High Cholesterol (Hypercholesterolaemia) — Causes, Symptoms & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Cholesterol is an essential lipid molecule used for cell membrane synthesis, steroid hormone production, bile acid production, and vitamin D synthesis. It is transported in the bloodstream in lipoproteins: LDL (low-density lipoprotein — 'bad cholesterol' — carries cholesterol to tissues; excess accumulates in arterial walls as atherosclerotic plaques), HDL (high-density lipoprotein — 'good cholesterol' — transports cholesterol from tissues back to the liver for excretion), and VLDL (carries triglycerides). Hypercholesterolaemia — elevated LDL cholesterol — is a major, independent, modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) — specifically coronary artery disease, ischaemic stroke, and peripheral artery disease. The WHO estimates that raised cholesterol contributes to 4.4 million deaths per year globally. High cholesterol has no symptoms — it is detected only by a blood test (lipid profile/fasting lipids).

Primary (genetic) hypercholesterolaemia: Familial Hypercholesterolaemia (FH) — most important genetic lipid disorder — autosomal dominant mutation in the LDL receptor gene (LDLR, most common), apolipoprotein B (APOB), or PCSK9; heterozygous FH affects 1 in 250 people; causes very high LDL from birth (5-10 mmol/L); markedly elevated risk of premature coronary artery disease (heart attack before 55 in men, before 60 in women) if untreated. Polygenic hypercholesterolaemia — common form — multiple gene variants each contributing modest LDL elevation. Secondary (acquired) hypercholesterolaemia: diet (high saturated and trans fat intake — cheese, butter, red meat, pastries), obesity, type 2 diabetes, hypothyroidism, nephrotic syndrome, cholestatic liver disease, excessive alcohol, and medications (corticosteroids, cyclosporin, atypical antipsychotics, some antiretrovirals). Lifestyle factors: sedentary lifestyle and a diet high in saturated fatty acids raise LDL by reducing hepatic LDL receptor expression.

High cholesterol is entirely asymptomatic — it does not cause pain, fatigue, or any perceptible symptoms. It is detected only by a blood lipid profile (ideally fasting for triglyceride accuracy, though non-fasting is acceptable for LDL and total cholesterol screening). This is why population screening programmes are essential — the first manifestation of untreated FH or severe hypercholesterolaemia is often a heart attack or stroke. Physical signs (in severe or longstanding cases, particularly FH): Tendon xanthomata — cholesterol deposits in tendons, typically Achilles tendons and extensor tendons of the hands — pathognomonic of FH when present. Corneal arcus (greyish-white ring around the cornea periphery) — before age 50 suggests FH. Xanthelasma (yellowish cholesterol deposits around the eyelids) — associated with hypercholesterolaemia but less specific.

Fasting lipid profile: total cholesterol, LDL cholesterol, HDL cholesterol, non-HDL cholesterol (total - HDL), and triglycerides. Target levels for general population: LDL below 3.0 mmol/L (115 mg/dL); for high CV risk: below 2.6 mmol/L (100 mg/dL); for very high CV risk or established CVD: below 1.8 mmol/L (70 mg/dL) and at least 50% reduction from baseline. Cardiovascular risk calculators: QRISK3 (UK), Framingham, SCORE2 (ESC) — calculate 10-year ASCVD risk using age, sex, cholesterol, blood pressure, diabetes, smoking, to guide treatment threshold. Cascade screening for FH: when a patient is diagnosed with FH, first-degree relatives should be tested. Simon Broome or Dutch Lipid Clinic criteria diagnose FH clinically. Genetic testing for LDLR/APOB/PCSK9 mutations confirms FH and identifies family members. Secondary causes excluded by TFTs, HbA1c, renal function, liver function, and urinary protein.

