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Homocysteine as a Risk Factor for Disease

October 2006

By Laura J. Ninger, ELS

Since 1990, the National Library of Medicine has posted thousands of scientific studies showing that homocysteine is a significant risk factor for disease.1

These published reports discuss the lethal illnesses associated with excess homocysteine, how elevations in blood homocysteine levels result in incremental increases in disease risks, the mechanisms by which homocysteine exerts its multiple pathological effects, and methods to reduce toxic homocysteine levels in the body.

Elevated homocysteine levels may be caused by B-vitamin deficiency, genetic factors, increasing age, kidney impairment, or other factors. Homocysteine overload increases the risk of disease in healthy people and magnifies adverse effects in those with pre-existing conditions.

Since 1981, the Life Extension Foundation has published hundreds of pages of text describing the dangers of excess homocysteine in the blood. What follows is a brief chronological review of landmark studies published in major medical journals that describe specific disease risks associated with excess homocysteine.


Cardiovascular Disease: Researchers found that men with premature coronary artery disease (who averaged 50 years of age) had significantly higher homocysteine levels than healthy men. Scientists thus determined that high levels of homocysteine are an independent risk factor for premature coronary atherosclerosis in men.1


Early-Onset Vascular Disease: Higher levels of homocysteine raise the risk of premature cardiovascular disease affecting the heart, brain, and peripheral blood vessels. In subjects who developed cardiovascular disease before the age of 55, elevated blood levels of homocysteine were found in 42% of patients with cerebrovascular disease, 30% with coronary vascular disease, and 28% with peripheral vascular disease—but not in any of the healthy control subjects. People with elevated homocysteine had three times the risk of cardiovascular disease compared to healthy individuals.2

Cardiovascular Disease Progression: Patients with blocked arteries in the lower body or brain were found to have significantly higher homocysteine levels than healthy individuals. In addition, patients with high homocysteine (versus normal levels) had significantly faster progression of lower-extremity vascular disease and coronary artery disease.3


Heart Attack: In a large study, men who had markedly higher homocysteine levels had over three times the risk of heart attack compared to men with lower homocysteine values.4

Stroke: Elevated homocysteine levels were independently associated with all types of stroke (ischemic, hemorrhagic, and embolic). Stroke survivors were more likely to demonstrate elevated homocysteine levels (40%) than healthy individuals (6%).5


Blood Clotting: High homocysteine levels have been linked with increased blood-clotting tendency. In the laboratory, homocysteine increased the activity of a blood-clotting factor in human cells by 25-100%, and this negative effect increased with rising homocysteine concentrations.6 In a similar study, homocysteine decreased the production of a substance that helps prevent blood clots by 65%.7


Early-Onset Coronary Artery Disease: Noting that high homocysteine raises the risk of early-onset coronary artery disease, scientists proposed that boosting plasma folate concentration may help reduce homocysteine levels and decrease coronary artery disease risk.8


Atherosclerosis: In elderly adults, dangerous narrowing of the arteries that direct blood to the brain was more than twice as common in those with higher homocysteine levels (greater than 14.4 μmol/L) than in those with low levels (less than 9.1 μmol/L).9 Another study found that individuals with high homocysteine were much more likely to have atherosclerosis (72%) than those with normal homocysteine (44%).10 In patients already at risk for atherosclerosis because of high lipid levels, elevated homocysteine further increased the risk by nearly three times.10

Coronary Artery Disease: High homocysteine was found to be an independent risk factor for coronary artery disease among healthy people. Each 4-μmol/L increase in homocysteine level increased risk by 32%.11

Birth Defects: Abnormal homocysteine metabolism may be associated with birth defects that affect the coverings of the nervous system (neural tube defects).12 Elevated homocysteine levels have been found in the amniotic fluid of fetuses with neural tube defects and in blood samples of women carrying fetuses with these birth defects.12,13 Folic acid supplements may help prevent such birth defects by correcting high homocysteine levels.12,13


Pediatric Atherosclerosis: In boys and girls aged 10-19, elevated homocysteine levels were significantly associated with atherosclerosis in the carotid arteries, which supply the brain with blood. This suggests that homocysteine levels correlate with atherosclerosis, even as early as in the second decade of life.14

Cardiovascular Disease: In another pediatric study, homocysteine levels were significantly higher among children who had a male relative who died prematurely (under 55 years of age) of heart attack. Nutritional modifications may help reduce cardiovascular risk in children with a family history of heart disease.15

Coronary Artery Disease: Scientists discovered that one of the causes of elevated homocysteine levels is a particular genetic mutation, and that people with this mutation had a significantly higher risk of premature coronary heart disease.16

Birth Defects: Scientists again noted that homocysteine levels are significantly higher in women with fetuses that have neural tube birth defects than in those with healthy fetuses, further supporting the theory that folic acid supplementation may help prevent birth defects by improving homocysteine metabolism.17


Atherosclerosis: Scientists found that elevated homocysteine was just as serious a risk factor for atherosclerosis as smoking or high lipid levels, and that it dramatically aggravated the risk associated with smoking or high blood pressure.18 In one study, every 5-μmol/L increase in homocysteine level led to a 30% increased risk of severe atherosclerosis.19 In addition, researchers found that people with higher levels of homocysteine had more blocked arteries than people with lower homocysteine levels.19

