Hypercholesterinaemia

Hypercholesterinaemia is a condition characterized by persistently elevated cholesterol levels in the blood, most notably high low-density lipoprotein cholesterol (LDL-C). It raises the risk of atherosclerotic cardiovascular disease (ASCVD) and can be inherited (familial hypercholesterolaemia) or acquired due to other medical conditions or medications.

Causes and pathophysiology

The most common hereditary form is familial hypercholesterolaemia (FH), usually inherited in an autosomal dominant pattern, caused by mutations in LDLR, APOB, or PCSK9 that reduce clearance of LDL particles from the bloodstream. Secondary causes include hypothyroidism, nephrotic syndrome, liver disease, diabetes, obesity, high-calorie or high-saturated-fat diets, and certain drugs. In all forms, excess LDL-C promotes deposition of cholesterol in arterial walls, accelerating atherogenesis.

Presentation and diagnosis

Many individuals are asymptomatic until ASCVD develops. Physical signs may include tendon xanthomas, xanthelasma, and corneal arcus, particularly in younger patients with FH. Diagnosis relies on lipid testing, typically a fasting lipid panel showing elevated LDL-C, total cholesterol, and sometimes triglycerides. In adults, an LDL-C level of 4.9 mmol/L (190 mg/dL) or higher suggests probable FH, especially with a family history or premature ASCVD. Genetic testing and cascade screening of relatives support diagnosis and management decisions.

Management

Lifestyle modification is foundational, including a diet low in saturated fat and cholesterol, regular physical activity, weight management, and smoking cessation. Pharmacotherapy is central to treatment: statins are first-line to reduce LDL-C; ezetimibe can be added if needed. For high-risk or statin-intolerant individuals, PCSK9 inhibitors, bempedoic acid, and other agents such as lomitapide or mipomersen may be used in selected cases (notably for homozygous FH). In severe cases, LDL apheresis or liver transplantation may be considered. Pregnancy requires avoidance of statins.

Epidemiology and prognosis

Heterozygous FH affects about 1 in 200–250 people globally; homozygous FH is much rarer. With effective treatment, the excess ASCVD risk is substantially reduced, though lifelong management is often required.