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Epidemiology of familial hypercholesterolaemia: Community and clinical

  • Antonio J. Vallejo-Vaz
    Correspondence
    Corresponding author. Department of Primary Care and Public Health, School of Public Health, Imperial College London; Charing Cross campus, W6 8RP, London, United Kingdom.
    Affiliations
    Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom
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  • Kausik K. Ray
    Affiliations
    Imperial Centre for Cardiovascular Disease Prevention (ICCP), Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, United Kingdom
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      Highlights

      • Contemporary studies suggest FH is more prevalent than considered historically.
      • FH prevalence varies among populations and regions based on different factors.
      • FH entails a significantly higher CVD risk, mainly driven by coronary heart disease.
      • FH is, in general, insufficiently treated or treatment introduced too late.
      • Low rates of patients meet therapeutic targets for cardiovascular prevention.

      Abstract

      Familial hypercholesterolaemia (FH) is a genetic disorder affecting the metabolism of low-density lipoprotein (LDL) particles, leading to high LDL-cholesterol levels maintained over time and higher risk of cardiovascular disease (CVD) early in life.
      Contemporary studies have challenged prior estimations of FH prevalence and suggest this condition to be more frequent than previously considered, with an overall prevalence rate of 1:200–300 individuals in the general population (1:160,000–300,000 for homozygous FH). However, prevalence of FH varies around the world. In part this is due to an artefact of approaches of detection and methods used to diagnose FH (e.g. lack of gold standard for diagnosis of FH, different criteria applied, availability of genetic testing). But also due to intrinsic characteristic of different populations, e.g. higher presence of founder effects or rates of consanguinity. Additionally, results from many regions are lacking and it is estimated that only a small percentage of subjects with FH would have been diagnosed overall.
      FH entails a significantly higher risk of CVD, reported to be higher than that estimated by conventional risk assessment tools for the general population. This risk is mainly driven by coronary heart disease. Despite this evidence, low rates of patients meet therapeutic targets for cardiovascular prevention, and implementation of therapy (high intensity statins, combination therapy) is needed. The introduction of novel lipid-lowering therapies may improve this situation.
      In the present review, we discuss the epidemiology of FH overall, with special attention to different aspects related to prevalence, cardiovascular risk and prognosis, and treatment of FH.

      Keywords

      1. Introduction

      Since C. Muller first reported, in 1938, the clustering of xanthomas, high blood cholesterol and myocardial infarction [
      • Xanthomata Muller C.
      hypercholesterolemia, angina pectoris.
      ] (MI) and years later (1970s) Brown and Goldstein described the genetic defects in the low-density lipoprotein (LDL) receptor (LDLR) as the cause of familial hypercholesterolaemia (FH) [
      • Brown M.S.
      • Goldstein J.L.
      A receptor-mediated pathway for cholesterol homeostasis.
      ], our understanding of this condition has grown considerably. The subsequent introduction of statins substantially improved the prognosis of the disease [
      • Versmissen J.
      • Oosterveer D.M.
      • Yazdanpanah M.
      • Defesche J.C.
      • Basart D.C.
      • Liem A.H.
      • Heeringa J.
      • Witteman J.C.
      • Lansberg P.J.
      • Kastelein J.J.
      • Sijbrands E.J.
      Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.
      ,
      Simon broome register group. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific steering committee on behalf of the Simon broome register group.
      ]. And the recent development of novel therapies such as pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has raised expectations with regards to achieving therapeutic goals and further reductions of adverse outcomes associated with FH [
      • Kastelein J.J.
      • Ginsberg H.N.
      • Langslet G.
      • Hovingh G.K.
      • Ceska R.
      • Dufour R.
      • Blom D.
      • Civeira F.
      • Krempf M.
      • Lorenzato C.
      • Zhao J.
      • Pordy R Baccara-Dinet M.T.
      • Gipe D.A.
      • Geiger M.J.
      • Farnier M.
      ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.
      ,
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • Honarpour N.
      • Wiviott S.D.
      • Murphy S.A.
      • Kuder J.F.
      • Wang H.
      • Liu T.
      • Wasserman S.M.
      • Sever P.S.
      • Pedersen T.R.
      FOURIER steering committee and investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease.
      ].
      FH is a genetic disorder with an autosomal dominant inheritance affecting LDL-cholesterol (LDL-C) metabolism resulting in reduced catabolism of LDL particles, high levels of LDL-C and premature cardiovascular disease (CVD) [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ,
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ]. Mutations in the LDLR gene are the most frequent cause of FH (85–90% of cases) [
      • Sniderman A.D.
      • Tsimikas S.
      • Fazio S.
      The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies.
      ,
      • Hovingh G.K.
      • Davidson M.H.
      • Kastelein J.J.
      • O'Connor A.M.
      Diagnosis and treatment of familial hypercholesterolaemia.
      ]. Although a few mutations are responsible for most FH cases in regions with founder effects, a wide range of mutations have been described, and currently >1700 mutations in the LDLR have been reported worldwide [
      • Leigh S.
      • Futema M.
      • Whittall R.
      • Taylor-Beadling A.
      • Williams M.
      • den Dunnen J.T.
      Humphries SE.The UCL low-density lipoprotein receptor gene variant database: pathogenicity update.
      ]. Both heterozygous FH (HeFH) and homozygous FH (HoFH, resulting from the same mutation in the same gene [true homozygous] or, more often, compound heterozygous mutations whereby there are mutations at different sites in the same gene) have been described [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ,
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ]. Additionally, mutations in the apolipoprotein B (apoB)-100 gene (which is the ligand for the LDLR, whereby mutations in the protein may prevent/alter the binding of LDL particles to its receptor) or mutations in the PCSK9 gene (gain-of-action mutations leading to increased lysosomal LDLR degradation) can cause FH with an indistinguishable phenotype to that produced by mutations in LDLR [
      • Sniderman A.D.
      • Tsimikas S.
      • Fazio S.
      The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies.
      ,
      • Hovingh G.K.
      • Davidson M.H.
      • Kastelein J.J.
      • O'Connor A.M.
      Diagnosis and treatment of familial hypercholesterolaemia.
      ]. Additionally there are the so-called double heterozygotes where individuals carry mutations in different genes (e.g. LDLR and apoB). Occasionally mutations in other genes have also been described resembling the classical FH phenotype, leading to forms of autosomal dominant hypercholesterolaemia (e.g. mutations in gene STAP1 [signal transducing adaptor family member 1]) [
      • Fouchier S.W.
      • Dallinga-Thie G.M.
      • Meijers J.C.
      • Zelcer N.
      • Kastelein J.J.
      • Defesche J.C.
      • Hovingh G.K.
      Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia.
      ]; or the rare autosomal recessive loss-of-function mutation in gene LDLRAP (LDLR adaptor protein 1) [
      • Soutar A.K.
      • Naoumova R.P.
      • Traub L.M.
      Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia.
      ]. Finally, in a variable percentage of patients no mutations are identified [
      • Palacios L.
      • Grandoso L.
      • Cuevas N.
      • Olano-Martín E.
      • Martinez A.
      • Tejedor D.
      • Stef M.
      Molecular characterization of familial hypercholesterolemia in Spain.
      ], suggesting that other genes/type of mutations (others than those tested in a particular setting) could be involved or that a polygenic basis results in higher LDL-C in these subjects [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ].
      New evidence on the epidemiology of FH from large studies and from different regions have been accumulating during the last few years; a renewed interest in this condition has emerged, partly related to the recognition of a likely higher frequency of the disease than previously considered, and partly due to the development of new lipid-lowering medications (LLM) that could improve the management of FH. Notably, data has emerged from outside of Europe demonstrating that FH is a global public health issue. In the present review we aim to present a general overview, with a focus on the most recent data available, of some epidemiological aspects of FH prevalence, cardiovascular risk and prognosis, and patterns of treatment and goals achievement in FH. Other topics will be more extensively covered in other articles of the present FH series. For the present review we carried out a search in Medline to identify relevant papers on the topic, including “familial hypercholesterolaemia”, “primary hyperlipidaemia”, “prevalence” and related terms, not restricted to a particular time frame (though we focus on more recent data, as most of the global evidence has accrued since 2011).

