Dr David Milne discusses how implementation of the NICE guideline on familial hypercholesterolaemia requires significant improvements in access to local services

NICE Clinical Guideline 71 on Identification and management of familial hypercholesterolaemia has been awarded the NHS Evidence Accreditation Mark.
This Mark identifies the most robustly produced guidance available. See evidence.nhs.uk/accreditation for further details.

NICE Clinical Guideline 71 on Identification and management of familial hypercholesterolaemia (FH; see www.nice.org.uk/guidance/CG71) was published in August 2008.1 It provided a clear pathway for the evaluation of patients with suspected FH. Following the publication of the guideline, there was an optimistic outlook and the Guideline Development Group believed that, '... it is an achievable aim that the majority of FH patients in the UK will be identified and treated over the next 10 years.'2

Unfortunately nearly 4 years on, the guideline recommendations from NICE have not been implemented in any coherent way in England, although implementation is proceeding in Scotland, Wales, and Northern Ireland. Many primary care trusts admitted to a lack of formal planning for identification and management of FH when asked (through freedom of information requests) in 2011.3

Is this because the guideline was wrong? NICE clearly does not feel that this is the case—its regular 3-year-review decision on the FH guideline was published in August 2011, in which it recommended that the guideline should not be updated at this time.4 Although new evidence was identified in areas covered by the guideline, none was felt to be sufficiently influential to change the direction of the current recommendations.

However, concerns around the implementation of Clinical Guideline 71 prompted NICE to issue new implementation advice in January 2012,5 which included positive advice on identifying a lead and building an action plan—this document urges the implementation of the guideline as soon as possible.5

The problem is relatively straightforward: we need to identify accurately those individuals who carry a gene that causes FH and screen the families of these 'proband' individuals for carriage of that gene.

This article highlights key recommendations from the NICE guideline on FH and the steps that are needed to promote implementation of the guideline.


Raised cholesterol is present from birth in people with FH and may lead to early development of atherosclerosis and coronary heart disease. Familial hypercholesteroalemia is caused by an inherited genetic defect, which has an autosomal dominant pattern of inheritance. Siblings and children of a person with FH have a 50% risk of inheriting the gene.1

The prevalence of heterozygous FH in the UK is estimated to be 1 in 500. This means that approximately 100,000 people in England are affected. However, only 10%–15% of people with FH have been identified.2 If left untreated, coronary heart disease will develop in approximately 50% of men and 30% of women with FH by the age of 50 years.1

Individuals who inherit a defective gene from both parents will have homozygous FH, which is more appropriately called compound heterozygous FH because it is extremely unlikely that the mutation inherited from each parent will be identical. The chances of compound heterozygous FH occurring are approximately one per million.1 In these individuals, symptoms appear in childhood and the condition is associated with very early death from coronary heart disease unless it is recognised extremely early in the person's life.

Diagnosis of FH

A diagnosis of FH should be based on the Simon Broome criteria (see Box 1), which specify that the person has the clinical features of abnormal cholesterol levels or a positive DNA test for the underlying genetic abnormality. Measurement of the low density lipoprotein fraction of cholesterol (LDL-C) concentration (confirmed on two separate measurements) should be used rather than total cholesterol (TC).

The distinctive features of tendon xanthomata are rarely seen, but should be looked for in patients with suspected FH. These are a clinically detectable nodularity and/or thickening of the tendons caused by infiltration with lipid-laden histiocytes. It most frequently affects the Achilles tendons, but can also be observed in the back of the hands, elbows, and knees.

Although the genetic background sounds simple, there is no single mutation that accounts for all cases of FH. Approximately 1400 unique mutations have been identified of which over 200 have been reported in the UK population.6 The vast majority (93%) of genetic mutations associated with FH occur in the LDL-C receptor gene,6 but testing for this specific abnormality with comprehensive genetic analysis is complicated and costly.6

Age and gender specific LDL-C thresholds are available to help improve accuracy of diagnosis in relatives of index cases.1 Concentrations of LDL-C differ in men and women, and generally increase with age so different cut-off values are used when diagnosing FH in relatives.7

Children who have a parent with known FH should be offered a DNA test for the identified mutation by the age of 10 years. If the mutation is unknown, LDL-C should be measured by this age and repeated after puberty.1 This 'cascade testing' of first-, second-, and potentially third-degree relatives, is recommended using a combination of DNA testing and LDL-C measurements. Where the family mutation is known, DNA testing rather than LDL-C level should be used to identify relatives affected by the disease.All children and young people diagnosed with, or being investigated for, a diagnosis of FH should be offered referral to a specialist with expertise in FH in children and young people.1 It should be noted that false positive and negative rates are lower in children than in adults.2

Box 1: Simon Broome criteria for a diagnosis of FH1
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 at: www.nice.org.uk/CG71

Treatment of FH

Treatment of FH with statins is effective—a high-intensity statin should be used, with the aim of reducing the LDL-C concentration by >50% from baseline.1 This therapy is relatively cheap, particularly as high-intensity statins are now available as generic formulations.

