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LE Magazine October 2006

Nutritional Therapies for Managing Homocysteine

By William Davis, MD

Scientists have accumulated an immense amount of data associating excessive levels of homocysteine with coronary disease and other pathological conditions. Moreover, emerging research is uncovering important correlations between elevated homocysteine with chronic diseases such as macular degeneration, Alzheimer’s disease, and osteoporosis.

In this article, we take a look at established research on the dangers of elevated homocysteine, as well as some of the more recent findings concerning this important marker of cardiovascular health. We also outline strategies that aging adults can use to lower homocysteine naturally, as well as our rationale for pursuing such a preventive approach.

Homocysteine is an amino acid that plays key roles in cellular metabolism and protein manufacture. At elevated levels in the body, however, homocysteine may have far-reaching, perhaps even deadly consequences, ranging from heart disease and stroke to osteoporosis and depression.

It is now widely accepted that food sources alone cannot consistently supply the levels of nutrients necessary to sustain optimal homocysteine metabolism. While the FDA has mandated folic acid fortification in wheat products, that is not nearly enough for many aging adults.

Emerging studies are uncovering novel nutritional strategies for lowering high homocysteine levels, offering new possibilities for effective control of this potentially lethal amino acid.

Vascular diseases. Cutaway artwork of a blood clot (lower center) approaching a junction (center) of the left carotid artery that has been narrowed by atherosclerotic plaques (yellow). These are fatty deposits of cholesterol on the artery walls. They have caused narrowing of the artery, and if the blood clot lodges, then the oxygenated blood supply to the head and brain will be interrupted. This will cause a stroke, where the brain is damaged due to lack of oxygen. The backbone, its nerves (yellow), and skull bones and throat structures are also seen.

Homocysteine and Vascular Disease Risk

Following the discovery of homocysteine in 1931, little was known about this amino acid for several decades. This changed in the 1960s, when Dr. Kilmer McCully of Harvard proposed that extraordinarily advanced atherosclerosis observed in children and teenagers suffering from heart attacks and stroke was due to an extreme excess of homocysteine. Blood levels of homocysteine in these unfortunate children ranged as high as 300 micromoles per liter (µmol/L), high enough to be easily detected in the urine, thus the initial misnomer “homocystinuria.” For years after his initial observations in children, and despite intense opposition, Dr. McCully argued that homocysteine was also a major risk factor for heart disease in the broader population.

Subsequent studies have confirmed Dr. McCully’s proposition. An epidemiological study has demonstrated that homocysteine levels above 10 µmol/L are associated with an up to threefold increase in heart attack risk.1 Such levels are widespread, occurring in 5-10% of the US population and 40% of patients with vascular disease.2 The risk from homocysteine is “continuous,” having no threshold levels where risk suddenly develops. Instead, the higher your homocysteine level, the greater your risk. Levels commonly thought of as normal because they are average for Americans have been shown to contribute to heart disease and stroke risk. Levels as low as 9 µmol/L carry long-term risk, with risk escalating even more sharply at levels of 15 µmol/L or greater.3 Unfortunately, many blood laboratories still consider “normal” levels to be 5–15 µmol/L. Thus, if your doctor tells you your homocysteine level is “normal,” you should ask, “How normal?”

Since Dr. McCully’s initial observations, homocysteine has been tied to a constellation of biochemically related disorders. The lack of deep-pocketed drug company support has, to some degree, slowed the evolution of confirmatory clinical data. However, we are beginning to see the formation of a broad consensus across a variety of disease states. Homocysteine and a deficiency of the nutrients that lower it are taking center stage. Fortunately, treatment to lower excess homocysteine is inexpensive, safe, and readily available.

Homocysteine, Plaque, and Arterial Injury

Homocysteine has been implicated in multiple stages of the process leading to coronary and arterial plaque growth and activity. Among the most important of the damaging effects observed are:

  • Homocysteine induces the growth of vascular muscle cells, which are principal components of atherosclerotic plaque.4-6 Elevated homocysteine levels stimulate production of interleukin-8 and monocyte chemoattractant protein-1, both of which are responsible for attracting inflammatory cells into the arterial wall.7,8 Inflammation drives injury and plaque rupture, causing heart attack.9,10
  • High homocysteine levels are associated with the oxidation of low-density lipoprotein (LDL) particles, a more damaging form of LDL.11-16
  • Homocysteine may promote blood clot formation through various mechanisms that are still not well understood. It appears to have effects that increase clotting factors, increase tissue factor expression, increase platelet aggregation, and inhibit an anticoagulant protein called thrombomodulin. It may also cause abnormalities in the function of fibrinogen and thrombin generation.17-26 Blood clot formation is the final step in heart attack after a plaque ruptures.

