Homocysteine Risks Include Stroke, Heart Disease and Other Health Concerns
By Ward Dean, MD
Homocysteine is an amino acid that forms naturally in the body as a byproduct of the metabolism of methionine, an amino acid found in red meat. Elevated blood levels of homocysteine are now recognized as an important risk factor for heart disease, possibly surpassing other risk factors such as cholesterol, fibrinogen, C Reactive Protein (CRP), smoking, age and gender.
Homocysteine Increases Cardiovascular Risk
More than twenty studies with over 2,000 subjects reveal “remarkably consistent” findings regarding the relationship between elevated homocysteine levels and cardiovascular diseases. Patients suffering from stroke and other cardiovascular diseases tend to have higher blood levels of homocysteine (hyperhomocysteinemia) than do subjects without disease. Importantly, even minor elevation of homocysteine levels can significantly increase the risk of stroke and heart disease. A number of studies have shown that homocysteine increases platelet adhesion and coagulation abnormalities, resulting in increased arterial and venous clots, leading to strokes and heart attacks. (1,2) One paper that reviewed eight studies totaling 2,400 patients revealed that risk of developing thrombosis (clots in blood vessels) was up to thirteen times greater in people with elevated homocysteine. (3)
When researchers conducted a meta-analysis of 35 studies they discovered consistently higher homocysteine levels in patients diagnosed with atherosclerotic diseases. In fact, those subjects diagnosed with atherosclerosis were shown to have homocysteine levels averaging 26 percent higher than those of healthy subjects. (4)Another study by Dr. Jacob Selhub of Tufts University and associates involved more than 1,000 elderly people enrolled in the long-running Framingham Heart Study. The authors reported that individuals with the highest levels of homocysteine had twice the risk of a carotid artery blockage (stenosis) than people with the lowest levels. Moreover, their research revealed that patients with the greatest blockage also had the lowest intake of folic acid and vitamin B6. (5)
The Physicians’ Health Study, a Harvard-based study that tracked nearly 15,000 male physicians (aged 40-84 years) came to a similar conclusion. At the start of the study, none of the physicians had ever suffered a heart attack or stroke. During the course of the five year study 271 men subsequently suffered a heart attack. When researchers compared homocysteine levels of those suffering a heart attack with those who remained healthy, they discovered that the men with the highest homocysteine levels were three times as likely to experience a heart attack as those with the lowest homocysteine levels. (6)
These findings are supported by a recent prospective study of homocysteine and heart disease conducted in the United Kingdom. When the researchers compared blood collected from 21,520 people (aged 35-64 years) they found that men who had died from heart attacks had homocysteine levels that were significantly higher than men who did not die from heart attack. Additionally, men with the highest levels of homocysteine faced up to four times the risk of suffering a fatal heart attack as those with the lowest levels. The investigation revealed a continuous dose-response relationship, with risk of heart attack increasing by 41 percent for each additional 5 mM/Lincrease in homocysteine levels. (7)
When Norwegian scientists followed 600 men diagnosed with coronary artery disease for up to six years they found that those with the highest homocysteine levels suffered the highest incidence of heart attacks. Higher homocysteine levels also correlated with poor prognosis for survival (Figs. 1 and 2). In their paper the Norwegian researchers concluded that blood homocysteine levels were the strongest predictor of death, surpassing all other study parameters, including cholesterol, triglycerides, apolipoprotein B, apolipoprotein A-I, and lipoprotein (a) [Lp(a)]. (8)
Homocysteine Not Just Bad for the Heart and Arteries
Homocysteine has been implicated in a number of other serious and life-threatening illnesses as well, including kidney disease, psoriasis, acute lymphoblastic leukemia, hypothyroidism, rheumatoid arthritis, gout, depression, Systemic Lupus Erythematosis (SLE), HIV/AIDS, and cancer. (9)
High levels of homocysteine are even related to worsening cognitive performance (Fig. 3). In a group of 156 individuals who ranged in age from 60-91, none of whom had any overt memory-related problems, researchers found that those who had the highest levels of homocysteine had the poorest cognitive performance. (10)
Homocysteine and Aging
Not surprisingly, homocysteine blood levels have also been found to increase with age (Fig. 4). (11,12) In this regard, the findings of scientists at the Georgetown School of Medicine are of particular interest. Dr. Dong Xu and colleagues examined the effects of homocysteine on the length of telomeres of endothelial cells. Telomeres are unique molecular “caps” found attached to the ends of chromosomes. Telomeres are known to protect the ends of the chromosome from degradation and are involved in the division (mitosis) of cells. Each time a cell divides the length of the telomeres is slightly shortened. In due time, after a number of cell division cycles (or “population doublings”) the telomeres reach a critical length marked by the cessation of cell division and potential death of the cell. Telomeres are thus believed to act as a cellular clock to regulate lifespan. Dr. Xu and colleagues found that homocysteine in cell cultures greatly increased the rate of telomere shortening (Fig. 5), leading the authors to conclude that “a link exists between chronic exposure to homocysteine and the rate of aging.” (13)
Causes of Elevated Homocysteine
Inadequate B6, B12, Folate: In adults elevated homocysteine levels are usually related to the inadequate intake of B vitamins, particularly folic acid, B6, B12, and betaine (trimethylglycine). The reason these nutrients are so important is that they all act as cofactors in the metabolism of homocysteine (Fig. 6). The conversion of homocysteine to cysteine—known as transsulfuration—requires an enzyme called cystathionine b-synthase (CBS) along with vitamin B6 as a cofactor. In the absence of vitamin B6, transsulfuration cannot proceed, and homocysteine begins to build up and damage blood vessels. The conversion of homocysteine back to methionine is called remethylation. Folic acid and vitamins B6 and B12 are required for this reaction. Betaine can also facilitate remethylation. When levels of these nutrients are low, remethylation cannot proceed efficiently, allowing homocysteine to accumulate.
