). In children with probable non-FH, the geometric mean Lp(a) level was 12.7 mg/dL (95%CI: 11.1–14.6).
- High Lp(a) levels (>50 mg/dL) were more frequently seen in children with probable FH compared with children with definite FH (31.5% vs. 10.2%; P<0.0001). Of note, 9.7% of the unaffected siblings also showed high Lp(a) levels.
- Mean (95%CI) LDL-c levels corrected for Lp(a)-c were 5.2 mmol/L (5.1–5.2) for children with definite FH, 4.2 mmol/L (4.0–4.3) for those with probable FH, 2.7 mmol/L (2.7–2.8) for those with probable non-FH, and 2.4 mmol/L (2.3–2.5) for those with definite non-FH (P<0.001).
This Dutch cross-sectional study in a referral population of children suspected of having FH showed that Lp(a) levels were higher and more often elevated (>50 mg/dL) in children with probable FH compared with children with definite FH and their unaffected siblings. The authors believe that high Lp(a) levels are not a direct genetic cause of clinical FH but a separate entity and that children with a clinical presentation of FH but no mutation detected “make up a separate patient group that cannot be classified as having FH.”
They therefore recommend that both DNA analysis and Lp(a) measurement be performed in all children suspected of having FH. This is especially important to identify the high-risk group who has both an FH-causing mutation and high Lp(a) levels and distinguish children with definite FH from those without a mutation but with high Lp(a) levels.