Dr Mary Seed explains how familial hypercholesterolaemia is an under-recognised condition that can be managed effectively with pharmacotherapy and lifestyle modification

Familial hypercholesterolaemia (FH) is a severe form of hyperlipidaemia that leads to premature coronary heart disease (CHD). It is an inherited genetic disorder caused by mutations in genes that clear low-density lipoprotein cholesterol (LDL-C) from the blood: most frequently an abnormality in the LDL-C receptor gene. Thus, circulating LDL-C is raised from birth, leading to early atherosclerosis and a greater than 50% risk of CHD in affected men by the age of 50 years, and at least 30% in women by the age of 60 years if untreated. The condition has a dominant pattern of inheritance, so children and siblings of a person with FH have a 50% chance of inheriting the heterozygous form.1

The prevalence of FH in the UK population is 1 in 500, with 110,000 people estimated to have the condition.1 This would represent a handful of patients on a typical GP practice list. However, less than 17% of the predicted number of cases in the UK have been identified, and less than 10% are receiving appropriate treatment.2

Role of primary care

There is powerful evidence for the efficacy of lipid-lowering interventions in reducing total and CHD mortality in patients with FH,3,4 and NICE has published a guideline on FH with the intention of increasing diagnostic rates and improving management of identified cases.1,5 The contribution of primary care to this goal will be pivotal, since in many respects this condition is amenable to both diagnosis and management in primary care, although some aspects of care (see below) call for referral to specialist centres.

The diagnosis of new cases hinges on a thorough family history being taken and simple investigations being carried out. Lifestyle advice is critically important, but it is also essential to use statins as drug therapy to lower LDL-C. Key issues in primary care include:1,5

  • consideration of FH in all individuals with a family history of premature CHD
  • measurement of cholesterol and LDL-C
  • prescribing a potent statin to reduce LDL-C by at least 50%.


Diagnosis of heterozygous FH is made on the basis of (Simon Broome) criteria as shown in Box 1. If an individual fulfils these criteria, the GP should:1,5

  • take a second measurement of fasting lipids to allow for biological and analytical variability, and calculate LDL-C. Measure glucose, and renal, liver, and thyroid function to exclude causes of secondary hyperlipidaemia. It is especially important to establish normal thyroid function as hypothyroidism precludes use of statin therapy until treated
  • obtain a personal and family history of cardiovascular disease (CVD), and record at least a three-generation family tree to document the onset of CHD in relatives, their lipid levels, and presence of xanthomata. If relatives have died, record age, cause of death, and smoking history
  • assess cardiovascular (CV) risk factors—smoking, blood pressure, diabetes, and obesity. Risk estimation tools for CHD, such as Framingham, or QRISK, should not be used as patients with FH are already at high risk of premature CHD
  • assess for presence of CVD; consider a baseline electrocardiogram and refer to a cardiologist as necessary
  • examine for tendon xanthomata in the extensor tendons of the hands on the knuckles and the Achilles tendons—hard nodules that move with the tendon. The absence of tendon xanthomata does not exclude FH, but their presence confirms the diagnosis.

Box 1: Criteria for a diagnosis of FH1,5

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
  • 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

Child/young person
(aged <16 years)



(aged ?16 years or over)



FH=familial hypercholesterolaemia; LDL-C=low-density lipoprotein cholesterol
National Institute for Health and Care Excellence (NICE) (2008) CG71. Identification and management of familial hypercholesterolaemia. London: NICE. Reproduced with kind permission. Available from www.nice.org.uk/CG71


Referral is recommended for:1,5

  • adult and younger patients with homozygous FH—this condition is caused by inheritance of a defective gene from each parent and has an incidence of one in a million. Such individuals will present in early childhood with cutaneous lipid deposits and CHD. Treatment should be undertaken in a specialist centre with access to LDL-C apheresis together with cardiological assessment
  • children and young people who have been diagnosed with FH or who are being investigated for possible diagnosis. These patients should be referred to a specialist with expertise in FH in children and young people
  • patients in whom the maximum tolerated dose of high-intensity statin and/or ezetimibe has not achieved the recommended reduction in LDL-C of greater than 50% from baseline, or if the patient is intolerant or there are contraindications to these drug therapies
  • those in whom treatment with a bile acid sequestrant (resin), nicotinic acid, or a fibrate is being considered
  • patients who have a positive DNA test showing a specific gene abnormality; this increases the certainty of diagnosis of FH and can be coupled with family tracing and screening to identify other family members—a process termed ‘cascade testing’. This should be carried out by the local specialist clinic. If DNA testing is not available, family tracing may be carried out using levels of LDL-C for diagnosis3
  • evaluation of CHD if there is a family history of CHD in early adulthood, or in the presence of two or more further CV risk factors (for example, male smoker)
  • any patient with symptoms that could indicate possible CHD. Even with a low threshold of suspicion, urgent referral to a cardiologist is recommended.

