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Folate, vitamin B12, homocysteine status and
chromosome damage rate in lymphocytes of older men.
Fenech MF Dreosti IE Rinaldi JR
Fenech MF, CSIRO, Div Human Nutr, POB 10041, Gouger St,
Adelaide, SA 5000, Australia
Carcinogenesis 1997 JUL;18(7):1329-1336
Deficient levels of folic acid and vitamin B12 are
associated with elevated chromosome damage rate and high
concentrations of homocysteine in the blood. We have therefore
performed a study to determine the prevalence of folate
deficiency, vitamin B12 deficiency and hyperhomocysteinemia in
64 healthy men aged between 50 and 70 years, and evaluate the
relationship of these micronutrient levels in the blood with
the micronucleus frequency in peripheral blood lymphocytes. We
also performed a placebo-controlled, double-blind intervention
study to determine whether supplementation of the diet with a
daily dose of 0.7 mg (as a supplement in cereal) or 2.0 mg (in
a tablet) over a period of 4 months resulted in a significant
alteration of folate status, homocysteine status and the
micronucleus index. Twenty-three per cent of the men were
serum folate deficient (6.8 nmol/l), 16% were red blood cell
folate deficient (317 nmol/l), 4.7% were vitamin B12 deficient
(150 pmol/l) and 37% has plasma homocysteine levels 10 mu
mol/l. In total, 56% of the men had one or more abnormal blood
values for folate, vitamin B12 or homocysteine. The
micronucleus index of these men (n = 34) in
cytokinesis-blocked binucleated cells (19.2 +/- 1.1) was
significantly elevated (P = 0.02) when compared to the
micronucleus index of the rest of the men who had normal
levels of folate, vitamin B12 and homocysteine (16.3 +/- 1.3,
n = 30). Interestingly, the micronucleus index in men with
normal folate and vitamin B12, but homocysteine levels >10
mu mol/l (19.4 +/- 1.7, n = 15) was also significantly higher
(P = 0.05) when compared to those with normal folate, vitamin
B12 and homocysteine. This novel result was also supported by
the observation that the micronucleus index and plasma
homocysteine were significantly (P = 0.0086) and positively
correlated (r(2) = 0.172) in those subjects who were not
deficient in folate or vitamin B12. The micronucleus index was
not significantly correlated with folate indices, but there
was a significant (P = 0.013) negative correlation with serum
vitamin B12 (r(2) = 0.099). Daily supplementation of the diet
with 0.7 mg free folic acid in cereal for 2 months followed by
2.0 mg free folic acid via a tablet produced a 4-fold increase
in plasma folate, a 2.6-fold increase in red blood cell folate
and a 11% reduction in plasma homocysteine; however, these
changes were not accompanied by a reduction in the
micronucleus index. In conclusion, it is apparent that
elevated homocysteine status, in the absence of vitamin
deficiency and low but not deficient, vitamin B12 status are
important risk factors for increased chromosome damage in
lymphocytes.
Relations of vitamin B-12, vitamin B-6, folate, and
homocysteine to cognitive performance in the Normative Aging
Study
Riggs K.M.; Spiro III A.; Tucker K.; Rush D.
Jean Mayer USDA, Human Nutrition Res. Center on Aging, Tufts
University, 711 Washington Street, Boston, MA 02111 USA
American Journal of Clinical Nutrition (USA) , 1996, 63/3
(306-314)
We investigated the relations between plasma concentrations
of homocysteine and vitamins B-12 and B-6 and folate, and
scores from a battery of cognitive tests for 70 male subjects,
aged 54-81 y, in the Normative Aging Study. Lower
concentrations of vitamin B-12 (P = 0.04) and folate (P =
0.003) and higher concentrations of homocysteine (P = 0.0009)
were associated with poorer spatial copying skills. Plasma
homocysteine was a stronger predictor of spatial copying
performance than either vitamin B-12 or folate. The
association of homocysteine with spatial copying performance
was not explained by clinical diagnoses of vascular disease.
Higher concentrations of vitamin B-6 were related to better
performance on two measures of memory (P = 0.03 and P = 0.05).
The results suggest that vitamins (and homocysteine) may have
differential effects on cognitive abilities. Individual
vitamins and homocysteine should be explored further as
determinants of patterns of cognitive impairment.
