- What Is Vitamin B12 Deficiency Anemia?
- Maternal multivitamin intake, plasma folate and vitamin B12 levels and Autism Spectrum Disorder risk in offspring
- Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women
- SUBJECTS AND METHODS
- Assays of metabolites
- Definitions of vitamin deficiency
- Statistical analysis
- Demographics of study population
- Folate-Deficiency Anemia
- What causes folate-deficiency anemia?
- Who is at risk for folate-deficiency anemia?
- What are the symptoms of folate-deficiency anemia?
- How is folate-deficiency anemia diagnosed?
- How is folate-deficiency anemia treated?
- What are the complications of folate-deficiency anemia?
- Key points about folate-deficiency anemia
- Next steps
What Is Vitamin B12 Deficiency Anemia?
This type of anemia means that your body doesn't have enough healthy red blood cells because you're low in vitamin B12. These cells transport oxygen throughout your body. You need vitamins — including B12 — to make them.
When you don't have enough red blood cells, your body doesn’t get the oxygen it needs to work it should. Anemia may make you feel tired, weak, and short of breath.
You can get vitamin B12 deficiency anemia if you don't get enough vitamin B12 in your diet from foods milk, eggs, and meat. You're more ly to be low in this vitamin if you're older, or you eat a vegetarian diet. It can also happen if your body can't absorb enough of it from the foods you eat.
Your intestines absorb vitamin B12 from food. A protein your stomach makes called “intrinsic factor” helps your body absorb it. When you don't have enough, you have a type of vitamin B12 deficiency anemia called “pernicious anemia.”
You can get pernicious anemia if:
- You have an autoimmune disease that makes your immune system attack the cells in your stomach that produce intrinsic factor.
- You have surgery to remove part of your stomach, where intrinsic factor is made.
Your body also might not absorb enough vitamin B12 if:
- You have a disease that affects how nutrients are absorbed in your intestines, such as Crohn's disease, HIV, or some infections.
- You have certain bad bacteria in your intestines.
- You take some medicines, such as antibiotics and anti-seizure drugs.
- You've had surgery to remove part of your intestines.
- You've been infected with a tapeworm.
Anemia can make you feel tired and short of breath. Here are some other signs:
- Your skin looks pale or yellow.
- You feel dizzy.
- You have no appetite.
- You've lost weight without trying.
- Your hands and feet feel they're numb or tingling.
- Your heart beats too fast or you have chest pain.
- Your muscles feel weak.
- You often have mood changes.
- You're confused or forgetful.
Because these can also be symptoms of other conditions, see your doctor for a diagnosis. Your doctor will do a physical exam and might order one or more of these tests:
- Complete blood count. This test checks the size and number of your red blood cells. If you're low in vitamin B12, your red blood cells won't look normal. They'll be much bigger and shaped differently than healthy ones.
- Vitamin B12 level. This test checks to see if you have enough of it in your blood.
- Intrinsic factor antibodies. These proteins tell your immune system to attack intrinsic factor. If you have pernicious anemia, you'll have them in your blood.
- Schilling test. This test uses a radioactive form of B12 to see if your body has enough intrinsic factor.
- Methylmalonic acid level (MMA). This test measures the amount of MMA in your blood. When your vitamin B12 level is low, your level of MMA rises.
Usually, vitamin B12 deficiency anemia is easy to treat with diet and vitamin supplements. To increase the amount of vitamin B12 in your diet, eat more of foods that contain it, such as:
- Beef, liver, and chicken
- Fish and shellfish such as trout, salmon, tuna fish, and clams
- Fortified breakfast cereal
- Low-fat milk, yogurt, and cheese
Your doctor might recommend that you also take a vitamin B12 supplement. It comes in pills or a nasal spray. If you are very low in this vitamin, you can get higher-dose vitamin B12 shots. You may need to take vitamin B12 for the rest of your life. You might also need to get treated for the condition that causes your anemia.
But increasing your vitamin B12 levels is a key thing you can do. If you let it go for too long, it can damage your heart, brain, nerves, bones, and other organs in your body. With treatment, you should feel better and avoid any long-term problems.
Johns Hopkins Medicine: “Vitamin B12 Deficiency Anemia.”
Mayo Clinic: “Vitamin deficiency anemia: Diagnosis.” “Vitamin deficiency anemia: Overview.” “Vitamin deficiency anemia: Symptoms and causes.” “Vitamin deficiency anemia: Treatment.”
