Homocysteine Reduction-1

How Much Is Safe?


Since its discovery in 1932, homocysteine's journey into mainstream medicine has been rocky. For the first 36 years after its discovery, little was understood about it. Then in 1968 a Harvard researcher named Dr. Kilmer McCully noticed that children with genetically elevated homocysteine levels experienced heart disease similar to the heart disease found in middle-aged patients. He proposed that homocysteine might be an independent risk factor for heart disease. Like many medical pioneers, McCully’s proposal concerning homocysteine was met with scorn.

McCully's homocysteine theory has since been proven beyond a doubt: people with elevated homocysteine levels are more likely to have strokes, Alzheimer's disease and dementia, kidney disease, diseases of the eye, erectile dysfunction, and, especially, heart disease (De Bree A et al 2002).

Conventional medicine, however, has still been slow to react to this news. Even today, the message on homocysteine from major mainstream medical groups is murky. Not so for the Life Extension Foundation, which has been alert to the dangers of elevated homocysteine levels since 1981. In that year, the Foundation published an article suggesting that people take aggressive action to lower their homocysteine levels (Life Extension Foundation 1981). It took conventional medicine another 15 years to catch up, when studies first appeared in major medical journals advocating the use of supplements, especially the B vitamins, to lower homocysteine levels.

Scientists have worked hard to understand why our homocysteine level increases throughout life, and how that impacts our health. Homocysteine level is affected by a number of influences, including lifestyle, dietary choices, and genetics. As we age, our ability to absorb nutrients decreases. As a result, less of the important B vitamins are available to help metabolize homocysteine. Homocysteine level is also increased by certain pharmaceuticals, an aging metabolism, smoking, drinking too much alcohol or coffee, lack of exercise, obesity, and stress.

There are various interpretations of how much homocysteine is dangerous. The Life Extension Foundation prefers an aggressive stance: based on numerous published studies, we advocate relatively low homocysteine levels to help lower risk of disease. By ages 40 to 42, mean homocysteine levels are about 11 micromoles per liter (µmol/L) in men and 9 µmol/L in women. Even homocysteine levels this low has been associated with disease. The Life Extension Foundation recommends homocysteine level between 7 µmol/L and 8 µmol/L.

For the vast majority of people, a high homocysteine level is related to the gradual breakdown of the body’s ability to metabolize homocysteine. However, some people have a high homocysteine level because of a rare genetic defect. This condition, called homocystinuria, is associated with developmental delays, osteoporosis, diseases of the eye, stroke, and severe heart disease that can occur at a young age

Now that you know some of the conditions associated with high homocysteine levels, we will discuss in detail its effects and how to lower this disease marker.

What You Have Learned So Far
An elevated homocysteine level is linked to heart attack and atherosclerosis.
Other diseases and conditions—including vascular disease, diseases of the eye, stroke, Alzheimer's disease and dementia, erectile dysfunction, and poor outcome in pregnancy—have also been associated with having elevated homocysteine.
Homocysteine level rises as we age, along with the incidence of diseases associated with this elevation.
The Life Extension Foundation prefers an aggressive stance on homocysteine, striving for a level between 7 µmol/L and 8 µmol/L.


Homocysteine and Heart Disease: A Clear Connection
The evidence is clear that having an elevated homocysteine level is an independent risk factor for heart disease. One large study conducted among physicians who had no history of heart disease showed that having a highly elevated homocysteine level was associated with a more than 3-fold increase in the risk of heart attack over a 5-year period (Stampfer MJ et al 1992).

Homocysteine has a number of direct effects on the arteries that help explain its association with heart disease. It causes thickening of the intima, or inner wall of the arteries. And it encourages blood platelets to accumulate, which may lead to the formation of blood clots (Harker LA et al 1976). In animal studies, homocysteine has been shown to affect the production of nitric oxide, a substance that causes arteries to relax and blood flow to increase (Stuhlinger MC et al 2001).

