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October 08: Guideline will aid early detection of familial hypercholesterolaemia

How should FH be diagnosed?

When should patients be referred?

How should patients be followed up?

How should FH be diagnosed?

When should patients be referred?

How should patients be followed up?

Familial hypercholesterolaemia (FH) is a genetic disease that disrupts the clearance of LDL cholesterol from the blood. It has an autosomal dominant pattern of inheritance and the most common mutation involves the LDL receptor.

It is estimated that heterozygous FH affects 1 in 500 people in the UK but the vast majority remain undiagnosed, with only 15,000 patients currently identified. It can result in significantly raised LDL cholesterol levels and if left untreated, patients have a high risk of premature CHD, with a >50% risk in men by the age of 50 and >30% in women by the age of 60. If treated early, most patients will have a normal life expectancy.

Homozygous FH is a rare condition with an estimated prevalence of one in a million in the UK. In homozygous FH plasma LDL cholesterol can exceed 10mmol/l. Symptoms become apparent in childhood and patients are at risk of early coronary mortality.

NICE has recently produced a guideline for the diagnosis and management of this potentially devastating disease.1


The NICE guidance does not propose a specific approach to identify patients with FH. However, patients with a personal and/or family history of premature CHD should have a baseline lipid profile. The proposed vascular screening programme for patients over 40 will no doubt identify a further cohort of patients with possible heterozygous FH.

The guideline suggests that FH should be suspected in adults with a total cholesterol >7.5mmol/l, especially if there is a strong personal or family history of premature CHD. GPs should confirm that the LDL cholesterol is >4.9mmol/l on two blood samples. Other causes of hypercholesterolaemia, such as thyroid, renal and hepatic disease, should be excluded before a diagnosis of FH is made.

The diagnosis should be formalised using the Simon Broome criteria, see box 1, attached.

A clinical diagnosis of homozygous FH should be considered in adults with an LDL cholesterol >13mmol/l and in children with an LDL cholesterol >11mmol/l.


All patients with FH should be offered lifestyle advice to reduce their cardiovascular risk. GPs should recommend that patients exercise aerobically for at least 30 minutes a day five times a week, limit alcohol intake (maximum of 3-4 units per day for men and 2-3 units per day for women), and eat a healthy diet low in saturated fat (no more than 10% of total calorie intake) with five portions of fruit and vegetables a day and two portions of oily fish a week.

Patients should also commence high-dose statin therapy, such as simvastatin 80mg, or equivalent doses of atorvastatin or rosuvastatin for example. The aim of treatment should be to reduce LDL cholesterol levels by more than 50% and the dose should be titrated accordingly.

Ezetimibe should be considered either in combination with a statin or as monotherapy in patients who are intolerant to statins.

If these therapies are not effective, alternatives include bile acid sequestrants, fibrates and nicotinic acid. The decision to use these alternative lipid-lowering drugs will often be made by a specialist, particularly if they are used in combination with a statin.

GPs should also consider the use of other preventative therapies such as aspirin and ACE inhibitors in patients felt to be at particularly high risk of CHD, and treat concomitant hypertension and diabetes aggressively.


The NICE guideline recommends that all patients should be offered referral to a specialist to confirm the diagnosis of FH and that patients with known FH should be referred for consideration of further treatment if they have:

• Established CHD
• A family history of premature CHD
• Two or more additional cardiovascular risk factors such as smoking, diabetes or hypertension.

Patients with FH are at a high risk of CHD and traditional risk assessment charts should not be used to estimate cardiovascular risk. All homozygous FH patients should be referred to a cardiologist for consideration of functional testing and/or cardiac catheterisation because of the extremely high probability of significant CHD in these patients.

Patients with heterozygous FH should be offered referral to a cardiologist for evaluation of CHD if there is any suspicion of cardiac ischaemia and as a general rule GPs should have a very low threshold for such referral.

Referral to a specialist is also necessary for cascade testing with appropriate DNA analysis, advice on combination lipid-lowering therapy if required, to initiate appropriate follow up of individuals and family members and consideration of more radical therapies such as LDL apheresis and liver transplantation.

The guideline states that GPs should refer patients to a specialist with a particular interest in FH. In practice this is likely to be the local lipid clinic or, if this is not available, a cardiologist or general physician with a particular interest in lipids.

Cascade testing

Cascade testing involves searching for family members of an index case at risk of an inherited disorder by family tracing. The process is repeated when another affected relative is found.

In around 80% of index cases a genetic mutation will be identified and cascade testing can be based on a DNA test.

Although most mutations involve the LDL receptor, there are other possible mutations that cannot be detected at present. If a mutation is not identified the NICE guideline recommends using age- and sex-specific LDL cholesterol criteria to diagnose FH, as the Simon Broome criteria may lead to underdiagnosis.

The problem with this approach is that there are three possible outcomes based on the recommended criteria: likely, uncertain and unlikely to have FH. The guideline acknowledges that up to 50% of adults and 15% of children screened for FH could fall into the uncertain category.2 This is clearly an unsatisfactory situation and it would be better to have a clear cut-off point where FH is likely or unlikely.

The NICE guideline recommends that patients in the uncertain category should be reviewed annually. If the patient's LDL cholesterol remains in this category they should be assessed and managed as in the general population.

In practical terms, the clinical assessment of individual cases, taking into consideration other cardiovascular risk factors and family history, should guide treatment in patients in whom there is diagnostic uncertainty.


Children with an affected parent who has an identified genetic mutation should be offered a DNA test by the age of ten. If no mutation has been identified in the parent, then the child's LDL cholesterol should be measured by the age of ten and the test repeated after puberty.

Children with two affected parents or clinical features of FH (cutaneous lipid deposits) should have their LDL cholesterol level measured at five years of age.

GPs should consider treatment with an appropriately licensed statin for children with FH, usually by the age of ten.


Women with FH who are planning to become or are pregnant require shared care with an obstetrician and cardiologist, especially if they have homozygous FH.

Women who are planning to conceive should stop taking any statin or lipid-lowering therapy three months before they plan to become pregnant; women with unplanned pregnancies should stop lipid-lowering therapy immediately and be referred to an obstetrician.

Resins are safe in women who are breastfeeding.


Patients with FH should be followed up annually. This should focus on:

• Response to treatment
• Side-effects of therapy
• Lifestyle advice
• Identification and treatment of concomitant cardiovascular risk factors, such as hypertension
• Review of the progress of cascade testing
• Assessment for symptoms suggestive of cardiac ischaemia.

In children, both growth and pubertal development should be monitored on a regular basis.


Dr Peter Savill
GPwSI cardiology, Southampton

Box 1: Simon Broome criteria for FH in adults Key points Guideline will aid early detection of familial hypercholesterolaemia

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