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Homocysteine At The Crossroads: Vitamin Status and Disease Prevention

Homocysteine At The Crossroads: Vitamin Status and Disease Prevention. Dr. Samuel N. Grief, MD, FCFP University of Illinois at Chicago Family Medicine Chair, Panel on Homocysteine and Screening/Treatment Recommendations. OUTLINE. Homocysteine and its metabolism.

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Homocysteine At The Crossroads: Vitamin Status and Disease Prevention

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  1. Homocysteine At The Crossroads:Vitamin Status and Disease Prevention Dr. Samuel N. Grief, MD, FCFP University of Illinois at Chicago Family Medicine Chair, Panel on Homocysteine and Screening/Treatment Recommendations

  2. OUTLINE • Homocysteine and its metabolism. • Homocysteine and nutrition: The vitamin connection. • Food sources of vitamins Betaine, B12, and Folate. • Homocysteine and its link to various diseases. • Recommendations regarding homocysteine screening and treatment.

  3. OBJECTIVES • Based on scientific evidence, attending physician will be able to: • 1.   Define homocysteine • 2.   Outline homocysteine metabolic pathway • 3. List metabolic and vitamin influences on homocysteine level • 4.  Identify risk factors for elevated homocysteine level • 5. Determine whether to screen for, and treat, elevated homocysteine level

  4. Homocysteine has been confirmed in many independent studies to be a risk factor for cardiovascular disease. References: Eikelboom JW, Lonn E, et.al. HCY and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 1999;131(5):363-375. Singh H. Selections from current literature: HCY: a modifiable risk factor for cardiovascular disease. Fam Pract 1997;14(4):335-9. Refsum H, Ueland PM, Nygard O, Vollset SE. HCY and cardiovascular disease. Annu Rev Med. 1998;49:31-62.

  5. Etiology of Cardiovascular Disease • Traditional risk factors for coronary artery disease such as smoking, hypertension, diabetes, and dyslipidemias can only explain approximately two thirds of observed clinical events. • Other factors/biochemical markers to consider include: • CRP • Homocysteine • Other? • Reference: Maxwell SR, Coronary Artery Disease-free radical damage, antioxidant protection and the role of HCY. Basic Res Cardiol. 2000;95 Supple 1:165-71.

  6. Homocysteine and Cardiovascular Disease • Increased incidence and progression of CAD in patients with diabetes when homocysteine levels are >11.21 micromol/l was found in a study of Polish men aged <55 (mean age 49.5 +/- 5.7 years). • Reference: Skibinska E, Sawicki R, et.al. Kardiol Pol. 2004 Mar;60(3):197-205.

  7. Homocysteine and Endothelial Effects • The mechanism by which homocysteine exerts its cardiovascular disease effects are now being elucidated. Many authorities have studied this link. The working hypothesis is that elevated homocysteine levels: • 1. promote oxidant injury to the vascular endothelium • 2. impairs endothelium-dependent relaxation • 3. alters the coagulant properties of blood • References: • Ozdemir R, Barutcu I, et.al. Vascular Endothelial Function and Plasma Homocysteine Levels in Behcet’s Disease, Am J Cardiol 2004;94:522-525. • Austin RC, Lentz SR, Werstuck GH. Role of HyperHCYemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ. 2004 Jul;11 Supple 1:S56-64.

  8. Homocysteine and Endothelial Effects Other theories include: a) Elevated homocysteine levels release extracellular superoxide dismutase from the endothelial wall, causing a higher likelihood of atherosclerotic changes to the blood vessels • b) Moderate HyperHCYemia may develop secondary to cellular immune activation, usually in response to a chronic disease condition c) Hyperhomocysteinemia decreases bioavailability of nitric oxide, thus decreasing endothelial vasodilator function. References: Nihei S, Tasaki H, et.al. HyperHCYemia is associated with human coronary atherosclerosis through the reduction of the ratio of endothelium-bound to basal extracellular superoxide dismutase. Circ J. 2004 Sep;68(9):822-8 Schroecksnadel K, Frick B, Winkler C, et.al. HyperHCYemia and immune activation. Clin Chem Lab Med. 2003;41:1438-1443.

