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):
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:

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 /- 5.7 years).
Reference: Skibinska E, Sawicki R, et.al. Kardiol Pol Mar;60(3):

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:
Austin RC, Lentz SR, Werstuck GH. Role of HyperHCYemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 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 Sep;68(9):822-8
Schroecksnadel K, Frick B, Winkler C, et.al. HyperHCYemia and immune activation. Clin Chem Lab Med. 2003;41:

9. Epidemiology Prevalence of hyperhomocysteinemia is not insignificant:
1. general population: %
2. elderly population: %
3. pts with vascular disease: %.
References:
Annu Rev Med 1998;49: HCY and cardiovascular disease. Refsum H, Ueland PM, et.al.
JAMA 1993;270: 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:

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 Jul;66(1): 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 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

12. Reference: Booth, G. CMAJ. 2000 Jul; 163(1):21-9.

13. 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.

14. Reference: Booth, G. CMAJ. 2000 Jul; 163(1):21-9.

15. 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):

16. Reference: Booth, G. CMAJ. 2000 Jul; 163(1):21-9.

17. 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:

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

19. 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 May;7(3):
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.

20. Food sources of Vitamin B12
BEST FOOD SOURCES OF VITAMIN B12
FOOD PORTION SIZE AMOUNT (MCG)
Liver grams
Seafood grams
Salmon grams
Beef Hamburger 100 grams
Eggs grams
___________________________________________________________
MCG: Micrograms
NB: 100 grams=3.5 ounces

21. 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:
Folate is also important for the synthesis of purine and thymidine nucleotides.

22. 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:
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):
Riddell, LJ, Chisholm A, et.al. Dietary strategies for lowering HCY concentrations. Am J Clin Nutr. 2000; 71(6):
Supplementation of cereals with folic acid derivatives produces an increase in folate plasma levels and a decrease in HCY plasma concentration.

23. 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
Vitamin B6 is found in both foods of plant and animal origin.

24. 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 May;133(5):
Choline is found in acetylcholine, phosphatidylcholine, and sphingomyelin and plays an important role in neurotransmitter function, cell membrane integrity, and methyl donor function.

25. Betaine is required for remethylation of HCY to MET in the human liver and kidneys.
Reference: Booth, G. CMAJ Jul; 163(1):21-9.

26. 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 May;133(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 Dec;133(12):

27. Food sources of Betaine
Choline and Betaine Food Sources Amount (mg/100g food)
Wheat Bran
Wheat Germ
Spinach
Beef Liver
Chicken Liver
Eggs
Pretzels
Shrimp
Wheat Bread
Bacon
Dried Soybeans
Pork
Methionine intake is typically excessive in the westernized countries due to diets rich in meats.

28. 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:

29. 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:

30. 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:

31. RDA for Vitamins B6, B12 and Folate
Vitamin B6 2 mg
Vitamin B mcg
Folate mcg
Recommended Dietary Allowance for comparison between VISP dosages (high and low).

32. 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:

33. 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:

34. 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.

35. 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.

36. 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:
If homocysteine is above target level of 10 micromol/l, recommend vitamin B12 and folate levels to determine if these are causing the elevation in HCY.

37. 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:
Fallest-Strobl PC, Koch DD, et.al. HCY: A New Risk Factor for Atherosclerosis. American Family Physician. Oct.15, 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:
Nilsson M. Cobalamin and folate deficiency. Paradigm shift in screening. Rondel 2004;18.
Numerous sources recommend Homocysteine screening in certain hi-risk populations.

38. 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):
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:
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:

39. Some experts suggest that target homocysteine levels should be realistically below values where risk for cardiovascular disease substantially increases.
Reference:Booth, G. CMAJ July; 163(1):
TABLE 3: Homocysteine level relation to overall mortality and CAD-related death.
Linear relationship between increasing HCY level and risk for death due to coronary artery disease.

40. Vitamins B6, B12, Folate May recommend MVI
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

41. 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.

42. RDA for Vitamins B6, B12 and Folate
Vitamin B6 2 mg
Vitamin B mcg
Folate mcg

43. 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 B mg

44. Cost of Recommendations*
Folic Acid 1.0 mg 3 cents
Vitamin B6 10mg 2 cents
Vitamin B mg 6 cents
TOTAL COST: 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

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

46. 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

47. 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 Deeply Air 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 Water Water 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 Peacefully Sleep 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 Nutritiously Food 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:

48. 10 Essentials for Healthy Living
5. Enjoy Activity Your 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 Love As 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 Forgiving It 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:

49. 10 Essentials for Healthy Living
8. Practice Gratitude Sincere gratitude will lift and inspire you. Recognizing and appreciating all you have empowers you to find and express true joy.
9. Develop Acceptance When 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 God You 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:

50. REFERENCES Homocysteine and nutrition: The vitamin connection
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
2.        Brosnan JT, Jacobs RL, et.al. Methylation demand: a key determinant of homocysteine metabolism. Acta Biochim Pol. 2004;51(2):
3.        Selhub J, Jacques PF, et.al. Vitamin Status and intake as primary determinants of HCYemia in an elderly population. JAMA 1993; 270:
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:
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:
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:
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:
9.        Marcucci R, Zanazzi M, Bertoni E, et.al. Vitamin supplementation reduced the progression of atherosclerosis in hyperHYCemic renal-transplant recipients. Transplantation. 2003;75:
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:
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:
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):
13.     Waldmann A, Koschizke JW, et.al. HCY and cobalamin status in German vegans. Public Health Nutr May;7(3):
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 Mar;74(2):
16.     Zeisel SH, Mar MH, et.al. Concentrations of choline-containing compounds and betaine in common foods. J Nutr May;133(5):
17.     Steenge GR, Verhoef P, Katan MB. Betaine supplementation lowers plasma HCY in healthy men and women. J Nutr May;133(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 Dec;133(12):
19.     McGregor DO, Dellow WJ, et.al. Betaine supplementation decreases post-methionine HyperHCYemia in chronic renal failure. Kidney Int Mar;61(3):
20.     Riddell, LJ, Chisholm A, et.al. Dietary strategies for lowering HCY concentrations. Am J Clin Nutr. 2000; 71(6):
21.     Clarke R, Refsum H, et.al. Screening for vitamin B12 and folate deficiency in older persons. Am J Clin Nutr 2003; 77:

51. REFERENCES Homocysteine and nutrition: Part B
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4.        Haulrik N, Toubro S, et.al. Effect of protein and methionine intakes on plasma HCY concentrations: a 6-month randomized controlled trial in overweight subjects. Am J Clin Nutr Dec;76(6):
5.        Lourenco R, Camilo ME. Taurine: a conditionally essential amino acid in humans? An overview in health and disease. Nutr Hosp Nov-Dec;17(6):
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9.        Tamura T, Turnlund JR. Effect of long-term, high copper intake on the concentrations of plasma HCY and B vitamins in young men. Nutrition 2004 Sep;20(9):757-9.
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52. REFERENCES Homocysteine and endothelial effects
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55. QUESTIONS?
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