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Complementary and Alternative Medicine - Cam

Search Health Information    High Homocysteine (Holistic)

High Homocysteine (Holistic)

About This Condition

The lower the better when it comes to homocysteine levels. According to research or other evidence, the following self-care steps may be helpful.
  • Seek support from supplements

    Lower homocysteine levels in the blood by taking a daily supplement of over-the-counter folic acid, vitamin B6, and vitamin B12

  • Back up the B

    When B-vitamin supplements do not sufficiently lower your levels, take 1,500 mg of betaine or 2,000 mg of choline each day

  • Diet right

    Help lower homocysteine levels by eating plenty of fruits and vegetables

About

About This Condition

Homocysteine, a normal breakdown product of the essential amino acid methionine , is believed to exert several toxic effects.

A growing body of evidence suggests that an elevated homocysteine level is a risk factor for heart disease , independent of other known risk factors, such as elevated serum cholesterol and hypertension .1 , 2 The evidence is not all one-sided, however. In some research the link has appeared only in women,3 and a few scientists still have doubts about the importance of elevations in homocysteine for anyone.4 The clear association between elevated homocysteine levels and heart disease reported in most studies5 does not conclusively prove that homocysteine causes heart disease. It might only be a marker for something else that is the real culprit.6 Nonetheless, many cardiologists take seriously the association between elevations in homocysteine and increased risk of heart disease.

Anger and hostility correlate with the risk of heart disease .7 , 8 A preliminary study found a link between high homocysteine levels and hostility and repressed anger.9 While anger, hostility, high homocysteine, and heart disease all appear to be tied together, which of these is cause and which is effect remains somewhat unclear.

Increased homocysteine levels may also be a risk factor for the development of many other conditions, including stroke ,10 thromboembolism11 (blood clots that can dislodge and cause stroke, heart attack , and other complications), osteoporosis ,12 Crohn’s disease , ulcerative colitis ,13 Alzheimer’s disease ,14 death from diabetes ,15 miscarriage,16 , 17 , 18 , 19 , 20 other complications of pregnancy ,21 , 22 , 23 , 24 , 25 and hypothyroidism .26

Scientists have yet to prove that elevated homocysteine levels cause any of these diseases. However, most doctors believe that high homocysteine increases the risk of at least heart disease. Fortunately, homocysteine levels can easily be reduced with safe and inexpensive B vitamin supplementation.

Symptoms

Extremely high homocysteine can cause blood clots, rapid bone loss, and, in children, mental retardation. But in general, high homocysteine does not cause symptoms until and unless one of the diseases with which it is associated, appears.

Healthy Lifestyle Tips

According to a recent study, both cigarette smoking and coffee consumption were associated with increased homocysteine levels.27 These findings are consistent with studies that have found both smoking and caffeine consumption to be associated with an increased risk of both cardiovascular disease and osteoporosis . The link between coffee and increased homocysteine has been confirmed by some researchers,28 but not others.29

In one study, a diverse group of people participated in a week-long program that included a strict vegan diet, stress management and spirituality enhancement sessions, group support, and exclusion of tobacco, alcohol , and caffeine.30 B vitamin supplements known to reduce blood homocysteine levels were not provided. After only one week in the program, the average homocysteine level fell 13%.

Eating Right

The right diet is the key to managing many diseases and to improving general quality of life. For this condition, scientific research has found benefit in the following healthy eating tips.

Recommendation Why
Get your beans and whole grains
In one study, men with heart disease who ate whole-grain and a powder made from legumes at breakfast, instead of their usual breakfast of refined rice, significantly lowered their homocysteine.

Another study of men with heart disease demonstrated that consumption of whole-grain and legume powder at breakfast, instead of their usual breakfast of refined rice, resulted in a significant reduction in homocysteine levels.31

Cut down on meat and eggs
Presumably, it is advisable to avoid eating too much methionine, found in sources like meat and eggs, as homocysteine is produced from this compound.

