• Familial hypercholesterolemia is an inherited autosomal dominant disorder, characterized by high serum cholesterol (LDL-specific) at a young age.
• Associated with early cardiovascular disease.
• Underlying genetic cause can be identified (80%)

Epidemiology

• Very common disease
• Heterozygous 1:250--500
• Certain populations: Afrikaners 1:70 and French Canadian 1:200
• Homozygous 1:1,000,000
• Underdiagnosis is a global challenge, with only <50% of patients identified

Importance/Prognosis

• High risk of mortality due to high concentrations of plasma LDL from birth --> CVD and atherosclerosis
• Half of untreated heterozygous men and 30% of untreated women will have a myocardial infarction by the age of 50 and 60 years respectively
• Homozygous --> usually die before the age of 20 (life expectancy 18-32)
• 20% of MIs under age 45 are related to FHC
• Statins prolong life by approximately nine years

Pathophysiology

• Most common (60-80%): LDL receptor (LDLR) mutation, autosomal dominant

• Mutation: reduced expression or reduced function mainly in hepatocytes

• Increased serum LDL due to decreased clearance

• Compromised normal vasodilatory response of arteries

• Internalization of oxidized LDL by arterial wall macrophages --> intimal inflammation --> atherosclerosis

• Other mutations: ApoB100, PSCK9

Diagnosis

• There is no individual diagnostic test with sufficient specificity and sensitivity to reliably detect familial hypercholesterolaemia
• Diagnosis is based on clinical signs, family history, and cholesterol measurements
• Simon Broome Register Group definition of familial hypercholesterolemia

Clinical Features

• Relatives with early heart disease
• Physical examination
  • Signs are unusual and suspicious before age 45
  • Tendon/cutaneous xanthomas
    • Common: dorsum of hands, Achilles
    • Rarely: extensor hallucis longus and triceps tendons
    • Classically not present until the third decade of life --> not useful in younger patients
  • Xanthelasma
    • lipid deposits underneath the skin on or around the eye­ lids
  • Premature corneal arcus (a white or grey opaque ring in the corneal margin)
    • These are normal in older adults

Investigations

• Fasting total cholesterol > 7.5 mM
• Normal TGs
• Confirm measurements at least twice
• Cascade screening of first degree relatives
• Rule out common causes of secondary hypercholesterolemia

Management

• Lifestyle advice
• Risk stratification such as the Framingham score underestimate the risk with this disease

• Subclinical atherosclerotic disease

• CT angiography

• High-dose statin

• Goal: reduce LDL by >50%

• Mechanism: HMG-CoA reductase (RDS) inhibitor
• Promotion of cholesterol intake via increased LDLR (secondary effect)
• Statins reduce CVD risk in both homozygous and heterozygous familial hypercholesterolaemia

•  There is evidence towards putting everyone on statins.

• Ezetimibe

• Mechanism: cholesterol absorption inhibitor

• Bile acid sequestrants

• PCSK9 inhibitors

• Increasing in use

• Very expensive
• Last-line

Aphoresis (dialysis for cholesterol)

Transplant (liver)

Differential

• Sitosterolemia
• Hyperchylomicronemia
• Homozygous AR hypercholesterolemia (ARH)
• Polygenic hypercholesterolemia

Sources

• BMJ 2012;344:e3228
• Nature Reviews Disease Primers 2017; 17093