  9. Epidemiology • Prevalence of hyperhomocysteinemia is not insignificant: • 1. general population: 5 - 10% • 2. elderly population: 30 - 40% • 3. pts with vascular disease: 20 - 40%. • References: • Annu Rev Med 1998;49:31-62. HCY and cardiovascular disease. Refsum H, Ueland PM, et.al. • JAMA 1993;270:2693-8. Vitamin status and intake as primary determinants of HCYemia in an elderly population. Selhub J, Jacques PF, et.al. • Jacques PF, Bostom AG, Wilson PW, et.al. Determinants of plasma total HCY concentration in the Framingham Offspring cohort. Am J Clin Nutr. 2001;73:613-621.

  10. Homocysteine and disease • Homocysteine elevation is also known to be strongly associated and linked to several other medical conditions, including: • osteoporosis • cognitive impairment and decline • increased prenatal complications to women and unborn children • chronic kidney disease • other conditions • References: • Kidney Int. 2004 Jul;66(1):338-47. Potential cardiovascular risk factors in chronic kidney disease: AGEs, total homocysteine and metabolites, and the C-reactive protein. Busch M, Franke S, et.al. • Clin Chem. 2004 Aug 19. Screening for Serum Total HCY in Newborn Children. Refsum H, Grindflek AW, Ueland PM, et.al

  11. HOMOCYSTEINE • Homocysteine, a sulfur containing amino acid, is formed from methionine, an essential amino acid found in many animal and plant foods. Methionine is especially abundant in animal and cereal proteins. • Reference: Aleman G, Tovar AR, Torres N. Homocysteine metabolism and risk of cardiovascular disease: Importance of the nutritious status in folic acid, vitamins B6 and B12. La Revista de Investigacion Clinica. Vol.53, Issue 2, March-April 2001, pp. 141-151.

  12. Homocysteine Metabolism • Homocysteine is removed either by its irreversible conversion to cysteine (transsulfuration) or by remethylation to methionine. • There are two separate remethylation reactions, catalyzed by betaine:homocysteine methyltransferase and methionine synthase, respectively.

  13. Homocysteine and Nutrition:The Vitamin Connection • The reactions that remove homocysteine are dependent upon B vitamin status, as both the transsulfuration enzymes contain pyridoxal phosphate (B6), while methionine synthase contains cobalamin (B12), is copper-dependent, and receives its methyl group from the folic acid one-carbon pool. • Reference: Brosnan JT, Jacobs RL, et.al. Methylation demand: a key determinant of homocysteine metabolism. Acta Biochim Pol. 2004;51(2):405-13.

  14. Homocysteine and Nutrition:The Vitamin Connection • It is estimated that in about two-thirds of cases of hyperhomocysteinemia, vitamin deficiency is the primary cause. • Reference: Selhub J, Jacques PF, et.al. Vitamin Status and intake as primary determinants of HCYemia in an elderly population. JAMA 1993; 270: 2693-2698.

  15. Fig. 2 - Physiological determinants of total homocysteine levels

  16. Vitamin B12 and Homocysteine • Vitamin B12 is found in foods of animal origin. • Vitamin B12 status has been studied in different populations, especially vegetarians. • Evidence confirms: low vitamin B12 levels predispose to elevated homocysteine levels. • References: • Waldmann A, Koschizke JW, et.al. HCY and cobalamin status in German vegans. Public Health Nutr. 2004 May;7(3):467-72. • Flood VM, Webb KL, Smith W, et.al. Prevalence of low serum folate, red cell folate, serum vitamin B12 and elevated HCY. Asia Pac J Clin Nutr. 2004;13(Suppl):S85.

  17. Food sources of Vitamin B12 BEST FOOD SOURCES OF VITAMIN B12 FOODPORTION SIZEAMOUNT (MCG) Liver 100 grams 70.58 Seafood 100 grams 6.88 Salmon 100 grams 2.80 Beef Hamburger 100 grams 2.50 Eggs 100 grams 1.11 ___________________________________________________________ MCG: Micrograms NB: 100 grams=3.5 ounces

  18. FOLATE • Folate, aka folic acid, found in numerous foods, is a water-soluble B-vitamin and enzymatic co-substrate for the synthesis of methionine from homocysteine. • Folic acid deficiency is the most common cause of elevated HCY levels. • Reference: Jacques PF, Selhub J, et.al The effect of folic acid fortification on plasma folate and total HCY concentration. N Engl J Med 1999;13:1449-1454.

