Lipids Explianed by Dr Sarma

Transcript Lipids Explianed by Dr Sarma

Dr. R.V.S.N.Sarma,

M.D., M.Sc (Canada) Consultant Physician and Chest Specialist 1, Jayanagar, Tiruvallur, Chennai -602 001 (04116) – 260593, 263665 Mobile : +91-98940 60593 [email protected]

Dr.Sarma

Best Wishes to You All

LIPIDS

An overview of Normal and Abnormal Lipids Dr.Sarma

Lipid Abnormalities

Sedentary Life Style Diets rich in Saturated Fat, Chol Excess body weight/ Obesity Less perfect Genetic make-up ROS Lipid abnormalities tHcy Atherosclerotic vascular disease CHD, CVD, PVD Dr.Sarma

AVD – Clinical Manifestations

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

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, hydrophilic – Phospholipids (PL) and Free Cholesterol (C) • Apoproteins are the outer coat amphipathic Dr.Sarma

Size < RBC

Lipoprotein

Lipids or Fats (Hydrophobic) TG, EC Phospholipids Free Cholesterol (Hydrophilic) Apoproteins A, B, C, E, (a) (Amphipathic) Dr.Sarma

Lipid Transport

Apo A = HDL Apo B100 = LDL TG EC Apoprotein boat Solubilizes Apo B100+C+E = VLDL, IDL Apo B48+C+A+E = Chylomicrons Dr.Sarma

TG 95 %

Composition

TG 80 % EC 5% Chylomicrons VLDL EC 20% Dr.Sarma

TG 15 %

Composition

TG 5 % LDL EC 85% HDL EC 95% Dr.Sarma

Particle size & Density

Chylomicrons << 1.006

VLDL < 1.006

IDL < 1.019

LDL Small LDL HDL < 1.063

< 1.085

Atherogenicity is a function of the density < 1.210

Dr.Sarma

Lipoproteins

Lipoprotein Chylomicrons VLDL IDL LDL Small LDL HDL Lp(a) TG 95 80 30 15 10 5 10 Chol

5 20 70 85 90 95 90 Apoprotein B48+C+E+A B100+C+E B100+E B100 B100 AI, AII B100+(a) Dr.Sarma

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 Dr.Sarma

Reverse Cholesterol Transport

Vascular Endothelial Cell Free Chol.

UEC EC

HDL

L CAT Enzyme LIVER Dr.Sarma

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 (HTGL) – Removes TG from VLDL, IDL LDL – Clears the Cholesterol remnants into liver – Converts HDL 2 to HDL 3 in the liver Dr.Sarma

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 Dr.Sarma

LDL, IDL Oxidized LDL, IDL

Lipid Peroxidation

Not normally taken up by the vessel wall ROS – Free radicals and Pro-oxidants Freely enters the vessel wall Scavenger pathway Endothelium Foam Cells Atherosclerosis Macrophages Cytokines, GF Dr.Sarma

Lipid Peroxidation

Dr.Sarma

Primary Hyperlipidaemias

Familial Hyper Cholesterolemia II a ↑ LDL Familial defect in apo B 100 Polygenic Hyper Cholesterolemia Familial Hyper Triglyceridemia Familial LPL deficiency Familial apo CII deficiency Combined Hyperlipedemia Dys Beta lipoproteinemia II a II a IV I, V I, V II b III ↑ LDL ↑ LDL ↑ VLDL ↑ Chylo ↑ Chylo ↑ VLDL, ↑ LDL ↑ VLDL, ↑ IDL Dr.Sarma

Secondary Hyperlipidemia

Cholesterol Nephrotic syndrome.

Hypothyroidism Obstr. liver disease Anorexia nervosa Acute Int. Porphyria Progestogens Thiazides Anabolic steroids TG Obesity Diabetes Uraemia Alcoholism, Smoking Oral contraceptives Beta blockers Pregnancy Steroids, Thiazides Dr.Sarma

Clinical Photos

Tuberous xanthoma. Flat-topped, yellow, firm tumor Xanthelasma. Multiple, longitudinal, creamy orange, slightly elevated papules on eyelids .

