dr. r.v.s.n.sarma, m.d., m.sc (canada)
DESCRIPTION
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]. Best Wishes to You All. From IMA Tamil Nadu. LIPIDS. An overview of - PowerPoint PPT PresentationTRANSCRIPT
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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
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Best Wishes to You All
From IMA Tamil Nadu
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LIPIDS
An overview of
Normal and Abnormal Lipids
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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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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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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
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Lipoprotein
TG, EC
Phospholipids Free Cholesterol
(Hydrophilic)
Apoproteins A, B, C, E, (a) (Amphipathic)
Lipids or Fats (Hydrophobic)Size < RBC
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ECTG
Lipid Transport
Apoprotein boat
Apo A = HDL Apo B100+C+E = VLDL, IDL
Apo B100 = LDL Apo B48+C+A+E = Chylomicrons
Solubilizes
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Composition
TG 95 %
EC 5%
TG 80 %
EC 20%
Chylomicrons VLDL
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Composition
TG 15 %
EC 85%
TG 5 %
EC 95%
LDL HDL
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Particle size & Density
Chylomicrons
<< 1.006
VLDL
< 1.006
IDL
< 1.019
LDL
< 1.063
Small LDL
< 1.085
HDL
< 1.210
Atherogenicity is a function of the density
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Lipoproteins
Lipoprotein TG Chol. Apoprotein
Chylomicrons 95 5 B48+C+E+A
VLDL 80 20 B100+C+E
IDL 30 70 B100+E
LDL 15 85 B100
Small LDL 10 90 B100
HDL 5 95 AI, AII
Lp(a) 10 90 B100+(a)
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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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LIVER
Reverse Cholesterol Transport
Vascular Endothelial Cell
Free Chol.
L CAT Enzyme
UECEC
HDL
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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 (HTGL)– 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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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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Lipid Peroxidation
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Primary HyperlipidaemiasFamilial Hyper Cholesterolemia II a ↑LDL
Familial defect in apo B 100 II a ↑LDL
Polygenic Hyper Cholesterolemia II a ↑LDL
Familial Hyper Triglyceridemia IV ↑VLDL
Familial LPL deficiency I, V ↑Chylo
Familial apo CII deficiency I, V ↑Chylo
Combined Hyperlipedemia II b ↑VLDL,↑LDL
Dys-Beta lipoproteinemia III ↑VLDL,↑IDL
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Secondary Hyperlipidemia
Cholesterol TG
Nephrotic syndrome. Obesity
Hypothyroidism Diabetes
Obstr. liver disease Uraemia
Anorexia nervosa Alcoholism, Smoking
Acute Int. Porphyria Oral contraceptives
Progestogens Beta blockers
Thiazides Pregnancy
Anabolic steroids Steroids, Thiazides
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Clinical Photos
Tuberous xanthoma. Flat-topped, yellow, firm tumor
Xanthelasma. Multiple, longitudinal, creamy-orange, slightly elevated papules on eyelids .
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Clinical Photos
Tendinous xanthomas. Large sub-cutaneous tumors adherent to the Achilles tendons.
Papular eruptive xanthomas. Multiple, discrete, red-to-yellow confluent papules
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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
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Treatment StrategyLipid Profile, Risk Assessment
LDL > 100 Look For Sec. Causes
Treat the cause, if found
Treatment
Sec. PreventionPrimary Prevention
High Risk Low Risk
LDL > 130
LDL >160
CHD +
NO CHD
< 2 RF 2 or > RF
LDL > 100
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Treatment StrategyFasting TG Level TG < 150
↑Fasting TG LevelNormal
< 2 RF
TG >150, No CHD
TG > 150, CHD +
TG > 500, CHD +/-
Diet Modif.
Diet + Fibrate
2 or > RF
Diet + Fibrate + Niasyn
Diet + Fibrate + Statin
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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
LIPIDS ESTIMATED
TOTAL CHOLESTEROL TRIGLICERIDES
HDL LDL VLDL Chylomicrons VLDL
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Lipid Profile Report
LIPID TYPE LIPOPROTEIN Normal Remarks
TC = 250 HDL = 50 > 45 N
LDL = 170 < 130 Abnormal
VLDL = 30 < 60 N
TG = 150 VLDL = 135 < 150 N
Chylomicron=15 < 30 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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Adult Treatment Panel III (ATP III) Guidelines -2002
National Cholesterol Education Program - NCEP
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Categories of Risk Factors
1. Major, independent risk factors
2. Life-habit risk factors
3. Emerging risk factors
4. CHD risk equivalents
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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;.
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Risk factor Relative risk P Value
Smoking 2.30.001
LDL cholesterol (mg/dl)130-160 1.90.01>160 4.30.001
Hypertension 1.80.001
HDL cholesterol (mg/dl)55 - 45 1.70.01< 45 2.70.001
Triglycerides (mg/dl)105- 167 1.60.01>167 2.60.001
Fasting blood glucose (mg%)110-126 1.40.05> 126 1.90.01
Family history of MI 1.40.05
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Dyslipidemia in Indiansuncomplicated non diabetic
hypertensives(3182) vs controls (4131)
A. Hypercholesterolemia 32.90%
B. Low HDL 21.35%
C. Isolated elevated triglycerides 10.45%
D. Abnormal TC/HDL ratio 32.00%
E. Abnormal TC/HDL ratio with elevated Tg 15.35%
D+E 47.35%
IHJ, 2000, 52: 173-177Am J Med, 1998, vol 105(1A), 48S-56S
The Triad
↑LDL
↓HDL
↑TG
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Life-Habit Risk Factors
1. Obesity (BMI 30)
2. Physical inactivity
3. Atherogenic diet
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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
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CHD Risk Equivalents
• Diabetes Mellitus
• Reno-vascular Disease
• Chronic Nephropathy
• Peripheral Vascular Disease
• Established CVA
All forms of AVD
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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)
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• 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.