National Heart, Lung, and Blood Institute: “How Is Pernicious Anemia Diagnosed?” “How Is Pernicious Anemia Treated?” “What Causes Pernicious Anemia?” “What Is Pernicious Anemia?”
National Institutes of Health: “Vitamin B12 Dietary Supplement Fact Sheet.”
University of Rochester Medical Center: “What Are Red Blood Cells?”
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Maternal multivitamin intake, plasma folate and vitamin B12 levels and Autism Spectrum Disorder risk in offspring
1. Liptak GS, Benzoni LB, Mruzek DW, Nolan KW, Thingvoll MA, Wade CM, et al. Disparities in diagnosis and access to health services for children with autism: data from the National Survey of Children's Health. Journal of Developmental and Behavioral Pediatrics. 2008;29:152–160. [PubMed] [Google Scholar]
2. Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Schmidt LC, Tancredi DJ, et al. Prenatal vitamins, one-carbon metabolism gene variants, and risk for autism. Epidemiology. 2011;22:476–485. [PMC free article] [PubMed] [Google Scholar]
3. DeVilbiss EA, Gardner RM, Newschaffer CJ, Lee BK. Maternal folate status as a risk factor for autism spectrum disorders: a review of existing evidence. Br J Nutr. 2015:1–10. [PubMed] [Google Scholar]
4. Developmental Disabilities Monitoring Network Surveillance Year Principal I, Centers for Disease C, Prevention. Prevalence of autism spectrum disorder among children aged 8 years – autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR: Surveillance Summaries. 2014;63:1–21. [PubMed] [Google Scholar]
5. Xu G, Jing J, Bowers K, Liu B, Bao W. Maternal diabetes and the risk of autism spectrum disorders in the offspring: a systematic review and meta-analysis. Journal of Autism and Developmental Disorders. 2014;44:766–775. [PMC free article] [PubMed] [Google Scholar]
6. Gardener H, Spiegelman D, Buka SL. Prenatal risk factors for autism: comprehensive meta-analysis. British Journal of Psychiatry. 2009;195:7–14. [PMC free article] [PubMed] [Google Scholar]
7. Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate's role. Advances in Nutrition. 2012;3:21–38. [PMC free article] [PubMed] [Google Scholar]
8. Christensen KE, Mikael LG, Leung KY, Levesque N, Deng L, Wu Q, et al. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. American Journal of Clinical Nutrition. 2015;101:646–658. [PMC free article] [PubMed] [Google Scholar]
9. Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF. Folic acid intake from fortification in United States exceeds predictions. Journal of Nutrition. 2002;132:2792–2798. [PubMed] [Google Scholar]
10. Pfeiffer CM, Hughes JP, Lacher DA, Bailey RL, Berry RJ, Zhang M, et al. Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010. Journal of Nutrition. 2012;142:886–893. [PMC free article] [PubMed] [Google Scholar]
11. Pfeiffer CM, Sternberg MR, Fazili Z, Yetley EA, Lacher DA, Bailey RL, et al. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. Journal of Nutrition. 2015;145:520–531. [PMC free article] [PubMed] [Google Scholar]
12. Wang G, Hu , Mistry KB, Zhang C, Ren F, Huo Y, et al. Association Between Maternal Prepregnancy Body Mass Index and Plasma Folate Concentrations With Child Metabolic Health. JAMA Pediatrics. 2016;170:e160845. [PMC free article] [PubMed] [Google Scholar]
13. Suren P, Roth C, Bresnahan M, Haugen M, Hornig M, Hirtz D, et al. Association between maternal use of folic acid supplements and risk of autism spectrum disorders in children. JAMA. 2013;309:570–577. [PMC free article] [PubMed] [Google Scholar]
14. Beard CM, Panser LA, Katusic SK. Is excess folic acid supplementation a risk factor for autism? Medical Hypotheses. 2011;77:15–17. [PubMed] [Google Scholar]
15. Rogers EJ. Has enhanced folate status during pregnancy altered natural selection and possibly Autism prevalence? A closer look at a possible link. Medical Hypotheses. 2008;71:406–410. [PubMed] [Google Scholar]
16. King CR. A novel embryological theory of autism causation involving endogenous biochemicals capable of initiating cellular gene transcription: a possible link between twelve autism risk factors and the autism ‘epidemic’ Medical Hypotheses. 2011;76:653–660. [PubMed] [Google Scholar]