Dr.Sarma

Clinical Photos

Tendinous xanthomas. Large sub cutaneous tumors adherent to the Achilles tendons.

Papular eruptive xanthomas. Multiple, discrete, red-to-yellow confluent papules Dr.Sarma

Evaluation

1. History of eruptive xanthomas, Abd. pain 2. H/o wt. gain, DM, estrogens, Alcohol, Ex.

3. Fasting Lipid profile (TC, LDL, HDL, TG) 4. OGTT, TSH, Liver & Renal Function tests 5. CHD assessment by ECG, TMT, Angio 6. Risk factor assessment, Family H/o P.CHD

Dr.Sarma

Treatment Strategy

Lipid Profile, Risk Assessment LDL > 100 Treatment CHD + Sec. Prevention 2 or > RF LDL > 100 High Risk Look For Sec. Causes Treat the cause, if found NO CHD Primary Prevention < 2 RF Low Risk LDL > 130 LDL >160 Dr.Sarma

Treatment Strategy

Fasting TG Level ↑ Fasting TG Level TG >150, No CHD < 2 RF 2 or > RF TG < 150 Normal Diet Modif.

TG > 150, CHD + TG > 500, CHD +/ Diet + Fibrate Diet + Fibrate + Niasyn Diet + Fibrate + Statin Dr.Sarma

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 Dr.Sarma

Lipid Profile Report

LIPIDS ESTIMATED TOTAL CHOLESTEROL TRIGLICERIDES HDL LDL VLDL Chylomicrons VLDL Dr.Sarma

Lipid Profile Report

LIPID TYPE TC = 250 TG = 150 LIPOPROTEIN HDL = 50 LDL = 170 VLDL = 30 VLDL = 135 Chylomicron=15 Normal Remarks > 45 < 130 N Abnormal < 60 < 150 < 30 N N N

Dr.Sarma

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 Dr.Sarma

National Cholesterol Education Program NCEP

Adult Treatment Panel III (ATP III) Guidelines -2002 Dr.Sarma

Categories of Risk Factors

1. Major, independent risk factors 2. Life-habit risk factors 3. Emerging risk factors 4. CHD risk equivalents Dr.Sarma

Major Risk Factors for CHD - LDLc

1. Cigarette smoking 2. Hypertension (BP  140/90 mmHg or on antihypertensive medication) 3. Diabetes Mellitus 4. Low HDL cholesterol (< 40 mg/dl)† 5. Family history of premature CHD • CHD in first degree ♂ relative of < 55 years • CHD in first degree ♀ relative < 65 years 6. Age (men  45 years; women  55 years) † HDL cholesterol  60 mg/dL counts as a “negative” risk factor;.

Dr.Sarma

Risk Factors Ranking in the PROCAM Study Risk factor Relative risk

Value Smoking LDL cholesterol (mg/dl) 130-160 >160 Hypertension HDL cholesterol (mg/dl) 55 - 45 < 45 Triglycerides (mg/dl) 105- 167 >167 Fasting blood glucose (mg%) 110-126 > 126 Family history of MI 2.3

1.9

4.3

1.8

1.7

2.7

1.6

2.6

1.4

1.9

1.4

0.001

0.01

0.001

0.01

0.001

0.01

0.001

0.05

0.01

0.05

Dr.Sarma

Dyslipidemia in Indians

uncomplicated non diabetic hypertensives(3182) vs controls (4131) A. Hypercholesterolemia B. Low HDL C. Isolated elevated triglycerides D. Abnormal TC/HDL ratio E. D+E Abnormal TC/HDL ratio with elevated Tg ↑ TG ↑ LDL 32.90% 21.35% 10.45% 32.00% 15.35% 47.35%

IHJ, 2000, 52: 173-177 Am J Med, 1998, vol 105(1A), 48S-56S

↓ HDL The Triad Dr.Sarma

Life-Habit Risk Factors

1. Obesity (BMI  30) 2. Physical inactivity 3. Atherogenic diet

Dr.Sarma

Emerging Risk Factors

1. Lipoprotein (a) 2. Homocysteine 3. Prothrombotic factors 4. Pro-inflammatory factors 5. Impaired fasting glucose 110- 126 6. Sub-clinical atherosclerosis Dr.Sarma