      2. FH prevalence

      Prevalence of HeFH has been traditionally considered to be ∼1:500 individuals in most ethnic groups throughout the world [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. However, in most cases, these figures result from the extrapolation, e.g. by using the Hardy-Weinberg equation, of a limited number of data from selected populations or specific subgroups to the general population, and therefore may lack the precision of more contemporary estimates [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • Humphries S.E.
      Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
      ]. For instance, the prevalence of HeFH in Denmark was suggested to be ∼1:950 individuals from data from late 1970s [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • Humphries S.E.
      Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
      ], but recent analyses from the large community-based Copenhagen General Population Study (CGPS) in unselected individuals revealed that HeFH could be as frequent as ∼1:200 subjects [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ,
      • Benn M.
      • Watts G.F.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217.
      ]. In fact, overall contemporary data suggests HeFH to be much more frequent and affect ∼1:200–300 individuals globally [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ,
      • Akioyamen L.E.
      • Genest J.
      • Shan S.D.
      • Reel R.L.
      • Albaum J.M.
      • Chu A.
      • Tu J.V.
      Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis.
      ], which could mean that >30 million individuals worldwide could be affected of HeFH [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. HoFH is, on the contrary, much less frequent than HeFH, from 1:1,000,000 people, based on historical prevalence data, to 1:160,000–300,000, as suggested from recent studies [
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ].
      Additionally, the prevalence of the disease seems to vary with ethnicity and geographically, with higher prevalence reported in subpopulations with founder effects/communities sharing ascendants or in those with higher rates of consanguinity (e.g. Afrikaners in South Africa, Christian Lebanese, Tunisians, some French-Canadian) [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • Humphries S.E.
      Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
      ,
      • Moorjani S.
      • Roy M.
      • Gagné C.
      • Davignon J.
      • Brun D.
      • Toussaint M.
      • Lambert M.
      • Campeau L.
      • Blaichman S.
      • Lupien P.
      Homozygous familial hypercholesterolemia among French canadians in québec province.
      ,
      • Paquette M.
      • Genest J.
      • Baass A.
      Familial hypercholesterolemia: experience from the French-Canadian population.
      ]. Furthermore, a number of other factors complicate reliable estimation of the true prevalence of FH in the general population, e.g.: lack of large, standardised and comparable national registries; variability in clinical practice; lack of uniform criteria for the diagnosis of FH, limited availability of genetic tests, discordance between individuals identified by clinical and genetic diagnosis, the potential for mutations not yet known and the case of “polygenic” hypercholesterolaemia; differences in screening strategies and initiatives to identify FH patients and relatives, lack of resource provision, and concerns about their feasibility and cost-effectiveness; lack of FH awareness and education among healthcare professionals, other healthcare providers and policy-makers; misclassification of case fatalities to alternate causes [
      • Vallejo-Vaz A.J.
      • Kondapally Seshasai S.R.
      • Cole D.
      • Hovingh G.K.
      • Kastelein J.J.
      • Mata P.
      • Raal F.J.
      • Santos R.D.
      • Soran H.
      • Watts G.F.
      • Abifadel M.
      • Aguilar-Salinas C.A.
      • Akram A.
      • Alnouri F.
      • Alonso R.
      • Al-Rasadi K.
      • Banach M.
      • Bogsrud M.P.
      • Bourbon M.
      • Bruckert E.
      • Car J.
      • Corral P.
      • Descamps O.
      • Dieplinger H.
      • Durst R.
      • Freiberger T.
      • Gaspar I.M.
      • Genest J.
      • Harada-Shiba M.
      • Jiang L.
      • Kayikcioglu M.
      • Lam C.S.
      • Latkovskis G.
      • Laufs U.
      • Liberopoulos E.
      • Nilsson L.
      • Nordestgaard B.G.
      • O'Donoghue J.M.
      • Sahebkar A.
      • Schunkert H.
      • Shehab A.
      • Stoll M.
      • Su T.C.
      • Susekov A.
      • Widén E.
      • Catapano A.L.
      • Ray K.K.
      Familial hypercholesterolaemia: a global call to arms.
      ,
      • Vallejo-Vaz A.J.
      • Akram A.
      • Kondapally Seshasai S.R.
      • Cole D.
      • Watts G.F.
      • Hovingh G.K.
      • Kastelein J.J.
      • Mata P.
      • Raal F.J.
      • Santos R.D.
      • Soran H.
      • Freiberger T.
      • Abifadel M.
      • Aguilar-Salinas C.A.
      • Alnouri F.
      • Alonso R.
      • Al-Rasadi K.
      • Banach M.
      • Bogsrud M.P.
      • Bourbon M.
      • Bruckert E.
      • Car J.
      • Ceska R.
      • Corral P.
      • Descamps O.
      • Dieplinger H.
      • Do C.T.
      • Durst R.
      • Ezhov M.V.
      • Fras Z.
      • Gaita D.
      • Gaspar I.M.
      • Genest J.
      • Harada-Shiba M.
      • Jiang L.
      • Kayikcioglu M.
      • Lam C.S.
      • Latkovskis G.
      • Laufs U.
      • Liberopoulos E.
      • Lin J.
      • Lin N.
      • Maher V.
      • Majano N.
      • Marais A.D.
      • März W.
      • Mirrakhimov E.
      • Miserez A.R.
      • Mitchenko O.
      • Nawawi H.
      • Nilsson L.
      • Nordestgaard B.G.
      • Paragh G.
      • Petrulioniene Z.
      • Pojskic B.
      • Reiner Ž.
      • Sahebkar A.
      • Santos L.E.
      • Schunkert H.
      • Shehab A.
      • Slimane M.N.
      • Stoll M.
      • Su T.C.
      • Susekov A.
      • Tilney M.
      • Tomlinson B.
      • Tselepis A.D.
      • Vohnout B.
      • Widén E.
      • Yamashita S.
      • Catapano A.L.
      • Ray K.K.
      Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration.
      ].

      2.1 FH diagnosis

      Presently, it is estimated that as few as <5% of individuals affected by HeFH have been identified in most regions so far, with the only exception being a few countries where there have been active screening programmes [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. Even so, in these better performing countries the under-diagnosis is still patent when one considers the contemporary prevalence data [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. A key point which arbitrarily influences estimations of prevalence is how this condition is defined and the classification used to estimate the likelihood of having a diagnosis of FH. For example, the use of different LDL-C cut-off points or the inclusion or not of genetic mutation criteria may vary substantially the number of cases identified and classified as FH [
      • Khera A.V.
      • Won H.H.
      • Peloso G.M.
      • Lawson K.S.
      • Bartz T.M.
      • Deng X.
      • van Leeuwen E.M.
      • Natarajan P.
      • Emdin C.A.
      • Bick A.G.
      • Morrison A.C.
      • Brody J.A.
      • Gupta N.
      • Nomura A.
      • Kessler T.
      • Duga S.
      • Bis J.C.
      • van Duijn C.M.
      • Cupples L.A.
      • Psaty B.
      • Rader D.J.
      • Danesh J.
      • Schunkert H.
      • McPherson R.
      • Farrall M.
      • Watkins H.
      • Lander E.
      • Wilson J.G.
      • Correa A.
      • Boerwinkle E.
      • Merlini P.A.
      • Ardissino D.
      • Saleheen D.
      • Gabriel S.
      • Kathiresan S.
      Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
      ]. The identification of new FH subjects is currently mainly based on clinical criteria and, where available and indicated, genetic testing [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ,
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • Toth P.P.
      • Alonso R.
      • Brown W.V.
      • Bruckert E.
      • Defesche J.
      • Lin K.K.
      • Livingston M.
      • Mata P.
      • Parhofer K.G.
      • Raal F.J.
      • Santos R.D.
      • Sijbrands E.J.
      • Simpson W.G.
      • Sullivan D.R.
      • Susekov A.V.
      • Tomlinson B.
      • Wiegman A.
      • Yamashita S.
      • Kastelein J.J.
      Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation.
      ,
      • Hopkins P.N.
      • Toth P.P.
      • Ballantyne C.M.
      • Rader D.J.
      National lipid association expert panel on familial hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ]. However, currently there is no “gold standard” for the diagnosis of FH, with the presence of a positive mutation being widely acknowledged to define a definite diagnosis, though it has to be confirmed that such a mutation is pathogenic, i.e. affecting the LDL metabolism leading to increased LDL-C levels. On the other hand, however, a FH mutation is not found in a significant proportion of patients with a clinical diagnosis of FH, suggesting presence of unknown mutations, that in a number of cases a “polygenic” basis may account for this hypercholesterolaemic phenotype, or the potential for misclassification of some individuals as having FH (false positives) [
      • Khera A.V.
      • Won H.H.
      • Peloso G.M.
      • Lawson K.S.
      • Bartz T.M.
      • Deng X.
      • van Leeuwen E.M.
      • Natarajan P.
      • Emdin C.A.
      • Bick A.G.
      • Morrison A.C.
      • Brody J.A.
      • Gupta N.
      • Nomura A.
      • Kessler T.
      • Duga S.
      • Bis J.C.
      • van Duijn C.M.
      • Cupples L.A.
      • Psaty B.
      • Rader D.J.
      • Danesh J.
      • Schunkert H.
      • McPherson R.
      • Farrall M.
      • Watkins H.
      • Lander E.
      • Wilson J.G.
      • Correa A.
      • Boerwinkle E.
      • Merlini P.A.
      • Ardissino D.
      • Saleheen D.
      • Gabriel S.
      • Kathiresan S.
      Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
      ,
      • Talmud P.J.
      • Shah S.
      • Whittall R.
      • Futema M.
      • Howard P.
      • Cooper J.A.
      • Harrison S.C.
      • Li K.
      • Drenos F.
      • Karpe F.
      • Neil H.A.
      • Descamps O.S.
      • Langenberg C.
      • Lench N.
      • Kivimaki M.
      • Whittaker J.
      • Hingorani A.D.
      • Kumari M.
      • Humphries S.E.
      Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.
      ].
      Widely accepted diagnostic criteria to identify FH phenotype include the Dutch Lipid Clinic Network (DLCN) criteria, Simon-Broome criteria, and MEDPED (Make Early Diagnosis to Prevent Early Deaths) [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ,
      • Hovingh G.K.
      • Davidson M.H.
      • Kastelein J.J.
      • O'Connor A.M.
      Diagnosis and treatment of familial hypercholesterolaemia.
      ,
      • Watts G.F.
      • Gidding S.
      • Wierzbicki A.S.
      • Toth P.P.
      • Alonso R.
      • Brown W.V.
      • Bruckert E.
      • Defesche J.
      • Lin K.K.
      • Livingston M.
      • Mata P.
      • Parhofer K.G.
      • Raal F.J.
      • Santos R.D.
      • Sijbrands E.J.
      • Simpson W.G.
      • Sullivan D.R.
      • Susekov A.V.
      • Tomlinson B.
      • Wiegman A.
      • Yamashita S.
      • Kastelein J.J.
      Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation.
      ,
      • Hopkins P.N.
      • Toth P.P.
      • Ballantyne C.M.
      • Rader D.J.
      National lipid association expert panel on familial hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ]. The first two contain a number of variables including DNA analysis, LDL-C levels, physical signs related to hypercholesterolaemia, clinical history of premature CVD and family history, and classifies individuals into definite/probable/possible/unlike FH, in case of DLCN, or definite/possible in case of Simon-Broome criteria. On the contrary, MEDPED is based only on LDL-C levels according to age [
      • Hovingh G.K.
      • Davidson M.H.
      • Kastelein J.J.
      • O'Connor A.M.
      Diagnosis and treatment of familial hypercholesterolaemia.
      ]. These diagnostic criteria were produced some time ago and from Western populations; to what extent they fit well to changes in contemporary populations and to populations from other regions and ethnicities is an area of considerable uncertainty; for instance, lower average cholesterol levels have been described in Asian populations [
      • Livy A.
      • Lye S.H.
      Familial hypercholesterolemia in Asia: a review.
      ,
      • Zhou M.
      • Zhao D.
      Familial hypercholesterolemia in asian populations.
      ], which may lead to potential under-diagnosis of FH (false negative) if the same LDL-C cut-off points are used as suggested in some diagnostic criteria. Recently new algorithms have been developed trying to adapt these to other populations or simplify the diagnosis; this is the case of the new criteria proposed for the Japanese population [
      • Harada-Shiba M.
      • Arai H.
      • Oikawa S.
      • Ohta T.
      • Okada T.
      • Okamura T.
      • Nohara A.
      • Bujo H.
      • Yokote K.
      • Wakatsuki A.
      • Ishibashi S.
      • Yamashita S.
      Guidelines for the management of familial hypercholesterolemia.
      ] or that proposed by the American Heart Association [
      • Gidding S.S.
      • Champagne M.A.
      • de Ferranti S.D.
      • Defesche J.
      • Ito M.K.
      • Knowles J.W.
      • McCrindle B.
      • Raal F.
      • Rader D.
      • Santos R.D.
      • Lopes-Virella M.
      • Watts G.F.
      • Wierzbicki A.S.
      American heart association atherosclerosis, hypertension, and obesity in young committee of council on cardiovascular disease in young, council on cardiovascular and stroke nursing, council on functional genomics and translational biology, and council on lifestyle and cardiometabolic health. The agenda for familial hypercholesterolemia: a scientific statement. From the american heart association.
      ]. Another point to consider is the limited availability of genetic testing in many regions and the associated costs limiting their widespread implementation [
      • Vallejo-Vaz A.J.
      • Kondapally Seshasai S.R.
      • Cole D.
      • Hovingh G.K.
      • Kastelein J.J.
      • Mata P.
      • Raal F.J.
      • Santos R.D.
      • Soran H.
      • Watts G.F.
      • Abifadel M.
      • Aguilar-Salinas C.A.
      • Akram A.
      • Alnouri F.
      • Alonso R.
      • Al-Rasadi K.
      • Banach M.
      • Bogsrud M.P.
      • Bourbon M.
      • Bruckert E.
      • Car J.
      • Corral P.
      • Descamps O.
      • Dieplinger H.
      • Durst R.
      • Freiberger T.
      • Gaspar I.M.
      • Genest J.
      • Harada-Shiba M.
      • Jiang L.
      • Kayikcioglu M.
      • Lam C.S.
      • Latkovskis G.
      • Laufs U.
      • Liberopoulos E.
      • Nilsson L.
      • Nordestgaard B.G.
      • O'Donoghue J.M.
      • Sahebkar A.
      • Schunkert H.
      • Shehab A.
      • Stoll M.
      • Su T.C.
      • Susekov A.
      • Widén E.
      • Catapano A.L.
      • Ray K.K.
      Familial hypercholesterolaemia: a global call to arms.
      ].
      A frequent problem when trying to estimate the prevalence from general population epidemiological studies is that these studies frequently lack information on some criteria (e.g. physical signs, family history …) which are intrinsic to these classifications and a better fit for an outpatient referral clinic but unlikely to be applicable in a large general purpose population study. Thus, full algorithms cannot often be applied but modifications are used instead.
      Finally, it is worth mentioning the current debate on the extent to which high levels of lipoprotein(a) may contribute to the clinical diagnosis of FH (which may confound the population prevalence figures of FH), based on the recent findings from Langsted et al. [
      • Langsted A.
      • Kamstrup P.R.
      • Benn M.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study.
      ] These authors found that in subjects with clinical FH, lipoprotein(a) levels were around 40–60% higher than those classified as unlikely to have FH. The authors suggest that cholesterol in lipoprotein(a) contributes to the overestimation of LDL-C levels in some patients with a clinical diagnosis of FH; this suggests that a proportion of patients might obtain a clinical diagnosis of FH based on high lipoprotein(a) concentrations. The authors suggest that variations in the LPA gene leading to high lipoprotein(a) levels might be a possible “cause” of clinical FH [
      • Langsted A.
      • Kamstrup P.R.
      • Benn M.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study.
      ]. This term seems to be misleading as what data are implying is clinical misclassification. In support of a lack of causality is the data from the SAFEHEART study in molecularly-defined FH patients which suggest that LDLR defects would be partly responsible for the observed increase in lipoprotein(a) in these patients [
      • de Isla L.P.
      • Cerezo A.S.
      • Alonso R.
      • Mata P.
      Lipoprotein(a) and familial hypercholesterolaemia.
      ].
      Further discussions on FH diagnosis and screening strategies are covered specifically in other articles of the present FH series.

