Graphical Abstract Graphical Abstract Homozygous familial hypercholesterolaemia is a rare autosomal semi-dominant disease affecting males and females equally, characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) from conception and accelerated atherosclerotic cardiovascular disease, often resulting in early death. Homozygous familial hypercholesterolaemia is diagnosed late and undertreated; both established and novel therapies offer hope to patients, but treatment inequity exacerbates poorer outcomes in less affluent countries.12APOB, apolipoprotein B gene; CI, confidence interval; HR, hazard ratio; LDLR, low-density lipoprotein receptor gene; LDLRAP1, low-density lipoprotein adaptor protein 1 gene; PCSK9, proprotein conertase subtilisin/kexin type 9 gene.

/pdf/2023-update-on-european-atherosclerosis-society-consensus-2q2dzgqt.pdf

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance

Differences between men and women in lipids and lipoproteins are observed in distribution and trajectory from infancy to adulthood in the general population. However, these differences are more pronounced in hereditary lipid disorders such as familial hypercholesterolemia (FH) when absolute cholesterol levels are higher from birth onwards. In the early life course, girls compared to boys have higher low-density lipoprotein cholesterol (LDL-C) levels and total cholesterol, while high-density lipoprotein cholesterol (HDL-C) levels are similar. In early adulthood to middle-age, women have lower LDL-C and higher HDL-C levels, as LDL-C levels increase and HDLC levels decrease in men. In the elderly, all lipids – total cholesterol, LDL-C, HDL-C and triglyceride levels decrease but are more pronounced in men. Lipid levels are also affected by specific transitions in girls/women such as the menstrual cycle, pregnancy, breastfeeding and menopause. Lipid levels fluctuate during the menstrual cycle. During pregnancy a physiological increase of LDL-C and even a larger increase in triglyceride levels are observed. Pregnancy has a double impact on LDL-C accumulation in women with FH as they have to stop statins, and the absolute increase in LDL-C is higher than in women without FH. In the menopausal transition, women develop a more adverse lipid profile. Therefore, it is important to take into account both sex and the life course when assessing a lipid profile. 

Sex differences in lipids: A life course approach.

<h2>Summary</h2><h3>Background</h3> Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. <h3>Methods</h3> For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. <h3>Findings</h3> Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. <h3>Interpretation</h3> Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. <h3>Funding</h3> Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron. 

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Abstract Purpose of Review Lipid measurements and genetic testing are the main diagnostic tools for FH screening that are available in many countries. A lipid profile is widely accessible, and genetic testing, although available worldwide, in some countries is only performed in a research context. Still FH is diagnosed late, showing lack of early screening programs worldwide. Recent Findings Pediatric screening of FH was recently recognized by the European Commission Public Health Best Practice Portal as one on the best practices in non-communicable disease prevention. The early diagnosis of FH and the lowering of LDL-C values over lifespan can reduce the risk of coronary artery disease and offer health and socioeconomic gains. Summary Current knowledge about FH shows that early detection through appropriate screening needs to become a priority in healthcare systems worldwide. Governmental programs for FH identification should be implemented to unify the diagnosis and increase patient identification. 

/pdf/genetic-testing-in-familial-hypercholesterolemia-is-it-for-ezmwe8an.pdf

Genetic Testing in Familial Hypercholesterolemia: Is It for Everyone?

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.

/pdf/how-genetic-variants-in-children-with-familial-1v7r6ylq.pdf

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

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disorder characterized by high cholesterol and if left untreated leads to premature cardiovascular disease, such as heart attacks. Treatment that begins early in life, particularly in childhood, is highly efficacious in preventing cardiovascular disease and cost-effective, thus early detection of FH is crucial. However, in Europe, less than 10% of people living with FH are diagnosed and even less receive life-saving treatment. The Prague Declaration is a call to action for national and European Union policymakers and decision-makers and a result of the Czech EU Presidency meeting on FH Paediatric Screening (early detection of inherited high cholesterol) at the Czech Senate in Prague on 6th September 2022. It builds on a considerable body of evidence which was discussed at the Technical Meeting under the auspices of the Slovenian EU Presidency in October 2021. The Prague meeting addressed the outstanding barriers to the systematic implementation of FH paediatric screening across Europe. In this article, we present the key points from the Prague meeting and concrete actions needed to move forward.

The time is now: Achieving FH paediatric screening across Europe – The Prague Declaration

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The time is now: Achieving FH paediatric screening across Europe – The Prague Declaration