Physiology of vitamin B12 and folate deficiency
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Blood Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
Vitamin B12 (cobalamin, Cbl) and/or folate deficiency can cause a characteristic megaloblastic anemia with ineffective erythropoiesis [1,2]. The anemia of Cbl deficiency may be accompanied by characteristic neurologic abnormalities. This topic will review the normal physiologic functions of Cbl and folate and the mechanisms by which deficiency of these vitamins can lead to clinical disease. The causes and clinical manifestations of these disorders are discussed separately. (See "Etiology and clinical manifestations of vitamin B12 and folate deficiency".)
The terms "folate" and "folic acid" are sometimes used interchangeably; however, the vitamin is found in nature as a folate while folic acid (FA) is the synthetic, therapeutic form.
METABOLISM OF FOLATE AND VITAMIN B12
The megaloblastic features are identical in deficiencies of FA and Cbl. The two vitamins are intertwined biochemically so that the final common pathway that impairs DNA synthesis in hematopoietic cells is the same when either vitamin is deficient (figure 1). As will be described below, however, neuropathy occurs only with Cbl deficiency, indicating that additional mechanisms are involved in the central nervous system.
Folate — Folate occurs in animal products and in leafy vegetables in the polyglutamate form [1,3]. The daily folate requirement for unstressed adults is estimated to be approximately 50 mcg/day; the estimated requirement for infants and children ranges from 5 to 50 mcg/day. On a more practical level, however, the Recommended Dietary Allowance (RDA) for adults is 400 mcg of dietary folate equivalents per day; for lactating and pregnant women, RDA includes an additional 100 and 200 mcg per day, respectively, of dietary folate equivalents . The RDA for children in the toddler stage through adolescence ranges from 50 to 200 mcg/day.
Dietary folate in the form of the polyglutamates is cleaved to the monoglutamate in the jejunum where it is absorbed . Folates enter plasma and are rapidly cleared by entering hepatocytes and other cells. Surgical biliary drainage results in a reduction in serum folate within six hours, whereas dietary restriction does not produce a comparable fall for three weeks, presumably because total body stores of folate are estimated to be between 500 to 20,000 mcg . This observation indicates that there is a large enterohepatic circulation of folate.
- Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin Proc 1994; 69:144.
- Allen RH, Stabler SP, Savage DG, Lindenbaum J. Metabolic abnormalities in cobalamin (vitamin B12) and folate deficiency. FASEB J 1993; 7:1344.
- Tefferi A, Pruthi RK. The biochemical basis of cobalamin deficiency. Mayo Clin Proc 1994; 69:181.
- Bailey LB, Gregory JF 3rd. Folate metabolism and requirements. J Nutr 1999; 129:779.
- Anthony CA. Megaloblastic anemias. In: Hematology: Basic Principles and Practice, 2nd ed, Hoffman R, Benz EJ, Shattil SJ, et al. (Eds), Churchill Livingston, New York 1995. p.552.
- Moestrup SK. New insights into carrier binding and epithelial uptake of the erythropoietic nutrients cobalamin and folate. Curr Opin Hematol 2006; 13:119.
- Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin deficiency. Neurology 1995; 45:1435.
- SULLIVAN LW, HERBERT V. STUDIES ON THE MINIMUM DAILY REQUIREMENT FOR VITAMIN B12. HEMATOPOIETIC RESPONSES TO 0.1 MICROGM. OF CYANOCOBALAMIN OR COENZYME B12, AND COMPARISON OF THEIR RELATIVE POTENCY. N Engl J Med 1965; 272:340.
- Carmel R, Vasireddy H, Aurangzeb I, George K. High serum cobalamin levels in the clinical setting--clinical associations and holo-transcobalamin changes. Clin Lab Haematol 2001; 23:365.
- Andrès E, Serraj K, Zhu J, Vermorken AJ. The pathophysiology of elevated vitamin B12 in clinical practice. QJM 2013; 106:505.