Since homocysteine is produced from methionine , intake of large amounts of methionine would presumably increase homocysteine levels. Indeed, ingestion of supplemental methionine is used experimentally as a way to increase homocysteine levels.32 Foods high in methionine that have also been linked with an increased risk of heart disease include meat and eggs. The extent to which consumption of these foods affects the risk of heart disease as a result of their methionine content remains unknown.

Fill up folic acid–rich foods
Studies show foods containing folic acid may lower homocysteine. Try beans, leafy green vegetables, citrus fruits, beets, and wheat germ,

A controlled trial showed that eating a diet high in fruits and vegetables containing folic acid , beta-carotene and vitamin C effectively lowered homocysteine levels.33 Healthy people were assigned to either a diet containing a pound of fruits and vegetables per day, or to a diet containing three and a half ounces of fruits and vegetables per day. After four weeks, those eating the higher amount of fruits and vegetables had an 11% lower homocysteine level compared with those eating the lower amount of fruits and vegetables.

Supplements

What Are Star Ratings?

Our proprietary “Star-Rating” system was developed to help you easily understand the amount of scientific support behind each supplement in relation to a specific health condition. While there is no way to predict whether a vitamin, mineral, or herb will successfully treat or prevent associated health conditions, our unique ratings tell you how well these supplements are understood by the medical community, and whether studies have found them to be effective for other people.

For over a decade, our team has combed through thousands of research articles published in reputable journals. To help you make educated decisions, and to better understand controversial or confusing supplements, our medical experts have digested the science into these three easy-to-follow ratings. We hope this provides you with a helpful resource to make informed decisions towards your health and well-being.

3 Stars Reliable and relatively consistent scientific data showing a substantial health benefit.

2 Stars Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit.

1 Star For an herb, supported by traditional use but minimal or no scientific evidence. For a supplement, little scientific support.

Supplement Why
3 Stars
Folic Acid, Vitamin B6, and Vitamin B12
400 to 1,000 mcg of folic acid daily, 10 to 50 mg of vitamin B6 daily, and 50 to 300 mcg of vitamin B12 daily
Vitamin B6, folic acid, and vitamin B12 all play a role in converting homocysteine to other substances within the body and have consistently lowered homocysteine levels in trials.

Vitamin B6 , folic acid , and vitamin B12 all play a role in converting homocysteine to other substances within the body. By so doing, they consistently lower homocysteine levels in research trials,34 , 35 , 36 a finding that is now well accepted. Several studies have used (and some doctors recommend) 400–1,000 mcg of folic acid per day, 10–50 mg of vitamin B6 per day, and 50–300 mcg of vitamin B12 per day.

Of these three vitamins, folic acid supplementation lowers homocysteine levels the most for the average person.37 , 38 It also effectively lowers homocysteine in people on kidney dialysis.39 In 1996, the FDA required that all enriched flour, rice, pasta, cornmeal, and other grain products contain 140 mcg of folic acid per 3½ ounces.40 This level of fortification has led to a measurable decrease in homocysteine levels.41 However, even higher levels of food fortification with folic acid have been reported to be more effective in lowering homocysteine,42 suggesting that the FDA-mandated supplementation is inadequate to optimally protect people against high homocysteine levels. Therefore, people wishing to lower their homocysteine levels should continue to take folic acid supplements despite the FDA-mandated fortification program.

2 Stars
Betaine (Trimethylglycine)
1.5 to 6 grams daily
Betaine (trimethylglycine) has been shown to lower homocysteine levels.

Betaine (trimethylglycine) (6 grams per day) and choline (2 grams per day) have each been shown to lower homocysteine levels.43 , 44 Choline in the amount of 2.6 grams per day (provided as 34 grams per day of soy lecithin) has also been shown to lower homocysteine levels in a double-blind trial.45 More recently, 1.5 grams of betaine per day, an amount similar to that in a typical diet, also has been found to lower homocysteine levels.46 Doctors usually consider supplementation with these nutrients only when supplementation with folic acid, vitamin B6, and vitamin B12 do not reduce homocysteine levels sufficiently. The results of this study, however, point to the potential benefit of increasing one’s intake of foods rich in betaine (such as whole wheat, spinach, beets, and other plant foods).

