Defined on the basis of solubility.Lipids are heterogeneous group of water

insoluble (hydrophobic) organic molecules, they are chemically diverse compound but have one feature: water insoluble

FunctionsThe biological functions of lipids are divers as

their chemistry 1. Lipids in form of a bilayer are essential

components of biological membranes. 2. Lipids containing hydrocarbon side chains

serve as energy stores.3. Many intra-and intercellular signaling events

involve lipid molecules.

Lipids

* dietary fats are absorbed in the small intestine

- dietary lipids are not digested to any extent in the mouth or stomach in adults.

The rate of action of acid-stable lipase is very slow in adults, because it is active only at neutral pH.

In the duodenum : emulsification of the dietary lipids occurs.

* Lipids are insoluble hydrolysis occurs only at the interfaces emulsification increase surface area of lipid droplets .- this occurs by:

1- bile salts act as detergents. bile salt = bile acid (steroid nucleus) + glycin or taurine.2- mechanical mixing due to peristalsis Forming of micelles

* Absorption of lipids by intestinal mucosal cellsThe primary products of dietary lipid degradation with the bile salts from mixed

micelles.

Short and medium chain length F.A don’t need micelles formation to be absorbed (pass directly)

Effect of unsaturated fatty acid on the absorption of Cholesterol !!!!Effect of unsaturated fatty acid on the absorption of Cholesterol !!!!

Hydro-phobic core

hydrophilic

Brush membrane

Resynthesis of triacylglycerol and cholesteryl esters by the intestinal mucosal cell

Formation of micelles increase the surface of lipids exposed to the enzymes which is water soluble.

Free Fatty acid are transported via albumin

T.G lipase 2-monogycerol + 2 F.A

Cholesterol ester cholesterol

Triacylglycerol is hydrolyzed by Hormone sensitive lipase

Free fatty acid are transported to muscle cells carried by Albumin

* Cholesterol and other lipids are carried on plasma lipoproteins:

- cholesterol, cholesterol esters and other lipids are essentially insoluble in water. To be moved from one part to another they should carried as plasma lipoprotein.

Plasma lipoproteinsPlasma lipoproteins

- Macromolecular complexes of lipids and specific proteins called apolipoprotein with a various combination of phospholipids, cholesterol, cholesterol esters and TG.

* Function : to keep the lipid soluble for transporting them between organs and also provide efficient mechanism for delivering their lipid contents to the tissues.

Chylomicrons

* Composition of plasma lipoproteins

- TG and cholesterol esters are mainly carried by lipoprotein (In the core : TG + cholesterol ester, In the surface : hydrophilic parts of cholesterol, phospholipids and hydrophilic parts of apolipoproteins

Each class of lipoprotein has specific function determined by point of synthesis, lipid composition and apolipoprotein content.

The composition of the circulating lipoproteins is not staticThe composition of the circulating lipoproteins is not static. They are in dynamic state with continuous exchange of components between the various types

* Size and density of lipoprotein particles different combinations of lipids and proteins produce different densities - can be separated by ultra centrifugation.

Classification and characteristics of lipoproteins

Functions of apolipoproteins

Apolipoproteins : the free

form, have several

functions, structural

component, recognition

sites, activators or

coenzymes.

The composition of circulating lipoproteins are in dynamic state with continuous exchange of components between the various types.

*TG-rich particles

Chylomicrons-exogenous TG

VLDL: endogenous lipids from liver to cells

IDL: normally it is transient intermediate lipoprotein undetectable in plasma, formed during the conversion of VLDL into LDL

These particles, because of their large size reflect light and plasma containing high concentration appears turbid or milky (lipemia), it a turbid plasma sample is left standing for 18 hr at 4°C the larger chylomicrons( lowest density) form a creamy layer on the surface

Lipemia:Lipemia: presence of high amount of TG in plasma and it appears turbid because these particles are large in size so they scatter light

* Lipoproteins that contain mostly cholesterol

LDL formed from VLDL

HDL

These lipoproteins of small size do not scatter light, even at high concentration in plasma do not produce lipaemia.

