Dr.Sarma@works1 LIPIDS An over view of Normal and Abnormal Lipids.

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LIPIDS

An over view of

Normal and Abnormal Lipids

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All are One

• This not about the GOD

• There is only one disease – Over nutrition• Its faces are many such as

– Over weight / Obesity

– Diabetes mellitus, IR, Syndrome X

– Atherosclerosis – HT- CHD – CVD – RVD – PVD

– Hyper lipidemias – endothelial dysfunction

– Wear and tear of joints …. So on

• What are we to do ? - Avoid over-indulgence

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Weight in kgs

Height2 in mtsBMI =

How much is much ?

70

1.65 x 1.65BMI = = 25.71

Underweight < 20 Over weight > 25 to 30

Normal 20 to 25 Obesity >30

Waist / Hip ratio = 35” /38” = 0.92

Normal for Males < 0.90, Females <0.80

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Lipid Abnormalities

Sedentary Life Style

Less perfect Genetic make-up

Diets rich in Saturated Fat, Chol

Excess body weight/ Obesity

Lipid abnormalities

Atherosclerotic vascular disease

CHD, CVD, PVD

tHcy

ROS

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Why are lipids important ?

• Complications of Atherosclerosis are– CHD (Coronary Heart Disease)– CVD (Cerebro Vascular Disease)– RVD (Reno Vascular Disease)– PVD (Peripheral Vascular Disease)– These cause > 50% of all deaths - mortality– The Angina, MI, - TIA, Stroke, - HT, RF, -

IC, Gangrene all reduce the Quality of Life - morbidity

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AVD – Clinical Manifestations

Organ Condition Impairment Clinical Presentation

Heart Coronary Heart

Disease (CHD)

Ischemia

Infarction

Angina Pectoris

Myocardial Infarction

Brain Cerebro vascular

Disease (CVD)

Ischemia

Infarction

Transient Ischemia attack

Stroke

Kidney Reno vascular

Disease (RVD)

Ischemia

Infarction

Reno vascular hypertension

Renal impairment

Renal Failure

Leg Muscles

Peripheral Vascular Disease (PVD)

Ischemia

Infarction

Intermittent Claudication

Gangrene

For every thing the common denominator is ED

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Lipid Transport

TG EC

Apoprotein boat

Apo A = HDL Apo B100+C+E = VLDL, IDL

Apo B100 = LDL Apo B48+C+A+E = Chylomicrons

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Lipids and Lipoproteins

• Lipids or Fats in our body are mainly

• The non polar, hydrophobic, inner core of– Triglycerides (TG)– Cholesterol Esters (EC)

• The polar, surface monolayer – Phospholipids (PL) and Free Cholesterol (C)

• Apoproteins are the outer coat -amphiphatic

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Lipoprotein

TG, EC

Phospholipids Free Cholesterol

(Hydrophilic)

Apoproteins A, B, C, E, (a) (Amphiphatic)

Lipids or Fats (Hydrophobic)Size < RBC

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Lipoproteins

Lipoprotein TG Chol. Apoprotein

Chylomicron 95 5 B48+C+E+A

Remnants 2 98 B48

VLDL 80 20 B100+C+E

IDL 30 70 B100+E

LDL 10 90 B100

Small LDL 10 90 B100

HDL 5 45+50 AI, AII

Lp(a) 10 90 B100+(a)

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Major Lipoproteins

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Lipoprotein Metabolism

• Exogenous – Transport of dietary fats – TG to Adipose tissue,

Muscle and Cholesterol to Liver as Chylomicrons

• Endogenous– Transport of TG and CE from Liver to the

peripheral tissues like muscle, adipose tissues and vascular endothelium via VLDL,IDL, LDL

• Reverse Cholesterol transport –HDL Path– from the vessels and periphery to liver

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Enzymes

1. Lipo Protein Lipase (LPL)– Synthesized in Adipose and Muscle tissues– Essential for TG metabol – FFA and Glycerol– Insulin activates LPL,- CII apo binds to LPL

2. Hepatic TG Lipase (HGTL)– Removes TG from VLDL, IDL LDL– Clears the Cholesterol remnants into liver

– Converts HDL2 to HDL3 in the liver

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Enzymes contd..