Having an elevated homocysteine level has been associated with:

First and second heart attacks (Al-Obaidi MK et al 2000; Matetzky S et al 2003)
Coronary artery disease (Nygard O et al 1997)
Total cardiovascular mortality (Anderson JL et al 2000)
Adverse outcomes after coronary balloon angioplasty (Schnyder G et al 2002)
Heart failure (Vasan RS et al 2003)
In 1999, the American Heart Association recognized the role of homocysteine in atherosclerosis when it issued an advisory statement emphasizing the importance of reducing homocysteine blood levels and of screening people who are at high risk (Malinow MR et al 1999). The New England Journal of Medicine (Oakley GP 1998) and the Journal of the American Medical Association (Tucker KL et al 1996) suggested that vitamin supplements could be used to lower homocysteine levels.

Testing Homocysteine Levels
Homocysteine levels are measured directly in the blood. An acceptable level of homocysteine depends partly on your age and gender. It is clear, however, that our homocysteine level rises as we age and that (above a certain level) homocysteine is dangerous. Conventional medicine classifies homocysteine levels as follows:

Normal—5 to 15 µmol/L
Moderate—16 to 30 µmol/L
Intermediate—31 to 100 µmol/L
Severe—Above 100 µmol/L
However, because of the evidence linking homocysteine to heart disease (even at relatively low levels), the Life Extension Foundation recommends that people try to keep their homocysteine level between 7 µmol/L and 8 µmol/L. A homocysteine level over 12 µmol/L should be treated aggressively. One study found that each 3-µmol/L increase in homocysteine caused a significant increase in the risk of having a heart attack (Verhoef P et al 1996).

Homocysteine: What Is It?
Homocysteine is an intermediary amino acid; its role in the body is complex, but very important. Homocysteine is a necessary byproduct of a healthy metabolism. Homocysteine is produced as part of the methionine cycle, in which methionine is converted to S-adenosylmethionine (SAMe). SAMe is valuable because of its ability to donate methyl groups during chemical reactions throughout the body. Homocysteine is synthesized when SAMe donates its methyl group. In scientific terms, this means the SAMe has been methylated (lost a methyl group). Methylation is crucial to the health of our cells and tissues by regulating gene expression, protein function, and RNA metabolism.

The methionine cycle is responsible for the creation of all the homocysteine in the body. Most of the resulting homocysteine is bound to plasma and considered stored, or inactive. It may be released into the bloodstream as free homocysteine in response to adverse changes in the body's biochemistry. Thus, high levels of homocysteine are linked to specific health problems. There is also evidence that homocysteine itself causes damage to the cells within blood vessels.

Homocysteine in the bloodstream is metabolized through two principal pathways. It may be remethylated back into methionine through a process that involves folic acid (folate) and vitamin B12. This is called the remethylation pathway and is responsible for consuming most of the body's free homocysteine. The remethylation pathway creates more SAMe to support healthy methylation. (Some organs, namely the kidney and liver, are able to remethylate homocysteine directly back into SAMe, but only a fraction of homocysteine is processed in this way.)

Alternatively, some of the excess homocysteine may be used to create cysteine, which is then converted into glutathione. Glutathione is an important and powerful antioxidant. The conversion of homocysteine into glutathione may be accelerated when the body is under oxidative stress. This second process is called the transsulfuration pathway because it produces sulfate byproducts that are flushed from the body in urine. The transsulfuration pathway depends on vitamin B6 to work properly.

There are many reasons free homocysteine levels might rise in the blood. We may be suffering from oxidative damage because of a shortage of glutathione, or our methylation capacity may be decreased, which affects our cells' ability to grow, differentiate, and function properly.

