Familial hypercholesterolaemia (FH) is a common inherited disorder of lipid meta- bolism, which affects approximately one in 500 of the population.
This means that in the UK there are approximately 120,000 affected individuals, and many of these remain undiagnosed.
FH is characterised by a substantial elevation in serum total and LDL cholesterol with premature development of atherosclerotic vascular disease.
If FH remains undiagnosed and untreated, the risk of CHD in men is greater than 50 per cent by the age of 50, and in women the cumulative CHD risk is greater than 30 per cent by age 60.
Many individuals with FH are identified only after they present with clinical CVD.
It is important to maintain awareness of this condition and to carry out family screening when it is suspected.
In particular, identification of affected children is important as it offers the opportunity to intervene at an early stage to lower cholesterol and hence prevent the development of vascular disease.
FH is caused in over 90 per cent of cases by a mutation in the gene for the LDL receptor.
A very large number of different mutations have been described in the UK population, so that genetic testing is relatively difficult. In around 5 per cent of cases, there is a mutation in the gene for apoB, the protein which binds to the LDL receptor.
Individuals with two abnormal genes are uncommon (around one in 1 million), and present with vascular disease before the age of 20. The vast majority of affected patients, therefore, have one abnormal gene. Within families, FH behaves as an autosomal dominant condition, with a one-in-two chance that a sibling or child of a patient with FH will be affected.
As a consequence of the genetic abnormality, affected individuals have significantly elevated total and LDL cholesterol from birth. However, cholesterol levels in FH patients show a degree of overlap with the non-affected population, meaning that reliance on cholesterol measurements alone to make a diagnosis of FH will result in a false positive and false negative rate of between 8 per cent and 18 per cent.
Because cholesterol levels are significantly lower in childhood than in adult life, there are particular difficulties in using cholesterol measurements to diagnose FH in children. In order to address these difficulties, a diagnostic definition for FH which incorporates family history and clinical signs, as well as laboratory results, has become widely used in the UK (see box for the Simon Broome register definition of FH ).
The Simon Broome definition of FH uses a lower serum cholesterol cut-off for the diagnosis of FH in children, which improves diagnostic accuracy.
However, because cholesterol levels vary throughout childhood, diagnostic difficulties remain with this approach.
A clear diagnosis can be made by genetic testing of children in families where the genetic defect has been identified.
This overcomes the uncertainty associated with cholesterol measurement.
As methods for genetic diagnosis improve, it is increasingly likely that this will be a key part of the diagnostic process in future, but at present genetic testing for FH in the UK is limited and is available primarily through lipid clinics.
More widespread measurement of cholesterol in primary care as a consequence of the GMS contract will inevitably lead to the identification of patients and families in whom a diagnosis of FH is considered possible.
If a patient fulfils the clinical criteria for definite or possible FH, they should be referred to a lipid clinic.
The lipid clinic should attempt to make a definite diagnosis, using genetic testing if appropriate, and will provide advice and counselling with regard to the nature of the condition and will offer cascade screening of family members.
Children should be tested between the ages of two and 10.
Treatment of FH from an early age is indicated to reduce cholesterol and prevent vascular disease.
It is not appropriate to estimate CHD risk for affected individuals using tables or risk calculators, and all should be offered treatment with lipid-lowering drugs in addition to dietary and lifestyle advice.
Action to address other cardiovascular risk factors, such as smoking, is particularly important in patients with FH.
For adults, statins will form the mainstay of treatment to lower cholesterol, and often a high dose of a potent statin will be needed.
Combination lipid-lowering therapy - for instance, statin plus ezetimibe - will be required in many cases.
Treatment decisions in children are more complex, but there is increasing evidence that cholesterol reduction in affected children improves vascular function.
Initially, affected children should adhere to a low-fat diet from the age of two. Education about the importance of maintaining a healthy lifestyle should be provided throughout childhood and into adult life.
In the past, children would have been offered cholesterol-lowering treatment with a resin such as cholestyramine, but this treatment was modestly effective at best and was often poorly tolerated.
It is now clear that statins are effective in children in lowering cholesterol, although evidence with regard to long-term safety is limited.
Of the available statins, only atorvastatin (children 10-17 years) and pravastatin (children over eight years) are licensed for use in children in the UK.
As in adults, atorvastatin is more effective at reducing cholesterol than pravastatin in children.
Treatment with both atorvastatin and pravastatin is well tolerated in children, and statin treatment is likely to be increasingly used in this setting in the future.
- Professor Ian S Young is professor of medicine, Queen's University, Belfast.
SCREENING AND AWARENESS OF FH
- FH is an important inherited condition, which is a cause of premature CHD.
- Screening of relatives in families in whom the condition is suspected is important.
- Children should be tested between the ages of two and 10 years.
- Early treatment to reduce cholesterol is important to prevent premature vascular disease.
THE SIMON BROOME REGISTER DEFINITION
A definite diagnosis of FH requires:
(a) Total cholesterol level above 7.5 mmol/l in adults or a total cholesterol level above 6.7 mmol/l for children under 16 or LDL levels above 4.9 mmol/l in adults (4.0 mmol/l in children) (either pre-treatment or highest on treatment) plus
(b) Tendon xanthomas in patient or relative (parent, child, sibling, grandparent, aunt,uncle) or
(c) DNA-based evidence of an LDL receptor mutation or familial defective apo B-100.
Possible FH is defined as:
(a) above, plus one of (d) or (e) below:
(d) Family history of MI before the age of 50 in grandparent, aunt or uncle or before the age of 60 in parent, sibling or child.
(e) Family history of raised cholesterol in parent, sibling or child, or level above 7.5 mmol/l in grandparent, aunt or uncle.
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- Civeira F; International Panel on Management of Familial Hypercholesterolemia. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis 2004; 173: 55-68.
- Marks D, Thorogood M, Neil HA , Humphries S E. A review on the diagnosis, natural history and treatment of familial hypercholesterolaemia. Atherosclerosis 2003; 168: 1-14.
- JBS2: Joint British Societies Guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 1(Suppl V): v1-v52.