Familial hypercholesterolaemia

Cardiology GPSI Dr Jonathan Morrell on spotting, diagnosing and managing this congenital disease

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Familial hypercholesterolaemia (FH) is a genetic condition caused by mutations in genes of the pathway that clears LDL cholesterol from the bloodstream. It is present from birth and may lead to early development of atherosclerosis and coronary heart disease. It is as common as insulin-dependent diabetes and is the most common inherited disorder in people of European descent.

The prevalence of heterozygous FH in the UK population is estimated to be one in 500, which means that about 110,000 people are affected.1

The elevated serum cholesterol concentrations that characterise untreated heterozygous FH lead to CHD in about 50% of men by the age of 50 years with women following a decade later.2

The problem of underdiagnosis

Only a fifth of those affected are currently diagnosed and despite the relatively high prevalence, awareness of FH and its consequences remains low.

So it is worth considering FH in patients with raised cholesterol and asking about their family history.

In 2008, NICE published guidance to help all healthcare professionals – including GPs – diagnose and manage the FH patient and, importantly, their family.1

Patients with FH are at high risk of developing premature atherosclerosis and CHD, so early and accurate identification is essential to help protect long-term health.

Suspecting and diagnosing FH

People with FH may have few, if any, symptoms of the condition until they experience the consequences of CHD, often in their 30s or 40s. As they often look young and relatively healthy, serious symptoms are easily overlooked.

GPs should be mindful of the clinical features of FH that can sometimes be identified.

Look out for:

• Tendon xanthomata, typically occurring over the knuckles on the hands and in the Achilles tendons. They may appear from the age of 20 onwards, but 20% of FH patients have no xanthomata at death.

• Xanthelasma of the eyelids and corneal arcus also appear in FH, although less commonly than in other forms of hyperlipidaemia.

Also, consider FH if cholesterol is above 7.5mmol/l. Average cholesterol levels in adult heterozygote FH patients are about 9mmol/l with a range of 7-20mmol/l.

NICE recommends that the diagnosis of FH should be made using the Simon Broome criteria, which include family history, clinical examination and the lipid profile or DNA analysis.

Testing and screening

41248451All individuals with suspected FH should be referred to a specialist for confirmation of diagnosis and initiation of cascade testing – assessing all first- and second-degree relatives for the condition.

Children of parents with FH can be tested as young as two but should definitely have a blood cholesterol test before they reach 10 and this should be repeated after puberty. Family tracing can help identify a patient with FH once one individual has been diagnosed. The Department of Health has run a successful pilot project using DNA testing to identify affected individuals using cascade screening. This type of system is well established in other European countries, such as the Netherlands.

The new NICE guidance recommends the introduction of DNA testing and family cascade screening to the UK to diagnose patients with FH .

Bear in mind that a family history of FH is not always seen in patients with FH, where the affected relatives have been spared early cardiac events, particularly when female. So watch for raised cholesterol levels and the signs and symptoms of FH.

Management

Don't use cardiovascular risk calculators in patients with FH. NICE recommends that cardiovascular risk calculators, such as Framingham and QRISK, should not be used to assess risk and inform future management in people who fit the FH criteria – that is, those with extreme risk factor values such as a TC:HDL of more than 6mmol/l. People suspected for FH should be referred to a specialist for confirmation of diagnosis.1,2

Once identified, FH should be treated initially with statins with the aim of reducing LDL cholesterol by more than 50%. This usually requires higher-intensity statins and often combination therapy with other lipid-lowering drugs, particularly ezetimibe. A healthy diet and lifestyle, and the avoidance of smoking, are essential. People with FH who are well-managed can go on to lead normal lives despite their condition. Some people with FH who have very high cholesterol levels or who cannot tolerate other treatments will require LDL apheresis – a process like dialysis where cholesterol is removed from the bloodstream.

Currently, the availability of this treatment is extremely limited in the UK – NICE recommends it in exceptional cases in individuals with heterozygous FH with progressive, symptomatic CHD, despite maximal tolerated lipid modifying medication and optimal medical therapy.1 Guidelines on apheresis have been produced by the charity Heart UK.

Once diagnosed, patients with FH should be regularly monitored, at least annually. People with FH who do not receive support and treatment to control their cholesterol levels may be disabled or die from premature heart disease or stroke, often in their 40s or 50s and sometimes earlier.3

Dr Jonathan Morrell is a cardiology GPSI and hospital practitioner in cardiology in Hastings

Competing interests Dr Morrell has received honoraria for lecturing and advisory work from MSD, Schering-Plough, AstraZeneca, Bristol-Myers Squibb, Pfizer, Novartis and Unilever

This article is part of the Pulse Plus series on lipid management. Please click here to read the full series.

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