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9
Vitamin B12

SUMMARY

Vitamin B12 (cobalamin) functions as a coenzyme for a critical methyl transfer reaction that converts homocysteine to methionine and for a separate reaction that converts L-methylmalonyl-coenzyme A (CoA) to succinyl-CoA. The Recommended Dietary Allowance (RDA) for vitamin B12 is based on the amount needed for the maintenance of hematological status and normal serum vitamin B12 values. An assumed absorption of 50 percent is included in the recommended intake. The RDA for adults is 2.4 µg/ day of vitamin B12. Because 10 to 30 percent of older people may be unable to absorb naturally occurring vitamin B12, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B12 or a vitamin B12-containing supplement. Individuals with vitamin B12 deficiency caused by a lack of intrinsic factor require medical treatment. The median intake of vitamin B12 from food in the United States was estimated to be approximately 5 µg/day for men and 3.5 µg/day for women. The ninety-fifth percentile of vitamin B12 intake from both food and supplements was approximately 27 µg/day. In one Canadian province the mean dietary intake was estimated to be approximately 7 µg/day for men and 4 µg/day for women. There is not sufficient scientific evidence to set a Tolerable Upper Intake Level (UL) for vitamin B12 at this time.



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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline 9 Vitamin B12 SUMMARY Vitamin B12 (cobalamin) functions as a coenzyme for a critical methyl transfer reaction that converts homocysteine to methionine and for a separate reaction that converts L-methylmalonyl-coenzyme A (CoA) to succinyl-CoA. The Recommended Dietary Allowance (RDA) for vitamin B12 is based on the amount needed for the maintenance of hematological status and normal serum vitamin B12 values. An assumed absorption of 50 percent is included in the recommended intake. The RDA for adults is 2.4 µg/ day of vitamin B12. Because 10 to 30 percent of older people may be unable to absorb naturally occurring vitamin B12, it is advisable for those older than 50 years to meet their RDA mainly by consuming foods fortified with vitamin B12 or a vitamin B12-containing supplement. Individuals with vitamin B12 deficiency caused by a lack of intrinsic factor require medical treatment. The median intake of vitamin B12 from food in the United States was estimated to be approximately 5 µg/day for men and 3.5 µg/day for women. The ninety-fifth percentile of vitamin B12 intake from both food and supplements was approximately 27 µg/day. In one Canadian province the mean dietary intake was estimated to be approximately 7 µg/day for men and 4 µg/day for women. There is not sufficient scientific evidence to set a Tolerable Upper Intake Level (UL) for vitamin B12 at this time.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline BACKGROUND INFORMATION Cobalamin is the general term used to describe a group of cobalt-containing compounds (corrinoids) that have a particular structure that contains the sugar ribose, phosphate, and a base (5, 6-dimethyl benzimidazole) attached to the corrin ring. Vitamin B12 can be converted to either of the two cobalamin coenzymes that are active in human metabolism: methylcobalamin and 5-deoxyadenosylcobalamin. Although the preferred scientific use of the term vitamin B12 is usually restricted to cyanocobalamin, in this report, B12 will refer to all potentially biologically active cobalamins. In the United States, cyanocobalamin is the only commercially available B12 preparation used in supplements and pharmaceuticals. It is also the principal form used in Canada (B. A. Cooper, Department of Hematology, Stanford University, personal communication, 1997). Another form, hydroxocobalamin, has been used in some studies of B12. Compared with hydroxocobalamin, cyanocobalamin binds to serum proteins less well and is excreted more rapidly (Tudhope et al., 1967). Function B12 is a cofactor for two enzymes: methionine synthase and L-methylmalonyl-CoA mutase. Methionine synthase requires methylcobalamin as a cofactor for the methyl transfer from methyltetrahydrofolate to homocysteine to form methionine and tetrahydrofolate. L-Methymalonyl-CoA mutase requires adenosylcobalamin to convert L-methymalonyl-CoA to succinyl-CoA in an isomerization reaction. In B12 deficiency, folate may accumulate in the serum as a result of slowing of the B12-dependent methyltransferase. An adequate supply of B12 is essential for normal blood formation and neurological function. Physiology of Absorption, Metabolism, Storage, and Excretion Small amounts of B12 are absorbed via an active process that requires an intact stomach, intrinsic factor (a glycoprotein that the parietal cells of the stomach secrete after being stimulated by food), pancreatic sufficiency, and a normally functioning terminal ileum. In the stomach, food-bound B12 is dissociated from proteins in the presence of acid and pepsin. The released B12 then binds to R proteins (haptocorrins) secreted by the salivary glands and the gastric mucosa. In the small intestine, pancreatic proteases partially de-

