Practice Easily Missed?

Familial hypercholesterolaemia

BMJ 2012; 344 doi: (Published 11 May 2012) Cite this as: BMJ 2012;344:e3228
  1. Peter J Gill, MD/PhD student12,
  2. Anthony Harnden, university lecturer in general practice1,
  3. Fredrik Karpe, professor of metabolic medicine3
  1. 1Department of Primary Care Health Sciences, University of Oxford, Oxford OX1 2ET, UK
  2. 2Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
  3. 3Oxford Centre for Diabetes, Endocrinology & Metabolism, Churchill Hospital, Oxford OX3 7LJ
  1. Correspondence to: P J Gill peter.gill{at}
  • Accepted 5 April 2012

A 25 year old man visits his general practitioner concerned after his 52 year old father suddenly died of a heart attack. His paternal uncle and grandfather died of heart attacks in their 40s. On examination he has xanthomas on the extensor tendons of his hands. Laboratory investigations reveal total cholesterol 9.3 mmol/L and low density lipoprotein (LDL) cholesterol 6.6 mmol/L. He is diagnosed with familial hypercholesterolaemia, given lifestyle advice, started on simvastatin 80 mg, and referred to a specialist for genetic testing and cascade screening of his relatives.

What is familial hypercholesterolaemia?

Familial hypercholesterolaemia is an inherited autosomal dominant genetic disorder characterised by high serum cholesterol concentrations detectable at a young age.1 2 It is associated with early cardiovascular disease, and an underlying genetic cause can be identified in about 80% of cases.2 3

How common is familial hypercholesterolaemia?

  • Heterozygous familial hypercholesterolaemia affects about 1 in 500 people (about 110 000 people in the UK)1 2

  • An average UK general practice with 8000 patients will have about 16 patients with familial hypercholesterolaemia clustered in five to seven families4 5

  • Certain populations have a higher frequency of familial hypercholesterolaemia such as Afrikaners in South Africa (1 in 70) and French Canadians (1 in 200)1 2

  • Homozygous familial hypercholesterolaemia occurs with a frequency of 1 in 1 000 000 people1

Why is familial hypercholesterolaemia missed?

Underdiagnosis is a global challenge, with correct identification ranging from less than 1% in Russia to 20% in the Netherlands and 44% in Iceland.2 In the UK only 15% of patients with familial hypercholesterolaemia are expected to have been recognised in general practice.5 6 7

It is not known why patients with familial hypercholesterolaemia are often missed in primary care, but many seem to be diagnosed in middle age when family members present with coronary heart disease.5 Although patients diagnosed with familial hypercholesterolaemia are instructed to contact their relatives, several studies have shown that this is not effective in practice.6 The low referral rate to specialists for cascade DNA testing, the lack of national screening programmes, and the limited usefulness of clinical evaluation in relatives all probably contribute.4 8 9 Underdiagnosis is an even greater challenge among children and young adults, in whom clinical signs are rarely present.1 10

Why does this matter?

Patients with familial hypercholesterolaemia have a high risk of mortality as they are exposed to high concentrations of plasma LDL cholesterol from birth.1 3 By early adulthood, without treatment they will have a 100-fold greater mortality risk from coronary disease than other young adults aged 20–39 years.11 12 Half of untreated heterozygous men and 30% of untreated women will have a myocardial infarction by the age of 50 and 60 years respectively.3 13 However, the development of effective cholesterol lowering drugs has reduced cardiovascular mortality, prolonging life by approximately nine years.12 14 15 A long term follow-up study showed that statins can delay atherosclerotic progression in children and young adults with familial hypercholesterolaemia.16 The risk of coronary heart disease is considerably higher in patients with homozygous familial hypercholesterolaemia.1 17

How is familial hypercholesterolaemia diagnosed?

There is no individual diagnostic test with sufficient specificity and sensitivity to reliably detect familial hypercholesterolaemia.10 18 Therefore, three international groups have developed diagnostic tools for familial hypercholesterolaemia based on clinical signs, family history, and cholesterol measurements.10 The National Institute for Health and Clinical Excellence (NICE) guideline on identification and management of familial hypercholesterolaemia recommends using the definition developed by the UK based Simon Broome Register Group (see box).10

Simon Broome Register Group definition of familial hypercholesterolaemia210

  • Definite diagnosis of familial hypercholesterolaemia requires presence of (a) plus (b) below

  • Possible familial hypercholesterolaemia requires presence of (a) plus one of (c) or (d)