CHD Risk Equivalents

• Diabetes Mellitus • Reno-vascular Disease • Chronic Nephropathy • Peripheral Vascular Disease • Established CVA All forms of AVD Dr.Sarma

New Features of ATP III

• • • • • Focus on Multiple Risk Factors Diabetes: CHD risk equivalent Framingham projections of 10-year CHD risk Identify patients with multiple risk factors for more intensive treatment Multiple metabolic risk factors (metabolic / X syndrome, IR)

Dr.Sarma

• • • •

New Features of ATP III cont..

Modification of Lipid and Lipoprotein Classification LDL cholesterol < 100 mg/dl—optimal HDL cholesterol < 40 mg/dl • Categorical risk factor • Raised from < 35 mg/dl Lower triglyceride classification cut points • More attention to moderate elevations • > 150 mg itself is indication for Rx.

Dr.Sarma

New Features of ATP III cont..

• LDL cholesterol is the primary target for therapy • Non HDL Cholesterol is the secondary target for therapy Non HDLc = (TC – HDLc) = (LDLc + VLDLc) Dr.Sarma

New Features of ATP III (continued)

New Recommendation for Screening/Detection 1. Complete lipoprotein profile preferred • Fasting (12 h) TC, LDL, HDL, TG 2. Secondary option • • Non-fasting total cholesterol and HDL If TC. is  200 mg/dL or HDL < 40, then proceed to do a full Lipid Profile Dr.Sarma

Approach to Therapy

• Education on diet and exercise • Increase physical activity • Decrease body weight • Employ drug therapy Dr.Sarma

Treatment Plan - LDLc

Clinical Status No CHD < 2 RF No CHD 2 or more RF CHD Present Goal <160 <130 <100 Diet >160 Drugs >190 >130 >100 >160 >130 Dr.Sarma

TG Level < 150 mg%

Triglycerides

Classification Normal TG 150 to 200 mg% Borderline high Treatment No Rx.

Diet alone 201 to 500 mg% High > 500 mg% Very high Diet + drugs Diet + Intensive Rx NCEP 2002 Guidelines by expert panel on TG Dr.Sarma

Treatment Options

• • Diet – Two step approach Drug therapy 1. HMG ¢ CoA Reductase Inhibitors 2. Bile Acid binding Resins 3. Nicotinic Acid 4. Fibric Acid derivatives 5. Probucol ¢ HMG is Hydroxy Methyl Glutaryl Dr.Sarma

Therapeutic Lifestyle Changes - TLC

• • • • • • • • Nutrient Saturated fat PUFA fat MUFA fat Total fat Carbohydrate Fiber Protein Cholesterol Recommended Intake < 7% of calories Up to 10% of calories Up to 20% of calories 25–35% of calories 50–60% of calories 20–30 grams per day Approx. 15% of calories Less than 200 mg/day DIETARY THERAPY Dr.Sarma

ATP III Guidelines

Drug Therapy

Dr.Sarma

• • • • •

HMG CoA Reductase Inhibitors (Statins)

Chol. synthesis is ↓ by enzyme inhibition Reduce LDL-C 18–55% & TG 7–30% Raise HDL-C 5–15%, No action on Lp(a) Major side effects – (< 5%) 1. Myopathy 2. Increased liver enzymes Contraindications 1. Absolute: liver disease 2. Relative: use with certain drugs Dr.Sarma

HMG CoA Reductase Inhibitors (Statins)

Statin Dose Range Lovastatin 20–80 mg Pravastatin 20–40 mg Simvastatin 20–80 mg Fluvastatin 20–80 mg Atorvastatin 10–80 mg Cerivastatin 0.4–0.8 mg Dr.Sarma

HMG CoA Reductase Inhibitors (Statins) (continued)

• • • • • Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality Reduce coronary procedures (PTCA/CABG) Reduce stroke Reduce total mortality Dr.Sarma