*The small chylomicron remnants are composed mainly of cholesterol, apoB and apoE

Endogenous Lipid pathway

- the liver is the main source of endogenous lipids

These lipids are transported from the liver in VLDL

Plasma taken from a fasting subject contains only LDL, VLDL, and HDL, CM and IDL are not seen in fasting normal subjects.

70% of plasma cholesterol is incorporated in LDL and only 20% in HDL, the measured plasma cholesterol conc. primarily reflects LDL conc. and TG conc. those of VLDL

The Exogenous and Endogenous lipid cycle.

Metabolism of lipoproteins

* Metabolism of ChylomicronsMetabolism of Chylomicrons* The “nascent chylomicron” that released by intestinal mucosal cells contain apo B-48 (unique for chylomicrons) then this nascent chylomicron is rapidly modified receiving apo E and apo C.II from circulating HDL.* Function: transport dietary TG to adipocysts and muscle and also to transport Cholesterol and lipid soluble vitamin to the liver* Degradation of chylomicrons lipoprotein lipase : (activated by apo C.II) hydrolyses TG in these particles into free fatty acids and glycerol.

*Chylomicrons lipoprotein lipase chylomicron remnants (decrease size, increase density)- apolipoprotein C NOT E is returned to HDL and the remnant is taken up by hepatocytes.- Receptors of hepatocytes recognize the remnant through apo E activation of up taking by endocytosis degradation by lysosomes release cholesterol.- The release of cholesterol regulate the cholesterol synthesis in the liver by decrease HMG CoA reductase and also inhibit allosterically this enzyme.*The small chylomicron remnants are composed mainly of cholesterol, apoB and apoEThe remnants enter to the liver cells (apo E is binds to its receptors) release chol and degrade proteins*Dietary TG have been delivered to adipose tissue and muscle and cholesterol to liverThe uptake of Cholesterol remnants, unlike of LDL, is not influenced by the amount of Cho in hepatic cells.

* Metabolism of Chylomicrons

- The largest in size and least density of lipoproteins.- Synthesized in the endoplasmic reticulum of epithelial cells that line the small intestine, then they are packaged in secretary vesicles by Golgi and exported to lymphatic system then enter the blood stream.

* Metabolism of very low density lipoprotein (VLDL)

* VLDL : produced in liver and composed mainly of TG and their

function to carry lipids from liver to peripheral tissues and are

degraded by lipoprotein lipaseVLDL are the principal transport form of endogenous TG TG are removed by

lipoprotein lipase (LPL).

- Excess of F.A can be converted into TG in the liver and packaged with

specific apolipoprotein to form VLDL.

- Excess CHO can be converted into F A in the liver and converted into

TG packaged as VLDL

VLDL contain TG , some cholesterol, apo B100, apo CII and apo E

Apo E and some apo CII is transferred from the circulating HDL

* VLDL are transported in the blood from the liver to muscle and adipose tissue. VLDL lipoprotein lipase free F.A - oxidation (myocytes) OR resynthesis of TG (adipocytes)

Metabolism of very low density lipoprotein (VLDL)

* Cholesterol that was transferred

to HDL is esterified and then is

transferred to VLDL which became

denser and smaller (IDL)

*Cholesterol esters transfer from

HDL to VLDL by cholesterol ester

binding protein CEPT in exchange

with TG and PL

*Some IDL taken up by liver via

LDL receptors

Further TG in IDL is removed by

hepatic triglyceride lipase located

on the hepatic endothelial cells

and IDL is converted into LDL

Metabolism of LDL

* LDL are the principal carriers of cholesterol mainly in the cholesterol ester.

* They are formed from VLDL via IDL

-LDL particles have apo B-100, contain less TG, high concentration of cholesterol and cholesterol esters.

- The primary function of LDL is to provide the peripheral tissue with cholesterol by known mechanism called Receptor- mediated endocytosis.