2 Stars
Folic Acid (Sickle Cell Anemia)
Consult a qualified healthcare practitioner
In one trial, patients with sickle cell anemia who were given folic acid plus aged garlic extract, vitamin C, and vitamin E saw significant improvement and less painful crises.

In a preliminary trial, 20 patients with sickle cell anemia were given either 1 mg of folic acid per day or folic acid plus 6 grams of aged garlic extract, 6 grams of vitamin C, and 1,200 mg of vitamin E per day for six months.48 Patients taking the combination had a significant improvement in their hematocrit (an index of anemia) and less painful crises than those taking just folic acid.

Preliminary research has found that patients with sickle cell anemia are more likely to have elevated blood levels of homocysteine compared to healthy people.49 , 50 Elevated homocysteine is recognized as a risk factor for cardiovascular disease .51 In particular, high levels of homocysteine in sickle cell anemia patients have been associated with a higher incidence of stroke .52 Deficiencies of vitamin B6 , vitamin B12, and folic acid occur more frequently in people with sickle cell anemia than in others53 , 54 , 55 and are a cause of high homocysteine levels.56 A controlled trial found homocysteine levels were reduced 53% in children with sickle cell anemia receiving a 2–4 mg supplement of folic acid per day, depending on age, but vitamin B6 or B12 had no effect on homocysteine levels.57 A double-blind trial of children with sickle cell anemia found that children given 5 mg of folic acid per day had less painful swelling of the hands and feet compared with those receiving placebo, but blood abnormalities and impaired growth rate associated with sickle cell anemia were not improved.58 In the treatment of sickle cell anemia, folic acid is typically supplemented in amounts of 1,000 mcg daily.59 Anyone taking this amount of folic acid should have vitamin B12 status assessed by a healthcare professional.

2 Stars
Folic Acid (Osteoporosis)
5 mg with 1,500 mcg of vitamin B12 daily
Homocystinuria, a condition associated with high homocysteine levels, frequently causes osteoporosis. By lowering homocysteine levels, folic acid may help prevent osteoporosis.
Folic acid , vitamin B6 , and vitamin B12 are known to reduce blood levels of the amino acid homocysteine, and homocystinuria, a condition associated with high homocysteine levels, frequently causes osteoporosis. Therefore, some researchers have suggested that these vitamins might help prevent osteoporosis by lowering homocysteine levels.60 In a double-blind study of people who had suffered a stroke and had high homocysteine levels, daily supplementation with 5 mg of folic acid and 1,500 mcg of vitamin B12 for two years reduced the incidence of fractures by 78%, compared with a placebo.61 The reduction in fracture risk appeared to be due to an improvement in bone quality, rather than to a change in bone mineral density. However, supplementation with these vitamins did not reduce fracture risk in people who had only mildly elevated homocysteine levels and relatively high pretreatment folic acid levels.62 For the purpose of lowering homocysteine, amounts of folic acid and vitamins B6 and B12 found in high-potency B-complex supplements and multivitamins should be adequate.
2 Stars
Folic Acid, Vitamin B6, and Vitamin B12 (Schizophrenia)
Take folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) daily
People with schizophrenia who have high homocysteine levels may improve symptoms by supplementing with folic acid, vitamin B6, and vitamin B12.
In another double-blind study, daily supplementation with folic acid (2 mg), vitamin B6 (25 mg), and vitamin B12 (400 mcg) for three months improved symptoms of schizophrenia compared with a placebo.63 All of the participants in this study had elevated blood levels of homocysteine, which can be decreased by taking these three B vitamins. Based on this study, it would seem reasonable to measure homocysteine levels in people with schizophrenia and, if they are elevated, to supplement with folic acid, vitamin B6, and vitamin B12.
2 Stars
Lecithin (Phosphatidyl Choline)
2 grams daily choline or 34 grams daily lecithin
Choline has been shown to lower homocysteine levels.

