Cobalamin, folic acid, and homocysteine
Varela-Moreiras G, Murphy MM, Scott JM. Departamento de Nutrición, Bromatología y Tecnología de los Alimentos, Universidad San Pablo CEU, Facultad de Farmacia, Madrid, Spain. Nutr Rev. 2009 May
Cobalamin deficiency can lead to several adverse health consequences: folate trapping in the methylation cycle and subsequent impaired DNA biosynthesis; pernicious anemia hematologically, similar to that caused by folate deficiency; elevated blood homocysteine (tHcy) (risk factor for cardiovascular disease and adverse pregnancy outcomes); and neural tube defects (NTDs). Population-wide folate status is expected to improve where folic acid fortification policies for reducing NTD occurrence are established. However, there is concern that cobalamin deficiency and its characteristic neuropathy could be masked when hematological abnormalities in risk groups such as the elderly and vegetarians are reversed through folic acid supplementation. Folate-cobalamin interactions and their impact on health are reviewed here.
Plasma folate and total homocysteine levels are associated with the risk of myocardial infarction, independently of each other and of renal function.
Van Guelpen B, Hultdin J, Johansson I, Witthöft C, Weinehall L, Eliasson M, Hallmans G, Palmqvist R, Jansson JH, Winkvist A.
Department of Medical Biosciences, Umeå University, Umeå, Sweeden. J Intern Med. 2009 Aug
OBJECTIVES: To investigate the relationship between plasma folate, vitamin B12 and total homocysteine concentrations, dietary intake of folate and vitamins B12, B6 and B2, and the risk of first acute myocardial infarction (MI). DESIGN: Nested case-referent study with up to 13 years of follow-up. SETTING: The population-based Northern Sweden Health and Disease Study, with 73 879 participants at the time of case ascertainment. SUBJECTS: A total of 571 MI cases (406 men) and 1569 matched referents. Of the cases, 530 had plasma samples available, and 247 had dietary B-vitamin intake data. RESULTS: Plasma concentrations of folate were inversely associated, and total homocysteine positively associated, with the risk of MI, independently of each other and of a number of established and novel cardiovascular risk factors, including renal function [multivariate odds ratio for highest vs. lowest quintile of folate 0.52 (95% CI 0.31-0.84), P for trend = 0.036, and homocysteine 1.92 (95% CI 1.20-3.09), P for trend = 0.006]. For plasma vitamin B12 concentrations, and vitamin B12, B6 and B2 intake, no clear risk relationship was apparent. Though not statistically significant, the results for folate intake were consistent with those for plasma concentrations. CONCLUSIONS: In this large prospective study of a population without mandatory folic acid fortification, both folate and homocysteine were strongly associated with the risk of myocardial infarction, independently of each other and of renal function. Although randomized trials of folic acid supplementation are needed to determine causality, our findings highlight the potential importance of folate, or sources of folate, in incident cardiovascular disease.
Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women's Antioxidant and Folic Acid Cardiovascular Study.
Christen WG, Glynn RJ, Chew EY, Albert CM, Manson JE. Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, USA. Arch Intern Med. 2009 Feb
BACKGROUND: Observational epidemiologic studies indicate a direct association between homocysteine concentration in the blood and the risk of age-related macular degeneration (AMD), but randomized trial data to examine the effect of therapy to lower homocysteine levels in AMD are lacking. Our objective was to examine the incidence of AMD in a trial of combined folic acid, pyridoxine hydrochloride (vitamin B(6)), and cyanocobalamin (vitamin B(12)) therapy. METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 5442 female health care professionals 40 years or older with preexisting cardiovascular disease or 3 or more cardiovascular disease risk factors. A total of 5205 of these women did not have a diagnosis of AMD at baseline and were included in this analysis. Participants were randomly assigned to receive a combination of folic acid (2.5 mg/d), pyridoxine hydrochloride (50 mg/d), and cyanocobalamin (1 mg/d) or placebo. Our main outcome measures included total AMD, defined as a self-report documented by medical record evidence of an initial diagnosis after randomization, and visually significant AMD, defined as confirmed incident AMD with visual acuity of 20/30 or worse attributable to this condition. RESULTS: After an average of 7.3 years of treatment and follow-up, there were 55 cases of AMD in the combination treatment group and 82 in the placebo group (relative risk, 0.66; 95% confidence interval, 0.47-0.93 [P = .02]). For visually significant AMD, there were 26 cases in the combination treatment group and 44 in the placebo group (relative risk, 0.59; 95% confidence interval, 0.36-0.95 [P = .03]). CONCLUSIONS: These randomized trial data from a large cohort of women at high risk of cardiovascular disease indicate that daily supplementation with folic acid, pyridoxine, and cyanocobalamin may reduce the risk of AMD.
Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism
Miousse IR, Watkins D, Coelho D, Rupar T, Crombez EA, Vilain E, Bernstein JA, Cowan T, Lee-Messer C, Enns GM, Fowler B, Rosenblatt DS. Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada. J Pediatr. 2009 Apr
OBJECTIVES: To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated homocystinuria, isolated methylmalonic aciduria, or combined homocystinuria and methylmalonic aciduria. STUDY DESIGN: Patient clinical records were reviewed. Biochemical and somatic cell genetic studies were performed on cultured fibroblasts. Sequence analysis of the MMADHC gene was performed on patient DNA. RESULTS: Patient 1 presented with isolated methylmalonic aciduria, patient 3 with isolated homocystinuria, and patient 2 with combined methylmalonic aciduria and homocystinuria. Studies of cultured fibroblasts confirmed decreased synthesis of adenosylcobalamin in patient 1, decreased synthesis of methylcobalamin in patient 3, and decreased synthesis of both cobalamin derivatives in patient 2. The diagnosis of cblD was established in each patient by complementation analysis. Mutations in the MMADHC gene were identified in all patients. CONCLUSIONS: The results emphasize the heterogeneous clinical, cellular and molecular phenotype of the cblD disorder. The results of molecular analysis of the MMADHC gene are consistent with the hypothesis that mutations affecting the N terminus of the MMADHC protein are associated with methylmalonic aciduria, and mutations affecting the C terminus are associated with homocystinuria.
Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development.
Molloy AM, Kirke PN, Brody LC, Scott JM, Mills JL. School of Medicine, Trinity College Dublin, Ireland. Food Nutr Bull. 2008 Jun
The importance of folate in reproduction can be appreciated by considering that the existence of the vitamin was first suspected from efforts to explain a potentially fatal megaloblastic anemia in young pregnant women in India. Today, low maternal folate status during pregnancy and lactation remains a significant cause of maternal morbidity in some communities. The folate status of the neonate tends to be protected at the expense of maternal stores; nevertheless, there is mounting evidence that inadequate maternal folate status during pregnancy may lead to low infant birthweight, thereby conferring risk of developmental and long-term adverse health outcomes. Moreover, folate-related anemia during childhood and adolescence might predispose children to further infections and disease. The role of folic acid in prevention of neural tube defects (NTD) is now established, and several studies suggest that this protection may extend to some other birth defects. In terms of maternal health, clinical vitamin B12 deficiency may be a cause of infertility or recurrent spontaneous abortion. Starting pregnancy with an inadequate vitamin B12 status may increase risk of birth defects such as NTD, and may contribute to preterm delivery, although this needs further evaluation. Furthermore, inadequate vitamin B12 status in the mother may lead to frank deficiency in the infant if sufficient fetal stores of vitamin B12 are not laid down during pregnancy or are not available in breastmilk. However, the implications of starting pregnancy and lactation with low vitamin B12 status have not been sufficiently researched.
Predictors of multivitamin use during pregnancy in Brazil.
Wehby GL, Castilla EE, Lopez-Camelo JS, Murray JC. College of Public Health, Department of Health Management and Policy, University of Iowa, USA. Int J Public Health. 2009
OBJECTIVES: The study aimed at identifying predictors of multivitamin use during pregnancy in Brazil. METHODS: Birth registry data of 1,774 infants at maternity hospitals in Brazil were used. The effects of maternal health and fertility risk indicators, enabling factors and other maternal characteristics on multivitamin use were evaluated both pooled and stratified by African ancestry. RESULTS: About 14% of the women used multivitamins during pregnancy. Number of previous live births, maternal age and education, number of ultrasound exams and year of pregnancy had significant effects on multivitamin use in the group reporting African ancestry. Maternal acute illnesses and education had significant effects on use in the group without African ancestry. Significant geographic variation in multivitamin use was observed in both groups. CONCLUSIONS: The study identifies several risk indicators, health care access and enabling factors that are predictive of multivitamin use with differences by African ancestry. The study highlights the importance of increasing the awareness of women of childbearing age of the benefits of multivitamin use and identifies barriers that need to be addressed to promote use.
Folic acid supplements in pregnancy and early childhood respiratory health.
Håberg SE, London SJ, Stigum H, Nafstad P, Nystad W. Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway.
