• Suspect familial hypercholesterolaemia (FH) in:
• Adults with total cholesterol concentrations greater than 7.5 mmol/L.
• People with a family history of premature coronary heart disease (before 60 years of age in a first-degree relative, or before 50 years of age in a second-degree relative).
• People with tendon xanthomata.

Tendon xanthomata:

• Appear in people with heterozygous FH from 20 years of age onwards (unless the person was started on a statin early in life), but are often evident in homozygous FH from childhood.
• May be difficult to detect.
• Are hard, non-tender, nodular enlargements of tendons.
• Are most commonly found on the dorsum (knuckles) of the hands and in the Achilles tendons, and may rarely be present on the extensor hallucis longus and triceps tendons.
• Feel hard because they are fibrotic, and may become inflamed in the Achilles tendons (sometimes presenting as chronic Achilles tenosynovitis, which may be exacerbated by a statin).
• Do not appear yellow; the overlying skin is of normal colour.
• Are highly suggestive of FH:
• But their absence does not exclude FH.
• Other types of xanthomata (such as xanthelasmata on the eyelids) and premature corneal arcus may occur in people with FH, but are less specific.

[WHO, 1998; Winder et al, 1998; Warrell et al, 2003; Moruisi et al, 2006]

These recommendations are in line with a guideline published by the National Institute for Health and Clinical Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

• If familial hypercholesterolaemia (FH) is suspected in an adult:
• Take two measurements of plasma lipid concentrations (including low-density lipoprotein cholesterol [LDL-C] concentration), preferably after a fast of at least 10 hours.
• Look for tendon xanthomata.
• Take a family history (if possible) of myocardial infarction and raised cholesterol.
• Exclude secondary hypercholesterolaemia:
• An underlying cause can usually be detected from the history and examination, and by checking thyroid stimulating hormone, fasting blood glucose concentration, renal function, electrolytes, and liver function tests.
• An underlying condition or drug may be exacerbating primary FH, and serum lipids should be rechecked (if possible) after the condition has resolved or the drug has been stopped.
• To confirm a diagnosis of FH, see Diagnosis in adults.
• If FH is suspected in a child or young person (up to 15 years of age):
• Diagnosis in children and young people should be made by a specialist:
• Either do an initial assessment in primary care as for adults, or refer to a specialist for the initial assessment to be carried out.
• Ideally, referral will be to a specialist with particular expertise in FH in children and young people. If unavailable locally, refer to a specialist with expertise in FH (usually at a lipid or metabolic clinic).
• Diagnosis should be made by 10 years of age or at the earliest opportunity thereafter.

Causes of secondary hypercholesterolaemia

• The following may cause hypercholesterolaemia (without hypertriglyceridaemia):
• Hypothyroidism (see the CKS topic on Hypothyroidism).
• Cholestatic liver disease (such as primary biliary cirrhosis).
• Nephrotic syndrome.
• Cushing's syndrome.
• Drugs:
• Androgens.
• Ciclosporin.
• Anti-retrovirals (protease inhibitors).
• Anorexia nervosa.
• The following may also cause hypercholesterolaemia, but, usually, hypertriglyceridaemia would also be present:
• Diabetes mellitus or obesity (although hypertriglyceridaemia alone is the more common presentation). See the CKS topics on Diabetes - type 2 and Obesity.
• Pregnancy.
• Renal dialysis or advanced renal failure.
• Monoclonal gammopathy.
• Excess alcohol consumption.
• HIV infection.
• Drugs:
• Thiazide diuretics.
• Glucocorticoids.
• Retinoic acid derivatives.
• Beta-blockers.
• Anti-retrovirals (protease inhibitors, nucleoside analogue reverse transcriptase inhibitors such as stavudine).

[Warrell et al, 2003; Aronson, 2006; Bhatnagar et al, 2008]

These recommendations are in line with a guideline published by the National Institute for Health and Clinical Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

• The need for fasting when checking serum lipids is based on expert opinion [Bhatnagar et al, 2008]; the calculation of LDL-C is based on the assumption of fasting samples and triglyceride levels less than 4.5 mmol/L (the opinion of a CKS expert reviewer).
• The method suggested for detecting an underlying cause is based on expert opinion in a textbook [Kumar and Clark, 1994].

• Use the Simon Broome criteria to make a diagnosis of heterozygous familial hypercholesterolaemia (FH):
• Diagnose definite FH in an adult with:
• Total cholesterol greater than 7.5 mmol/L, low-density lipoprotein cholesterol (LDL-C) concentration greater than 4.9 mmol/L, and tendon xanthomata (or evidence of tendon xanthomata in a first- or second-degree relative), or
• An identified genetic mutation for familial hypercholesterolaemia.
• Diagnose possible FH in an adult with total cholesterol greater than 7.5 mmol/L, LDL-C greater than 4.9 mmol/L, and at least one of the following:
• Family history of myocardial infarction: before 60 years of age in a first-degree relative, or before 50 years of age in a second-degree relative.
• Family history of raised total cholesterol: greater than 7.5 mmol/L in an adult first- or second-degree relative, or greater than 6.7 mmol/L in a child, brother, or sister younger than 16 years of age.
• Consider a clinical diagnosis of homozygous FH in adults with LDL-C greater than 13 mmol/L.
• Refer to a specialist with expertise in FH for confirmation of the diagnosis.

These recommendations are in line with a guideline published by the National Institute for Health and Clinical Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

• NICE recommend the use of the Simon Broome diagnostic criteria. These are validated criteria, recommended by NICE because their development was based on a UK population, and they are simpler to use than other criteria with a comparable or better positive likelihood ratio [National Collaborating Centre for Primary Care, 2008b].

• Use the Simon Broome criteria for children (which differ from the criteria for adults in terms of the lipid concentrations) to make a diagnosis of familial hypercholesterolaemia (FH) in children and young people (up to 15 years of age):
• Diagnose definite FH in a child or young person with:
• Total cholesterol greater than 6.7 mmol/L, low-density lipoprotein cholesterol (LDL-C) greater than 4.0 mmol/L, and tendon xanthomata (or evidence of tendon xanthomata in a first- or second-degree relative), or
• An identified genetic mutation for FH.
• Diagnose possible FH in a child or young person with total cholesterol greater than 6.7 mmol/L, LDL-C greater than 4.0 mmol/L, and at least one of the following:
• Family history of myocardial infarction: before 60 years of age in a first-degree relative, or before 50 years of age in a second-degree relative.
• Family history of raised total cholesterol: greater than 7.5 mmol/L in an adult first- or second-degree relative or greater than 6.7 mmol/L in a child, brother, or sister younger than 16 years.
• Consider a clinical diagnosis of homozygous FH in children and young people with LDL-C greater than 11 mmol/L.
• Refer to a specialist for confirmation of the diagnosis.
• Ideally, referral will be to a specialist with particular expertise in FH in children and young people. If unavailable locally, refer to a specialist with expertise in FH (usually at a lipid or metabolic clinic).
• Diagnosis should be made by 10 years of age or at the earliest opportunity thereafter.

These recommendations are in line with a guideline published by the National Institute for Health and Clinical Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

• NICE recommend the use of the Simon Broome diagnostic criteria. These are validated criteria, recommended by NICE because their development was based on a UK population, and they are simpler to use than other criteria with a comparable or better positive likelihood ratio [National Collaborating Centre for Primary Care, 2008b].