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 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.
Hundreds of pages of text describing the dangers of excess
homocysteine in the blood have been published. 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
1996
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
Alzheimer’s Disease: Rising levels of homocysteine could be
an early warning signal of impending dementia and Alzheimer’s in
elderly men and women. High homocysteine (greater than 14 μmol/L)
almost doubled the risk of Alzheimer’s disease, suggesting a
possible cause-and-effect relationship between homocysteine and
Alzhiemer’s.41
Cardiovascular Disease: High homocysteine levels make the
cardiovascular risks of smoking even more dangerous. In one
study, smokers with high homocysteine levels had 12 times the
risk of cardiovascular disease compared to nonsmokers with
normal homocysteine.42
Ischemic Heart Disease and Stroke: Lowering homocysteine
levels may decrease the risk of heart disease and stroke.43-45
Studies have suggested that lowering one’s homocysteine level by
3 μmol/L could decrease the risk of ischemic heart disease by
11-16%, while decreasing the risk of stroke by 19-24%.43,44
Dementia: Because elevated homocysteine plays a role in
stroke and Alzheimer’s disease—two major causes of
dementia—researchers proposed that dietary supplementation to
normalize homocysteine levels could reduce rates of dementia.46
Cognitive Impairment: Healthy people who wish to maintain
their cognitive function should monitor their homocysteine
levels. Over the course of six years, healthy individuals with
high homocysteine levels at the study’s onset had much poorer
scores on word-learning tests than their counterparts with low
homocysteine levels.47
Inflammatory Bowel Disease: High levels of homocysteine in
the colon and blood may predispose individuals to two
inflammatory bowel diseases: ulcerative colitis and Crohn’s
disease. Homocysteine levels were significantly elevated in the
colons of patients with inflammatory bowel diseases compared to
healthy subjects.48
Ischemic Heart Disease and Stroke: People with high
homocysteine levels have a much greater risk of ischemic heart
disease and stroke.49 In
patients with coronary heart disease, those with the highest
homocysteine levels had an almost fivefold greater risk of
stroke.50 Some research
suggests that lowering homocysteine by 25% may lead to an 11%
decrease in ischemic heart disease risk and a 20% decrease in
stroke risk.49
Aneurysm: One of the most dangerous manifestations of
cardiovascular disease is aortic aneurysm, a bulging of the
body’s largest artery that can lead to rupture, a potentially
fatal surgical emergency. Researchers found that 68% of adults
with abdominal aortic aneurysm had elevated homocysteine levels,
compared to only 6% of unaffected individuals. Patients with
aneurysm had an average homocysteine level of 19.4 μmol/L,
compared to 10.9 μmol/L among unaffected adults.51
Cardiovascular Disease: About half of all deaths occur
because of cardiovascular disease, and elevated homocysteine may
contribute to 10% of cardiovascular disease cases and deaths.52
Cardiovascular disease risk grows as homocysteine increases, and
the risk is especially high in people with high blood pressure,
diabetes, or high lipid levels.52
Homocysteine damages blood vessels, promotes blood clotting, and
generates oxidative stress.52
Some experts estimate that lowering homocysteine could prevent
25% of cardiovascular events,52
and some recommend that all individuals at risk for heart
disease should be treated regardless of their baseline
homocysteine values.53
Homocysteine poses risks to men, women, and children, and
particularly to people with underlying illnesses.54-56
Cognitive Impairment: High levels of homocysteine are
associated with detrimental changes in the nervous system that
can be detected using radiological imaging57
or clinical assessments.58
In one study, people with the highest homocysteine levels had
lower scores on cognitive function tests. High homocysteine
levels were also associated with a 4.3 times higher risk of
dementia and a 3.7 times greater risk of Alzheimer’s disease.58
Osteoporosis: Elevated homocysteine levels may increase the
risk of osteoporotic fractures in older men and women.59,60
In one report, the risk of hip fracture increased with rising
levels of homocysteine in both sexes.59
Men with the highest levels had about four times the risk of
fracture as men with the lowest levels, and women with the
highest values had twice the risk as those with the lowest
levels.59 Lowering
homocysteine levels using nutritional strategies may thus help
protect bone health.59
Alzheimer’s Disease: Rising levels of homocysteine may
predict impending cognitive decline and Alzheimer’s disease.61,62
In one study, high levels of homocysteine were associated with
worse cognitive function, and elevated homocysteine predicted
more severe cognitive decline during seven years of follow-up.61
Moreover, elevated homocysteine was associated with a three
times higher risk of Alzheimer’s disease and a 2.6 times higher
risk of mild cognitive impairment, which typically precedes more
severe dementia.62
Aneurysm: People who have high homocysteine levels may have
