Insufficient intake or disrupted absorption of B12 will cause a deficiency. According to the recommended dietary intake (RDI) guidelines from the National Research Council of the US National Academy of Sciences, adults should ingest 2.4 μg B12 daily, pregnant women up to 6 μg (1). The calculation of the required amount is based on the amount of B12 that is necessary to sustain a normal hematological status [normal hemoglobin and mean corpuscular volume of erythrocytes (MCV)] and to maintain remission in pernicious anemia. The RDI was not based on metabolic studies relating B12 intake with MMA concentrations. Plasma concentration of MMA and tHcy falls at higher B12 intake, whereas the holoTC concentration increases (2). A minimum daily intake of 6 μg B12 was associated with optimal plasma concentrations of the investigated biomarkers (2). The recommended daily intake of B12 should be reconsidered and seems too low, especially for older people.
Vitamin B12 is important for DNA synthesis, the formation and maintenance of myelin sheaths, the synthesis of neurotransmitters, and erythropoiesis. Clinical B12 deficiency has two main manifestations: hematological and neuropsychiatric disorders. Symptoms often develop before a shortfall on the lower B12 reference limit. Macrocytic anemia is not specific and not sensitive for B12 deficiency. The macrocytosis caused by B12 deficiency can be masked by concomitant iron deficiency. The B12 deficiency can cause an additional loss of iron by means of a secondary effect on the enterocytes. B12 deficiency develops after many years of depletion. The depletion of the B12 stores is followed by metabolic-functional deficiency (enzyme activities are limited, increase of HCY and MMA), and finally the clinical manifestation.
Patients with vitamin B12 deficiency develop hyperhomocysteinemia (HHCY) which is an atherogenic risk factor and a sign of hypomethylation. Hypomethylation reflects the reduced availability of S-adenosylmethionine (SAM), which is a universal methyl group donor. B12 deficiency causes lower methionine synthesis, with subsequent lowering of the SAM concentration. Funicular spinal cord disease (myelosis) is a common neurological sequel of B12 deficiency. Morphological changes to blood and bone marrow cells are among the main symptoms of B12 deficiency. Because of their high cell turnover rate, hematopoiesis reacts rapidly and sensitively to the blocked nucleic acid metabolism. Megaloblastic anemia in B12 deficiency develops as a result of disrupted DNA synthesis and the resultant maturation disorder of the cell nucleus, whereas the cytoplasm develops normally. In the periphery, macrocytic erythrocytes (MCV > 110 fL) and hypersegmented neutrophils can be observed.
The psychiatric and neurological disorders and the cognitive disorders, depression, or dementia that are observed in B12 deficiency can precede hematological anomalies by years. Hematological anomalies might be completely absent in severely B12 deficient patients.
Pernicious anemia (PA) is the most famous disorder of vitamin B12 absorption and one of the most frequent among elderly patients (up to 50% of the cases). PA is an autoimmune disease that relates on antibodies against intrinsic factor (IF). Atrophic gastritis is also an autoimmune condition that eventually manifests itself as PA. Antibodies against parietal cells or those against IF are considered as characteristics of the disease. Parietal cell antibodies can cause lack of IF resulting in B12 deficiency. Without IF B12 cannot be absorbed by the receptor-mediated pathway. IF antibodies are only detected in about 50% of patients with PA whereas parietal cell antibodies which target the H+/K+ adenosine triphosphatase α and β subunits, are more frequent and found in > 90% of PA patients; but their specificity is much lower (50%) (3). In a study on patients with atrophic gastritis, B12 deficiency, and macrocytic anemia were found in about 50% of the cases and IF antibodies were detected in 27% but parietal cell antibodies were positive in 81% of the atrophic body gastritis patients (4).
1. Institute of Medicine. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. USA: Washington, DC, National Academy Press, 2000:150-95.
2. Bor MV, Lydeking-Olsen E, Moller J, Nexo E. A daily intake of approximately 6 microg vitamin B-12 appears to saturate all the vitamin B-12-related variables in Danish postmenopausal women. Am J Clin Nutr 2006;83:52-8.
3. Toh BH, van Driel I, Gleeson PA. Pernicious anemia. N Engl J Med 1997;337:1441-8.
4. Lahner E, Norman GL, Severi C, Encabo S, Shums Z, Vannella L et al. Reassessment of intrinsic factor and parietal cell autoantibodies in atrophic gastritis with respect to cobalamin deficiency. Am J Gastroenterol 2009;104:2071-9.