Homocyst(e)ine, Diet, and Cardiovascular Diseases
1999; Lippincott Williams & Wilkins; Volume: 99; Issue: 1 Linguagem: Inglês
10.1161/01.cir.99.1.178
ISSN1524-4539
AutoresM.R. Malinow, Andrew G. Bostom, Ronald M. Krauss,
Tópico(s)Fluoride Effects and Removal
ResumoHomeCirculationVol. 99, No. 1Homocyst(e)ine, Diet, and Cardiovascular Diseases Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessOtherPDF/EPUBHomocyst(e)ine, Diet, and Cardiovascular Diseases A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association M. René Malinow, Andrew G. Bostom and Ronald M. Krauss M. René MalinowM. René Malinow , Andrew G. BostomAndrew G. Bostom and Ronald M. KraussRonald M. Krauss Originally published12 Jan 1999https://doi.org/10.1161/01.CIR.99.1.178Circulation. 1999;99:178–182Homocysteine and DietHomocysteine is a sulfur-containing amino acid, rapidly oxidized in plasma to the disulfides homocystine and cysteine-homocysteine (Figure 1). Plasma/serum total homocysteine, also termed homocyst(e)ine, is the sum of homocysteine in all 3 components. Figure 2 displays factors involved in the metabolism of homocysteine, including its metabolic relationship to methionine. Although dietary intake of total protein and methionine does not correlate significantly with blood homocyst(e)ine,1 a single dose of oral methionine (100 mg/kg body weight) can elevate homocyst(e)ine levels, and as described further below, this has been used as a diagnostic test to detect disordered homocyst(e)ine metabolism. Because variable changes in homocyst(e)ine levels have been observed postprandially,2 it is customary to obtain measurements in the fasting state. Normal levels of fasting plasma homocyst(e)ine are considered to be between 5 and 15 μmol/L. Moderate, intermediate, and severe hyperhomocyst(e)inemia refer to concentrations between 16 and 30, between 31 and 100, and >100 μmol/L, respectively.3Several vitamins function as cofactors and substrates in the metabolism of methionine and homocysteine (Figure 2). Folic acid and cyanocobalamin (vitamin B12) regulate metabolic pathways catalyzed by the enzymes methylenetetrahydrofolate reductase (MTHFR) and methionine synthase, respectively, whereas pyridoxine (vitamin B6) is a cofactor for cystathionine β-synthase. A number of studies have shown inverse relationships of blood homocyst(e)ine concentrations with plasma/serum levels of folic acid, vitamin B6, and vitamin B12.456Administration of supplemental folic acid in doses between 0.2 and 15 mg/d can lower plasma homocyst(e)ine levels without apparent toxicity.789 On the basis of meta-analysis of 12 clinical studies, all but 1 of which was a placebo-controlled trial, it has been estimated that a 25% reduction in homocyst(e)ine concentration can be achieved with mean supplementation of 0.5 to 5.7 mg of folic acid per day; an additional 7% lowering has been observed after the addition of vitamin B12 (0.02 to 1 mg/d; mean, 0.5 mg).10 A recent report of the Food and Nutrition Board of the Institute of Medicine has recommended an upper limit of 1 mg/d folic acid on the basis of the possibility that higher doses may mask signs of vitamin B12 deficiency in some subjects.11 In overt cobalamin deficiency with intermediate and severe hyperhomocyst(e)inemia, vitamin B12 can normalize homocyst(e)ine concentration in ≈70% of cases.12 In an open-label, uncontrolled study, vitamin B6 at ≤250 mg/d was without effect in reducing basal homocyst(e)ine levels, but doses of 50 to 250 mg/d reduced homocyst(e)ine levels after a methionine-loading test by ≈25%.13 Subsequently, a study that used a randomized, placebo-controlled, 2×2 factorial design demonstrated that 50 mg of vitamin B6 per day independently reduced the post–methionine-loading increase in homocyst(e)ine levels by 22%.14 In a placebo-controlled study,15 a combination of multiple agents including folic acid (0.65 mg/d), vitamin B6 (10 mg/d), and vitamin B12 (0.4 mg/d) was very effective in reducing homocyst(e)ine levels in patients with moderate or intermediate hyperhomocyst(e)inemia. It has been reported, however, that increased vitamin intake from food sources (1 mg of folic acid, 12.2 mg of pyridoxine, and 50 μg of cyanocobalamin per day) failed to maintain normal homocyst(e)ine levels attained previously by vitamin supplementation.16Other vitamins may also influence plasma homocyst(e)ine levels. Daily