* apo B-100 is recognized by LDL- receptor internalization and lysosomal degradation with release of free cholesterol

- VLDL contains apo B-100, but can’t bind to LDL receptors. (the conversion of VLDL into LDL) exposes of the receptor- binding domain of apo B-100

* Fate of cholesterol

- cholesterol that enter the cell can be incorporated into the cell membrane or can be re-esterified by acyl-CoA:cholesterol tansferase (ACAT) for storage as form of cholesterol esters.

* LDL also con be up taken by liver cells mediated by apo E.

*Receptor- mediated endocytosis

Cholesterol is delivered from LDL into the peripheral cells.

Peripheral cells uptake cholesterol.

* LDL receptors deficiency elevation of plasma LDL increase plasma cholesterol.

How can the body distinguish between the exogenous or endogenous cholesterol

Practically the live can distinguish the particles that carry the cholesterol;

Endogenous: carried by LDL and the uptake of LDL by the liver or other cells is highly regulated.

Exogenous (from diet): carried by chylomicrons, the chylomicron remnants transport dietary cholesterol to the liver.

High level of exogenous cholesterol increase its entrance to the liver decrease the synthesis of cholesterol and decrease the synthesis of LDL receptors decrease the uptake and increase the level of circulating cholesterol.

* Exercises increase the LDL receptors reduce the LDL-cholesterol level

* Estrogens also increase the LDL receptors reduce the circulating cholesterol level LDL of female is less than male

* thyroid hormones (T3) has +ve effect on the binding of LDL to its receptors hypothyroidism is a common cause of Hypercholesterolemia

Role of oxidized lipoproteins in plaque formation in arterial wallPathogenesis of atherosclerosis

Macrophages derived from monocytes can take up LDL via specific receptors

The uptake will

be activated

when LDL will be

oxidized via non-

specific

receptors

oveloading with

CE foam cells

component of

plaques

atherosclerosis

Factors influencing plasma LDL concentrations

-The plasma LDL concentration (the measured plasma cholesterol concentration), is determined mainly by the rate of uptake by LDL receptors.

*The liver has a central role in cholesterol metabolism because it:

1. Contains most of the LDL receptors

2. Synthesizes most of the endogenous cholesterol

3. Receives cholesterol from the diet and from lipoproteins

4. Is the only organ that can excrete cholesterol from the body in the bile

*The concentration of LDL receptors on hepatic cell surfaces depends on the amount of cholesterol accumulated in the liver cells.

High intracellular cholesterol level number of receptors is reduced increase the circulating cholesterol.*Factors that lead to the accumulation of cholesterol in the liver will, by reducing receptor numbers, increase plasma LDL concentrations.

Cholesterol absorption from the intestine is increased if the diet is rich

in saturated fat, efficient micelle formation chylomicrons

transported to the liver in chylomicron remnant particles that are taken

up by chylomicron-remnant receptors.

These receptors are not down regulated as LDL receptors

Inhibition of hepatic cholesterol synthesis, by suppression of the enzyme

HMG CoA reductase, may not prevent intracellular accumulation if dietary

intake is excessive.

Intracellular cholesterol accumulation leads to a reduction in LDL receptor

activity. LDL entry into cells therefore falls and plasma concentrations

rise.

Cholesterol can be excreted from the body in bile either as

cholesterol or as bile salts. Some bile acids are reabsorbed from the

intestinal lumen. Any interruption to the enterohepatic circulation results

in an increased conversion of cholesterol to bile acids reduction in

hepatic cholesterol stores increase in the number of LDL receptors.

*The rate of hepatic LDL receptor synthesis is also increased by

estrogens and by thyroid hormones.

* Metabolism of HDL

- Synthesized in the liver and small intestine as small, protein- rich particles that contain little cholesterol and no cholesterol esters. (nascent HDL, depleted HDL)

- Contain apo A.I, C.II, C.III and others and

LCAT (lecithin- cholesterol acyl transferase) which is called also

PCAT (phosphatidyl choline- cholesterol acyl transferase)

- LCAT is found at the surface of nascent HDL converts the cholesterol and PL of chylomicron as VLDL remnant to cholesterol esters that forms the core of HDL and formation of mature spherical HDL particle.

