Within the last decade, homocysteine has, arguably, attracted more attention from biochemists than any other amino acid. Homocysteine is a sulfur-containing amino acid produced during the metabolism of the essential amino acid methionine. Because of this, homocysteine may be renewed into methionine. It may also be converted into either cysteine or taurine via trans-sulphuration. If specific cofactors are lacking, homocysteine may not be converted into any beneficial compounds within the body.
Homocysteine is toxic in nature, and the accumulation (or build up) of this amino acid will often result in plasma toxicity. Various epidemiological studies indicate that this homocysteine toxicity, in concurrence with genetic and dietary factors, accounts for the elevated risks of coronary heart disease, stroke, and peripheral vascular disease. 
Figure 1: Factors contributing to individual, “total” homocysteine levels
The most prominent dietary components for homocysteine metabolism include the vitamins pyridoxine (B6), folate (B9), and cobalamins (B12). Homocysteine is either metabolized by re-methylation or via the trans-sulphuration pathway and may be affected by the availability of these nutrients. It is also theorized that higher levels of B vitamins are, in part, responsible for lower blood serum levels of homocysteine. More research is, however, is necessary to assess the benefits of vitamin supplementation and it impact on decreasing homocysteine levels.
In addition, homocysteine levels are directly dependant upon the consumption of methionine, and how much of this particular amino acid is metabolized. (See methionine for selected food sources) 
Hyperhomocysteinemia, or elevated homocysteine, is linked to the deterioration of the inner linings of arteries and veins. It is thought that this irritation in the circulatory system hampers the expansion and dilation of blood vessels located throughout the body, causing the initiation of cardiovascular disease. Cardiovascular disease remains an epidemic, claiming the responsibility for an estimated 44% of all deaths in the United States.
Cardiovascular disease manifests itself in many different forms. The arteries of veins become diseased, resulting in the thickening of arterial walls (arteriosclerosis). Proliferation of cells lining the artery with proteins and lipids leads to the development atherosclerotic plaque. If not recognized or treated, plaques may gather cholesterol and fat, becoming artheromas. Artheromas cause a distortion in the artery walls allowing for the deposition of calcium. They can also block the flow of blood to critical organs, which often results in impotency, stroke, heart attack, and possibly, the rupturing of specific arteries or veins (aneurysms).
Coronary artery disease, peripheral artery disease, myocardial infarction, extracranial carotoid artery, and stenosis are auxiliary conditions associated with cardiovascular disease.
According to various studies, some 40% of stroke victims exhibit signs of homocysteine toxicity. Homocysteine levels are most elevated in lacunar, hemorrhagic, and embolic type strokes. Chronic elevations in homocysteine blood levels may cause an obstruction or rupturing of blood vessels in the brain, resulting in stroke.
In recent years, there has been increasing criticism regarding vitamin supplementation and its effectiveness at combating elevated homocysteine levels. Many individuals using vitamin supplements, in union with a proper diet, ultimately believe that increased supplementation will protect them from the diseases associated with hyperhomocysteinemia. Research, however, suggests that even supplement users may have homocysteine levels far above the so-called “safe” level. But is there truly a safe and tolerable level for homocysteine?
Recent scientific findings indicate that there is no perceivable safe and normal range for blood serum levels of homocysteine. Many independent studies propose that normal homocysteine levels exist within the ranges of 5 to 15 micromoles per liter of blood. (A mole is an amount of a substance that contains a certain number of molecules or atoms. A micromole is one-millionth of a mole.) The American Heart Association, in contrast, has declared that homocysteine levels above 6.3 micromoles per liter of blood cause a “progressive” risk towards heart attack and other irregular conditions of the heart. 
|Risk For Coronary Artery Disease|
|(micromoles per liter of blood)|
|Lowest risk: 0-6.3|
|Moderate risk: 6.3-10|
|Highest risk: Over 10|
Nearly 40% of all Americans supplemented with vitamins in 2000.  This figure has unquestionably increased in the past half decade. With the average American homocysteine level at 10 micromoles per liter of blood, one must question the effectiveness of dietary supplements in suppressing dangerously high homocysteine levels. 
A promising 14 year follow-up study (dubbed the Nurses’ Health Study) included over 80,000 women and chronicled the number of nonfatal and fatal cases of coronary heart disease.  These women provided detailed information on diet and vitamin supplements at the beginning of trial. The goal of the study was to evaluate the correlation between increased intakes of vitamins, especially B vitamins, and heart disease. The results were as follows: Women consuming the highest intake of folate (B9) reduced their incidence of disease by 31%. Vitamin B6 users exhibited a 33% reduction in risk. Finally, women supplementing with increased levels of both B9 and B6 reduced the risk of heart disease by nearly 46%.
