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An over view of Normal and Abnormal Lipids

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1 An over view of Normal and Abnormal Lipids

2 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

3 Normal for Males < 0.90, Females <0.80
How much is much ? Weight in kgs Height2 in mts BMI = 70 1.65 x 1.65 BMI = = 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

4 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 ROS tHcy

5 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

6 AVD – Clinical Manifestations
Organ Condition Impairment Clinical Presentation Heart Coronary Heart Disease (CHD) Ischemia Infarction Angina Pectoris Myocardial Infarction Brain Cerebro vascular Disease (CVD) Transient Ischemia attack Stroke Kidney Reno vascular Disease (RVD) Reno vascular hypertension Renal impairment Renal Failure Leg Muscles Peripheral Vascular Disease (PVD) Intermittent Claudication Gangrene For every thing the common denominator is ED

7 Lipid Transport TG EC Apoprotein boat
Apo A = HDL Apo B100+C+E = VLDL, IDL Apo B100 = LDL Apo B48+C+A+E = Chylomicrons

8 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

9 Lipoprotein Lipids or Fats (Hydrophobic) Size < RBC TG, EC
Phospholipids Free Cholesterol (Hydrophilic) Apoproteins A, B, C, E, (a) (Amphiphatic)

10 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 HDL 45+50 AI, AII Lp(a) B100+(a)

11 Major Lipoproteins

12 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

13 Enzymes Lipo Protein Lipase (LPL) Hepatic TG Lipase (HGTL)
Synthesized in Adipose and Muscle tissues Essential for TG metabol – FFA and Glycerol Insulin activates LPL,- CII apo binds to LPL Hepatic TG Lipase (HGTL) Removes TG from VLDL, IDL LDL Clears the Cholesterol remnants into liver Converts HDL2 to HDL3 in the liver

14 Enzymes contd.. 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- Cholesterol Ester Transfer Protein (CETP) Secreted into plasma from liver Transfers EC from HDL to VLDL Converts LDL to small Dense LDL

15 E X O G E N O U S

16 E N D O G E N O U S

17 H D L P A T H W A Y

18 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 Endothelium Macrophages Scavenger pathway Foam Cells Cytokines, GF Atherosclerosis

19 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

20 Primary Hyperlipidemia

21 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

22 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

23 Lipid Profile Report LIPID TYPE LIPOPROTEIN Remarks TC = 250 HDL = 50
LDL = 170 Abnormal VLDL = 30 TG = 150 VLDL = 135 Chylomicron=15

24 LDLc Calculation LDLc = TC – (HDLc + TG/5)
e.g. if TC = 250, HDLc = 50, TG = 150 LDLc = 250 – ( /5) = 250 – (50+30) = 250 – (80) LDLc = 170

25 Risk Factors for CHD

26 Treatment Plan - LDLc Clinical Status Diet Drugs Goal No CHD < 2 RF
>160 >190 <160 2 or more RF >130 <130 CHD Present >100 <100

27 Therapeutic Goals

28 Cholesterol Levels

29 NCEP Guidelines by expert panel on TG
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

30 Diet Regimen Nutrient Step I Step II Total Fats < 30% Saturated
< 10% < 5% PUFA MUFA 15% CHO 55% Protein Cholesterol < 300 mg < 200 mg

31 Treatment Options Diet – Two step approach Drug therapy
HMG CoA Reductase Inhibitors Bile Acid binding Resins Nicotinic Acid Fibric Acid derivatives Probucol

32 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.

33 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

34 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

35 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

36 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

37 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

38 What’s in a name ? Statins Bile acid sequestering resins
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

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

40 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

41 Risk Factors for AVD Hyperhomocyst(e)inemia Diabetes mellitus
Hypertension Dyslipidemia Positive family history, Smoking, obesity and physical inactivity Oxidative Stress AVD

42 Free Radical Formation
Homolytic fission of a covalent bond Single covalent bond A B Homolytic fission Heterolytic fission B A A B Ions Free radicals

43 ROS damage biological tissues- membranes
Reactive Oxygen Species Lipid peroxidation Protein denaturation DNA Damage Free radicals released Cell Dysfunction and death

44 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

45 ROS and their Antioxidants
Superoxide free radical Superoxide dismutase Vitamin E, -carotene OH Hydroxyl free radical Vitamin C H2O2 Hydrogen peroxide Glutathione peroxidase Singlet Oxygen Vitamin A, E

46 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

47 What is Homocysteine ? Metabolism Digestion Protein diet Methionine
Auto-oxidation Protein synthesis 2)Homocystine 3) Homocysteine thiolactone HS-CH2-CH2-CH-COOH Generation of ROS NH2 Homocysteine 1+2+3= homocyst(e)ine homocyst(e)ine = tHcy Homocyst(e)inemia=hyper - tHcy Sulfur-containing amino acid By product of methionine metabolism

48 Homocysteine : Metabolic Pathways
Remethylation Cycle Demethylation Cycle Diet Tetra hydrofolate Methionine Folic acid MTHFR Vitamin B6 (MS) Methyl tetrahydrofolate Homocysteine Vitamin B6 (C beta S) MS – Methionine synthase MTHFR – Methyl tetrahydro folate reductase C beta S – Cystathionine beta synthase Cystathionine Transsulfuration Pathway Cysteine Sulphate Glutathione

49 Hyperhomocyst(e)inemia
Blood Homocyst(e)ine Levels Classification Values in mmol/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 % of the general population % of patients with AVD

50 Causes of Hyperhomocyst(e)inemia
Nutritional : Vitamin deficiency Folic Acid Vitamin B12 Vitamin B6 Genetic : Enzyme Abnormality Drugs : Methotrexate, Phenytoin, Theophylline

51 Homocysteine & Pathogenesis of AVD
Auto-oxidation Generation of ROS H2O OH/O2 Damages endothelium Lipid peroxidation Oxidizes LDL Exposure of smooth muscle, subendothelium ¯ Nitric Oxide formation Foam cells (chol) Proliferation of SM cells, Chemotaxis ¯ Vasodilation Hypertension ATHEROSCLEROSIS

52 All these mean a very healthy and Happy HEART
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

53 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

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