Pharmacological therapy

Lipid-lowering drug therapy is of vital importance and will need to be lifelong so concordance and adherence are especially important. Statins are the initial treatment for all adults with FH; therapy should be increased to the maximum tolerated or licensed dose to achieve the target of a reduction in LDL-C of at least 50% from the untreated level.1,5 In practice this is likely to require a high-intensity statin, such as atorvastatin or rosuvastatin. Treatment should be started with atorvastatin 20 mg or rosuvastatin 10 mg, and the dose should be increased as required to meet the target.6

Ezetimibe (a second-line drug that inhibits cholesterol transport across the intestinal mucosal cell, thereby reducing cholesterol absorption) can be used as monotherapy in the case of intolerance or contraindication to statin therapy. Ezetimibe can also be used in addition to a statin:1,5

  • if total or LDL-C level has not been controlled after dose titration of initial statin therapy, or because dose titration is limited by intolerance to initial statin therapy


  • a change in initial statin therapy to an alternative statin is being considered.

It may be worth considering:6

  • drug treatment to lower blood pressure to a target of less than 140/85 mmHg
  • 75 mg aspirin daily for adults aged over 40 years if there are no contraindications.

Children and young people with FH

Children at risk of FH should be tested before the age of 10 years in a child-focused setting, and an appropriate specialist should undertake treatment with lipid-lowering therapy. In general, statins should be considered by the age of 10 years.7,8 When deciding to initiate statin therapy, the following should be considered: the age of onset of CHD in the family; the level of LDL-C; and the presence of other CV risk factors. The routine monitoring of growth and pubertal development is recommended.1,5

Lifestyle modification

Lifestyle advice should be offered in addition to lipid-lowering therapy. Smoking is an especially strong risk factor in people with FH, and support should be offered for cessation. Advice with regard to physical activity and weight control should be similar to that offered to the general population, with emphasis on exercise for prevention of CHD.

Ideally, nutritional advice from a healthcare professional with expertise should be given. Patients should be advised to follow a diet with total fat not more than 30% of energy intake, with a saturated fat intake no more than 10% of total energy intake. Patients should be encouraged to eat five portions of fruit and vegetables daily as well as two portions of fish per week. Healthcare professionals should not advise against the use of food products containing stanols or sterols, but patients with FH should be made aware that these products are not available on prescription, and should be taken consistently to be effective.1,5

Pregnancy and contraception

Information and counselling about lipid-lowering drug therapy is of particular importance for girls and women of child-bearing age, and contraception should be discussed with them on a regular basis. Women with FH should be offered a choice of all effective contraceptive methods. There is no reason to counsel against pregnancy in FH, but because there is a small risk of foetal abnormality associated with lipid-lowering drug therapy (including statins), girls and women are advised to stop treatment 3 months before conceiving.9–11

In the event of an unplanned pregnancy, lipid-lowering drug therapy should be discontinued, medical advice sought, and an urgent referral made to an obstetrician for foetal assessment. All women with FH, and crucially those with homozygous FH who are considering pregnancy or who are pregnant, should have a cardiac assessment. In women who wish to breastfeed, the only lipid-lowering drug therapy that can be used during lactation is the resin group as these are not absorbed.

Ongoing assessment and monitoring

All individuals with FH should have a structured review at least annually of lifestyle (particularly smoking), presence of other CV risk factors, enquiry with regard to symptoms of CHD, treatment side-effects, and discussion of the treatment plan.1,5 Measurement of LDL-C should be performed to assess whether the treatment target has been achieved. Fertility issues in girls and women should also be discussed. The results of DNA analysis and progress in cascade testing should be recorded, together with any changes in CHD status of relatives.1,5

Barriers to implementation

There are a number of challenges to the implementation of the NICE guideline on FH, including a shortage of:

  • paediatric services to assess children and young people with FH
  • specialist lipid clinics; these are necessary to further explain and confirm the diagnosis, to discuss genetic tests, to initiate family screening/cascade testing, and also to overcome any problems with therapy
  • nutritional advisers
  • genetic counsellors to promote and follow through cascade testing and use of DNA diagnosis.

