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the importance of homocysteine


  1. 1. Homocysteine Dr Hussam elmouzi Clinical pathologist Alborg Laboratory The new cholesterol
  2. 2. True Facts <ul><li>Cardiovascular Disease is the world’s number one killing disease. About 30% of annual worldwide deaths are cause by this disease. </li></ul><ul><li>Up to 80% of all heart attacks occur in people with normal cholesterol </li></ul><ul><li>In 25% of adults, the first sign of heart disease is sudden death from a heart attack. </li></ul>Copyright 2010 - July, 2006 Vol. 3 No. 4 Homocysteine - Revisited
  3. 3. The right idea but the wrong era <ul><li>Dr Kilmer McCully, a researcher who graduated from Harvard Medical School in the mid-1960s and came up with the hypothesis that moderate elevations of homocysteine could lead to heart attacks and strokes. </li></ul><ul><li>It was the time that the cholesterol-heart-attack theory was gaining tremendous momentum and Mc Cully’s hypothesis clearly challenged its future </li></ul><ul><li>He found himself moved down to the basement, funding for his research dried up and he was eventually asked to leave Harvard. </li></ul>
  4. 4. Annual publication rates within the fields of homocysteine and folate at present there is virtually a &quot;new paper every day&quot; on the subject
  5. 5. <ul><li>Prevalence of hyperhomocysteinemia is not insignificant: </li></ul><ul><li>1 . general population: 5 - 10% </li></ul><ul><li>2. elderly population: 30 - 40% </li></ul><ul><li>3. pts with vascular disease: 20 - 40%. </li></ul>Epidemiology Annu Rev Med 1998;49:31-62. HCY and cardiovascular disease. Refsum H, Ueland PM, Jacques PF, Bostom AG, Wilson PW, Determinants of plasma total HCY concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73:613-621
  6. 6. Homocysteine metabolism Methionine Homocysteine Cysteine meat, eggs, milk, cheese, white flour, canned foods and highly processed foods. Methyl transferase <ul><li>Vitamin B12 </li></ul><ul><li>Folic Acid </li></ul>Cystathionine synthase <ul><li>Vitamin B 6 </li></ul>Circulation. 1999;99:178-182
  7. 7. Increase homocysteine concentration Methionine Homocysteine Cysteine Methyl transferase Cystathionine synthase Genetics: altered enzyme activity of HCy related pathways 【 nutritional deficiencies, life style , drugs , some diseases 】 <ul><li>Vitamin B 6 </li></ul>Family history: of heart disease, stroke, cancr,Alezheimer’s disease, diabetes <ul><li>Vitamin B12 </li></ul><ul><li>Folic Acid </li></ul>
  8. 8. Why is homocysteine harmful? <ul><li>Experiments on arteries of both animals and humans with an elevated level of homocysteine showed that homocysteine level in blood is an independent risk factor for atherosclerotic vascular disease affecting the coronary (arteries supplying the heart), cerebral (arteries supplying the brain) and peripheral arteries (supplying the rest of the body). </li></ul>Copyright 2010 - Jeremy E. Kaslow, M.D. - all rights reserved
  9. 9. <ul><li>High levels of homcysteine, or a high &quot;H Score,&quot; predicts the risk of more than 100 diseases and medical conditions </li></ul>
  10. 10. Homocysteine and disease
  11. 11. Risk Factors for CVD <ul><li>Non-modifiable </li></ul><ul><li>Advancing age </li></ul><ul><li>Heredity or family history </li></ul><ul><li>Gender </li></ul><ul><li>Ethnicity or race </li></ul><ul><li>Major modifiable </li></ul><ul><li>High blood pressure. </li></ul><ul><li>Abnormal blood lipids </li></ul><ul><li>Tobacco use. </li></ul><ul><li>Physical inactivity </li></ul><ul><li>Obesity </li></ul><ul><li>Diabetes mellitus </li></ul><ul><li>Unhealthy diets </li></ul><ul><li>Novel Risk Factors </li></ul><ul><li>Excess homocysteine in blood </li></ul><ul><li>Inflammation e.g CRP </li></ul><ul><li>Abnormal blood coagulation. e.g Fibrinogen </li></ul><ul><li>Lp ( a) </li></ul>
