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Patients with familial hypercholesterolaemia (FH) have a significantly raised coronary heart disease (CHD) risk: greater than 50% in men by the age of 50 years, and at least 30% in women by the age of 60 years.¹ Although healthcare teams in primary care are skilled in assessing and managing CHD risk, FH is under recognised. This is significant because management of individuals with FH is different to that of non-inherited or secondary hypercholesterolaemia.

Familial hypercholesterolaemia is a genetic condition that results in high serum cholesterol levels, comprising mainly low-density lipoprotein cholesterol (LDL-C). The condition is inherited in an autosomal dominant pattern, and the principal defect leads to an altered LDL receptor. This means that siblings and children (i.e. first-degree relatives) of an individual with FH will have a 50% chance of inheriting a mutation and developing FH.¹ The prevalence of FH is approximately 1 in 500, meaning that every GP will have a number of affected patients on their practice list. It is estimated that throughout the UK 110,000 people have FH, but only a small proportion of these individuals have been diagnosed.¹

The NICE guideline on Identification and management of familial hypercholesterolaemia was published in August 2008.^1,2 It aims to improve diagnosis and identification strategies while highlighting the priorities for management and stimulating development of services. Some of the guideline recommendations have been based on consensus extrapolated from small amounts of lower quality evidence; the guideline development group (GDG) has provided research recommendations and these are highlighted throughout this article.

The key priorities for the implementation of the guideline are:

• diagnosis
• cascade testing
• management
• information needs and support for women and girls with FH
• ongoing assessment and monitoring.

Diagnosis

Diagnosis is the first key priority for implementation, and the diagnostic criteria for ‘definite’ or ‘possible’ FH (the Simon Broome criteria) are clearly described in the guideline (see Box 1). For the purposes of cardiovascular (CV) risk assessment, many patients will have been asked routinely in primary care about a family history of CHD. The challenge is to ensure that all patients with a relevant family history (as listed in Box 1) are offered testing for serum total cholesterol and LDL-C, and conversely that all patients with a raised serum cholesterol or LDL-C meeting the diagnostic criteria are asked about family history.

The NICE guideline recommends that all adults who meet the Simon Broome criteria should be referred for confirmation of the diagnosis and initiation of cascade screening. Patients who meet certain criteria as specified by the guideline should be referred for evaluation of CHD.¹

Children should be referred for diagnostic tests by the age of:¹

• 10 years if they have one affected parent
• 5 years if they have two affected parents, or the presence of clinical signs.

Box 1: Simon Broome diagnostic criteria for index individuals1,3
Diagnose a person with definite FH if they have: Cholesterol concentrations as defined in the table below and tendon xanthomas, or evidence of these signs in first- or second- degree relative or DNA-based evidence of an LDL-receptor mutation, familial defective apo B-100, or a PCSK9 mutation Diagnose a person with possible FH if they have cholesterol concentrations as defined in the table below and at least one of the following: Family history of myocardial infarction: aged younger than 50 years in second-degree relative or aged younger than 60 years in first-degree relative Family history of raised total cholesterol: greater than 7.5 mmol/l in adult first- or second-degree relative; or greater than 6.7 mmol/l in child, brother, or sister aged younger than 16 years Cholesterol levels to be used as diagnostic criteria for the index individual (either pre-treatment, or highest on treatment)
	Total cholesterol (mmol/l)	LDL-C (mmol/l)
Child/young person (aged <16 years)	>6.7	>4.0
Adult (aged ≥16 years or over)	>7.5	>4.9
FH=familial hypercholesterolaemia; LDL-C=low-density lipoprotein cholesterol National Institute for Health and Clinical Excellence (NICE) (2008) CG71. Identification and management of familial hypercholesterolaemia. London: NICE. Reproduced with kind permission. Available from www.nice.org.uk/CG71

Using cascade testing to identify patients with FH

Cascade testing involves using a combination of DNA testing and LDL-C concentration measurements in first-, second-, and, if possible, third-degree relatives of a patient with FH. The current model involves sending letters to relatives recommending testing; if these relatives live in a different region they are advised to attend their own GP. This process may change as specialist clinics are set up and a nationwide register developed, as recommended in the guideline.¹

Healthcare professionals should offer all patients with FH a referral to a specialist with expertise in FH (although the guideline does not specify a particular clinical speciality) for confirmation of diagnosis and initiation of cascade testing. In most areas of the UK, services for cascade testing are still being developed, and may ultimately be hosted by cardiologists, geneticists, or lipidologists. Primary care practitioners will need to be aware of their local services in order to refer appropriately.¹

Cascade testing has been shown to be more cost-effective than population screening, but will still only identify 50% of cases. In primary care, case finding could be performed through searching of electronic records for patients with:

• early myocardial infarction
• pre-treatment or highest total cholesterol meeting diagnostic criteria
• family history of CHD or raised cholesterol.