17. Braun JM, Froehlich T, Kalkbrenner A, Pfeiffer CM, Fazili Z, Yolton K, et al. Brief report: are autistic-behaviors in children related to prenatal vitamin use and maternal whole blood folate concentrations? Journal of Autism and Developmental Disorders. 2014;44:2602–2607. [PMC free article] [PubMed] [Google Scholar]
18. Steenweg-de Graaff J, Ghassabian A, Jaddoe VW, Tiemeier H, Roza SJ. Folate concentrations during pregnancy and autistic traits in the offspring. The Generation R Study. European Journal of Public Health. 2015;25:431–433. [PubMed] [Google Scholar]
19. Zhang Y, Hodgson NW, Trivedi MS, Abdolmaleky HM, Fournier M, Cuenod M, et al. Decreased Brain Levels of Vitamin B12 in Aging, Autism and Schizophrenia. PloS One. 2016;11:e0146797. [PMC free article] [PubMed] [Google Scholar]
20. Wang X, Zuckerman B, Pearson C, Kaufman G, Chen C, Wang G, et al. Maternal cigarette smoking, metabolic gene polymorphism, and infant birth weight. JAMA. 2002;287:195–202. [PubMed] [Google Scholar]
21. Li M, Fallin MD, Riley A, Landa R, Walker SO, Silverstein M, et al. The Association of Maternal Obesity and Diabetes With Autism and Other Developmental Disabilities. Pediatrics. 2016;137:1–10. [PMC free article] [PubMed] [Google Scholar]
22. Schmidt RJ, Tancredi DJ, Ozonoff S, Hansen RL, Hartiala J, Allayee H, et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. American Journal of Clinical Nutrition. 2012;96:80–89. [PMC free article] [PubMed] [Google Scholar]
23. Arendt JF, Nexo E. Unexpected high plasma cobalamin : proposal for a diagnostic strategy. Clinical Chemistry and Laboratory Medicine. 2013;51:489–496. [PubMed] [Google Scholar]
24. Tamura T, Picciano MF. Folate and human reproduction. American Journal of Clinical Nutrition. 2006;83:993–1016. [PubMed] [Google Scholar]
25. Milman N, Byg KE, Bergholt T, Eriksen L, Hvas AM. Cobalamin status during normal pregnancy and postpartum: a longitudinal study comprising 406 Danish women. European Journal of Haematology. 2006;76:521–525. [PubMed] [Google Scholar]
26. Raubenheimer D, Lee KP, Simpson SJ. Does Bertrand's rule apply to macronutrients? Proceedings: Biological Sciences. 2005;272:2429–2434. [PMC free article] [PubMed] [Google Scholar]
27. Barua S, Kuizon S, Ted Brown W, Junaid MA. High Gestational Folic Acid Supplementation Alters Expression of Imprinted and Candidate Autism Susceptibility Genes in a sex-Specific Manner in Mouse Offspring. Journal of Molecular Neuroscience. 2015 [PubMed] [Google Scholar]
28. Daly LE, Kirke PN, Molloy A, Weir DG, Scott JM. Folate levels and neural tube defects. Implications for prevention. JAMA. 1995;274:1698–1702. [PubMed] [Google Scholar]
29. Wilson RD, Genetics C, Wilson RD, Audibert F, Brock JA, Carroll J, et al. Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies. Journal d'Obstétrique et Gynécologie du CanadaJournal of Obstetrics and Gynaecology Canada. 2015;37:534–552. [PubMed] [Google Scholar]
30. Zahran KM, Adb Elaal DEM, Kamel HS, Samy EI, Ismail AM, Abbas AM. A combination treatment of folic acid, aspirin, doxycycline and progesterone for women with recurrent early pregnancy loss; hospital based study. Middle East Fertility Society Journal. 2016;21:22–26. [Google Scholar]
31. Czeizel AE, Puho E. Maternal use of nutritional supplements during the first month of pregnancy and decreased risk of Down's syndrome: case-control study. Nutrition. 2005;21:698–704. discussion 774. [PubMed] [Google Scholar]
32. Orozco AM, Yeung LF, Guo J, Carriquiry A, Berry RJ. Characteristics of U.S. Adults with Usual Daily Folic Acid Intake above the Tolerable Upper Intake Level: National Health and Nutrition Examination Survey, 2003-2010. Nutrients. 2016;8:195. [PMC free article] [PubMed] [Google Scholar]
33. Georgieff MK. Nutrition and the developing brain: nutrient priorities and measurement. American Journal of Clinical Nutrition. 2007;85:614S–620S. [PubMed] [Google Scholar]
34. Fuglestad AJ, Rao R, Georgieff MK. The role of nutrition in cognitive development. Available from: http://hirezz.com/satvenandmer.com/pdf/dha/Nutrition and Cognitive Development.pdf.