  19. Folate • The U.S. Food and Drug Administration’s implementation of mandatory fortification of grains and cereals with folic acid on January 1, 1998 is a direct result of research studies confirming folate’s HCY-lowering effects, as well as studies linking low folate levels with an increased incidence of neural tube defects. • References: • Tucker KL, Selhub K, et.al. Dietary intake pattern related to plasma folate and HCY concentrations in the Framingham Heart Study. J Nutr 1996;126:3025-3031. • Food and Drug Administration. Food Standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register. 1996;61(44):8781-97. • Riddell, LJ, Chisholm A, et.al. Dietary strategies for lowering HCY concentrations. Am J Clin Nutr. 2000; 71(6): 1448-54.

  20. Vitamins and Food sources • Folic acid - Green leafy vegetables (e.g. spinach, broccoli), legumes (e.g. lentils, chick peas, lima beans), orange • Vitamin B6 - Meat, poultry, fish, green leafy vegetables, legumes, seeds, potatoes, cantaloupe, milk, egg yolks, cereals, grains, wheat, wheat germ • Vitamin B12 - Beef, poultry, fish (particularly crab, oyster, salmon and herring), liver, kidney, soy, fruit juice, dairy products, egg yolks, fortified cereals, breads

  21. Homocysteine and Nutrition:The Vitamin Connection • Betaine, a choline derivative, is important because of its role in methyl group donation to homocysteine to form methionine. • Reference: Zeisel SH, Mar MH, et.al. Concentrations of choline-containing compounds and betaine in common foods. J Nutr. 2003 May;133(5): 1302-7.

  22. Many foods are rich in Betaine Studies confirm betaine’s ability to reduce homocysteine levels in the face of excess methionine intake. References: Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma HCY in healthy men and women. J Nutr. 2003 May;133(5):1291-5. Olthof MR, van Vliet, et.al. Low dose betaine supplementation leads to immediate and long term lowering of plasma HCY in healthy men and women. J Nutr. 2003 Dec;133(12):4135-8.

  23. Food sources of Betaine Choline and Betaine Food Sources Amount (mg/100g food) Wheat Bran 1339 Wheat Germ 1293 Spinach 645 Beef Liver 418 Chicken Liver 290 Eggs 251 Pretzels 237 Shrimp 218 Wheat Bread 201 Bacon 125 Dried Soybeans 116 Pork 103

  24. VISP STUDY • In the recently completed Vitamin Intervention for Stroke Prevention (VISP) study, Toole, et.al. investigated the homocysteine-lowering effects of B vitamins in over 40,000 men with established history of cerebrovascular accidents. • Reference: Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.

  25. VISP STUDY • The VISP randomized controlled trial was undertaken to assess whether reducing HCY levels by vitamin supplementation would reduce risk of recurrent strokes, CHD, and death. • Reference: Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.

  26. VISP STUDY • High-dose vitamin supplementation participants received: • 25mg of pyridoxine • 400mcg of cobalamin • 2.5mg of folic acid • low-dose was 200mcg, 6mcg, and 20mcg, respectively. • Reference: Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.

  27. RDA for Vitamins B6, B12 and Folate • Vitamin B6 2 mg • Vitamin B12 6 mcg • Folate 400 mcg

  28. VISP STUDY • Even though a mean reduction of HCY in the high-dose vitamin supplementation group of 2 micromol/l greater than in the low-dose group was achieved, no significant effect on the above end points occurred. • Reference: Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.

  29. VISP STUDY • The results did not confirm a reduction in recurrent strokes in study patients, however, the homocysteine-lowering effects of folic acid, vitamin B6 and vitamin B12 were confirmed. • Reference: Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575.