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline grade the R proteins, releasing B12 to bind with intrinsic factor. The resulting complex of intrinsic factor and B12 attaches to specific receptors in the ileal mucosa; after internalization of the complex, B12 enters the enterocyte. Approximately 3 to 4 hours later, B12 enters the circulation. All circulating B12 is bound to the plasma binding proteins—transcobalamin I, II, or III (TCI, TCII, or TCIII). Although TCI binds approximately 80 percent of the B12 carried in the blood, TCII is the form that delivers B12 to the tissues through specific receptors for TCII (Hall and Finkler, 1966; Seetharam and Alpers, 1982). The liver takes up approximately 50 percent of the B12 and the remainder is transported to other tissues. If there is a lack of intrinsic factor (as is the case in the condition called pernicious anemia), malabsorption of B12 results; if this is untreated, potentially irreversible neurological damage and life-threatening anemia develop. The average B12 content of liver tissue is approximately 1.0 µg/g of tissue in healthy adults (Kato et al., 1959; Stahlberg et al., 1967). Estimates of the average total-body B12 pool in adults range from 0.6 (Adams et al., 1972) to 3.9 mg (Grasbeck et al., 1958), but most estimates are between 2 and 3 mg (Adams, 1962; Adams et al., 1970; Heinrich, 1964; Reizenstein et al., 1966). The highest estimate found for an individual’s total body B12 store was 11.1 mg (Grasbeck et al., 1958). Excretion of B12 is proportional to stores (see “Excretion”). Absorption Studies to measure the actual absorption of B12 involve wholebody counting of radiolabeled B12, counting of radiolabeled B12 in the stool, or both. No data are available on whether B12 absorption varies with B12 status, but fractional absorption decreases as the oral dose is increased (Chanarin, 1979). Total absorption increases with increasing intake. Adams and colleagues (1971) measured fractional absorption of radiolabeled cyanocobalamin and reported that nearly 50 percent was retained at a 1-µg dose, 20 percent at a 5-µg dose, and just over 5 percent at a 25-µg dose. The second of two doses of B12 given 4 to 6 hours apart is absorbed as well as the first (Heyssel et al., 1966). When large doses of crystalline B12 are ingested, up to approximately 1 percent of the dose may be absorbed by mass action even in the absence of intrinsic factor (Berlin et al., 1968; Doscherholmen and Hagen, 1957).

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Absorption from Food. The approximate percentage absorption of B12 from a few foods is presented in Table 9-1. These values apply to normal, healthy adults. No studies were found on the absorption of B12 from dairy foods or from red meat other than mutton and liver. The absorption efficiency of B12 from liver reportedly was low because of its high B12 content. Although evidence indicates that a B12 content of 1.5 to 2.5 µg/meal saturates ileal receptors and thus limits further absorption (Scott, 1997), absorption of as much as 7 µg in one subject (18 percent) was reported from a serving of liver paste that contained 38 µg of B12 (average absorption was 4.1 µg or 11 percent) (Heyssel et al., 1966). Assumptions Used in this Report. Because of the lack of data on dairy foods and most forms of red meat and fish, a conservative adjustment for the bioavailability of naturally occurring B12 is used in this report. In particular, it is assumed that 50 percent of dietary B12 is absorbed by healthy adults with normal gastric function. A smaller fractional absorption would apply, however, if a person consumed a large portion of foods rich in B12. Different levels of absorption are assumed under various conditions, as shown in Table 9-2. Crystalline B12 appears in the diet only in foods that have been fortified with B12, such as breakfast cereals and liquid meal replacements. Enterohepatic Circulation B12 is continually secreted in the bile. In healthy individuals most of this B12 is reabsorbed and available for metabolic functions. El Kholty et al. (1991) demonstrated that the secretion of B12 into the bile averaged 1.0 ± 0.44 nmol/day (1.4 µg/day) in eight cholecystectomized patients, and this represented 55 percent of total corrinoids. If approximately 50 percent of this B12 is assumed to be TABLE 9-1 Percentage Absorption of Vitamin B12 from Foods by Healthy Adults Reference Food Absorption (%) Heyssel et al., 1966 Mutton 65 Heyssel et al., 1966 Liver 11 Doscherholmen et al., 1975 Eggs 24–36 Doscherholmen et al., 1978 Chicken 60 Doscherholmen et al., 1981 Trout 25–47

