Causes of Vitamin B12 and Folate Deficiency

This review describes current knowledge of the main causes of vitamin B12 and folate deficiency. The most common explanations for poor vitamin B12 status are a low dietary intake of the vitamin (i.e., a low intake of animal-source foods) and malabsorption. Although it has long been known that strict vegetarians (vegans) are at risk for vitamin B12 deficiency, evidence now indicates that low intakes of animal-source foods, such as occur in some lacto-ovo vegetarians and many less-industrialized countries, cause vitamin B12 depletion. Malabsorption of the vitamin is most commonly observed as food-bound cobalamin malabsorption due to gastric atrophy in the elderly, and probably as a result of Helicobacter pylori infection. There is growing evidence that gene polymorphisms in transcobalamins affect plasma vitamin B12 concentrations. The primary cause of folate deficiency is low intake of sources rich in the vitamin, such as legumes and green leafy vegetables, and the consumption of these foods may explain why folate status can be adequate in relatively poor populations. Other situations in which the risk of folate deficiency increases include lactation and alcoholism.

[1]  T. Green,et al.  Maternal Folate Status and Lactation , 1997, Journal of Mammary Gland Biology and Neoplasia.

[2]  P. Wilson,et al.  Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. , 1993, JAMA.

[3]  P. Taylor,et al.  Folate requirement and metabolism in nonpregnant women. , 1987, The American journal of clinical nutrition.

[4]  P. Toskes,et al.  Malabsorption of crystalline vitamin B 12 in cystic fibrosis. , 1973, The New England journal of medicine.

[5]  Shriniwas,et al.  Mechanism of malabsorption in giardiasis: a study of bacterial flora and bile salt deconjugation in upper jejunum. , 1977, Gut.

[6]  D. Savage,et al.  Anemia in Alcoholics , 1986, Medicine.

[7]  Anne-Lise Bjørke Monsen,et al.  Determinants of cobalamin status in newborns. , 2001, Pediatrics.

[8]  S. J. James,et al.  Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G. Dallal,et al.  Fundic Atrophic Gastritis in an Elderly Population: Effect on Hemoglobin and Several Serum Nutritional Indicators , 1986, Journal of the American Geriatrics Society.

[10]  T. Tamura,et al.  Hepatic folate metabolism in the chronic alcoholic monkey. , 1981, The Journal of laboratory and clinical medicine.

[11]  L. Allen,et al.  Low plasma vitamin B-12 in Kenyan school children is highly prevalent and improved by supplemental animal source foods. , 2007, The Journal of nutrition.

[12]  R. Carmel Prevalence of undiagnosed pernicious anemia in the elderly. , 1996, Archives of internal medicine.

[13]  H. Hata,et al.  A long-term controlled folate feeding study in young women supports the validity of the 1.7 multiplier in the dietary folate equivalency equation. , 2005, The Journal of nutrition.

[14]  P. Khazanie,et al.  Omeprazole Therapy Causes Malabsorption of Cyanocobalamin (Vitamin B12) , 1994, Annals of Internal Medicine.

[15]  Joshua W. Miller,et al.  Transcobalamin II 775G>C polymorphism and indices of vitamin B12 status in healthy older adults. , 2002, Blood.

[16]  R. Carmel,et al.  Associations of food-cobalamin malabsorption with ethnic origin, age, Helicobacter pylori infection, and serum markers of gastritis , 2001, American Journal of Gastroenterology.

[17]  L. Allen,et al.  Vitamin B-12 deficiency is very prevalent in lactating Guatemalan women and their infants at three months postpartum. , 1997, The Journal of nutrition.

[18]  Á. Remacha,et al.  Cobalamin deficiency in patients infected with the human immunodeficiency virus. , 1999, Seminars in hematology.

[19]  P. Dagnelie,et al.  Long-term ovo-lacto vegetarian diet impairs vitamin B-12 status in pregnant women. , 2004, The Journal of nutrition.

[20]  L. Glória,et al.  Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status. , 1996, The American journal of clinical nutrition.

[21]  I. Rosenberg,et al.  Increased urinary excretion and prolonged turnover time of folic acid during ethanol ingestion. , 1983, The American journal of clinical nutrition.