35. Hellegers A, Okuda K, Nesbitt RE, Jr, Smith DW, Chow BF. Vitamin B12 absorption in pregnancy and in the newborn. American Journal of Clinical Nutrition. 1957;5:327–331. [PubMed] [Google Scholar]
36. West AA, Yan J, Perry CA, Jiang X, Malysheva OV, Caudill MA. Folate-status response to a controlled folate intake in nonpregnant, pregnant, and lactating women. American Journal of Clinical Nutrition. 2012;96:789–800. [PubMed] [Google Scholar]
37. Mahoney AD, Minter B, Burch K, Stapel-Wax J. Autism spectrum disorders and prematurity: a review across gestational age subgroups. Advances in Neonatal Care. 2013;13:247–251. [PubMed] [Google Scholar]
38. Tau GZ, Peterson BS. Normal development of brain circuits. Neuropsychopharmacology. 2010;35:147–168. [PMC free article] [PubMed] [Google Scholar]
39. Cusick SE, Georgieff MK. The Role of Nutrition in Brain Development: The Golden Opportunity of the “First 1000 Days” Journal of Pediatrics. 2016;175:16–21. [PMC free article] [PubMed] [Google Scholar]
40. Georgieff MK, Brunette KE, Tran PV. Early life nutrition and neural plasticity. Development and Psychopathology. 2015;27:411–423. [PMC free article] [PubMed] [Google Scholar]
41. Barua S, Kuizon S, Brown WT, Junaid MA. DNA Methylation Profiling at Single-Base Resolution Reveals Gestational Folic Acid Supplementation Influences the Epigenome of Mouse Offspring Cerebellum. Frontiers in Neuroscience. 2016;10:168. [PMC free article] [PubMed] [Google Scholar]
42. Barua S, Chadman KK, Kuizon S, Buenaventura D, Stapley NW, Ruocco F, et al. Increasing maternal or post-weaning folic acid alters gene expression and moderately changes behavior in the offspring. PloS One. 2014;9:e101674. [PMC free article] [PubMed] [Google Scholar]
43. Ly A, Ishiguro L, Kim D, Im D, Kim SE, Sohn KJ, et al. Maternal folic acid supplementation modulates DNA methylation and gene expression in the rat offspring in a gestation period-dependent and organ-specific manner. The Journal of Nutritional Biochemistry. 2016;33:103–110. [PubMed] [Google Scholar]
44. Friso S, Choi SW. Gene-nutrient interactions and DNA methylation. Journal of Nutrition. 2002;132:2382S–2387S. [PubMed] [Google Scholar]
45. Haggarty P, Hoad G, Campbell DM, Horgan GW, Piyathilake C, McNeill G. Folate in pregnancy and imprinted gene and repeat element methylation in the offspring. American Journal of Clinical Nutrition. 2013;97:94–99. [PubMed] [Google Scholar]
46. Bourgeron T. From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nature Reviews: Neuroscience. 2015;16:551–563. [PubMed] [Google Scholar]
47. Robertson CE, Ratai EM, Kanwisher N. Reduced GABAergic Action in the Autistic Brain. Current Biology. 2016;26:80–85. [PubMed] [Google Scholar]
48. Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food and Nutrition Bulletin. 2008;29:S126–131. [PMC free article] [PubMed] [Google Scholar]
49. McCullough LE, Miller EE, Mendez MA, Murtha AP, Murphy SK, Hoyo C. Maternal B vitamins: effects on offspring weight and DNA methylation at genomically imprinted domains. Clinical Epigenetics. 2016;8:8. [PMC free article] [PubMed] [Google Scholar]
50. Ba Y, Yu H, Liu F, Geng X, Zhu C, Zhu Q, et al. Relationship of folate, vitamin B12 and methylation of insulin- growth factor-II in maternal and cord blood. European Journal of Clinical Nutrition. 2011;65:480–485. [PMC free article] [PubMed] [Google Scholar]
51. Falkmer T, Anderson K, Falkmer M, Horlin C. Diagnostic procedures in autism spectrum disorders: a systematic literature review. European Child and Adolescent Psychiatry. 2013;22:329–340. [PubMed] [Google Scholar]
52. Galloway M, Rushworth L. Red cell or serum folate? Results from the National Pathology Alliance benchmarking review. Journal of Clinical Pathology. 2003;56:924–926. [PMC free article] [PubMed] [Google Scholar]
53. Branum AM, Bailey R, Singer BJ. Dietary supplement use and folate status during pregnancy in the United States. Journal of Nutrition. 2013;143:486–492. [PMC free article] [PubMed] [Google Scholar]