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline TABLE 9-2 Assumed Vitamin B12 Absorption under Different Conditions Form of Vitamin B12 Normal Gastric Function (%) Pernicious Anemiaa (%) Naturally occurringb 50 0 Crystalline, low dose (< 5 µg)b 60 0 Crystalline, high dose (≥ 500 µg) with waterc 1 1 Crystalline, high dose with foodc 0.5 ≤ 0.5 a A disorder in which lack of intrinsic factor severely limits the absorption of vitamin B12. b Heyssel et al. (1966). c Berlin et al. (1968). reabsorbed, the average loss of biliary B12 in the stool would be 0.5 nmol/day (0.7 µg/day). Research with baboons (Green et al., 1982) suggests that the form of B12 present in bile may be absorbed more readily than is cyanocobalamin, but the absorption of both forms was enhanced by intrinsic factor. Both Green and colleagues (1982) and Teo and coworkers (1980) reported data suggesting that bile enhances B12 absorption. However, in the absence of intrinsic factor, essentially all the B12 from the bile is excreted in the stool rather than recirculated. Thus, B12 deficiency develops more rapidly in individuals who have no intrinsic factor or who malabsorb B12 for other reasons than it does in those who become complete vegetarians and thus ingest no B12. Excretion If the circulating B12 exceeds the B12 binding capacity of the blood, the excess is excreted in the urine. This typically occurs only after injection of B12. The highest losses of B12 ordinarily occur through the feces. Sources of fecal B12 include unabsorbed B12 from food or bile, desquamated cells, gastric and intestinal secretions, and B12 synthesized by bacteria in the colon. Other losses occur through the skin and metabolic reactions. Fecal (Reizenstein, 1959) and urinary losses (Adams, 1970; Heinrich, 1964; Mollin and Ross, 1952) decrease when B12 stores decrease. Various studies have indicated losses of 0.1 to 0.2 percent of the B12 pool per day (Amin et al., 1980; Boddy and Adams, 1972; Bozian et al., 1963; Heinrich, 1964; Heyssel et al., 1966; Reizenstein et al., 1966) regardless of the size of the store, with the 0.2 percent value generally applicable to those with pernicious anemia.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Clinical Effects of Inadequate Intake Hematological Effects of Deficiency The major cause of clinically observable B12 deficiency is pernicious anemia (see “Pernicious Anemia”). The hematological effects of B12 deficiency are indistinguishable from those of folate deficiency (see Chapter 8). These include pallor of the skin associated with a gradual onset of the common symptoms of anemia, such as diminished energy and exercise tolerance, fatigue, shortness of breath, and palpitations. As in folate deficiency, the underlying mechanism of anemia is an interference with normal deoxyribonucleic acid (DNA) synthesis. This results in megaloblastic change, which causes production of larger-than-normal erythrocytes (macrocytosis). This leads first to an increase in the erythrocyte distribution width index and ultimately to an elevated mean cell volume. Oval macrocytes and other abnormally shaped erythrocytes are present in the blood. Typically, as with folate deficiency, the appearance of hypersegmentation of polymorphonuclear leukocytes precedes the development of macrocytosis. However, the sensitivity of this finding has recently been questioned (Carmel et al., 1996). By the time anemia has become established, there is usually also some degree of neutropenia and thrombocytopenia because the megaloblastic process affects all rapidly dividing bone marrow elements. The hematological complications are completely reversed by treatment with B12. Neurological Effects of Deficiency Neurological complications are present in 75 to 90 percent of individuals with clinically observable B12 deficiency and may, in about 25 percent of cases, be the only clinical manifestation of B12 deficiency. Evidence is mounting that the occurrence of neurological complications of B12 deficiency is inversely correlated with the degree of anemia; patients who are less anemic show more prominent neurological complications and vice versa (Healton et al., 1991; Savage et al., 1994a). Neurological manifestations include sensory disturbances in the extremities (tingling and numbness), which are worse in the lower limbs. Vibratory and position sense are particularly affected. Motor disturbances, including abnormalities of gait, also occur. Cognitive changes may occur, ranging from loss of concentration to memory loss, disorientation, and frank dementia, with or without mood changes. In addition, visual disturbances, insomnia, impotency, and impaired bowel and bladder control may devel-

