Question

homocysteine Metabolism: Nutritional Modulation and Impact on Health and Disease.

Answer 1

Homocysteine is an intermediate in the conversion of the amino acid methionine to cysteine. Elevated homocysteine levels are an independent risk factor for coronary heart disease, stroke, and other vascular conditions. Homocysteine and its relationship to cardiovascular disease emerged in the late 1960s, when Kilmer McCully, MD encountered two children with homocystinuria (a rare autosomal recessive condition) who had advanced atherosclerosis, although the coronary plaques contained no lipids. Increased homocysteine levels have been implicated in several other clinical conditions, including neural tube defects, spontaneous abortion, placental abruption, renal failure, non–insulin-dependent diabetes and complications of diabetes, rheumatoid arthritis, alcoholism, osteoporosis, and neuropsychiatric disorders.

1. Homocysteine Metabolism

Homocysteine is metabolized along two pathways: remethylation to methionine (which requires methionine synthase along with vitamin B12 and folic acid or betaine) or transsulfuration to cysteine (which requires vitamin B6). A defect in either of these pathways leads to accumulation of homocysteine. Insufficient dietary intake of vitamin B6, vitamin B12, and folic acid can lead to increased homocysteine levels.

The re- methylation pathway is comprised of two intersecting bio-
chemical pathways, and results in the transfer
of a methyl group (CH3
) to homocysteine by
either methylcobalamin or betaine (trimethyl-
glycine). Methylcobalamin originally receives
its methyl group from S-adenosylmethionine
(SAM) or 5-methyltetrahydrofolate (5-
methylTHF), an active form of folic acid. Af-
ter re-methylation, methionine can be re-uti-
lized to produce SAM, the body’s “universal
methyl donor,” which participates in several
key metabolic pathways, including methyla-
tion of DNA and myelin, synthesis of carnitine,
coenzyme Q10, creatine, epinephrine, mela-
tonin, methylcobalamin, and phospha-
tidylcholine, as well as phase II methylation
detoxification reactions.
The trans-sulfuration pathway of me-
thionine/homocysteine degradation (see Fig-
ure 1) produces the amino acids cysteine and
taurine, which are important nutrients for car-
diac health, hepatic detoxification, cholesterol
excretion, bile salt formation, and glutathione
production. This pathway is dependent on ad-
equate dietary intake and hepatic conversion
of vitamin B6 into its active form, P5P. Also
necessary is the amino acid serine, a downline
metabolite generated from betaine via the ho-
mocysteine-remethylation pathway.

@ Homocysteine impact on health and diseases.

A) Homocysteine and Heart Disease:
A significant component in the patho-
genesis, prevention, and treatment of heart dis-
ease involves the amino acid homocysteine.
Increased blood levels of homocysteine are
correlated with significantly increased risk of
coronary artery disease (CAD),19-22 myocardial
infarction,23, 24 peripheral occlusive disease,25-
28 cerebral occlusive disease,25, 28 and retinal
vascular occlusion.29
For over 25 years researchers have
known inborn errors of homocysteine metabo-
lism result in high levels of homocysteine in
the blood and severe atherosclerotic disease.
We now know, even within the range which is
considered normal (4-16 mumol/L), there is a
graded increase in risk for CAD. In a study of
304 patients with CAD vs. controls, Robinson
et al found the odds ratio for CAD increased
as plasma homocysteine increased, even withinthe normal range. A 5 µmol/L increase in
plasma homocysteine was correlated with an
increase in the odds ratio of 2.4 (p<.001), with
no “threshold effect.”22
Data gathered by Boers30 from a num-
ber of studies indicated that, after a methio-
nine load test, mild hyperhomocysteinemia
occured in 21%, 24%, and 32% of patients
with CAD, cerebrovascular disease, and peri-
pheral vascular disease, respectively. Selhub
et al found the incidence of hyper-
homocysteinemia (>14 mumol/L by their defi-
nition), in a group of 1160 elderly individuals
(ages 67-96) in the Framingham Heart Study,
to be 29.3%. The study also indicated plasma
homocysteine levels increase with age.25
Homocysteine facilitates the genera-
tion of hydrogen peroxide.31 By creating oxi-
dative damage to LDL cholesterol and endo-
thelial cell membranes, hydrogen peroxide
can then catalyze injury to vascular
endothelium.31, 32
Nitric oxide and other oxides of
nitrogen released by endothelial cells (also
known as endothelium-derived relaxing factor,
or EDRF) protect endothelial cells from
damage by reacting with homocysteine,
forming S-nitrosohomocysteine, which
inhibits hydrogen peroxide formation.
However, as homocysteine levels increase, this
protective mechanism can become overloaded,
allowing damage to endothelial cells to
occur.32-34 Because of the role of sulfate
compounds in the formation of amino sugars
needed to form the basement membrane of
blood vessels, high levels of homocysteine are
likely to contribute to the formation of blood
vessels which are more susceptible to oxidative
stress.34 The end result of the combination of
oxidative damage and endothelial collagen
instability is the formation of atherosclerotic
plaques.
Re-methylation of homocysteine and
the subsequent formation of SAM is critical
for biosynthesis of L-carnitine, CoQ10, and
creatine. Similarly, the trans-sulfuration path-
way must be functioning properly for optimal
biosynthesis of cysteine, GSH, pantethine, and
taurine. All of these nutrients are used clini-
cally to either reduce oxidative stress, improve
risk factor markers, or treat heart disease.
Decreased plasma folate levels are cor-
related with increased levels of homocysteine,
and a subsequent increased incidence of CAD.
In a 15-year Canadian study of CAD mortal-
ity in 5056 men and women 35-79 years of
age, lower serum folate levels were correlated
with a significantly increased risk of fatal
CAD.35 In a cohort from the Framingham Heart
Study, concentrations of folate and P5P were
inversely correlated with homocysteine levels
and the risk of extracranial carotid-artery
stenosis.25 Low P5P and low vitamin B12 have
also been linked with hyperhomocysteinemia
and a significantly increased risk of CAD.