54. Aaltonen J, Ojala T, Laitinen K, Piirainen TJ, Poussa TA, Isolauri E. Evidence of infant blood pressure programming by maternal nutrition during pregnancy: a prospective randomized controlled intervention study. Journal of Pediatrics. 2008;152:79–84. 84 e71–72. [PubMed] [Google Scholar]
55. Heavner K, Burstyn I. A Simulation Study of Categorizing Continuous Exposure Variables Measured with Error in Autism Research: Small Changes with Large Effects. International Journal of Environmental Research and Public Health. 2015;12:10198–10234. [PMC free article] [PubMed] [Google Scholar]
Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women
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Background: Many previous investigations of cobalamin and folate status were performed in white populations.
Objective: Our objective was to determine whether there are racial differences in the prevalence of cobalamin and folate deficiency.
Design: The study was a cross-sectional comparison of baseline serum cobalamin, folate, methylmalonic acid (MMA), total homocysteine (tHcy), and creatinine concentrations, complete blood count, and vitamin supplementation in 550 white and 212 African American subjects from a cohort of physically disabled older women.
Results: The mean (±SD) serum MMA concentration was significantly higher in whites than in African Americans: 284 ± 229 compared with 218 ± 158 nmol/L (P = 0.0001). tHcy concentration was higher in African Americans than in whites: 12.4 ± 7.0 compared with 10.9 ± 4.6 μmol/L (P = 0.001). Serum cobalamin was lower in whites (P = 0.0002).
Cobalamin deficiency (serum cobalamin 271 nmol/L) was more frequent in the white women (19% compared with 8%; P < 0.0003). Folate deficiency (serum folate 13.9 μmol/L, and MMA 85 y, African American race, serum creatinine >90 μmol/L, and high MMA concentration were all significantly correlated with higher tHcy.
Creatinine > 90 μmol/L, white race, and folate concentration were positively associated with MMA concentration.
Conclusions: Cobalamin deficiency with elevated serum MMA concentration is more prevalent in elderly white than in African American women and elevated serum tHcy and folate deficiency are more prevalent in elderly African American than in white women.
Virtually all patients with clinical abnormalities due to cobalamin (vitamin B-12) deficiency that are correctable by cobalamin therapy have elevated serum methylmalonic acid (MMA) (1–5) or total homocysteine (tHcy) (1–3, 6) concentrations, or both, even when serum cobalamin concentrations are in the normal range (3, 7).
Homocysteine concentration is elevated in most folate-deficient patients with megaloblastic anemia (1, 8) despite serum folate concentrations in the low-normal range in ≈25% of them (1). Previous studies showed that elevated concentrations of MMA and tHcy associated with low or low-normal serum cobalamin values are highly prevalent (10–20%) in elderly cohorts (9–14).
After vitamin treatment, the elevated MMA and tHcy concentrations fall into the normal ranges seen in younger individuals (9, 15). The response to cobalamin therapy alone or combined with folic acid and vitamin B-6 suggests that many older people have unrecognized cobalamin, folate, vitamin B-6, or combined deficiencies.
Most of the subjects studied previously were white Americans or Europeans. Therefore, it is not known whether elderly African Americans have a similar prevalence of cobalamin or other vitamin deficiencies. Previous investigations found that pernicious anemia is as prevalent in African Americans as it is in white Americans (1, 16–19).
However, most elderly cobalamin-deficient subjects do not appear to have pernicious anemia (9, 10). Information on the underlying prevalence of cobalamin and folate deficiency in racial and ethnic subgroups of the population would be useful because the recently implemented food folate fortification program in the United States will have universal effects (20).