3. Lecithin Chol Acyl Transferase (LCAT)• Secreted into plasma by the liver• Binds to HDL and transfers linoleate from

lecithin to free Chol and converts it into EC-

4. Cholesterol Ester Transfer Protein (CETP)– Secreted into plasma from liver– Transfers EC from HDL to VLDL– Converts LDL to small Dense LDL

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EXOGENOUS

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ENDOGENOUS

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HDL

PATHWAY

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Lipid Peroxidation

LDL, IDL Not normally taken up by the vessel wall

ROS – Free radicals and Pro-oxidants

Oxidized LDL, IDL

Freely enters the vessel wall

Scavenger pathway

Endothelium Macrophages

Foam Cells Cytokines, GF

Atherosclerosis

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Synthesis of VLDL (TG)

• In the liver VLDL is synthesized– It is dependent on substrate flow

– Obesity

– Excessive consumption of simple sugars

– Increased intake of saturated fats

– Inactivity

– Alcoholism

– Insulin resistance

– Low HDL

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Primary Hyperlipidemia

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Secondary Hyperlipidemia

TG EC

Obesity Nephrotic syndrome.

Diabetes Hypothyroidism

Uraemia Obstr. liver disease

Alcoholism Anorexia nervosa

Oral contraceptives Acute Int. Porphyria

Beta blockers Progestogens

Pregnancy Thiazides

Steroids, Thiazides

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Clinical Action• Presence of secondary causes of Hyperlipidemia

– Order for full lipid profile (LP) – HT also

• Presence of Hyperlipidemia – increased TG or EC– Investigate for all secondary causes

• For all above 20 years once in every 5 years – LP• For those above 45 yrs – once in 2 years• For those with already known lipid abnormality

follow-up every 3-6 months

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Lipid Profile Report

LIPID TYPE LIPOPROTEIN Remarks

TC = 250 HDL = 50 N

LDL = 170 Abnormal

VLDL = 30 N

TG = 150 VLDL = 135 N

Chylomicron=15 N

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LDLc Calculation

LDLc = TC – (HDLc + TG/5)

e.g. if TC = 250, HDLc = 50, TG = 150

LDLc = 250 – (50 + 150/5)

= 250 – (50+30)

= 250 – (80)

LDLc = 170

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Risk Factors for CHD

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Treatment Plan - LDLc

Clinical Status Diet Drugs Goal

No CHD

< 2 RF

>160 >190 <160

No CHD

2 or more RF

>130 >160 <130

CHD Present >100 >130 <100

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Therapeutic Goals

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Cholesterol Levels

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Triglycerides

TG Level Classification Treatment

< 200 mg% Normal TG No Rx.

200 to 400 mg% Borderline high Diet alone

400 to 1000 mg% High Diet + drugs

> 1000 mg% Very high Diet + Intensive Rx

NCEP Guidelines by expert panel on TG

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Diet Regimen

Nutrient Step I Step II

Total Fats < 30% < 30%

Saturated < 10% < 5%

PUFA < 10% < 10%

MUFA < 10% 15%

CHO 55% 55%

Protein 15% 15%

Cholesterol < 300 mg < 200 mg

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Treatment Options

• Diet – Two step approach

• Drug therapy1. HMG CoA Reductase Inhibitors

2. Bile Acid binding Resins

3. Nicotinic Acid

4. Fibric Acid derivatives

5. Probucol

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HMG CoA Red. Inh.

• Called Statins – Atorvastatin, Simvastatin, Lovastatin etc.,

• 10 mg of Atorvastatin/Simvastatin OD, up to 40mg/day -

• Synthesis of Cholesterol is blocked by inhibiting the enzyme hydroxy-methyl-Glutaryl Coenzyme A reductase

• Increase in LDL receptors – traps LDL from plasma

• Decrease in LDL by 25-45%, and VLDL TG by 10-20%

• Increase HDL by 8-10%, No action on Lp(a)

• Free of side effects - < 5%, Rise in Liver enzymes

• Rare but serious complication is myopathy –CPK increase

• Caution if combined with Gemfibrozil for combined hyperlipids.

