Transcript Lipids Explianed by Dr Sarma

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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
[email protected]
Dr.Sarma
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Best Wishes to You All
From IMA Tamil
Nadu
Dr.Sarma
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LIPIDS
An overview of
Normal and Abnormal Lipids
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Lipid Abnormalities
Sedentary Life Style
Diets rich in
Saturated Fat, Chol
Excess body weight/
Obesity
Less perfect Genetic
make-up
tHcy
Atherosclerotic
vascular disease
ROS
Lipid abnormalities
CHD, CVD,
PVD
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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
Ischemia
Infarction
Intermittent Claudication
Gangrene
Leg
Peripheral Vascular
Muscles Disease (PVD)
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
Lipids or Fats
(Hydrophobic)
Size < RBC
TG, EC
Phospholipids
Free Cholesterol
(Hydrophilic)
Apoproteins
A,
B, C, E, (a)
(Amphipathic)
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Lipid Transport
TG
EC
Apoprotein boat
Solubilizes
Apo A = HDL
Apo B100+C+E = VLDL, IDL
Apo B100 = LDL
Apo B48+C+A+E = Chylomicrons
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Composition
TG 95 %
TG 80 %
EC 20%
EC 5%
Chylomicrons
VLDL
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Composition
TG 15 %
TG 5 %
EC 95%
EC 85%
LDL
HDL
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Particle size & Density
Chylomicrons
VLDL
IDL
<< 1.006
< 1.006
< 1.019
LDL
Small LDL
HDL
< 1.063
< 1.085
< 1.210
Atherogenicity is a function of the density
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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)
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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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Reverse Cholesterol Transport
Vascular
Endothelial Cell
LIVER
EC
Free Chol.
UEC
HDL
L CAT
Enzyme
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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
Endothelium
Scavenger
pathway
Foam Cells
Atherosclerosis
Macrophages
Cytokines, GF
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Lipid Peroxidation
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Primary Hyperlipidaemias
Familial 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, creamyorange, slightly elevated papules on eyelids .
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Clinical Photos
Tendinous xanthomas. Large subcutaneous 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 Strategy
Lipid Profile, Risk Assessment
LDL > 100
Look For Sec. Causes
Treat the cause, if found
Treatment
CHD +
NO CHD
Primary Prevention
Sec. Prevention
LDL > 100
2 or > RF
< 2 RF
LDL > 130
High Risk
Low Risk
LDL >160
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Treatment Strategy
Fasting TG Level
TG < 150
Normal
↑Fasting TG Level
TG >150, No CHD
TG > 150, CHD +
TG > 500, CHD +/-
< 2 RF
Diet Modif.
2 or > RF
Diet + Fibrate
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
HDL
LDL
VLDL
TRIGLICERIDES
Chylomicrons
VLDL
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Lipid Profile Report
LIPID TYPE
LIPOPROTEIN
TC = 250
HDL = 50
> 45
N
LDL = 170
< 130
Abnormal
VLDL = 30
< 60
N
VLDL = 135
< 150
N
Chylomicron=15
< 30
N
TG = 150
Normal Remarks
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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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National Cholesterol
Education Program - NCEP
Adult Treatment Panel III
(ATP III) Guidelines -2002
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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;.
Dr.Sarma
Risk Factors Ranking in the PROCAM Study
Risk factor
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
Relative risk
P Value
2.3
0.001
1.9
4.3
1.8
0.01
0.001
0.001
1.7
2.7
0.01
0.001
1.6
2.6
0.01
0.001
1.4
1.9
1.4
0.05
0.01
0.05
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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. Abnormal TC/HDL ratio with elevated Tg
D+E
↑TG
↑LDL
IHJ, 2000, 52: 173-177
Am J Med, 1998, vol 105(1A), 48S-56S
↓HDL
32.90%
21.35%
10.45%
32.00%
15.35%
47.35%
The Triad
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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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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.
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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)
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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%
Diet + Intensive Rx
Very high
NCEP 2002 Guidelines by expert panel on TG
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Treatment Options
•
•
Diet – Two step approach
Drug therapy
1.
2.
3.
4.
5.
¢
HMG¢ CoA Reductase Inhibitors
Bile Acid binding Resins
Nicotinic Acid
Fibric Acid derivatives
Probucol
HMG is Hydroxy Methyl Glutaryl
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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
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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
Lovastatin
Pravastatin
Simvastatin
Fluvastatin
Atorvastatin
Cerivastatin
Dose Range
20–80 mg
20–40 mg
20–80 mg
20–80 mg
10–80 mg
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
Act by interfering with entero-hepatic
circulation of bile acids and Cholesterol
sequestration
Demonstrated Therapeutic Benefits
•
Reduce major coronary events
•
Reduce CHD mortality
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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)
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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 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
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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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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
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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
Dr.Sarma
Coronary heart disease and HDL-C
Framingham Heart Study
200
Rate/1000
150
100
Women
50
Men
0
<25
25–34
35–44
45–54
55–64
65–74
75+
HDL-C (mg/dl)
Gordon, Castelli et al. Am J Med 1977; 62: 707–714
Dr.Sarma
Relative risks of MI
The Physicians Health Study
3.78
3.21
2.41
1.00
Low total cholesterol
<212 mg/dl
Low HDL cholesterol
<47 mg/dl
High HDL cholesterol
47 mg/dl
High total cholesterol
212 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
HDL-C
1.5
25 mg/dl
45 mg/dl
65 mg/dl
85 mg/dl
1
0.5
0
100 mg/dl
160 mg/dl
220 mg/dl
LDL-C
*Men aged 50–70
Gordon, Castelli et al. Am J Med 1977; 62: 707–714
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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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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)
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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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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
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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 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 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
Dr.Sarma
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Best
Wishes
for
a
Sarvae Jana Sukhino Bhavantu
Happy New Year
Dr.Sarma