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ALL / Endocrinology
Familial hypercholesterolaemia
Familial hypercholesterolaemia
Familial hypercholesterolaemia (FH) is usually an autosomal dominant condition that is thought to affect around 1 in 250 people. It results in high levels of LDL cholesterol which, if untreated, may cause premature cardiovascular disease (CVD). FH is most commonly caused by pathogenic variants in the LDL-receptor gene (LDLR), although variants in other genes, including APOB and PCSK9, may also be responsible.Case finding:
- NICE suggests that FH should be suspected in adults with:
- a total cholesterol level greater than 7.5 mmol/L and/or
- a personal or family history of premature coronary heart disease (an event before 60 years in the index individual or a first-degree relative)
- exclude secondary causes of hypercholesterolaemia before making a diagnosis
- children of affected parents:
- if one parent is affected by familial hypercholesterolaemia, offer testing by the age of 10 years
- if both parents are affected by familial hypercholesterolaemia, offer testing before the age of 5 years or at the earliest opportunity thereafter
Clinical diagnosis may be assessed using the Simon Broome criteria or Dutch Lipid Clinic Network criteria.
Simon Broome criteria:
- adults: total cholesterol > 7.5 mmol/L or LDL-C > 4.9 mmol/L
- children: total cholesterol > 6.7 mmol/L or LDL-C > 4.0 mmol/L
- plus, for definite FH:
- tendon xanthomata in the patient or a first- or second-degree relative, or
- DNA-based evidence of an FH-causing variant
- plus, for possible FH:
- family history of myocardial infarction before age 50 years in a second-degree relative or before age 60 years in a first-degree relative, or
- family history of total cholesterol > 7.5 mmol/L in an adult first- or second-degree relative, or > 6.7 mmol/L in a child or sibling younger than 16 years
Management
- standard CVD risk-estimation tools should not be used because they substantially underestimate the lifetime risk of CVD in people with FH
- refer people meeting the Simon Broome criteria for possible or definite FH, or with a Dutch Lipid Clinic Network score of 5 or more, to a specialist for confirmation of the diagnosis and consideration of DNA testing
- offer a high-intensity statin at the maximum tolerated dose, aiming for at least a 50% reduction in LDL-C from baseline
- when a pathogenic variant has been identified, offer DNA-based cascade testing to first- and second-degree biological relatives and, when possible, third-degree relatives
- advise women to stop statins 3 months before attempting conception and not to restart them until breastfeeding has finished
+PassMedicine Notes
Familial hypercholesterolaemia (FH) is usually an autosomal dominant condition that is thought to affect around 1 in 250 people. It results in high levels of LDL cholesterol which, if untreated, may cause premature cardiovascular disease (CVD). FH is most commonly caused by pathogenic variants in the LDL-receptor gene (LDLR), although variants in other genes, including APOB and PCSK9, may also be responsible.
Case finding:- NICE suggests that FH should be suspected in adults with:
- a total cholesterol level greater than 7.5 mmol/L and/or
- a personal or family history of premature coronary heart disease (an event before 60 years in the index individual or a first-degree relative)
- exclude secondary causes of hypercholesterolaemia before making a diagnosis
- children of affected parents:
- if one parent is affected by familial hypercholesterolaemia, offer testing by the age of 10 years
- if both parents are affected by familial hypercholesterolaemia, offer testing before the age of 5 years or at the earliest opportunity thereafter
Clinical diagnosis may be assessed using the Simon Broome criteria or Dutch Lipid Clinic Network criteria.
Simon Broome criteria:- adults: total cholesterol > 7.5 mmol/L or LDL-C > 4.9 mmol/L
- children: total cholesterol > 6.7 mmol/L or LDL-C > 4.0 mmol/L
- plus, for definite FH:
- tendon xanthomata in the patient or a first- or second-degree relative, or
- DNA-based evidence of an FH-causing variant
- plus, for possible FH:
- family history of myocardial infarction before age 50 years in a second-degree relative or before age 60 years in a first-degree relative, or
- family history of total cholesterol > 7.5 mmol/L in an adult first- or second-degree relative, or > 6.7 mmol/L in a child or sibling younger than 16 years
- standard CVD risk-estimation tools should not be used because they substantially underestimate the lifetime risk of CVD in people with FH
- refer people meeting the Simon Broome criteria for possible or definite FH, or with a Dutch Lipid Clinic Network score of 5 or more, to a specialist for confirmation of the diagnosis and consideration of DNA testing
- offer a high-intensity statin at the maximum tolerated dose, aiming for at least a 50% reduction in LDL-C from baseline
- when a pathogenic variant has been identified, offer DNA-based cascade testing to first- and second-degree biological relatives and, when possible, third-degree relatives
- advise women to stop statins 3 months before attempting conception and not to restart them until breastfeeding has finished