      2.2 FH prevalence in the general population

      A recent (2017) systematic review assessing the prevalence of HeFH included a total of 21 studies from Europe (9 studies), North America (4), Australia (3), Asia (2), South Africa (1), or pooled from international cohorts (2 studies) [
      • Akioyamen L.E.
      • Genest J.
      • Shan S.D.
      • Reel R.L.
      • Albaum J.M.
      • Chu A.
      • Tu J.V.
      Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis.
      ]; this work, though, exposes the challenges to making precise estimates due to the variability in the methods used to assess FH, with different criteria used to diagnose FH (DLCN criteria, genetic sequencing, LDL-C measurements only, Simon-Broome criteria, MEDPED criteria). In this contemporary review the estimated prevalence in individual studies ranged from 0.05% to 5.62%. A meta-analysis of 19 of these studies yielded an overall FH prevalence in the general population of 0.40% (1:250 individuals, 95% confidence interval [CI]: 1:192 to 1:345) [
      • Akioyamen L.E.
      • Genest J.
      • Shan S.D.
      • Reel R.L.
      • Albaum J.M.
      • Chu A.
      • Tu J.V.
      Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis.
      ]; however, a substantial between-study heterogeneity was observed (I2 = 99.3%), supporting the variability of the studies (design, population, methods, FH diagnosis …) and regional variations. Taken together, it is perhaps inappropriate without standardization and systematic approaches to generate an overall figure to apply to all populations.
      An overview of HeFH prevalence in the general population from contemporary studies is shown in Fig. 1.
      Fig. 1
      Fig. 1Overview (non-systematic review) of overall prevalence rates reported from contemporary studies for heterozygous familial hypercholesterolaemia in the general population (without [unknown] founder effects).
      See text for further details and explanations. Modified diagnostic criteria where frequently applied (see main text). Map created from https://mapchart.net/. CI: confidence interval; DLCN: Dutch Lipid Clinic Network; FH: familial hypercholesterolaemia; MEDPED: Make Early Diagnosis to Prevent Early Deaths; Ref: reference.
      Europe. The first large study aiming to directly estimate the prevalence of FH in unselected general population was published in 2012 and carried out in Denmark using the CGPS, a community-based population including >69,000 individuals [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ]. Using a modified DLCN definition (e.g. to account for the lack of information on xanthomas, arcus corneal or some family history data), the prevalence of definite/probable FH combined was estimated to be as high as ∼1:137 participants (0.73%) (definite FH –DLCN score >8 points– 0.20% [1:504]; probable FH –DLCN 6–8 points– 0.53% [1:189]). However, it was observed that this prevalence varied substantially depending on the diagnostic classifications used; for instance, applying the MEDPED criteria led to an estimated prevalence of 0.80% (1:128) for probable FH, whereas using the Simon-Broome criteria yielded a prevalence of definite or possible FH of 4.1% (1:25) [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ]. A later study (2016) from the same authors on the same population-based study, including now >98,000 participants, genotyping for LDLR and apoB variants accounting for almost 40% of pathogenic FH mutations in Copenhagen, suggested an overall prevalence of known FH-causing mutations of 0.46% (1:217) [
      • Benn M.
      • Watts G.F.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217.
      ]. This latter prevalence is higher than that reported from the National FINRISK and Health 2000 Studies in Finland by genotyping 5 common LDLR founder mutations in this country (estimated to account for 78% of FH cases in Finland) in >28,500 individuals; this study estimated the overall prevalence of FH in Finland to be at least 0.17% (at least 1:600 individuals) [
      • Lahtinen A.M.
      • Havulinna A.S.
      • Jula A.
      • Salomaa V.
      • Kontula K.
      Prevalence and clinical correlates of familial hypercholesterolemia founder mutations in the general population.
      ].
      Other recent data published in Europe broadly agree with the aforementioned estimated prevalence range, though the results are not always consistent, likely suggesting cross-regional/country differences (apart from potential variations in study designs or FH definitions). For instance, a meta-analysis of 6 population-based studies in Poland including almost 38,900 individuals suggested a prevalence of potential FH (definite and probable FH according to DLCN criteria) of 1:247 (0.41%, 95%CI 0.28%–0.53%), with FH being more prevalent in women than men and with highest prevalence figures in age groups 45–54 years in men (0.33%) and 55–64 years in women (0.77%) [
      • Pajak A.
      • Szafraniec K.
      • Polak M.
      • Drygas W.
      • Piotrowski W.
      • Zdrojewski T.
      • Jankowski P.
      Prevalence of familial hypercholesterolemia: a meta-analysis of six large, observational, population-based studies in Poland.
      ]. In Spain, an overall prevalence of FH of 1:300 has been suggested [
      • Lázaro P.
      • Pérez de Isla L.
      • Watts G.F.
      • Alonso R.
      • Norman R.
      • Muñiz O.
      • Fuentes F.
      • Mata N.
      • López-Miranda J.
      • González-Juanatey J.R.
      • Díaz-Díaz J.L.
      • Blasco A.J.
      • Mata P.
      Cost-effectiveness of a cascade screening program for the early detection of familial hypercholesterolemia.
      ] (estimated to affect at least 100,000 people in Spain [
      • Mata P.
      • Alonso R.
      • Pérez-Jiménez F.
      Screening for familial hypercholesterolemia: a model for preventive medicine.
      ]), and 1:319 people have been estimated to have FH in the Netherlands [
      • Sjouke B.
      • Kusters D.M.
      • Kindt I.
      • Besseling J.
      • Defesche J.C.
      • Sijbrands E.J.
      • Roeters van Lennep J.E.
      • Stalenhoef A.F.
      • Wiegman A.
      • de Graaf J.
      • Fouchier S.W.
      • Kastelein J.J.
      • Hovingh G.K.
      Homozygous autosomal dominant hypercholesterolaemia in The Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.
      ], whereas in Germany, a figure of 1:278, based on DLCN criteria (definite/probable FH), or 1:295, based on MEDPED criteria, have been recently reported [
      • Schmidt N.
      • Schmidt B.
      • Dressel A.
      • Gergei I.
      • Klotsche J.
      • Pieper L.
      • Scharnagl H.
      • Kleber M.E.
      • März W.
      • Lehnert H.
      • Pittrow D.
      • Stalla G.
      • Wittchen H.U.
      • Grammer T.B.
      Familial hypercholesterolemia in primary care in Germany. Diabetes and cardiovascular risk evaluation: targets and Essential Data for Commitment of Treatment (DETECT) study.
      ]. In primary care setting in Italy, a prevalence of 0.19% (1:526) for FH with a DLCN score ≥6 was found [
      • Guglielmi V.
      • Bellia A.
      • Pecchioli S.
      • Medea G.
      • Parretti D.
      • Lauro D.
      • Sbraccia P.
      • Federici M.
      • Cricelli I.
      • Cricelli C.
      • Lapi F.
      What is the actual epidemiology of familial hypercholesterolemia in Italy? Evidence from a National Primary Care Database.
      ], whereas figures based on LDL-C levels only yielded a prevalence of 1:1038 (∼0.1%) among non-treated subjects and 1:369 (∼0.3%) among statin-treated patients when using the cut-off of ≥250 mg/dL (1:34 and 1:29, respectively, if cut-off used is ≥ 190 mg/dL) [
      • Casula M.
      • Catapano A.L.
      • Rossi Bernardi L.
      • Visconti M.
      • Aronica A.
      Detection of familial hypercholesterolemia in patients from a general practice database.
      ].
      Middle East. Retrospective screening of a large regional healthcare database comprising 685,314 insured individuals <75 years in Israel found a prevalence of probable FH of 1:355 based on MEDPED criteria, with FH being more prevalent in certain communities (e.g. Israeli Druze, Christian Arabs) due to founder effects and higher rates of consanguinity [
      • Zafrir B.
      • Jubran A.
      • Lavie G.
      • Halon D.A.
      • Flugelman M.Y.
      • Shapira C.
      Clinical determinants and treatment gaps in familial hypercholesterolemia: data from a multi-ethnic regional health service.
      ]. In Christian Lebanese, due to similar reasons, an estimated prevalence of 1:85 was previously reported [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • Humphries S.E.
      Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
