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TABLE 1 Dietary Reference Intakes for Vitamin B 12 by Life Stage Group DRI values (mg/day) EARa RDAb AIc ULd males females males females Life stage group 0 through 6 mo 0.4 7 through 12 mo 0.5 1 through 3 y 0.7 0.7 0.9 0.9 4 through 8 y 1.0 1.0 1.2 1.2 9 through 13 y 1.5 1.5 1.8 1.8 14 through 18 y 2.0 2.0 2.4 2.4 19 through 30 y 2.0 2.0 2.4 2.4 31 through 50 y 2.0 2.0 2.4 2.4 2.4e 2.4e 51 through 70 y 2.0 2.0 2.4e 2.4e > 70 y 2.0 2.0 Pregnancy £ 18 y 2.2 2.6 19 through 50 y 2.2 2.6 Lactation £ 18 y 2.4 2.8 19 through 50 y 2.4 2.8 a EAR = Estimated Average Requirement. b RDA = Recommended Dietary Allowance. c AI = Adequate Intake. d UL = Tolerable Upper Intake Level. Data were insufficient to set a UL. In the absence of a UL, extra caution may be warranted in consuming levels above the recommended intake. e Because 10 to 30 percent of older people may malabsorb food-bound vitamin B12, for adults over 50 years old it is advisable for most of this amount to be obtained by consuming foods fortified with vitamin B12 or a vitamin B12-containng supplement.

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PART III: VITAMIN B12 189 VITAMIN B12 V itamin B12 (cobalamin) functions as a coenzyme for a critical reaction that converts homocysteine to methionine and in the metabolism of fatty acids of odd chain length. An adequate supply of vitamin B12 is essential for normal blood formation and neurological function. The requirements for vitamin B12 are based on the amount needed to main- tain hematological status and normal serum vitamin B12 values. An assumed absorption of 50 percent is included in determining the Estimated Average Re- quirement (EAR). Data were insufficient to set a Tolerable Upper Intake Level (UL). DRI values are listed by life stage group in Table 1. Because 10–30 percent of older people may be unable to absorb naturally occurring vitamin B12, most likely due to atrophic gastritis, it is advisable for those older than 50 years to meet their needs mainly by consuming foods forti- fied with vitamin B12 or by taking a supplement that contains it. Individuals with vitamin B12 deficiency caused by a lack of intrinsic factor require medical treatment. Naturally occurring vitamin B12 is found primarily in foods of animal ori- gin. Many plant-based foods are fortified with the vitamin. The major cause of vitamin B12 deficiency is pernicious anemia, a condition in which the stomach does not produce intrinsic factor. The hematological effects that occur with this deficiency are identical to those that accompany folate deficiency. No adverse effects have been associated with excess vitamin B12 intake from food or supple- ments in healthy individuals. The apparent low toxicity of the vitamin may be because, when high doses are given orally, only a small percentage of it can be absorbed from the gastrointestinal tract. VITAMIN B12 AND THE BODY Function Vitamin B12 (cobalamin) functions as a coenzyme for a critical reaction that converts homocysteine to methionine and for a separate reaction in the me- tabolism of fatty acids and amino acids. An adequate supply of vitamin B12 is essential for normal blood formation and neurological function. Although the preferred scientific use of the term vitamin B12 is usually restricted to cyanoco- balamin, in this publication vitamin B12 refers to all potentially biologically ac- tive cobalamins.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 190 Absorption, Metabolism, Storage, and Excretion Small amounts of vitamin B12 are absorbed by an active process that requires an intact stomach, intrinsic factor (a glycoprotein that the parietal cells of the stom- ach secrete after being stimulated by food), pancreatic sufficiency, and a nor- mally functioning terminal ileum. Vitamin B12 is processed in the stomach and the small intestine before being released into the circulation. The liver takes up approximately 50 percent of circulating nutrient; the remainder is transported to other tissues. There is a lack of data on the absorption of vitamin B12 from many foods. Therefore, for this publication, a conservative adjustment for the bioavailability of naturally occurring vitamin B12 was used. In particular, it is assumed that 50 percent of dietary vitamin B12 is absorbed by healthy adults with normal gastric function. If there is a lack of intrinsic factor (as in the case of pernicious anemia), malabsorption of the vitamin results. If untreated, this may lead to potentially irreversible neurological damage and possibly life-threatening anemia. Malab- sorption also results from atrophic gastritis with low stomach acid secretion, a condition estimated to occur in 10–30 percent of people older than 50 years. Vitamin B12 is continually secreted in the bile. In healthy individuals, most of it is reabsorbed and available for metabolic functions. However, in the ab- sence of intrinsic factor, essentially all the vitamin B12 from the bile is excreted in the stool rather than recirculated. Thus, deficiency develops more rapidly in individuals who have no intrinsic factor or who malabsorb vitamin B12 for other reasons than it does in those who do not ingest it (such as those with complete vegetarian diets). The excretion of vitamin B12 is proportional to body stores; it is excreted mainly in the stool but also in the urine and through the skin. DETERMINING DRIS Determining Requirements The requirements for vitamin B12 are based on the amount needed to maintain hematological status and normal serum vitamin B12 values. An assumed ab- sorption of 50 percent is included in determining the EAR. Special Considerations Aging and atrophic gastritis: Vitamin B12 status tends to decline with age, per- haps due to a decrease in gastric acidity and the presence of atrophic gastritis and of bacterial overgrowth accompanied by malabsorption of food-bound vitamin B12. It is estimated that approximately 10–30 percent of elderly people

