Familial hypercholesterolaemia: identification and management

National Institute for Health and Care Excellence


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Introduction

  • Familial hypercholesterolaemia (FH) is a genetic condition that causes a high cholesterol concentration in the blood. It is caused by mutations in genes of the pathway that clears low-density lipoprotein (LDL) from the bloodstream (in most cases the LDL receptor). This is present from birth and may lead to early development of atherosclerosis and coronary heart disease. The disease is transmitted from generation to generation in a dominant pattern, such that siblings and children of a person with FH have a 50% risk of inheriting FH
  • The prevalence of heterozygous FH in the UK population is estimated to be 1 in 500, which means that approximately 110,000 people are affected. Having this condition leads to a greater than 50% risk of coronary heart disease in men by the age of 50 years and at least 30% in women by the age of 60 years, if left untreated
  • Homozygous FH is rare, with an incidence of approximately one case per one million. Symptoms appear in childhood, and are associated with early death from coronary heart disease

Key priorities for implementation

Diagnosis

  • A family history of premature coronary heart disease should always be assessed in a person being considered for a diagnosis of FH (see Simon Broome criteria below)
  • In children at risk of FH because of one affected parent, the following diagnostic tests should be carried out by the age of 10 years or at the earliest opportunity thereafter
    • a DNA test if the family mutation is known
    • LDL-C concentration measurement if the family mutation is not known. When excluding a diagnosis of FH a further LDL-C measurement should be repeated after puberty because LDL-C concentrations change during puberty
  • Coronary heart disease risk estimation tools such as those based on the Framingham algorithm should not be used because people with FH are already at a high risk of premature coronary heart disease

Identifying people with FH using cascade testing

  • Healthcare professionals should offer all people with FH a referral to a specialist with expertise in FH for confirmation of diagnosis and initiation of cascade testing
  • Cascade testing using a combination of DNA testing and LDL-C concentration measurement is recommended to identify affected relatives of those index individuals with a clinical diagnosis of FH. This should include at least the first- and second- and, when possible, third-degree biological relatives
  • The use of a nationwide, family-based, follow-up system is recommended to enable comprehensive identification of people affected by FH

Management

  • Adults
    • healthcare professionals should consider prescribing a high-intensity statin to achieve a recommended reduction in LDL-C concentration of greater than 50% from baseline (that is, LDL-C concentration before treatment)
  • Children and young people
    • healthcare professionals should offer all children and young people diagnosed with, or being investigated for, a diagnosis of FH a referral to a specialist with expertise in FH in children and young people. This should be in an appropriate child/young person-focused setting that meets the standards within the ‘National service framework for children, young people and maternity services’ (available from www.dh.gov.uk)

Information needs and support

  • Information and counselling on contraception for women and girls with FH
    • when lipid-modifying drug therapy is first considered for women and girls, the risks for future pregnancy and the fetus while taking lipid-modifying drug therapy should be discussed. This discussion should be revisited at least annually

Ongoing assessment and monitoring

  • Review
    • all people with FH should be offered a regular structured review that is carried out at least annually

Simon Broome diagnostic criteria for index individuals*

  • Diagnose a person with definite FH if they have:
    • cholesterol concentrations as defined in table 1 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 table 1 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
    *Marks D, Thorogood M, Neil HA, Humphries SE (2003) A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168 (1): 1–14.
Cholesterol levels to be used as a diagnostic criteria for the index individual1
STAGE TOTAL CHOLESTEROL LDL-C
Child/young person >6.7 mmol/l >4.0 mmol/l
Adult >7.5 mmol/l >4.9 mmol/l
1Levels either pre-treatment or highest on treatment
LDL-C=low-density lipoprotein cholesterol

References

full guideline available from…
National Institute for Health and Care Excellence, Level 1A, City Tower, Piccadilly Plaza, Manchester, M1 4BT
www.nice.org.uk/guidance/CG71

National Institute for Health and Care Excellence. Familial hypercholesterolaemia: identification and management. August 2008
First included: Oct 08.


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