Coffee: Several studies have indicated that coffee consumption appears to cause a dose-related increase in homocysteine. A large study (4,754 participants) by scientists from Johns Hopkins University found that the more coffee one consumes the higher ones’ homocysteine levels (Fig. 7). Although this may appear as bad news for coffee drinkers, a solution (other than giving up coffee) is offered later in this article. (14)
Niacin: Another cause of elevated homocysteine is high dose nicotinic acid (Vitamin B3). This is especially surprising given the proven track record for niacin’s ability to dramatically improve lipid profiles. Niacin is one of the most economical and effective ways to lower total cholesterol, triglycerides, and lipoprotein (a) [lp(a)], and to raise HDL (the “good” cholesterol). However, doses of niacin in excess of 1,000 mg have been shown to cause an increase in homocysteine. (15) This increase may be offset by the benefits of niacin, and may be mitigated by the use of homocysteine-lowering substances described below.
Metformin: Another surprise is that the drug Metformin (Glucophage) has been shown in several studies to cause an increase in homocysteine. (16-18) This at first appears to be a disturbing finding, as many people take Metformin for its broad range of potential anti-aging effects—especially its ability to restore insulin and cortisol receptor sensitivity. Metformin’s homocysteine-raising effects may be due to its known effect of causing a decrease in absorption of vitamin B12. As mentioned previously, vitamin B12 is required to convert homocysteine back into methionine (remethylation), so Metformin-related deficiency of vitamin B12 could explain the reported increase in homocysteine. Obviously, this effect can likely be countered by taking supplemental B12, sublingually or by injection.
Keeping Homocysteine Levels Low
Lifestyle Modification: Relatively straight-forward lifestyle changes can help to maintain favorable homocysteine levels, including exercise, avoiding alcohol, and eating a diet high in protein. Although a high protein diet might seem contradictory, since homocysteine is produced from an amino acid found in meat, data from a large study demonstrates that the more meat one consumes, the lower one’s blood homocysteine level (Fig. 8). (19) Since hyperinsulinemia (elevated insulin) is also associated with higher levels of homocysteine, higher meat consumption probably results in a reduction in carbohydrate consumption, and a consequent reduction in insulin levels.
Folic Acid: Folic acid enhances the remethylation process that converts homocysteine into methionine, and thereby further reduces homocysteine levels. Doses of folic acid ranging from 800 mcg up to 5 mg/day have been recommended. (20,21,22)
Vitamin B6 (Pyridoxine): Vitamin B6 has been safely used in doses ranging as high as 750 mg per day for up to 24 years by patients with elevated levels of homocysteine.21 This is a remarkable record of safety, considering reports of peripheral neuropathyat doses as low as 500 mg per day of B6. One possible explanation is that since the metabolism of some people diagnosed with hyperhomocysteinemia is so severely altered that, not only can they tolerate such high doses of B6, they may actually require them. More common recommendations for B6 range from 100-300 mg per day. (22, 23)
Vitamin B12 (cobalamin): Vitamin B12 is also a cofactor in the remethylation of homocysteine to methionine. Vitamin B12 is effective in doses up to 1 mg per day. In a small study from the Denver VA Medical Center, physicians treated ten patients with high homocysteine levels with weekly injections of 1 mg of vitamin B12 per week for 8 weeks, followed by monthly injections for the next four months. This single therapy led to dramatic drops in the homocysteine levels of all patients (Fig. 9). (11)
Betaine (TMG): Some people are deficient in enzymes required to facilitate transsulfuration or folate-based methylation. Such a deficiency can result in elevated homocysteine levels regardless of the presence of adequate levels of folate and/or vitamin B6. In such cases betaine (trimethylglycine, or TMG) has been shown to be quite effective in reducing high homocysteine levels by enhancing the remethylation of homocysteine by a different pathway than vitamin B6. (24,25,26) Betaine has been shown to be effective in doses of 6 to 9 grams daily. (27) Although that seems like a lot, betaine is an inexpensive, pleasant tasting, fast-dissolving powder that mixes well in just about any beverage. For those who don’t want to give up their homocysteine-raising cups of coffee every day, I’ve found that a teaspoon of Betaine (about 5 grams) added to a cup of coffee actually improves the flavor.
Choline: Choline has also been reported to be helpful in reducing elevated homocysteine levels, when administered in doses in the range of two grams daily. (28)
SAMe: Elevated levels of homocysteine have been shown to be related to low levels of S-Adenosyl-Methionine (SAMe). (29)
Vitamins C and E: Italian scientists studied the effects of 800 IU of Vitamin E and 1 gram of vitamin E on 20 healthy men and women after experimentally induced hyperhomocystenemia (elevated blood homocysteine) in the subjects. The researchers reported that “Pretreatment with antioxidant vitamin supplements normalized both the level of cardiovascular risk and the impairment of endothelial functions following acute hyperhomocystenemia.” It appears from this study that consumption of high amounts of antioxidant vitamins may be protective against elevated homocysteine levels. (30)
Elevated blood levels of homocysteine are clearly shown to increase risks of developing cardiovascular and other diseases. Research shows that increased intake of folic acid, betaine, vitamin B6, and vitamin B12 is associated with a decrease in homocysteine levels and a concomitant drop in risks of cardiovascular disease. Given the deadly consequences of elevated homocysteine levels it is truly remarkable when one considers the ease with which these levels can be reduced and maintained within a safe range by simply taking folic acid (folate), vitamins B6 (pyridoxine) and B12, SAMe, Choline, betaine (TMG), and antioxidants.
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