      ]. The prevalence of FH in other Middle Eastern countries is not well known, though a high frequency is expected in some regions and communities due to higher rates of shared ascendants, consanguinity and ethnic minorities [
      • Al-Rasadi K.
      • Al-Waili K.
      • Al-Sabti H.A.
      • Al-Hinai A.
      • Al-Hashmi K.
      • Al-Zakwani I.
      • Banerjee Y.
      Criteria for diagnosis of familial hypercholesterolemia: a comprehensive analysis of the different guidelines, appraising their suitability in the omani arab population.
      ].
      Americas. In North America, the National Health and Nutrition Examination Survey (NHANES) 1999–2012 (derived from general populations) have been used to estimate the frequency of FH and extrapolate it to the overall US adult population [
      • de Ferranti S.D.
      • Rodday A.M.
      • Mendelson M.M.
      • Wong J.B.
      • Leslie L.K.
      • Sheldrick R.C.
      Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States national health and nutrition examination surveys (NHANES).
      ]; applying a restricted DLCN score (information on some criteria was not collected in NHANES, including genetic testing) suggests that the overall US prevalence of probable/definite FH is estimated to be 0.40% (1:250, 95%CI 1:311 to 1:209), similar in men and women, suggesting that ∼834,500 US adults may have probable or definite FH; of interest, the prevalence varied with race/ethnicity, e.g. 0.40% (1:249) in whites, 0.47% (1:211) in blacks, or 0.24% (1:414) in Mexican Americans [
      • de Ferranti S.D.
      • Rodday A.M.
      • Mendelson M.M.
      • Wong J.B.
      • Leslie L.K.
      • Sheldrick R.C.
      Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States national health and nutrition examination surveys (NHANES).
      ]. A significantly higher frequency of FH has been observed in French-Canadians in certain regions in the province of Quebec in Canada, ranging from 1:167 up to 1:81, which is explained by the presence of a genetic founder effect [
      • Paquette M.
      • Genest J.
      • Baass A.
      Familial hypercholesterolemia: experience from the French-Canadian population.
      ]. Information on the prevalence of FH in Latin-American countries is generally lacking [
      • Mehta R.
      • Zubirán R.
      • Martagón A.J.
      • Vazquez-Cárdenas A.
      • Segura-Kato Y.
      • Tusié-Luna M.T.
      • Aguilar-Salinas C.A.
      The panorama of familial hypercholesterolemia in Latin America: a systematic review.
      ,
      • Santos R.D.
      • Bourbon M.
      • Alonso R.
      • Cuevas A.
      • Vasques-Cardenas N.A.
      • Pereira A.C.
      • Merchan A.
      • Alves A.C.
      • Medeiros A.M.
      • Jannes C.E.
      • Krieger J.E.
      • Schreier L.
      • Perez de Isla L.
      • Magaña-Torres M.T.
      • Stoll M.
      • Mata N.
      • Dell Oca N.
      • Corral P.
      • Asenjo S.
      • Bañares V.G.
      • Reyes X.
      • Mata P.
      Ibero-American Familial Hypercholesterolemia Network. Clinical and molecular aspects of familial hypercholesterolemia in Ibero-American countries.
      ]; some reports have cited an LDL-C >190 mg/dL to be present in 11.2% of adults in Mexico and 5% in Brazil [
      • Mehta R.
      • Zubirán R.
      • Martagón A.J.
      • Vazquez-Cárdenas A.
      • Segura-Kato Y.
      • Tusié-Luna M.T.
      • Aguilar-Salinas C.A.
      The panorama of familial hypercholesterolemia in Latin America: a systematic review.
      ], and a preliminary report from a systematic FH detection program in Argentina suggests that as many as 1:152 individuals might have FH according to DLCN criteria [
      • Corral P.
      • López G.I.
      • Cristaldi A.
      • Tuseddo J.C.
      • Cacciagiú L.
      • Berg G.
      • Schreier L.
      High prevalence of familial hypercholesterolemia in Argentina: results of the first detection program [Abstract EAS16–0076].
      ].
      Asia. Asian countries have been described to have, in general, lower levels of cholesterol compared to Western countries, which may have favoured an under-diagnosis in these regions [
      • Livy A.
      • Lye S.H.
      Familial hypercholesterolemia in Asia: a review.
      ,
      • Zhou M.
      • Zhao D.
      Familial hypercholesterolemia in asian populations.
      ]. However, mean total cholesterol levels have been increasing in some Asian regions in the last few decades, particularly east and southeast Asia, including China and Japan, partly due to changes in lifestyles [
      • Farzadfar F.
      • Finucane M.M.
      • Danaei G.
      • Pelizzari P.M.
      • Cowan M.J.
      • Paciorek C.J.
      • Singh G.M.
      • Lin J.K.
      • Stevens G.A.
      • Riley L.M.
      • Ezzati M.
      Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Cholesterol). National, regional, and global trends in serum total cholesterol since 1980: systematic analysis of health examination surveys and epidemiological studies with 321 country-years and 3·0 million participants.
      ]. As a result of more systematic assessment of cholesterol levels FH may be more prevalent than previously envisaged in these populations. Though there is a growing interest of this condition in Asia, data to infer true estimates of the frequency of FH are broadly lacking and in some cases discordant. An early report from Japan in 1977 reported a frequency of FH of 0.11% out of 2700 consecutive outpatients attending their clinics (∼1:900) using an alternative, more restrictive, definition of FH [
      • Mabuchi H.
      • Haba T.
      • Ueda K.
      • Ueda R.
      • Tatami R.
      • Ito S.
      • Kametani T.
      • Koizumi J.
      • Miyamoto S.
      • Ohta M.
      • Takeda R.
      • Takegoshi T.
      • Takeshita H.
      Serum lipids and coronary heart disease in heterozygous familial hypercholesterolemia in the Hokuriku District of Japan.
      ], which contrasts with a more contemporary (2011) estimation of the prevalence in the same district in Japan of 1:208 [
      • Mabuchi H.
      • Nohara A.
      • Noguchi T.
      • Kobayashi J.
      • Kawashiri M.A.
      • Tada H.
      • Nakanishi C.
      • Mori M.
      • Yamagishi M.
      • Inazu A.
      • Koizumi J.
      Hokuriku FH Study Group. Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan.
      ]. A recent report from China in 2014, applying a modified definition of DLCN to adapt it to the Chinese population, estimated a prevalence of probable/definite FH of 0.28%, yielding an age-standardised FH prevalence in China of 0.31% based on the 2000 Chinese census data [
      • Shi Z.
      • Yuan B.
      • Zhao D.
      • Taylor A.W.
      • Lin J.
      • Watts G.F.
      Familial hypercholesterolemia in China: prevalence and evidence of underdetection and undertreatment in a community population.
      ].
      Pacific region. Watts et al. have described a prevalence of definite/probable FH (modified DLCN definition) of 1:353 (0.28%, 95%CI 0.16%–0.41%) in a large unselected population-wide study across Australia including almost 11,000 adults [
      • Watts G.F.
      • Shaw J.E.
      • Pang J.
      • Magliano D.J.
      • Jennings G.L.
      • Carrington M.J.
      Prevalence and treatment of familial hypercholesterolaemia in Australian communities.
      ]. In another cohort, comprising >7300 individuals who volunteered for a risk assessment for CVD and clinical trials, the corresponding prevalence was 1:229 (0.44%, 95% CI 0.26%–0.62%) [
      • Watts G.F.
      • Shaw J.E.
      • Pang J.
      • Magliano D.J.
      • Jennings G.L.
      • Carrington M.J.
      Prevalence and treatment of familial hypercholesterolaemia in Australian communities.
      ].
      Africa. The prevalence of FH in Africa is largely unknown. FH frequency has been described to be amongst the highest in the world in some communities in South Africa; in fact, it has been reported to affect ∼1% of Afrikaners, Jews and Indians in South Africa (estimated prevalence between 1:70 to 1:100), likely due to the presence of founder effects, at least in the first two populations [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • Humphries S.E.
      Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
      ,
      • Rubinsztein D.C.
      • van der Westhuyzen D.R.
      • Coetzee G.A.
      Monogenic primary hypercholesterolaemia in South Africa.
      ]. An estimated frequency of 1:165 for HeFH in Central and Southern Tunisia has been reported based on data on HoFH in this region [
      • Slimane M.N.
      • Pousse H.
      • Maatoug F.
      • Hammami M.
      • Ben Farhat M.H.
      Phenotypic expression of familial hypercholesterolaemia in central and southern Tunisia.
      ].