Betaine (trimethylglycine) (6 grams per day) and choline (2 grams per day) have each been shown to lower homocysteine levels.64 , 65 Choline in the amount of 2.6 grams per day (provided as 34 grams per day of soy lecithin) has also been shown to lower homocysteine levels in a double-blind trial.66 More recently, 1.5 grams of betaine per day, an amount similar to that in a typical diet, also has been found to lower homocysteine levels.67 Doctors usually consider supplementation with these nutrients only when supplementation with folic acid, vitamin B6, and vitamin B12 do not reduce homocysteine levels sufficiently. The results of this study, however, point to the potential benefit of increasing one’s intake of foods rich in betaine (such as whole wheat, spinach, beets, and other plant foods).

2 Stars
Vitamin B12 (Osteoporosis)
1,500 mcg with 5 mg of folic acid daily
Homocystinuria, a condition associated with high homocysteine levels, frequently causes osteoporosis. By lowering homocysteine levels, vitamin B12 may help prevent osteoporosis.
Folic acid , vitamin B6 , and vitamin B12 are known to reduce blood levels of the amino acid homocysteine, and homocystinuria, a condition associated with high homocysteine levels, frequently causes osteoporosis. Therefore, some researchers have suggested that these vitamins might help prevent osteoporosis by lowering homocysteine levels.68 In a double-blind study of people who had suffered a stroke and had high homocysteine levels, daily supplementation with 5 mg of folic acid and 1,500 mcg of vitamin B12 for two years reduced the incidence of fractures by 78%, compared with a placebo.69 The reduction in fracture risk appeared to be due to an improvement in bone quality, rather than to a change in bone mineral density. However, supplementation with these vitamins did not reduce fracture risk in people who had only mildly elevated homocysteine levels and relatively high pretreatment folic acid levels.70 For the purpose of lowering homocysteine, amounts of folic acid and vitamins B6 and B12 found in high-potency B-complex supplements and multivitamins should be adequate.
2 Stars
Vitamin B2
1.6 mg daily
Vitamin B2 (riboflavin) supplementation has been shown to lower homocysteine levels in certain people.

Vitamin B2 (riboflavin) supplementation (1.6 mg per day) has been shown to lower homocysteine levels by 22 to 40% in a subset of the population that has a certain genetic variant of an enzyme involved in folic acid metabolism (the 677Cà T polymorphism for the methylenetetrahydrofolate reductase gene).71 Approximately 15 to 20% of the population carries this gene and could benefic from taking riboflavin. Since genetic testing is expensive and not readily available, it would seem reasonable for all people trying to lower their homocysteine levels to include riboflavin in their regimen of B vitamin supplementation.

2 Stars
Vitamin B6 (Pregnancy and Postpartum Support)
750 mg daily taken under the supervision of a doctor
Women who habitually miscarry have been found to have high homocysteine levels. Vitamin B6 may reduce these levels and increase the chances of a successful pregnancy.
The relationship between folate status and the risk of miscarriage is also somewhat unclear. In some studies, women who have had habitual miscarriages were found to have elevated levels of homocysteine (a marker of folate deficiency).72 , 73 , 74 , 75 In a preliminary study, 22 women with recurrent miscarriages who had elevated levels of homocysteine were treated with 15 mg per day of folic acid and 750 mg per day of vitamin B6 , prior to and throughout their next pregnancy. This treatment reduced homocysteine levels to normal and was associated with 20 successful pregnancies.76 It is not known whether supplementing with these vitamins would help prevent miscarriages in women with normal homocysteine levels. As the amounts of folic acid and vitamin B6 used in this study were extremely large and potentially toxic, this treatment should be used only with the supervision of a doctor.
1 Star
Folic Acid (Stroke)
Refer to label instructions
Elevated blood levels of homocysteine have been linked to stroke risk in most studies. Supplementing with folic acid may lower homocysteine levels and reduce stroke risk.