New Features of ATP III cont..
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• LDL cholesterol is the primary target for therapy
• Non HDL Cholesterol is the secondary target for therapy
Non HDLc = (TC – HDLc)
= (LDLc + VLDLc)
New Features of ATP III cont..
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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
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Approach to Therapy
• Education on diet and exercise
• Increase physical activity
• Decrease body weight
• Employ drug therapy
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Treatment Plan - LDLc
Clinical Status Goal Diet Drugs
No CHD
< 2 RF
<160 >160 >190
No CHD
2 or more RF
<130 >130 >160
CHD Present <100 >100 >130
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Triglycerides
TG Level Classification Treatment
< 150 mg% Normal TG No Rx.
150 to 200 mg% Borderline high Diet alone
201 to 500 mg% High Diet + drugs
> 500 mg% Very high Diet + Intensive Rx
NCEP 2002 Guidelines by expert panel on TG
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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
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Therapeutic Lifestyle Changes - TLC
Nutrient Recommended Intake• Saturated fat < 7% of calories• PUFA fat Up to 10% of calories• MUFA fat Up to 20% of calories• Total fat 25–35% of calories• Carbohydrate 50–60% of calories• Fiber 20–30 grams per day• Protein Approx. 15% of
calories• Cholesterol Less than 200 mg/day
DIETARY THERAPY
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ATP III Guidelines
Drug Therapy
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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
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HMG CoA Reductase Inhibitors (Statins)
Statin Dose Range
Lovastatin 20–80 mgPravastatin 20–40 mgSimvastatin 20–80 mgFluvastatin 20–80 mgAtorvastatin 10–80 mgCerivastatin 0.4–0.8 mg
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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
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Bile Acid Sequestrants
Demonstrated Therapeutic Benefits
• Reduce major coronary events
• Reduce CHD mortality
Act by interfering with entero-hepatic
circulation of bile acids and Cholesterol
sequestration
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Bile Acid SequestrantsMajor 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)
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Bile Acid Sequestrants
Drug Dose Range
Cholestyramine 4–16 g
Colestipol 5–20 g
Colesevelam 2.6–3.8 g
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Nicotinic AcidMajor 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 arrythmiasContra indications Liver disease, severe gout, peptic ulcer
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Nicotinic Acid
Drug Form Dose Range
Immediate release 1.5–3 g
(crystalline)
Extended release 1–2 g
Sustained release 1–2 g
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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
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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
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Fibric Acid Derivatives
Drug Dose
Gemfibrozil 600 mg BID
Fenofibrate 200 mg QD
Clofibrate 1000 mg BID
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Fibric Acid Derivatives
Demonstrated Therapeutic Benefits• Reduce progression of coronary lesions
• Reduce major coronary events
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ProbucolProbucol (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
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Summary of Drug choice• LDLc is more – Hypercholesterolemia 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
• TG alone is elevated – Hyper-triglyceridemia– 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
Fenfibrate - Lipicard
• Probucol – Lorelco
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Coronary heart disease and HDL-CFramingham Heart Study
Gordon, Castelli et al. Am J Med 1977; 62: 707–714
0
50
100
150
200
Rat
e/10
00
<25 25–34 35–44 45–54 55–64 65–74 75+
HDL-C (mg/dl)
Women
Men
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Relative risks of MI
3.21
3.78
1.00
2.41 Low HDL cholesterol<47 mg/dl
High HDL cholesterol47 mg/dl
Low total cholesterol<212 mg/dl
High total cholesterol212 mg/dl
Stampfer, Sacks et al. N Engl J Med 1991; 325: 373–381
The Physicians Health Study
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HDL-C vs LDL-C as a predictor of CHD risk
*Men aged 50–70
Gordon, Castelli et al. Am J Med 1977; 62: 707–714
100 mg/dl 160 mg/dl 220 mg/dl0
0.5
1
1.5
2
2.5
3
Risk of CAD over 4years of follow-up*
LDL-C
85 mg/dl
65 mg/dl
45 mg/dl
25 mg/dl
CHD RR
HDL-C
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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)
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• 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)
Management of Low HDLc
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Homocystine
• Normal value is up to 15 μ mols./l
• Folic acid, Vitamin B6 and B12 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. B6 and B12 are to be given on regular basis
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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
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• 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
Association of Lp(a) to CAD
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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
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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
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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
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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 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
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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
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The AlmightyWill 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 as normo-
tensive, normo-glycemic, and normo-lipemic as possible (This is applicable to all common diseases)
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Do You Who I am ?
I am the primary care physician
on whom my patients bestow all trust
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Thanks Everyone
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Sarvae Jana Sukhino BhavantuBest Wishes for a
Happy New Year