      2.3 Homozygous FH

      HoFH is a rare disorder but life-threatening [
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ]. Individuals affected use to have very high LDL-C, usually >500 mg/dL, and develop overt atherosclerotic CVD (ASCVD) early in life, often in the adolescence and not surviving past 30 years if left untreated [
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ]. Estimates based on historical data suggested that HoFH affected ∼1 in one million people [
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ], except for higher frequencies in populations where a founder effect exists (e.g. French-Canadians, Afrikaners in South Africa, Christian Lebanese) [
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ,
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • Humphries S.E.
      Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
      ,
      • Moorjani S.
      • Roy M.
      • Gagné C.
      • Davignon J.
      • Brun D.
      • Toussaint M.
      • Lambert M.
      • Campeau L.
      • Blaichman S.
      • Lupien P.
      Homozygous familial hypercholesterolemia among French canadians in québec province.
      ].
      However, as with the case of HeFH, this overall prevalence has been questioned by more recent studies, which suggest its frequency to be much higher than previously anticipated, in the range of 1:160,000 from some estimations in Denmark to 1:300,000 people [
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ]. For instance, Sjouke et al. found a prevalence of molecularly-defined HoFH of ∼1:300,000 after screening >104,600 individuals in the Netherlands (∼1:400,000 for homozygous/compound heterozygous for LDLR mutation carriers; over 1:4,180,000 for homozygous apoB mutation carriers) [
      • Sjouke B.
      • Kusters D.M.
      • Kindt I.
      • Besseling J.
      • Defesche J.C.
      • Sijbrands E.J.
      • Roeters van Lennep J.E.
      • Stalenhoef A.F.
      • Wiegman A.
      • de Graaf J.
      • Fouchier S.W.
      • Kastelein J.J.
      • Hovingh G.K.
      Homozygous autosomal dominant hypercholesterolaemia in The Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.
      ]. Of interest, these and other authors have found the clinical phenotype of HoFH to be more variable than that described previously with only around half of these HoFH subjects meeting the classical HoFH diagnosis criteria with LDL-C >500 mg/dL, and not necessarily restricted to very young individuals [
      • Sjouke B.
      • Kusters D.M.
      • Kindt I.
      • Besseling J.
      • Defesche J.C.
      • Sijbrands E.J.
      • Roeters van Lennep J.E.
      • Stalenhoef A.F.
      • Wiegman A.
      • de Graaf J.
      • Fouchier S.W.
      • Kastelein J.J.
      • Hovingh G.K.
      Homozygous autosomal dominant hypercholesterolaemia in The Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.
      ,
      • Raal F.J.
      • Sjouke B.
      • Hovingh G.K.
      • Isaac B.F.
      Phenotype diversity among patients with homozygous familial hypercholesterolemia: a cohort study.
      ,
      • Sánchez-Hernández R.M.
      • Civeira F.
      • Stef M.
      • Perez-Calahorra S.
      • Almagro F.
      • Plana N.
      • Novoa F.J.
      • Sáenz-Aranzubía P.
      • Mosquera D.
      • Soler C.
      • Fuentes F.J.
      • Brito-Casillas Y.
      • Real J.T.
      • Blanco-Vaca F.
      • Ascaso J.F.
      Pocovi M.Homozygous familial hypercholesterolemia in Spain: prevalence and phenotype-genotype relationship.
      ]. In Spain 97 genetic HoFH patients were identified from a total of 16,751 genetic studies for FH diagnosis performed between 1996 and 2015; these data applied to the mean Spanish population for the same period yielded an estimated prevalence of genetically diagnosed HoFH of 1:450,000 [
      • Sánchez-Hernández R.M.
      • Civeira F.
      • Stef M.
      • Perez-Calahorra S.
      • Almagro F.
      • Plana N.
      • Novoa F.J.
      • Sáenz-Aranzubía P.
      • Mosquera D.
      • Soler C.
      • Fuentes F.J.
      • Brito-Casillas Y.
      • Real J.T.
      • Blanco-Vaca F.
      • Ascaso J.F.
      Pocovi M.Homozygous familial hypercholesterolemia in Spain: prevalence and phenotype-genotype relationship.
      ]. In Germany, however, a lower prevalence of ∼1:860,000 has been estimated [
      • Walzer S.
      • Travers K.
      • Rieder S.
      • Erazo-Fischer E.
      • Matusiewicz D.
      Homozygous familial hypercholesterolemia (HoFH) in Germany: an epidemiological survey.
      ]. In the Hokuriku district in Japan a prevalence of 1:171,167 was reported in 2011 [
      • Mabuchi H.
      • Nohara A.
      • Noguchi T.
      • Kobayashi J.
      • Kawashiri M.A.
      • Tada H.
      • Nakanishi C.
      • Mori M.
      • Yamagishi M.
      • Inazu A.
      • Koizumi J.
      Hokuriku FH Study Group. Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan.
      ]. In all these studies, the majority of HoFH cases were true homozygotes or compound heterozygotes for the LDLR.

      2.4 FH in children

      Overall, it has been suggested that 20%–25% of FH patients around the world would be children and adolescents [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • Chapman M.J.
      • Ginsberg H.N.
      • Cuchel M.
      • Ose L.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Defesche J.C.
      • Descamps O.S.
      • Hegele R.A.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Kuivenhoven J.A.
      • Masana L.
      • Nordestgaard B.G.
      • Pajukanta P.
      • Parhofer K.G.
      • Raal F.J.
      • Ray K.K.
      • Santos R.D.
      • Stalenhoef A.F.
      • Steinhagen-Thiessen E.
      • Stroes E.S.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      • Wiklund O.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ]. Assuming an overall prevalence of 1:250, based on reported rates of ∼258 worldwide births per minute, it would mean that ∼1 child with FH is born per minute worldwide [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • Chapman M.J.
      • Ginsberg H.N.
      • Cuchel M.
      • Ose L.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Defesche J.C.
      • Descamps O.S.
      • Hegele R.A.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Kuivenhoven J.A.
      • Masana L.
      • Nordestgaard B.G.
      • Pajukanta P.
      • Parhofer K.G.
      • Raal F.J.
      • Ray K.K.
      • Santos R.D.
      • Stalenhoef A.F.
      • Steinhagen-Thiessen E.
      • Stroes E.S.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      • Wiklund O.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ,
      ]. An LDL-C >190 mg/dL in children, or >160 mg/dL if having a relative with high LDL-C or premature CHD, suggests a high probability for the child to have a genetically-based FH [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • Chapman M.J.
      • Ginsberg H.N.
      • Cuchel M.
      • Ose L.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Defesche J.C.
      • Descamps O.S.
      • Hegele R.A.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Kuivenhoven J.A.
      • Masana L.
      • Nordestgaard B.G.
      • Pajukanta P.
      • Parhofer K.G.
      • Raal F.J.
      • Ray K.K.
      • Santos R.D.
      • Stalenhoef A.F.
      • Steinhagen-Thiessen E.
      • Stroes E.S.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      • Wiklund O.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ]. Since the potential influence of dietary and hormonal factors are limited during childhood compared to older ages, this period has been suggested to be optimal to identify FH individuals and discriminate them from non-FH subjects [
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • Chapman M.J.
      • Ginsberg H.N.
      • Cuchel M.
      • Ose L.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Defesche J.C.
      • Descamps O.S.
      • Hegele R.A.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Kuivenhoven J.A.
      • Masana L.
      • Nordestgaard B.G.
      • Pajukanta P.
      • Parhofer K.G.
      • Raal F.J.
      • Ray K.K.
      • Santos R.D.
      • Stalenhoef A.F.
      • Steinhagen-Thiessen E.
      • Stroes E.S.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      • Wiklund O.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ], specially within the interval of 1–9 years of age [
      • Klančar G.
      • Grošelj U.
      • Kovač J.
      • Bratanič N.
      • Bratina N.
      • Trebušak Podkrajšek K.
      • Battelino T.
      Universal screening for familial hypercholesterolemia in children.
      ]. However, the initiatives to identify subjects with FH at this early stage of life are scarce. In Slovenia, a national universal screening programme for hypercholesterolaemia in 5-year-old children has been implemented during the last few decades [
      • Klančar G.
      • Grošelj U.
      • Kovač J.
      • Bratanič N.
      • Bratina N.
      • Trebušak Podkrajšek K.
      • Battelino T.
      Universal screening for familial hypercholesterolemia in children.
      ]; simulated detection rates of FH from this programme has been estimated to be >96% in the last years considering an incidence of 1:500; however, if an FH incidence of 1:200 is assumed only ∼38% of the at-risk population would have been detected [
      • Klančar G.
      • Grošelj U.
      • Kovač J.
      • Bratanič N.
      • Bratina N.
      • Trebušak Podkrajšek K.
      • Battelino T.
      Universal screening for familial hypercholesterolemia in children.
      ].
      Information on the frequency of the diagnosis and detection rates of FH in children is broadly lacking. Secondary analyses from NHANES in US adolescents 12–19 years of age defining FH as an LDL-C >190 mg/dL (no information on personal and family history of early ASCVD and high cholesterol collected in NHANES participants of these ages) estimated a FH prevalence ranging from 0.42% (1:237; 95%CI 0.15%–0.70%) (similar to that estimated for US adult population) to 0.17% (1:583; 95%CI 0.06%–0.28%) with a more conservative approach [
      • de Ferranti S.D.
      • Rodday A.M.
      • Mendelson M.M.
      • Wong J.B.
      • Leslie L.K.
      • Sheldrick R.C.
      Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States national health and nutrition examination surveys (NHANES).
      ]. In 217 children and adolescents 8–18 years old (median 15 years) with a molecular confirmation of FH included in the SAFEHEART cohort in Spain, numbers of FH males and females were similar, a history of ASCVD was not present in any of them (but over 16% had history of premature familial ASCVD) and only 1 had xanthomas [
      • Saltijeral A.
      • Pérez de Isla L.
      • Alonso R.
      • Muñiz O.
      • Díaz-Díaz J.L.
      • Fuentes F.
      • Mata N.
      • de Andrés R.
      • Díaz-Soto G.
      • Pastor J.
      • Pinilla J.M.
      • Zambón D.
      • Pinto X.
      • Badimón L.
      • Mata P.
      SAFEHEART investigators. Attainment of LDL cholesterol treatment goals in children and adolescents with familial hypercholesterolemia. The SAFEHEART follow-up registry.
      ]. Nevertheless, these characteristics could vary significantly among different world regions, based, for example, on awareness of FH by physicians and rates of suspicion and early detection.