Homocysteine is an important marker of increased risk for both carotid and aortic plaque, both of which signal heightened risk for stroke. The higher your homocysteine level, the greater the extent of plaque in the aorta, the large artery that emerges from the heart.27,28 The European Concerted Action Project reported more than a doubling of vascular disease when homocysteine levels exceed 12 µmol/L.29 For patients with coronary artery disease, homocysteine levels of 20 µmol/L or higher predict a startling fivefold higher mortality risk compared to patients with a level of 9 µmol/L.5

Does homocysteine cause heart attacks in humans? Substantial epidemiological observations show that the higher the homocysteine level, the higher the risk of heart attack. For example, a study reported in the New England Journal of Medicine followed 587 people with coronary disease, many of whom had undergone bypass surgery or angioplasty. Over the ensuing five years, the mortality rate of those with homocysteine levels below 9 µmol/L was 3.8%. The mortality rate for those with homocysteine levels of 15 µmol/L or greater was 24.7%—more than six times higher!5 Similar observations have been made in several other large studies.31-33

Homocysteine Levels Predict Atherosclerosis Progression

In a recent publication, researchers from UCLA and Johns Hopkins reported a relationship between elevated homocysteine levels and the progression of atherosclerotic plaques.

In patients with elevated homocysteine, the progression of coronary artery calcification (an indicator of atherosclerotic plaque burden) doubled within a 20-month period compared to that of individuals with lower homocysteine values.30

Among the newly emerging cardiovascular risk factors are homocysteine and C-reactive protein (CRP). Electron beam computed tomography (EBT) has also emerged as a useful tool to assess coronary artery calcification, and thereby measure atherosclerotic plaque burden and help predict the risk of future coronary events.

In their study, the UCLA-John Hopkins researchers enrolled 100 men and 33 women. All were without symptoms of coronary artery disease or kidney disease, and had undergone EBT scans within the previous 8-80 months. The participants received repeat EBT scans and their blood was tested for CRP, homocysteine, and other cardiovascular risk factors upon enrollment in the study.30

Participants whose homocysteine levels were equal to or greater than 12 µmol/L were found to have a 35% mean increase in the progression of coronary artery calcification, compared to a 17% increase in those whose homocysteine levels were below 12 µmol/L. No other factors considered in the study, such as cholesterol or body mass index, predicted coronary calcification progression. The authors concluded that elevated homocysteine “strongly and independently predicts progression of coronary plaque burden.”30

Gender, Aging, and Other Risk Factors

Homocysteine levels increase gradually as we age, with an abrupt jump in females during the menopausal years. From early adulthood to the age of 60 and above, increases in homocysteine levels of 50–100% are often seen.34 Increases of 2-5 µmol/L are common over several years in both men and women, particularly after the age of 65. Therefore, a single favorable laboratory assessment does not necessarily mean that one’s homocysteine will not rise to dangerous levels several years later. It is advisable to re-test your homocysteine level every year, even if an initial reading is favorable.

Certain lifestyle factors may increase the risk of elevated homocysteine levels. Vegetarians, for example, tend to have 20-30% higher homocysteine levels than their meat-eating counterparts. This observation is likely due to less vitamin B12 intake in the vegetarian diet.35-36 Smoking, excessive coffee consumption (more than 5-6 cups daily), and alcohol abuse can also raise homocysteine.37

Elevated homocysteine levels take on special significance in the presence of other risk factors for vascular disease. For example, Dutch researchers have shown that while a 5-µmol/L increase in homocysteine in non-diabetics confers a 38% greater risk of cardiovascular disease, the same 5-µmol/L increase in diabetics carries a 238% greater risk!38 People who smoke have a tremendously magnified risk of cardiovascular disease in the presence of higher homocysteine levels. One study from Europe showed a 12-fold higher risk for cardiovascular disease in smokers with homocysteine levels above 12 µmol/L.39

Other data show that the higher your homocysteine, the more it increases the dangers of other risk factors such as high cholesterol, magnifying risk several-fold.39 A particularly lethal combination of risk factors is a high homocysteine level (in this study, above 12 µmol/L for females and greater than 15 µmol/L for males) combined with a lipoprotein(a) level of greater than 40 mg/dL.40

Does Treatment Reduce Risk?