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PART III: VITAMIN B12 191 have atrophic gastritis, although the condition may often go undiagnosed. Thus, it is advisable for those older than 50 years to meet their needs mainly by consuming foods fortified with vitamin B12 or by taking a supplement that contains it. Infants of vegan mothers: Infants of vegan mothers should be supplemented with vitamin B12 at the level of the AI from birth because their stores at that time are low and their mothers’ milk may supply very small amounts of the vitamin. Individuals with increased needs: A person with any malabsorption syndrome will likely require increased amounts of vitamin B12. Patients with pernicious anemia or Crohn’s disease involving the terminal ileum and patients who have had a gastrectomy, gastric bypass surgery, or ileal resection will require the nu- trient under a physician’s direction. People who are HIV-positive with chronic diarrhea may also require either increased oral or parenteral vitamin B12. Pa- tients with atrophic gastritis, pancreatic insufficiency, or prolonged omeprazole treatment will have decreased bioavailability of food-bound vitamin B12 and will require normal amounts of crystalline vitamin B12 (either in fortified foods or in a supplement). Criteria for Determining Vitamin B12 Requirements, by Life Stage Group Life stage group Criterion 0 through 6 mo Human milk content 7 through 12 mo Extrapolation from younger infants 1 through 18 y Extrapolation from adults 19 through > 70 y Amount needed to maintain hematological status and normal serum vitamin B12 values Pregnancy £ 18 y through 50 y Age-specific requirement + fetal deposition of the vitamin B12 Lactation £ 18 y through 50 y Age-specific requirement + amount of vitamin B12 secreted in human milk The UL The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse effects for almost all people. Due to inadequate data on adverse effects of excess vitamin B12 consumption, a UL for the vitamin could not be determined.

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 192 Based on data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994), the highest median intake of B12 from diet and supplements for any life stage and gender group was 17 mg/day; the highest reported intake at the 95th percentile was 37 mg/day. Furthermore, there appear to be no risks associated with intakes from supplemental B12 that are more than two orders of magnitude higher than the 95th percentile intake. However, this does not mean that there is no potential for adverse effects to occur with high intakes. DIETARY SOURCES Foods Vitamin B12 is naturally found in foods of animal origin. It is also found in plant-based foods that have been fortified, such as ready-to-eat cereals and meal replacement formulas. Particularly rich sources of natural vitamin B12 such as shellfish, organ meats such as liver, some game meats (such as venison and rabbit), and some fish (such as herring, sardines, and trout) are not a regular part of many people’s diets. According to the Continuing Survey of Food In- takes by Individuals (CSFII, 1994–1996), the greatest contributors to vitamin B12 intake in U.S. adults were mixed foods (including sandwiches) with meat, fish, or poultry as the main ingredient. For women, the second highest con- tributor to intake was milk and milk beverages; for men it was beef. Fortified ready-to-eat cereals contributed a greater proportion of dietary vitamin B12 for women than for men. Although milk is a good source of vitamin B12, cooking it may greatly re- duce its vitamin content. For example, boiling milk for 10 minutes reduces vitamin B12 content by about 50 percent. Dietary Supplements In the United States, cyanocobalamin is the only commercially available vita- min B12 preparation used in supplements and pharmaceuticals. It is also the principal form used in Canada. Approximately 26 percent of all adults reported taking a supplement that contained vitamin B12, according to the 1986 National Health Interview Survey (NHIS). For adults over age 60 years who took sup- plements and participated in the Boston Nutritional Status Survey, median supplemental vitamin B12 intakes were 5.0 mg/day for men and 6.0 mg/day for women.