  12. 13. What Homocysteine Does to Arteries <ul><li>Homocysteine change the Low Density Lipoprotein (LDL) cholesterol in the body into what is called oxidized LDL </li></ul><ul><li>It changes coagulation factor levels so as to encourage blood clot formation </li></ul><ul><li>It causes the smooth muscle cells that support the arterial wall to multiply-part of the atherogenic process. </li></ul><ul><li>It causes platelets to aggregate-part of the clotting process . </li></ul><ul><li>The net result is a threefold increase in heart attack risk </li></ul>( Loscalzo et al., 1998;Maxwal., 2000 )
  13. 15. <ul><li>If cholesterol and a high-fat diet are the key culprits in heart disease, why haven't we seen more of a reduction in our number-one disease killer over these past several decades? </li></ul>
  14. 16. Homocysteine vs. Cholesterol <ul><li>Researchers conclude that homocysteine is up to 40 times more predictive than cholesterol in assessing cardiovascular disease risk. </li></ul><ul><li>Many studies concluded that the risk of arteriosclerotic vascular disease does in fact increase with the homocysteine level, regardless of whether cholesterol is normal or elevated. </li></ul>heart44; 11-01-2004
  15. 17. High Sensitivity C-Reactive Protein (hs-CRP) <ul><li>In 2002, the AHA and CDC recommended measurement of hs-CRP as an aid in the diagnosis and treatment of CVD. At low levels,it can detect those at risk for cardiac heart disease. </li></ul><ul><li>CRP levels seem to be correlated with levels of cardiac risk. In fact, CRP seems to be at least as predictive of cardiac risk as cholesterol levels. </li></ul><ul><li>Harvard Women's Health Study, results of the CRP test were more accurate than cholesterol levels in predicting coronary problems. </li></ul>2010 Cleveland Clinic .
  16. 18. Ranges of hs-CRP in prediction of risk for CVD are <ul><li><1.0 mg/L Low CVD risk </li></ul><ul><li>1.0-3.0 mg/L Average risk for CVD </li></ul><ul><li>>3.0 mg/L High risk for future CVD </li></ul><ul><li>If results are >10.0 mg/L , the patient should be evaluated for an acute inflammatory condition . </li></ul>
  17. 19. FOUR WAYS FIBRINOGEN CAUSES HEART DISEASE <ul><li>As a key factor in blood viscosity (thickness) </li></ul><ul><li>Promote the formation of abnormal blood clots inside coronary arteries </li></ul><ul><li>Fibrinogen appears to directly contribute to the atherosclerosis process by binding to LDL and stimulating the proliferation of vascular smooth muscle, thereby disrupting the endothelium </li></ul><ul><li>Fibrinogen may facilitate platelet aggregation inside blood vessels, thus initiating occlusive arterial blood clots </li></ul>Circulation. 2003 Jan 28;107(3):499-511 .
  18. 20. Lipoprotein (a) <ul><li>Lp(a) has two potential ways to contribute to development of atherosclerotic plaque formation: deposition of LDL and accumulation of clots in the arteries . For this reason, Lp(a) could potentially increase the risk of atherosclerosis more than LDL </li></ul><ul><li>The Lp(a) level is genetically determined and remains relatively constant over an individual's lifetime. </li></ul><ul><li>It should also be tested if LDL cholesterol doesn't respond well to drug treatment. </li></ul>2011 by American Association for Clinical Chemistry  
  19. 21. <ul><li>Abnormally raised insulin seen in most diabetics stops the body from lowering and maintaining a healthier homocysteine level. </li></ul><ul><li>One third of the diabetic patients had elevated blood Homocysteine </li></ul><ul><li>Type 2 diabetic patients with elevated homocysteine levels are nearly 200% more likely to die from a heart attack within 5 years than those with normal Homocysteine levels </li></ul>Homocysteine & Diabetes Vasc Health Risk Manag. 2010; 6: 327–332.