Elevated blood levels of homocysteine , a toxic amino acid byproduct, have been linked to risk of stroke in most studies.77 , 78 , 79 Supplementation with folic acid , vitamin B6 , and vitamin B12 generally lowers homocysteine levels in humans.80 , 81 , 82 In a pooled analysis (meta-analysis) of eight randomized trials, folic acid supplementation in varying amounts (usually 0.5 mg to 5 mg per day) reduced stroke risk by 18%.83

1 Star
Vitamin B12 (Stroke)
Refer to label instructions
Elevated blood levels of homocysteine have been linked to stroke risk in most studies. Supplementing with vitamin B12 may lower homocysteine levels and reduce stroke risk.

Elevated blood levels of homocysteine , a toxic amino acid byproduct, have been linked to risk of stroke in most studies.84 , 85 , 86 Supplementation with folic acid , vitamin B6 , and vitamin B12 generally lowers homocysteine levels in humans.87 , 88 , 89 In a pooled analysis (meta-analysis) of eight randomized trials, folic acid supplementation in varying amounts (usually 0.5 mg to 5 mg per day) reduced stroke risk by 18%.90

1 Star
Vitamin B6 (Osteoporosis)
Refer to label instructions
Homocystinuria, a condition associated with high homocysteine levels, frequently causes osteoporosis. By lowering homocysteine levels, vitamin B6 may help prevent osteoporosis.
Folic acid , vitamin B6 , and vitamin B12 are known to reduce blood levels of the amino acid homocysteine, and homocystinuria, a condition associated with high homocysteine levels, frequently causes osteoporosis. Therefore, some researchers have suggested that these vitamins might help prevent osteoporosis by lowering homocysteine levels.91 In a double-blind study of people who had suffered a stroke and had high homocysteine levels, daily supplementation with 5 mg of folic acid and 1,500 mcg of vitamin B12 for two years reduced the incidence of fractures by 78%, compared with a placebo.92 The reduction in fracture risk appeared to be due to an improvement in bone quality, rather than to a change in bone mineral density. However, supplementation with these vitamins did not reduce fracture risk in people who had only mildly elevated homocysteine levels and relatively high pretreatment folic acid levels.93 For the purpose of lowering homocysteine, amounts of folic acid and vitamins B6 and B12 found in high-potency B-complex supplements and multivitamins should be adequate.
1 Star
Vitamin B6 (Stroke)
Refer to label instructions
Elevated blood levels of homocysteine have been linked to stroke risk in most studies. Supplementing with vitamin B6 may lower homocysteine levels and reduce stroke risk.

Elevated blood levels of homocysteine , a toxic amino acid byproduct, have been linked to risk of stroke in most studies.94 , 95 , 96 Supplementation with folic acid , vitamin B6 , and vitamin B12 generally lowers homocysteine levels in humans.97 , 98 , 99 In a pooled analysis (meta-analysis) of eight randomized trials, folic acid supplementation in varying amounts (usually 0.5 mg to 5 mg per day) reduced stroke risk by 18%.100

References

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2. Bostom AG, Silbershatz H, Rosenberg IH, et al. Nonfasting plasma total homocysteine levels and all-cause and cardiovascular disease mortality in elderly Framingham men and women. Arch Intern Med 1999;159:1077–80.

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14. Clarke R, Smith D, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neruol 1998;55:1449–55.

15. Hoogeveen EK, Kostense PJ, Jakobs C, et al. Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes : 5-year follow-up of the Hoorn Study. Circulation 2000;101:1506–11.

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21. de Vries JI, Dekker GA, Huijgens PC, et al. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997;104:1248–54.

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23. Leeda M, Riyazi N, de Vries JI, et al. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998;179:135–9.

24. Dekker GA, de Vries JI, Doelitzsch PM, et al. Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 1995;173:1042–8.

25. Rajkovic A, Catalano PM, Malinow MR. Elevated homocyst(e)ine levels with preeclampsia. Obstet Gynecol 1997;90:168–71.