[22]  M. Garcia-Casal,et al.  High prevalence of folic acid and vitamin B12 deficiencies in infants, children, adolescents and pregnant women in Venezuela , 2005, European Journal of Clinical Nutrition.

[23]  S. Daly,et al.  Thermolabile variant of 5, 10-methylenetetrahydrofolate reductaseassociated with low red-cell folates: implications for folate intake recommendations , 1997, The Lancet.

[24]  K. Boddy,et al.  Absorption of cyanocobalamin, coenzyme B 12 , methylcobalamin, and hydroxocobalamin at different dose levels. , 1971, Scandinavian journal of gastroenterology.

[25]  L. Allen,et al.  Prevalent vitamin B-12 deficiency in twelve-month-old Guatemalan infants is predicted by maternal B-12 deficiency and infant diet. , 2007, The Journal of nutrition.

[26]  R. Berlin,et al.  Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. , 2009, Acta medica Scandinavica.

[27]  H. McNulty,et al.  Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. , 1997, QJM : monthly journal of the Association of Physicians.

[28]  A. Pærregaard,et al.  Giardiasis: haematological status and the absorption of vitamin B12 and folic acid , 1992, Acta paediatrica.

[29]  L. Allen,et al.  Iron, vitamin B-12 and folate status in Mexico: associated factors in men and women and during pregnancy and lactation. , 1994, The Journal of nutrition.

[30]  T. Tamura,et al.  Trienzyme Treatment for Food Folate Analysis: Optimal pH and Incubation Time for α-Amylase and Protease Treatments , 1998 .

[31]  I. Aimone-Gastin,et al.  Isoelectrofocusing phenotype and relative concentration of transcobalamin II isoproteins related to the codon 259 Arg/Pro polymorphism. , 1998, Biochemical and biophysical research communications.

[32]  H. McNulty,et al.  Determining bioavailability of food folates in a controlled intervention study. , 2004, The American journal of clinical nutrition.

[33]  L. Allen,et al.  Lack of hemoglobin response to iron supplementation in anemic mexican preschoolers with multiple micronutrient deficiencies. , 2000, The American journal of clinical nutrition.

[34]  A. Devlin,et al.  Reduced folate carrier: tissue distribution and effects of chronic ethanol intake in the micropig. , 2001, Alcoholism, clinical and experimental research.

[35]  R. Carmel Reassessment of the relative prevalences of antibodies to gastric parietal cell and to intrinsic factor in patients with pernicious anaemia: influence of patient age and race , 1992, Clinical and experimental immunology.

[36]  L. Allen,et al.  Vitamin B12 metabolism and status during pregnancy, lactation and infancy. , 1994, Advances in experimental medicine and biology.

[37]  R. Carmel Mild transcobalamin I (haptocorrin) deficiency and low serum cobalamin concentrations. , 2003, Clinical chemistry.

[38]  P. Malfertheiner,et al.  Helicobacter pylori Infection, Vitamin B12 and Homocysteine , 2003, Digestive Diseases.

[39]  K. Goulston,et al.  Cimetidine and malabsorption of cobalamin , 1982, Digestive diseases and sciences.

[40]  V. Herbert,et al.  Staging vitamin B-12 (cobalamin) status in vegetarians. , 1994, The American journal of clinical nutrition.

[41]  J. Nicolas,et al.  Malabsorption of Vitamin B12 in Pancreatic Insufficiency of the Adult and of the Child , 1990, Pancreas.

[42]  M. Narayanan,et al.  Dietary deficiency of vitamin B12 is associated with low serum cobalamin levels in non‐vegetarians , 1991, European journal of haematology.

[43]  L. Allen Impact of vitamin B-12 deficiency during lactation on maternal and infant health. , 2002, Advances in experimental medicine and biology.

[44]  C. Leitzmann,et al.  Homocysteine and cobalamin status in German vegans , 2004, Public Health Nutrition.

[45]  Christopher M Thomas,et al.  Bioavailability of Folate from Processed Spinach in Humans , 2000, Annals of Nutrition and Metabolism.

[46]  P. Wilson,et al.  Prevalence of cobalamin deficiency in the Framingham elderly population. , 1994, The American journal of clinical nutrition.