Death from Coronary Artery Disease: Higher homocysteine levels strongly predict mortality risk in people with coronary heart disease. People with homocysteine levels above 15 μmol/L had a 25% mortality rate over four years, compared to only 4% for those who had homocysteine levels below 9 μmol/L. Death rates rose dramatically as homocysteine levels rose from 9 to 20 μmol/L.20


Cardiovascular Disease and Stroke: High levels of homocysteine increase the risk of diseased arteries of the extremities, heart, and brain.21,22 One study suggested that every 5-μmol/L increase in homocysteine level increases the risk of peripheral vascular disease by 44%, coronary artery disease by 25%, cerebrovascular disease by 24%, and any cardiovascular disease by 39%.21 In people who have type II diabetes or impaired glucose tolerance, elevated homocysteine poses even greater dangers to the cardiovascular system.21 In one study, elderly men with high homocysteine had almost twice the risk of heart attack and more than four times the risk of stroke, as well as six times the risk of fatal stroke.23

Ischemic Heart Disease: Men with higher homocysteine levels were up to three times more likely to die of ischemic heart disease—caused by a diminished supply of blood and oxygen to the heart muscle—than those who had lower levels. This correlation was so strong that scientists proposed that elevated homocysteine might actually cause heart disease, rather than simply be a risk factor for it.24


Cardiovascular Disease: Homocysteine damages endothelial cells, promotes blood clots, and supports free radical damage.25 Homocysteine is associated with risks in both adults and children. In fact, healthy children with higher homocysteine levels were more likely to have increased blood pressure compared to their peers with normal homocysteine. These children have a higher risk for future cardiovascular disease.26 Testing blood homocysteine levels in children may help to identify those with a high level of heart disease risk, so that preventive strategies can be started as soon as possible.26

Colon Cancer: Women with higher homocysteine had a higher risk of colorectal cancer than women with lower levels. Those with the highest homocysteine levels had a more than 70% higher colorectal cancer risk than those with the lowest values. This led scientists to suggest that vitamin supplementation strategies to lower homocysteine levels might also decrease colorectal cancer risk.27

Birth Defects: Because high homocysteine levels are associated with both neural tube birth defects and heart disease, scientists proposed that disturbances in homocysteine breakdown might underlie both conditions. By supporting homocysteine breakdown, folic acid supplements might help prevent birth defects as well as heart disease.28


Atherosclerosis: Elevated homocysteine is associated with an increased risk of atherosclerosis, heart attack, and heart disease mortality.29 Elevated homocysteine levels are strongly associated with severe atherosclerosis in one of the body’s main blood vessels, the aorta.30

Kidney and Heart Disease: In patients with early- or end-stage kidney disease, elevated homocysteine is an independent predictor of cardiovascular disease.31

Cervical Cancer: Elevated homocysteine levels may increase the risk of cervical cancer. One study found that women who had a precursor to cervical cancer had higher homocysteine levels than healthy subjects. High homocysteine also increased the cervical cancer risk associated with smoking, having several previous births, and infection with a virus associated with cervical cancer. Elevated homocysteine increases the risk of cervical tissue changes that can lead to cancer, and enhances the effects of other risk factors.32

Depression: Scientists noted that 52% of patients with severe depression had elevated homocysteine levels, as well as decreased levels of folate and impaired metabolism of certain neurotransmitters. A significant correlation between elevated homocysteine and decreased folate concentrations was noted in depressed people. Scientists thus proposed that measuring homocysteine levels may help identify people with depression, and that homocysteine-lowering therapies might elevate mood.33

Pregnancy Complications: Elevated homocysteine levels may increase the risk of several complications of pregnancy. In a large study, scientists found that pregnant women with the highest homocysteine levels had an increased risk of premature births, low-birth-weight infants, and stillbirths.34


Alzheimer’s Disease: Elevated homocysteine levels may contribute to cognitive decline and Alzheimer’s disease.35,36 In healthy older adults, high homocysteine was associated with poorer cognitive function and faster cognitive decline over the course of five years.36 Although scientists do not know whether homocysteine causes cognitive decline or Alzheimer’s, they have noted that high homocysteine correlates with the progression and severity of these conditions.35

Invasive Cervical Cancer: Homocysteine may increase the risk for cervical cancer. Researchers found that women with elevated homocysteine levels were two to three times more likely to have invasive cervical cancer.37

Coronary Artery Disease: Since 1998, grain products in the United States have been fortified with folic acid to promote good health. By lowering homocysteine levels, grain fortification could reduce heart attacks and heart disease deaths by 8% in women and 13% in men. This strategy may save several hundred thousand lives and several billion dollars in health care costs over the course of 10 years, according to one analysis.38

Blood Clots: One study found that when homocysteine levels are high, the risk of dangerous blood clots (deep vein thrombosis) more than doubled. Blood clots are potentially lethal, since they can lead to heart attack or stroke.39

Overall Mortality: Elevated homocysteine increases the risk of death due to cancer and other causes. A 2001 study showed that each 5-μmol/L increase in homocysteine was associated with a 26% increase in cancer deaths, a 49% increase in all-cause mortality, a 50% increase in cardiovascular deaths, and a 104% increase in deaths not due to cancer or cardiovascular disease. Managing homocysteine levels may thus be crucial to prolonging life and preventing death from numerous health conditions.40