Familial Hypercholesterolaemia

Definition/diagnostic criteria Familial hypercholesterolaemia (FH) is a genetic disorder characterised by high cholesterol levels, specifically low-density lipoprotein cholesterol (LDL-C), leading to early cardiovascular disease. FH is typically diagnosed using criteria such as the Simon Broome criteria, which take into account total cholesterol levels, family and personal history of coronary heart disease, and clinical signs like tendon xanthomas. DNA testing is recommended for definitive diagnosis​​.

The Simon Broome criteria define FH as follows:

• ‘Definite’ FH: Total cholesterol levels greater than 7.5 mmol/l in adults or 6.7 mmol/l in children, or LDL cholesterol levels greater than 4.9 mmol/l in adults or 4.0 mmol/l in children, along with either tendon xanthomas in the patient or a first- or second-degree relative, or DNA evidence of an LDL receptor mutation, familial defective apo-B-100 or a PCSK9 mutation.
• ‘Possible’ FH: Similar cholesterol levels but without tendon xanthomas but with a family history of premature myocardial infarction (a second-degree relative aged 50 years or younger, or in a first-degree relative aged 60 years or younger) or a family history of raised total cholesterol greater than 7.5 mmol/l in adult first- or second-degree relatives, or greater than 6.7 mmol/l in a child, brother or sister aged younger than 16 years.

Epidemiology FH is one of the most common inherited metabolic disorders, affecting about 1 in 250 people worldwide. It significantly increases the risk of coronary artery disease.

Diagnosis
Clinical features:

• Elevated cholesterol levels: Total cholesterol >7.5 mmol/l (6.7 mmol/l in children), or LDL-C >4.9 mmol/l (4.0 mmol/l in children).
• Physical signs: Tendon xanthomas

Investigations:

• Blood tests for lipid profile.
• Genetic testing to confirm mutation.
• Exclusion of secondary causes of hyperlipidaemia​​.

Treatment
Adults: Lifelong lipid-modifying therapy, typically high-intensity statins, is recommended. If statins are not suitable, ezetimibe may be considered. If such treatment is not tolerated or effective, specialist referral is required. NICE guidance on FH recommends a target reduction of low-density lipoprotein (LDL) cholesterol of more than 50% from baseline.
Children: Treatment generally starts by age 10, with statins being the first-line therapy. Specialist referral is essential for management and monitoring​​.

Prognosis With early diagnosis and appropriate management, including lifestyle interventions and treatment, individuals with FH can have a life expectancy similar to the general population. However, untreated, FH results in a greater than 50% risk of coronary heart disease (CHD) in men by age 50 and at least 30% in women by age 60.

Continuous patient education and support for lifestyle modifications, as well as regular monitoring of therapy and lipid levels, are crucial for managing FH effectively. Cascade testing for family members is also recommended​​.