BACKGROUND: Folate supplementation is recommended for pregnant women to reduce the risk of congenital malformations. Maternal intake of folate supplements during pregnancy might also influence childhood immune phenotypes via epigenetic mechanisms. OBJECTIVE: To investigate the relationship between folate supplements in pregnancy and risk of lower respiratory tract infections and wheeze in children up to 18 months of age. METHODS: In the Norwegian Mother and Child Cohort Study, questionnaire data collected at several time points during pregnancy and after birth on 32,077 children born between 2000 and 2005 were used to assess the effects of folate supplements during pregnancy on respiratory outcomes up to 18 months of age, while accounting for other supplements in pregnancy and supplementation in infancy. RESULTS: Folate supplements in the first trimester were associated with increased risk of wheeze and respiratory tract infections up to 18 months of age. Adjusting for exposure later in pregnancy and in infancy, the relative risk for wheeze for children exposed to folic acid supplements in the first trimester was 1.06 (95% CI 1.03 to 1.10), the relative risk for lower respiratory tract infections was 1.09 (95% CI 1.02 to 1.15) and the relative risk for hospitalisations for lower respiratory tract infections was 1.24 (95% CI 1.09 to 1.41). CONCLUSIONS: Folic acid supplements in pregnancy were associated with a slightly increased risk of wheeze and lower respiratory tract infections up to 18 months of age. The results suggest that methyl donors in the maternal diet during pregnancy may influence respiratory health in children consistent with epigenetic mechanisms.
Effect of B1-, B6- and iron intake during pregnancy on neonatal behavior.
Cucó G, Fernandez-Ballart J, Arija V, Canals J. Unit of Preventive Medicine and Public Health, Faculty of Medicine and Health Sciences, Rovira i Virgili University, Reus, Spain. Int J Vitam Nutr Res. 2005 Sep
The aim of this study was to analyze how micronutrient intake during preconception and pregnancy affects neonatal behavior. A total of 66 healthy women volunteers were studied during preconception and in weeks 6, 10, 26, and 38 of pregnancy using the seven-day dietary record. The behavior of the newborn infant was assessed after three days of life using the Neonatal Behavioral Assessment Scale (NBAS). Multiple linear regression models were built and adjusted for the confounding variables in each of the periods studied and for each one of the various NBAS clusters. The intake of vitamins B1 and B6 in the sixth week of pregnancy and of iron in the 38th week of pregnancy have a positive and significant effect on the motor cluster of the NBAS independently of the body mass index (BMI), preconception age, gestational age, educational level, whether the mother is a smoker, the mother's personality dimensions, and the weight and sex of the newborn. The intake of B1, B6, and iron during pregnancy might contribute to the neuromotor maturity of the newborn.
Vitamin D and cardiovascular disease.
Gouni-Berthold I, Krone W, Berthold HK. Department of Internal Medicine II, University of Cologne, Germany. Curr Vasc Pharmacol. 2009 Jul
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Recently vitamin D deficiency has been identified as a potential risk factor for many diseases not traditionally associated with vitamin D, such as cancer and CVD. This review discusses the evidence suggesting an association between low 25-hydroxyvitamin D levels and CVD and the possible mechanisms mediating it. Vitamin D deficiency has been associated with CVD risk factors such as hypertension and diabetes mellitus, with markers of subclinical atherosclerosis such as intima-media thickness and coronary calcification as well as with cardiovascular events such as myocardial infarction and stroke as well as congestive heart failure. It could be suggested that vitamin D deficiency contributes to the development of CVD through its association with risk factors, such as diabetes and hypertension. However, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells and vitamin D has been shown to affect inflammation and cell proliferation and differentiation. While much evidence supports a potential antiatherosclerotic effect of vitamin D, prospective, placebo-controlled randomized as well as mechanistic studies are needed to confirm this association. Since vitamin D deficiency is easy to screen for and treat, the confirmation of such an association could have important implications for both, patient care and health policy.
Vitamin D and health in the 21st century: federal initiatives to advance research.
Costello RB. NIH Office of Dietary Supplements, Bethesda, Maryland, USA. Am J Med Sci. 2009 Jul
The role for dietary supplements for health maintenance and disease prevention is receiving increasingly more attention in the public media as well as in academic institutions and research centers. The mission of the National Institutes of Health Office of Dietary Supplements is to support and promote the science on the benefits and risks of dietary supplements. To this end, Office of Dietary Supplements supports a number of initiatives to advance the evidence base on vitamin D. These initiatives include an evidence-based review on the relationship of vitamin D and calcium intakes to nutrient status indicators and health outcomes; developing and validating analytical methods for measuring vitamin D in biological fluids and foods; support for continued collection of vitamin D status indicators through the National Health and Nutrition Examination Survey; and funding for National Institutes of Health grants on vitamin D and related health outcomes. Taken together, these programs address research gaps and needs to further the science and exploration of the role of vitamin D in health.
