Homocysteine The Amino Acid with Life or Death Implications

Studies conducted over the last 30 years have consistently linked elevated levels of the amino acid homocysteine with an increased risk for developing heart disease. These findings led one group of scientists to suggest that up to 50,000 deaths a year in the United States could be prevented by fortifying food supplies with folic acid, one of a number of B vitamins shown to reduce homocysteine levels.1 Other researchers have estimated that two-thirds of all cases of hyperhomocystinemia are due to a deficiency of B vitamins.2 In addition to cardiovascular disease, recent studies are now suggesting that elevated levels of homocysteine may play a role in such conditions as Alzheimer's and Parkinson's diseases, rheumatoid arthritis, miscarriages, pregnancy-induced hypertension, diabetes, chronic fatigue syndrome and fibromyalgia.

Recent reports in scientific journals have raised the question - are elevated homocysteine levels due to a particular health condition, or are they the cause of ill health? This issue is being debated among scientists, along with the question of whether supplementation with B vitamins can provide protection against elevated homocysteine and disease.

 
Homocysteine Metabolism
Homocysteine is an amino acid formed from the metabolism of the essential amino acid, methionine. High dietary consumption of methionine, which can be found in meats and dairy products, can result in the overproduction of homocysteine. Once homocysteine is produced it is metabolized in the body through one  of two possible pathways - remethylation or transsulfuration (Figure 1). Remethylation is a process that utilizes folate, vitamin B12 or betaine (trimethylglycine) to convert homocysteine back to methionine. Alternately, transsulfuration utilizes vitamin B6, pyridoxal-5-phosphate, to catabolize excess homocysteine into a number of metabolites for eventual excretion from the body. Plasma homocysteine concentrations may differ, depending on which metabolic homocysteine pathway is defective. Even a mildly impaired remethylation pathway will significantly increase plasma fasting homocysteine concentrations. This impairment may be caused by reduced levels of folate, vitamin B12 or genetic defects. In contrast, a mild impairment in the transsulfuration pathway can lead to a very slight increase in fasting plasma homocysteine levels. A transsulfuration impairment may be due to genetic defects or inadequate levels of vitamin B6. It is usually characterized by elevated plasma homocysteine following a methionine loading test, where scientists administer high doses of methionine to subjects and observe homocysteine levels.3-5

vitamins

 

Cause or Consequence?
An abundance of research indicates that an increased homocysteine level may indicate an increased risk of cardiovascular disease. One analysis of 27 studies involving more than 4,000 patients with cardiovascular diseases and the same number of controls showed that homocysteine was an independent risk factor for atherosclerotic disease in coronary, cerebral and peripheral vessels. It was estimated that for every 5-µM (micrometer) increase in total homocysteine plasma levels there followed an increased risk of coronary heart disease of 60% for men and 80% for women.6

Other scientists came to a similar conclusion after reviewing 42 additional studies of homocysteine and cardiovascular disease mortality. Only six of these additional studies were not able to link elevated homocysteine with disease or mortality. The remainder showed a clear association with disease, including an increased risk of thrombosis. One convincing study examined cardiovascular disease patients for 4.6 years. During this period, only 3.6% of those with a homocysteine level less than 9µM died, whereas 24.7% of patients with a homocysteine greater than 15µM died. In a study that used physicians as subjects, baseline homocysteine concentrations were significantly higher in men who later had myocardial infarctions than in matched control subjects.7-9
 

Recently, some research has contradicted homocysteine's role in disease. At issue is whether homocysteine actually causes disease or if it is merely a consequence of cardiovascular conditions, diabetes, and other diseases.

In one review, scientists pointed out that many case-control studies have examined patients soon after a cardiovascular event, when homocysteine levels peak. Similarly, in the British Regional Heart Study, homocysteine level predicted stroke only in men with preexisting coronary heart disease.10 In patients with CHD, elevated homocysteine strongly predicts a poor outcome, further suggesting that it reflects the severity of CHD and possibly the risk of thrombosis.11 In support of this hypothesis, recent evidence suggests that the endothelial dysfunction found after a heart attack may raise plasma homocysteine. The inconsistent results found in homocysteine studies also provide some skepticism. Seven prospective, case-control studies support homocysteine's role in cardiovascular disease whereas five do not. Two of the seven positive prospective studies, however, included patients known to have preexisting coronary disease.

 

The extremely high, nonphysiologic doses of homocysteine used in many studies is another reason why some researchers are awaiting results of randomized, controlled trials before drawing any conclusions.

Despite the controversy, evidence still exists to support the causal link between homocysteine and disease. While it is true that a 7.5-year follow-up of the physicians study mentioned above indicated a weakening relationship between homocysteine and cardiovascular disease over time, it is also true that the physicians who experienced a cardiovascular event had baseline measurements higher than controls prior to developing their cardiovascular condition.

