Etiology
Your Organizational Guidance
ebpracticenet urges you to prioritize the following organizational guidance:
Évaluation du risque cardiovasculaire en première lignePublished by: Domus MedicaLast published: 2010Cardiovasculaire risicobepaling in de eerste lijnPublished by: Domus MedicaLast published: 2020The etiology of hypercholesterolemia can be classified into primary and secondary causes.
Primary causes are due to single or multiple gene mutations resulting in a disturbance of low-density lipoprotein (LDL) and/or triglyceride production or clearance. These vary in location of genetic defect, inheritance pattern, prevalence, clinical features, and treatment. At least 18 separate entities have been described.[13] The suspicion for a primary lipid disorder should be especially high in patients with premature atherosclerotic cardiovascular disease (ASCVD), a family history of early ASCVD, a significantly elevated serum cholesterol level (>240 mg/dL), or physical signs of hyperlipidemia. Primary dyslipidemias are most commonly seen in children and young adults and cause a small percentage of cases in adults. LDL-cholesterol (LDL-C) ≥190 mg/dL in adults, and ≥160 mg/dL in children and adolescents, may indicate the presence of familial hypercholesterolemia (FH). In that circumstance, first-degree family members must also be checked for dyslipidemia, as FH is an autosomal co-dominant disease (meaning that inheriting just one affected allele can cause hyperlipidemia). If other cases are found, relatives must also be checked for elevated LDL-C (cascade screening). FH is usually characterized by a family history of both early coronary heart disease and physical exam findings such as xanthomas within affected family members.
Most adult cases of dyslipidemia are due to a combination of the effects of polygenes and unhealthy lifestyle. In many Western countries, sedentary lifestyle and excessive consumption of saturated fats and trans-fatty acids are the most important secondary causes.[14] Certain medical conditions are commonly associated with dyslipidemia, including chronic renal insufficiency, abdominal obesity, diabetes mellitus, hypothyroidism, cholestatic liver disease, and alcohol dependency. Certain drugs, including high-dose thiazide diuretics, oral estrogens, glucocorticoids, anabolic steroids, anti-HIV agents, and atypical antipsychotics such as olanzapine and clozapine have also been implicated in causing mild-to-moderate degrees of dyslipidemia.[15] Use of atypical antipsychotics, such as olanzapine and clozapine, and of beta-blockers without intrinsic sympathomimetic or alpha-blocking activities are associated with reduced high-density lipoprotein cholesterol (HDL-C). Notably, the role HDL-C plays in dyslipidemia remains debatable, with very high levels of HDL-C conversely being associated with increased mortality in individuals with coronary artery disease.[16]
Pathophysiology
Hypercholesterolemia develops as a consequence of abnormal lipoprotein metabolism, mainly reductions in low-density lipoprotein (LDL) receptor expression or activity, and consequently diminishing hepatic LDL clearance from the plasma. This is a major predisposing risk factor for the development of atherosclerosis. This mechanism is classically seen in familial hypercholesterolemia and when excess saturated or trans fat is ingested. In addition, excessive production of very low-density lipoprotein by the liver, as seen in familial combined hyperlipidemia and insulin resistance states such as abdominal obesity and type 2 diabetes, can also induce hypercholesterolemia or mixed dyslipidemia.
A current theory for the initiating event in atherogenesis is that apolipoprotein B-100-containing lipoproteins are retained in the subendothelial space, by means of a charge-mediated interaction with extracellular matrix and proteoglycans.[17] This allows reactive oxygen species to modify the surface phospholipids and unesterified cholesterol of primarily LDL-cholesterol (LDL-C), but also other lipoproteins. Circulating LDL-C can also be taken up into macrophages through unregulated scavenger receptors. As a result of LDL-C oxidation, isoprostanes are formed. Isoprostanes are chemically stable, free radical-catalyzed products of arachidonic acid, and are structural isomers of conventional prostaglandins. Isoprostane levels are increased in atherosclerotic lesions, but they may also be found as F2 isoprostanes in the urine of asymptomatic patients with hypercholesterolemia.[18]
A strong association exists between elevated plasma concentrations of oxidized LDL-C and coronary heart disease.[19] The mechanisms through which oxidized LDL-C promotes atherosclerosis are multiple and include damage to the endothelium, induction of growth factors, inflammatory pathway stimulation, and recruitment of macrophages and monocytes.
Vasoconstriction in the setting of high levels of oxidized LDL-C seems to be related to a reduced release of the vasodilator nitric oxide from the damaged endothelial wall, as well as increased platelet aggregation and thromboxane release.
Smooth muscle proliferation has also been linked to the release of cytokines from activated platelets.[20]
The state of hypercholesterolemia leads invariably to an excess accumulation of oxidized LDL-C within the macrophages, thereby transforming them into "foam" cells. The rupture of these cells can lead to further damage of the vessel wall due to the release of oxygen free radicals, oxidized LDL-C, and intracellular enzymes.
Classification
World Health Organization/Fredrickson classification[2]
Classically, dyslipidemia can be classified phenotypically by lipid electrophoresis based on which lipoprotein is raised.
Type:
I - elevated chylomicrons; associated with lipoprotein lipase deficiency, apolipoprotein C-II deficiency
IIa - elevated LDL; associated with familial hypercholesterolemia, polygenic hypercholesterolemia, nephrosis, hypothyroidism, familial combined hyperlipidemia
IIb - elevated LDL and very low-density lipoprotein (VLDL); associated with familial combined hyperlipidemia
III - elevated intermediate-density lipoprotein; associated with dysbetalipoproteinemia
IV - elevated VLDL; associated with familial hypertriglyceridemia, familial combined hyperlipidemia, sporadic hypertriglyceridemia, abdominal obesity, diabetes
V - elevated chylomicrons and VLDL; associated with diabetes.
Clinical classification
In a more simple and practical way, dyslipidemia can also be classified as:
Isolated hypercholesterolemia: mostly due to LDL-C elevation
Mixed or combined dyslipidemia: elevations in total or LDL-C, and in triglycerides
Isolated hypertriglyceridemia: elevation in triglycerides only
Low HDL-cholesterol (HDL-C): either isolated or in association with hypercholesterolemia or hypertriglyceridemia. Causes of low HDL-C include abdominal obesity with insulin resistance, hypertriglyceridemia, smoking, and genetic diseases such as apoA-I, ABCA1 (adenosine triphosphate-binding cassette transporter), or lecithin-cholesterol acyltransferase deficiency.
Use of this content is subject to our disclaimer