Homocysteine: Linked to Diseases of Aging
Although homocysteine's association with heart disease attracts the most attention, researchers are continually learning more about its effect on other diseases and conditions. So far, elevated homocysteine levels have been linked to the following disorders or diseases:

Stroke—Homocysteine's effect on the arteries that supply the brain with blood (carotid arteries) is similar to its effect on the arteries in the heart. One study that analyzed 1077 people found that overall risk of "silent stroke" or other risk factors for a stroke were strongly associated with elevated homocysteine levels (Vermeer SE et al 2003). Larger, more focused studies are underway.

Vascular disease—There is evidence that homocysteine combines with low-density lipoprotein (LDL) cholesterol and contributes to the creation of plaque inside artery walls (McCully KS 1996). Some forms of homocysteine have been shown to damage the inner walls of blood vessels directly (Jakubowski H 2003). Homocysteine has also been implicated in the formation of blood clots, which can cause a heart attack, stroke, or peripheral vascular disease.
Liver disease—Elevated homocysteine and low levels of SAMe are linked to liver toxicity and cirrhosis (Martinez-Chantar ML et al 2002; Ventura P et al 2005). Homocysteine likely contributes to liver damage, leading to the formation of fibrin, clots, and vascular complications (de la Vega MJ et al 2001).

Kidney disease—The kidneys filter, reabsorb, and metabolize amino acids, including homocysteine. In kidney failure, homocysteine levels rise due to improper kidney filtration (Friedman AN et al 2001). Folic acid, trimethylglycine (TMG; also known as betaine), and vitamins B6 and B12 reduce homocysteine in people with kidney failure. High doses of folic acid can normalize homocysteine levels. Once kidney failure occurs, folic acid is much less effective, and high doses of vitamin B12 are required to help normalize homocysteine levels (Righetti M et al 2004).
Thyroid conditions—Elevated homocysteine levels may contribute to accelerated heart disease among people who have hypothyroidism (Morris MS et al 2001).
Alzheimer’s disease and dementia—High levels of homocysteine indicate impaired methylation in the brain. Individuals with Alzheimer's disease have been shown to have elevated homocysteine levels (Joosten E et al 1997; McCaddon A et al 1998).
Depression—Depression has been linked to low levels of folic acid in women (Ramos MI et al 2004). Low folic acid levels have been shown to decrease the effectiveness of the antidepressant fluoxetine (Prozac®) (Fava M et al 1997), and vitamin B6 may alleviate depression (Hvas AM et al 2004). Deficiencies in these vitamins are also closely associated with high homocysteine levels.
Erectile dysfunction—Homocysteine has been shown to reduce the production of nitric oxide. Nitric oxide causes blood vessels to relax, increasing blood flow to organs and tissues. Folic acid and vitamin B12 may help lower homocysteine levels. In one case study, a man with erectile dysfunction, who also had a genetic defect that causes elevated homocysteine levels, did not initially respond to treatment with sildenafil (Viagra®). However, after treatment with 5000 micrograms (mcg) of folic acid and 1000 mcg of vitamin B12, his erectile dysfunction was successfully treated with sildenafil (Lombardo F et al 2004).

Diseases of the eye—Homocysteine's ability to damage blood vessels also has implications for the tiny blood vessels in the eye. Elevated homocysteine levels are associated with serious eye conditions, including glaucoma and macular degeneration. A study showed that homocysteine levels of 11.6 µmol/L were the average concentrations in patients who had central retinal vein occlusion; the average level was 9.5 µmol/L in control subjects (Vine AK 2000).

Why Homocysteine Levels Rise
Homocysteine levels are responsive to a wide range of influences. They rise naturally as we age. Genes also play a large role in the body's metabolism of homocysteine. However, there are many lifestyle factors that can also cause homocysteine levels to rise. For instance, excessive coffee and alcohol consumption have been shown to increase homocysteine levels (De Bree A et al 2002).

Dietary choices affect homocysteine levels. Eating foods that contain large amounts of methionine, such as red meat and chicken, has been shown to increase blood levels of homocysteine. Similarly, low intake of foods rich in vitamin B, such as green leafy vegetables, may also increase homocysteine levels (Devlin TM 2002).