B) Homocysteine and Peripheral
Vascular Disease:
Elevated homocysteine levels have
been established as an independent risk factor
for intermittent claudication (IC) and deep vein
thrombosis. Elevated homocysteine levels cor-
responded with an increased incidence of in-
termittent claudication and decreased serum
folate levels in a study of 78 patients with IC.39
A four-fold increase in risk of peripheral vas-
cular disease was noted in individuals with
hyperhomocysteinemia compared to people
with normal homocysteine levels.40 A group
of researchers in the Netherlands found high
homocysteine levels to be a significant risk
factor for deep-vein thrombosis, with a stron-
ger relationship among women than men.41
An increased risk of peripheral vascu-
lar occlusion has been noted in women taking
oral contraceptives, which might be linked to
the significantly increased homocysteine lev-
els in women so affected. Oral contraceptives
can cause declines or deficiencies in vitamins
B6, B12, and folate, nutrients integral to the
processing of homocysteine. Laboratory as-
sessment of plasma homocysteine levels might
be helpful to detect women who are predis-
posed to peripheral vascular occlusion while
on oral contraceptives. 42
In a group of 48 patients with periph-
eral atherosclerotic vascular disease, 50% had
abnormally high fasting plasma homocysteine
levels, while 100% had abnormal plasma ho-
mocysteine after a methionine load. Treatment
with 5 mg folic acid and 250 mg pyridoxine
for 12 weeks normalized 95% of the fasting
levels and 100% of post-load homocysteine
levels.26
C) Homocysteine and Stroke:
Stroke patients have significantly el-
evated homocysteine levels compared to age-
matched controls,43 with a linear relationship
existing between risk of stroke and homocys-
teine levels.44 Decreased blood folate concen-
trations in stroke patients might be a possible
cause of the observed hyperhomo-
cysteinemia.45
D) Homocysteine and Pregnancy:
Biochemical enzyme defects and nu-
tritional deficiencies are receiving increasing
attention for their role in causing neural tube
defects (NTD) as well as other negative preg-
nancy outcomes, including spontaneous abor-
tion, placental abruption (infarct), pre-term
delivery, and low infant birth weight. Recent
evidence has suggested derangement of me-
thionine-homocysteine metabolism could be
the underlying mechanism of pathogenesis of
neural tube defects and might be the mecha-
nism of prevention observed with folic acid
supplementation.46, 47 A low dietary intake of
folic acid increases the risk for delivery of a
child with an NTD, and periconceptional folic
acid supplementation reduces the NTD occur-
rence.48-54 Supplemental folic acid intake also
results in increased infant birth weight and
improved Apgar scores, along with a concomi-
tant decreased incidence of fetal growth retar-
dation and maternal infections.55-58A derange-
ment in methionine-homocysteine metabolism
has also been correlated with recurrent mis-
carriage and placental infarcts (abruption).59
The amino acid homocysteine, when
elevated, might be a teratogenic agent contrib-
uting to congenital defects of the heart and
neural tube. Evidence from experimental ani-
mals lends support to this belief. When avian
embryos were fed homocysteine to raise se-
rum homocysteine to over 150 nmol/ml.dysmorphogenesis of the heart and neural tube,
as well as of the ventral wall, were observed.60
Because homocysteine metabolism,
through the re-methylation and trans-
sulfuration pathways, affects several biochemi-
cal pathways involving the production of nu-
trients which are essential to the optimal func-
tioning of the cardiovascular, skeletal, and
nervous systems, it is not surprising these other
nutrients have been linked to complications of
pregnancy in animal models and humans. Low
plasma vitamin B12 levels have been shown
to be an independent risk factor for NTD.61,62
Methionine supplementation has been shown
to reduce the incidence of NTD by 41% in an
animal model.63,64 This evidence indicates that
a disturbance in the re-methylation pathway,
with a subsequent decrease in SAM, might be
a contributing factor to these complications of
pregnancy. Phosphatidylcholine, due to its role
as a precursor to acetylcholine and choline, is
acknowledged as a critical nutrient for brain
and nerve development and function.65-67 Since
the metabolic pathways of choline (via be-
taine), methionine, methylcobalamin, and 5-
methylTHF are interrelated, intersecting at the
regeneration of methionine from homocys-
teine, a disturbance in the metabolism of ei-
ther of these two methyl-donor pathways, due
to limited availability of key nutrients or de-
creased enzyme activity, will have a direct
impact on the body’s ability to optimize SAM
levels.
Evidence suggests women with a his-
tory of NTD-affected pregnancies have altered
folic acid metabolism.68-71 Patients with a se-
