In an international cross-sectional registry study, classic diagnostic features of familial hypercholesterolemia were uncommon in individuals aged <18 years, and the diagnosis therefore relied on LDL-c levels or genetic confirmation. Most participants were not on lipid-lowering therapy.

This summary is based on the publication of European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration - Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study. Lancet. 2023 Dec 12:S0140-6736(23)01842-1. doi: 10.1016/S0140-6736(23)01842-1

Introduction and methods

Background

For patients with familial hypercholesterolemia (FH), identification in childhood and early treatment can mitigate the risk of premature ASCVD [1-6]. However, only 2.1% of adults with FH were diagnosed in their childhood or adolescence [1].

Aim of the study

The study aim was to characterize children and adolescents with heterozygous FH (HeFH) and provide evidence-based insights that may guide future public health approaches for the detection and management of FH early in life.

Methods

For this cross-sectional study, the authors collected individual-level data of children and adolescents aged <18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between October 1, 2015, and January 31, 2021. Data in this registry were collected from 55 regional or national registries in 48 countries. Exclusion criteria were diagnoses relying on a self-reported history of FH or suspected secondary hypercholesterolemia, as well as untreated LDL-c levels ≥13.0 mmol/L. Of the 63,093 individuals in the FHSC registry, 11,848 (18.8%) were <18 years old who also had HeFH.

Outcome

The main outcome was to assess current identification and management methods for children and adolescents with FH.

Results

Diagnosis

• Of 11,235 included children and adolescents, 10,099 (89.9%) had a final genetically confirmed diagnosis of FH and 1136 (10.1%) had a clinical diagnosis. Data on a genetically confirmed or clinical diagnosis were missing for 613 of 11,848 individuals (5.2%).
• A genetic diagnosis was more common in individuals from high-income countries (9427/10,202 (92.4%)) than in children and adolescents from non-high-income countries (199/415 (48.0%)).
• Of 10,804 included children and adolescents, 3414 (31.6%) were index cases.
• The median age at FH diagnosis was 9.1 years (IQR: 5.3–13.0), whereas the median age at registry entry was 9.6 years (IQR: 5.8–13.2).
• Children and adolescents who had been diagnosed using clinical criteria intended for use in adults had a higher median LDL-c level (DLCN criteria: 5.24 mmol/L; IQR: 4.94–5.53; MEDPED criteria: 5.13 mmol/L; IQR: 4.90–5.27) compared with individuals with a genetic FH diagnosis only (4.34 mmol/L; IQR: 4.27–4.42). In contrast, those diagnosed based on clinical criteria adapted for children and adolescents showed a median LDL-c concentration (Simon Broome criteria: 4.50 mmol/L; IQR: 4.06–4.96; JAS criteria: 4.50 mmol/L; IQR: 4.03–6.31) similar to that seen in genetically diagnosed individuals.
• If the (unadapted) DLCN criteria had been used, 50%–75% of the children and adolescents who had been detected directly through genetic testing would have been missed. Using the (adapted) Simon Broome criteria, would have resulted in 28%–55% of the children with a genetic diagnosis being missed.

Clinical characteristics

• Classic FH-related physical signs (including corneal arcus and xanthoma), CVD risk factors (including hypertension and diabetes), and CVD (including coronary artery disease and stroke) were uncommon in the study population, although these features were more common in non–high-income countries compared with high-income countries.

Management

• At registry entry, 7903 of 11,046 participants (71.6%) were not taking lipid-lowering medication. Their median LDL-c level was 5.00 mmol/L (IQR: 4.05–6.08), compared with 4.35 mmol/L (IQR: 3.44–5.34) in those who were on lipid-lowering therapy (n=3143; 28.5%).
• In individuals not taking lipid-lowering medication, the median LDL-c level was highest at age 2–3 years (5.97 mmol/L; IQR: 5.04–6.90).
• Statins were prescribed to 814 of 2799 participants (29.1%), 154 of 2724 individuals received ezetimibe (5.7%), and 10 of 2871 (0.4%) were taking PCSK9 inhibitors. The most common prescribed statins were atorvastatin (43.2%), simvastatin (24.4%), and rosuvastatin (18.4%).
• After adjusting for age and combination treatment with statins and ezetimibe, the likelihood of reaching the LDL-c target (<3.4 mmol/L) was lower in females than in males (adjusted OR: 0.74; 95%CI: 0.61–0.90). Statin and ezetimibe combination therapy was associated with an increased likelihood of having LDL-c <3.4 mmol/L compared with no therapy (adjusted OR: 1.83; 95%CI: 1.19–2.82).

Conclusion

This international cross-sectional registry study covering 48 countries showed that most children and adolescents with HeFH were not index cases, which probably reflected the use of family cascade screening of affected adult relatives. As classic diagnostic features of FH (e.g., physical signs and premature CVD) were uncommon in children and adolescents, diagnosis relied on either LDL-c measurements or genetic confirmation. At registry entry, ~70% of the participants were not on lipid-lowering therapy.

Distribution of LDL-c levels by age suggested that the LDL-c concentration can be used to identify individuals with FH as early as the first year of life. However, the authors believe the LDL-c cutoffs currently used in different clinical criteria need to be adapted to avoid missing potential diagnoses in individuals ages <18 years. Their “study suggests that initial screening of LDL-c should be followed by genetic testing (where available and accessible) to support diagnosis of children and adolescents with mild phenotypes.” Furthermore, once identified, children and adolescents with FH will require “increased use of and improved lifelong adherence to high-intensity statins or combination therapies” to reach the recommended LDL-c targets, similar to adults.

References

1. Vallejo-Vaz AJ, Stevens CA, Lyons AR, et al. Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet 2021; 398: 1713–25.
2. National Organization for Rare Disorders. Familial hypercholesterolemia. 2023. https://rarediseases.org/rare-diseases/familial-hypercholesterolemia/ (accessed Dec 4, 2023).
3. Benito-Vicente A, Alves AC, Etxebarria A, Medeiros AM, Martin C, Bourbon M. The importance of an integrated analysis of clinical, molecular, and functional data for the genetic diagnosis of familial hypercholesterolemia. Genet Med 2015; 17: 980–88.
4. Galema-Boers JM, Versmissen J, Roeters van Lennep HW, Dusault-Wijkstra JE, Williams M, Roeters van Lennep JE. Cascade screening of familial hypercholesterolemia must go on. Atherosclerosis 2015; 242: 415–17.
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6. Hovingh GK, Kastelein JJ. Diagnosis and management of individuals with heterozygous familial hypercholesterolemia: too late and too little. Circulation 2016; 134: 710–12.

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