food intake of 0.6 mg of riboflavin, a vitamin that can function as a cofactor for MTHFR,17 results in modest reductions in homocyst(e)ine (0.475 μmol/L),1 and pharmacological doses of nicotinic acid (3000 mg/d) may cause significant elevations.18 Users of multivitamin supplements in observational studies have lower homocyst(e)ine levels than nonusers, as well as higher concentrations of plasma folic acid and vitamins B6 and B12.19 The daily intake of fortified cereals containing 499 and 650 μg of folic acid per serving and the recommended dietary amount (RDA) of other vitamins reduced homocyst(e)ine by 11% and 14%, respectively.20A relatively common prevalence of the heat-labile variant of MTHFR has been shown to result from a cytosine to thymine (C to T) mutation at nucleotide 677.2122 Although an increased prevalence of thermolabile MTHFR and T/T homozygotes has been reported among patients with coronary artery disease (CAD),1921222324 this has not been confirmed in several other studies.25262728 T/T homozygotes have been reported to have higher geometric mean fasting homocyst(e)ine levels than C/T heterozygotes or C/C homozygotes when folate status was below the population median, but no differences in fasting homocyst(e)ine levels were detected between persons with different genotypes when plasma folate was at or above the population median.29 The MTHFR genotype has been reported to influence the homocyst(e)ine response to folic acid. Reduction was greater in subjects with T/T than with C/C or C/T genotypes.19 Moreover, in 21 of 37 subjects with homocyst(e)ine ≥40 μmol/L, in whom the frequency of the T/T genotype was 92%, homocyst(e)ine levels were normalized with supplemental intake of folic acid as low as 200 μg/d.8 It is likely but not proven that a folate-rich diet ingested by subjects with the T/T genotype may be more effective in lowering homocyst(e)ine levels than a similar diet ingested by subjects with C/C or C/T genotypes.Homocyst(e)ine and Coronary, Cerebral, and Peripheral Arterial DiseasesHomocystinuria is a rare autosomal recessive genetic disorder (≈1:200 000 births) that usually results from defective activity of cystathionine β-synthase. Patients have severe hyperhomocyst(e)inemia and a variety of abnormalities, including a high incidence of vascular pathology that may result in early death from myocardial infarction, stroke, or pulmonary embolism.30 Biochemical and pathological studies in homocystinuric children led McCully and Wilson31 to propose that elevated blood homocysteine may cause arteriosclerosis. Observations in ≈80 clinical and epidemiological studies have suggested that elevated homocyst(e)ine is a risk factor for atherosclerotic vascular disease and for arterial and venous thromboembolism.32 Moreover, moderate and intermediate hyperhomocyst(e)inemia is present in 12% to 47% of patients with coronary, cerebral, or peripheral arterial occlusive diseases3 ; these patients do not exhibit the systemic abnormalities characteristic of homocystinuria (see reviews in Reference 33 and References 3333 to 38).In a meta-analysis,36 the odds ratio (OR) for CAD in subjects with hyperhomocyst(e)inemia was 1.7 in 15 studies (95% confidence interval [CI], 1.5 to 1.9). For stroke, the OR was 2.5 in 9 studies (95% CI, 2.0 to 3.0), and for peripheral vascular disease, the OR was 6.8 in 5 studies (95% CI, 2.9 to 15.8). Since this meta-analysis,36 22 reports involving 7800 subjects, including 9 cross-sectional394041424344454647 and 13 case-controlled48495051525354555657585960 studies analyzed by Refsum et al,32 have provided further evidence for a relationship between homocyst(e)ine and coronary, cerebral, and peripheral atherosclerosis. In this period, only 2 cross-sectional6162 and 2 case-control studies5763 on 850 subjects failed to show an association between homocyst(e)ine and atherosclerosis; these studies included patients in the acute phase of myocardial infarction or stroke, in which homocyst(e)ine levels are decreased.6465 The strongest evidence for a relationship between homocyst(e)ine and cardiovascular disease risk was provided by 6 prospective studies396667686970 with follow-ups from 1.4 to 12.8 years on 830 cases and 1872 controls. However, 5 prospective studies2871727374 on 995 cases and 1850 controls with follow-ups from 3.3 to 11 years failed to demonstrate such an association. For