vere congenital deficiency of the enzyme 5,
10-methylenetetrahydrofolate reductase
(MTHFR), which is needed for the formation
of 5-methylTHF, have reduced levels of both
methionine and SAM in the cerebrospinal
fluid, and show demyelination in the brain and
degeneration of the spinal cord.2, 72 Because of
its direct impact in the activation of folic acid
to its methyl derivative, a milder version of
this enzyme defect is also strongly suspected
to increase incidence of NTD.73
High vitamin A intake during the first
two months of pregnancy is associated with a
several-fold higher incidence of birth de-
fects.74,75 Although the mechanism of action
remains to be elicited, in an animal model the
activity of hepatic MTHFR is suppressed with
high vitamin A levels,76 suggesting its terato-
genic effect during early pregnancy might be
associated with subsequent derangement in the
re-methylation of homocysteine.
Since a significant correlation has been
found between higher homocysteine levels in
women experiencing placental abruption, in-
farction, and spontaneous abortion than in con-
trol women, and since homocysteine and
CoQ10 synthesis are both dependent on the
methionine-SAM-homocysteine pathway, it is
possible low CoQ10 and elevated homocys-
teine, independently found in complicated
pregnancy, might also in fact be found to be
related conditions.77, 78
E)Homocysteine and the Nervous
System
In addition to the known impact of
homocysteine on the cardiovascular system
and micro-nutrient biochemical pathways,
numerous diseases of the nervous system are
correlated with high homocysteine levels and
alterations in B12, folate, or B6 metabolism,
including depression, schizophrenia, multiple
sclerosis, Parkinson’s disease, Alzheimer’s
disease, and cognitive decline in the elderly.
Methylation reactions via SAM,
including methylation of DNA and myelin, are
vitally important in the CNS. The neurologic
complications of vitamin B12 deficiency are
thought to be due to a reduction of activity of
the B12-dependent enzyme methionine
synthase, and the subsequent reduction of
SAM production. The CNS lacks the alternate
betaine pathway of homocysteine
remethylation; therefore, if methioninesynthase is inactivated, the CNS has a greatly
reduced methylation capacity.79 Other causes
of reduced methionine synthase activity
include folic acid deficiency and nitrous oxide
anesthesia exposure.80
Homocysteine has also been found to
be a neurotoxin, especially in conditions in
which glycine levels are elevated, including
head trauma, stroke,81 and B12 deficiency. Ho-
mocysteine interacts with the N-methyl-D-as-
partate receptor, causing excessive calcium
influx and free radical production, resulting
in neurotoxicity.81 The neurotoxic effects of
homocysteine and/or reduced methylation re-
actions in the CNS contribute to the mental
symptomatology seen in B12 and folate defi-
ciency. Increased homocysteine levels can also
be seen in schizophrenics.82
Significant deficiencies in B12 and
folate are common in the elderly population,
and can contribute to a decline in cognitive
function.83-85 An investigation of cognitive abil-
ity in older men (ages 54-81) found poorer
spatial copying skills in those individuals with
higher homocysteine levels. Better memory
performance was correlated with higher vita-
min B6 levels.86
B12 deficiency and increasing severity
of cognitive impairment has been seen in
Alzheimer’s disease (AD) patients compared
to controls and patients with other dementias.87
In a study of 52 AD patients, 50 hospitalized
non-demented controls, and 49 elderly subjects
living at home, patients with AD were found
to have the highest homocysteine levels and
the highest methylmalonic acid (an indicator
of B12 deficiency) levels.88 In a study of 741
psychogeriatric patients, high plasma
homocysteine levels were found in demented
and non-demented patients; however, only
demented patients also had lower blood folate
concentrations compared to controls. Patients
with concomitant vascular disease had
significantly higher plasma homocysteine than
those without diagnosed vascular disease.
Significantly higher homocysteine levels,
compared to controls, have also been found in
Parkinson’s patients.89
Homocysteine’s effects on neurotrans-
mitter metabolism, along with its potential re-
duction of methylation reactions, could be a
contributing factor to the etiology of depres-
sion. Folate and B12 deficiency can cause neu-
ropsychiatric symptoms, including dementia
and depression. Although no studies have been
performed to date investigating depression,
folate and B12 deficiency, and homocysteine
levels, the informatiuon regarding these defi-
ciencies and methionine synthase inhibition
suggests this connection will be revealed in
the future. SAM is used therapeutically as an
antidepressant in Europe,90, 91 and was the third
most popular antidepressant treatment in Italy
