Paediatric familial hypercholesterolaemia screening in Europe: public policy background and recommendations

Gidding, Samuel S.; Wiegman, Albert; Grošelj, Urh; Freiberger, Tomáš; Peretti, Noël; Dharmayat, Kanika; Daccord, Magdalena; Bedlington, Nicola; Šikonja, Jaka; Ray, Kausik K.; Santos, Raul D.; Halle, Martin; Tokgözoğlu, Lâle; Gutiérrez-Ibarluzea, Iñaki; Pinto, Fausto J.; Geanta, Marius

doi:10.1093/eurjpc/zwac200

Cited by 40 publications

(28 citation statements)

References 47 publications

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“…Screening in children for FH will now be widely introduced in Europe, since the European Commission Public Health Best Practice Portal recognized FH pediatric screening as one on the best practices in noncommunicable disease prevention. Different types of screening strategies will be used and hopefully lead to tailored treatment [20,21 ▪ ]. According to Peretti et al , genetic testing for HeFH during childhood is preferable over clinical diagnosing, because a genetic diagnosis is better associated with statin treatment in HeFH children, as is a history of CVD in a parent.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia

Reijman¹,

Defesche

Wiegman³

2023

Current Opinion in Lipidology

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BackgroundFamilial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature cardiovascular disease (CVD). Both the heterozygous form and the very severe homozygous form can be diagnosed by genetic testing and by clinical criteria. Genetic testing can discern FH in a form caused by complete absence of the LDL-receptors, the negative variant and a form leading to reduced activity of the LDL receptors, the defective variant. The aim of this study is to provide more insight in the genotype--phenotype correlation in children and adolescents diagnosed with heterozygous FH (HeFH) and with homozygous FH (HoFH), specifically in relation to the clinical and therapeutic consequences of the negative and defective variant of FH. Methods and ResultsData of 5904 children with a tentative diagnosis of FH referred to our center for genetic testing were collected. A lipid-profile was present in 3494 children, who became the study cohort. In this large cohort of children, which includes 2714 HeFH and 41 HoFH patients, it is shown that receptor negative variants are associated with significant higher LDL-C levels in HeFH patients than receptor defective variants (6.0 versus 4.9 mmol/L; p < 0.001). A negative/negative variant is associated with a significant higher LDL-C level jn HoFH patients than a negative/defective variant, which in itself has a higher LDL-C level than a defective/defective variant. Significantly more premature CVD is present in close relatives of children with HeFH with negative variants compared to close relatives of HeFH children with defective variants (75% vs 59%; p < 0.001). ConclusionsPerforming genetic testing and identifying the type of underlying genetic variant is of added value in order to distinguish between pediatric patients with higher risks of premature CVD and to identify those that will benefit most from new types of lipid-lowering therapies. Since in children the phenotype of FH is less affected by environmental factors, the study substantiates the genotype-phenotype correlation in this large pediatric population.

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Section: Discussionmentioning

confidence: 99%

Genotype–phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia

Reijman¹,

Defesche

Wiegman³

2023

Current Opinion in Lipidology

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“…A major health-economic analysis in Australia showed that FH screening at the age of 10, and initiating treatment if diagnosed, resulted in 7.77 life-years gained (LYG) and 7.53 quality-adjusted life years (QALYs) per person screened [ 9 ]. Due to the nature of FH (the chance of a first-degree relative being affected by the disease in case of HeFH is 50%; in case of HoFH the chance is close to 100%), this disease would also be an excellent candidate for the implementation of a national screening program in children and a subsequent reverse cascade screening to detect the affected parent(s) [ 10 , 11 , 12 , 13 ]. At this moment, the majority of FH cases are diagnosed too late, when a person already has symptomatic ASCVD [ 7 ].…”

Section: Prevalence and Screeningmentioning

confidence: 99%

How Genetic Variants in Children with Familial Hypercholesterolemia Not Only Guide Detection, but Also Treatment