Researchers in Ontario, Canada, reported that a homocysteine level above 14 µmol/L identified a group showing much more rapid growth of carotid plaque; however, treatment with 2500 mcg of folic acid, 25 mg of vitamin B6, and 250 mcg of vitamin B12 daily completely eliminated any further plaque growth.41 Dutch researchers have reported extensively on treating high homocysteine levels using folic acid and vitamin B6 in patients with peripheral arterial disease (usually of the leg arteries), demonstrating reduction of heart attack risk and slowed growth of carotid and leg artery plaque.42,43

In a Swiss study, 553 patients were given a placebo or 1000 mcg of folic acid, 10 mg of B6, and 400 mcg of B12 daily following coronary angioplasty. After six months, 9.9% of the patients receiving the B vitamins had to undergo a repeat procedure for re-growth of blockage or a new blockage, while 16.0% of placebo patients required another procedure. Overall cardiac events, including death, were reduced from 22.8% in the placebo group to 15.4% in the B-vitamin group. Interestingly, both groups started with a homocysteine level of only 11.0 µmol/L, which was reduced to 7.2 µmol/L with B vitamins.44 Another trial of folic acid alone (5 mg daily) versus placebo in 283 Dutch patients—all heart attack survivors—yielded conflicting results. All the participants took a cholesterol-lowering medication along with folic acid or placebo. This trial revealed no benefit of folic acid in addition to the cholesterol drug over a one-year period.45

Narrowed carotid artery. Colored three-dimensional computed tomography (CT) scan of the interior of a 59-year-old patient's carotid artery, showing stenosis (narrowing). The carotid artery supplies blood to the head. The artery has become narrowed by fatty deposits (yellow) that thicken the inner coating of the arteries.

A carotid ultrasound study showed that supplementation with 2500 mcg of folic acid, 25 mg of vitamin B6, and 250 mcg of vitamin B12 daily achieved modest regression of carotid plaque. Two groups were examined: those with baseline homocysteine levels above 14 µmol/L and those with levels below 14 µmol/L. Participants with higher homocysteine levels achieved greater regression using supplements, but even the group with initial levels below 14 µmol/L obtained plaque regression, suggesting that ideal homocysteine levels are well below 14 µmol/L.41

A study from Wake Forest University produced somewhat conflicting results. A comparison of a so-called “high-dose” B-vitamin formulation of 2500 mcg of folic acid, 25 mg of vitamin B6, and 400 mcg of vitamin B12 versus a “low-dose” regimen of 200 mcg of folic acid, 0.2 mg of B6, and 6 mcg of B12 showed no difference in stroke or heart attack risk over two years. In this study comparing “low-dose” to “high-dose” vitamins, the baseline average homocysteine reading was 13.4 µmol/L of blood. The “low-dose” vitamin group experienced very little change in homocysteine levels after two years. The so-called “high-dose” arm (which did not provide particularly high doses) declined from the baseline of 13.4 µmol/L to 11.0 µmol/L. This decline was not enough to bring these so-called “high-dose” subjects into the safe homocysteine range needed to reduce stroke risk.46

Despite the strong epidemiological association between homocysteine and heart attack and stroke risk, the treatment trials still need to better define how best to manage vitamin replacement. Studies that include participants with higher homocysteine levels are needed in order to generate statistically meaningful results. Most of the participants in studies that failed to show benefit had low homocysteine levels. It is therefore no surprise that a treatment benefit over a brief time period might not be measured. Imagine giving an antibiotic to people whether or not they had an infection. No benefit would likely be measured because of a dilutional effect of treating people without infection. Additional trials may shed further light on these questions. However, the association between homocysteine and disease is so overwhelmingly strong that most authorities agree that treatment is readily justified and advisable.

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