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LIPIDS. An over view of Normal and Abnormal Lipids. 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

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lipids

LIPIDS

An over view of

Normal and Abnormal Lipids

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all are one
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
How much is much ?

BMI =

Weight in kgs

Height2 in mts

70

1.65 x 1.65

BMI =

= 25.71

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

Lipid abnormalities

Atherosclerotic vascular disease

CHD, CVD, PVD

Lipid Abnormalities

ROS

tHcy

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why are lipids important
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 > 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
AVD – Clinical Manifestations

For every thing the common denominator is ED

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lipid transport
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 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
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
Lipoproteins

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major lipoproteins
Major Lipoproteins

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lipoprotein metabolism
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
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 HDL3in the liver

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enzymes contd
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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e x o g e n o u s
EXOGENOUS

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e n d o g e n o u s
ENDOGENOUS

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h d l p a t h w a y
HDLPATHWAY

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lipid peroxidation
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
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
Secondary Hyperlipidemia

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clinical action
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 Profile Report

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ldlc calculation
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
Risk Factors for CHD

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treatment plan ldlc
Treatment Plan - LDLc

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therapeutic goals
Therapeutic Goals

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cholesterol levels
Cholesterol Levels

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triglycerides
Triglycerides

NCEP Guidelines by expert panel on TG

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diet regimen
Diet Regimen

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treatment options
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
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
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
Anion Resins
  • 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
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
  • 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
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- Statin+Nicotinic acid

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what s in a name
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
The Research

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the future research
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
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
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
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
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 and their Antioxidants

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reactive oxygen species ros
Reactive Oxygen Species (ROS)

ROS are highly reactive….and can damage biological tissues and membranes

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what is homocysteine
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

  • 1+2+3= homocyst(e)ine
  • homocyst(e)ine = tHcy
  • Homocyst(e)inemia=hyper - tHcy
  • Sulfur-containing amino acid
  • By product of methionine metabolism

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homocysteine metabolic pathways
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)

MS – Methionine synthase

MTHFR – Methyl tetrahydro folate reductase

C beta S – Cystathionine beta synthase

Cystathionine

Transsulfuration

Pathway

Cysteine

Sulphate

Glutathione

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hyperhomocyst e inemia
Hyperhomocyst(e)inemia

Blood Homocyst(e)ine Levels

  • 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
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 & Pathogenesis of AVD

Homocysteine

Auto-oxidation

Generation of ROS

H2O2 OH/O2

Oxidizes LDL

Damages endothelium

Lipid peroxidation

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
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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slide53
True !

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