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Nicotinic Acid

• Decrease the synthesis of VLDL and LDL in liver• 50 – 100 mg t.i.d – increase up to 2 to 5g/day• Do not use sustained release preparation• Decreases TG by 25 to 85%, VLDL by 20-35%• Decreases LDL by 10-15%, may increase HDL?• Only agent – lowering Lp(a) by 25% • Flushing, pruritus, dry skin – tachycardia and

atrial arrythmias – hyper uricemia, peptic ulcer disease, glucose intolerance, hepatic dysfunction

• Poor side effect profile is the limitation.• Can be combined with resins, fibrates, statins

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Anion Resins

• Interrupt the enterohepatic circulation of bile acids

• Increased synthesis of bile acids–cholesterol sequestration

• Cholestyramine (Questran) 378g containers or 4g sachets

• Colestipol (Colestid) in 300g or 500g jars/5g packs/ 1g tab

• Decrease LDL by 20-30%, Increase HDL and TG

• Constipation, bloating, nausea, bleeding piles

• Contra ind. : Biliary obstruction, G.Outlet obst., Incr. TG

• Can be combined with Nicotinic acid, Statins

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Fibric Acid derivatives

• Increase LPL activity – Increased hydrolysis of TG

• Decrease VLDL synthesis, Increase LDL catabolism

• Only Gemfibrozil is approved – 600mg b.i.d

• Decrease TG by 25-40%, LDL may rise, modest rise HDL

• Adv. Effects -Incr. Bile lithogenicity, abn. LFT, Myositis

• Contr. In hepatic or biliary disease, caution in renal failure

• Increase the anti-coagulant action of Warfarin

• Can be combined with bile acid binding resins

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Probucol

• Probucol (Lorelco) 500mg b.i.d with food• Third line drug – erratic effect on LDL & decrease

of HDL• Lowers Cholesterol and only drug which regresses

xanthomas• It is an antioxidant of LDL• Diarrohea, flatulence, nausea, increases QTc• Can be combined with bile acid sequestrating

resins

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What is for what• If LDLc is more – Hypercholesterilimia alone

– Statins 1st line – Simvastatin – Atorvastatin– Statins + Anion resin (Questron)– 2nd line– Or Statins + nicotinc acid – 2nd line– Probucol 3rd line specially for xanthomas– But not Statins + gemfibrozil

• If TG alone is elevated – Hypertriglyceridemia– Gemfibrozil – 1st line– Nicotinic acid with or without Gemfibrozil– 2nd line

• For mixed – combination- Statin+Nicotinic acid

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What’s in a name ?

• Statins– Atorvastatin – Storvas, TG-tor, Avastin

Simvastatin – Sim, Simvotin

• Bile acid sequestering resins– Cholysteramine – Questron

– Colistipal – Colestid

• Nicotinic Acid – Niasyn • Fibric acid -Gemfibrozil– Lopid, Lipizyl• Probucol – Lorelco

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The Research

ADMIT Arterial disease multiple intervention trial (Niacin, Anti-oxidants, vitamins)

CHAOS Cambridge heart anti-oxidant study

MRC/BHF HPS MRC/BHF heart protection study (anti-oxidants)

SU.VI.MAX Supplementation en Vitamines et Mineraux Antioxydants

CELL Cost Effectiveness of Lipid Lowering (pravastatin)

CIS Coronary Intervention Study (simvastatin)

HHS Helsinki Heart Study (Gemfibrozil for TG)

SSSS (4S) Scandinavian Simvastatin Survival Study (Land mark trial

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The Future Research

• We do not have yet any drug which increase the HDL

• We do not know the precise role of Lp(a) and how to reduce it.