Folate, vitamin B-12, and neuropsychiatric
disorders.
Bottiglieri T
Bottiglieri T, Baylor Univ, Med Ctr, Kimberly H Courtwright
& Joseph W Summers Inst Me, Dallas,TX 75246 USA
Nutr Rev 1996 Dec;54(12):382-390
Folate and vitamin B-12 are required both in the
methylation of homocysteine to methionine and in the synthesis
of S-adenosylmethionine. S-adenosylmethionine is involved in
numerous methylation reactions involving proteins,
phospholipids, DNA, and neurotransmitter metabolism. Both
folate and vitamin B-12 deficiency may cause similar
neurologic and psychiatric disturbances including depression,
dementia, and a demyelinating myelopathy. A current theory
proposes that a defect in methylation processes is central to
the biochemical basis of the neuropsychiatry of these vitamin
deficiencies. Folate deficiency may specifically affect
central monoamine metabolism and aggravate depressive
disorders. In addition, the neurotoxic effects of homocysteine
may also play a role in the neurologic and psychiatric
disturbances that are associated with folate and vitamin B- 12
deficiency.
Lipid peroxidation induced in vivo by
hyperhomocysteinaemia in pigs.
Young PB Kennedy S Molloy AM Scott JM Weir DG Kennedy
DG
Young PB, Dept Agr No Ireland, Dept Biochem, Vet Sci Div,
Stoney Rd, Belfast BT4 3SD, Antrim, North Ireland
Atherosclerosis 1997 Feb 28;129(1):67-71
Much attention has been focused recently on the
relationship between homocysteinaemia and the development of
premature atherosclerosis. Hyperhomocysteinaemia constitutes
as strong a risk factor for the development of the disease as
either hypercholesterolaemia or smoking. Although the
mechanism involved is unclear homocysteine exhibits
prooxidative activity in vitro. This finding suggests that it
may be involved in the oxidative modification of low density
lipoprotein (LDL). In the current study hyperhomocysteinaemia
was induced in eight domestic pigs by intermittent exposure to
nitrous oxide for 4 weeks. At necropsy, cardiac tissue was
removed and malondialdehyde (MDA) and the unsaturated fatty
acid content were measured and compared with values obtained
from air-breathing control animals. Nitrous oxide treated
animals had significantly higher tissue concentrations of MDA
than the controls. There was also a reduction in the
contribution of linoleic and linolenic acids to the total
fatty acid content of heart. The hyperhomocysteinaemic animals
also had a significantly higher iron concentration in the
heart than controls. Hyperhomocysteinaemia was associated with
elevations in tissue iron stores and increased in vivo lipid
peroxidation.
Reduction of plasma homocyst(e)ine levels by
breakfast cereal fortified with folic acid in patients with
coronary heart disease.
Malinow MR, Duell PB, Hess DL, Anderson PH, Kruger WD,
Phillipson BE, Gluckman RA, Block PC, Upson BM
Division of Pathobiology and Immunology, Oregon Regional
Primate Research Center, Beaverton 97006-3448, USA.
N Engl J Med 1998 Apr 9;338(15):1009-15
BACKGROUND: The Food and Drug Administration (FDA) has
recommended that cereal-grain products be fortified with folic
acid to prevent congenital neural-tube defects. Since folic
acid supplementation reduces levels of plasma homocyst(e)ine,
or plasma total homocysteine, which are frequently elevated in
arterial occlusive disease, we hypothesized that folic acid
fortification might reduce plasma homocyst(e)ine levels.
METHODS: To test this hypothesis, we assessed the effects
of breakfast cereals fortified with three levels of folic
acid, and also containing the recommended dietary allowances
of vitamins B6 and B12, in a randomized, double-blind,
placebo-controlled, crossover trial in 75 men and women with
coronary artery disease.
RESULTS: Plasma folic acid increased and plasma
homocyst(e)ine decreased proportionately with the folic acid
content of the breakfast cereal. Cereal providing 127 microg
of folic acid daily, approximating the increased daily intake
that may result from the FDA's enrichment policy, increased
plasma folic acid by 31 percent (P=0.045) but decreased plasma
homocyst(e)ine by only 3.7 percent (P= 0.24). However, cereals
providing 499 and 665 microg of folic acid daily increased
plasma folic acid by 64.8 percent (P<0.001) and 105.7
percent (P=0.001), respectively, and decreased plasma
homocyst(e)ine by 11.0 percent (P<0.001) and 14.0 percent
(P=0.001), respectively.