Bile Acid Sequestrants

Act by interfering with entero-hepatic circulation of bile acids and Cholesterol sequestration • • Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality Dr.Sarma

Bile Acid Sequestrants

Major actions • Reduce LDL-C 15–30% • Raise HDL-C 3–5% • May increase TG Side effects • GI distress/constipation/nausea • Decreased absorption of other drugs Contra indications • Dys-betalipoproteinemia, • Biliary Obstruction • Raised TG (especially >400 mg/dL) Dr.Sarma

Bile Acid Sequestrants

Drug Cholestyramine Colestipol Colesevelam Dose Range 4–16 g 5–20 g 2.6–3.8 g Dr.Sarma

Nicotinic Acid

Major Actions – Lowers TG 20–50%, – VLDL by 20-35% – Raises HDL-C 15–35% – Only agent – lowering Lp(a) by 25% Side effects Flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity, pruritus tachycardia and atrial arrythmias Contra indications Liver disease, severe gout, peptic ulcer Dr.Sarma

Drug Form

Nicotinic Acid

Dose Range Immediate release (crystalline) Extended release Sustained release 1.5–3 g 1–2 g 1–2 g Dr.Sarma

Nicotinic Acid

• • • • Demonstrated therapeutic benefits Reduces major coronary events Possible reduction in total mortality Poor side effect profile is the limitation Can be combined with statins, fibric acid derivatives

Dr.Sarma

Fibric Acid Derivatives

• Major actions – Lower LDL-C 5–20% (with normal TG) – May raise LDL-C (with high TG) – Lower TG 20–50%, ↓ VLDL synthesis – Raise HDL-C 10–20% – Act by ↑ LPL activity and TG hydrolysis • Side effects Dyspepsia, gallstones, myopathy, Abn. LFT • Contraindications Severe renal or hepatic/ biliary disease Dr.Sarma

Fibric Acid Derivatives

Drug Gemfibrozil Fenofibrate Clofibrate Dose 600 mg BID 200 mg QD 1000 mg BID Dr.Sarma

Fibric Acid Derivatives

• • Demonstrated Therapeutic Benefits Reduce progression of coronary lesions Reduce major coronary events

Dr.Sarma

Probucol

Probucol (Lorelco) 500mg b.i.d with food Third line drug – erratic effect on LDL & decrease of HDL Lowers Cholesterol and the only drug which regresses xanthomas It is an antioxidant of LDL Diarrohea, flatulence, nausea, increases QTc Can be combined with bile acid sequestrating resins Dr.Sarma

Summary of Drug choice

• LDLc is more – Hypercholesterolemia alone – Statins 1 st line – Simvastatin – Atorvastatin – Statins + Anion resin (Questron)– 2 nd line – Or Statins + nicotinc acid – 2 nd – Probucol 3 rd line line specially for xanthomas – But not Statins + gemfibrozil • TG alone is elevated – Hyper-triglyceridemia – Gemfibrozil – 1 st line – Nicotinic acid with or without Gemfibrozil– 2 nd line • For mixed – combination- Statin + Nicotinic acid Dr.Sarma

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 Fenfibrate - Lipicard • Probucol – Lorelco Dr.Sarma

Coronary heart disease and HDL-C Framingham Heart Study

200 150 100 50 0 <25 25–34 35–44 45–54 55–64 65–74 HDL-C (mg/dl)

Gordon, Castelli et al. Am J Med 1977; 62: 707–714

75+ Women Men

Dr.Sarma

Relative risks of MI

The Physicians Health Study

3.78

3.21

1.00

Low total cholesterol <212 mg/dl

2.41

High total cholesterol



212 mg/dl Low HDL cholesterol <47 mg/dl



47 mg/dl Stampfer, Sacks et al. N Engl J Med 1991; 325: 373–381

Dr.Sarma

HDL-C vs LDL-C

as a predictor of CHD risk

Risk of CAD over 4 years of follow-up* CHD RR 3 2.5

2 1.5

1 0.5

100 mg/dl 160 mg/dl 220 mg/dl

*Men aged 50–70 LDL-C

Gordon, Castelli et al. Am J Med 1977; 62: 707–714

HDL-C

25 mg/dl 45 mg/dl 65 mg/dl 85 mg/dl

Dr.Sarma

Low HDL Cholesterol (< 40)