in 1995.91 As yet, SAM is not available as a
supplement in the United States.
Methylation of myelin basic protein is
vital to maintenance of the myelin sheath. The
worst-case scenario of folate and B12 defi-
ciency includes demyelination of the posterior
and lateral columns of the spinal cord, a dis-
ease process called subacute combined degen-
eration of the spinal cord (SCD).79 SCD can
also be precipitated by nitrous oxide anesthe-
sia, which causes an irreversible oxidation of
the cobalt moiety of the B12 molecule and the
subsequent inhibition of methionine synthase
activity, a decrease in homocysteine re-methyl-
ation, and decreased SAM production.80 This
has been treated using supplemental methio-
nine, which further supports the theory of a
nitrous oxide-induced biochemical block at
methionine synthase.92 Particularly at risk for
this condition are B12-deficient individuals
who visit their dentist and receive nitrous ox-
ide.80, 93
Abnormal methylcobalamin metabo-
lism is a proposed mechanism for the
pathophysiology of the demyelinating disease
multiple sclerosis (MS). Deficiency of vitamin
B12 has been linked to some MS cases, and it
is suggested dietary deficiency, or more likely,defect in R-protein-mediated absorption or
methylation of B12, might be a significant
contributor to MS pathogenesis.94
Patients with congenital MTHFR de-
ficiency, which is needed for the formation of
5-methylTHF, have reduced levels of both me-
thionine and SAM in the cerebrospinal fluid
(CSF) and show demyelination in the brain and
degeneration of the spinal cord. Methionine is
effective in the treatment of some of these pa-
tients; however, betaine was shown to restore
CSF SAM levels to normal and to prevent the
progress of neurological symptoms in all pa-
tients in whom it was tried.95
F) Homocysteine and Diabetes Mellitus:
Homocysteine levels appear to be
lower in individuals with type I diabetes mel-
litus. Forty-one type I diabetic subjects (age
34.8 ± 12 yr, duration of illness; 10.7 ± 11.1
yr) were compared to 40 age-matched control
subjects (age 34.2 ±9.1 yr). Following an over-
night fast, homocysteine was significantly
lower (p = 0.0001) in the diabetic group (6.8
± 2.2) than in controls (9.5 ± 2.9). This differ-
ence was apparent in male and female sub-
groups.96 However, increased levels of ho-
mocysteine have been reported in type I dia-
betics with proliferative retinopathy97 and
nephropathy.97, 98
Evidence to date suggests metabolism
of homocysteine is also impaired in patients
with non-insulin-dependent diabetes mellitus
(NIDDM). Following a methionine load,
hyperhomocysteinemia occurred with
significantly greater frequency in patients with
NIDDM (39%) as compared with age-matched
controls (7%). The area under the curve over
24 hours, reflecting the total period of exposure
to increased homocysteine, was also elevated
with greater frequency in patients with
NIDDM and macrovascular disease (33%) as
compared with controls (0%). The authors
concluded hyperhomocysteinemia is
associated with macrovascular disease in a
significant proportion of patients with
NIDDM.99 Araki et al also reported increased
homocysteine levels correlate with the
occurrence of macroangiopathy in patients
with NIDDM. Intramuscular injection of 1000
micrograms methylcobalamin daily for three
weeks reduced the elevated plasma levels of
homocysteine in these individuals.100
Elevated homocysteine levels appear
to be a risk factor for diabetic retinopathy. This
might be due to a point mutation on the gene
for the enzyme MTHFR,101, 102 as a significantly
higher percentage of diabetics with retinopa-
thy exhibit this mutation.102 Elevated homocys-
teine levels cause cell injury to the small ves-
sels, which might contribute to develop-
ment of retinopathy and cardiovascular
macroangiopathy.101
G) Homocysteine and Rheumatoid
Arthritis:
Elevated total homocysteine levels
have been reported in patients with rheumatoid
arthritis (RA). Twenty-eight patients with RA
and 20 healthy age-matched control subjects
were assessed for homocysteine levels, while
fasting and in response to a methionine
challenge. Fasting levels were 33% higher in
RA patients than in controls. Four hours
following the methionine challenge, the
increase in plasma homocysteine
concentration was also higher in patients with
rheumatoid arthritis.103 Another study found
statistically significant increases in
homocysteine in RA patients (p = 0.003), with
20% of the patients having homocysteine
levels above the reference range.104 A
mechanism for this increased homocysteine in
RA patients has not been elucidated.
Penicillamine, a common sulfhydryl-
containing arthritis treatment, has been found
to lower elevated homocysteine levels in
vivo.
105 Further investigation into both the
prevalence of hyperhomocysteinemia and the
mechanism of action impacting rheumatoid artheritis is needed.