  30. SCREENING AND TREATMENT RECOMMENDATIONS FOR HOMOCYSTEINE In 2000, the Canadian Task Force on Preventive Health Care concluded that there was a link between total HCY levels and CAD based on cohort and case-control studies, but found the evidence insufficient to recommend for or against HCY screening in both the general and high-risk populations. Reference: CMAJ.2000 Jul 11;163(1):21-9. Preventive health care, 2000 update: screening and management of hyperHCCYemia for the prevention of CAD evens. The Canadian Task Force on Preventive Health Care. Booth GL, Wang EE.

  31. SCREENING AND TREATMENT RECOMMENDATIONS FOR HOMOCYSTEINE An expert panel led by Refsum reviewed multiple, well-designed, randomized controlled trials and concluded the following: • A)   Vitamin “B” intake directly impacts the level of homocysteine • B)    Folate deficiency is a strong determinant on homocysteine levels • C)  Coffee consumption may very well increase total homocysteine levels • D) Unhealthy lifestyle and poor diet is a cause of moderately high levels of homocysteine (15-30 micromol/l). • Reference: Refsum H, Smith DA, et.al. Facts and Recommendations about Total Homocysteine Determinations: An Expert Opinion. Clin Chem 2004; 50: 3-32.

  32. HOMOCYSTEINE IS AT THE CROSSROADS OF VITAMIN STATUS (B6, B12, FOLATE) • 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. • Total homocysteine measurements are now recommended to screen for vitamin deficiency in both the general and high risk populations. • Reference: Clarke R, Refsum H, et.al. Screening for vitamin B12 and folate deficiency in older persons. Am J Clin Nutr 2003; 77: 1241-7.

  33. Screening Recommendations • HCY evaluation is now recommended for the following high risk populations: • age 65 years and over with or without co-morbid conditions • in patients with any of the following medical conditions, including: • diabetes • smoking history • established cardiovascular disease or multiple cardiovascular risk factors • renal disease • nutritional deficiencies • cognitive disorders • References: • Nygard O, Nordrehaug JE, Refsum H, et.al. Plasma HCY levels and mortality in patients with CAD. N Engl J Med. 1997;337:230-236. • Fallest-Strobl PC, Koch DD, et.al. HCY: A New Risk Factor for Atherosclerosis. American Family Physician. Oct.15, 1997. Vol.56, No.6. • Malinow MR, Bostom AG, Krauss RM. HCY, diet, and cardiovascular diseases: a statement for health care professionals from the Nutrition Committee, American Heart Association. Circulation 1999;99:178-182. • Nilsson M. Cobalamin and folate deficiency. Paradigm shift in screening. Rondel 2004;18. http://www.rondellen.net.

  34. Therapeutic Goals • Target plasma HCY levels of <10 micromol/l are now being recommended by various medical authorities. • References: • Stanger O, Herrmann W, et.al. Clinical use and rational management of HCY, folic acid, and B vitamins in cardiovascular and thrombotic disease. Z Kardiol.2004 Jun; 93(6):439-53. • Malinow MR, Bostom AG, et.al. Homocysteine, diet, and cardiovascular diseases: a statement for healthcare professionals from the Nutrition Committee, American Heart Association. Circulation 1999; 99: 178-82. • Ubbink JB. What is a desirable homocysteine level? In: Carmel R, Jacobsen DW, eds. Homocysteine in health and disease. Cambridge, UK: Cambridge University Press, 2001: 485-90.

  35. Some experts suggest that target homocysteine levels should be realistically below values where risk for cardiovascular disease substantially increases. Reference:Booth, G. CMAJ. 2000 July; 163(1): 21-29. TABLE 3: Homocysteine level relation to overall mortality and CAD-related death.

  36. High Risk Population a Yes No Screen for HCY Do not screen for HCY Level > 10 micromol/l Level < 10 micromol/l Continue monitoring/treating other medical conditions Treatment No treatment aHigh risk population defined in “Recommendations regarding HCY screening” section. Vitamins B6, B12, Folate May recommend MVI

  37. Why Rx Vitamins? • Appropriate vitamin awareness, knowledge of Rxing vitamins, and ability to recommend nutritional sources of vitamins will become more critical for physicians to master as the future of medicine changes from a diagnostic/therapeutic mode to a more preventive/holistic style.