Another important study in Jerusalem examined 1788 residents between 1985 and 1987 with a 9-to-11 year follow-up. During the study, the 405 deaths that occurred from all causes - not just cardiovascular disease - were strongly linked to elevated homocysteine levels, even after excluding pre-existing cases of cardiovascular disease and diabetes. The one exception was cancer, which did not appear to be related to elevated homocysteine levels, a finding consistent with other studies reporting that homocysteine can actually inhibit the growth of some cancer cell lines.12

One concern is that elevated homocysteine might not be a risk factor in itself; rather, some have proposed that homocysteine exacerbates conventional risk factors, such as smoking or high cholesterol. One study of 750 atherosclerotic vascular disease patients and 800 controls showed that homocysteine levels were as strongly related to vascular disease as cholesterol levels and smoking. Those subjects whose homocysteine levels were in the top fifth had twice the chance of contracting vascular disease compared with the remaining four fifths. However, when adjusted for the presence of conventional risk factors the relative risks for homocysteine levels were reduced only marginally and remained independent and strong predictors of vascular disease despite interactions with other risk factors. Although homocysteine was a risk factor in and of itself, researchers also discovered that elevated fasting homocysteine level multiplied the negative effects of cholesterol, smoking and blood pressure. "It is conceivable," the researchers stated, "That homocysteine may augment smoking-related platelet and clotting effects or exert a toxic effect on the endothelium, and these might be more relevant to the genesis of vascular disease than reported effects of homocysteine and lipoprotein oxidation."13

Another argument that homocysteine precedes vascular disease revolves around vitamin intake. An association exists between folate and vitamin B6 deficiency and vascular disease. These vitamins have also been found to lower homocysteine levels. The fact that elevated homocysteine levels are common in elderly persons further supports this amino acid's role in life extension.

The Role of Vitamins
Numerous studies have shown the powerful effects B vitamins have on homocysteine. In one study of 750 subjects and 800 controls, plasma homocysteine concentration dropped as blood levels of folate, cobalamin and pyridoxine rose. Users of vitamin preparations containing these nutrients appeared to experience substantial protection from vascular disease compared to nonusers.14 In most cases, including genetic, vitamin supplementation results in a near normalization of plasma homocysteine.15

The normalization evident with folate supplementation may be dose dependent. In one study of 491 adults with hypertension, dyslipidemia, and/or Type 2 diabetes, serum total homocysteine concentrations were elevated in participants consuming less than 400 mcg folate/day, but fell as folate intakes exceeded 400 mcg/day.16

The effect of B vitamins is also dependent upon the type of elevated homocysteine. A placebo-controlled study of healthy kidney transplant recipients showed that whereas fasting homocysteine can be lowered by a combination of folate and vitamin B12, post-methionine load homocysteine can only be lowered by B6 supplementation.17

Another important homocysteine-regulating nutrient is betaine, which is essential in recycling homocysteine back to methionine.18 Betaine has been shown to lower homocysteine levels in the majority of patients unresponsive to vitamin B6 therapy. In one study, daily doses of 250 mg of vitamin B6, 5 mg of folic acid, and 6 gm of betaine by themselves or in combination normalized the majority of high homocysteine levels in patients administered high doses of methionine.19

Interestingly, many researchers call for the use of vitamin supplements while waiting for more conclusive randomized trials to investigate whether homocysteine precedes disease. One group of researchers questioned whether the current recommended daily allowances of vitamins that modulate homocysteine metabolism are adequate.20 Another group of  scientists stated, "Because vitamins are relatively inexpensive, there is little incentive on the part of drug companies to support such a trial, and it is up to government agencies to assume this task." The researchers went on to emphasize the importance of supplementing all three participants in homocysteine metabolism-folate, vitamin B12 and B6, as reduction of homocysteine levels in plasma requires all three vitamins.21

Recent research suggests that cardiovascular disease is only one aspect of the protective effect of B vitamins. The implications have become substantially more far-reaching as scientists have begun unearthing links between homocysteine and numerous other diseases.