G) Homocysteine and Kidney Failure:
Because homocysteine is cleared by
the kidneys, chronic renal failure, as well as
absolute or relative deficiencies of 5-
methylTHF, methylcobalamin, P5P, or betaine,
results in increased homocysteine levels. In
176 patients with end-stage renal disease on
peritoneal- or hemodialysis, homocysteine
concentrations averaged 26.6 ± 1.5 µmol/L in
patients with renal failure as compared to 10.1
± 1.7 µmol/L in normals. Abnormal values
exceeded the 95th percentile for normal con-
trols in 149 of the patients with renal failure.106
Data also indicates plasma homocysteine val-
ues represent an independent risk factor for
vascular events in patients on peritoneal- and
hemodialysis. Patients with a homocysteine
concentration in the upper two quintiles (> 27.8
µmol/L) had an independent odds ratio of 2.9
(CI, 1.4 to 5.8; P = .007) of vascular compli-
cations. B vitamin levels were also lower in
patients with vascular complications than in
those without.107
H) Homocysteine and Ethanol
Ingestion:
Chronic alcoholism is known to inter-
fere with one-carbon metabolism. Because of
this, it is not surprising to find mean serum
homocysteine concentrations twice as high in
chronic alcoholics as compared to nondrink-
ers (p < 0.001). Beer consumers have lower
concentrations of homocysteine than drinkers
of wine or spirits (p = 0.05). In chronic alco-
holics, serum P5P and red blood cell folate
concentrations have been shown to be signifi-
cantly lower than in control subjects.10
Hultberg et al reported a significantly higher
concentration of plasma homocysteine, com-
pared with controls, in 42 active alcoholics
hospitalized for detoxification. In another
group of 16 alcoholics, abstaining from etha-
nol ingestion, plasma homocysteine did not
deviate from levels found in controls.11
Feeding ethanol to rats produces
prompt inhibition of methionine synthase as
well as a subsequent increase in activity of
betaine homocysteine methyltransferase. De-
spite the inhibition of methionine synthase, the
enhanced betaine homocysteine methyltrans-
ferase pathway utilizes hepatic betaine pools
to maintain levels of SAM.108 Results indicate
ethanol feeding produces a significant SAM
loss in the first week, with a return to normal
SAM levels the second week. Betaine feeding
enhances hepatic betaine pools in control as
well as ethanol-fed animals, attenuates the
early SAM loss in ethanol-fed animals, pro-
duces an early increase in betaine homocys-
teine methyltransferase activity, and generates
increased SAM levels in both control and etha-
nol-fed groups.109 Minimal supplemental di-
etary betaine at the 0.5% level generates SAM
twofold in control animals and fivefold in etha-
nol-fed rats. Concomitant with betaine-gener-
ated SAM, ethanol-induced hepatic fatty in-
filtration was ameliorated.121 Betaine supple-
mentation also reduces the accumulation of
hepatic triglycerides produced after ethanol
ingestion.109
I) Homocysteine and Gout:
Although homocysteine levels have
been positively correlated with increased uric
acid levels,2, 110, 111 no studies exist to date which
have investigated homocysteine levels in gout
patients. It is possible increased uric acid levels
in gout are due to decreased SAM production
because of the reduction in homocysteine
recycling. The excess adenosine, which would
have reacted with methionine to form SAM,
is degraded to form uric acid as its end product.
Niacin is contraindicated in gout, as it
competes with uric acid for excretion.112 In
animal studies, increased levels of
S-adenosylhomocysteine (SAH), and thus
homocysteine, cause significant reductions in
SAM-dependent methylation reactions.12
Therefore, since degradation of the niacin-
containing coenzyme nicotinamide adenine