an eightfold greater risk of abdominal aortic aneurysm. When an
aneurysm ruptures, fatal bleeding can occur unless the patient
receives prompt surgical care.63
Atherosclerosis: Elevated homocysteine may speed the
progression of atherosclerosis. One study showed that
atherosclerosis progressed by 35% annually for patients with
high homocysteine levels (greater than or equal to 12 μmol/L),
but by only 17% per year in people with lower levels (less than
12 μmol/L).64
Cardiovascular Disease: When researchers followed healthy men
for 10 years, they noticed that the men with the highest
homocysteine levels had nearly twice the risk of cardiovascular
disease death.65
Homocysteine was even more dangerous in smokers and in men with
high cholesterol.65 In
healthy women, increased homocysteine levels were associated
with decreased oxygen uptake, indicating poorer cardiovascular
fitness.66
Cognitive Impairment: Homocysteine may interfere with healthy
mental function.67-69 In
one report, healthy elderly people with high homocysteine levels
experienced more dramatic cognitive decline over six years than
did their counterparts with lower homocysteine levels.68
One study suggested that homocysteine may prematurely age the
brain. A rise in homocysteine was equivalent to an extra 4.2
years of age on cognitive performance tests. Homocysteine might
thus be a modifiable cause of cognitive decline.69
Depression: Depression and high homocysteine appear to be
closely related. In people aged 60-64, a higher homocysteine
level was associated with a higher prevalence of depression.70
Macular Degeneration: Homocysteine may damage eye health and
threaten visual function. In fact, scientists found that
patients with age-related macular degeneration had significantly
higher homocysteine levels than healthy subjects.71,72
Bipolar Disorder: Homocysteine may be associated with bipolar
(manic depressive) disorder. One study showed that young men
with bipolar disorder had much higher homocysteine levels than
healthy subjects, and homocysteine levels were highest in those
with progression of the disease.73
Osteoporosis: Elevated homocysteine may adversely affect bone
health and fracture risk.74
In healthy adults, high homocysteine was associated with 3.8
times the risk of fracture in men and 2.8 times the risk in
women.75 Scientists
believe that elevated homocysteine could be a clinical sign of
osteoporosis related to nutritional deficiencies.74
High homocysteine may especially increase the risk of fractures
in people suffering from underlying illnesses, such as
Parkinson’s disease or a history of stroke.76,77
Schizophrenia: Some scientists believe that schizophrenia
begins even before birth. Pregnant women with high levels of
homocysteine were found to be more likely to have children who
later developed schizophrenia. Researchers believe this may be
one more reason why pregnant women should take steps to correct
elevated homocysteine levels.78
Stroke: Over the course of 10 years, men with high
homocysteine levels had nearly three times the risk of stroke as
men with low levels of homocysteine. High serum folate levels,
however, were associated with protection against stroke.79
Coronary Artery Disease: People with elevated levels of
homocysteine were found to have more calcification of the
coronary arteries than people with lower homocysteine values.
Coronary artery calcification is a measure of the severity of
coronary artery disease.80
Kidney Disease: Patients with chronic kidney disease were
found to have significantly higher levels of homocysteine than
healthy people. In fact, 89% of these patients had homocysteine
levels greater than 14 μmol/L, which may increase their risk of
developing many other diseases.81
Macular Degeneration: Patients with age-related macular
degeneration, a common cause of visual loss, were found to have
higher homocysteine levels than healthy subjects. Levels above
12 μmol/L particularly increased the risk of macular
degeneration. High homocysteine level may thus be an independent
risk factor for age-related macular degeneration.82
Osteoporosis: Women with high homocysteine levels were found
to have significantly lower bone mineral density in the hip than
control subjects. In fact, the risk of low bone density was 96%
higher among women with high homocysteine (greater than 15 μmol/L)
compared to women with lower homocysteine (less than 9 μmol/L).
Homocysteine may be a modifiable risk factor for osteoporosis in
women.83
Schizophrenia: Homocysteine levels are extremely high in many
patients with schizophrenia. When these individuals used
vitamins to decrease homocysteine, their symptoms of
schizophrenia lessened.84
Elevated homocysteine levels have now been correlated with a
wide array of illnesses, including heart disease, stroke,
osteoporosis, depression, schizophrenia, macular degeneration,
cervical cancer, and birth defects.
Fortunately, those seeking to safeguard their health and
longevity can readily modulate elevated homocysteine levels
using nutritional therapies such as vitamins B6 and B12, folic
acid, and trimethylglycine.85
These important nutritional strategies may help you avert the
wide array of diseases that have been found to accompany
excessive levels of homocysteine.
By Laura J. Ninger, ELS
Reprinted with exclusive permission of Life Extension,
October 2006
