Transcript Lipids Simple by Dr Sarma

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
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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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How much is much ?
BMI =
Weight in kgs
Height2 in mts
70
BMI =
= 25.71
1.65 x 1.65
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
Diets rich in
Saturated Fat, Chol
Sedentary Life Style
Excess body weight/
Obesity
Less perfect Genetic
make-up
tHcy
ROS
Lipid abnormalities
Atherosclerotic
vascular disease
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CHD, CVD,
PVD
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Why are lipids important ?
• Complications of Atherosclerosis are
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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
Ischemia
Infarction
Intermittent Claudication
Gangrene
Leg
Peripheral Vascular
Muscles Disease (PVD)
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
Lipids or Fats
(Hydrophobic)
Size < RBC
TG, EC
Apoproteins
A,
B, C, E, (a)
(Amphiphatic)
Phospholipids
Free Cholesterol
(Hydrophilic)
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Lipoproteins
Lipoprotein
Chylomicron
Remnants
VLDL
IDL
LDL
Small LDL
HDL
Lp(a)
TG
95
2
80
30
10
10
5
10
Chol.
5
98
20
70
90
90
45+50
90
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Apoprotein
B48+C+E+A
B48
B100+C+E
B100+E
B100
B100
AI, AII
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)
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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)
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Removes TG from VLDL, IDL LDL
Clears the Cholesterol remnants into liver
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Converts HDL2 to HDL3 in the liver
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Enzymes contd..
3. Lecithin Chol Acyl Transferase (LCAT)
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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)
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Secreted into plasma from liver
Transfers EC from HDL to VLDL
Converts LDL to small Dense LDL
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E
X
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G
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N
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E
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D
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G
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N
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H
D
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P
A
T
H
W
A
Y
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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
Macrophages
Cytokines, GF
Atherosclerosis
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Synthesis of VLDL (TG)
• In the liver VLDL is synthesized
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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
TC = 250
TG = 150
LIPOPROTEIN Remarks
HDL = 50
N
LDL = 170
Abnormal
VLDL = 30
N
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
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Diet – Two step approach
Drug therapy
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HMG CoA Reductase Inhibitors
Bile Acid binding Resins
Nicotinic Acid
Fibric Acid derivatives
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
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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
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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
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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
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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
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Hyperhomocyst(e)inemia
Diabetes mellitus
Hypertension
Dyslipidemia
Positive family history,
Smoking, obesity and
physical inactivity
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Oxidative
Stress
AVD
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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
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ROS damage biological tissues- membranes
Reactive Oxygen Species
Lipid peroxidation
Protein denaturation
DNA Damage
Free radicals released
Cell Dysfunction and death
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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
Antioxidants
O2
Superoxide free
radical
Superoxide dismutase Vitamin E,
-carotene
OH
Hydroxyl free radical
Vitamin C
Hydrogen peroxide
Glutathione peroxidase
Singlet Oxygen
Vitamin A, E
H2O2
O2
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Reactive Oxygen Species (ROS)
Free Radicals
Superoxide O2
Hydroxyl OH
Non Radicals
Hydrogen peroxide H2O2
Singlet oxygen O2
ROS are highly reactive….and can damage biological
tissues and membranes
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What is Homocysteine ?
Protein diet
Metabolism
Digestion
Methionine
1)Homocysteine
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
• Sulfur-containing amino acid
•homocyst(e)ine = tHcy
•By product of methionine metabolism
•Homocyst(e)inemia=hyper - tHcy
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Homocysteine : Metabolic Pathways
Remethylation
Cycle
Diet
Tetra hydrofolate
Folic acid
MTHFR
Demethylation
Cycle
Methionine
Vitamin B6
(MS)
Methyl
tetrahydrofolate
MS – Methionine synthase
MTHFR – Methyl tetrahydro
folate reductase
C beta S – Cystathionine
beta synthase
Homocysteine
Cystathionine
Vitamin B6
(C beta S)
Cysteine
Sulphate
Glutathione
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Hyperhomocyst(e)inemia
Blood Homocyst(e)ine Levels
Values in mmol/L
Classification
05 – 15
16 – 30
31 – 100
> 100
Normal
Moderate
Intermediate
Severe
• 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
H2O2
Damages endothelium
OH/O2
Lipid peroxidation
Exposure of smooth
Nitric Oxide formation muscle, subendothelium
Vasodilation
Proliferation of SM
cells, Chemotaxis
Hypertension
ATHEROSCLEROSIS
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Oxidizes LDL
Foam cells (chol)
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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
Drink
Indulge
Think
Be quiet
Have high Chol
Be high spirited
Smoke
but not over-eat
but not alcohol
but not in junk food
but not worry
but with exercise
but not LDL Cholesterol
but not be on ‘spirits’
any brand of incense
stick, but not cigarettes
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