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

Abstract

Aims: The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD).

Methods and results: Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD.

Conclusion: Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.

Keywords: Atherosclerosis; Cardiovascular disease; Cholesterol; Coronary heart disease; Low-density lipoprotein.

Figure 1

Estimated per cent of individuals diagnosed with familial hypercholesterolaemia in different countries/territories, as a fraction of those theoretically predicted based on a frequency of 1/500 in the general population. As most countries do not have valid nationwide registries for familial hypercholesterolaemia, several values in this figure represent informed estimates from clinicians/scientists with recognized expertise in and knowledge of familial hypercholesterolaemia in their respective countries. Numbers were provided by Michael Livingston, Steve E. Humphries (UK), Olivier S. Descamps (Belgium).

Figure 2

Prevalence of definite or probable familial hypercholesterolaemia according to Dutch Lipid Clinic Network Criteria in the Copenhagen General Population Study by 20-year age groups and by gender. Based on 69 016 individuals. This was originally reported as 1/137 but recalculation suggested that the prevalence of definite or probable familial hypercholesterolaemia combined is closer to 1/200 (personal communication Børge G Nordestgaard). FH, familial hypercholesterolaemia. Adapted from Benn et al.

Figure 3

Estimated millions of individuals worldwide with familial hypercholesterolaemia by WHO regions and by income groups. Estimates are shown for the theoretical frequency of heterozygous familial hypercholesterolaemia of 1/500 in the general population, as well as for the directly detected frequency of ∼1/200 in the Danish population, a typical country in Northern Europe.

Figure 4

Risk of coronary heart disease as a function of the Dutch Lipid Clinic Network Criteria for a diagnosis of familial hypercholesterolaemia in individuals on or off statin from the general population. Data are based on 69 016 individuals from the Copenhagen General Population Study. CI, confidence interval; FH, familial hypercholesterolaemia; CHD, coronary heart disease = ischaemic heart disease. Adapted from Benn et al.

Figure 5

Pathophysiology of heterozygous familial hypercholesterolaemia. LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9.

Figure 6

Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia. This figure illustrates the fractions of three different clinical scenarios in a study from Spain, and therefore not necessarily the exact proportions for these three groups in other countries. ‘Mutation without clinical diagnosis’ means definite, probable, or possible familial hypercholesterolaemia with a familial hypercholesterolaemia-causing mutation but with less severely elevated LDL cholesterol (i.e. below the diagnostic threshold). LDL, low-density lipoprotein cholesterol; FH, familial hypercholesterolaemia.

Figure 7

Pedigree of a family with familial hypercholesterolaemia. Red and green colours indicate family members with and without heterozygous familial hypercholesterolaemia. CHD, coronary heart disease; LDL, low-density lipoprotein; FH, familial hypercholesterolaemia.

Figure 8

LDL cholesterol burden in individuals with or without familial hypercholesterolaemia as a function of the age of initiation of statin therapy. Data derived from Huijgen et al. and Starr et al. LDL, low-density lipoprotein; LDL-C, LDL cholesterol; HDL-C, high-density lipoprotein cholesterol; CHD, coronary heart disease; FH, familial hypercholesterolaemia.

Figure 9

Kaplan–Meier curve estimates of cumulative CHD-free survival among individuals with familial hypercholesterolaemia according to statin treatment (P < 0.001 for difference). Based on 413 and 1537 Dutch subjects with heterozygous familial hypercholesterolaemia on or off statin treatment. CHD, coronary heart disease; FH, familial hypercholesterolaemia. Adapted from Versmissen et al.

Figure 10

Summary of diagnostic and treatment strategies.