Familial Hypercholesterolaemia (FH) is an autosomal dominant disorder causing elevated cholesterol, particularly LDL-C, which accelerates atherosclerosis.
It presents in two forms:
- Homozygous FH: Extremely rare (~1 in 1,000,000), LDL-C 6–10× normal.
- Heterozygous FH: More common (~1 in 500), LDL-C 2–3× normal.

🧪 Lipid Physiology

Dietary fats: Absorbed as chylomicrons (cholesterol + triglycerides). Lipoprotein lipase breaks down triglycerides for energy → remnants cleared by liver via LDL receptors.
Endogenous triglycerides: Liver releases VLDL → fatty acids removed → LDL remains. HDL matures and helps reverse cholesterol transport.

⚡ Aetiology

Most cases due to mutations in the LDL receptor gene → defective clearance of LDL.
Other genetic causes include:
- ApoB100 mutations: Defective binding to LDL receptor.
- PCSK9 gain-of-function mutations: Accelerated LDL receptor degradation.

🩺 Clinical Presentation

Premature CAD: Common in heterozygotes, presenting in 30s–40s.
Peripheral vascular disease & stroke: ↑ risk compared with general population.
Physical signs:
- Tendon xanthomata: Firm nodules (Achilles, extensor tendons) → highly suggestive.
- Corneal arcus & xanthelasma → possible but nonspecific.

🔍 Investigations

Bloods: Markedly raised LDL-C; triglycerides and HDL usually normal.
Family history: Premature CAD or hyperlipidaemia.
Clinical findings: Presence of xanthomas supports diagnosis.
Genetic testing: May confirm mutations in LDLR, ApoB100, or PCSK9.

💊 Management

Lifestyle: Smoking cessation, BP & diabetes control, low-saturated-fat diet.
Medications:
- 📍 First-line: Statins (e.g. Atorvastatin 20 mg OD).
- 📍 Second-line: Ezetimibe → blocks gut cholesterol absorption.
- 📍 Third-line: PCSK9 inhibitors (e.g. Alirocumab) → potent LDL reduction.
- Other: Fibrates, cholestyramine, nicotinic acid (less commonly used now).
Advanced (Homozygous FH): May require LDL apheresis, liver transplant, or experimental approaches.
Hypertriglyceridaemia component: Treat with fibrates, nicotinic acid, or omega-3 fatty acids.

📌 Key Exam Tip

Tendon xanthomas + family history = classic clue for FH ⚡
Always consider in patients with premature CAD.
Remember PCSK9 inhibitors for resistant cases 🧬.

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Familial Hyperlipidaemias

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