- Then the cholesterol rich HDL returns to the liver where the cholesterol is unloaded that can be converted into bile salts.

* Depleted HDL can be pick up cholesterol stored in extra hepatic tissues and carry it to the liver in “ Reverse Cholesterol Transport ” pathway.

Nascent HDL binding cholesterol rich cell passive movement of cholesterol from cell to the HDL goes to the liver.

- up taking of cholesterol from cells by enzyme LCAT and storing of cholesterol ester in the core of HDL.

* Metabolism of HDL

*Nascent HDL acquires free cholesterol from extrahepatic cells, chylomicrons and VLDL, the nascent HDL is converted into HDL3.

*Nascent HDL binding cholesterol rich cell passive movement of cholesterol from cell to the HDL

*The cholesterol is esterified by LCAT and CE is transferred to remnant lipoproteins by cholesteryl ester transfer protein (CETP) in exchange for TG

* apo A is activator for LCAT

*Remnant particles are removed from circulation by the liver

*Cholesterol is excreted in bile as it is or as bile salts

* HDL is taken up by liver. “ Reverse Cholesterol Transport ” pathway

Reverse Cholesterol Transport

1-HDL as reservoir of apolipoproteins

It act as circulating reservoir of apo C.II that can be transferred to VLDL and chylomicron.

And also takes back the apoprotiens before VLDL remnants and chylomicron remnants are taken by the liver.

2-Up taking of free cholesterol

3-Esterification of free cholesterol into CE by LCAT.

* CE (cholesterol esters) that stored in HDL can be transferred into VLDL and exchanged by TG or PE by CE transfer protein.

VLDL LDL CE is utilized by cells.

* Fate of HDL

- HDL is taken by liver by receptor- mediated endocytosis. And CE are degraded and cholesterol can be repackaged in lipoprotein, converted into bile acids or secreted into bile.

* Role of lipoproteins in heart disease

- high levels of cholesterol increase risk of atherosclerosis

linked to high level of LDL, decrease HDL.

HDL functions HDL functions

Arterial walls. -It is the most important manifestation of lipid disorders. -Cholesterol accumulation and associated cellular proliferation and fibrous tissue formation produces atheromatous plaques.-Atherosclerosis is due to deformation and obstruction of the artery that may result from calcification and ulceration of plaques. The small lipoproteins LDL and IDL are atherogenic.

Disorders of lipid metabolismClinical manifestation of hyperlipidaemia:Prolonged hyperlipidaemia results in accumulation of lipid in tissues and causes cell damage. Lipids may accumulate in arterial wall, subcutaneous tissue, tendons and cornea

Xanthelasma

Soft yellow-orange plaques on the eyelids are lipid deposits under the

periorbital skin and may be associated with high plasma LDL-cholesterol

concentrations

TendonsTendons

Tendinous Xanthomata and usually on Achilles tendons or the extensor

tendons of the hands occur in familial hypercholesterolaemia

Cornea:Cornea:

Corneal arcus under the age of 40 may

be caused by the deposition of lipids and

associated with high plasma LDL-

cholesterol concentrations.

Appear over extensors of the

elbows and knees, and on the back

and buttocks of patients with

severe hyperlipidaemia

Subcutaneous tissue

The accumulation of lipids in subcutaneous

tissue causes xanthomatosis (xanthoma: is

a yellow nodule plaque). The nature of the

lipid fraction most affected usually

determines the clinical appearance:

Eruptive xanthomata are crops of

small, itchy, yellow nodules (1-4mm)

yellowish-brown papules. They are

associated with very high plasma VLDL

or chylomicron (triglyceride)

concentrations, which disappear if

plasma lipid concentrations fall to

normal.

Classification of Disorders of lipid metabolism

Currently there is no satisfactory comprehensive classification of

lipoprotein disorders.