  38. RDA for Vitamins B6, B12 and Folate • Vitamin B6 2 mg • Vitamin B12 6 mcg • Folate 400 mcg

  39. Treatment Recommendations • Add to the overall treatment plan of your high-risk patient a B-complex vitamin containing, at a minimum, the following B-vitamins: • Folic acid 1.0 mg • Vitamin B6 10mg • Vitamin B12 1.0mg

  40. Cost of Recommendations* Folic Acid 1.0 mg 3 cents • Vitamin B6 10mg 2 cents • Vitamin B12 1.0 mg 6 cents • TOTAL COST: 11 cents/day 11 cents x 30 days = $3.30/month • 1 Tall Caffe Latte (Starbucks) : $3.30 (plus tax!) • *Cost taken from AWP at UIC Hospital

  41. Future Recommendations • Future research should include various vitamin preparations and their ability to lower specific endpoints, i.e. CVD, cancer, kidney disease, etc.

  42. TOP FIVE HEALTH RESOLUTIONS • 5. Stop Smoking • 4. Exercise More • 3. Lose Weight • 2. Become a Better Person And the #1 Health Resolution is… • 1. Eat Healthier

  43. 10 Essentials for Healthy Living In order to achieve a quality of life that permits both physical and psychological wellness, it is important to do positive acts that promote both your well being and those around you. Reflect on these 10 essentials for healthy living as you move along your life’s journey. • 1. Breathe DeeplyAir is the cornerstone of life. Every moment of every day your body exchanges carbon dioxide for oxygen to keep each cell in your body alive and functioning. A rich supply of oxygen can make the difference between feeling tired and stressed and youthful and focused. Take at least five deep breaths from your abdomen several times per day. • 2. Drink WaterWater is essential for everything your body does. In fact, you are mostly water! Nutrient absorption, blood flow, respiration, elimination and your ability to see and hear require adequate consumption of pure, clean water. Your body cannot effectively store the water you need throughout the day. Drink water often. • 3. Sleep PeacefullySleep is the only time your body has to repair and rejuvenate every organ and system in your body. Sleep deprivation causes cellular damage, and limits the production of enzymes and hormones your body needs to keep your cells healthy, and prevent premature aging. Sleep also has a powerful impact on your emotional health - it eases stress and helps you cope with the ups and downs of your day. • 4. Eat NutritiouslyFood has a powerful impact on your body. Every day, food, in large part, determines how you feel and how your body functions. A balanced diet, rich in whole foods, combined with quality nutritional supplements created to meet your specific needs, will give you the energy you need today, and the disease-fighting strength you need to build a healthy future. Reference: www.trivita.com

  44. 10 Essentials for Healthy Living • 5. Enjoy ActivityYour body was created to move - and move often. Activity increases your circulation, speeding oxygen, nutrients and water to your cells. Your lymphatic system requires activity to purge your body of deadly toxins. Activity also triggers your brain to release health-giving hormones and enzymes, which lift your spirit while they bolster your immune system. A small investment in daily moderate activity will enable you to reap tremendous health benefits. • 6. Give and Receive LoveAs you give and receive love freely and generously, you will be blessed with meaningful, lifelong relationships and cherished memories that will bring joy in happy times, and strength and peace in difficult times. • 7. Be ForgivingIt sounds so simple, and yet can be so difficult. Extending and asking for forgiveness is one of the four principles of emotional health because it is a key to your ability to give and receive love. In its purest form, forgiveness is not an act, but an attitude. As you cultivate the ability to live in a state of forgiveness, your anger, frustration and guilt are replaced with peace, love and acceptance. • Reference: www.trivita.com

  45. 10 Essentials for Healthy Living • 8. Practice GratitudeSincere gratitude will lift and inspire you. Recognizing and appreciating all you have empowers you to find and express true joy. • 9. Develop AcceptanceWhen you develop the ability to identify and accept the circumstances in your life you cannot change, yet strive to make positive changes whenever and wherever you can, you will discover lasting peace and hope. • 10. Develop a Relationship with GodYou develop a relationship with God the same way you build a relationship with those around you - through sharing and listening. By offering a simple prayer daily, you will enjoy a sense of well being you will not experience in any other way. Reference: www.trivita.com