In addition, the following pharmaceuticals are associated with elevated homocysteine levels:

Fenofibrate—Used in the treatment of high cholesterol (Dierkes J et al 1999).

Niacin—Used in the treatment of lipid management (e.g. Cholesterol & Lipoprotein (a)).

Metformin—Used to treat diabetes (Carlsen SM et al 1997).

Antiepileptic drugs—Used to control seizures (Schwaninger MC et al 1999).

Levodopa—Used to manage Parkinson's disease (Muller T et al 1999).

Methotrexate—Used to treat cancer, psoriasis, arthritis, and lupus (Haagsma CJ et al 1999).


The Life Extension Foundation Approach to Hyperhomocysteinemia

In general, there are two strategies used to lower homocysteine: increase the rate at which it is metabolized by the body, or prevent excess homocysteine from being formed in the first place. It also makes sense to address the damage caused by an elevated homocysteine level and any underlying conditions that may be contributing to the condition. The Life Extension Foundation's approach to lowering homocysteine relies on several principles:

Directly addressing high homocysteine levels by increasing metabolization of homocysteine. Nutrients that increase metabolization of homocysteine fall into two categories: those that increase the remethylation of homocysteine back into SAMe, and those that act along the transsulfuration pathway to remove excess homocysteine from the body.
Routine blood testing to monitor homocysteine levels. This should include genetic testing to check for abnormalities. Slight genetic defects in as few as two enzymes may cause moderate hyperhomocysteinemia. As mentioned previously in this chapter, the most serious form of hyperhomocysteinemia (homocystinuria) is caused by an extremely rare genetic disorder.
Addressing the damage directly caused by homocysteine. This may mean supplementing with antioxidants and other nutrients to reduce damage caused by homocysteine.
Managing underlying conditions—including high blood pressure, coronary artery disease, diabetes, and hypothyroidism—that are associated with a high homocysteine level.
Fortunately, homocysteine levels are responsive to dietary supplements, and it is possible for even moderate or high levels to be brought under control.

The B Vitamins: A Powerful Weapon
Management of hyperhomocysteinemia begins with folic acid, vitamin B6, and vitamin B12. To varying degrees, folic acid and vitamin B12 increase the remethylation of homocysteine back into SAMe. Vitamin B6 is necessary for the conversion of homocysteine into glutathione along the transsulfuration pathway. (For safety information on vitamin B6, see the Safety Caveats section at the end of this chapter.)

The following studies have shown a rapid and dramatic decrease in homocysteine levels caused by folic acid and some B vitamins:

In 1996, the Food and Drug Administration (FDA) mandated that cereal-grain flour products be fortified with folic acid. Modest but significant decreases in homocysteine levels followed (Jacques PF et al 1999; Anderson JL et al 2004).
One set of patients with a history of myocardial infarction or unstable angina was given 2000 mcg of folic acid daily. Another group of patients with the same conditions received only 200 mcg. The higher dosage significantly reduced total homocysteine levels (Neal B et al 2002).
Daily supplementation with 350 mcg of folic acid for 17 weeks reduced serum homocysteine levels by nearly 20 percent, enough to reduce the risk of vascular disease (Venn BJ et al 2002).
Folic acid and vitamins B6 and B12 reduced homocysteine levels, restored endothelial function, and reduced arterial plaque (Spence JD et al 2001).
Middle-aged to elderly men and women with initially modest to significantly elevated homocysteine levels (>8 µmol/L) who took a multivitamin and mineral supplement for 56 days had significantly higher vitamin B and lower homocysteine levels when retested. Plasma folic acid and vitamin B12 concentrations rose by 42 percent and 14 percent, respectively, while homocysteine concentrations fell 10 percent (McKay DL et al 2000).
Another B vitamin, vitamin B2, is also involved in remethylation pathways in the body (Devlin TM 2001).