• Elevated triglycerides • Overweight / Obesity, Physical inactivity • Type 2 diabetes • Cigarette smoking • Very high carbohydrate intake (> 60% cal.) • Certain drugs (beta-blockers, anabolic steroids, progestational agents) Dr.Sarma

Management of Low HDLc

• LDL cholesterol is primary target of therapy • Weight reduction and increased physical activity (if the metabolic syndrome is present) • Non-HDL cholesterol is secondary target of therapy (if triglycerides  200 mg/dL) • Consider nicotinic acid or fibrates (for patients with CHD or CHD risk equivalents) Dr.Sarma

Homocystine

• Normal value is up to 15 μ mols./l • Folic acid, Vitamin B 6 and B 12 are essential for the normal transulfuration and remethylation cycles • Excess of homocystine generates oxidative stress on the cell membranes. DNA and protein denaturation through ROS formation • Folic acid 5 mg/ day + Vit. B 6 to be given on regular basis and B 12 are Dr.Sarma

• • • • • •

Lp (a) or Little a

Similar to LDL molecule A single apo-A is attached by a disulfide bond to apo-B 100 Primary determinant is genetic Normal value 20 mg %, > 30 high risk It competes with plasminogen because of its structural similarity and so interferes with plasmin synthesis and thrombolytic pathway Nicotinic acid , ? Benzafibrate, Estrogens ↓ it

Dr.Sarma

Association of Lp(a) to CAD

• Meta analysis of 27 prospective studies, 5436 CHD cases, F/u of 10 yrs • People with Lp(a) levels in the top third of baseline measurement are at about 70% increased risk of CHD compared with those in the bottom third.

Circulation, 2000, 102: 1082-1085

• Serum Lp(a) is an independent risk factor for CAD in NIDDM patients in south India

Diabetes care, 1998, 21, 1819-1823

Dr.Sarma

Insulin Resistance

• • • • Metabolic syndrome Multi system disorder Predisposes to DM & CVD Contributors to IR 1. Genetic 2. Obesity – abdominal 3. Physical inactivity 4. Advancing age Dr.Sarma

Insulin Resistance

• Atherogenic dyslipidemia –  In VLDL,  in small LDL,  in HDL • Prothrombotic state –  –  In fibrinogen levels In plasminogen activator inhibitor – Various platelet abnormalities • G.T. Abnormalities – IGT, hyper glycemia • Hypertension Dr.Sarma

Evidence for Insulin Resistance

• Abdominal obesity • B.P – High normal or Mild HT • TG high normal  250 • Lowered HDL  40 for men,  50 women • Boarder line LDL - 130- 155 mg% • IGT -- FPG – 110- 126 mg% Having Diabetes is equivalent to having IHD Dr.Sarma

The Research

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

SU.VI.MAX

CELL Arterial disease multiple intervention trial (Niacin, Anti-oxidants, vitamins) Cambridge heart anti-oxidant study

Supplementation en Vitamines et Mineraux Antioxydants

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 Dr.Sarma

The Future Research

• We do not have yet any drug which increases 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 Dr.Sarma

The Almighty

May pardon and grant me heaven – Even if I don't know a single letter about – Crutz Feld Jacob’s Disease – Tsutsugamushi Fever – Criggler Nazzar Syndrome – South American equine encephalitis and – Many and much more BUT Dr.Sarma

The Almighty

Will drag me to hell and will not pardon my • Ignorance of even the minute details common diseases like DM, HT, IHD, Dyslipedimias etc., • Indifference to apply current knowledge • Negligence in screening for Lipid abnormalities • Despondency about preventing CHD, DM, IR • Inadequacy in maintaining my patients a s normo tensive, normo-glycemic, and normo-lipemic as possible (This is applicable to all common diseases) Dr.Sarma

Do You Who I am ?

I am the primary care physician on whom my patients bestow all trust

Dr.Sarma

Thanks Everyone

Dr.Sarma

Happy New Year Dr.Sarma