[47]  O. Paltiel,et al.  Clinical correlates of subnormal vitamin B12 levels in patients infected with the human immunodeficiency virus , 1995, American journal of hematology.

[48]  R. Gräsbeck Biochemistry and clinical chemistry of vitamin B12 transport and the related diseases. , 1984, Clinical biochemistry.

[49]  J. Buring,et al.  Micronutrients and HIV‐1 disease progression , 1995, AIDS.

[50]  L. Allen,et al.  Kenyan school children have multiple micronutrient deficiencies, but increased plasma vitamin B-12 is the only detectable micronutrient response to meat or milk supplementation. , 2003, The Journal of nutrition.

[51]  K. Jeejeebhoy,et al.  Tropical malabsorption syndrome in West India. , 1968, The American journal of clinical nutrition.

[52]  A. Parle‐McDermott,et al.  Evaluation of transcobalamin II polymorphisms as neural tube defect risk factors in an Irish population. , 2005, Birth defects research. Part A, Clinical and molecular teratology.

[53]  C. Castaneda,et al.  Nutritional status indicators and their interactions in rural Guatemalan elderly: a study in San Pedro Ayampuc. , 1997, The American journal of clinical nutrition.

[54]  B. Gazzard,et al.  Intestinal inflammation, ileal structure and function in HIV , 1996, AIDS.

[55]  J. Mann,et al.  Nutrient intake and haematological status of vegetarians and age-sex matched omnivores. , 1994, European journal of clinical nutrition.

[56]  E. Brass,et al.  Inhibition of cobalamin-dependent enzymes by cobalamin analogues in rats. , 1991, The Journal of clinical investigation.

[57]  R. Donaldson,et al.  Effect of cimetidine on intrinsic factor and pepsin secretion in man , 1978 .

[58]  E. J. Norman,et al.  Vitamin B-12 status in a macrobiotic community. , 1991, The American journal of clinical nutrition.

[59]  R. Chandra,et al.  Low serum vitamin B-12 concentrations are associated with faster human immunodeficiency virus type 1 (HIV-1) disease progression. , 1997, The Journal of nutrition.

[60]  F. Santolaria,et al.  High prevalence of hyperhomocysteinemia in chronic alcoholism: the importance of the thermolabile form of the enzyme methylenetetrahydrofolate reductase (MTHFR). , 2001, Alcohol.

[61]  W. Steinberg,et al.  Malabsorption of protein-bound cobalamin but not unbound cobalamin during cimetidine administration , 1980, Digestive Diseases and Sciences.

[62]  P. Correa,et al.  Transmission of Helicobacter pylori among siblings , 2000, The Lancet.

[63]  L. Allen,et al.  Predictors of Cobalamin Deficiency in Guatemalan School Children: Diet, Helicobacter pylori, or Bacterial Overgrowth? , 2003, Journal of pediatric gastroenterology and nutrition.

[64]  I. Rosenberg Tropical enteritis: nutritional consequences and connections with the riddle of cholera. , 2003, Journal of NutriLife.

[65]  L. Allen,et al.  High prevalence of cobalamin deficiency in Guatemalan schoolchildren: associations with low plasma holotranscobalamin II and elevated serum methylmalonic acid and plasma homocysteine concentrations. , 2003, The American journal of clinical nutrition.

[66]  E. Hertrampf,et al.  Prevalence of anemia in elderly subjects living at home: role of micronutrient deficiency and inflammation , 2000, European Journal of Clinical Nutrition.

[67]  P. Toskes,et al.  Vitamin B 12 malabsorption in chronic pancreatic insufficiency. , 1971, The New England journal of medicine.

[68]  P. Kannus,et al.  Determinants of bone mineralization in 8 to 20 year old Finnish females , 1997, European Journal of Clinical Nutrition.

[69]  Marie E. Latulippe,et al.  Milk folate but not milk iron concentrations may be inadequate for some infants in a rural farming community in San Mateo, Capulhuac, Mexico. , 2003, The American journal of clinical nutrition.

[70]  H. Refsum,et al.  Homocysteine and methylmalonic acid levels in pregnant Nepali women. Should cobalamin supplementation be considered? , 2001, European Journal of Clinical Nutrition.

