LIPIDS

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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
• 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 ?

• Weight in kgs
• Height2 in mts

BMI
70 1.65 x 1.65
BMI
25.71
Underweight lt 20 Over weight gt 25 to 30 Normal
20 to 25 Obesity gt30
Waist / Hip ratio 35 /38 0.92 Normal for
Males lt 0.90, Females lt0.80
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Lipid Abnormalities
ROS
tHcy
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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 gt 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
Leg Muscles Peripheral Vascular Disease (PVD) Ischemia Infarction Intermittent Claudication Gangrene
For every thing the common denominator is ED
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Lipid Transport
TG
EC
Apoprotein boat
Apo A HDL Apo B100CE VLDL, IDL Apo B100
LDL Apo B48CAE 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 lt RBC
TG, EC
Apoproteins A, B, C, E, (a) (Amphiphatic)
Phospholipids Free Cholesterol (Hydrophilic)
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Lipoproteins
Lipoprotein TG Chol. Apoprotein
Chylomicron 95 5 B48CEA
Remnants 2 98 B48
VLDL 80 20 B100CE
IDL 30 70 B100E
LDL 10 90 B100
Small LDL 10 90 B100
HDL 5 4550 AI, AII
Lp(a) 10 90 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

• 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
• Hepatic TG Lipase (HGTL)
• 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..

• 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

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EXOGENOUS
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ENDOGENOUS
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HDLPATHWAY
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Lipid Peroxidation
LDL, IDL
Not normally taken up by the vessel wall
ROS Free radicals and Pro-oxidants
Freely enters the vessel wall
Oxidized LDL, IDL
Macrophages
Endothelium
Scavenger pathway
Foam Cells
Cytokines, GF
Atherosclerosis
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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

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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 LIPOPROTEIN Remarks
TC 250 HDL 50 N
LDL 170 Abnormal
VLDL 30 N
TG 150 VLDL 135 N
Chylomicron15 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 (5030)
• 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 lt 2 RF gt160 gt190 lt160
No CHD 2 or more RF gt130 gt160 lt130
CHD Present gt100 gt130 lt100
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Therapeutic Goals
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Cholesterol Levels
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Triglycerides
TG Level Classification Treatment
lt 200 mg Normal TG No Rx.
200 to 400 mg Borderline high Diet alone
400 to 1000 mg High Diet drugs
gt 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 lt 30 lt 30
Saturated lt 10 lt 5
PUFA lt 10 lt 10
MUFA lt 10 15
CHO 55 55
Protein 15 15
Cholesterol lt 300 mg lt 200 mg
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Treatment Options

• Diet Two step approach
• Drug therapy
• 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 - lt 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

• 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

• Interrupt the enterohepatic circulation of bile
  acids
• Increased synthesis of bile acidscholesterol
  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

• 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
• 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- StatinNicotinic acid

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Whats 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

• Hyperhomocyst(e)inemia
• Diabetes mellitus
• Hypertension
• Dyslipidemia
• Positive family history,
• Smoking, obesity and
• physical inactivity

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
  sacrificialantioxidants
• -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
H2O2 Hydrogen peroxide Glutathione peroxidase
O2 Singlet Oxygen Vitamin A, E
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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
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What is Homocysteine ?
Metabolism
Digestion
Protein diet
Methionine
1)Homocysteine
Auto-oxidation
Protein synthesis
2)Homocystine 3) Homocysteine thiolactone
HS-CH2-CH2-CH-COOH
Generation of ROS
NH2
Homocysteine

• 123 homocyst(e)ine
• homocyst(e)ine tHcy
• Homocyst(e)inemiahyper - tHcy

• Sulfur-containing amino acid
• By product of methionine metabolism

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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)
Cystathionine
MS Methionine synthase MTHFR Methyl
tetrahydro folate reductase C beta S
Cystathionine beta synthase
Transsulfuration Pathway
Cysteine
Sulphate
Glutathione
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Hyperhomocyst(e)inemia
Blood Homocyst(e)ine Levels
Classification Values in mmol/L
Normal Moderate Intermediate Severe 05 15 16 30 31 100 gt 100

• 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

• Nutritional Vitamin deficiency
• Folic Acid
• Vitamin B12
• Vitamin B6
• Genetic Enzyme Abnormality
• Drugs
• Methotrexate, Phenytoin, Theophylline

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Homocysteine Pathogenesis of AVD
Homocysteine
Auto-oxidation
Generation of ROS
H2O2 OH/O2
Oxidizes LDL
Lipid peroxidation
Damages endothelium
Exposure of smooth muscle, subendothelium
Nitric Oxide formation
Foam cells (chol)
Proliferation of SM cells, Chemotaxis
Vasodilation
Hypertension
ATHEROSCLEROSIS
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New Year Best Wishes

• We wish you to be blessed always with
• BMI of lt 25 W/H ratio of 0.80
• FBG of 60 to100
• Blood pressure of about 120/80
• LDLc of lt100
• TG of lt200
• Normal ECG and Treadmill test
• All these mean a very healthy and Happy HEART

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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