16 Pathology of Lipid Met

8/6/2019 16 Pathology of Lipid Met

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Pathology of lipidmetabolism



LIPOPROTEIN METABOLISM



• Fredrickson (WHO)classification is based on theappearance of a fastingplasma sample after standing for 12 hours at 4’C

and analysis of it’scholesterol and triglyceride

content.



FREDRICKSON (WHO) CLASSIFICATION OF DYSLIPIDAEMIA



GENETIC REASONS OF DYSLIPIDAEMIA

IIa IIb

IIa IIb

I

I



XANTHELASMAS in younger individuals (age <40

years) usually indicate hypercholesterolaemia



TENDON XANTHOMAS are associated withfamilial hypercholesterolaemia



ARCUS SENILIS



ERUPTIVE XANTHOMAS (hypertriglyceridaemia)



COMMON REASONS OF SECONDARY HYPERLIPIDAEMIA



LIPID- LOWERING DIETARY GUIDELINES



LIPID-LOWERING DRUGS



PALMAR XANTHOMAS BEFORE TREATMENT



AFTER TREATMENT



• Atherosclerosis is a wide-spread pathology, manifestedchiefly by the deposition of cholesterol in arterial walls,which results in the formation of

lipid plaques (atheromas).



ATHEROMA IN CORONARY ARTERIES



• Lipid plaques are specificforeign bodies around whichthe connective tissue develops

abnormally (this process iscalled sclerosis). This leads to

the calcification of the impairedsite of a blood vessel .



• The blood vessels becomeinelastic and compact, theblood supply through thevessels is impeded, and theplaques may develop intothrombi.

Th i f h l i i



• The main reason of atherosclerosis ishyperlipoproteinemia.

• All of the lipoproteins, exceptingchylomicrons (large size), are capableof penetrating the vessel wall.

• However, α -lipoproteins (HDL) which

are rich in proteins and phospholipids,are liable to an easy breakdown withinthe vessel wall or can be easy removedbecause of their small size.∀β -lipoproteins (LDL) and, partly, pre- β -

lipoproteins (VLDL) containing muchcholesterol exhibit atherogenic

properties.





Composition

of theplasmalipoproteins.



• It is considered to be that modified(oxidized) LDL are very dangerous.Because they are captured by the cells(macrophages with non-specific receptors innon-regulating process). That’s whyantioxidants as V. E., β -carotene andascorbic acid can decrease development of

atherosclerosis.



Role of oxidazed lipoproteins in plaqueformation in arterial wall.











The vascular wall can exert asubstantial effect on both:

• 1) the rate of penetration of

lipoproteins inside the vessel and

• 2) their subsequent history (for example, hypertension)



The main internal factors of atherosclerosis development are:

• 1) hypercholesterolemia;

•2) hypertension.



3 groups of patients1) Concentration of cholesterol in the blood is

less than 2 g/L2) Concentration of cholesterol in the bloodis within 2-3,5 g/L ( carry out prophylaxis,dietetics )

3) Concentration of cholesterol in the blood ismore than 3,5 g/L ( drug therapy and radicalmethods (plasmophoresis, hemosorbtion )



Risk factors of atherosclerosis development • Genetic predisposition (high

concentration of LDL)• Action of stress (increase in FFA

and Acetyl-CoA ⇒ more substrate for cholesterol synthesis). Epinephrine cause

hypertension, which helps deposition of cholesterol.• Overeating of food especially reach in

cholesterol, fats and carbohydrates

(Acetyl-CoA and NADPH 2 are necessaryfor cholesterol synthesis). Usually inhumans with obesity.



• Smoking.It has been observed that ischemia of

heart occurs by 2-2,5 times morefrequent , if the patient is smoking(smoking decreases HDL concentrationin the blood).

• Hypodynamia.Physical exercises promote to theincrease of HDL concentration (that iswhy hypodynamia is risk factor of atherosclerosis development).



Dietetics.• We should limitconcentration of cholesterol

and saturated fatty acids.

• Fats of animal origin wemust try to exchange onvegetable fats , because theycontain unsaturated fatty acids mainlywhich are necessary for the synthesis of phospholipids.



Dietetics.• We should include in the diet the

products of vegetable origin,because heteropolysaccharidesabsorb cholesterol and remove itout of the intestine.