In 1999, the UK Simon Broome register reported that the relative risk for coronary mortality in patients with FH aged 20–59 years had more than halved between 1992 and 1995.8 Even relatively modest doses of statins can reduce the risk of coronary heart disease by about 80% in people with FH.9 Treatment of children with statins and other lipid-lowering medications requires referral to an appropriate paediatric specialist. Treatment of women in their childbearing years also requires special attention. A continuing discussion about contraception and planning pregnancy is necessary because of cardiovascular risk from certain contraceptives and the small risk of foetal abnormality associated with lipid-lowering therapy, especially statins.2

Benefits of genetic testing

A diagnosis of FH can be confirmed in an individual without either genetic testing or a positive DNA result through LDL-C levels (the absence of a mutation does not exclude FH as molecular techniques are not 100% sensitive). It is likely that this person will have previously been identified as being at high risk of cardiovascular disease and will already be receiving appropriate pharmacological treatment. The benefits of genetic testing are received by the family of the proband or individual with FH. Testing of close relatives should result in identification of (previously unrecognised) individuals with FH. This puts healthcare professionals in a strong position to reduce the risk of coronary heart disease through lipid-lowering treatment. Indeed, some of these individuals may not have had diagnostically raised LDL-C concentrations at the time of their diagnosis, so cholesterol testing alone would have failed to identify them.

NICE Clinical Guideline 71 recommends the use of a nationwide family based follow-up system of cascade testing (a combination of DNA testing and LDL-C) for FH.1

Barriers to implementation and missed opportunities

Recommendations that are currently not being followed consistently in England include offering all people with FH:10

  • referral to a specialist for confirmation of diagnosis and initiation of cascade testing
  • regular structured review that is carried out at least annually, with a nationwide family based follow-up system.

With the highly developed computer-based clinical medical record systems used in primary care, it is relatively straightforward to identify people with a personal history of premature ischaemic heart disease and to recall cholesterol levels for a large number of patients. However, even with these assets, identification of patients with possible FH is not all that easy.

Primary care clinicians do not always have access to LDL-C levels, and even if the laboratory agrees to the request, the LDL-C concentration is usually assessed using an estimated figure calculated from total cholesterol, high-density lipoprotein cholesterol, and triglyceride measurements. The triglyceride level varies with fasting status; measurements are usually performed after an overnight fast, putting the patient at increased inconvenience. Unfortunately, applying the Simon Broome criteria to practice patients requires time and effort, which may be a barrier to guideline implementation.

It is unfortunate that the LDL-C concentration by itself is neither sufficiently sensitive nor specific. There is considerable overlap in levels between patients with FH and individuals with non-genetic hypercholesterolaemia particularly in adults.7

For clinicians working in primary care it may be that the quality and outcomes framework has placed too much emphasis on total cholesterol levels and not enough on LDL-C levels as the major risk factor.11 Also, the implementation of risk-assessment programmes such as QRISK has not stressed strongly enough the need to treat individuals with high LDL-C levels on the basis of this risk factor alone (i.e. because of their extremely high lifetime risk of CVD rather than submitting them to
CVD risk assessment).

A significant amount of money has been invested in the NHS Health Check programme, but the information obtained on cholesterol levels has not been used systematically to find the 'missing thousands' of patients with FH.12

Diagnostic tests

Recently, NICE reviewed two commercially available genetic tests that detect mutations most frequently associated with FH.6 It had been suggested that these two diagnostic tests might be useful in speeding up the process of identifying patients with FH. Unfortunately, after reviewing the tests, NICE came to the conclusion that:6

  • greater health benefits could be achieved cost effectively through the use of comprehensive genetic analysis for index cases
  • targeted sequencing for relatives is less expensive with no reduction in health benefits.

Service access

Large areas of England do not have access to specialist lipid advisory services, and lack of access to genetic testing for FH in particular is a barrier to implementation of the NICE guideline. An audit performed by the Royal College of Physicians in 2010 showed that, although over 97% of acute hospital trust sites have access to lipid testing, only 15% received funding for DNA testing.13

Investment in services for FH

Uptake of NICE Clinical Guideline 71 has taken place in Scotland, Wales, and Northern Ireland, perhaps because the scale of the problem seems manageable and the overall costs reasonable. However, in England the responsibility for implementation has fallen between organisations—with PCTs not allocating money locally and strategic health authorities believing that the problem is 'too common' for specialist commissioning mechanisms.