this reason, and in the absence of a controlled clinical intervention trial, it is premature to conclude that homocyst(e)ine levels are predictive of the development of cardiovascular disease.Risk of CAD showed a dose-response effect across the entire distribution of basal36395759 and post–methionine-load59 levels of homocyst(e)ine, and this effect was statistically independent of most conventional factors for atherosclerosis,32395975 although a multiplicative interaction with smoking and blood pressure has been reported.59 Moreover, a recent study68 demonstrated that the risk of death in 587 men and women with CAD was highly correlated with basal levels of homocyst(e)ine; after a median follow-up of 4.6 years, the mortality estimate for subjects with homocyst(e)ine ≥15.0 μmol/L was 24.7% compared with 3.8% in subjects with homocyst(e)ine 15 and <10 μmol/L after adjustment for other cardiovascular risk factors and suggested that such risk difference is similar to that between total serum cholesterol levels of 7.1 and 4.9 mmol/L (275 and 189 mg/dL).Vitamin Intake, Homocyst(e)ine, and Cardiovascular DiseaseIn the case-control study of arterial diseases described above,559 folate deficiency was more common in cases, and plasma vitamin B6 below the lowest 20th percentile ( 14 μmol/L, in whom high doses of folic acid (2.5 and 5 mg/d) together with pyridoxine and vitamin B12 resulted in reduced rate of progression of carotid plaque determined by ultrasonography after a mean follow-up of 4.4±1.5 years.94 In the study of men and women younger than 60 years quoted above,59 risk began to rise from the middle of the distribution (10.3 μmol/L). In a study contrasting survivors of myocardial infarction and noncoronary subjects,57 the referent level (OR=1.0) was 9.8 μmol/L. Moreover, the referent value for risk of death associated with homocyst(e)ine was <9.0 μmol/L68 or <10.0 μmol/L.76 Thus, a basal homocyst(e)ine level <10 μmol/L is a reasonable therapeutic goal for subjects at increased risk, rather than the definition of "normal" based on population statistical values of the mean±2 SDs.Accordingly, subjects with basal homocyst(e)ine ≥10.0 μmol/L should be advised to consume the diet indicated above. Chait et al95 demonstrated that a folic acid–fortified diet reduced homocyst(e)ine in certain patients at high risk for cardiovascular disease, but other studies1696 failed to show effectiveness of nonfortified, self-selected prescribed diets. Consequently, patients should repeat the homocyst(e)ine analysis after 1 month on the prescribed diet. If reduction in plasma homocyst(e)ine is not achieved, daily supplementation with a multivitamin containing inter alia 400 μg of folic acid, 2 mg of vitamin B6, and 6 μg of vitamin B12 or intake of "100% fortified" breakfast cereal also containing those amounts of vitamins per serving may be suggested, with repeat analysis at the end of 1 month. If such treatment is ineffective in lowering basal homocyst(e)ine in high-risk patients, a combination of folic acid (1 mg), vitamin B6 (25 mg), and vitamin B12 (0.5 mg) can be prescribed daily, after vitamin B12 deficiency has been ruled out or adequately treated. If repeat analysis after 1 month shows ineffective homocyst(e)ine lowering, a trial of betaine (3 g BID) may be considered, although this remains investigational. Betaine, an intermediate metabolite from choline, is a methyl group donor for the enzymatic remethylation of homocysteine to methionine30 (see Figure 2). Betaine has been found to be effective in reducing basal hyperhomocyst(e)inemia in subjects resistant to B vitamin therapy.97Methionine-Load TestHomocyst(e)ine levels after a methionine-load test may be measured in high-risk patients with normal basal levels of homocyst(e)ine to identify those individuals with postload hyperhomocyst(e)inemia. The test measures homocyst(e)ine before and after the intake of 100 mg of methionine (dissolved in orange juice) per kilogram of body weight. Although multiple sampling strategies have been described, the 2-hour test has been validated extensively,98 and it seems more practical than later blood sampling. This test may uncover 39% of subjects with homocyst(e)ine-related cardiovascular disease risk but with normal basal homocyst(e)ine levels.99 The Table shows the 80th percentile of delta and absolute homocyst(e)ine levels in 2-hour