I have known for many years that a substance called homocysteine is associated with an increased risk of birth defects and heart attacks. Since certain B vitamins support the body’s ability to lower homocysteine levels, I mistakenly assumed that individuals who were taking supplements containing 50 to 100 mg. of B-6, 50 to 100 mcg. of B-12 and 400 to 800 mcg. of folic acid did not need to check homocysteine levels.

When individuals did check their homocysteine level, however, I observed that some of them were at increased risk despite adequate B vitamin supplementation. I was forced to question my belief that supplementing B vitamins would allow the body to maintain safe homocysteine levels. While the question has not been studied in a controlled manner, it appears that approximately 1 in 5 individuals will have an unsafe level of homocysteine despite B vitamin supplementation.

Keith Mullen is one of the leading homocysteine researchers in the United States. His interest in homocysteine arose from personal experience.

Keith had is first heart attack when he was only 44 years old. Although his total cholesterol of less than 200 and his cholesterol to HDL ratio of less than 4 indicated that he should be at low risk for heart disease, his cardiologist recommended that he reduce his cholesterol further. He was also advised him to lose weight even though he was 5’ 6” tall and weighed only 132 pounds.

His second heart attack occurred nine years later. His cholesterol was less than 200, his risk ratio less than 4, and his weight less than 135 pounds. Once again his cardiologist recommended that he lower his cholesterol and lose weight.

When he was advised to lower his cholesterol and lose weight following his third heart attack at age 54 Keith concluded that something was missing in the doctor’s recommendations. He began to look for other factors that might account for his proclivity to heart attacks.

Elevated levels of homocysteine, he discovered, dramatically increase one’s risk of having a heart attack. He found his homocysteine level to be 58 mmol/L, making him more than 12 times more likely than average to suffer a heart attack.

Keith began supplementing B vitamins, but was only able to lower his homocysteine to 27 mmol/L, still far about the 6 or 7 than is generally regarded as safe. Addition of N-acetyl cysteine dropped his homocysteine into the safe range. He has not had a heart attack in the ten years since doing so.

Nearly everyone in the United States knows what cholesterol is and most can quote their cholesterol number. In contrast, relatively few people have heard of homocysteine and it is rare to find an individual who knows his or her homocysteine level.

Homocysteine is an amino acid. Amino acids are the building blocks from which proteins are made. Many amino acids are essential to health. Homocysteine, however, is toxic, damaging the walls of arteries and triggering the deposition of plaque. It is also known to induce DNA damage and accelerate cell death.

Detecting an increased risk of direct homocysteine toxicity may not be the most important reason for checking homocysteine levels, however. Researchers are beginning to realize that elevated levels of homocysteine often reflect the body’s inability to perform ongoing maintenance and repair through a process called methylation.

Although most people have never heard the term, methylation is extremely important. Biochemically it is the transfer of a methyl group, which is comprised of one carbon atom and three hydrogen atoms (CH3), from one molecule to another. Practically it is the process the body uses to manufacture critical hormones like adrenaline and melatonin, to tell genes when to exert their influence, to detoxify foreign substances in the liver, to manufacture new cells, and to repair free radical damage.

Homocysteine forms when methionine, an amino acid obtained from various foods, is used as a source of methyl groups. Diet does not play a major role in the process, however. It has been demonstrated that dietary intakes of methionine up to five times that typically consumed do not cause homocysteine levels to rise. The primary reason levels rise is a loss of methylation capacity.

When the body’s methylation reserve is adequate, homocysteine is converted to either glutathione, an important antioxidant, or back to methionine. When the body’s methylation reserve is inadequate or methylation does not proceed normally, homocysteine accumulates. Methylation deficiencies are associated with heart disease, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, liver disease, depression, birth defects, cancer, premature aging, and other chronic illnesses.

It is difficult to find a condition that is not linked to inadequate methylation. An analysis of elderly hospitalized patients in France, published in 2003, showed that 100 % had unsafe levels of homocysteine. A startling 45 % had levels above 15 mmol/L. A three-year study of elderly hospitalized patients in Italy, published in 2001, found that the mean homocysteine level was 16.8. Patients with the highest levels tended to present with the most serious diseases and had the highest incidence of atherosclerosis and impaired mental function.

Analysis of homocysteine levels in population subgroups is revealing. Individuals who are receiving dialysis treatments have some of the highest homocysteine levels of any group, often above 50. They also have one of the highest rates of heart attack.

