Familial Hypercholesterolaemia (FH)

FH is a monogenic disorder of LDL clearance. It is the commonest monogenic cardiovascular condition, and it is considerably commoner than any of the cardiomyopathies or channelopathies covered elsewhere on this site.

A meta-analysis of 11 million people gives the following prevalences for heterozygous FH.^[1]

Population	Prevalence
General population	0.32%, about 1 in 313
Ischaemic heart disease	3.2%, about 1 in 31
Premature ischaemic heart disease	6.7%, about 1 in 15
Severe hypercholesterolaemia (LDL at or above 190 mg/dL, roughly 4.9 mmol/L)	7.2%, about 1 in 14

Put another way, FH is around 10 times more common in people with ischaemic heart disease, and 20 times more common in people with premature ischaemic heart disease, than in the general population.^[1] That gradient is the reason a premature coronary family history is worth acting on.

Homozygous FH is far rarer, presents in childhood with very high LDL cholesterol and early cardiovascular disease, and is managed in highly specialist centres. It is outside the scope of this page.

When to suspect it. NICE advises suspecting FH in an adult with a total cholesterol above 7.5 mmol/L, or with a personal or family history of coronary heart disease before the age of 60 in the person or a first-degree relative.^[2]

Formal diagnosis uses structured criteria that combine lipid levels, personal and family history and clinical signs. These are set out in full below. Applying them is the job of the lipid service rather than of an ICC clinic.

Clinical signs worth knowing:

• Tendon xanthomata are the specific sign. Look at the Achilles tendons and the extensor tendons of the hands
• Corneal arcus before age 45 is supportive
• Xanthelasma is common in the general population and is not specific for FH on its own

Exclude secondary causes of a raised cholesterol before pursuing a familial diagnosis, in particular hypothyroidism, nephrotic syndrome, cholestatic liver disease and relevant drug therapy.

FH is a clinical diagnosis supported by genetic testing, not a genetic diagnosis alone. Two structured systems are in use: the Simon Broome criteria, which NICE recommends for UK practice^[2], and the Dutch Lipid Clinic Network (DLCN) score, which is the usual instrument in European guidance and in research cohorts^[6].

Simon Broome criteria

Category	Requirement
Cholesterol threshold (required for both categories)	Adult: total cholesterol >7.5 mmol/L or LDL-C >4.9 mmol/L Child or young person under 16: total cholesterol >6.7 mmol/L or LDL-C >4.0 mmol/L
Definite FH	The cholesterol threshold above, plus tendon xanthomata in the patient or in a first- or second-degree relative, or DNA evidence of a pathogenic variant in LDLR, APOB (familial defective apo B-100) or PCSK9
Possible FH	The cholesterol threshold above, plus at least one of: family history of myocardial infarction before age 60 in a first-degree relative or before age 50 in a second-degree relative; family history of raised total cholesterol (>7.5 mmol/L in an adult first- or second-degree relative, or >6.7 mmol/L in a sibling or child under 16)

Dutch Lipid Clinic Network score. Choose only one score per group, the highest that applies, then total them.

Group	Criterion	Points
Family history	First-degree relative with premature coronary or vascular disease, or with LDL-C above the 95th percentile	1
	First-degree relative with tendon xanthomata or corneal arcus, or a child under 18 with LDL-C above the 95th percentile	2
Clinical history	Premature coronary artery disease (men under 55, women under 60)	2
	Premature cerebral or peripheral vascular disease	1
Examination	Tendon xanthomata	6
	Corneal arcus before age 45	4
LDL-C, untreated	≥8.5 mmol/L	8
	6.5–8.4 mmol/L	5
	5.0–6.4 mmol/L	3
	4.0–4.9 mmol/L	1
DNA analysis	Functional variant in LDLR, APOB or PCSK9	8

DLCN score interpretation

Total score	Diagnosis
Above 8	Definite FH
6–8	Probable FH
3–5	Possible FH
0–2	Unlikely FH

FH does not cause cardiomyopathy, a channelopathy or an aortopathy. It reaches inherited cardiac conditions services in two recognisable situations.

1. A premature coronary family history referred for an inherited cardiac opinion. This is a common reason for referral and is frequently the wrong door, but it is not a wasted referral if FH is then considered. Around 1 in 15 people with premature ischaemic heart disease have FH.^[1] A fasting lipid profile in the relative is a cheap and high-yield addition to the assessment.

2. After a young sudden death where the autopsy shows coronary disease. In a prospective population study of sudden death aged 1 to 35, coronary artery disease accounted for 24% of cases and was the commonest finding in the 31 to 35 age band.^[5] Where a young sudden death is attributed to coronary disease, the familial question is usually FH rather than a cardiomyopathy or channelopathy, and the family should be directed accordingly. The wider pathway after a sudden death is covered on the Sudden Cardiac Death and SADS page.

DNA-based cascade testing of first-degree relatives is recommended in UK practice, and FH is the most established cascade testing programme in cardiovascular medicine.^[2] It is the model that the rest of this site's cascade guidance is built on, so its limitations are instructive.

A negative genetic test does not exclude FH. Around 60% of patients with a clinical diagnosis of FH have no detectable causal variant. In a UK and Belgian study, 52% of mutation-negative UK patients had an LDL cholesterol gene score in the top three deciles of the population distribution, indicating that their raised LDL cholesterol had a polygenic rather than monogenic basis. The authors noted that this could compromise the efficiency of cascade testing.^[3]

The practical consequence is that a family with a clinical diagnosis but no identified variant cannot be cascaded by DNA, and relatives are instead screened on lipid levels. The same principle, that a negative test in an affected proband does not overturn a clinical diagnosis, runs through the Genetic Testing page.

Cascade can run upwards as well as downwards. In a UK primary care study, 10,095 children were screened at routine immunisation visits. The mutation prevalence was 1 in 273, and for every 1,000 children screened, 8 people were identified as at high risk, 4 children and 4 parents.^[4] Identifying an affected child is often how an affected parent is found.

This page does not cover lipid-lowering therapy. FH is managed in specialist lipid services, and treatment recommendations change often enough that a secondary summary would go out of date faster than it could be maintained. Use the primary sources.

Where to send people:

• Adults meeting the suspicion criteria above, to a specialist lipid service for formal diagnosis and cascade testing^[2]
• People with FH who are intolerant of statins, to a specialist for consideration of other therapy^[2]
• Children in affected families, according to the current NICE recommendations on testing in childhood^[2]

Primary sources: NICE clinical guideline CG71, Familial hypercholesterolaemia: identification and management, and HEART UK, the UK cholesterol charity, which maintains clinician and patient resources.^[2]

• Do not assume an ICC assessment covers this. FH is commoner than every condition on this site, and a normal echocardiogram and ECG say nothing about it.
• Do not read a negative DNA test as excluding FH. About 60% of clinically diagnosed patients have no detectable variant, and much of that is polygenic.^[3]
• Do consider FH after a young sudden death with coronary disease at autopsy. Coronary artery disease accounted for 24% of sudden deaths aged 1 to 35 in a prospective population study.^[5]
• Tendon xanthomata are the specific sign. Xanthelasma and corneal arcus alone are not.
• Exclude secondary causes of hypercholesterolaemia before pursuing a familial diagnosis.
• Do not manage lipids from this page. Refer, and work from the current NICE guideline.^[2]