Lifestyle modification (all patients): Mediterranean diet (replace saturated fats with monounsaturated fats — olive oil, nuts, avocado; increase oily fish, legumes, fibre; reduce red and processed meat, butter, pastry, coconut oil), regular aerobic exercise (150 minutes per week), smoking cessation, weight reduction, and limit alcohol. Dietary changes achieve LDL reductions of 10-20%. Pharmacotherapy — first-line: Statins (HMG-CoA reductase inhibitors) are the cornerstone of lipid-lowering therapy. High-intensity statins (atorvastatin 40-80mg, rosuvastatin 20-40mg) reduce LDL by 40-55% and reduce major cardiovascular events (MI, stroke, CV death) by 25-35% per mmol/L LDL reduction. Indicated in: established ASCVD (secondary prevention), 10-year CV risk above 10%, FH, and diabetes with cardiovascular risk factors. Second-line add-on therapy: ezetimibe (Zetia) — inhibits intestinal cholesterol absorption, reduces LDL by additional 15-25%; used when statin monotherapy insufficient or statin intolerant. PCSK9 inhibitors (evolocumab — Repatha, alirocumab — Praluent): monoclonal antibodies injected every 2-4 weeks, reducing LDL by 55-60% in addition to statin; indicated for very high CV risk or FH with elevated LDL on maximum tolerated statin + ezetimibe; FOURIER and ODYSSEY OUTCOMES trials show significant CV event reduction. Inclisiran (siRNA — Leqvio): twice-yearly subcutaneous injection, similar LDL reduction to PCSK9 inhibitors; newer mechanism. Bile acid sequestrants (cholestyramine, colesevelam): modest LDL reduction, useful adjuncts.

Untreated hypercholesterolaemia causes progressive atherosclerosis — the gradual accumulation of lipid-rich plaques in arterial walls — with potentially life-threatening cardiovascular consequences. Acute myocardial infarction (heart attack) occurs when an atherosclerotic plaque ruptures, triggering acute coronary thrombosis with myocardial ischaemia and necrosis; statin therapy reduces this risk by 25-35% per mmol/L LDL reduction. Ischaemic stroke results from carotid or cerebral artery atherosclerosis causing thromboembolism and cerebral infarction. Peripheral artery disease causes intermittent claudication, critical limb ischaemia, non-healing ulcers, and amputation risk. Familial hypercholesterolaemia (FH) untreated from childhood — with LDL levels 5-10 mmol/L from birth — accumulates decades of excessive cholesterol exposure, causing coronary artery disease before age 55 in men and before 60 in women if untreated; homozygous FH is life-threatening without aggressive treatment including LDL apheresis and PCSK9 inhibitors. Ischaemic cardiomyopathy and heart failure result from repeated or extensive myocardial infarction. Aortic stenosis is accelerated by hypercholesterolaemia through similar plaque-forming mechanisms as coronary atherosclerosis. In FH, tendon xanthomata and corneal arcus signify decades of severe LDL elevation requiring urgent intensification of lipid-lowering treatment, including PCSK9 inhibitors (evolocumab or alirocumab) achieving additional 55-60% LDL reduction beyond maximum-dose statin therapy.

Mediterranean dietary pattern: emphasise fruits, vegetables, wholegrains, legumes, nuts, olive oil, and oily fish (salmon, mackerel, sardines — omega-3 fatty acids); replace butter and tropical oils with olive oil; reduce red meat to 2-3 times weekly; minimise ultra-processed foods, pastries, and full-fat dairy. Plant sterols and stanols (2g/day in fortified margarines, yoghurts) reduce LDL by 10%. Soluble fibre (oats, barley, psyllium, legumes) reduces LDL by 5-10%. Regular aerobic exercise raises HDL by 5-10% and lowers triglycerides. Maintain healthy weight — central obesity drives insulin resistance and dyslipidaemia. Quit smoking — smoking lowers HDL and promotes LDL oxidation. Limit alcohol — heavy alcohol raises triglycerides and blood pressure. NHS Health Check / routine GP screening: all adults should have lipid profile measured every 5 years from age 40 (more frequently in FH, diabetes, or established CVD). Family members of FH patients should be cascade-screened from childhood.

See your GP to have your cholesterol checked if you are over 40 and have not had a recent test, you have a family history of high cholesterol or early heart disease (heart attack or stroke before 60 in a first-degree relative), you have diabetes, high blood pressure, or obesity, or you have noticed xanthomata (lumps on tendons) or xanthelasma (yellowish deposits around eyelids). Seek urgent medical attention for symptoms of a heart attack (chest pain, breathlessness, arm or jaw pain) or stroke (FAST symptoms) — these may be the first sign of untreated hypercholesterolaemia. Children from families with known FH should be tested by age 10 and started on statins if LDL is elevated.