[71]  L. Allen,et al.  Plasma vitamin B-12 concentrations in an elderly latino population are predicted by serum gastrin concentrations and crystalline vitamin B-12 intake. , 2003, The Journal of nutrition.

[72]  S. Vollset,et al.  Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. , 2001, The American journal of clinical nutrition.

[73]  A. Mackey,et al.  Maternal folate status during extended lactation and the effect of supplemental folic acid. , 1999, The American journal of clinical nutrition.

[74]  J. Olivier,et al.  Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation to transcobalamin and homocysteine concentration in blood. , 2001, Blood.

[75]  H. Mykkänen,et al.  Vitamin B-12 status of long-term adherents of a strict uncooked vegan diet ("living food diet") is compromised. , 1995, The Journal of nutrition.

[76]  P. Dagnelie,et al.  Vitamin B-12 from algae appears not to be bioavailable. , 1991, The American journal of clinical nutrition.

[77]  P. Wilson,et al.  The glutamate carboxypeptidase gene II (C>T) polymorphism does not affect folate status in the Framingham Offspring cohort. , 2002, The Journal of nutrition.

[78]  L. Glória,et al.  Nutritional deficiencies in chronic alcoholics: relation to dietary intake and alcohol consumption. , 1997, The American journal of gastroenterology.

[79]  B. von Bonsdorff,et al.  Castle's test (with vitamin B12 and normal gastric juice) in the ileum in patients with genuine and patients with tapeworm pernicious anaemia. , 2009, Acta medica Scandinavica.

[80]  E. Mendes,et al.  Effect of Helicobacter pylori eradication on G-cell and D-cell density in children , 1994, The Lancet.

[81]  F. Vijver,et al.  Signs of impaired cognitive function in adolescents with marginal cobalamin status. , 2000, The American journal of clinical nutrition.

[82]  L. Bailey,et al.  Absorption of folate from fortified cereal-grain products and of supplemental folate consumed with or without food determined by using a dual-label stable-isotope protocol. , 1997, The American journal of clinical nutrition.

[83]  R. Russell,et al.  Bacterial overgrowth without clinical malabsorption in elderly hypochlorhydric subjects. , 1994, Gastroenterology.

[84]  K. West,et al.  Micronutrient deficiencies in the first months of life , 2003 .

[85]  H. van den Berg,et al.  Long-term effects of a vegetarian diet on the nutritional status of elderly people (Dutch Nutrition Surveillance System). , 1990, Journal of the American College of Nutrition.

[86]  L. Allen,et al.  Vitamin B-12 deficiency and malabsorption are highly prevalent in rural Mexican communities. , 1995, The American journal of clinical nutrition.

[87]  W. Thompson,et al.  The relation between ileal resection and vitamin B12 absorption. , 1977, Canadian journal of surgery. Journal canadien de chirurgie.

[88]  L. Allen,et al.  Vitamin B-12: low milk concentrations are related to low serum concentrations in vegetarian women and to methylmalonic aciduria in their infants. , 1990, The American journal of clinical nutrition.

[89]  B. Seetharam,et al.  Polymorphism of human transcobalamin II: substitution of proline and/or glutamine residues by arginine. , 1994, Biochimica et biophysica acta.

[90]  E. Haddad,et al.  Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. , 1999, The American journal of clinical nutrition.

[91]  P. Schneider,et al.  Quantitation of in vivo human folate metabolism. , 2004, The American journal of clinical nutrition.

[92]  E. Hertrampf,et al.  Folic acid fortification of wheat flour: Chile. , 2004, Nutrition reviews.

[93]  A. Melse-Boonstra,et al.  Bioavailability of heptaglutamyl relative to monoglutamyl folic acid in healthy adults. , 2004, The American journal of clinical nutrition.

[94]  D. Weir,et al.  Folate metabolism, the enterohepatic circulation and alcohol. , 1985, Biochemical pharmacology.

[95]  G. Shaw,et al.  Gene–Nutrient Interactions: Importance of Folic Acid and Vitamin B12 During Early Embryogenesis , 2008, Food and nutrition bulletin.

[96]  C. Beyan,et al.  Helicobacter pylori--is it a novel causative agent in Vitamin B12 deficiency? , 2000, Archives of internal medicine.