CONCLUSIONS: Cereal fortified with folic acid has the
potential to increase plasma folic acid levels and reduce
plasma homocyst(e)ine levels. Further clinical trials are
required to determine whether folic acid fortification may
prevent vascular disease. Until then, our results suggest that
folic acid fortification at levels higher than that
recommended by the FDA may be warranted.
Vitamin B-12, vitamin B-6, and folate nutritional
status in men with hyperhomocysteinemia.
Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ
Department of Chemical Pathology, Faculty of Medicine,
University of Pretoria, South Africa.
Am J Clin Nutr 1993 Jan;57(1):47-53
We measured the vitamin B-6, vitamin B-12, and folic acid
nutritional status in a group of apparently healthy men (n =
44) with moderate hyperhomocysteinemia (plasma homocysteine
concentration > 16.3 mumol/L). Compared with control
subjects (n = 274) with normal plasma homocysteine (< or =
16.3 mumol/L) concentrations, significantly lower plasma
concentrations of pyridoxal-5'-phosphate (P < 0.001),
cobalamin (P < 0.001), and folic acid (P = 0.004) were
demonstrated in hyperhomocysteinemic men. The prevalence of
suboptimal vitamin B-6, B-12, and folate status in men with
hyperhomocysteinemia was 25.0%, 56.8%, and 59.1%,
respectively. In a placebo-controlled follow-up study, a daily
vitamin supplement (10 mg pyridoxal, 1.0 mg folic acid, 0.4 mg
cyanocobalamin) normalized elevated plasma homocysteine
concentrations within 6 wk. Because hyperhomocysteinemia is
implicated as a risk factor for premature occlusive vascular
disease, appropriate vitamin therapy may be both efficient and
cost-effective to control elevated plasma homocysteine
concentrations.
Hyperhomocysteinemia and low pyridoxal phosphate.
Common and independent reversible risk factors for coronary
artery disease.
Robinson K, Mayer EL, Miller DP, Green R, van Lente F, Gupta
A, Kottke-Marchant K, Savon SR, Selhub J, Nissen SE, et
al
Department of Cardiology, Cleveland Clinic Foundation, OH
44195, USA.
Circulation 1995 Nov 15;92(10):2825-30
BACKGROUND: High plasma homocysteine is associated with
premature coronary artery disease in men, but the threshold
concentration defining this risk and its importance in women
and the elderly are unknown. Furthermore, although low B
vitamin status increases homocysteine, the link between these
vitamins and coronary disease is unclear.
METHODS AND RESULTS: We compared 304 patients with coronary
disease with 231 control subjects. Risk factors and
concentrations of plasma homocysteine, folate, vitamin B12,
and pyridoxal 5'-phosphate were documented. A homocysteine
concentration of 14 mumol/L conferred an odds ratio of
coronary disease of 4.8 (P < .001), and 5-mumol/L
increments across the range of homocysteine conferred an odds
ratio of 2.4 (P < .001). Odds ratios of 3.5 in women and of
2.9 in those 65 years or older were seen (P < .05).
Homocysteine correlated negatively with all vitamins. Low
pyridoxal 5'-phosphate (< 20 nmol/L) was seen in 10% of
patients but in only 2% of control subjects (P < .01),
yielding an odds ratio of coronary disease adjusted for all
risk factors, including high homocysteine, of 4.3 (P <
.05).
CONCLUSIONS: Within the range currently considered to be
normal, the risk for coronary disease rises with increasing
plasma homocysteine regardless of age and sex, with no
threshold effect. In addition to a link with homocysteine, low
pyridoxal-5'-phosphate confers an independent risk for
coronary artery disease.
Homocysteine metabolism and risk of myocardial
infarction: relation with vitamins B6, B12, and folate.
Verhoef P, Stampfer MJ, Buring JE, Gaziano JM, Allen RH,
Stabler SP, Reynolds RD, Kok FJ, Hennekens CH, Willett
WC
Department of Epidemiology and Public Health, Agricultural
University, Wageningen, Netherlands.