A failure to think beyond the end of the year has inhibited investment in a process that could save both lives and money in the medium term. Certainly NICE is in no doubt about the cost effectiveness of the suggested interventions. A recent report on FH commissioned by HEART UK suggests that if 50% of patients with FH were to be diagnosed and treated, the NHS could save £1.7 million annually on health treatment otherwise required for heart disease. The impact of not implementing cascade testing is costing the NHS £1.4 million per year.10


The aim of identifying the carriers of the genes responsible for FH remains worthwhile and achievable, but there needs to be an integrated national and local approach, which has been lacking in the last 3 to 4 years. Primary care clinicians need to identify high-risk individuals within their practices and to lobby for specialist services to provide first-class care for people with FH and their extended families.

NICE implemation tools
NICE has developed the following tools to support implementation of Clinical Guideline 71 on Identification and management of familial hypercholesterolaemia. The tools are now available to download from the NICE website: www.nice.org.uk/CG71


NICE support for commissioners

Costing reportcommissioning icon

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 templatecommissioning icon

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.

NICE support for service improvement systems and audit

Audit supportAudit

Audit support aims to assist NHS organisations 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.

Electronic audit toolAudit

Electronic audit tools are developed to assist organisations with clinical audit and to ensure that practice is in line with the NICE recommendations.

NICE support for education and learning

Slide setEducation and learning

The slides provide a framework for discussing the NICE guideline with a variety of audiences and can assist in local dissemination. This information does not supersede or replace the guidance itself.

Implementation adviceEducation and learning

This advice tool considers implementation issues that are specific to Clinical Guideline 71 on familial hypercholesterolaemia.

CMG45: Integrated commissioning for the prevention of cardiovascular diseaseEducation and learning

This resource supports commissioners from public health, regulatory services (trading standards, environmental health and licensing), and planning and clinical commissioning groups to work with health and wellbeing boards and other partners to commission integrated, high-quality, and evidence-based services to help prevent cardiovascular disease in England.

Key to NICE implementation icons

commissioning icon

NICE support for commissioners

  • Support package for commissioners and others for quality standards
  • NICE guide for commissioners
  • NICE cost impact support for guidance (selection from national report/local template/costing statement, dependent on topic)


NICE support for service improvement systems and audit

  • Forward planner
  • 'How to' guides (generic advice on processes)
  • Local government briefings (with Centre for Public Health Excellence)
  • Baseline assessment tool for guidance
  • Audit support including electronic data collection tools
  • E-learning modules (commissioned)

Education and learning

NICE support for education and learning

  • Clinical case scenarios
  • Learning packages including slide sets
  • Podcasts
  • Shared learning and other local best practice examples
  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 nhs_accreditation
  2. Seed M, Humphries S, Thorogood M. A commentary on the NICE guideline on identification and management of familial hypercholesterolaemia. Prim Care Cardiovascular J 2009; 2: 141–144.
  3. Morrell J. Familial hypercholesterolaemia—a developing English scandal. Br J Cardiol 2011; 18: 54?55.
  4. National Institute for Health and Care Excellence. Review of clinical guideline (CG71) —identification and management of familial hypercholesterolaemia. London: NICE, 2011. Available at: www.nice.org.uk/guidance/index.jsp?action=download&o=55873
  5. National Institute for Health and Care Excellence. Familial hypercholesterolaemia. implementation advice. Genetic testing recommendations. London: NICE, 2012. Available at: www.nice.org.uk/guidance/CG71/ImplementationAdvice/doc/English
  6. National Institute for Health and Care Excellence. Elucigene FH20 and LIPOchip for the diagnosis of familial hypercholesterolaemia. Diagnostics Guidance 2. London: NICE, 2011. Available at: www.nice.org.uk/guidance/DG2
  7. Starr B, Hadfield S, Hutten B et al. Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing. Clin Chem Lab Med 2008; 46 (6): 791–803.
  8. 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.
  9. Versmissen J, Oosterveer D, Yazdanpanah M et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008; 337: a2423.
  10. HEART UK. Saving lives, saving families. Maidenhead: HEART UK, 2012. Available at: www.heartuk.org.uk/pressroom/images/uploads/HUK_SavingLivesSavingFamilies_FHreport_Feb2012
  11. British Medical Association. NHS Employers. Quality and outcomes framework guidance for GMS contract 2012/13. London: BMA, NHS Employers, 2012. Available at: www.bma.org.uk/employmentandcontracts/independent_contractors/quality_outcomes_framework/qofchanges2012.jsp
  12. HEART UK. Cholesterol and a healthier nation: shared responsibility for better public health. Maidenhead: HEART UK, 2011. Available at: heartuk.org.uk/latest-news/article/cholesterol-and-a-healthier-nation/
  13. Pedersen K, Humphries S, Roughton M, Besford J. National clinical audit of the management of familial hypercholesterolaemia 2010: full report. London: Clinical Standards Department, Royal College of Physicians, 2010. G