      3. FH and cardiovascular risk and prognosis

      Individuals with FH are exposed to elevated LDL-C levels since birth. The exposure to this lifelong burden of LDL-C and its accumulation results in the development of atherosclerotic lesions early in live [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ,
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ,
      • Wiegman A.
      • Gidding S.S.
      • Watts G.F.
      • Chapman M.J.
      • Ginsberg H.N.
      • Cuchel M.
      • Ose L.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Defesche J.C.
      • Descamps O.S.
      • Hegele R.A.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Kuivenhoven J.A.
      • Masana L.
      • Nordestgaard B.G.
      • Pajukanta P.
      • Parhofer K.G.
      • Raal F.J.
      • Ray K.K.
      • Santos R.D.
      • Stalenhoef A.F.
      • Steinhagen-Thiessen E.
      • Stroes E.S.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      • Wiklund O.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.
      ]. The burden of atherosclerosis and the likelihood of CVD is both “dose”-related and cumulative and can be considered the product of LDL-C levels and duration of exposure [
      • Ference B.A.
      • Ginsberg H.N.
      • Graham I.
      • Ray K.K.
      • Packard C.J.
      • Bruckert E.
      • Hegele R.A.
      • Krauss R.M.
      • Raal F.J.
      • Schunkert H.
      • Watts G.F.
      • Borén J.
      • Fazio S.
      • Horton J.D.
      • Masana L.
      • Nicholls S.J.
      • Nordestgaard B.G.
      • van de Sluis B.
      • Taskinen M.R.
      • Tokgözoglu L.
      • Landmesser U.
      • Laufs U.
      • Wiklund O.
      • Stock J.K.
      • Chapman M.J.
      • Catapano A.L.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
      ]. In support of this is the observation that those with the highest LDL-C levels require the shortest exposure before there is clinical manifestation of CVD; for instance, in cases of HoFH, most patients develop overt atherosclerosis before the age of 20 years, and generally do not survive past 30 years if remained untreated [
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • Raal F.J.
      • Santos R.D.
      • Hegele R.A.
      • Kuivenhoven J.A.
      • Nordestgaard B.G.
      • Descamps O.S.
      • Steinhagen-Thiessen E.
      • Tybjærg-Hansen A.
      • Watts G.F.
      • Averna M.
      • Boileau C.
      • Borén J.
      • Catapano A.L.
      • Defesche J.C.
      • Hovingh G.K.
      • Humphries S.E.
      • Kovanen P.T.
      • Masana L.
      • Pajukanta P.
      • Parhofer K.G.
      • Ray K.K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Wiegman A.
      • Wiklund O.
      • Chapman M.J.
      European atherosclerosis society consensus panel on familial hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the european atherosclerosis society.
      ]. Similarly, individuals with HeFH also have a significantly higher risk of CHD [
      • Sniderman A.D.
      • Tsimikas S.
      • Fazio S.
      The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies.
      ,
      • Hopkins P.N.
      • Toth P.P.
      • Ballantyne C.M.
      • Rader D.J.
      National lipid association expert panel on familial hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ,
      • Shi Z.
      • Yuan B.
      • Zhao D.
      • Taylor A.W.
      • Lin J.
      • Watts G.F.
      Familial hypercholesterolemia in China: prevalence and evidence of underdetection and undertreatment in a community population.
      ]. This risk is especially high in those <40 years old [
      • Simon Broome Register Group
      Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.
      ], with much higher rates of CHD mortality in both sexes compared to the general population [
      Simon broome register group. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific steering committee on behalf of the Simon broome register group.
      ]. Hence, HeFH entails a significantly greater risk of CHD, estimated to be at least 30% higher in women by the age of 60 years and as high as 50% in men by the age of 50 compared to those without HeFH [
      • Sniderman A.D.
      • Tsimikas S.
      • Fazio S.
      The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies.
      ,
      • Hopkins P.N.
      • Toth P.P.
      • Ballantyne C.M.
      • Rader D.J.
      National lipid association expert panel on familial hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ,
      • DeMott K.
      • Nherera L.
      • Shaw E.J.
      • Minhas R.
      • Humphries S.E.
      • Kathoria M.
      • Ritchie G.
      • Nunes V.
      • Davies D.
      • Lee P.
      • McDowell I.
      • Neil A.
      • Qureshi N.
      • Rowlands P.
      • Seed M.
      • Stracey H.
      • Thorogood M.
      • Watson M.
      Clinical Guidelines and Evidence Review for Familial Hypercholesterolaemia: the Identification and Management of Adults and Children with Familial Hypercholesterolaemia.
      ]. Thus FH accelerates the natural atherosclerosis process due to ageing in a time and dose-dependent fashion. In addition, importantly, it has been observed that for any LDL-C level considered, the risk of CHD is significantly higher among FH mutation carriers than non-carriers [
      • Khera A.V.
      • Won H.H.
      • Peloso G.M.
      • Lawson K.S.
      • Bartz T.M.
      • Deng X.
      • van Leeuwen E.M.
      • Natarajan P.
      • Emdin C.A.
      • Bick A.G.
      • Morrison A.C.
      • Brody J.A.
      • Gupta N.
      • Nomura A.
      • Kessler T.
      • Duga S.
      • Bis J.C.
      • van Duijn C.M.
      • Cupples L.A.
      • Psaty B.
      • Rader D.J.
      • Danesh J.
      • Schunkert H.
      • McPherson R.
      • Farrall M.
      • Watkins H.
      • Lander E.
      • Wilson J.G.
      • Correa A.
      • Boerwinkle E.
      • Merlini P.A.
      • Ardissino D.
      • Saleheen D.
      • Gabriel S.
      • Kathiresan S.
      Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
      ]. As such, Khera et al. found that in patients with an LDL-C >190 mg/dL (compared to subjects with an LDL-C <130 mg/dL), those carrying a FH mutation had a 22-fold higher risk of CHD, whereas this risk was limited to 6-fold higher among patients without a mutation [
      • Khera A.V.
      • Won H.H.
      • Peloso G.M.
      • Lawson K.S.
      • Bartz T.M.
      • Deng X.
      • van Leeuwen E.M.
      • Natarajan P.
      • Emdin C.A.
      • Bick A.G.
      • Morrison A.C.
      • Brody J.A.
      • Gupta N.
      • Nomura A.
      • Kessler T.
      • Duga S.
      • Bis J.C.
      • van Duijn C.M.
      • Cupples L.A.
      • Psaty B.
      • Rader D.J.
      • Danesh J.
      • Schunkert H.
      • McPherson R.
      • Farrall M.
      • Watkins H.
      • Lander E.
      • Wilson J.G.
      • Correa A.
      • Boerwinkle E.
      • Merlini P.A.
      • Ardissino D.
      • Saleheen D.
      • Gabriel S.
      • Kathiresan S.
      Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
      ].
      ASCVD risk in FH patients is mainly driven by CHD, whereas the risk posed by FH in stroke is more controversial. Analysis from Denmark in >100,000 individuals found no significant difference in the cumulative incidence of stroke (unless the participants already suffered from ischemic heart disease) between those with and without FH causative mutations (4% and 7%, respectively, developed ischemic stroke, p = 0.5) unlike the results for MI (20% and 8% had MI, respectively, p < 0.001) [
      • Beheshti S.
      • Madsen C.M.
      • Varbo A.
      • Benn M.
      Nordestgaard BG.Relationship of familial hypercholesterolemia and high LDL cholesterol to ischemic stroke: the copenhagen general population study.
      ]. Data from the SAFEHEART registry in molecularly-defined HeFH patients (compared with unaffected relatives as controls) have shown results in the same direction, with significant differences in the frequency of history of CHD in FH but no differences with controls in cerebrovascular events [
      • Pérez de Isla L.
      • Alonso R.
      • Mata N.
      • Saltijeral A.
      • Muñiz O.
      • Rubio-Marin P.
      • Diaz-Diaz J.L.
      • Fuentes F.
      • de Andrés R.
      • Zambón D.
      • Galiana J.
      • Piedecausa M.
      • Aguado R.
      • Mosquera D.
      • Vidal J.I.
      • Ruiz E.
      • Manjón L.
      • Mauri M.
      • Padró T.
      • Miramontes J.P.
      Mata P; SAFEHEART investigators. Coronary heart disease, peripheral arterial disease, and stroke in familial hypercholesterolaemia: insights from the SAFEHEART registry (Spanish familial hypercholesterolaemia cohort study).
      ]. In this study, peripheral artery disease was also more frequent in patients with FH compared with controls.
      As expected, based on the aforementioned comments, the prevalence of FH among patients with CHD is elevated and it suggests that the CHD population, in particular when the disease is premature, should be subjected to screening for FH. For instance, the EUROSPIRE IV study found that as much as 1 in 5 patients with MI under the age of 50 years in Europe had potential FH (defined as definite/probable FH –modified DLCN criteria), though the age-standardised prevalence of potential FH varied substantially among countries [
      • De Backer G.
      • Besseling J.
      • Chapman J.
      • Hovingh G.K.
      • Kastelein J.J.
      • Kotseva K.
      • Ray K.
      • Reiner Ž.
      • Wood D.
      • De Bacquer D.
      EUROASPIRE Investigators. Prevalence and management of familial hypercholesterolaemia in coronary patients: an analysis of EUROASPIRE IV, a study of the European Society of Cardiology.