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline op. The progression of neurological manifestations is variable but generally gradual. Whether neurological complications are reversible after treatment depends on their duration. The neurological complications of B12 deficiency occur at a later stage of depletion than do the indicators considered below and were, therefore, not used for estimating the requirement for B12. Moreover, neurological complications are not currently amenable to easy quantitation nor are they specific to B12 deficiency. Gastrointestinal Effects of Deficiency B12 deficiency is also frequently associated with various gastrointestinal complaints, including sore tongue, appetite loss, flatulence, and constipation. Some of these complaints may be related to the underlying gastric disorder in pernicious anemia. SELECTION OF INDICATORS FOR ESTIMATING THE REQUIREMENT FOR VITAMIN B12 Search of the literature revealed numerous indicators that could be considered as the basis for deriving an Estimated Average Requirement (EAR) for vitamin B12 for adults. These include but are not limited to hematological values such as erythrocyte count, hemoglobin concentration or hematocrit, and mean cell volume (MCV), blood values such as plasma B12, and the metabolite methylmalonic acid (MMA). Indicators of Hematological Response Measurements used to indicate a hematological response that could be considered as indicative of B12 sufficiency have consisted of either a minimal but significant increase in hemoglobin, hematocrit, and erythrocyte count; a decrease in MCV; or an optimal rise in reticulocyte number. In the earliest studies, MCV was a calculated value that was derived from relatively imprecise erythrocyte counts. Although MCV is now directly measured and precise, the response time of this measurement to changes in dietary intake is slow because of the 120-day longevity of erythrocytes. Consequently, the MCV is of limited usefulness. The erythrocyte count, hemoglobin, and hematocrit values are all robust measurements of response. Again, however, the response time is slow before an improvement in B12 status leads to a return to normal values. Partial responses are of limited value

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline because they do not predict the ultimate completeness or maintenance of response. The reticulocyte count is a useful measure of hematological response because an increase is apparent within 48 hours of B12 administration and reaches a peak at 5 to 8 days. Serum or Plasma Vitamin B12 The concentration of B12 in the serum or plasma reflects both the B12 intake and stores. The lower limit is considered to be approximately 120 to 180 pmol/L (170 to 250 pg/mL) for adults but varies with the method used and the laboratory conducting the analysis. As deficiency develops, serum values may be maintained at the expense of B12 in the tissues. Thus, a serum B12 value above the cutoff point does not necessarily indicate adequate B12 status (see the section “Vitamin B12 Deficiency”) but a low value may represent a long-term abnormality (Beck, 1991) or prolonged low intake. Methylmalonic Acid The range that represents expected variability (2 standard deviations) for serum MMA is 73 to 271 nmol/L (Pennypacker et al., 1992). The concentration of MMA in the serum rises when the supply of B12 is low. Elevation of MMA may also be caused by renal failure or intravascular volume depletion (Stabler et al., 1988), but Lindenbaum and coworkers (1994) reported that moderate renal dysfunction in the absence of renal failure does not affect MMA values as strongly as does inadequate B12 status. MMA values tend to rise in the elderly (Joosten et al., 1996); in most cases this appears to reflect inadequate B12 intake or absorption. Lindenbaum and coworkers (1988) reported that elevated serum MMA concentrations are present in many patients with neuropsychiatric disorders caused by B12 deficiency. Pennypacker and colleagues (1992) found that intramuscular injections of B12 reduced the elevated MMA values in their elderly subjects. The reduction of elevated MMA values with B12 therapy has also been reported in other studies (Joosten et al., 1993; Naurath et al., 1995; Norman and Morrison, 1993). Increased activity of anaerobic flora in the intestinal tract may increase serum MMA values; treatment with antibiotics decreases the serum MMA concentration in this situation (Lindenbaum et al., 1990). Because the presence of elevated concentrations of MMA in serum represents a metabolic change that is highly specific to B12 deficiency, the serum MMA concentration is a preferred indicator