  46. REFERENCES • Homocysteine and nutrition: The vitamin connection • 1.        Aleman G, Tovar AR, Torres N. Homocysteine metabolism and risk of cardiovascular disease: Importance of the nutritious status in folic acid, vitamins B6 and B12. La Revista de Investigacion Clinica. Vol.53, Issue 2, March-April 2001, pp. 141-151. • 2.        Brosnan JT, Jacobs RL, et.al. Methylation demand: a key determinant of homocysteine metabolism. Acta Biochim Pol. 2004;51(2):405-13. • 3.        Selhub J, Jacques PF, et.al. Vitamin Status and intake as primary determinants of HCYemia in an elderly population. JAMA 1993; 270: 2693-2698. • 4.        Boushey CJ, Beresford SA, et.al. A quantitative assessment of plasma HCY as a risk factor for vascular disease. Probably benefits of increasing folic acid intakes. JAMA 1995;274:1049-57. • 5.        Rasmussen K, Moller J, et.al. Age- and gender-specific reference intervals for total HCY and methylmalonic acid in plasma before and after vitamin supplementation. Clin Chem 1996;42:630-6. • 6.        Wald DS, Bishop L, Wald NJ, et.al. Randomized trial of folic acid supplementation and serum HCY levels. Arch Intern Med. 2001;161:695-700. • 7.        Toole JF, Malinow MR, Chambless LE, et.al. Lowering HCY in pts. With ischemic stroke to prevent recurrent stroke, MI, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-575. • 8.        Schnyder G, Roffi M, Pin R, et.al. Decreased rate of coronary restenosis after lowering of plasma HCY levels. N Engl J Med. 2001;345:1593-1600. • 9.        Marcucci R, Zanazzi M, Bertoni E, et.al. Vitamin supplementation reduced the progression of atherosclerosis in hyperHYCemic renal-transplant recipients. Transplantation. 2003;75:1551-1555. • 10.     Jacques PF, Selhub J, et.al The effect of folic acid fortification on plasma folate and total HCY concentration. N Engl J Med 1999;13:1449-1454. • 11.     Tucker KL, Selhub K, et.al. Dietary intake pattern related to plasma folate and HCY concentrations in the Framingham Heart Study. J Nutr 1996;126:3025-3031. • 12.     Food and Drug Administration. Food Standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register. 1996;61(44):8781-97. • 13.     Waldmann A, Koschizke JW, et.al. HCY and cobalamin status in German vegans. Public Health Nutr. 2004 May;7(3):467-72. • 14.     Flood VM, Webb KL, Smith W, et.al. Prevalence of low serum folate, red cell folate, serum vitamin B12 and elevated HCY. Asia Pac J Clin Nutr. 2004;13(Suppl):S85. • 15.     Strassburg A, Krems C, Luhrmann PM, et.al. Effect of age on plasma HCY concentrations in young and elderly subjects considering serum vitamin concentrations and different lifestyle factors. Int J Vitam Nutr Res. 2004 Mar;74(2): 129-36. • 16.     Zeisel SH, Mar MH, et.al. Concentrations of choline-containing compounds and betaine in common foods. J Nutr. 2003 May;133(5): 1302-7. • 17.     Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma HCY in healthy men and women. J Nutr. 2003 May;133(5):1291-5. • 18.     Olthof MR, van Vliet, et.al. Low dose betaine supplementation leads to immediate and long term lowering of plasma HCY in healthy men and women. J Nutr. 2003 Dec;133(12):4135-8. • 19.     McGregor DO, Dellow WJ, et.al. Betaine supplementation decreases post-methionine HyperHCYemia in chronic renal failure. Kidney Int. 2002 Mar;61(3):1040-6. • 20.     Riddell, LJ, Chisholm A, et.al. Dietary strategies for lowering HCY concentrations. Am J Clin Nutr. 2000; 71(6): 1448-54. • 21.     Clarke R, Refsum H, et.al. Screening for vitamin B12 and folate deficiency in older persons. Am J Clin Nutr 2003; 77: 1241-7.

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