• We must increase the concentration of vitamins (especially E, C and A ) in the

diet.



Treatment• Drug therapy:

• Cholesteramine,• Cholestipole,• Clofibrate (activate lipoproteinlipase),

• Nicotinic acid (decrease the secretion of VLDL)• Radical methods : plasmopheresis,

hemosorbtion.We decrese concentration of cholesterol inplasma. That is why it’s concentration in thecells also decreases.



Fatty liver (FL) Normal liver contains about 4% as total lipids

(three-fourths of which is phospholipids (PL)and one-fourth as neutral fats (TG).For a variety of reasons, lipid – mainly astriacylglycerol – can accumulate in the liver.When accumulation of lipid in liver becomeschronic, fibroid changes occur in the cells thatprogress to cirrhosis and impaired liver

function.



NORMAL LIVER HISTOLOGY



NORMAL LIVER HISTOLOGY



FATTY LIVER



ACUTE FATTY LIVER



ACUTE FATTY LIVER



CHRONIC FATTY LIVER



CIRRHOTIC LIVER



Accumulation of lipids depends upon activationfactors that lead to increase of liver fat and inhibition

of factors that lead to decrease of liver fat. Whenthere is an imbalance between 4) Mobilization

of fats intoblood to depots

from liver (hepatotoxicsubstances,

DH, starvation)

1) Influx of DietaryLipids (fat fuding)

2) Synthesis of FA(fat fuding)

3) Mobilization of FAfrom Depots to liver (DM, starvation)

5) Degradation of FA inthe liver (PM, starvation)

Factors that lead to

decrease liver fat

Factors that lead to

increase liver fat

Total lipids in normalliver = 4%

¾ as PL and ¼ as TG



2 main categories of Fatty liver

– FL which is associated with raisedlevels of plasma free fatty acids.

– The second type of FL is usually due

to a metabolic block in the productionof plasma lipoproteins (VLDL).



– FL which is associated with raised levels of plasma free fatty acids.

– Increasing amounts of FA are taken up by theliver and esterified. The production of VLDLdoesn’t keep pace with the influx of FFA. TGs areaccumulated, causing FL.

Increased influx of FFA and development of FLcan be in cases of

1) feeding of high fat diets,2) starvation,3) uncontrolled diabetes mellitus .In starvation and DM it can be also due to decreased

ability to secrete VLDL, because of low levels of insulin and impaired protein synthesis.



– The second type of FL is usually due to a

metabolic block in the production of plasmalipoproteins (VLDL).

– The lesion may be due to

a)a block in apolipoprotein synthesis,b)a block in the synthesis of the lipoprotein

from lipid and apoliprotein combination,c)a failure in the secretory mechanism itself.



• Several antibiotics (puromycin)inhibit protein synthesis and cancause FL.

• Other hepatotoxic substances actsimilarly. They include, for example,carbon tetrachloride(CCL4),chloroform, phosphorus, lead andarsenic.

• Chronic consumption of alcohol caninduce FL.

Li i f



Lipotropic factorsAll substances that increase the synthesis of PLs decrease the tissue

deposition of TGs. Such substances are called lipotropic factors.

They includecholine,serine,structural components of phospholipids ,

pyridoxal phosphate (as an agent facilitating thedecarboxylation of serine phosphatides,

methionine (as a donor of methyl group)

folic acid (B9) cobalamin (B12).

They may be used as drugs preventing excessive deposition of triglycerides in the liver.





• 1 gr. : There is no need to carry out prophylaxisof atherosclerosis in the first group.

• 2 gr. : In group number 2, it is necessary to(carry out prophylaxis ) of atherosclerosis bymeans of diet and optimal physical exertion,refusal from smoking, limitation of stress.

• 3 gr. : >3,5 g/L. It is necessary the measures of drug therapy and radical methods of treatment(plasmophoresis, hemosorbtion)



• Carbon tetrachloride induces the formation of

free radicals (CCL3) that disrupt lipidmembranes in the endoplasmic reticulum bythe formation of lipid peroxides.

• As the result, this affects the secretorymechanism itself or the conjugation of the lipidwith apolipoprotein.

• That’s why some protection against carbon

tetrachloride can be provided by theantioxidant action of vitamin E – supplementeddiets.

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16 Pathology of Lipid Met

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