Another case study involved a healthy adult male who supplemented with 500 milligrams of trimethylglycine, 4000 micrograms of folic acid, and other vitamins. A blood test revealed homocysteine levels far above what is universally accepted as tolerable [11.3]. Following a daily regimented supplement program, his levels dropped below 6 within 60 days. This study suggests that persons at high risk for the development of diseases of the heart must be certain to obtain enough folic acid, B6, and B12 via diet, or through nutritional supplements. 
Measuring blood levels of homocysteine through scrutinized laboratory testing is the only way one can determine if he/she is achieving the proper nutrients to adequately reduce elevated homocysteine levels. These blood tests can improve ones assessment of personal risk, providing useful information about methylation and vitamin status, as well as determining levels of toxic homocysteine. As previously stated, certain scientific studies have indicated that elevated blood serum levels of homocysteine are a marker for the potential development of cardiovascular and other degenerative diseases. These tests may be particularly beneficial to high risk individuals, or those people with a family history of stroke, heart disease, and Alzheimer's Disease. Persons who smoke, suffer from high blood cholesterol, and high blood pressure are also advised to monitor homocysteine levels through testing.
In conclusion, supplementation alone may not lower elevated homocysteine levels. Diet may prove as the greatest determinant in the elevation of blood homocysteine levels. The consensus by many researches is that eating right, taking a multivitamin, exercising, and receiving blood tests to determine personal homocysteine levels, provides the most accurate and best method of protecting one’s self against the affects of homocysteine toxicity.
Deficiencies caused by amino acid imbalance may promote the elevation of homocysteine levels throughout the body. Higher homocysteine levels are often paralleled with an underlying deficiency of methionine. This deficiency is critical, as methylation is paramount in the repair of DNA. If this reparation does not take place, the DNA structure is compromised, resulting in accelerated aging.  Methionine is also required by the liver as a detoxifier, and is critical in the formation of new cells. Homocysteine interferes with the methylation processes needed to complete these tasks, while promoting oxidative stress upon cellular structures located throughout the body.
Severe abbreviations in the methylation cycle may also contribute to dementia of the Alzheimer’s type. Again, elevated homocysteine levels are found in methionine deficiencies, and interruptions in the methylation cycle as the result of this deficiency may result in brain damage and/or neurological impairments.  The health of the myelin sheath, and reparation of DNA in the brain is dependant on proper methylation processes. A severe elevation of homocysteine levels in Alzheimer’s patients may be indicative of a severe disruption in the methylation pathways within the brain.
Elevated homocysteine levels may also be an indicator of homocystinuria, a rare autosomal recessive disease often accompanied by the onset of osteoporosis. This may provide understanding of the relationship between the elevation of homocysteine levels and age-related osteoporotic fractures.  Recent studies of individuals 55 years of age or older, have assessed the risk between circulating homocysteine levels and the probability of osteoporotic fracture. The results found that a severe and chronic elevation of homocysteine levels were an autonomous risk factor for osteoporotic fractures in older men and women. [12, 13]
Supplements demonstrating effectiveness in lowering homocysteine levels (alone or in combination):
|Supplement||Dosage in Micro- and Milligrams|
|Folic Acid||800-5000 mcg per day|
|Vitamin B12||1000-3000 mcg per day|
|Vitamin B6||100-500 mg per day|
|Zinc||30-90 mg per day|
|Choline||250-3000 mg per day|
|Trimethylglycine (TMG)||500-9000 mg per day|
|SAMe||200-800 mg per day|
|Inositol||250-1000 mg per day|
1. AHA Science Advisory: Homocyst(e)ine, Diet, and Cardiovascular Diseases, #71-0157 Circulation. 1999;99:178-182.
2. Bolander-Gouialle, Christina. “Homocysteine.” Business Briefing: European Pharmacotherapy. 2003. 21 Jan. 2005. http://www.pdrhealth.com/drug_info/nmdrugprofiles/herbaldrugs/101840.shtml
3. American Heart Association. Circulation. Nov. 15 1995, 2825-30.
4. Source: Life Extension Foundation. Circulation. 1995, 92. 2835-2930.
5. Archives of Family Medicine 2000;9:258-262
6. Cardiologia, 1999, Apr, 44:341-45.
7. EB Rimm, WC Willett, FB Hu et al. Folate and vitamin B6 from diet and supplements in relation to coronary heart disease among women. JAMA 1998 279: 359-64.
8. AHA Science Advisory on Folic Acid, Homocysteine and Atherosclerosis (July 3, 1996)
9. Medical Hypothesis, 1998, 51: 179-221.
10. Journal of Neural Transmission, 1998, 105:[2-3]: 287-94.
11. (2004). An association between Homocysteine and Fractures. Journal Watch (General) 2004: 1-1.
12. Raisz, L. G. (2004). Homocysteine and Osteoporotic Fractures—Culprit of Bystander? N Engl J Med 350: 2089-2090.
13. Seeman, E., Strewler, G.J. (2004). Clinical and Basic Research Papers-May and June 2004 selections. BoneKEy-Osteovision 1:1-13.