26. Catargi B, Parrot-Roulaud F, Cochet C, et al. Homocysteine, hypothyroidism, and effect of thyroid hormone replacement. Thyroid 1999;9:1163–6.

27. Nygård O, Refsum H, Ueland PM, Vollset SE. Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am J Clin Nutr 1998;67:263–70.

28. Stolzenberg-Solomon RZ, Miller ER 3rd, Maguire MG, et al. Association of dietary protein intake and coffee consumption with serum homocysteine concentrations in an older population. Am J Clin Nutr 1999;69:467–75.

29. Nieto FJ, Comstock GW, Chambless LE, Malinow RM. Coffee consumption and plasma homocyst(e)ine: results from the Atherosclerosis Risk in Communities Study. Am J Clin Nutr 1997;66:1475–85 [letter].

30. DeRose DJ, Charles-Marcel ZL, Jamison JM, et al. Vegan diet-based lifestyle program rapidly lowers homocysteine levels. Prev Med 2000;30:225–33.

31. Jang Y, Lee JH, Kim OY, et al. Consumption of whole grain and legume powder reduces insulin demand, lipid peroxidation, and plasma homocysteine concentrations in patients with coronary artery disease: randomized controlled clinical trial. Arterioscler Thromb Vasc Biol2001;21:2065–71.

32. Boers GHJ, Smals AGH, Trijbels FJM, et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985;313:709–15.

33. Broekmans WM, Klopping-Ketelaars IA, Schuurman CR, et al. Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans. J Nutr 2000;130:1578–83.

34. Glueck CJ, Shaw P, Land JE, et al. Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. Am J Cardiol 1995;75:132–6.

35. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ. Vitamin B12, vitamin B6, and folate nutritional status in men with hyperhomocysteinemia. Am J Clin Nutr 1993;57:47–53.

36. Ubbink JB, Vermaak WJH, ven der Merwe A, et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927–33.

37. Dierkes J, Kroesen M, Pietrzik K. Folic acid and vitamin B6 supplementation and plasma homocysteine concentrations in healthy young women. Int J Vitam Nutr Res 1998;68:98–103.

38. Stein JH, McBride PE. Hyperhomocysteinemia and atherosclerotic vascular disease: pathophysiology, screening, and treatment. Arch Intern Med 1998;158:1301–6.

39. McGregor D, Shand B, Lynn K. A controlled trial of the effect of folate supplements on homocysteine, lipids and hemorheology in end-stage renal disease. Nephron 2000;85:215–20.

40. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist 1996;61:8781–97.

41. Jacques PF, Selhub J, Bostom AG, et al. The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999;340:1449–54.

42. Malinow MR, Duell PB, Hess DL, et al. Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease. N Engl J Med 1998;338:1009–15.

43. Wilcken DEL, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria—the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309:448–53.

44. Jancin B. Amino acid defect causes 20% of atherosclerosis in CHD. Fam Pract News 1994(Oct 15):7.

45. Olthof MR, Brink EJ, Katan MB, Verhoef P. Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr 2005;82:111–7.

46. Olthof MR, van Vliet T, Boelsma E, Verhoef P. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women. J Nutr 2003;133:4135–8.

47. Huang T, Zheng J, Chen Y, et al. High consumption of omega-3 polyunsaturated fatty acids decrease plasma homocysteine: a meta-analysis of randomized, placebo-controlled trials. Nutrition 2011;27:863–7.

48. Ohnishi ST, Ohnishi T, Ogunmola GB. Sickle cell anemia: A potential nutritional approach for a molecular disease. Nutrition 2000;16:330–8.

49. van der Dijs FP, Schnog JJ, Brouwer DA, et al. Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients. Am J Hematol 1998;59:192–8.

50. Houston PE, Rana S, Sekhasaria S, et al. Homocysteine in sickle cell disease: relationship to stroke. Am J Med 1997;103:192–6.