Bosch

Corpeleijn

Hutten

et al. 2023

Genes

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Familial hypercholesterolemia (FH) is a hereditary disorder that causes severely elevated low-density lipoprotein (LDL-C) levels, which leads to an increased risk for premature cardiovascular disease. A variety of genetic variants can cause FH, namely variants in the genes for the LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and/or LDL-receptor adaptor protein 1 (LDLRAP1). Variants can exist in a heterozygous form (HeFH) or the more severe homozygous form (HoFH). If affected individuals are diagnosed early (through screening), they benefit tremendously from early initiation of lipid-lowering therapy, such as statins, and cardiovascular imaging to detect possible atherosclerosis. Over the last years, due to intensive research on the genetic basis of LDL-C metabolism, novel, promising therapies have been developed to reduce LDL-C levels and subsequently reduce cardiovascular risk. Results from studies on therapies focused on inhibiting PCSK9, a protein responsible for degradation of the LDLR, are impressive. As the effect of PCSK9 inhibitors (PCSK9-i) is dependent of residual LDLR activity, this medication is less potent in patients without functional LDLR (e.g., null/null variant). Novel therapies that are expected to become available in the near future focused on inhibition of another major regulatory protein in lipid metabolism (angiopoietin-like 3 (ANGPTL3)) might dramatically reduce the frequency of apheresis in children with HoFH, independently of their residual LDLR. At present, another independent risk factor for premature cardiovascular disease, elevated levels of lipoprotein(a) (Lp(a)), cannot be effectively treated with medication. Further understanding of the genetic basis of Lp(a) metabolism, however, offers a possibility for the development of novel therapies.

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“…Cascade screening has been the most cost‐effective approach that has been implemented in multiple guidelines, but is often lackluster with its effectiveness to detect a larger number of FH families. Based on a study of the European Union, the availability of universal screening for FH is extremely limited compared to availability of cascade screening and traditional cholesterol testing 126 . Yet, it was suggested that universal screening combined with cascade and opportunistic screening could significantly improve the rate of identification and early treatment.…”

Section: Future Recommendations In the Post‐covid 19 Eramentioning

confidence: 99%

“…Based on a study of the European Union, the availability of universal screening for FH is extremely limited compared to availability of cascade screening and traditional cholesterol testing. 126 Yet, it was suggested that universal screening combined with cascade and opportunistic screening could significantly improve the rate of identification and early treatment. In Slovenia, the universal 3-step FH screening approach amongst children was successful in reaching >91% of the pediatric population and detecting positive genetic variants in first-degree relatives with high cholesterol with a cost-effective analysis at around $900 for every screened case.…”

Section: Future Recommendations In the Post-covid 19 Eramentioning

confidence: 99%

Barriers and shortcomings in access to cardiovascular management and prevention for familial hypercholesterolemia during the COVID‐19 pandemic

Huang

Leung

Garg

et al. 2023

Clinical Cardiology

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Familial hypercholesterolemia (FH) is a hereditary condition caused by mutations in the lipid pathway. The goal in managing FH is to reduce circulating low‐density lipoprotein cholesterol and, therefore, reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). Because FH patients were considered high risk groups due to an increased susceptible for contracting COVID‐19 infection, we hypothesized whether the effects of the pandemic hindered access to cardiovascular care. In this review, we conducted a literature search in databases Pubmed/Medline and ScienceDirect. We included a comprehensive analysis of findings from articles in English related and summarized the effects of the pandemic on cardiovascular care through direct and indirect effects. During the COVID‐19 pandemic, FH patients presented with worse outcomes and prognosis, especially those that have suffered from early ASCVD. This caused avoidance in seeking care due to fear of transmission. The pandemic severely impacted consultations with lipidologists and cardiologists, causing a decline in lipid profile evaluations. Low socioeconomic communities and ethnic minorities were hit the hardest with job displacements and lacked healthcare coverage respectively, leading to treatment nonadherence. Lock‐down restrictions promoted sedentary lifestyles and intake of fatty meals, but it is unclear whether these factors attenuated cardiovascular risk in FH. To prevent early atherogenesis in FH patients, universal screening programs, telemedicine, and lifestyle interventions are important recommendations that could improve outcomes in FH patients. However, the need to research in depth on the disproportionate impact within different subgroups should be the forefront of FH research.

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Paediatric familial hypercholesterolaemia screening in Europe: public policy background and recommendations

Cited by 40 publications

References 47 publications

Genotype–phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia

Genotype–phenotype correlation in a large cohort of pediatric patients with heterozygous and homozygous familial hypercholesterolemia

How Genetic Variants in Children with Familial Hypercholesterolemia Not Only Guide Detection, but Also Treatment

Barriers and shortcomings in access to cardiovascular management and prevention for familial hypercholesterolemia during the COVID‐19 pandemic

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