Also, the Food and Nutrition Board recently recommended that elderly people obtain their cobalamin from a synthetic source because of the underlying risk of malabsorption of food cobalamin (21).
An elevated concentration of tHcy (hyperhomocysteinemia) is recognized as an independent risk factor for vascular disease (22). Serum tHcy concentrations correlate inversely with serum cobalamin and folate concentrations and directly with creatinine concentration and age (23).
Previous investigations in mostly white populations showed that most elderly subjects with hyperhomocysteinemia also have elevated MMA concentrations due to cobalamin deficiency and, in some cases, renal insufficiency (9, 10, 24).
Our objective was to determine whether there are racial differences in the prevalence of cobalamin and folate deficiency.
SUBJECTS AND METHODS
The data for these analyses are from the baseline assessment of the Women's Health and Aging Study (WHAS; 25), an epidemiologic study of the causes and course of disability in a representative sample of physically disabled older women without severe dementia living in the community.
The sampling strategy and study eligibility criteria were described in detail previously (25). Briefly, an age-stratified random sample of 6521 community-dwelling women aged ≥65 y, with oversampling of those aged ≥85 y, was selected from the Health Care Financing Administration's Medicare enrollment file for 12 contiguous zip code areas in Baltimore.
After we excluded those who had died, were institutionalized, or had moved from the area, 5316 women were eligible for screening; 4137 participated in the screening and 3841 (982 African Americans and 2859 whites or other) finished the interview themselves.
Of these, 1409 women (367 African Americans and 1042 whites or other) met the criteria for study eligibility, scoring ≥18 on the Mini-Mental State Examination and reporting difficulty in performing daily tasks in ≥2 domains of functioning.
Among those eligible, 1002 (284 African Americans, 713 whites, and 5 others) participated in the full baseline interview and then underwent a comprehensive examination 1–2 wk later in their homes. Women self-reported their race; those who reported races other than white or African American were combined with whites.
At the time of the examination, participants were invited to give a blood sample, which was collected by a phlebotomist at a third home visit.
This report uses data from 762 women (212 African Americans and 550 whites) for whom blood test results were available for all relevant measures. Compared with women who provided blood samples, those refusing to provide them were significantly older (81.
1 y compared with 77.5 y) and more disabled in self-care tasks, but were not different in terms of race or educational status.
At the baseline interview, participants were requested to present all multivitamin and vitamin medication containers. Interviewers recorded vitamin names, forms, strengths, prescribed dosage, and whether the vitamins were prescribed or over-the-counter. Information was also sought on vitamins for which containers were not available.
Chronic disease status was ascertained for 17 conditions by using standardized algorithms that work with information from the interview, examination, medications, radiographs, laboratory tests, physicians' reports, and medical records.
The Joint Committee on Clinical Investigation approved the investigation at the Johns Hopkins University School of Medicine, Baltimore.
Assays of metabolites
MMA, tHcy, cystathionine, 2-methylcitric acid, and total cysteine (26–29) were assayed as described previously by stable-isotope dilution and capillary gas chromatography–mass spectrometry with selected ion monitoring.
Serum samples were collected and coded in Baltimore and the frozen serum was shipped to the University of Colorado Health Sciences Center for metabolite assays.
The normal ranges for the serum metabolites had been determined previously for 60 normal blood donors (30 male) aged 18–65 y and were defined as 2 SD above and below the mean after log normalization to correct for skewness of the data (28, 29). The normal ranges were as follows: tHcy, 5.4–13.
9 μmol/L; MMA, 73–271 nmol/L; cystathionine, 44–342 nmol/L; total 2-methylcitric acid, 60–228 nmol/L; and total cysteine, 203–369 μmol/L. The previous normal range for tHcy was 5.4–16.2 μmol/L and was determined in serum samples from 60 normal blood donors (30 male) aged 18–65 y.
Blood was allowed to clot for 1–4 h (with an even distribution and a mean of 2.4 h). The current normal range was determined in a second group of 60 similar normal blood donors but blood was clotted for only 30 min before separation by centrifugation. The higher previous normal range was due to release of homocysteine by blood cells at room temperature before separation of the serum.
