AKT · Endocrine/Lipids, metabolic & inheritedlow yield

Familial hypercholesterolaemia

Autosomal-dominant LDL-receptor pathway defect → very high LDL

Overview

An autosomal-dominant defect of LDL clearance (LDL-receptor, ApoB or PCSK9 gain-of-function) causing lifelong very high LDL cholesterol and premature atherosclerotic disease. Recognised by very high cholesterol, tendon xanthomata and a family history of early coronary disease. Needs early high-intensity statin (often + ezetimibe/PCSK9) and cascade testing of relatives.

Recognise

Very high LDL/total cholesterol from a young age; premature coronary disease (often <55 men / <60 women) in the patient or family
Tendon XANTHOMATA (Achilles, knuckle extensors), xanthelasma, premature corneal arcus
Homozygous FH: extreme cholesterol, childhood atherosclerosis — rare, severe

Red flags

Premature/cardiac death in the family; homozygous FH in childhood → specialist lipid clinic
Total cholesterol >9 / non-HDL >7.5 should trigger the diagnosis

Differentials & how to tell them apart

Polygenic/common hypercholesterolaemiahigh cholesterol without the very high levels, xanthomata or AD family pedigree

Secondary hypercholesterolaemiahypothyroidism, nephrotic, cholestasis — treat the cause

Investigations

Lipid profile (very high LDL), Simon Broome/Dutch criteria, family history, genetic testing; exclude secondary causes. CASCADE testing of first-degree relatives.

Management

High-intensity statin ± ezetimibe/PCSK9 + cascade-test relatives

1Diagnose clinically (criteria) ± genetics; refer to a lipid specialist. High-intensity statin (often plus ezetimibe), aiming for substantial LDL reduction.Gate: CASCADE-test first-degree relatives (50% inherit it) — finding and treating them early prevents premature coronary death; statins remain contraindicated in pregnancy
2Add ezetimibe then PCSK9 inhibitor/inclisiran to reach targets; apheresis for homozygous FH; manage all cardiovascular risk factors.

High-intensity statin (atorvastatin/rosuvastatin) — first-line, often from a young age

Ezetimibe; PCSK9 inhibitor / inclisiran — add to reach LDL targets

Apheresis — homozygous/refractory FH (specialist)

Key points

Very high cholesterol + tendon xanthomata + premature family coronary disease = FH. The exam points: the >9 / >7.5 thresholds, and cascade-testing relatives. Treat early and hard.

Monitor & prognosis

LDL targets; cardiovascular surveillance; family screening.

Good if treated early; premature CVD if untreated.

Source: NICE CG71 (familial hypercholesterolaemia)