In practice, lipoprotein disorders are classified as being:

1. Primary-when the disorder is not due to an identifiable underlying

disease.

2. Secondary-when the disorder is a manifestation of some other

disease.

Primary lipid Disorders:

Genetic classifications: are becoming increasingly complex as different

mutations are discovered Familial hypercholesterolaemia (FH), may

be due to any of over 500 different mutations of the LDL receptor

gene.

*The same genotype can be expressed as more than one phenotype in

different individuals. i.e different clinical manifestations (signs and

symptoms) in different individuals for the same genetic disorder.

*These manifestations*These manifestations depend on the severity of the case, and on the

life style

*Until gene therapy*Until gene therapy and/or specific substitution therapy become more

available, genetic classifications, are unlikely to prove very useful in

practice.

WHO classification of dyslipidemia: based on Fredrickson

work and it is phenotypic classification based on the observation

pattern of lipoprotein abnormality

*The Fredrickson or World Health Organization classification is the

most widely accepted for the primary hyperlipidaemias.

* It is based the appearance of fasting plasma sample after

standing for 12 hr at 4°C and analysis of its cholesterol and

TG

* As a result, patients with the same genetic defect may fall into

different groups, or may change grouping as the disease

progresses or treated.

* The major advantage of this classification is that it is widely

accepted and gives some guidance for treatment

*The six types by Fredrickson are not equally common. Type I and

V are rare, while types IIa, IIb and IV are very common.

Fredrickson (WHO) classification of dyslipidaemia

Fredrickson (WHO) classification of dyslipidaemia

Genetic classifications:

Disease Genetic defect Fredrickson Risk

Familial Hypercholesterolemia

Reduced number of functional LDL receptors

IIa or IIb CHD

Familial hypertriglyceridemia

Possibly single gene defect

IV or V

Familail combined hyperlipidemia

Possibly single gene defect

IIa, IIb, IV or V CHD

Lipoprotein lipase deficiency

Reduced levels of functional LPL

I Pancreatitis

Apo C-II deficiency Inability to synthesize apo C-II (cofactor of LPL)

I Pancreatitis

Abetalipoproteinemia Inability to synthesize apo B

Normal Fat soluble vitamins deficiencies, neurological deficit

Analphalipoproteinemia Inability to synthesize apo A

Normal Neurological deficit, CE storage in abnormal places

The risk of developing cardiovascular disease increases as the plasma

cholesterol concentration rises above 200 mg/dl in the absence of other risk

factors this value could be raised

Causes of hypercholesterolaemia

- Hypercholesterolaemia associated with little or no elevation of plasma

triglyceride concentration is almost always due to a raised plasma LDL

*The coexistence of an underlying genetic defect or other lipid disorders

cause a greater increase in plasma cholesterol with age.

Secondary hypercholesterolaemia.

Disorders that may produce a secondary increase in plasma total and LDL-

cholesterol

-primary hypothyroidism,

-diabetes mellitus,

-nephrotic syndrome,

-cholestasis

-drugs (e.g.; thiazides).

Predominant hypercholesterolaemia

Primary hyperlipidaemiasFamilial hypercholesterolaemia (FH)

* This condition is characterized by high plasma cholesterol

concentrations which are present from early childhood and do not

depend upon the presence of environmental factors

* Different mutations can affect LDL synthesis, transport, ligand

binding, and recycling but all cause a similar phenotype.

*The familial incidence of hypercholesterolaemia, often associated

with an increased risk of ischemic heart disease, suggests an

inherited disorder.

* Environmental and dietary factors may determine the

expression of the defect.

* The risk of developing cardiovascular disease is higher than

normal, compared with an age- and sex matched population.

Familial (monogenic) hypercholesterolaemiaFamilial (monogenic) hypercholesterolaemia

Caused by a LDL receptor defect reduced cellular uptake of

LDL, particularly by the liver causes an increase in plasma

total and LDL- cholesterol concentrations.

Plasma triglyceride concentrations are either normal or only

slightly increased it is the most lethal of the inherited disorders.