51. Alpert MA. Homocysteine, atherosclerosis, and thrombosis. South Med J 1999;92:858–65 [review].

52. Houston PE, Rana S, Sekhasaria S, et al. Homocysteine in sickle cell disease: relationship to stroke. Am J Med 1997;103:192–6.

53. al-Momen AK. Diminished vitamin B12 levels in patients with severe sickle cell disease. J Intern Med 1995;237:551–5.

54. Lin YK. Folic acid deficiency in sickle cell anemia. Scand J Haematol 1975;14:71–9.

55. Natta CL, Reynolds RD. Apparent vitamin B6 deficiency in sickle cell anemia. Am J Clin Nutr 1984;40:235–9.

56. Alpert MA. Homocysteine, atherosclerosis, and thrombosis. South Med J 1999;92:858–65 [review].

57. van der Dijs FP, Schnog JJ, Brouwer DA, et al. Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients. Am J Hematol 1998;59:192–8.

58. Rabb LM, Grandison Y, Mason K, et al. A trial of folate supplementation in children with homozygous sickle cell disease. Br J Haematol 1983;54:589–94.

59. Waterbury L. Anemia. In Barker LR, Burton JR, Zieve PD. Principles of ambulatory medicine, 4th ed. Baltimore: Williams & Wilkins, 1995, 605.

60. Gaby AR. Preventing and Reversing Osteoporosis. Rocklin, CA: Prima Publishing, 1994, 88–9 [review].

61. Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA 2005;293:1082–8.

62. Sawka AM, Ray JG, Yi Q, et al. Randomized clinical trial of homocysteine level lowering therapy and fractures. Arch Intern Med 2007;167:2136–9.

63. Levine J, Stahl Z, Sela BA, et al. Homocysteine-reducing strategies improve symptoms in chronic schizophrenic patients with hyperhomocysteinemia. Biol Psychiatry 2006;60:265–9.

64. Wilcken DEL, Wilcken B, Dudman NP, Tyrrell PA. Homocystinuria—the effects of betaine in the treatment of patients not responsive to pyridoxine. N Engl J Med 1983;309:448–53.

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66. Olthof MR, Brink EJ, Katan MB, Verhoef P. Choline supplemented as phosphatidylcholine decreases fasting and postmethionine-loading plasma homocysteine concentrations in healthy men. Am J Clin Nutr 2005;82:111–7.

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88. Ubbink JB, Hayward WJ, van der Merwe A, et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927–33.

89. Manson JB, Miller JW. The effects of vitamin B12, B6, and folate on blood homocysteine levels. Ann NY Acad Sci 1992;669:197–204 [review].

90. Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007;369:1876–82.

91. Gaby AR. Preventing and Reversing Osteoporosis. Rocklin, CA: Prima Publishing, 1994, 88–9 [review].

92. Sato Y, Honda Y, Iwamoto J, et al. Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial. JAMA 2005;293:1082–8.

93. Sawka AM, Ray JG, Yi Q, et al. Randomized clinical trial of homocysteine level lowering therapy and fractures. Arch Intern Med 2007;167:2136–9.

94. Lalouschek W, Aull S, Serles W, et al. Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects. J Lab Clin Med 1999;133:575–82.

95. Ridker PM, Manson JE, Buring JE, et al. Homocysteine and risk of cardiovascular disease among postmenopausal women. JAMA 1999;281:1817–21.

96. Perry IJ. Homocysteine, hypertension and stroke. J Hum Hypertens 1999;13:289–93 [review].

97. Genest J Jr. Hyperhomocyst(e)inemia—determining factors and treatment. Can J Cardiol 1999;15:35B–38B [review].

98. Ubbink JB, Hayward WJ, van der Merwe A, et al. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 1994;124:1927–33.

99. Manson JB, Miller JW. The effects of vitamin B12, B6, and folate on blood homocysteine levels. Ann NY Acad Sci 1992;669:197–204 [review].

100. Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 2007;369:1876–82.

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