Am J Epidemiol 1996 May 1;143(9):845-59
Elevated plasma homocyst(e)ine levels are an independent
risk factor for vascular disease. In a case-control study, the
authors studied the associations of fasting plasma
homocyst(e)ine and vitamins, which are important cofactors in
homocysteine metabolism, with the risk of myocardial
infarction. The cases were 130 Boston area patients
hospitalized with a first myocardial infarction and 118
population controls, less than 76 years of age, enrolled in
1982 and 1983. Dietary intakes of vitamins B6, B12, and folate
were estimated from a food frequency questionnaire. After
adjusting for sex and age, the authors found that the
geometric mean plasma homocyst(e)ine level was 11% higher in
cases compared with controls (p = 0.006). There was no clear
excess of cases with extremely elevated levels. The age- and
sex-adjusted odds ratio for each 3-mumol/liter (approximately
1 standard deviation) increase in plasma homocyst(e)ine was
1.35 (95% confidence interval 1.05-1.75; p trend = 0/007).
After further control for several risk factors, the odds ratio
was not affected, but the confidence interval was wider and
the p value for trend was less significant. Dietary and plasma
levels of vitamin B6 and folate were lower in cases than in
controls, and these vitamins were inversely associated with
the risk of myocardial infarction, independently of other
potential risk factors. Vitamin B12 showed no clear
association with myocardial infarction, although methylmalonic
acid levels were significantly higher in cases. Comparing the
mean levels of several homocysteine metabolites among cases
and controls, the authors found that impairment of
remethylation of homocyst(e)ine (dependent of folate and
vitamin B12 rather than on vitamin B6-dependent
transsulfuration) was the predominant cause of high
homocyst(e)ine levels in cases. Accordingly, plasma folate
and, to a lesser extent, plasma vitamin B12, but not vitamin
B6, correlated inversely with plasma homocyst(e)ine, even for
concentrations at the high end of normal values. These data
provide further evidence that plasma homocyst(e)ine is an
independent risk factor for myocardial infarction. In this
population, folate was the most important determinant of
plasma homocyst(e)ine, even in subjects with apparently
adequate nutritional status of this vitamin.
Total serum homocysteine in senile dementia of
Alzheimer type.
McCaddon A, Davies G, Hudson P, Tandy S, Cattell H
Wrexham Maelor Hospital, North Wales, UK
andrew@mccaddon.demon.co.uk
Int J Geriatr Psychiatry 1998 Apr;13(4):235-9
OBJECTIVE: The main hypothesis was that subtle vitamin B12
deficiencies occur more commonly in senile dementia of
Alzheimer type (SDAT) that in healthy elderly individuals, and
may be revealed by elevated total serum homocysteine (tHcy). A
subsidiary hypothesis was that such deficiencies would be
nutritionally independent as determined by retinol binding
protein (RBP).
DESIGN: A prospective case-controlled survey.
SETTING: A Welsh urban psychogeriatric assessment centre
and local general practice.
PATIENTS: Thirty patients, aged 65 or over, seen
consecutively in 1994 with features compatible with DSM-III-R
criteria for primary degenerative dementia of Alzheimer type
and 30 cognitively intact age-matched control subjects.
MEASURES: Diagnosis was assessed using the CAMDEX.
Cognitive scores were evaluated with the CAMCOG scale for
patients and MMSE scores for control subjects. THcy was
measured using high performance liquid chromatography (HPLC),
and RBP assayed by a radial immunodiffusion method.
RESULTS: Patients had a highly significant elevation of
tHcy compared with control (p < 0.0001). Multiple
regression highlighted the interrelated effects of tHcy and
total serum cobalamin on cognitive scores. RBP did not differ
between groups. Macrocytosis was absent, and neutrophil
hypersegmentation uncommon, in hyperhomocysteinaemic
patients.
CONCLUSIONS: SDAT patients have significantly elevated
tHcy. This is independent of RBP determined nutritional
status. 'Classical' haematological changes of cobalamin or
folate deficiency are poor predictors of tHcy in these
patients. Aberrant cobalamin tissue delivery appears to
contribute to SDAT cognitive decline. Relative contributions
of other tHcy determinants require further investigation.
Abnormal amino acid metabolism in patients with
early stage Alzheimer dementia.
