Hypercholesterolemia and familial hypercholesterolemia

Definition

Hypercholesterolemia is a form of dyslipidemia with raised plasma cholesterol, particularly LDL cholesterol, that contributes to the development of atherosclerosis. Familial hypercholesterolemia (FH) is an inherited disorder of LDL clearance, usually due to a defect of the LDL receptor.

Classification

• By lipid pattern: isolated (pure) hypercholesterolemia, isolated hypertriglyceridemia or combined (mixed) hyperlipidemia; the former Fredrickson phenotype classification has largely been replaced.
• By cause: primary (genetic) or secondary.
• Heterozygous FH: frequency about 1:200; total cholesterol about 6.5–13 mmol/l (250–500 mg/dl).
• Homozygous FH: frequency about 1:250,000 to 1:1 million; total cholesterol above 13 mmol/l (above 500 mg/dl).
• Familial defective apolipoprotein B-100: defect of the LDL receptor-binding region, dominant, about 1:700.
• Gain-of-function mutations of PCSK9: increased degradation of LDL receptors, dominant, picture similar to FH.
• Polygenic hypercholesterolemia: common, total cholesterol about 6.5–9.0 mmol/l (250–350 mg/dl).

Aetiopathogenesis

• Primary: mutations of single or multiple genes leading to overproduction or reduced clearance of LDL. In FH (codominant inheritance) LDL clearance is reduced by the receptor defect.
• Secondary: in high-income countries mainly a sedentary way of living with excessive intake of calories, saturated fat, cholesterol and trans fats; also diabetes mellitus, chronic kidney disease, primary biliary cholangitis and other cholestatic liver diseases, hypothyroidism, alcohol overuse and certain drugs.

Clinical features

• Hypercholesterolemia itself causes no symptoms; the clinically relevant consequences are those of atherosclerosis.
• Heterozygous FH: tendon xanthomas, arcus corneae, premature coronary artery disease (about ages 30–50); FH is responsible for about 5 % of myocardial infarctions in people under 60.
• Homozygous FH: planar, tendon and tuberous xanthomas, coronary artery disease before the age of 18.
• Skin findings with markedly raised LDL (above 4.9 mmol/l or 190 mg/dl): tendon xanthomas at the Achilles tendon, elbows, knees and over the metacarpophalangeal joints; planar xanthomas (flat yellowish patches) and tuberous xanthomas (firm, painless nodules over the extensor surfaces of joints); arcus corneae; xanthelasma at the medial eyelids (also seen with normal lipid levels).

Diagnosis

• Lipid profile: total cholesterol, triglycerides and HDL cholesterol are measured directly, LDL cholesterol is usually calculated. Total cholesterol varies by about 10 % from day to day, triglycerides by up to 25 %. Fasting measurement is needed only in specific situations, for example with triglycerides above 4.5 mmol/l (400 mg/dl).
• Confounders: in acute illness triglycerides and lipoprotein(a) rise and cholesterol falls; after an acute myocardial infarction values fluctuate for about 30 days.
• Pointers to a primary disorder: premature atherosclerotic disease (men under 55, women under 60 years), a corresponding family history or severe hyperlipidemia in the family, LDL cholesterol above 4.9 mmol/l (190 mg/dl), xanthomas.
• Secondary causes are specifically sought (e.g. diabetes, kidney, liver and thyroid disease).

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Further reading (open access)

1. MSD Manual Professional: Dyslipidemia
2. StatPearls: Hypercholesterolemia
3. StatPearls: Familial Hypercholesterolemia

Cross-references