In homozygotes LDL

receptors are virtually absent and plasma LDL-cholesterol is 3

to 4 times higher than those in normal subjects patients usually

die before the age of 20 from ischaemic heart disease.

In heterozygotes

The number of LDL receptors is reduced by 50% and the plasma

cholesterol concentrations are about twice those in normal

subjects. They have a 10 to 20-fold higher risk of developing

ischaemic heart disease than normal

Predominant hypertriglyceridaemiaPredominant hypertriglyceridaemia

* Elevated plasma triglyceride concentrations may be due to an

increase in plasma VLDL, or chylomicrons or both.

* Sustained and very high plasma concentrations of chylomicrons are

associated with abdominal pain and even acute pancreatitis, as well

as eruptive xanthomata.

* Many cases of hypertriglyceridaemia are symptom free. These large

lipoproteins are unlikely to cause artheroma, per se. However, many

patients with increased concentrations of VLDL-triglyceride have

reduced concentration of plasma HDL and increased plasma

concentration of LDL or IDL, which contain cholesterol.

* Hypertriglyceridaemia is usually secondary to another disease:

obesity and excessive carbohydrate intake, alcohol, drugs (thiazide

diuretics) and acute pancreatitis).

Familial endogenous hypertriglyceridaemia is caused by

hepatic triglyceride overproduction with increased VLDL

secretion.

* The condition usually becomes apparent only after the fourth

decade.

* It may be associated with: obesity, glucose intolerance,

decrease in plasma HDL-cholesterol concentration and

hyperuricaemia.

* Insulin resistance may be a common factor in the above

conditions.

* High plasma triglyceride concentrations may cause eruptive

xanthomata.

* primary hypertriglyceridaemia is less than primary

hypercholesterolaemia

Familial combined hyperlipidaemia: Mixed hyperlipidaemiaMixed hyperlipidaemia

It is common disorder

Associated with excessive hepatic production of apoB, increase

LDL and VLDL-triglyceride synthesis due to either a primary or

secondary disorder.

Family members have a variety of different phenotypes.

In one-third there is an increase in plasma LDL-cholesterol

In another third there is an increase in both LDL-cholesterol

and VLDL-triglycerides

The remaining third have VLDL-hypertriglyceridaemia.

The lipid abnormalities appear significantly in the after the age 30

The risk of ischaemic heart disease in all cases is higher

Raised plasma concentrations of both cholesterol and triglycerides are

commonest in patients with poorly controlled diabetes mellitus, severe

hypothyroidism or the nephrotic syndrome.

Hyperchylomicronaemia

* is usually due either to an acquired or inherited deficiency of

lipoprotein lipase.

* Insulin is needed for optimal enzyme activity

hyperchylomiconaemia may occur in poorly controlled diabetic

patients.

Inherited lipoprotein lipase deficiency may be due to:

A) True deficiency of the enzyme

B) Reduced activity of the enzyme because of apo C-II

deficiency. Which is an activator for lipoprotein lipase

-The plasma is very turbid because of the accumulation of

chylomicrons.

-True lipoprotein lipase deficiency usually presents during

childhood, with signs and symptoms due to an excess of fat at skin,

liver (hepatomegaly) retinal vessels and abdomen.

- Hyperchylomiconaemia due to apoC-II deficiency is most likely to

present in adults.

Rare disorders associated with lipid metabolism-A few rare disorders, which are associated with reduced plasma lipid

concentration but with the accumulation of lipid in tissues- Inherited disorder of HDL deficiency (Tangier disease):-Called also Analphalipoproteinaemia -Associated with premature coronary heart disease. -An abnormal apoA leads to an increased rate of catabolism of HDL. -Plasma HDL concentrations are low and cholesterol esters accumulate in the

reticuloendothelial system.

Abetalipoproteinaemia (ApoB deficiency):

- absence of Apo B

- results in impaired synthesis of chylomicrons and VLDL, and therefore of LDL. -lipids cannot be transported from the intestine to the liver.- risk: decrease in fat soluble vitamins lead to neurological defects, for

treatment vitamins are given I. V is given

Hypobetalipoproteinaemia

In this condition there is partial deficiency of apo B; CM, VLDL and LDL are

present, but in low concentrations.