Serum folate, cobalamin, and pyridoxal phosphate tests were performed by Quest Diagnostics, Teterboro, NJ. Serum cobalamin and folate were measured by competitive protein binding assays using intrinsic factor and folate binding protein by the method of Ciba-Corning Diagnostics Corporation, Medfield, MA.
Serum creatinine was assayed by using sodium picrate with the Ciba-Corning creatinine procedure. The normal range is 50–100 μmol/L (0.6–1.1 mg/dL) for females.
Creatinine clearance was estimated by using the formula of Cockcroft and Gault (30): creatinine clearance (mL/s) = weight (kg) × [140 − age (y)]/[72 × serum creatinine (mg/dL)] × 0.85 × 0.
01667 (factor adjustment for Système International units).
Definitions of vitamin deficiency
Previous investigations showed that serum vitamin concentrations alone are too nonspecific and insensitive to be used to assign the diagnosis of deficiency (7, 9, 10).
We showed previously that >95% of subjects with cobalamin-deficient megaloblastic anemia or neurologic abnormalities have elevated MMA and tHcy concentrations and folate-deficient subjects with megaloblastic anemia have elevated tHcy concentration only (1).
Cystathionine concentrations are elevated in many subjects with clinically proven cobalamin or folate deficiency (28) and in animals with dietary vitamin B-6 deficiency (31). 2-Methylcitric acid concentrations are often elevated in patients with severe cobalamin deficiency, but are also elevated commonly by poor renal function (29).
The serum 2-methylcitric acid value is higher than the MMA value in most subjects with elevated serum creatinine (29). In contrast, the MMA concentration is always higher than the 2-methylcitric acid concentration in clinically proven cobalamin deficiency (29).
The study population was expected to have individuals with vitamin deficiency or renal insufficiency or both. Therefore, we developed definitions of vitamin deficiency our previous studies of clinically documented deficiency or renal insufficiency cited above. Cobalamin deficiency was defined as serum cobalamin 271 nmol/L and greater than the total methylcitric acid concentration.
For some analyses the cobalamin-deficient subjects were divided into “high cutoff” and “low cutoff” groups. Cobalamin-deficient subjects in the high-cutoff group had cobalamin and MMA values defined above. Cobalamin-deficient subjects in the low cutoff group had a serum cobalamin concentration 271 nmol/L and that was greater than the total methylcitric acid concentration.
Because both cobalamin and folate deficiencies cause elevated serum tHcy but only cobalamin deficiency causes elevated MMA, the relative pattern of the 2 metabolites was used in the definition of folate deficiency. Folate deficiency was defined as serum folate 13.9 μmol/L, and an MMA concentration ≤271 nmol/L.
Cobalamin deficiency with possible associated folate deficiency was defined according to the subset of subjects who met the definition of cobalamin deficiency (and therefore had elevated MMA concentrations) and also had a tHcy concentration >13.9 μmol/L and a serum folate concentration 13.9 μmol/L, cystathionine >342 nmol/L, or 2-methylcitric acid >228 nmol/L.
The category “no deficiency or renal failure” included all subjects who were not included in the above groups.
Differences in categorical variables between African Americans and whites were tested by using the chi-square statistic. Differences in means for continuous variables across 2 categories were evaluated with a t test.
For tests of trend for continuous variables across categories of serum creatinine, creatinine categories were classified as ordinal variables that were each used as the independent variable in simple linear regression models.
In analyses evaluating the effect of both serum creatinine concentration and multivitamin use on vitamin and metabolite concentrations, the interactions between these 2 variables were tested in linear regression models.
In cases in which an interaction was not present, the main effects of lower compared with higher serum creatinine concentration and multivitamin use compared with no use were evaluated by using t tests.
For those instances in which an interaction was present, analysis of variance was used to compare the effects of specific combinations of creatinine concentration and multivitamin use. Analysis of variance was used to test differences in means of serum metabolites across multiple categories of cobalamin supplementation.
All analyses used weighted data to adjust for the age-stratified sampling design. Finally, multiple linear regression models were used to evaluate the independent effects of several factors on tHcy and MMA concentrations. These variables were log transformed because of their skewed distribution, resulting in nearly normal distributions and a substantially better model fit. The analyses included age as a covariate so they did not use age-weighted data, and results of weighted regression models were virtually identical. Numbers in the tables do not total 762 in some cases because of missing values. The statistical program SAS (version 6.0; SAS Institute, Cary, NC) was used for the analyses.
