Transcript Homocystine by Dr Sarma

CHD
Newer Risk Factors
An over view on
Homocystinemia
Dr. R.V.S.N.Sarma
M.D., M.Sc., (Canada)
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
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
Macro-vascular Disease
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
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
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
Risk Factors for AVD
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Hyperhomocyst(e)inemia
Diabetes mellitus
Hypertension
Dyslipidemia
Positive family history,
Smoking, obesity and
physical inactivity
Oxidative
Stress
AVD
Free Radical Formation
Homolytic fission of a covalent bond
Single covalent bond
A
B
Homolytic fission
A
Heterolytic fission
B
Free radicals
A
B
Ions
ROS damage biological tissues- membranes
Reactive Oxygen Species
Lipid peroxidation
Free radicals
released
Protein denaturation
Cell Dysfunction and death
DNA Damage
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
ROS and their Antioxidants
O2
OH
H2O2
O2
ROS
Antioxidants
Superoxide
free radical
Hydroxyl free
radical
Hydrogen
peroxide
Singlet Oxygen
Superoxide dismutase
Vitamin E, -carotene
Vitamin C
Glutathione peroxidase
Vitamin A, E
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
What is Homocysteine ?
Protein diet
Metabolism
Digestion
Methionine
1)Homocysteine
Auto-oxidation
Protein synthesis
HS-CH2-CH2-CH-COOH
NH2
Homocysteine
2)Homocystine
3) Homocysteine
thiolactone
Generation
of ROS
• 1+2+3= homocyst(e)ine
• Sulfur-containing amino acid
•homocyst(e)ine = tHcy
•By product of methionine metabolism
•Homocyst(e)inemia=hyper - tHcy
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
Hyperhomocyst(e)inemia
Blood Homocyst(e)ine Levels
Classification
Values in mmol/L
Normal
Moderate
Intermediate
Severe
05 – 15
16 – 30
31 – 100
> 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
Causes of Hyperhomocyst(e)inemia
A. Nutritional : Vitamin deficiency
Folic Acid
Vitamin B12
Vitamin B6
B. Genetic : Enzyme Abnormality
C. Drugs :
Methotrexate, Phenytoin, Theophylline
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
Oxidizes LDL
Foam cells (chol)
Physicians Health Study
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271 male physicians who had MI and
matched controls were studied
Various risk factors were analyzed
Plasma tHcy is significantly higher in those
with MI compared to controls
The R.R for tHcy levels above 13 is 3.4 after
adjusting for all other risk factors
482 hyperlipedemic subjects – 72 % with
↑tHcy had atheroscleoris v/s 44 % without
Treatment of
Hyperhomocyst(e)inemia
A. Nutritional : Vitamin Supplimentation
Folic Acid – 5 mg daily (Folvite)
Supplementation of Vitamin B12
Supplementation of Vitamin B6
B. Drugs : Care while using drugs like
Methotrexate, Phenytoin, Theophylline
C. Role of anti-oxidants – no RCTs
Lp (a) or Little a
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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 may compete with plasminogen because of
structural similarity and so interfere with plasmin
synthesis and thrombolytic pathway
Nicotinic acid, ? Benzafibrate, estrogens lower it
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 only HDL Cholesterol
but not be on ‘spirits’
any brand of incense stick,
but not cigarettes