  20. 22. Homocysteine Levels May Be Related to Osteoporosis <ul><li>An increased homocysteine level appears to be a strong and independent risk factor for osteoporotic fractures in older men and women </li></ul><ul><li>high serum homocysteine concentration may weaken bone by interfering with collagen cross-linking, thereby increasing the risk of osteoporotic fracture </li></ul>N Engl J Med. 2004;350:2033-2041
  21. 23. Homocysteine & Pregnancy Complication <ul><li>Women who have higher levels of homocysteine are more likely to have delivered prematurely, had recurrent abortions and had offspring with low birth weights. </li></ul><ul><li>Folic acid supplements decrease homocysteine levels during pregnancy and substantially reduce the risk of central nervous system malformations </li></ul><ul><li>women with high levels of homocysteine have a much higher risk of developing preeclampsia </li></ul><ul><li>2004 issue of &quot;Clinical Chemistry </li></ul>
  22. 24. <ul><li>5,883 women in Norway were followed through 14,492 pregnancies with their outcomes and complications recorded against their homocysteine levels. Higher homocysteine level led to a 32% increase in risk of pre-eclampsia, 38% increase in premature birth and 101% increase in very low birth weight. </li></ul>The Hordaland Homocysteine Study. JAMA 1995;274:1526–33
  23. 25. MTHFR deficiency <ul><li>prevalence MTHFR have shown near 15% in European, Middle Eastern and Japanese populations, compared with a range at or below 1.4% in African Americans. </li></ul><ul><li>MTHFR deficiency is a mild to moderate condition associated with a higher risk of neural tube defects and pregnancy loss </li></ul><ul><li>Mother with the MTHFR mutation who have normal homocysteine levels are not at increased risk for clots . </li></ul>den Heijer M. J Thomb Haemost 2005;3:292-9
  24. 26. Homocysteine and Alzheimer's Disease <ul><li>People with the highest levels of blood homocysteine had almost double the risk of Alzheimer's and other dementia as compared to people with lower blood homocysteine. </li></ul><ul><li>Increase of 5 micromoles of homocysteine per liter of blood increased the risk of Alzheimer's Disease by 40% . </li></ul><ul><li>The mechanism linking Hcy and Alzheimer’s disease is poorly understood, it is possible that Hcy is toxic to brain cells , possibly by excessive stimulation, resulting in neuronal damage due to CNS ischemia </li></ul>New England Journal of Medicine&quot;, 2002;346(7):466-468. :
  25. 27. CANCER – CUT YOUR RISK BY A THIRD <ul><li>Cancer is triggered by damage to DNA – and having a high homocysteine level means your DNA is more vulnerable to damage </li></ul><ul><li>homocysteine levels have been found to be a very good indicator of whether cancer therapies are working. The homocysteine level rises when tumours grow, and falls when they shrink. </li></ul>Cancer Council Victoria 2011
  26. 28. HALVE YOUR RISK OF DEATH FROM ALL CAUSES <ul><li>One of the best ways to extend your lifespan is by reducing your homocysteine level. With every five-point decrease in your H score, you will gain: </li></ul><ul><li>A 49 per cent reduced risk of death from all causes. </li></ul><ul><li>A 50 per cent reduced risk of death from cardiovascular disease . </li></ul><ul><li>A 26 per cent reduced risk of death from cancer . </li></ul><ul><li>A 104 per cent reduced risk of death from causes other than cancer or heart disease </li></ul><ul><li>2005 Orthomolecular conference </li></ul>
  27. 30. Homocysteine New studies <ul><li>Raised homocysteine levels are seen in sufferers of chronic fatigue syndrome [CFS] </li></ul><ul><li>Homocysteine accelerates the aging process by shortening telomeres. </li></ul><ul><li>RA patients are 20-30% more likely to have higher homocysteine levels than the normal population </li></ul><ul><li>In traditionally-treated dialysis patients, 91% of HD and 67% of PD patients have elevated Hcy levels </li></ul>Nutridisk 2011
  28. 31. How is the homocysteine level measured ? <ul><li>Homocysteine is measured using a simple blood test. It can be measured at any time of day . No special preparations </li></ul><ul><li>The Serum sample should separated within 1 hr after blood collection </li></ul><ul><li>Homocysteine levels increase ~10% for every hour the serum/plasma is not separated from the RBCs at room temperature. </li></ul>
  29. 32. Should Hyperhomocysteinemia Be Treated? (Part 1) <ul><li>Arguments favoring treatment </li></ul><ul><li>Approximately 80 clinical and epidemiological studies suggest that elevated homocysteine is a risk factor for coronary heart , cerebrovascular, and peripheral vascular diseases </li></ul><ul><li>Risk factor treatment of cardiovascular disease is an accepted clinical practice </li></ul><ul><li>Treatment is inexpensive and unobtrusive under medical supervision </li></ul>Coronary Heart Disease ,Homocysteine,heart disease and stroke 2008
  30. 34. Should Hyperhomocysteinemia Be Treated? (Part 2) <ul><li>Arguments against treatment </li></ul><ul><li>Many prospective studies shows that Lowering homocysteine with folic acid supplementation is safe, but does not reduce the risk of vascular events </li></ul><ul><li>The American Heart Association has not yet called hyperhomocysteinemia (high homocysteine level in the blood) a major risk factor for cardiovascular disease. </li></ul>Coronary Heart Disease ,Homocysteine,heart disease and stroke 2008
  31. 35. Who should have their Homocysteine level tested?