dinucleotide (NAD) is dependent on
methylation by SAM, and SAM activity is
severely reduced in hyperhomocysteinemia,
niacin levels might be higher in these people,
resulting in less uric acid excretion, higher uric
acid levels, and increased gout symptoms in
susceptible individuals.
Additionally, one study indicates nia-
cin supplementation increases homocysteine
levels. In the Arterial Disease Multiple Inter-
vention Trial,113 niacin supplementation of less
than one gram per day increased serum ho-
mocysteine levels by 55% over an 18-week
period. A similar outcome was noted in an
animal study, which took the investigation one
step further by adding vitamin B6 to the regi-
men. B6-supplemented animals showed a re-
versal of the niacin-induced hyperhomo-
cysteinemia compared to non-B6-supple-
mented animals.114 Extrapolating from this re-
search, it seems prudent to supplement vita-
min B6 if high-dose niacin is to be used for
hyperlipidemia treatment. And, since niacin
needs to be methylated for its degradation,
providing the methyl-donating nutrients be-
taine, B12, and folate also makes sense.
J) Homocysteine and Osteoporosis:
Homocystinuria due to cystathionine
synthase deficiency is an autosomal recessive
error of sulfur amino acid metabolism
characterized clinically by lens dislocation,
mental retardation, skeletal abnormalities, and
thromboembolic phenomena.115 Individuals
with this enzyme deficiency have increased
concentrations of homocysteine and decreased
concentrations of cysteine and its disulfide
form, cystine. In children with homocystinuria,
osteoporosis is a common presenting
symptom.116 Because of the role of sulfur
compounds in formation of sulfated amino
sugars, disturbed cross-linking of collagen has
been proposed as a possible mechanism of
action. Lubec et al examined 10 patients with
homocystinuria. They found synthesis of
collagen was normal; however, they reported
a significant reduction of cross-links in the
group with homocysteine.

@@Conclusion:
Elevated homocysteine levels have
been confirmed as an independent risk factor
for atherosclerotic cardiovascular disease, and
are implicated in a number of other vascular,
neuropsychiatric, renal, skeletal, perinatal, and
endocrine diseases. Supplementation with the
nutrient cofactors required for optimal func-
tioning of the methionine/homocysteine meta-
bolic pathways significantly impacts homocys-
teine levels, and offers a new integrated possi-
bility for primary prevention. Betaine, vitamin
B12, folic acid, and vitamin B6 assist in opti-
mizing methyl and sulfur group metabolism
and their use might play a significant role in
the prevention and treatment of a wide array
of clinical conditions. With the current empha-
sis on homocysteine research (over 1000 ar-
ticles on homocysteine published in the sci-
entific literature in the past five years) it is very
likely that these disease connections will be
further confirmed and others will be revealed in the months and years to come.