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.

Nordestgaard BG, Chapman MJ, Humphries SE,et al; European Atherosclerosis Society Consensus Panel
Eur Heart J. 2013 Dec;34(45):3478-90. doi: 10.1093/eurheartj/eht273. Epub 2013 Aug 15

Familial hypercholesterolaemia (FH) brings about a high risk of premature coronary heart disease (CHD), due to lifelong elevated plasma LDL-c levels. If left untreated, homozygotes may die before age 20. Heterozygotes typically develop CHD before age 55 in men and 60 in women. Once diagnosed, heterozygotes can be treated with cholesterol-lowering medication to attenuate development of atherosclerosis and to prevent CHD.
It is commonly believed that 1/500 whites are heterozygous for FH, and 1/1000000 are homozygous, although these numbers may represents underestimates.
This consensus paper aimed to assess FH underdiagnosis and undertreatment. The European Atherosclerosis Society (EAS) panel furthermore proposes recommendations on how to better diagnose FH and how to treat these high-risk individuals to prevent CHD.

Underdiagnosis
Only few countries have documented numbers of people diagnosed with FH, making reliable estimates of its prevalences a challenge. For the first time, prevalence has been assessed in an unselected sample of the general population. When the Dutch Lipid Clinic Network (DLCN) criteria were used in 69016 individuals of the Copenhagen General Population Study, the prevalence of definite or probable FH was ~1/200. Considering this estimated prevalence, most countries show clear underdiagnosis.

Undertreatment
Using the same Copenhagen General Population Study, the prevalence of CHD among definite/probable FH was 33%. Only 48% of these FH subjects received statin therapy. Risk of CHD was 13-fold (95%CI: 10-17) increased among those not receiving statins as compared to people without FH. FH subjects on statins had a ten-fold (95%CI: 8-14) increased risk, suggesting that statin therapy was insufficient; due to inadequate dosing and/or started too late in life to prevent severe atherosclerosis.

Pathophysiology and genetics
The consensus document outlines the known underlying pathophysiological mechanism of FH that cause high plasma LDL-c and how those ultimately result in occlusive atherosclerosis.  The mutations in LDL-receptor (LDLR), APOB or PCSK9 that can cause heterozygous FH are described. Homozygous FH is generally the result of compound heterozygous mutations in either LDLR or LDLR adaptor protein (LDLRAP or ARH), or in rare cases, double heterozygotes in two of the four genes described.

Clinical vs. mutation diagnosis
While heterozygous FH used to be diagnosed primarily based on the clinical picture, understanding of the genetic causes of FH allows direct detection of these mutations. However, not all with a clinical diagnosis of FH, get a mutation diagnosis, suggestive of the existence of other key genes that are yet to be discovered, or a polygenic basis for LDL-c elevation without involvement of the classical FH genes.
Conversely, patients may receive a genetic diagnosis, while they do not meet clinical diagnostic criteria for FH, indicating they might have other favourable factors that modulate the impact of the mutation.
The consensus  document recommends whom to screen, to recognise index cases, according to criteria on plasma cholesterol levels and family history.
The diagnostic criteria for the DLCN are recommended in order to establish the clinical diagnosis of FH, taking into account family history, clinical history of premature CHD, physical examination for xanthomas and corneal arcus and very high LDL-c on repeated measurements. When DLCN score indicates probable or definite FH (DLCN > 5), molecular genetic testing is indicated.

Lifetime risk assessment and risk factors
Common risk calculators such as the European SCORE or the US Framingham Risk Score are not appropriate for patients with FH. Since not all FH subjects develop atherosclerosis and CHD to the same extent, risk counting is critical to assessing CHD risk.
The concept of a cumulative LDL cholesterol burden illustrates the importance of early treatment, in order to delay the moment that subjects with different risk profiles reach the threshold for CHD. Other known contributing risk factors are briefly touched upon.
Risk assessment may be improved by imaging techniques. Given the variability in CHD risk among FH subjects, it is recommended that also in asymptomatic FH subjects atherosclerosis is assessed. To identify asymptomatic coronary atherosclerosis, exercise electro- and echocardiography may be considered, as well as coronary calcium score, and angiography by computed tomography, or non-invasive imaging of atherosclerosis.

Cascade, opportunistic and universal screening
Cascade screening of family members of known index cases is the most cost-effective approach for identification of new FH subjects, after index cases have been identified by opportunistic or targeted systematic screening. Different targeted approaches are considered.

Treatment
LDL-c targets are recommended and discussed, in line with recent ESC/EAS guidelines.
Treatment should also include intensive education targeting lifestyle management, considering smoking, diet and physical activity.
Cholesterol-lowering medication should be initiated immediately after diagnosis in adults, and should be considered at age 8-10 in children, in combination with lifestyle management. A priority list for pharmacotherapy is given for both children and adults. The different strategies are discussed, along with the effect that may be expected.

A specific section is dedicated to children with FH, and how they should be managed, with regard to screening, diagnosis, establishment of the vertical transmission pattern in a family pedigree to reveal its genetic nature. Statins are only known to be safe from 8 to 10 onward. A registry of statin-treated children is needed to collect meaningful longer follow-up data than the short-term studies of low dosage in children performed thus far.

To conclude, the consensus document considers the cost-effectiveness of better diagnosis and treatment of FH. In addition, new classes of drugs currently under development, which should help in attaining LDL-c targets, are touched upon.
A ‘shared care’ approach between primary care and specialised lipid or FH clinics may contribute to better identification and management of FH patients.

Find this article on Pubmed