Familial Hypercholesterolaemia
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Direct answer
Familial hypercholesterolaemia is an autosomal dominant disorder of LDL clearance, most often caused by a mutation in the LDL receptor gene, that produces very high LDL cholesterol from birth and premature coronary atherosclerosis. Heterozygous disease is common enough to matter in practice, and its diagnosis rests on the Dutch Lipid Clinic Network score, tendon xanthomas and family history. Management is early high-intensity statin therapy with cascade screening of first-degree relatives.
What you must remember
- Inheritance: autosomal dominant; LDL receptor mutations are commonest, followed by APOB defects and PCSK9 gain-of-function mutations.
- Homozygous disease: LDL cholesterol typically above 13 mmol/L, with tuberous and tendon xanthomas in childhood and coronary disease in childhood or early adult life.
- Tendon xanthomas: the Achilles and extensor tendons of the hands are the classic sites, and their presence is strongly suggestive of the diagnosis.
- Corneal arcus: appearing before age 45 in a patient with raised LDL cholesterol points towards familial hypercholesterolaemia.
- Dutch Lipid Clinic Network score: 3 to 5 is possible, 6 to 8 probable and above 8 definite; family history, LDL level, physical signs and genetic testing contribute points.
- Treatment: a statin, high-intensity in adults and started from about age 8 to 10 in selected children, with ezetimibe and PCSK9 inhibitors added; LDL apheresis is reserved for homozygous disease and for failure of drug therapy.
A 35-year-old with LDL 260 and a father who had an infarct at 48
A 35-year-old man has an LDL cholesterol of 260 mg/dL on repeat testing, with no secondary cause on thyroid function, urine protein and liver tests. His father had a myocardial infarction at 48, which is premature coronary disease in a first-degree relative.
- Score the patient: The examiner's next step is to score him on the Dutch Lipid Clinic Network system, where the score rises with LDL level, premature coronary disease in a first-degree relative, tendon xanthoma and arcus before 45.
- Test the gene: A probable or definite score justifies genetic testing, which confirms the mutation and identifies the family variant.
- Start treatment: Treatment starts with a high-intensity statin, with ezetimibe added when the LDL target is still missed.
- Screen relatives: Cascade screening follows, because each first-degree relative has a fifty per cent chance of carrying the same mutation.
- Screen children early: Children of affected parents are screened early, and treatment is started from around age ten in selected children, per current paediatric guidance.
- Check the local picture: In India, familial hypercholesterolaemia is under-recognised, so a lipid profile in a relative with premature heart disease is a practical screening step.
Where the examiner separates the look-alikes
The commonest confusion is between familial and polygenic hypercholesterolaemia, and examiners add look-alikes on top.
- Trap: Labelling polygenic hypercholesterolaemia as familial. Correct: The polygenic form raises LDL moderately, lacks tendon xanthomas and has no strong family pattern.
- Trap: Expecting one lipid pattern across a family. Correct: Familial combined hyperlipidaemia raises both LDL and triglycerides with variable phenotype, so members' lipid profiles differ.
- Trap: Applying a genetic label before excluding secondary causes. Correct: Hypothyroidism, nephrotic syndrome, cholestasis and anorexia nervosa all raise LDL cholesterol and must be excluded first.
- Trap: Ignoring pregnancy when prescribing statins to a woman of reproductive age. Correct: Statins are traditionally stopped before conception and during breastfeeding, through a planned change in therapy; recent labelling has relaxed the pregnancy rule, but the exam answer remains avoidance.
Frequently asked questions
What does the Dutch Lipid Clinic Network score estimate?
The Dutch Lipid Clinic Network score estimates the probability of familial hypercholesterolaemia by combining family history, LDL cholesterol level, physical signs and genetic testing. A score of 3 to 5 is possible, 6 to 8 probable, and above 8 definite. The result decides whether genetic testing and cascade screening are pursued.
Which physical signs suggest familial hypercholesterolaemia?
Tendon xanthomas over the Achilles and extensor tendons of the hands are the classic physical sign of familial hypercholesterolaemia. Corneal arcus before age 45 and xanthelasma are supportive findings, while tuberous xanthomas over the elbows and knees are seen in homozygous disease.
What is cascade screening in familial hypercholesterolaemia?
Cascade screening is the testing of first-degree relatives of a confirmed index patient, because each child or sibling has a fifty per cent chance of inheriting the mutation. It finds affected relatives before premature coronary disease appears.
Why is early statin therapy recommended in familial hypercholesterolaemia?
Heterozygous familial hypercholesterolaemia exposes arteries to high LDL cholesterol from birth, so atherosclerosis begins early and cumulative exposure is far above normal. Early high-intensity statin therapy reduces that lifelong burden, which is why treatment is started in childhood for selected patients.