post–methionine-load tests observed in 363 subjects free of clinically apparent vascular disease. The data, stratified by age and sex, confirmed that women have higher deltas and absolute post–methionine-load homocyst(e)ine levels than men; these values increase with age in women but not in men. Values equal to or above those indicated in the Table could be associated with enhanced risk for vascular disease.59As noted above, it has been reported that post–methionine-load delta homocyst(e)ine levels were reduced by an average of 22% with vitamin B6 (50 mg/d)14 but not by folic acid supplementation up to 5 mg/d. Thus, it may not be possible to "normalize" the methionine-load response in all patients, and coupled with the lack of evidence for the benefit of a reduced response, the clinical value of this test remains uncertain. Moreover, when costs of the test and the need for adequate clinical facilities are considered, the methionine-load test may be reserved for research purposes.ConclusionsAlthough there is considerable epidemiological evidence for a relationship between plasma homocyst(e)ine and cardiovascular disease, not all prospective studies have supported such a relationship. Moreover, despite the potential for reducing homocyst(e)ine levels with increased intake of folic acid, it is not known whether reduction of plasma homocyst(e)ine by diet and/or vitamin therapy will reduce cardiovascular disease risk.100101 Until results of controlled clinical trials become available, population-wide screening is not recommended, and emphasis should be placed on meeting current RDAs for folate, as well as vitamins B6 and B12, by intake of vegetables, fruits, legumes, meats, fish, and fortified grains and cereals. A high-risk strategy may include screening for fasting plasma homocyst(e)ine associated with augmented risk status, ie, ≥10.0 μmol/L, in selected patients with personal or family history of premature cardiovascular disease, as well as in those with malnutrition, malabsorption syndromes, hypothyroidism, renal failure, or systemic lupus erythematosus; those taking certain medications, eg, nicotinic acid, theophylline, bile acid–binding resins, methotrexate, and L-dopa; or those with recent nitrous oxide exposure. In these patients, it may be advisable to increase their intake of vitamin-fortified foods and/or to suggest the daily use of supplemental vitamins, ie, 0.4 mg of folic acid, 2 mg of vitamin B6, and 6 μg of vitamin B12, with appropriate medical evaluation and monitoring. Treatment may include higher doses of those vitamins according to the response of homocyst(e)ine, as discussed in the text. However, such treatment is still considered experimental, pending results from intervention trials showing that homocyst(e)ine lowering favorably affects the evolution of arterial occlusive diseases.References for this article may be found in the on-line version that appears on the American Heart Association Web site (http://www.americanheart.org/Scientific/statements/1999/019901.html) and on the Circulation Web site listed below.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in September 1998. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0157.Download figureDownload PowerPoint Figure 1. Molecular species of homocysteine.Download figureDownload PowerPoint Figure 2. Simplified outline of methionine/homocysteine metabolism. Vitamin coenzymes and substrates: THF, tetrahydrofolate; B2, riboflavin; B6, vitamin B6 as its biological active form, ie, pyridoxal 5′-phosphate; and B12, methyl cobalamin. Intermediate metabolite: DMG, dimethylglycine. Table 1. Post–Methionine-Load Test in 363 Subjects Without Clinically Apparent Vascular DiseaseAge, yDelta Homocyst(e)ine, μmol/L1Absolute PML, μmol/L2WomenMenWomenMen<5020.3 (91)15.1 (95)28.0 (91)25.7 (95)≥5023.9 (110)15.0 (67)34.7 (110)25.5 (67)PML indicates post–methionine-load test.Values shown are 80th percentile distribution of 2-hour values. Number of subjects is shown in parentheses.1Postload minus preload values.2Absolute post–methionine-load values.Adapted from Bostom AG, Selhub J, Jacques PF; unpublished data; 1998.This work was supported in part by grants from the National Institutes of Health (RR00163 to Dr Malinow, HL-56908-01A1 to Dr Bostom, and HL-18574 to Dr Krauss).FootnotesCorrespondence to M. 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