• Small LDL needs further evaluation• RCTs to prove that the anti-oxidants have

a real role to play both in treatment and in prevention of AVD

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Risk Factors for AVD

• Hyperhomocyst(e)inemia• Diabetes mellitus• Hypertension• Dyslipidemia• Positive family history,

Smoking, obesity and

physical inactivity

Oxidative Stress

AVD

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Free Radical Formation

Homolytic fission of a covalent bond

A B

BAA B

Single covalent bond

Homolytic fissionHeterolytic fission

Free radicalsIons

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ROS damage biological tissues- membranes

Reactive Oxygen Species

Lipid peroxidation Protein denaturation DNA Damage

Cell Dysfunction and deathFree radicals released

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Classification

• Preventive antioxidants-Ceruloplasmin, transferrin, lactoferrin

• Enzyme antioxidants-Superoxide dismutase, catalase, glutathione peroxidase

• Scavenging or ‘chain-breaking’ or ‘sacrificial’antioxidants-Vitamins A,C, and E

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ROS and their Antioxidants

ROS AntioxidantsO2 Superoxide free

radicalSuperoxide dismutase Vitamin E, -carotene

OH Hydroxyl free radical Vitamin C

H2O2 Hydrogen peroxide Glutathione peroxidase

O2 Singlet Oxygen Vitamin A, E

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Reactive Oxygen Species (ROS)

Free Radicals Non Radicals

Superoxide O2 Hydrogen peroxide H2O2

Hydroxyl OH Singlet oxygen O2

ROS are highly reactive….and can damage biological tissues and membranes

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What is Homocysteine ?

Protein diet Methionine 1)Homocysteine

2)Homocystine

3) Homocysteine thiolactone

Generation of ROS

Homocysteine • 1+2+3= homocyst(e)ine

•homocyst(e)ine = tHcy

•Homocyst(e)inemia=hyper - tHcy

Digestion Metabolism

Auto-oxidationProtein synthesis

HS-CH2-CH2-CH-COOH

NH2

• Sulfur-containing amino acid

•By product of methionine metabolism

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Homocysteine : Metabolic Pathways

Remethylation Cycle

Demethylation Cycle

Transsulfuration

Pathway

Diet

Methionine

Homocysteine

Tetra hydrofolate

Methyl tetrahydrofolate

Cystathionine

Cysteine

GlutathioneSulphate

Vitamin B6 (C beta S)

Folic acid MTHFR

Vitamin B6 (MS)

MS – Methionine synthaseMTHFR – Methyl tetrahydro folate reductaseC beta S – Cystathionine beta synthase

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Hyperhomocyst(e)inemia

Blood Homocyst(e)ine Levels

Classification Values in mol/L

Normal

Moderate

Intermediate

Severe

05 – 15

16 – 30

31 – 100

> 100

• Moderate to severe hyper – tHcy : established risk factor for AVD 1-4

• Hyper – tHcy

- 5-7 % of the general population

- 12-47 % of patients with AVD

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Causes of Hyperhomocyst(e)inemia

A. Nutritional : Vitamin deficiency

Folic Acid

Vitamin B12

Vitamin B6

B. Genetic : Enzyme Abnormality

C. Drugs :

Methotrexate, Phenytoin, Theophylline

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Homocysteine & Pathogenesis of AVD

Homocysteine

Auto-oxidation

Generation of ROS

Lipid peroxidationDamages endothelium

H2O2 OH/O2

Oxidizes LDL

Foam cells (chol)Nitric Oxide formation

Vasodilation

Hypertension

Exposure of smooth muscle, subendothelium

Proliferation of SM cells, Chemotaxis

ATHEROSCLEROSIS

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New Year Best Wishes

We wish you to be blessed always with• BMI of < 25; W/H ratio of 0.80• FBG of 60 to100• Blood pressure of about 120/80• LDLc of <100• TG of <200• Normal ECG and Treadmill test

All these mean a very healthy and Happy HEART

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True !

Eat but not over-eat

Drink but not alcohol

Indulge but not in junk food

Think but not worry

Be quiet but with exercise

Have high Chol but not LDL Cholesterol

Be high spirited but not be on ‘spirits’

Smoke any brand of incense stick, but not cigarettes