[97]  Organic Acids in Selected Foods Inhibit Intestinal Brush Border Pteroylpolyglutamate Hydrolase in Vitro: Potential Mechanism Affecting the Bioavailability of Dietary Polyglutamyl Folate. , 1998, Journal of agricultural and food chemistry.

[98]  L. Allen,et al.  Assuring Micronutrient Adequacy in the Diets of Young Infants , 2003 .

[99]  C. S. Davidson,et al.  Correlation of folate deficiency with alcoholism and associated macrocytosis, anemia, and liver disease. , 1963, Annals of internal medicine.

[100]  J. Arcot,et al.  Folate retention in selected processed legumes , 2000 .

[101]  J. Gregory Bioavailability of folate. , 1997, European journal of clinical nutrition.

[102]  R. Carmel Malabsorption of food cobalamin. , 1995, Bailliere's clinical haematology.

[103]  P. Dagnelie,et al.  Macrobiotic nutrition and child health: results of a population-based, mixed-longitudinal cohort study in The Netherlands. , 1994, The American journal of clinical nutrition.

[104]  I. Darnton-Hill,et al.  Vitamin and iron status in new vegetarians. , 1987, The American journal of clinical nutrition.

[105]  B. Shane,et al.  Folate bioavailability in humans: effects of wheat bran and beans. , 1988, The American journal of clinical nutrition.

[106]  J. Malin Total folate activity in Brussels sprouts: the effects of storage, processing, cooking and ascorbic acid content , 2007 .

[107]  H. McNulty,et al.  The effect of different cooking methods on folate retention in various foods that are amongst the major contributors to folate intake in the UK diet. , 2002, The British journal of nutrition.

[108]  R. Donaldson Small bowel bacterial overgrowth. , 1970, Advances in internal medicine.

[109]  K. Hjelt,et al.  The Impact of Gluten on Haematological Status, Dietary Intakes of Haemopoietic Nutrients and Vitamin B12 and Folic Acid Absorption in Children with Coeliac Disease , 1990, Acta paediatrica Scandinavica.

[110]  M. Blaser,et al.  Helicobacter pylori infection and food-cobalamin malabsorption , 1994, Digestive Diseases and Sciences.

[112]  W. Herrmann,et al.  Total homocysteine, vitamin B(12), and total antioxidant status in vegetarians. , 2001, Clinical chemistry.

[113]  R. Carmel,et al.  Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels. , 1988, Archives of internal medicine.

[114]  P. Ueland,et al.  Homocysteine and methylmalonic acid in diagnosis and risk assessment from infancy to adolescence. , 2003, The American journal of clinical nutrition.

[115]  R. Obeid,et al.  Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. , 2003, The American journal of clinical nutrition.

[116]  L. Allen,et al.  Review of the Magnitude of Folate and Vitamin B12 Deficiencies Worldwide , 2008, Food and nutrition bulletin.

[117]  K. Shelnutt,et al.  The methylenetetrahydrofolate reductase 677C->T polymorphism and dietary folate restriction affect plasma one-carbon metabolites and red blood cell folate concentrations and distribution in women. , 2005, The Journal of nutrition.

[118]  E. Eichner,et al.  The evolution of anemia in alcoholic patients. , 1971, The American journal of medicine.

[119]  A. D. Smith,et al.  Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia. , 2000, Human molecular genetics.

[120]  R. Jensen,et al.  Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. , 1998, The American journal of medicine.

[121]  T. Dick,et al.  Diphyllobothriasis: update on human cases, foci, patterns and sources of human infections and future considerations. , 2001, The Southeast Asian journal of tropical medicine and public health.

[122]  C. M. Leevy,et al.  Incidence and significance of hypovitaminemia in a randomly selected municipal hospital population. , 1965, The American journal of clinical nutrition.

[123]  R. Carmel 10 Malabsorption of food cobalamin , 1995 .

[124]  L. Allen,et al.  Community and International Nutrition Iron, Vitamin B-12 and Folate Status in Mexico: Associated Factors in Men and Women and during Pregnancy and Lactation1'2'3 , 1994 .

[125]  R. Russell,et al.  Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. , 1991, Gastroenterology.