      ]. In the same direction a study in Switzerland including >4700 patients hospitalized for acute coronary syndrome (ACS) found that 1.6% had probable/definite FH and 18% possible FH according to DLCN criteria, whereas the Simon-Broome criteria identified 5.4% of patients having possible FH [
      • Nanchen D.
      • Gencer B.
      • Auer R.
      • Räber L.
      • Stefanini G.G.
      • Klingenberg R.
      • Schmied C.M.
      • Cornuz J.
      • Muller O.
      • Vogt P.
      • Jüni P.
      • Matter C.M.
      • Windecker S.
      • Lüscher T.F.
      • Mach F.
      • Rodondi N.
      Prevalence and management of familial hypercholesterolaemia in patients with acute coronary syndromes.
      ]. Importantly, these figures significantly increased among young patients having premature ACS; in these cases the prevalence significantly raised to 4.8% and 47% for probable/definite and possible FH, respectively, with DLCN, and 14.0% for possible FH with Simon-Broom criteria. The prevalence of genetically-confirmed FH in patients with ACS aged ≤65 years in a study in Spain has been recently reported to be 8.7% (95% CI 4.3%–16.4%) [
      • Amor-Salamanca A.
      • Castillo S.
      • Gonzalez-Vioque E.
      • Dominguez F.
      • Quintana L.
      • Lluís-Ganella C.
      • Escudier J.M.
      • Ortega J.
      • Lara-Pezzi E.
      • Alonso-Pulpon L.
      • Garcia-Pavia P.
      Genetically confirmed familial hypercholesterolemia in patients with acute coronary syndrome.
      ]. Finally, a recent study among patients referred to cardiac rehabilitation and prevention centres in Italy due to stable CHD or after an ACS found that overall ∼4.2% of them had potential FH according to DLCN criteria, but again this prevalence substantially increased to 10% among men <55 years/women <60 years of age [
      • Faggiano P.
      • Pirillo A.
      • Griffo R.
      • Ambrosetti M.
      • Pedretti R.
      • Scorcu G.
      • Werren M.
      • Febo O.
      • Malfatto G.
      • Favretto G.
      • Sarullo F.
      • Antonini-Canterin F.
      • Zobbi G.
      • Temporelli P.
      • Catapano A.L.
      Centro Studi e Formazione - Italian Association for Cardiovascular Prevention and Rehabilitation.
      ]. Of interest, in this study a similar overall prevalence of potential FH was found among those patients who were referred due to lower extremity peripheral arterial disease.
      Individuals with FH have a future cardiovascular risk that is considered to exceed that of the general population, meaning that conventional risk prediction tools may underestimate this risk when applied to individuals with FH. In support of this notion, a recent analysis of a clinical trial in men aged 45–64 years in primary prevention found that among those with primary elevations of LDL-C >190 mg/dL (i.e. at least possible FH according to DLCN criteria) the observed cardiovascular risk was twice the one predicted at baseline by a risk score (Fig. 2) [
      • Vallejo-Vaz A.J.
      • Robertson M.
      • Catapano A.L.
      • Watts G.F.
      • Kastelein J.J.
      • Packard C.J.
      • Ford I.
      • Ray K.K.
      Low-density lipoprotein cholesterol lowering for the primary prevention of cardiovascular disease among men with primary elevations of low-density lipoprotein cholesterol levels of 190 mg/dL or above: analyses from the WOSCOPS (west of scotland coronary prevention study) 5-year randomized trial and 20-year observational follow-up.
      ]. Recently there have been attempts to establish criteria aiming to assess and stratify the risk of CVD specifically in FH patients. For instance, a consensus panel from the International Atherosclerosis Society proposed in 2016 a definition of severe FH based on a number of criteria including LDL-C levels, high-risk factors and presence of subclinical and clinical atherosclerotic disease [
      • Santos R.D.
      • Gidding S.S.
      • Hegele R.A.
      • Cuchel M.A.
      • Barter P.J.
      • Watts G.F.
      • Baum S.J.
      • Catapano A.L.
      • Chapman M.J.
      • Defesche J.C.
      • Folco E.
      • Freiberger T.
      • Genest J.
      • Hovingh G.K.
      • Harada-Shiba M.
      • Humphries S.E.
      • Jackson A.S.
      • Mata P.
      • Moriarty P.M.
      • Raal F.J.
      • Al-Rasadi K.
      • Ray K.K.
      • Reiner Z.
      • Sijbrands E.J.
      • Yamashita S.
      International atherosclerosis society severe familial hypercholesterolemia panel. Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the international atherosclerosis society severe familial hypercholesterolemia panel.
      ]. Other authors have proposed a score based on 5 clinical variables to predict prevalent CVD in patients with HeHF (Montreal-FH-Score) [
      • Paquette M.
      • Brisson D.
      • Dufour R.
      • Khoury É.
      • Gaudet D.
      • Baass A.
      Cardiovascular disease in familial hypercholesterolemia: validation and refinement of the Montreal-FH-SCORE.
      ]. Recently, a risk prediction equation of incident atherosclerotic CVD has been proposed from the SAFEHEART longitudinal study [
      • Pérez de Isla L.
      • Alonso R.
      • Mata N.
      • Fernández-Pérez C.
      • Muñiz O.
      • Díaz-Díaz J.L.
      • Saltijeral A.
      • Fuentes-Jiménez F.
      • de Andrés R.
      • Zambón D.
      • Piedecausa M.
      • Cepeda J.M.
      • Mauri M.
      • Galiana J.
      • Brea Á.
      • Sanchez Muñoz-Torrero J.F.
      • Padró T.
      • Argueso R.
      • Miramontes-González J.P.
      • Badimón L.
      • Santos R.D.
      • Watts G.F.
      • Mata P.
      Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish familial hypercholesterolemia cohort study).
      ]. Age, male sex, history of previous ASCVD, high blood pressure, increased body mass index, smoking, and LDL-C and lipoprotein(a) levels were found to be independent predictors of incident CVD and used to develop this equation. The equation performed well to discriminate FH patients who experienced an event during the follow-up (mean 5.5 years) in this molecularly-defined FH cohort. Thus, though this SAFEHEART risk equation requires external validation in other different cohorts, these results suggest it might represent a useful tool to estimate incident CVD risk in patients with FH in daily practice [
      • Pérez de Isla L.
      • Alonso R.
      • Mata N.
      • Fernández-Pérez C.
      • Muñiz O.
      • Díaz-Díaz J.L.
      • Saltijeral A.
      • Fuentes-Jiménez F.
      • de Andrés R.
      • Zambón D.
      • Piedecausa M.
      • Cepeda J.M.
      • Mauri M.
      • Galiana J.
      • Brea Á.
      • Sanchez Muñoz-Torrero J.F.
      • Padró T.
      • Argueso R.
      • Miramontes-González J.P.
      • Badimón L.
      • Santos R.D.
      • Watts G.F.
      • Mata P.
      Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish familial hypercholesterolemia cohort study).
      ].
      Fig. 2
      Fig. 2Observed versus predicted risk of cardiovascular events in primary prevention patients with primary elevations of LDL-cholesterol above 190 mg/dL in the WOSCOPS trial.
      Male patients without evidence of vascular disease at baseline, without diabetes, with primary elevation of LDL-C above 190 mg/dL and an estimated 10-year predicted risk of cardiovascular events of less than 7.5% according to the Pooled Cohort Risk Equation. In the WOSCOPS trial, however, the risk observed for these patients (placebo-controlled arm) was already 7.5% at 5 years [
      • Vallejo-Vaz A.J.
      • Robertson M.
      • Catapano A.L.
      • Watts G.F.
      • Kastelein J.J.
      • Packard C.J.
      • Ford I.
      • Ray K.K.
      Low-density lipoprotein cholesterol lowering for the primary prevention of cardiovascular disease among men with primary elevations of low-density lipoprotein cholesterol levels of 190 mg/dL or above: analyses from the WOSCOPS (west of scotland coronary prevention study) 5-year randomized trial and 20-year observational follow-up.
      ].
      A variable that has risen a particular interest in FH in last years is lipoprotein(a), since it has been observed that its levels are often higher in patients with FH and may predict CVD risk independent of LDL-C [
      • Langsted A.
      • Kamstrup P.R.
      • Benn M.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study.
      ,
      • Alonso R.
      • Andres E.
      • Mata N.
      • Fuentes-Jiménez F.
      • Badimón L.
      • López-Miranda J.
      • Padró T.
      • Muñiz O.
      • Díaz-Díaz J.L.
      • Mauri M.
      • Ordovás J.M.
      • Mata P.
      SAFEHEART Investigators. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation.
      ]; Some studies have shown that among FH patients cardiovascular risk is considerably lower among those with lipoprotein(a) < 50 mg/dL [
      • Langsted A.
      • Kamstrup P.R.
      • Benn M.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study.
      ,
      • Alonso R.
      • Andres E.
      • Mata N.
      • Fuentes-Jiménez F.
      • Badimón L.
      • López-Miranda J.
      • Padró T.
      • Muñiz O.
      • Díaz-Díaz J.L.
      • Mauri M.
      • Ordovás J.M.
      • Mata P.
      SAFEHEART Investigators. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation.
      ]. Conversely FH patients with elevated lipoprotein(a) may benefit from even greater reductions in LDL-C as few therapies materially reduce lipoprotein(a) [
      • Raal F.J.
      • Stein E.A.
      • Dufour R.
      • Turner T.
      • Civeira F.
      • Burgess L.
      • Langslet G.
      • Scott R.
      • Olsson A.G.
      • Sullivan D.
      • Hovingh G.K.
      • Cariou B.
      • Gouni-Berthold I.
      • Somaratne R.
      • Bridges I.
      • Scott R.
      • Wasserman S.M.
      • Gaudet D.
      RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
      ].