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PART III: VITAMIN B12 193 Bioavailability Data on the bioavailability of vitamin B12 are few. Studies have found the ab- sorption of the nutrient in healthy adults to be 65 percent from mutton, 11 percent from liver, 24–36 percent from eggs, 60 percent from chicken, and 25– 47 percent from trout. Because of a lack of data on dairy foods and most forms of red meat and fish, a conservative adjustment for the bioavailability of natu- rally occurring vitamin B12 was used for this publication. In particular, it is assumed that 50 percent of dietary vitamin B12 is absorbed by healthy adults with normal gastric function. Dietary Interactions There is evidence that vitamin B12 may interact with certain nutrients (see Table 2). TABLE 2 Potential Interactions with Other Nutrients Substance Potential Interaction Notes NUTRIENTS THAT AFFECT VITAMIN B12 Folate Adequate or high folate intake There is no evidence that folate intake or status may mitigate the effects of changes the requirement for vitamin B12. a vitamin B12 deficiency on normal blood formation. INADEQUATE INTAKE AND DEFICIENCY The clinical effects of vitamin B12 deficiency are hematological, neurological, and gastrointestinal: • Hematological effects: The major cause of vitamin B12 deficiency is perni- cious anemia, a condition in which the gastric mucosa of the stomach does not produce intrinsic factor. The hematological effects of vitamin B12 deficiency include weakness, fatigue, shortness of breath, and palpi- tations. These effects are identical to those observed in folate deficiency. As in folate deficiency, the underlying mechanism of anemia is an inter- ference with normal deoxyribonucleic acid (DNA) synthesis. This re- sults in megaloblastic change, which causes the production of larger- than-normal erythrocytes (macrocytosis). By the time anemia is established, there is usually also some degree of neutropenia and throm- bocytopenia because the megaloblastic process affects all rapidly divid-

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DRIs: THE ESSENTIAL GUIDE TO NUTRIENT REQUIREMENTS 194 ing bone-marrow elements. The hematological complications are com- pletely reversed by treatment with vitamin B12. • Neurological effects: Neurological complications are present in 75–90 per- cent of individuals with clinically observable vitamin B12 deficiency and may, in about 25 percent of cases, be the only clinical manifestation of deficiency. Evidence is mounting that the occurrence of neurological complications is inversely correlated with the degree of anemia; that is, patients who are less anemic show more prominent neurological com- plications, and vice versa. Neurological manifestations include tingling and numbness in the extremities (worse in the lower limbs), gait distur- bances, and cognitive changes such as loss of concentration, memory loss, disorientation, and dementia, with or without mood changes. Vi- sual disturbances, insomnia, impotency, and impaired bowel and blad- der control. • Gastrointestinal effects: Vitamin B12 deficiency is also frequently associ- ated with various gastrointestinal complaints, including sore tongue, loss of appetite, flatulence, and constipation. Some of these gastrointes- tinal effects may be related to the underlying gastric disorder in perni- cious anemia. EXCESS INTAKE No adverse effects have been associated with excess vitamin B12 intake from food or supplements in healthy individuals. The apparent low toxicity of the vitamin may be because, when high doses are orally given, only a small per- centage of it can be absorbed from the gastrointestinal tract. Although there are extensive data showing no adverse effects associated with high intakes of supple- mental vitamin B12, the studies in which such intakes were reported were not designed to assess adverse effects.

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PART III: VITAMIN B12 195 KEY POINTS FOR VITAMIN B12 Vitamin B12 (cobalamin) functions as a coenzyme for a reaction 3 that converts homocysteine to methionine and for a separate reaction in the metabolism of certain fatty acids and amino acids. Although the preferred scientific use of the term vitamin B12 is 3 usually restricted to cyanocobalamin, in this publication vitamin B12 refers to all potentially biologically active cobalamins. The requirements for vitamin B12 are based on the amount 3 needed to maintain hematological status and normal serum vitamin B12 values. Data were insufficient to set a UL. 3 Because 10–30 percent of older people may be unable to 3 absorb naturally occurring vitamin B12, it is advisable for those older than 50 years to meet their needs mainly by consuming foods fortified with vitamin B12 or by taking a supplement that contains vitamin B12. A person with any malabsorption syndrome will likely require 3 increased amounts of vitamin B12. Individuals with vitamin B12 deficiency caused by a lack of 3 intrinsic factor require medical treatment. Vitamin B12 is naturally found in foods of animal origin. It is also 3 found in plant-based foods that have been fortified, such as ready-to-eat cereals and meal replacement formulas. Although milk is a good source, cooking it may greatly reduce its vitamin B12 content. The major cause of vitamin B12 deficiency is pernicious anemia, 3 a condition in which the gastric mucosa of the stomach does not produce intrinsic factor. The hematological effects that occur with this deficiency are identical to those observed in folate deficiency. No adverse effects have been associated with excess vitamin 3 B12 intake from food or supplements in healthy individuals. The apparent low toxicity of the vitamin may be because, when high doses are orally given, only a small percentage of it can be absorbed from the gastrointestinal tract.