There is also a lack of funding to create a national central register of all patients with FH to enable cascade testing to function across primary care trusts in England, Wales, Scotland, and Northern Ireland. On the positive side, primary care services are well placed to diagnose, treat, and follow up patients with FH.


Familial hypercholesterolaemia is a relatively common inherited condition associated with significant morbidity and mortality, which can be effectively treated. Monitoring and treatment must be lifelong. Although the majority of patients with FH in the UK have not been diagnosed, this is an achievable aim over the next 10 years.

Further sources of information


The author would like to thank the members of the Guideline Development Group, and in particular:

  • Professor Steve Humphries, Professor of Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College Medical School, London
  • Dr Rubin Minhas, General Practitioner, Primary Care CHD Lead, Medway Primary Care Trust and Honorary Senior Lecturer, Faculty of Science, Technology and Medical Studies, University of Kent
  • Professor Margaret Thorogood, Professor of Epidemiology, University of Warwick, Coventry.

Thanks also goes to Professor Gilbert Thompson, Emeritus Professor of Clinical Lipidology, for introducing the subject of FH to the author.

NICE implementation tools

NICE has developed the following tools to support implementation of its guideline on the Identification and management of familial hypercholesterolaemia. They are now available to download from the NICE website: www.nice.org.uk

Costing tools

National cost reports and local cost templates for the guideline have been produced:

  • costing reports are estimates of the national cost impact arising from implementation based on assumptions about current practice, and predictions of how it might change following implementation of the guideline
  • costing templates are spreadsheets that allow individual NHS organisations and local health economies to estimate the costs of implementation taking into account local variation from the national estimates, and they quickly assess the impact the guideline may have on local budgets.

Slide set

The slides are aimed at supporting organisations to raise awareness of the guideline and resulting implementation issues at a local level, and can be edited to cater for local audiences. This information does not supersede or replace the guidance itself.

Audit support

Audit support has been developed to support the implementation of the NICE guideline on familial hypercholesterolaemia. The aim is to help NHS organisations with a baseline assessment and to assist with the audit process, thereby helping to ensure that practice is in line with the NICE recommendations. The audit support is based on the key recommendations of the guidance and includes criteria and data collection tools.


  1. National Institute for Health and Care Excellence. Identification and management of familial hypercholesterolaemia. Clinical Guideline 71. London: NICE, 2008. Available at: www.nice.org.uk/Guidance/CG71
  2. Marks D, Thorogood M, Farrer J, Humphries S. Census of clinics providing specialist lipid services in the United Kingdom. J Public Health (Oxf) 2004; 26 (4): 353–354.
  3. Scientific Steering Committee on behalf of the Simon Broome Register Group. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Atherosclerosis 1999; 142 (1): 105–112.
  4. Neil A, Cooper J, Betteridge J et al. Reductions in all-cause, cancer and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J 2008; 29 (21): 2625–2633.
  5. DeMott K, Nherera L, Shaw E et al. Clinical guidelines and evidence review for familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners, 2008. Available at: www.nice.org.uk/Guidance/CG71
  6. NHS Clinical Knowledge Summaries website: Hypercholesterolaemia—familial—management. cks.library.nhs.uk/hypercholesterolaemia_familial (accessed 11 May 2009)
  7. Wiegman A, Hutten B, de Groot E et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA 2004; 292 (3): 331–337.
  8. Wiegman A, de Groot E, Hutten B et al. Arterial intima-media thickness in children heterozygous for familial hypercholesterolaemia. Lancet 2004; 363 (9406): 369–370.
  9. Manson J, Freyssinges C, Ducrocq M, Stephenson W. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol 1996; 10 (6): 439–446.
  10. Edison R, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004; 131 (3): 287–298.
  11. Ofori B, Rey E, Bérard A. Risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol 2007; 64 (4): 496–509.G