An article published in the December 18, 2003 issue of the New England Journal of Medicine found the same to be true concerning a disease called Systemic Lupus Erythematous, often referred to simply as “lupus”. People who have SLE often die prematurely from a heart attack. The study found no increase in cholesterol or cholesterol risk ratios in lupus patients. What it did find was a significant increase in homocysteine levels.

In contrast, people with Down’s syndrome have lower homocysteine levels than the general population, averaging between 2 and 3. This is due to the fact that a gene that regulates homocysteine metabolism is located on chromosome 21, an extra copy of which is carried by these individuals. While heart birth defects are common in Down’s syndrome, heart attacks are not. I could find only one reported instance of an individual with Down’s syndrome having a heart attack.

A study of the cholesterol patterns of people with Down’s syndrome reveals something very interesting. The prevailing attitude is that high levels of cholesterol and LDL cholesterol (the so-called “bad” cholesterol) and low levels of HDL cholesterol (the so-called “good” cholesterol) cause heart attacks. Individuals with Down’s syndrome have cholesterol and LDL levels that are no different than those in the general population and actually have LOWER than average levels of HDL cholesterol.

If the cholesterol and heart disease theory is correct, people with Down’s syndrome should be having more heart attacks than the rest of the population, not less.

It is therefore disappointing that the American Heart Association states, “The American Heart Association has not yet called hyperhomocysteinemia (high homocysteine level in the blood) a major risk factor for cardiovascular disease. We don't recommend widespread use of folic acid and B vitamin supplements to reduce the risk of heart disease and stroke.”

A clear and strong correlation of homocysteine levels to Alzheimer’s Disease has also been discovered. Studies in the International Journal of Geriatric Psychiatry, April 1998, and the Journal of Gerontology and Biological Sciences, March 1997, confirmed that people with Alzheimer’s disease have much higher homocysteine levels than others in their age group. A number of similar studies have confirmed the link.

Despite the mounting evidence that high levels of homocysteine are associated with Alzheimer’s disease, the Alzheimer's Disease Society has criticized the recommendation that people take folic acid supplements to lower their homocysteine levels. Their official position is, "No one knows whether taking (folic acid) supplements will help prevent the disease or whether it will affect the rate at which the disease progresses. The only way this will be discovered is by doing further studies on many, many more patients over a long period of time."

The American Heart Association and the Alzheimer’s Disease Society are not alone in their resistance to homocysteine testing. Medicare excludes homocysteine testing as a benefit. The official Medicare position is that homocysteine testing is “not medically necessary.”

Skeptics support the position that any link between homocysteine and disease is unproven by pointing to studies that appear to be inconclusive. These studies typically compare homocysteine levels in people having a particular disease with the levels in a control group of people without the disease using a “normal” cutoff of 15 mmol/L. These studies err in failing to recognize an important fact, which is that there is no “normal” level of homocysteine.

The American Journal of Epidemiology reported in 1996 that for each 3-point rise in homocysteine the risk of heart attack jumps 35 percent (Figure 1). Other studies looking at the incidence of disease at progressively rising homocysteine levels have shown similar results.

With the average level of homocysteine standing at 10, it is not surprising that studies comparing people who have had a heart attack or have developed Alzheimer’s disease with the population at large have reported inconclusive results. One must compare the disease incidence in individuals with high levels of homocysteine with that in those with low levels to draw a logical conclusion.

If it were not possible to support methylation and control homocysteine levels the reluctance of physicians and organizations to accept the link between homocysteine and degenerative diseases might be understandable. The truth, however, is that elevated homocysteine levels can be reduced easily, safely, and inexpensively.

Taking a broad-spectrum nutritional supplement that contains optimum levels of B vitamins as I recommended in last months newsletter will assure safe homocysteine levels in approximately 80 percent of those doing so. When homocysteine levels remain higher than 7 mmol/L a separate B Complex supplement should be added. This should lower the homocysteine to safe levels in an additional 10 percent of individuals.

While some advocate increasing the amount of B-6, B-12, and folic acid further when homocysteine levels remain elevated, this is rarely effective. Adding other nutrients is usually necessary and much more efficient in achieving the desired result.

One of these additional nutrients is N-acetyl cysteine. N-acetyl cysteine is an amino acid that combines with homocysteine to form a substance that is efficiently excreted by the kidneys. 500 mg. of N-acetyl cysteine should be taken twice daily.