Fekkes D, van der Cammen TJ, van Loon CP, Verschoor C, van
Harskamp F, de Koning I, Schudel WJ, Pepplinkhuizen L
Department of Psychiatry, Erasmus University Rotterdam, The
Netherlands.
J Neural Transm 1998;105(2-3):287-94
Plasma levels of several amino acids were studied in 14
patients with early stage probable Alzheimer's disease (AD)
and 17 age-matched controls. In the AD patients a possible
relationship between amino acid levels and behavioural
symptomatology was also investigated. We found significantly
reduced levels of tryptophan and methionine in plasma samples
from the AD patients compared to the control subjects.
Moreover, plasma tyrosine/large neutral amino acids (LNAA)
ratio and the ratio of plasma taurine and the product of the
plasma levels of methionine and serine (TSM-ratio) were
significantly increased in the AD patients in comparison with
the controls. However, no difference was found in plasma
tryptophan/LNAA ratio and in homocysteine levels between both
groups. Concerning the behavioural symptomatology no
significant correlation was found between the Reisberg Behave
AD scale and plasma amino acid levels or ratios. The reported
findings suggest that abnormal amino acid metabolism is
present in the early stages of AD. We hypothesize that this
abnormality could play a role in the pathogenesis of
behavioural changes occurring in later stages of AD.
Is metabolic evidence for vitamin B-12 and folate
deficiency more frequent in elderly patients with Alzheimer's
disease?
Joosten E, Lesaffre E, Riezler R, Ghekiere V, Dereymaeker L,
Pelemans W, Dejaeger E
Department of Pathophysiology, University Hospitals K. U.
Leuven, Belgium.
J Gerontol A Biol Sci Med Sci 1997
Mar;52(2):M76-9
BACKGROUND: It is still unclear whether there is an
association between Alzheimer's disease and vitamin B-12 or
folate deficiency. This study was designed to investigate
whether patients with Alzheimer's disease are particularly
prone to metabolically significant cobalamin or folate
deficiency as compared to nondemented hospitalized controls
and healthy elderly controls living at home.
METHODS: Evaluation for the diagnosis of Alzheimer's
disease, routine laboratory tests, serum folate and vitamin
B-12, serum methylmalonic acid (MMA), total homocysteine
(tHcy), and radiological tests was performed in 52 patients
with Alzheimer's disease (AD), 50 nondemented hospitalized
controls, and 49 healthy elderly subjects living at home.
RESULTS: Serum vitamin B-12 and folate levels are
comparable between patients with AD, hospitalized control
patients, and subjects living at home. Patients with AD have
the highest serum MMA and tHcy levels. The MMA levels of
patients with AD and hospitalized controls are not different,
but the mean tHcy level is significantly higher in patients
with AD as compared to nondemented patients or subjects living
at home.
CONCLUSION: The interpretation of the vitamin B-12 and
folate status in patients with AD depends largely on the
methodology (i.e., serum vitamin vs metabolite levels) and the
selection of the control group. Although patients with AD have
the highest tHcy and MMA levels, metabolically significant
vitamin B-12 and folate deficiency is also a substantial
problem in nondemented elderly patients.
Decreased methionine adenosyltransferase activity
in erythrocytes of patients with dementia disorders.
Gomes Trolin C, Regland B, Oreland L
Department of Medical Pharmacology, University of Uppsala,
Sweden.
Eur Neuropsychopharmacol 1995 Jun;5(2):107-14
ATP:1-methionine S-adenosyltransferase (EC 2.5.1.6, MAT)
activity was analyzed in erythrocytes from nine patients with
a clinical diagnosis of probable Alzheimer's disease (Pro.AD),
four with possible Alzheimer's disease (Pos.AD), three with
mild cognitive dysfunction (MCD) and two with dementia of
vascular origin (VD), and 10 age-matched control subjects.
Significantly lower kinetic parameters (Vmax and Km towards
methionine) for MAT were observed in all the dementia cases.
