This is an autosomal dominant disorder of chromosome 19 with homozygous and heterozygous forms; the latter occurs in one in 500 people (meaning that approximately 110,000 people are affected in the UK) (1). It is defined in the WHO classification as a type IIa hyperlipidaemia.
- tendon xanthomata are virtually diagnostic of heterozygous familial hypercholesterolaemia, and occur in about 70% of affected individuals after the age of 20 years
- xanthelasma and premature corneal arcus are commonly found but are less specific signs.
- the elevated serum cholesterol concentration that characterises heterozygous FH 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
- homozygous FH is rare, with symptoms appearing in childhood, and is associated with early death from coronary heart disease. Homozygous FH has an incidence of approximately one case per one million
There have been more recent genetic studies suggesting a prevalence of 1 in 200 to 250 (2,3)
- however these were based on data from a mainly white Danish population and so it is unclear how direcly applicable this data is to the UK population
- the prevalence of FH based on common LDLR and APOB mutations alone was one in 650 (2)
UK guidance states "..Most cases of FH remain undiagnosed, and only an estimated 8-15% of cases are known (based on prevalence estimates of 1:250 and 1:500)" (4)
Simon Broome diagnostic criteria for index individuals (probands) (1):
- definite familial hypercholesterolaemia (FH) :
- cholesterol concentrations as defined in table below and tendon xanthomas,
or evidence of these signs in first- or second-degree relative or
Cholesterol levels to be used as diagnostic criteria for the index individual
Total cholesterol LDL-C Child/young person > 6.7 mmol/l > 4.0 mmol/l Adult > 7.5 mmol/l > 4.9 mmol/l
- DNA-based evidence of an LDL-receptor mutation, familial defective apo
B-100, or a PCSK9 mutation
- cholesterol concentrations as defined in table below and tendon xanthomas, or evidence of these signs in first- or second-degree relative or
- possible FH (if patient has cholesterol concentrations as defined in table 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
There is a clearly raised fasting low-density lipoprotein (LDL) plasma concentration due to reduced clearance by defective LDL receptors.
Suspect familial hypercholesterolaemia (FH) as a possible diagnosis in adults with (1):
- a total cholesterol level greater than 7.5mmol/l and/or
- a personal or family history of premature coronary heart disease (an event before 60 years in an index individual or first-degree relative)
Systematically search primary care records for people (1):
- younger than 30 years, with a total cholesterol concentration greater
than 7.5 mmol/l and
- 30 years or older, with a total cholesterol concentration greater than 9.0 mmol/l
- as these are the people who are at highest risk of FH
Use the Simon Broome or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH in primary care settings (1)
Refer the person to an FH specialist service for DNA testing if they meet the Simon Broome criteria for possible or definite FH, or they have a DLCN score greater than 5.
- total cholesterol is usually >9 mmol/l in FH (5)
- FH people who have not already developed CHD have a CHD mortality rate at least 10 times greater than the general population (5)
- FH is present in about 5-10% of individuals who develop CHD before the age
of 55 years (5)
- therefore, it is especially important that all the first degree relatives of people with premature CHD (men < 55 years and women < 65 years) are screened for lipids.
- NICE (October 2019). Identification and management of familial hypercholesterolaemia
- Benn M, Watts GF, Tybjaerg-Hansen A, et al. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012 Nov;97(11):3956-64.
- Sjouke B, Kusters D, Kindt I, et al. Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome. Eur Heart J. 2014 Feb 28; doi: 10.1093
- Public Health England (August 2018).Familial Hypercholesterolaemia Implementing a systems approach to detection and management.
- JBS2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005; 91 (Supp 5).
Last edited 11/2019 and last reviewed 03/2021