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline of B12 status. However, data were not sufficient to use MMA as the criterion on which to base the EAR in this report. Serum MMA values from older studies may not be comparable with those obtained recently because of improvements of methods over time (Beck, 1991; Green and Kinsella, 1995). More importantly, no studies were found that examined directly the relationship of B12 intake and MMA concentrations. Homocysteine Serum total homocysteine concentration is commonly elevated in elderly persons whose folate status is normal but who have a clinical response to treatment with B12 (Stabler et al., 1996). Because a lack of folate, vitamin B6, or both also results in an elevated serum and plasma homocysteine concentration, this indicator has poor specificity and does not provide a useful basis for deriving an EAR. Formiminoglutamic Acid, Propionate, and Methylcitrate Although most patients with untreated B12 deficiency excrete an increased amount of formiminoglutamic acid (FIGLU) in the urine after an oral loading dose of histidine, FIGLU excretion is also almost invariably increased in folate deficiency as well. The test, therefore, lacks specificity for the diagnosis of either vitamin deficiency. Concentrations of propionate, the metabolic precursor of methylmalonate, also rise with B12 deficiency. Propionate may be converted to 2-methylcitrate, serum and cerebrospinal fluid concentrations of which also rise in B12 deficiency (Allen et al., 1993). However, the measurement of either propionate or methyl citrate offers no advantages over serum MMA for the detection of B12 deficiency. Holotranscobalamin II Among the three plasma B12 binding proteins, transcobalamin II (TCII) is responsible for receptor-mediated uptake of B12 into cells. However, only a small fraction of the plasma B12 (10 to 20 percent) is present as the TCII-B12 complex. This fraction, termed holoTCII, may provide a good indication of B12 status, and methods have been described to measure this fraction (Herzlich and Herbert, 1988; Vu et al., 1993). These methods are currently considered to be insufficiently robust for routine clinical use.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline METHODOLOGICAL ISSUES Vitamin B12 Content The two primary microbial organisms used to determine the vitamin B12 content of serum, urine, and stool are Euglena gracilis and Lactobacillus leichmannii. Although either organism will yield essentially similar results, L. leichmannii is the preferred method for reasons of convenience (Chanarin, 1969). Microbiological assays have been largely supplanted by radioligand binding assays. Until 1978 radioligand binding assays frequently gave higher results; the binding protein for B12 used in these assays would also bind analogues of B12 (Beck, 1991; Russell, 1992). Since 1978 the use of purified intrinsic factor as the binder in commercial radioisotope dilution assay kits has resulted in serum concentrations of B12 comparable with those obtained from microbiological assays. More recently, nonisotopic serum B12 assays have been introduced, which has resulted in cutoff levels for B12 deficiency again rising. Care must be taken in comparing studies because much variation has been noted across laboratories, and different cutoff points have been used to identify deficiency (Beck, 1991; Green and Kinsella, 1995; Miller et al., 1991; Rauma et al., 1995; WHO, 1970; Winawer et al., 1967). The serum B12 value may be misleading as an indicator because it includes all the B12 regardless of the protein to which it is bound. Transcobalamin II (TCII) is the key transport protein, and it has been proposed that only the TCII-bound fraction of the serum B12 (holoTCII) is important in relation to B12 nutritional and metabolic status (Herzlich and Herbert, 1988; Vu et al., 1993). However, at this time, there is no reliable method to determine holoTCII. Retention Studies of the retention of parenterally administered B12 indicate that percentage retention depends on the dose and the route of administration (intramuscular [IM] or intravenous). The expected percentage retention of IM cyanocobalamin is shown in Table 9-3. These values, which vary from 15 to 100 percent, are useful when IM doses of B12 are used to estimate the B12 requirement.