In the subgroup of Pro.AD patients who also had low plasma
levels of vitamin B12 (B12), the reduction in MAT Km was
significantly correlated with an increase in the serum levels
of homocysteine, while no such correlation was observed in all
the other dementia groups. Treatment for 6 months of this
subgroup of Pro.AD patients with B12 (1 mg x 7 days + 1
mg/week, i.m.), S-adenosylmethionine (SAM, 200 mg twice daily,
p.o.) and folate (2.5 mg every 2 days, p.o.) caused a
significant decrease in homocysteine in parallel with a
significant increase in Km for MAT. These findings support the
hypothesis that aberrations in the B12 dependent
transmethylation reactions might be involved in the
pathogenesis of dementia, and suggest that the evaluation of
erythrocyte MAT activity may be a useful marker for the
detection of such an aberration.
Homocysteine and arterial occlusive disease: a
concise review.
Andreotti F, Burzotta F, Mazza A, Manzoli A, Robinson K,
Maseri A
Istituto di Cardiologia, Universita Cattolica del Sacro
Cuore, Roma
felicita.andreotti@iol.it
Cardiologia 1999 Apr;44(4):341-5
Many cross-sectional and prospective studies have shown
that raised serum/plasma levels of total homocysteine increase
the risk of coronary, cerebral, and peripheral artery disease.
The risk associated with hyperhomocysteinemia appears to be
concentration-dependent and not attributable to traditional
risk factors. The odds ratio for ischemic heart disease has
been estimated to be 1.4 for every 5 mumol/l increase of total
plasma homocysteine. Median fasting total plasma homocysteine
in adult males is approximately 10 mumol/l. Mild
hyperhomocysteinemia is estimated to occur in 5-10% of the
general population. Plasma concentrations are increased as a
result of age, male gender, impaired renal function, low
vitamin B intake, and genetically-determined defects of the
enzymes involved in homocysteine metabolism. Folate
supplements can reduce total homocysteine levels by
approximately 25%. Studies in vitro and in vivo indicate that
homocysteine can impair endothelial function. Despite
increasing recognition of hyperhomocysteinemia as a risk
factor for arterial occlusive disease, irrefutable proof that
mild hyperhomocysteinemia contributes directly to the
pathogenesis of atherothrombosis will come if interventions to
lower total homocysteine reduce cardiovascular events. Family
studies may also provide evidence of causality if genetic
causes of hyperhomocysteinemia are found to segregate with
disease.
Homocysteine and short-term risk of myocardial
infarction and stroke in the elderly: the Rotterdam
Study.
Bots ML, Launer LJ, Lindemans J, Hoes AW, Hofman A, Witteman
JC, Koudstaal PJ, Grobbee DE
Department of Epidemiology and Biostatistics, Erasmus
University Medical School, Rotterdam, The Netherlands.
Arch Intern Med 1999 Jan 11;159(1):38-44
BACKGROUND: Elevated homocysteine level increases vascular
disease risk. Most data are based on subjects younger than 60
years; data for the elderly are more limited. We examined the
relationship of homocysteine level to incident myocardial
infarction and stroke among older subjects in a nested
case-control study.
METHODS: Subjects were participants in the Rotterdam Study,
a cohort study among 7983 subjects residing in the Ommoord
district of Rotterdam, the Netherlands. Baseline examinations
were performed from March 1, 1990, to July 31, 1993. The
analysis is restricted to myocardial infarction and stroke
that occurred before December 31, 1994. One hundred four
patients with a myocardial infarction and 120 with a stroke
were identified with complete data. Control subjects consisted
of a sample of 533 subjects drawn from the study base, free of
myocardial infarction and stroke. Nonfasting total
homocysteine levels were measured.
RESULTS: Results were adjusted for age and sex. The risk of
stroke and myocardial infarction increased directly with total
homocysteine. The linear coefficient suggested a risk increase
by 6% to 7% for every 1-micromol/L increase in total
homocysteine. The risk by quintiles of total homocysteine
level was significantly increased only in the group with
levels above 18.6 micromol/L (upper quintile): odds ratios
were 2.43 (95% confidence interval, 1.11-5.35) for myocardial
infarction and 2.53 (95% confidence interval, 1.19-5.35) for
stroke. Associations were more pronounced among those with
hypertension.
CONCLUSIONS: The present study, based on a relatively short
follow-up period, provides evidence that among elderly
subjects an elevated homocysteine level is associated with an
increased risk of cardiovascular disease.
Vitamin intake: a possible determinant of plasma
homocyst(e)ine among middle-aged adults.