Homocysteine, Rheumatoid Conditions and Chronic Fatigue
Researchers are now beginning to suspect a link between homocysteine and the high frequency of cardiovascular disease in rheumatoid arthritis patients. In one study, 38 women with rheumatoid arthritis showed significantly higher levels of total plasma homocysteine than 25, age-matched controls. Researchers have associated the rise in homocysteine with the folate antagonist drug, MethotrexateŞ (MTX), commonly used to treat rheumatoid arthritis patients, as MTX users experience raised homocysteine concentrations.22-23

Folic acid supplementation has been successful at lowering the MTX-induced rise in homocysteine levels. In a double blind, controlled trial, 79 patients taking low dose MTX were given either a placebo or folic acid supplements. Over one year, the placebo group more frequently experienced declining folate levels together with hyperhomocystinemia compared to the folic acid supplemented group.24

High homocysteine levels may also have an impact on fibromyalgia and chronic fatigue syndrome. In one study of 12 women diagnosed with both fibromyalgia and chronic fatigue syndrome, the cerebrospinal fluid of all the patients had increased levels of homocysteine. The researchers concluded that low vitamin B12 levels, a nutrient necessary for efficient remethylation of homocysteine,  contributed to the elevated homocysteine levels.25

Parkinson's Disease, Alzheimer's and Dementia
Increasing evidence suggests that homocysteine is associated with cognitive impairment and Alzheimer's disease. Homocysteine is, in fact, toxic to the medulloblastoma cells of the brain, one explanation why high homocysteine levels result in neural tube defects in prenatal humans, a condition that involves the same cell-type. This cell type may also be involved in the degenerative processes of Alzheimer's and Parkinson's.26 Oxidation products of homocysteine are excitatory sulfur amino acids and may act as excitatory neurotransmitters. During folate, cobalamin or pyridoxine deficiency, the profile of these sulfur amino acid neurotransmitters could be altered, possibly resulting in homocysteine-induced catabolism in the brain.27

The link between elevated homocysteine levels and psychiatric conditions was supported by recent research. In one study of 741 psychogeriatric-demented and non-demented patients with other psychiatric disorders, plasma homocysteine concentrations were significantly increased in both the demented and the non-demented patients, but only the demented patients had significantly lower blood folate concentrations than 163 control subjects.28 In Parkinson's patients, raised homocysteine levels have been attributed to the drug levodopa. Researchers have associated elevated homocysteine levels commonly found in Parkinson's patients with an increased risk of vascular disease.29

Pregnancy-induced Hypertension and Miscarriages
In women with recurrent miscarriages or those who had given birth to an infant with a neural tube defect, the remethylation of homocysteine to methionine is likely to be disturbed because of a decreased activity of one of the involved remethylation enzymes and/or folate or Vitamin B12 deficiencies. In addition, ovarian follicular fluid contains detectable amounts of homocysteine along with B12, B6, and folate. Because follicular fluid provides nourishment to the oocyte by facilitating transport from plasma, the ovum may be exposed to high homocysteine or low methionine concentrations or both, as well as a lack of vitamins. The vitamins fed to the ovum through this route, as well as the balance of homocysteine to methionine, may be important to fertilization and early embryogenesis.30

Pre-eclampsia, a complication of pregnancy characterized by increasing hypertension and edema, can lead to eclampsia if left untreated, a leading cause of fetal and maternal morbidity and death. In late gestation, levels of homocysteine are higher in preeclamptics as compared to pregnant women with normal blood pressure. In one study, a second trimester elevation of homocysteine was associated with a 3.2 fold increased risk of pre-eclampsia.31

Other Reasons for Elevated Homocysteine
Medications such as Azaribine (a vitamin B6 antagonist); phenytoin (Dilantin) and carbamazepine (Tegretol) (anticonvulsants that interfere with folate metabolism); and the administration of nitrous oxide in anesthesia during operations all have been shown to raise homocysteine levels. Homocysteine is also elevated in hypothyroidism, a disease possibly associated with an increased risk for coronary artery disease and lower levels of folate.32

Conclusion
Even if homocysteine is merely a consequence of disease, elevated levels could be as deadly as if it were the initial cause behind the condition. The ability to increase survival rates in renal failure patients by reducing their homocysteine levels demonstrates that taking action against high levels of this amino acid can have important consequences in life-extension.

With the wide availability of inexpensive B vitamins, supplementation would seem to be a logical choice for controlling hyperhomocystinemia. According to one group of researchers, "If the association between elevated plasma homocysteine level and mortality is even partly causal, the benefit from a simple intervention, such as folate fortification or supplementation, could be large."33

References
1. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995; 274:1049-57.

2. Swift ME, Schultz TD. Relationship of vitamins B6 and B12 to homocysteine levels: risk for coronary heart disease. Nutr Rep Int. 1986; 34:1-14.

3. Selhub J, Miller JW. The pathogenesis of homocyst(e)inemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1991; 55:131-38.

4. Miller JW, Nadeau MR, Smith D, Selhub J. Vitamin B6 deficiency vs folate deficiency: comparison of responses to methionine loading in rats. Am J Clin Nutr. 1994; 59:1033-39.