- Seetharam B, Christensen EI, Moestrup SK, et al. Identification of rat yolk sac target protein of teratogenic antibodies, gp280, as intrinsic factor-cobalamin receptor. J Clin Invest 1997; 99:2317.
- Fyfe JC, Madsen M, Højrup P, et al. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood 2004; 103:1573.
- He Q, Madsen M, Kilkenney A, et al. Amnionless function is required for cubilin brush-border expression and intrinsic factor-cobalamin (vitamin B12) absorption in vivo. Blood 2005; 106:1447.
- Moestrup SK, Kozyraki R, Kristiansen M, et al. The intrinsic factor-vitamin B12 receptor and target of teratogenic antibodies is a megalin-binding peripheral membrane protein with homology to developmental proteins. J Biol Chem 1998; 273:5235.
- Birn H, Willnow TE, Nielsen R, et al. Megalin is essential for renal proximal tubule reabsorption and accumulation of transcobalamin-B(12). Am J Physiol Renal Physiol 2002; 282:F408.
- Gasteyger C, Suter M, Gaillard RC, Giusti V. Nutritional deficiencies after Roux-en-Y gastric bypass for morbid obesity often cannot be prevented by standard multivitamin supplementation. Am J Clin Nutr 2008; 87:1128.
- Beedholm-Ebsen R, van de Wetering K, Hardlei T, et al. Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin. Blood 2010; 115:1632.
- Miller JW, Ramos MI, Garrod MG, et al. Transcobalamin II 775G>C polymorphism and indices of vitamin B12 status in healthy older adults. Blood 2002; 100:718.
- Ermens AA, Vlasveld LT, Lindemans J. Significance of elevated cobalamin (vitamin B12) levels in blood. Clin Biochem 2003; 36:585.
- Chiche L, Jean R, Romain F, et al. [Clinical implications of high cobalamin blood levels for internal medicine]. Rev Med Interne 2008; 29:187.
- Rachmilewitz B, Manny N, Rachmilewitz M. The transcobalamins in polycythaemia vera. Scand J Haematol 1977; 19:453.
- Jammal M, Deneuville T, Mario N, et al. [High plasmatic concentration of vitamin B12: an indicator of hepatic diseases or tumors]. Rev Med Interne 2013; 34:337.
- Weir DG, Scott JM. The biochemical basis of the neuropathy in cobalamin deficiency. Baillieres Clin Haematol 1995; 8:479.
- Scalabrino G, Peracchi M. New insights into the pathophysiology of cobalamin deficiency. Trends Mol Med 2006; 12:247.
- Scalabrino G, Veber D, Mutti E. New pathogenesis of the cobalamin-deficient neuropathy. Med Secoli 2007; 19:9.
- Smulders YM, Smith DE, Kok RM, et al. Cellular folate vitamer distribution during and after correction of vitamin B12 deficiency: a case for the methylfolate trap. Br J Haematol 2006; 132:623.
- Koury MJ, Horne DW. Apoptosis mediates and thymidine prevents erythroblast destruction in folate deficiency anemia. Proc Natl Acad Sci U S A 1994; 91:4067.
- Wickramasinghe SN. Morphology, biology and biochemistry of cobalamin- and folate-deficient bone marrow cells. Baillieres Clin Haematol 1995; 8:441.
- Ingram CF, Davidoff AN, Marais E, et al. Evaluation of DNA analysis for evidence of apoptosis in megaloblastic anaemia. Br J Haematol 1997; 96:576.
- METABOLISM OF FOLATE AND VITAMIN B12
- Vitamin B12
- - Elevated levels of vitamin B12
- Physiologic roles of vitamin B12 and folate
- CONSEQUENCES OF B12 AND FOLATE DEFICIENCY
- Pathophysiology of megaloblastosis
- Ineffective erythropoiesis
- Ineffective megakaryocytopoiesis
- INFORMATION FOR PATIENTS