    • (a) At least two confirmed measurements of total cholesterol >7.5 mmol/L and LDL cholesterol >4.9 mmol/L in adults (total >6.7 mmol/L and LDL >4.0 mmol/L in children aged <16 years)

    • (b) Tendon xanthoma in patient or DNA based diagnosis of familial hypercholesterolaemia in first or second degree relative

    • (c) Family history of myocardial infarction in second degree relative aged <50 years or in first degree relative aged <60 years

    • (d) Family history of high cholesterol in first degree relative or concentration >7.5 mmol/L in second degree relative

Clinical features

Ask about any relatives with early coronary heart disease.2 On physical examination, determine the presence of tendon xanthomas or yellow coloured cholesterol deposits, which are usually hard and non-tender.1 10 The most common sites for the nodules include the dorsum of the hands and the Achilles tendons, while, rarely, nodules can be present on the extensor hallucis longus and triceps tendons.1 2 A study of 133 patients with familial hypercholesterolaemia found they were seven times more likely to experience Achilles tendon pain lasting more than three days, but this rarely leads to diagnosis.19 While the overall diagnostic value is difficult to determine, in 825 patients referred to a specialist clinic for suspicion of familial hypercholesterolaemia, family history or presence of tendon xanthoma increased the odds of a relevant mutation being detected by 7.8 and 3.7 times respectively.20 However, tendon xanthoma is classically not present until the third decade of life and is therefore not helpful in diagnosis of younger patients.1 2 In two studies of children with familial hypercholesterolaemia, none had tendon xanthoma.21 22 Xanthelasma and premature corneal arcus are less useful, but their presence should prompt investigations.10 18


Consider familial hypercholesterolaemia in adults with a fasting total cholesterol concentration >7.5 mmol/L and in children aged <16 years with total cholesterol >6.7 mmol/L.10 Triglycerides are usually in the normal range.1 All measurements should be confirmed at least twice because of biological and analytical variability.10 Exclude common causes of secondary hypercholesterolaemia such as hypothyroidism, diabetes, pregnancy, and drugs (such as thiazide diuretics and steroid hormones).1 NICE does not recommend the use of ultrasonography of the Achilles tendon for diagnosis or detection of tendon xanthoma.10 A 2005 study found physical examination and ultrasound had similar detection rates.23

Patients with definite or possible familial hypercholesterolaemia according to the Simon Broome Register Group definition (see box) should have cascade screening of first degree relatives.10 Cascade screening is a cost effective way of detecting elevated cholesterol concentrations in family members.10 24 Genetic testing for familial hypercholesterolaemia can be helpful in future case identification and in cascade screening, but it probably has only a limited value in the clinical management of the individual.2 8

How is familial hypercholesterolaemia managed?

Do not use risk estimation tools (such as the Framingham risk score) in these patients, as such tools underestimate their increased risk of premature heart disease.10 12 Provide lifestyle advice (for example, diet, physical activity, and stopping smoking) and start a high dose statin (such as simvastatin 80 mg or atorvastatin 40 mg) with an aim of reducing LDL cholesterol concentration by >50%.10 18 Additional treatment may be required to achieve this.10 Monitor for drug side effects, annually reassess cardiovascular risk factors and symptoms, and attend to these as necessary.10 18 Children, adults at very high risk, and those who fail to respond to treatment should be referred to a specialist for consideration of further management options (such as combination drug therapy and lipoprotein apheresis).10 18

Key points

  • Familial hypercholesterolaemia carries a high risk of premature cardiovascular morbidity and mortality

  • Most cases of heterozygous familial hypercholesterolaemia are missed in general practice

  • Consider familial hypercholesterolaemia in patients with a fasting total cholesterol >7.5 mmol

  • Specific physical findings may occur after the third decade and include tendon xanthoma, corneal arcus, and xanthelasma

  • Ensure cascade screening of all first degree relatives

  • Early identification and treatment with statins can prolong life by about nine years


Cite this as: BMJ 2012;344:e3228


  • This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, university lecturer in general practice, Department of Primary Care Health Sciences, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic for this series, please email us at

  • Contributors: PG and AH conceived the article; PG drafted the original paper and edited subsequent drafts. FK provided the specialist perspective about familial hypercholesterolaemia and AH provided the general practice perspective. All authors commented on drafts and approved the final version. PG is the guarantor.

  • Competing interest statement: All authors have completed the ICMJE unified disclosure form at (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Patient consent not required (patient anonymised, dead, or hypothetical).

  • Provenance and peer review: Not commissioned, externally peer reviewed.