LCAT deficiency:

results in accumulation of free, mostly unesterified, cholesterol in tissues

Secondary lipid disorders

Secondary hyperlipoproteina is a well recognized feature of a

number of diseases

Common causes of secondary hyperlipidaemia including obesity

and diabetes mellitus.

Management should be directed towards the cause.

Effect of Alcohol on Lipid profileEffect of Alcohol on Lipid profile

Large quantity of Ethanol increases the synthesis of Fatty

acid, because of production of NADH and acetate

Fatty acid TG VLDL

Ethanol

Acetaladehyde

Acetate

Alcohol dehydrogenase

Aldehyde dehydrogenase

NADH

NADH

Lipoprotein metabolism in diabetes mellitus

Insulin has a major role in the control of fat metabolism. Both type I and type 2 DM are associated with abnormalities of plasma lipids

In uncontrolled type I DM

* Marked hypertriglyceridaemia, increase in VLDL and often chylomicronaemia as a result of decreased activity of lipoprotein lipase and increased activity of hormone-sensitive lipase leading to increased flux of free fatty acids from adipose tissue that act as a substrate for hepatic triglyceride synthesis VLDL synthesis and accumulation increase LDL.

* Both VLDL and chylomicrones need insulin for optimum catalysis.

The degree of hypertriglyceridaemia correlates well with glycaemic control and insulin treatment can reverse the hypertriglyceidaemia.

* LDL can also be increased, and HDL is decreased.

*The VLDL contains increased triglyceride and cholesteryl ester in relation to the amount of apolipoptotein

* Glycation of apolipoprotein B may enhance the atherogenicity of LDL by reducing its affinity for the LDL receptor, so leading to increased uptake by macrophage scavenger receptors.

* Treatment with lipid-lowering drugs may be appropriate, to reduce the risk of vascular disease

Investigation of lipid disorders

Plasma sampling

• Plasma lipid concentrations and lipoprotein patterns are affected by

eating, smoking, alcohol intake, stress and changes in posture.

• It is essential that the samples are taken under standard conditions.

The following points are important:

1) Plasma cholesterol concentrations are not significantly affected

after a fatty meal while plasma triglyceride concentrations are

affected. Therefore, specimens for analysis of both should be taken

after the patient has fasted for 12 hours.

2) The patient should be taking a 'normal' diet and his weight should

have remained constant for about two weeks before the tests.

3) Unless treatment is being monitored, the patient must not be on

any drugs designed to lower plasma lipid concentrations

Investigation of lipid disorders

Plasma sampling

3) Unless treatment is being monitored, the patient must not be on

any drugs designed to lower plasma lipid concentrations

4) Lipoprotein concentrations, like those of all large particles, are

affected by venous stasis and posture. A standardized collection

procedure is important if serial estimations to assess the effect of

treatment are used.

5) Stress may affect plasma lipid concentrations like myocardial

infarct, major operation, or any serious illness.

6) The blood sample should not be heparinized and plasma or

serum must be separated from cells as soon as possible

Lipid profileLDL-cholesterol is most commonly estimated from quantitative measurements of total and HDL-cholesterol and plasma triglycerides (TG) using the empirical relationship of Friedewald et al. (1972)

[LDL-chol] = [Total chol] - [HDL-chol] - ([TG]/5)where all concentrations are given in mg/dL

The ([TG]/5) is used as an estimate of VLDL-cholesterol concentration. It assumes, first, that virtually all of the plasma TG is carried on VLDL, and second, that the TG:cholesterol ratio of VLDL is constant at about 5:1 (Friedewald et al. 1972). Neither assumption is strictly true.

Limitations of the Friedewald equation:The Friedewald equation should not be used under the following circumstances:When chylomicrons are present.When plasma triglyceride concentration exceeds 400 mg/dL (4.52 mmol/L).In circumstances in which these conditions apply, LDL-cholesterol should be measured directly.

