Dyslipidemia and Dyslipoproteinemia

Dyslipidaemia is an abnormality in the concentration or composition of blood lipids and lipoproteins — most often raised LDL cholesterol or triglycerides, or low HDL cholesterol. As disturbances of the lipoprotein pathways, the dyslipidaemias range from common acquired patterns to monogenic disorders such as familial hypercholesterolaemia, and they are major contributors to atherosclerotic cardiovascular disease.

Definition

Dyslipidaemia (or dyslipoproteinaemia) is any abnormality in plasma lipid or lipoprotein levels — including elevated total or LDL cholesterol, elevated triglycerides, or reduced HDL cholesterol — arising from disturbed lipoprotein metabolism and associated with increased cardiovascular risk.

Scope

The topic covers the definition and classification of lipid and lipoprotein disorders, their primary (genetic) and secondary (acquired) causes, the historical Fredrickson phenotypes, key monogenic forms such as familial hypercholesterolaemia, and the link between dyslipidaemia and atherosclerosis. It is a reference and educational entry and does not provide individualised diagnostic thresholds or treatment regimens.

Core questions

• How are lipid and lipoprotein disorders defined and classified?
• What distinguishes primary (genetic) from secondary (acquired) dyslipidaemias?
• What is the molecular basis of familial hypercholesterolaemia?
• How does dyslipidaemia contribute to atherosclerosis and cardiovascular risk?

Key concepts

• Primary vs secondary dyslipidaemia
• Fredrickson phenotypes
• Familial hypercholesterolaemia
• LDL receptor and PCSK9
• Hypertriglyceridaemia
• Atherogenic dyslipidaemia

Key theories

Fredrickson phenotypic classification

Fredrickson and Lees classified the hyperlipoproteinaemias into phenotypes (I–V) according to which lipoprotein fraction is elevated, giving an early systematic framework for these disorders.

LDL-receptor basis of familial hypercholesterolaemia

Goldstein and Brown showed that familial hypercholesterolaemia results from defects in the LDL receptor, impairing LDL clearance and raising plasma cholesterol — a paradigm linking a single gene to a lipid disorder.

Mechanisms

Dyslipidaemias arise when any step of lipoprotein production, remodelling, or clearance is disturbed. In familial hypercholesterolaemia, loss-of-function defects in the LDL receptor (or gain-of-function mutations in PCSK9, which degrades the receptor) reduce LDL clearance and raise plasma LDL cholesterol; Abifadel and colleagues identified PCSK9 as a third gene causing autosomal dominant hypercholesterolaemia. Secondary dyslipidaemias result from conditions such as diabetes, obesity, hypothyroidism, or drugs that alter lipoprotein metabolism. Persistently elevated atherogenic lipoproteins drive the deposition of cholesterol in arterial walls, initiating atherosclerosis.

Clinical relevance

Dyslipidaemia is a central modifiable risk factor for atherosclerotic cardiovascular disease, and lipid assessment is routine in cardiovascular risk evaluation. This entry summarises definitions, causes, and mechanisms for reference; diagnostic cut-points and management belong to current clinical guidelines and individual clinical judgement, not to this educational summary.

Epidemiology

Elevated LDL cholesterol and related lipid abnormalities are highly prevalent worldwide and are leading contributors to the global burden of cardiovascular disease, which is why guidelines emphasise their detection and management.

Evidence & guidelines

Major guidelines, including the 2019 ESC/EAS dyslipidaemia guidelines and the earlier NCEP Adult Treatment Panel III report, codify how lipid disorders are defined and related to cardiovascular risk; they represent the consensus evidence framework for the topic.

History

Fredrickson and Lees introduced a phenotypic classification of the hyperlipoproteinaemias in 1967, organising the field. The molecular era followed: Goldstein and Brown traced familial hypercholesterolaemia to LDL-receptor defects, and in 2003 Abifadel and colleagues identified PCSK9 mutations as a further genetic cause, work that later inspired a new class of cholesterol-lowering biology.

Key figures

• Donald Fredrickson
• Joseph Goldstein
• Michael Brown
• Catherine Boileau
• Marianne Abifadel

Seminal works

• fredrickson-1967
• goldstein-brown-1979
• abifadel-2003

Frequently asked questions

What is the difference between primary and secondary dyslipidaemia?

Primary dyslipidaemias are caused by genetic defects in lipoprotein metabolism, such as familial hypercholesterolaemia, whereas secondary dyslipidaemias result from other conditions or drugs — for example diabetes, obesity, or hypothyroidism — that alter blood lipids.

Why does familial hypercholesterolaemia raise LDL cholesterol?

It is caused by defects in the LDL receptor pathway (in the receptor itself, its ligand apoB, or the regulator PCSK9) that impair clearance of LDL from the blood, so LDL cholesterol accumulates.