Familial hypercholesterolaemia and the defective LDL receptor
Familial hypercholesterolaemia (FH), an inherited condition of high LDL cholesterol, is usually caused by a faulty LDL receptor, so the liver clears LDL slowly.
Remember
In familial hypercholesterolaemia the usual fault is the LDL receptor: the liver removes LDL slowly, so LDL cholesterol is high from birth.
The liver is where LDL (low-density lipoprotein, the cholesterol-rich particle that carries cholesterol from the liver to the tissues) is mainly taken back out of the blood. The LDL receptor is a docking site on liver cells: it recognises apoB-100, a surface protein on LDL, so that the liver can remove it.
In familial hypercholesterolaemia (FH) the receptor gene is usually faulty, so the liver clears LDL slowly and LDL cholesterol is high from birth. That exposure is cumulative (it adds up over time), so the risk of premature (early) atherosclerosis and coronary heart disease rises sharply. FH is inherited in a dominant pattern: most people with it have one faulty copy of the gene, so each child of such a parent has a 50 percent chance of inheriting it.
The clues are a markedly raised LDL with a normal triglyceride, as in a lean, active young person, and a family history of early heart disease. Tendon xanthomas (hard cholesterol deposits in tendons, typically the Achilles) are highly suggestive of FH.
Exams still use the older Fredrickson classification, which groups lipid disorders by the lipoprotein that is raised on a blood test. Type IIa is the raised-LDL pattern, and its classic cause is a defective LDL receptor.
Before diagnosing FH, check for secondary causes (a high cholesterol caused by another illness or drug) and take two LDL measurements. A person with a clinical diagnosis is referred to a specialist to confirm it, and cascade testing means finding affected relatives.
Key facts
- Usual cause
- a faulty LDL receptor, so the liver clears LDL slowly.
- Typical pattern
- a markedly raised LDL with a normal triglyceride and early heart disease in the family.
- Fredrickson label
- type IIa, the raised-LDL pattern.
- Tendon xanthomas
- hard cholesterol deposits in tendons that appear from about 20 years of age in the common form of FH (one faulty copy of the gene).
- Inheritance
- dominant, so each child of a parent with one faulty copy of the gene has a 50 percent chance of inheriting FH.
- Next step
- specialist referral to confirm the diagnosis and test relatives (cascade testing).
- Treatment
- a statin (which inhibits an enzyme used in cholesterol production, HMG CoA reductase) increases the number of LDL receptors and so increases LDL clearance.
Exam traps
- Lipoprotein lipase deficiency (lipoprotein lipase strips triglyceride from chylomicrons, the particles that carry dietary triglyceride from the gut) does not explain a high LDL, because chylomicrons then cannot be stripped of their triglyceride and triglyceride rises very high.
- Making more chylomicrons would raise triglyceride after meals, and chylomicrons are not the main source of a raised LDL, so this does not fit a normal triglyceride with a high LDL.
- A faulty apoE (a surface protein that lets the liver take up remnant particles, such as the leftovers of chylomicrons) raises cholesterol and triglyceride together, so it does not give an isolated high LDL.
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