Hypercholesterolaemia

Hypercholesterolaemia is a raised blood cholesterol, defined in clinical practice as total cholesterol above 5.0 mmol/L (193 mg/dL) or LDL cholesterol (LDL-C) above 3.0 mmol/L (116 mg/dL), and it is the strongest lipid driver of atherosclerosis. Most cases are polygenic and made worse by diet, weight and medicines, but monogenic familial hypercholesterolaemia is common and under diagnosed.

• Familial hypercholesterolaemia affects about 1 in 250 people (heterozygous). LDL-C is usually above 4.9 mmol/L (190 mg/dL) in adults and above 4.0 mmol/L (155 mg/dL) in children, with a dominant family pattern. Untreated, men have coronary disease in their 40s to 50s and women in their 50s to 60s. Homozygous disease (about 1 in 300,000) causes cutaneous xanthomas and coronary disease in childhood.
• Secondary contributors: hypothyroidism, nephrotic syndrome, cholestasis, obesity, diabetes, pregnancy, anorexia nervosa, Cushing syndrome, high saturated fat diet, and drugs (thiazide, ciclosporin, corticosteroids, antipsychotics, retinoids, protease inhibitors).
• Each 1 mmol/L reduction in LDL-C reduces major vascular events by about 20 to 25 percent, so earlier and longer lowering confers greater benefit.

• Usually no symptoms. Tendon xanthomata (Achilles, hand extensor tendons), xanthelasma, corneal arcus before the age of 45, tuberous xanthomata over elbows and knees.
• Family history of premature coronary disease or high cholesterol; children of affected parents.
• Presentation with chest pain, myocardial infarction, stroke, or claudication.
• Look for secondary causes: weight, thyroid disease, oedema, jaundice, medicines.

• Non-fasting lipid profile with total cholesterol, LDL-C, HDL-C, triglycerides, non-HDL-C; repeat after 1 to 3 months to confirm.
• Exclude secondary causes: thyroid stimulating hormone, glucose or HbA1c, creatinine, eGFR, urine protein, liver function tests.
• Calculate cardiovascular risk (age, sex, smoking, blood pressure, diabetes, total to HDL ratio).
• Suspect familial hypercholesterolaemia in adults with LDL-C above 4.9 mmol/L, or LDL-C above 4.0 mmol/L with family history or tendon xanthomata; confirm by genetic testing for LDL receptor, apolipoprotein B and PCSK9 variants, and test relatives at risk (cascade testing).
• Lipoprotein(a) measured once.
• Coronary artery calcium score or carotid ultrasound when risk is uncertain.
• Differentials: other dyslipidaemias, sitosterolaemia (tendon xanthomata with a poor statin response), cerebrotendinous xanthomatosis.

Lifestyle

• Replace saturated with unsaturated fat; avoid trans fats; plant sterols or stanols 2 g daily; soluble fibre 5 to 10 g daily (oats, psyllium, pulses); weight loss when overweight; exercise 150 minutes per week; alcohol within 14 units per week; stop smoking.

Statin therapy (core)

• Atorvastatin 20 mg orally at night, increased to 40 to 80 mg; rosuvastatin 10 mg, increased to 20 to 40 mg; simvastatin 40 mg (maximum 20 mg with amlodipine, 10 mg with diltiazem and verapamil; not with clarithromycin, itraconazole or ciclosporin); pravastatin 40 mg when interactions matter.
• Familial hypercholesterolaemia: high intensity statin in adults, aiming for 50 percent or more reduction and LDL-C below 2.5 mmol/L (primary prevention) or below 1.4 mmol/L (established disease or high risk).
• Check ALT and lipids at baseline and 8 to 12 weeks, then yearly. Check creatine kinase only for muscle pain or weakness.

Combination therapy

• Add ezetimibe 10 mg once daily if the target is not reached after 4 to 6 weeks of maximum tolerated statin dose (further 15 to 20 percent reduction).
• Add bempedoic acid 180 mg once daily (tendon rupture risk; do not combine with simvastatin above 40 mg).
• PCSK9 inhibitors: evolocumab 140 mg subcutaneously every 2 weeks or 420 mg monthly; alirocumab 75 or 150 mg every 2 weeks; inclisiran 284 mg subcutaneously at 0 and 3 months, then every 6 months. These lower LDL-C by 50 to 60 percent and are for specialist use in familial hypercholesterolaemia or established disease not at target.
• Lomitapide, mipomersen and lipoprotein apheresis are homozygous disease options, in specialist centres.

Statin intolerance

• Exclude interacting drugs, hypothyroidism, low vitamin D and excess exercise; stop for 2 to 4 weeks, then re-challenge with the same statin at a lower dose, or change to rosuvastatin 5 mg daily or alternate days, or pravastatin or fluvastatin. If intolerance persists use ezetimibe, bempedoic acid or a PCSK9 inhibitor.

Special groups

• Children with familial hypercholesterolaemia: diet from diagnosis, statin from 8 to 10 years (pravastatin 10 to 20 mg, atorvastatin 10 mg, rosuvastatin 5 to 10 mg), growth and pubertal monitoring.
• Women planning pregnancy: stop statins 3 months before conception when possible, resume after breastfeeding; use a bile acid sequestrant (colesevelam) if needed.
• Older adults: continue statins; start low dose when frail.
• Chronic kidney disease: rosuvastatin 5 to 10 mg (not above 10 mg if eGFR below 30), atorvastatin with ezetimibe.

Follow up

• Lipid profile at 8 to 12 weeks, then annually; family cascade testing; refer to a lipid specialist for LDL-C above 5 mmol/L on treatment, suspected homozygous disease, children, or intolerance.