5. Miller JW, Ribaya-Mercado JD, Russell RM, Shepard DC, Morrow FD, et al. Total homocysteine in fasting plasma is not a good indicator of B6 deficiency. Am J Clin Nutr. 1992; 55:1154-60.

6. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995; 274:1049-57.

7. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998; 49:31-62.

8. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997; 337:230-36.

9. Stampfer MJ, Malinow MR, Willett WC, et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992;268:877-81.

10. Meleady R, Graham I. Plasma homocysteine as a cardiovascular risk factor: causal, consequential or of no consequence? Nutr Rev. 1999; 57(10):299-305.

11. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SM. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med. 1997; 337:230-36.

12. Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, Rosenberg IH. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999; 131(5): 321-30.

13. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997; 277(22):1775-81.

14. Graham IM, Daly LE, Refsum HM, Robinson K, Brattstrom LE, Ueland PM, Palma-Reis RJ, et al. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997; 277(22):1775-81.

15. Ubbink JB, Vermaak WJH, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocystinemia in humans. J Nutr. 1994; 124:1927-33.

16. Chait A, Malinow MR, Nevin DN, Morris CD, Eastgard RL, Kris-Etherton P, Pi-Sunyer FX, Oparil S, Resnick LM, et al. Increased dietary micronutrients decrease serum homocysteine concentrations in patients at high risk of cardiovascular disease. Am J Clin Nutr. 1999; 70(5):881-7.

17 Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999; 19:217-46.

18. Betaine for Homocystinuria. The Medical Letter. 1997; 39(993):12.

19. Boers GHJ. Hyperhomocystinemia: A Newly Recognized Risk Factor For Vascular Disease. Netherlands Journal of Medicine. 1994; 45:34-41.

20. Chait A, Malinow MR, Nevin DN, Morris CD, Eastgard RL, Kris-Etherton P, Pi-Sunyer FX, Oparil S, Resnick LM, et al. Increased dietary micronutrients decrease serum homocysteine concentrations in patients at high risk of cardiovascular disease. Am J Clin Nutr. 1999; 70(5):881-7.

21. Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999; 19:217-46.

22. Hernanz A, Plaza A, Martin-Mola E, De Miguel E. Increased plasma levels of homocysteine and other thiol compounds in rheumatoid arthritis women. Clin Biochem. 1999; 32(1):65-70.

23. Haagsma CJ, Blom HJ, van Riel PL, van't Hof MA, Giesendorf BA, et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis. 1999; 58(2):79-84.

24. Morgan SL, Baggott JE, Lee JY, Alarcon GS. Folic acid supplementation prevents deficient blood folate levels and hyperhomocystinemia during long term, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol. 1998; 25(3):441-6.

25. Regland B, Andersson M, Abrahamsson L, Bagby J, Dyrehag LE, Gottfries CG. Increased concentrations of homocysteine in the cerebrospinal fluid in patients with fibromyalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997; 26(4):301-7.

26. Parsons RB, Waring RH, Ramsden DB, Williams AC. In vitro effect of the cysteine metabolites homocysteic acid, homocysteine and cysteic acid upon human neuronal cell lines. Neurotoxicology. 1998; 19(4-5):599-603.

27. Santhosh-Kumar CR, Hassell KL, Deutsch JC, Kolhouse JF. Are neuropsychiatric manifestations of folate, cobalamin and pyridoxine deficiency mediated through imbalances in excitatory sulfur amino acids? Med Hypotheses. 1994; 43(4):239-44.

28. Nilsson K, Gustafson L, Faldt R, Andersson A, Brattstrom L, Lindgren A, Israelsson B, Hultberg B. Hyperhomocysteinaemia-a common finding in a psychogeriatric population. Eur J Clin Invest. 1996; 26(10):853-9.

29. Muller T, Werne B, Fowler B, Kuhn W. Nigral endothelial dysfunction, homocysteine, and Parkinson's disease. Lancet. 1999; 354(9173):126-7.

30. Steegers-Theunissen RP, Steegers EA, Thomas CM, Hollanders HM, et al. Study on the presence of homocysteine in ovarian follicular fluid. Fertil Steril. 1993; 60(6):1006-10.

31. Sorensen TK, Malinow MR, Williams MA, King IB, Luthy DA. Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia. Gynecol Obstet Invest. 1999; 48(2):98-103.

32. Catargi B, Parrot-Roulaud F, Cochet C, Ducassou D, Roger P, Tabarin A. Homocysteine, hypothyroidism, and effect of thyroid hormone replacement. Thyroid. 1999; 9(12):1163-6.

33. Kark JD, Selhub J, Adler B, Gofin J, Abramson JH, Friedman G, Rosenberg IH. Nonfasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jerusalem. Ann Intern Med. 1999; 131(5): 321-30.

 

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