GDG research recommendation

The GDG recommends that research is performed to determine the clinical and cost-effectiveness of methods of identifying patients with FH (other than cascade testing). This would entail development of algorithms that identify patients in primary and secondary care.

Management

Adults

Standard CV risk assessment tools should not be used for patients with FH because these individuals are already at high risk of CHD, and such tools will usually underestimate this risk.¹ This is an important difference in the management of FH compared with that of non-inherited (or secondary) hypercholesterolaemia, underlining the importance of diagnosing individuals with the condition.

The guideline contains recommendations on appropriate lipid-modifying therapy in adults (aged 16 years and over) to reduce CV risk, including the use of high-intensity statins, which produce a greater reduction in LDL-C than simvastatin 40 mg (e.g. simvastatin 80 mg or equivalent doses of atorvastatin or rosuvastatin).² The guideline stresses that lipid-modifying therapy should always be used as initial treatment; lifestyle advice is a component of medical management but is not an alternative to drug therapy.¹

Children

The consensus view of the GDG was that lipid-modifying therapy should be started in all children with a diagnosis of FH by the age of 10 years, as this is the earliest age at which atherosclerosis becomes evident.² However there is limited data to suggest what the target LDL-C should be in children, and data regarding safety do not extend past a treatment period of 2 years.¹ All children who are being investigated for, or who have a diagnosis of FH should be referred to a ‘specialist with expertise in FH in children and young people’.¹

GDG research recommendation

The GDG acknowledges that there are only small amounts of lower quality evidence regarding the clinical effectiveness and safety of lipid-modifying therapy in children, and recommends this as an area that requires further research.¹

Information needs and support for women and girls with FH

The guideline emphasises that information and support should be provided to all individuals with FH, but one key priority for implementation is the importance of ensuring that the needs of girls and women are addressed. Specific recommendations are made for this group, which cover choice of contraception, the risks of lipid-modifying therapy, and the problems that FH itself can cause in pregnancy and breastfeeding.

GDG research recommendation
The GDG recognises that there is a lack of data regarding the outcomes of pregnancy in women with FH; in particular, the exact level of risk of statins in the first trimester, and the risk of pregnancy itself (including cardiac death). Further research in these areas is recommended by the group.

Ongoing assessment and monitoring

The guideline includes a number of recommendations for annual review. Practitioners may wish to consider reiterating lifestyle advice and reviewing some factors that are assessed in patients without FH, such as:

• blood pressure
• body mass index
• fasting blood glucose
• liver function tests (if the patient is on statin therapy).

Discussion of psychosocial issues may also be important as, even if patients with FH are on treatment that aims to reduce risk, they are living with the knowledge that they have a greatly increased risk of potentially life-threatening CHD.

Challenges for primary care

The main challenges for primary care will be diagnosing patients with FH and appropriate referral. In terms of resource implications, primary care practitioners will need to assess their practice systems to improve identification of these individuals. Primary care trusts (PCTs) will also need to review the implications for prescribing budgets as patients with FH will be on high-intensity statins for many years. The publication of the guideline will hopefully prompt review and further development of services for individuals with FH. Practitioners will need to become aware of their local referral criteria and pathways. Management of individuals with FH will require an integrated care approach. Hopefully this will be reflected in further service development, and will be taken into consideration by PCTs and practice-based commissioning groups.

Summary

The NICE guideline on FH considers all key aspects in the diagnosis and management of individuals with this condition. It should, therefore, be instrumental in raising awareness and stimulating further service development, and used as a tool to this effect. However, it should be noted that several key recommendations were based largely on consensus within the GDG. The research recommendations made by the group should stimulate further necessary studies, which will inform future reviews of the guideline.

References

1. National Institute for Health and Clinical Excellence. Identification and management of familial hypercholesterolaemia. Clinical Guideline 71. London: NICE, 2008. Available at: www.nice.org.uk/Guidance/CG71
2. National Collaborating Centre for Primary Care, Royal College of General Practitioners. Identification and management of familial hypercholesterolaemia. London: RCGP, 2008. Available at: www.nice.org.uk/Guidance/CG71/Guidance/pdf/English
3. Marks D, Thorogood M, Neil H, Humphries S. A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 2003; 168 (1): 1-14.G

Judith Hayward
GP with a Special Interest in Genetics
YorkshireRegional Genetics Service