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High Homocysteine

Also indexed as: Hyperhomocysteinemia

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 inflammatory bowel disease (Crohn’s disease and 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. (See “Nutritional supplements that may be helpful” below.)

Checklist for High Homocysteine

Rating Nutritional Supplements Herbs
3Stars Folic acid, vitamin B6, and vitamin B12 (in combination)  
2Stars Betaine (trimethylglycine)
Choline		  
3Stars Reliable and relatively consistent scientific data showing a substantial health benefit.
2Stars Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit.
1Star An herb is primarily supported by traditional use, or the herb or supplement has little scientific support and/or minimal health benefit.

What are the symptoms of high homocysteine? 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.

How is it treated? People with high homocysteine are typically advised to reduce their consumption of processed foods, meat, and saturated fats, because these dietary changes lower the risk of heart disease. In addition, many doctors recommend supplementation with B-complex vitamins containing vitamin B6, vitamin B12, and folic acid.

Dietary changes that may be helpful: 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.27 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.

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.28 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.

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.29

Lifestyle changes that may be helpful: According to a recent study, both cigarette smoking and coffee consumption were associated with increased homocysteine levels.30 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,31 but not others.32

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.33 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%.

Nutritional supplements that may be helpful: 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.

Betaine (trimethylglycine) (6 grams per day)43 and choline (2 grams per day)44 have each been shown to lower homocysteine levels. Doctors usually consider supplementation with these nutrients only when supplementation with folic acid, vitamin B6, and vitamin B12 do not reduce homocysteine levels sufficiently.

Niacin, a form of vitamin B3, is sometimes given in large amounts to people with elevated cholesterol levels. A controlled study found that 1,000 mg or more per day of niacin raised homocysteine levels.45 Since other actions of niacin lower heart disease risk,46 47 the importance of this finding is unclear. Nonetheless, large amounts of niacin should never be taken without consulting a doctor.

Are there any side effects or interactions? Refer to the individual supplement for information about any side effects or interactions.

References:

1. Stampfer MJ, Malinow R, Willett WC, et al. A prospective study of plasma homocysteine and risk of myocardial infarction in US physicians. JAMA 1992;268:877–81.

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.

3. Folsom AR, Nieto J, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins. Circulation 1998;98:204–10.

4. Kuller LH, Evans RW. Homocysteine, vitamins, and cardiovascular disease. Circulation 1998;98:196–9 [editorial].

5. Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease. Arch Intern Med 2000;160:422–34.

6. Meleady R, Graham I. Plasma homocysteine as a cardiovascular risk factor: causal, consequential, or of no consequence? Nutr Rev 1999;57:299–305 [review].

7. Williams JE, Paton CC, Siegler IC, et al. Anger proneness predicts coronary heart disease risk: prospective analysis from the atherosclerosis risk in communities (ARIC) study. Circulation 2000;101:2034–9.

8. Kawachi I, Sparrow D, Spiro A 3rd, et al. A prospective study of anger and coronary heart disease. The Normative Aging Study. Circulation 1996;94:2090–5.

9. Stoney CM, Engebretson TO. Plasma homocysteine concentrations are positively associated with hostility and anger. Life Sci 2000;66:2267–75.

10. Perry IJ, Refsum H, Morris RW, et al. Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995;346:1395–8.

11. Langman LJ, Ray JG, Evrovski J, et al. Hyperhomocyst(e)inemia and the increased risk of venous thromboembolism: more evidence from a case-control study. Arch Intern Med 2000;160:961–4.

12. Brattstrom LE, Hultberg BL, Hardebo JE. Folic acid responsive postmenopausal homocysteinemia. Metabolism 1985;34:1073–7.

13. Cattaneo M, Vecchi M, Zighetti ML, et al. High prevalence of hyperhomocysteinemia in patients with inflammatory bowel disease: a pathogenic link with thromboembolic complications? Thromb Haemost 1998;80:542–5.

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.

16. Sutterlin M, Bussen S, Ruppert D, Steck T. Serum levels of folate and cobalamin in women with recurrent spontaneous abortion. Hum Reprod 1997;12:2292–6.

17. Wouters MG, Boers GH, Blom HJ, et al. Hyperhomocysteinemia: a risk factor in women with unexplained recurrent early pregnancy loss. Fertil Steril 1993;60:820–5.

18. Steegers-Theunissen RP, Boers GH, Blom HJ, et al. Hyperhomocysteinaemia and recurrent spontaneous abortion or abruptio placentae. Lancet 1992;339:1122–3 [letter].

19. Quere I, Bellet H, Hoffet M, et al. A woman with five consecutive fetal deaths: case report and retrospective analysis of hyperhomocysteinemia prevalence in 100 consecutive women with recurrent miscarriages. Fertil Steril 1998;69:152–4.

20. Nelen WL, Blom HJ, Steegers EA, et al. Homocysteine and folate levels as risk factors for recurrent early pregnancy loss. Obstet Gynecol 2000;95:519–24.

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.

22. Goddijn-Wessel TA, Wouters MG, van de Molen EF, et al. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996;66:23–9.

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. 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.

28. 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.

29. 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 Biol 2001;21:2065–71.

30. 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.

31. 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.

32. 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].

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

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 NPB, 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. Family Pract News 1994;Oct 15:7.

45. Garg R, Malinow M, Pettinger M, et al. Niacin treatment increases plasma homocyst(e)ine levels. Am Heart J 1999;138:1082–7.

46. Brown WV. Niacin for lipid disorders. Postgrad Med 1995;98:185–93 [review].

47. Guyton JR. Effect of niacin on atherosclerotic cardiovascular disease. Am J Cardiol 1998;82(12A):18U–23U [review].