Demographics of study population
Demographic and other characteristics of the total study population according to race are shown in Table 1. The age distribution of the African Americans compared with the whites was significantly different, with fewer African Americans in the group aged ≥85 y.
More African American women had 342 nmol/L (%)
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Folate-deficiency anemia is the lack of folic acid in the blood. Folic acid is a B vitamin that helps your body make red blood cells. If you don’t have enough red blood cells, you have anemia.
Red blood cells carry oxygen to all parts of your body. When you have anemia, your blood can’t bring enough oxygen to all your tissues and organs. Without enough oxygen, your body can’t work as well as it should.
Low levels of folic acid can cause megaloblastic anemia. With this condition, red blood cells are larger than normal. There are fewer of these cells. They are also oval-shaped, not round. Sometimes these red blood cells don’t live as long as normal red blood cells.
What causes folate-deficiency anemia?
You can develop folate-deficiency anemia if:
- You don’t eat enough foods that have folic acid. These include green leafy vegetables, fresh fruits, fortified cereals, yeast, and meats (including liver).
- You drink too much alcohol
- You have certain diseases of the lower digestive tract, such as celiac disease. This type of anemia also occurs in people with cancer.
- You take certain medicines, such as some used for seizures.
- You are pregnant. This is because the developing baby needs more folic acid. Also, the mother absorbs it more slowly. A lack of folate during pregnancy is linked to major birth defects that affect the brain, spinal cord, and spine (neural tube defects).
Some babies are born unable to absorb folic acid. This can lead to megaloblastic anemia. With this condition, red blood cells are larger than normal. They also have a different shape. Early treatment is needed to prevent problems such as poor reasoning and learning.
Who is at risk for folate-deficiency anemia?
You are more ly to have this type of anemia if you:
- Don’t eat a healthy diet
- Drink a lot of alcohol
- Are pregnant
- Can’t absorb folic acid
- Are taking certain medicines, such as those used to control seizures
What are the symptoms of folate-deficiency anemia?
Symptoms may include:
- Pale skin
- Decreased appetite
- Being grouchy (irritable)
- Lack of energy or tiring easily
- Smooth and tender tongue
The symptoms of folate-deficiency anemia may look other blood conditions or health problems. Always see your healthcare provider for a diagnosis.
How is folate-deficiency anemia diagnosed?
Your healthcare provider may think you have this type of anemia after taking your medical history and doing a physical exam. You may have several blood tests to confirm the diagnosis. You may also have a barium study if a digestive problem is the cause.
How is folate-deficiency anemia treated?
Your healthcare provider will figure out the best treatment :
- Your age, overall health, and medical history
- How sick you are
- How well you can handle certain medicines, treatments, or therapies
- How long the condition is expected to last
- Your opinion or preference
Treatment may include:
- Vitamin and mineral supplements
- Changes in your diet
- Treating the underlying disease
You may need to take folic acid supplements for at least 2 to 3 months. These may be pills or shots (injections). Eating foods high in folic acid and cutting your alcohol intake are also important. If a digestive tract problem causes your anemia, your provider may treat that first.
What are the complications of folate-deficiency anemia?
Folate-deficiency anemia during pregnancy may cause a neural tube defect. This is when the brain or spinal cord doesn’t develop normally. It can cause death before or soon after birth. Or it may cause paralysis of the legs.
Key points about folate-deficiency anemia
- Most folate-deficiency anemia is caused by a lack of folic acid in the diet.
- Leafy vegetables, citrus fruits, beans, and whole grains are natural sources of folic acid.
- Folate-deficiency anemia in pregnancy may cause a neural tube defect. This is when the brain or spinal cord doesn’t develop normally.
- Treatment includes a well-balanced diet of foods with folic acid, folic acid supplements, medicines, and treating underlying diseases.
Tips to help you get the most from a visit to your healthcare provider:
- Know the reason for your visit and what you want to happen.
- Before your visit, write down questions you want answered.
- Bring someone with you to help you ask questions and remember what your provider tells you.
- At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
- Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.
- Ask if your condition can be treated in other ways.
- Know why a test or procedure is recommended and what the results could mean.
- Know what to expect if you do not take the medicine or have the test or procedure.
- If you have a follow-up appointment, write down the date, time, and purpose for that visit.
- Know how you can contact your provider if you have questions.