  32. 36. How should be tested for hyperhomocysteinemia Other opinions <ul><li>Homocysteine should be measured: </li></ul><ul><ul><li>in patients with a history of atherothrombotic vessel diseases </li></ul></ul><ul><ul><li>in elderly subjects </li></ul></ul><ul><ul><li>In adipose subjects </li></ul></ul><ul><ul><li>in vegetarians </li></ul></ul><ul><ul><li>in post-menopausal women </li></ul></ul><ul><ul><li>in renal patients </li></ul></ul><ul><ul><li>in diabetics </li></ul></ul><ul><ul><li>in early pregnancy </li></ul></ul>Clin Chem Lab Med. 2001 Aug;39(8):666-74 .
  33. 37. Interpretation of Homocysteine Levels Plasma Total Homocysteine graded risk factor for cardiovascular disease (Clin Chem 2009; 55:378-84): Less than 11 µmol/L 11-14 µmol/L 15-29 µmol/L Greater than 29 µmol/L Desirable Intermediate High Very High
  34. 38. Homocysteine and Nutrition: The Vitamin Connection <ul><li>Screening for HCY may indirectly assess a patient’s vitamin B6, B12 and folate status, thus offering a useful window into the patient’s nutrition profile. </li></ul><ul><li>Total homocysteine measurements are now recommended to screen for vitamin deficiency in both the general and high risk populations. </li></ul><ul><li>Homocysteine may, in fact, be a more sensitive marker of Vitamin B12 , B6 or folate deficiency and… may precede deficiency of circulating vitamins. </li></ul>Screening for vitamin B12 and folate deficiency in older persons. Am J Clin Nutr 2003; 77: 1241-7.
  35. 40. Vitamins and Food sources <ul><li>Folic acid - Green leafy vegetables (e.g. spinach, broccoli), legumes (e.g. lentils, chick peas, lima beans), orange </li></ul><ul><li>Vitamin B6 - Meat, poultry, fish, green leafy vegetables, legumes, seeds, potatoes, cantaloupe, milk, egg yolks, cereals, grains, wheat, wheat germ. </li></ul><ul><li>Vitamin B12 - Beef, poultry, fish (particularly crab, oyster, salmon and herring), liver, kidney, soy, fruit juice, dairy products, egg yolks, fortified cereals, breads </li></ul>
  36. 41. <ul><li>Folic acid fortification of enriched grain products in the late 1990’s appears to have resulted in a decline in stroke and ischemic heart disease deaths. </li></ul><ul><li>There has been evidence of three-fold acceleration in the decline of stroke related mortality that has been temporarily related to folic acid fortification. </li></ul>American Journal of Clinical Nutrition, Vol. 86, No. 5, 1563S-1568S, November 2007
  37. 42. RDA for Vitamins B6, B12 and Folate <ul><li>Vitamin B6 2 mg </li></ul><ul><li>Vitamin B12 6 mcg </li></ul><ul><li>Folate 400 mcg </li></ul>
  38. 43. treatment of hyperhomocysteinemia Treatment of hyperhomocysteinemia <ul><ul><li>Recheck every 6 months </li></ul></ul>
  39. 44. Number of Homocysteine tests per year Alsalama Branch Year No. of Tests 2008 9 2009 43 2010 270
  40. 45. Homocysteine test results Alsalama Branch 2010 µmol/L 11 15 30 Desirable High Very High 40 % Intermediate
  41. 46. Take Home Message <ul><li>The lower the homocysteine level, the lower the risk of developing coronary artery disease and suffering fatal heart attacks and strokes . </li></ul><ul><li>Your Homocysteine level is the best single indicator of whether you are going to live a long and healthy life, or die young. A high homocysteine level is a greater risk factor for many health problems </li></ul><ul><li>Without any doubt, the demand for plasma homocysteine testing will increase in the coming months and years, perhaps explosively </li></ul>
  42. 48. Prevention is always better than cure Thank You For your Attention