The other beneficial nutrient is NN-diimethylglycine. Trimethylglycine has also been used, but it is less effective, since it must be converted to dimethylglycine in the body.  As dimethylglycine levels rise, the conversion rate slows, limiting trimethylglycine's effectiveness.

The combination of B vitamins, N-acetyl cysteine, and dimethylglycine will reduce homocysteine levels to a safe range in nearly all cases. These nutrients are readily available, they free of undesirable effects, and they are quite affordable.  I combined them in a single supplement, HCY Formula.  It is avaliable through Vitality Corporation, 800-423-8365.  

The connection between Vitamin B-6 and heart disease was reported as early as 1948 and the connection between B-12 deficiencies and dementia was reported in 1969. The homocysteine connection was recognized as early as 1980. The suggestion that people should wait to lower homocysteine until the results of long-term studies conclusively prove the consequences of ineffective methylation to everyone’s satisfaction is absurd.

If you do not know your homocysteine level I encourage you to have it checked immediately and, if it is over 7, take steps to bring it into a safer range. Because the body’s methylation capacity tends to diminish with age and can fall off quickly, everyone over the age of 70 should check their homocysteine level annually.

The mechanisms that trigger and direct the aging process are complex, but a great deal has been learned in the past two decades. The free radical theory of aging, which states that aging occurs primarily because the cells and tissues of the body are attacked and damaged by unbalanced molecules has led to a greater understanding of the body’s antioxidant defense system and the nutrients that must be provided to maintain its effectiveness.

It has become clear that methylation is the primary mechanism the body uses to repair free radical damage and that homocysteine levels are a reliable indicator of the body’s ability or inability to perform maintenance and repair tasks. By providing antioxidant nutrients to minimize free radical damage and methylation nutrients to support the repair of the damage that does occur each of us can expect to age gracefully and die biologically young at an advanced chronological age.

The April 13, 2006 New England Journal of Medicine carried two articles in which investigators concluded that B-vitamins are of no value in preventing heart disease and may, in fact, be harmful. Once again, it is important to look beyond the headlines.

Both studies were done on people who already had advanced cardiovascular disease at entry. All had a history of at least one heart attack, and many had a history of stroke or peripheral vascular disease as well. About half of the people in each group were still smoking, and about 40 % were diabetic. Nearly all were on multiple drugs - aspirin, beta-blockers, statins, ACE inhibitors, calcium-channel blockers, diuretics, warfarin, and diabetic drugs.

The baseline and end homocysteine levels are revealing.  In the Hope-2 trial the baseline homocysteine levels were 12.2 in both groups. This was lowered to 9.7 in the vitamin group, still well above the generally regarded as safe level of 7.2. In the Norvit trial the baseline was 13.2 and dropped to 9.5 in the treatment group.

The studies have been loudly trumpeted as conclusive proof that B-vitamins are of no benefit and are dangerous for people who have had a heart attack. However, anyone who thinks that lowering homocysteine to non-safe levels is going to significantly impact the outcome of these "sickest of the sick" must be living a rich fantasy life.

The authors assume a graded response to homocysteine - that a 10 % drop should result in a corresponding reduction in heart attack rates. But is this necessarily true, especially in the face of pre-existing disease?

Suppose a levee is designed to prevent flooding, provided that the water depth does not exceed 7 feet. What will happen if the water rises to 12 1/2 or 13 feet? The levee will overflow and surrounding property will be damaged. If the water level drops to 9 1/2 feet, what will happen? The levee will continue to overflow and property will continue to be damaged.

That is precisely what the Vitamin B studies demonstrate. Lowering homocysteine to unsafe levels does little, if anything, to stop the damage being done to arteries. Having said that, an accompanying editorial drew a particularly interesting conclusion:

"What, then, can we conclude from the results of these trials? Clearly, folic acid, vitamin B12, and vitamin B6 are not the therapeutic solution expected, and they do not provide a preventive benefit in patients with mild hyperhomocysteinemia . . . we should consider alternative approaches to reducing homocysteine concentrations, perhaps with new methods of enhancing the conversion of homocysteine to cysteine in the liver or enhancing the urinary excretion of the amino acid."

The studies, therefore, are a resounding endorsement of the importance of not only lowering homocysteine levels to a safe range, but using a comprehensive approach in doing so. This is precisely what I had in mind when I created HCY Formula, which addresses both homocysteine conversion by the liver and homocysteine excretion by the kidneys. It is not surprising that nearly all of those using the product are bringing their homocysteine levels into a safe range.