      4. FH and treatment

      Early detection and initiation of lipid-lowering treatment has resulted in significant improvements in outcomes in patients with FH [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ], and prognosis appears to be directly related to achieved LDL-C levels [
      • Thompson G.R.
      • Blom D.J.
      • Marais A.D.
      • Seed M.
      • Pilcher G.J.
      • Raal F.J.
      Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol.
      ]. In HeFH, a decline in rates of cardiovascular events has been observed since the introduction of statins. For instance, in the UK Simon-Broome Familial Hyperlipidaemia Register, a reduction in the risk of CHD and all-cause mortality among 20-79-year-olds with HeFH was observed when comparing the periods before 1992 and thereafter until 2006 [
      • Neil A.
      • Cooper J.
      • Betteridge J.
      • Capps N.
      • McDowell I.
      • Durrington P.
      • Seed M.
      • Humphries S.E.
      Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.
      ]. Furthermore, as shown in a cohort study by Versmissen et al., early initiation of therapy in HeFH patients is associated with a lower (almost 80%) risk of CHD compared to “untreated” (delay in starting statin therapy) patients, leading to almost similar rates of MI to that age-matched subjects from the general population [
      • Versmissen J.
      • Oosterveer D.M.
      • Yazdanpanah M.
      • Defesche J.C.
      • Basart D.C.
      • Liem A.H.
      • Heeringa J.
      • Witteman J.C.
      • Lansberg P.J.
      • Kastelein J.J.
      • Sijbrands E.J.
      Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.
      ]. However, even in those on statins, studies suggests that the risk of CVD still remains high as consequence of an insufficient therapy or a delay in starting therapy [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. In many cases FH patients will generally need intensive LLM, often including combined LLM treatment, to “normalize” LDL-C levels [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ].
      Available data suggest that, in general, FH is undertreated in those already diagnosed with FH (either not treated, insufficiently treated or treatment introduced too late) [
      • Versmissen J.
      • Oosterveer D.M.
      • Yazdanpanah M.
      • Defesche J.C.
      • Basart D.C.
      • Liem A.H.
      • Heeringa J.
      • Witteman J.C.
      • Lansberg P.J.
      • Kastelein J.J.
      • Sijbrands E.J.
      Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.
      ,
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • Ginsberg H.N.
      • Masana L.
      • Descamps O.S.
      • Wiklund O.
      • Hegele R.A.
      • Raal F.J.
      • Defesche J.C.
      • Wiegman A.
      • Santos R.D.
      • Watts G.F.
      • Parhofer K.G.
      • Hovingh G.K.
      • Kovanen P.T.
      • Boileau C.
      • Averna M.
      • Borén J.
      • Bruckert E.
      • Catapano A.L.
      • Kuivenhoven J.A.
      • Pajukanta P.
      • Ray K.
      • Stalenhoef A.F.
      • Stroes E.
      • Taskinen M.R.
      • Tybjærg-Hansen A.
      European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ,
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ,
      • Perez de Isla L.
      • Alonso R.
      • Watts G.F.
      • Mata N.
      • Saltijeral Cerezo A.
      • Muñiz O.
      • Fuentes F.
      • Diaz-Diaz J.L.
      • de Andrés R.
      • Zambón D.
      • Rubio-Marin P.
      • Barba-Romero M.A.
      • Saenz P.
      • Sanchez Muñoz-Torrero J.F.
      • Martinez-Faedo C.
      • Miramontes-Gonzalez J.P.
      • Badimón L.
      • Mata P.
      SAFEHEART investigators. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up.
      ,
      • deGoma E.M.
      • Ahmad Z.S.
      • O'Brien E.C.
      • Kindt I.
      • Shrader P.
      • Newman C.B.
      • Pokharel Y.
      • Baum S.J.
      • Hemphill L.C.
      • Hudgins L.C.
      • Ahmed C.D.
      • Gidding S.S.
      • Duffy D.
      • Neal W.
      • Wilemon K.
      • Roe M.T.
      • Rader D.J.
      • Ballantyne C.M.
      • Linton M.F.
      • Duell P.B.
      • Shapiro M.D.
      • Moriarty P.M.
      • Knowles J.W.
      Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the cascade-FH registry.
      ]. For instance, in the CGPS only 48% of subjects with FH were on statin [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication.
      ]. In a cross-sectional study in The Netherlands only 21% of FH patients achieved an LDL-C goal of <2.5 mmol/L, despite nearly all of them (96%) being on statins; among those not at target, 73% were not on combination therapy of maximum statin dose and ezetimibe [
      • Pijlman A.H.
      • Huijgen R.
      • Verhagen S.N.
      • Imholz B.P.
      • Liem A.H.
      • Kastelein J.J.
      • Abbink E.J.
      • Stalenhoef A.F.
      • Visseren F.L.
      Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands.
      ]. Recent cross-sectional analysis from the CASCADE-FH registry in US showed that only 42% of patients were on high-intensity statin therapy and less than half (45%) were taking more than one LLM; in terms of goal attainments, among patients receiving LLM only 25% achieved an LDL-C <100 mg/dL (or 41% achieved a reduction of at least 50% in LDL-C levels) [
      • deGoma E.M.
      • Ahmad Z.S.
      • O'Brien E.C.
      • Kindt I.
      • Shrader P.
      • Newman C.B.
      • Pokharel Y.
      • Baum S.J.
      • Hemphill L.C.
      • Hudgins L.C.
      • Ahmed C.D.
      • Gidding S.S.
      • Duffy D.
      • Neal W.
      • Wilemon K.
      • Roe M.T.
      • Rader D.J.
      • Ballantyne C.M.
      • Linton M.F.
      • Duell P.B.
      • Shapiro M.D.
      • Moriarty P.M.
      • Knowles J.W.
      Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the cascade-FH registry.
      ]. In the SAFEHEART study, despite a significant improvement in the use of LLM (increase use of statins and doses, combination therapy with ezetimibe) during the follow-up, still relevant low rates of FH patients achieved recommended LDL-C goals [
      • Perez de Isla L.
      • Alonso R.
      • Watts G.F.
      • Mata N.
      • Saltijeral Cerezo A.
      • Muñiz O.
      • Fuentes F.
      • Diaz-Diaz J.L.
      • de Andrés R.
      • Zambón D.
      • Rubio-Marin P.
      • Barba-Romero M.A.
      • Saenz P.
      • Sanchez Muñoz-Torrero J.F.
      • Martinez-Faedo C.
      • Miramontes-Gonzalez J.P.
      • Badimón L.
      • Mata P.
      SAFEHEART investigators. Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up.
      ]. The recent introduction of therapy with novel PCSK9 inhibitors may positively impact and change this situation, since these drugs, usually on top of statins, have shown in clinical trials to produce greater reductions of LDL-C levels and higher rates of LDL-C goal achievements in FH patients [
      • Kastelein J.J.
      • Ginsberg H.N.
      • Langslet G.
      • Hovingh G.K.
      • Ceska R.
      • Dufour R.
      • Blom D.
      • Civeira F.
      • Krempf M.
      • Lorenzato C.
      • Zhao J.
      • Pordy R Baccara-Dinet M.T.
      • Gipe D.A.
      • Geiger M.J.
      • Farnier M.
      ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.
      ,
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • Honarpour N.
      • Wiviott S.D.
      • Murphy S.A.
      • Kuder J.F.
      • Wang H.
      • Liu T.
      • Wasserman S.M.
      • Sever P.S.
      • Pedersen T.R.
      FOURIER steering committee and investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease.
      ].
      Factors which influence control of LDL-C levels are likely multifactorial and are summarized in Table 1. These include patient-related factors, physician-related factors and societal factors, to name a few.
      Table 1Potential factors influencing familial hypercholesterolaemia diagnosis, management and goals achievement.
      Patient-related factorsPhysician-related factors“System”-related factors
      FH education and awarenessFH education, awareness and knowledgeFH education and awareness, general and by policy-makers
      Identification of affected relatives. Presence of founder effectsAdherence to guidelines and recommendations. Variability in clinical practiceHealth policies and health systems
      Accessibility to health care and resourcesDegree of suspicionData available on FH in the specific region/country
      ComplianceDiagnostic criteria adapted to the specific populationNational/large registries
      Side effects of treatmentAvailability of genetic testingResources
      Costs of treatmentTherapy implementationSpecific detection programmes and initiatives (universal, cascade, opportunistic)
      Patients' organisationsAvailability of therapies (e.g. more potent statins, ezetimibe, PCSK9 inhibitors, apheresis)Reimbursement programmes for screening and therapy
      Media and general misinformationPerception of side effectsNetwork of FH specialists/lipid clinics, referral specialist centres
      Cultural factorsType of practice setting e.g. procedure vs. prevention, resources e.g. nurse specialistsMedia and general misinformation
      ….Cultural factorsCultural factors
      ….….
      FH: familial hypercholesterolaemia.

      5. Conclusions

      The prevalence of FH varies around the world and this is part an artefact of approaches to detection, methods used to diagnose FH and founder effects. Broadly, the prevalence estimated from contemporary studies seems to be about twice as common as previously perceived, and it results in premature morbidity and mortality. Globally ∼90–95% of patients affected by FH are thought to be undetected. Future work to identify cases earlier and institute effective treatment should result in significant benefits in public health globally.

      Conflicts of interest

      AJ Vallejo-Vaz reports honoraria for a lecture from Amgen and non-financial support from Regeneron, outside of the submitted work.
      KK Ray reports grants from Sanofi, Regeneron, Amgen, Pfizer, and MSD, and personal fees from Medicines Company, Sanofi, Amgen, Regeneron, Pfizer, Kowa, Algorithm, IONIS, Esperion, Novo Nordisk, Takeda, Boehringer Ingelheim, Resverlogix, Abbvie, Cerenis, Cipla, Mylan, Janssen, and Lilly, outside the submitted work.

      Authors contributions

      The present review article was conceived by KKR and AJVV. AJVV wrote the draft of the present paper. Both authors critically reviewed the manuscript and approved its submission.

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