Reference ranges and laboratory investigation

Plasma conc at birth is very low (total chol less than 100 mg/dL 2.6 mmol/L) and there is rapid increase in in first year of life

Elevated plasma chol is a major risk factor for CHD

There are many CHD risk factors

Smoking will increase the risk factor

There is an inverse correlation between HDL cholesterol and CHD risk.

So it is inappropriate to define a reference range for plasma chol concentration.

But it is preferable to consider an individual person's chol concentration taking in consideration all other CHD risk factors

Coronary Heart Disease Risk Factors Determined By The NCEP (National Cholesterol Education Program) and Adult

Treatment Panels

Positive Risk Factors

• Age: 45 years for men; 55 years or premature menopause for women

• Family history of premature CHD

• Current cigarette smoking

• Hypertension (BP 140/90 mmHg or taking antihypertensive medication)

• LDL cholesterol concentration 160 mg/dL ( 4.1mmol/L), with ≤ 1 risk

factor

• LDL cholesterol concentration 130 mg/dL (3.4 mmol/L), with ≤ 2 risk

factors

• LDL cholesterol concentration 100 mg/dL (2.6 mmol/L), with CHD or

risk equivalent

• HDL cholesterol concentration < 40 mg/dL (< 1.0 mmol/L)

• Diabetes mellitus = CHD risk equivalent

Negative Risk FactorsNegative Risk Factors

• HDL cholesterol concentration 60 mg/dL ( 1.6 mmol/L)

• LDL cholesterol < 100 mg/dL (2.6 < mmol/L)

Multiple metabolic risk Multiple metabolic risk

factorsfactors

A diagnosis of metabolic

syndrome is made if a

patient has three or more

of the following:

1. Abdominal obesity (a

waist circumference of

more than 40 inches [men]

or 35 inches [women])

2. An elevated triglyceride

level (150 mg/dL or higher) 3. A low HDL level (less than 40 mg/dL [men] or 50 mg/dL

[women])

4. A high-normal or high blood pressure level (130/85 mm Hg or

higher)

5. A high fasting glucose level (110 mg/dL or higher)

6

33

02

14

Means 20 of 100 people with this level of risk will have a heart attack in the next 10 years.

http://hp2010.nhlbihin.net/atpiii/calculator.asp

Risk Assessment Tool for Estimating Your 10-year Risk of Having a Heart Attack

10-Year Risk Calculator Results

10-Year Risk Calculator

Risk Factor Intervention

• Target treatment based on risk

High: 10 year risk > 20%

Intermediate: 10 year risk 10 –20%

Low: 10 year risk < 10%

• Preventive strategies differ depending on risk category

Aspirin

Cholesterol lowering

Risk Level LDL Goal (mg/dl) Consider Drug Therapy ___________________________________________________

High> 20% < 70 ≥100

Intermediate10 –20% < 100 ≥160

Low< 10% < 160 ≥190

The End

• Drugs: Thiaziade diuertics and b-blockers hypertriglyceridaemia since these drugs affect the homeostasis of K+ and Na+ which is important for the conversion of proinsulin into insulin low insulin levels similar events of diabetes

• Hypothyrodism low of T3, T4 decrease the uptake of LDL by the LDL-receptor mediated mechanism

• Nephrotic syndrome: increase the cholesterol level NS is associated with loss of protein with the urine This will trigger the body to increase the synthesis of protein including Apo B and other lipoproteins which lead to increase the cholesterolAlso may be due to loss of proteins responsible for regulation of lipid metabolism

* Metabolism of Chylomicrons

*Esterified cholesterol is transferred to the CM remnants from HDL, in exchange for triglyceride, by cholesteryl ester transfer protein*CM remnants depleted from TG and enriched in CE and taken up by liver

As the VLDL particles become smaller, PL, free cholesterol and apolipoproteins are released from VLDL and taken up by HDL converting the VLDL into IDL