HYPERLIPIDEMIAS The Basics

I. DISTURBANCIES OF LIPID METABOLISM Essential types of disturbances 1. Hyperlipoproteinemias 2. Hypolipoproteinemias 3. Dyslipidemias 4. Hyperlipidemias

DEFINITIONS Hyperlipoproteinemias : Pathologic process manifested by  concentration of one or more types of LPs in the blood Hyperlipidemia ( plasma cholesterol and/or triglyceride) is present in all hyperlipoproteinemias. Hypolipoproteinemias : – Decreased concentration of lipoproteins in the blood (usually VLDL, LDL) Dyslipidemias – disorder in lipid spectrum in blood, usually with increased concentration of cholesterol (TC, LDL-C, or HDL-C) and/or TG concentrations

ESSENTIAL TERMS a)Lipoproteins – spheric particles transporting non-polar lipids (TAGs, cholesterol esters)by blood Composition and properties – inside of sphere - non-polar lipids – surfice of sphere -polar molecules (phospholipids, non- esterified cholesterol- are important for transport of particles in plasma -apo-LPs - are important for LPs metabolism Different types of LPs differs by their density, by volume of transporting lipids, by size, by amount and kind of apo, by location of their creation, by their metabolism

CHARACTERISTICS OF MAIN TYPES OF LPS • Chylomicrons(CM) – the lowest density, the largest size • VLDL – smaller and more dense than CM – they transport endogenous TAGs synthetised in liver, mainly • IDL – particles with properties between VLDL and LDL • LDL – contain cholesterol esters, mainly • HDL – the smallest size and the highest density – they are able to transport cholesterol from peripheral tissues to liver (reversal transport of cholesterol)

• LDL receptor – it takes up LDL (IDL), it is localised at cells in different types of tissues, predominantly at hepatocytes In predisposed patients –  intake of cholesterol  down regulation of LDLr in liver   uptake of LDL from blood • HDL receptor – it takes up HDL from blood, it is localised predominantly in cells that create steroids

Scavenger receptors (SR) – uptake the LDL which were not bound by LDLr – uptake of oxidized LDL particles – they are present in macrophages, in smooth muscle cells in vessel wall  atherogenesis

Positive Family History Disease in a first-degree relative Characteristics That May Identify An Individual with a Genetic Predisposition to Cardiovascular Disease Positive Family History Disease in a first-degree relative Parents, siblings Disease in female relatives Disease in the absence of other recognized risk factors Early age-at-onset Genetically determined risk often characterized by an earlier age-at onset Hyperlipidemia resistant to dietary intervention

Mortality/Morbidity: If uncontrolled, there is a higher mortality from cardiovascular and cerebrovascular disease. Age: It may be present in children and young adults but is seen more frequently in later life. The secondary form is caused by other diseases, such as: diabetes mellitus, pancreatitis, renal disease, or hypothyroidism.

Classification of hyperlipoproteinemias (according Necas et al., 2000) Type  lipoprotein  lipid 1 CM TAG 2a LDL cholesterol 2b LDL,VLDL cholesterol, TAG 3 IDL,CM- remnants TAG, cholesterol 4 VLDL 5 VLDL,CM

Five classes of LDL-R mutations 1 Null (no protein synthesis) 2 Transport defect (Golgi) 3 LDL binding defect 4 Internalization-defective 5 Recycling-defective LDL-R bind LDL particles and endocytoses them via clathrin-coated vesicles LDL-R is recycled

 Main types of hyperlipoproteinemias (HLP) Primary 1. Familial combined HLP – it is the most frequent genetic HLP – it manifests most likely in phenotypes 2a, 2b, 5 – it is the strong risk factor for development of atherosclerosis and ischemic heart disease Mechanisms involved in development HLP • genetic predisposition • acquired (due to environmental factors) secretion of VLDL by liver 

2. FAMILIAL HYPERCHOLESTEROLEMIA (FH) – it manifests predominantly by phenotype 2a – it leads to significant acceleration of atherosclerosis development – myocardial infarction in 4th decade of life – xantomatosis of tendons and arcus lipoides corneae Mechanisms involved in FH development – mutation of LDL receptor  decreased uptake of LDL  concentration of LDL in blood

Tendon Xanthomas tendon xanthomas of the achilles and elbow

Tendon Xanthomas tendon xanthomas of the hand

Cutaneous Xanthomas

Hyperlipidemia signs Xanthoma- plaques or nodules composed of lipid-layden histiocytes (foamy cells) in the skin, especially the eyelids

Familial Hypercholesterolemia Findings in Homozygotes In patients with homozygous or heterozygous hypercholesterolemia, lipid is depostied along the ascending aorta and aortic valvular and supravalvar stenosis may occur ---- as demonstrated in this aorto-gram this coronary arteriogram shows ostial stenosis of the left coronary artery that typically occurs in hyperlipidemia. left coronary artery narrowing supravalvar lipid deposition

Eye Findings in Familial Hypercholesterolemia Arcus juvenilis----strong indication of hyperlipidemia and premature CAD Early corneal arcus Cholesterol deposits in retinal fundus

Corneal arcus Lipid deposit in cornea

Secondary Disorders of Lipid Metabolism Clinical Feature Obesity Increased TG, decreased HDL-C Diabetes mellitus Increased TG and TC, decreased HDL-C Chronic renal failure HIV/AIDS wasting Increased TG and TC, decreased HDL-C and LDL-C Hypothyroidism Increased TG, TC and LDL-C Nephrotic syndrome Increased TC and LDL-C Obstructive liver disease Increased TC Medications Variable C = Cholesterol; HAART = Highly-active antiretroviral therapy; HDL = High-density lipoprotein; LDL =Low-density lipoprotein; TC = Total cholesterol; TG = Triglyceride.

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