Shimakawa T, Nieto FJ, Malinow MR, Chambless LE, Schreiner
PJ, Szklo M
Division of Epidemiology and Clinical Applications, National
Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Ann Epidemiol 1997 May;7(4):285-93
PURPOSE: Many epidemiologic studies have identified
elevated plasma homocyst(e)ine as a risk factor for
atherosclerosis and thromboembolic disease. To examined the
relationship between vitamin intakes and plasma
homocyst(e)ine, we analyzed dietary intake data from a
case-control study of 322 middle-aged individuals with
atherosclerosis in the carotid artery and 318 control subjects
without evidence of this disease.
METHODS: All of these individuals were selected from a
probability sample of 15,800 men and women who participated in
the Atherosclerosis Risk in Communities (ARIC) Study.
RESULTS: Plasma homocyst(e)ine was inversely associated
with intakes of folate, vitamin B6, and vitamin B12 (controls
only for this vitamin)--the three key vitamins in
homocyst(e)ine metabolism. Among nonusers of vitamin
supplement products, on average each tertile increase in
intake of these vitamins was associated with 0.4 to 0.7
mumol/L decrease in plasma homocyst(e)ine. An inverse
association of plasma homocyst(e)ine was also found with
thiamin, riboflavin, calcium, phosphorus, and iron. Methionine
and protein intake did not show any significant association
with plasma homocyst(e)ine.
CONCLUSIONS: In almost all analyses, cases and controls
showed similar associations between dietary variables and
plasma homocyst(e)ine. Plasma homocyst(e)ine among users of
vitamin supplement products was 1.5 mumol/L lower than that
among nonusers. Further studies to examine possible causal
relationships among vitamin intake, plasma homocyst(e)ine, and
cardiovascular disease are needed.
Folic acid fortification of the food supply.
Potential benefits and risks for the elderly population.
Tucker KL, Mahnken B, Wilson PW, Jacques P, Selhub J
Jean Mayer US Department of Agriculture Human Nutrition
Research Center on Aging at Tufts University, Boston, Mass
02111, USA.
JAMA 1996 Dec 18;276(23):1879-85
Published erratum appears in JAMA 1997 Mar
5;277(9):714
OBJECTIVE: To estimate the potential benefits and risks of
food folic acid fortification for an elderly population.
Benefits are expected through the improvement of folate and
homocysteine status, but there is also a risk of masking or
precipitating clinical manifestations related to vitamin B12
deficiency with increasing exposure to folic acid.
DESIGN: Cross-sectional analysis, with projected change at
various levels of folic acid fortification.
SETTING: Participants in the Framingham Heart Study
original cohort.
PARTICIPANTS: A total of 747 subjects aged 67 to 96 years
who both completed usable food frequency questionnaires and
had blood concentrations of B vitamins and homocysteine
measured.
MAIN OUTCOME MEASURES: Projected blood folate and
homocysteine concentrations and combined high folate intake
and low plasma vitamin B12 concentration.
RESULTS: Percentages of this elderly population with folate
intake below 400 microg/d are projected to drop from 66% at
baseline to 49% with 140 microg of folate per 100 g of
cereal-grain product, to 32% with 280 microg, to 26% with 350
microg, and to 11% with 700 microg. Percentages with elevated
homocysteine concentrations (>14 micromol/L) are projected
to drop from 26% at baseline to 21% with 140 microg of folate
per 100 g, to 17% with 280 microg, to 16% with 350 microg, and
to 12% with 700 microg. Without fortification, the prevalence
of combined high folate intake (>1000 microg/d) and low
plasma vitamin B12 concentration (<185 pmol/L [<250
pg/mL]) was 0.1%. This is projected to increase to 0.4% with
folate fortification levels of 140 to 350 microg/100 g and to
3.4% with 700 microg.
CONCLUSION: The evidence suggests that, at the level of 140
microg/100 g of cereal-grain product mandated by the Food and
Drug Administration, the benefits of folate fortification,
through projected decreases in homocysteine level and heart
disease risk, greatly outweigh the expected risks. However,
quantification of the actual risks associated with vitamin B12
deficiency remains elusive. Before higher levels of folic acid
fortification are implemented, further research is needed to
better understand the clinical course of various forms of
vitamin B12 deficiency, to measure the potential effect of
high folate intake on this course, and to identify
cost-effective approaches to the identification and treatment
of all forms of vitamin B12 deficiency.
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