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline TABLE 9-3 Change in Percentage Retention of Vitamin B12 with Increasing Intramuscular Dose Vitamin B12 Dose (µg) Retention (%) 3 100 10 97 25 95 40 93 1,000 15 SOURCE: Chanarin (1969). DIAGNOSIS Vitamin B12 Deficiency Early detection of vitamin B12 deficiency depends on biochemical measurements. Lindenbaum and colleagues (1990) reported that metabolites that arise from B12 insufficiency are more sensitive indicators of B12 deficiency than is the serum B12 value. This was found in patients with pernicious anemia or previous gastrectomy who experienced early hematological relapse: serum methylmalonic acid (MMA), total homocysteine, or both were elevated in 95 percent of the instances of relapse whereas the serum B12 value was low (less than 150 pmol/L [200 pg/mL]) in 69 percent. Similarly, serum B12 was found to be an insensitive indicator in a review of records of patients with clinically significant B12 deficiency. Five deficient individuals had neurological disorders that were responsive to B12 and had elevated serum MMA and homocysteine values even though their serum B12 values were greater than 150 pmol/L (200 pg/mL) and anemia was absent or mild. In a recent series of 173 patients, 5.2 percent of those with recognized B12 deficiency had serum B12 values in the normal range. Similar findings were reported elsewhere (e.g., Carmel, 1988; Pennypacker et al., 1992; Stabler et al., 1996). At present, the techniques developed to measure serum MMA and homocysteine (capillary gas chromatography and mass spectrometry) are costly and may be beyond the scope of routine laboratories. Conditions that may warrant assessment of B12 status because they may result in B12 deficiency are summarized in Table 9-4.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Intake from Supplements Information from the Boston Nutritional Status Survey on supplement use of B12 by a free-living elderly population is given in Appendix F. For those taking supplements, the fiftieth percentile of supplemental B12 intake was 5.0 µg for men and 6.0 µg for women. Approximately 26 percent of all adults reported taking a B12-containing supplement in 1986 (Moss et al., 1989). TOLERABLE UPPER INTAKE LEVELS Hazard Identification Adverse Effects No adverse effects have been associated with excess B12 intake from food or supplements in healthy individuals. There is very weak evidence from animal studies suggesting that B12 intake enhances the carcinogenesis of certain chemicals (Day et al., 1950; Georgadze, 1960; Kalnev et al., 1977; Ostryanina, 1971). These findings are contradicted by evidence that increased B12 intake inhibits tumor induction in the human liver, colon, and esophagus (Rogers, 1975). Some studies suggest a possible association between high-dose, parenterally administered B12 (0.5 to 5 mg) and acne formation (Berlin et al., 1969; Dugois et al., 1969; Dupre et al., 1979; Puissant et al., 1967; Sherertz, 1991). However, the acne lesions were primarily associated with hydroxocobalamin rather than cyanocobalamin, the form used in the United States and Canada. Furthermore, iodine particles in commercial B12 preparations may have been responsible for the acne. In conclusion, the evidence from these data was considered not sufficient for deriving a Tolerable Upper Intake Level (UL). Studies involving periodic parenteral administration of B12 (1 to 5 mg) to patients with pernicious anemia provide supportive evidence for the lack of adverse effects at high doses (Boddy and Adams, 1968; Mangiarotti et al., 1986; Martin et al., 1992). Periodic doses of 1 mg are used in standard clinical practice to treat patients with pernicious anemia. As indicated earlier, when high doses are given orally (see “Absorption”) only a small percentage of B12 can be absorbed from the gastrointestinal tract, which may explain the apparent low toxicity.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Special Considerations B12-deficient individuals who are at risk for Leber’s optic atrophy should not be given cyanocobalamin to treat the B12 deficiency. Leber’s optic atrophy is a genetic disorder caused by chronic cyanide intoxication (present in tobacco smoke, alcohol, and some plants). Reduced serum B12 concentrations have been associated with a reduced ability to detoxify the cyanide in exposed individuals (Foulds, 1968, 1969a, b, 1970; Wilson and Matthews, 1966). Cyanocobalamin may increase the risk of irreversible neurological damage (from the optic atrophy). Hydroxocobalamin is a cyanide antagonist and therefore not associated with adverse effects when given to these individuals. Dose-Response Assessment The data on adverse effects of B12 intake were considered not sufficient for a dose-response assessment and derivation of a UL. Intake Assessment In 1986 approximately 26 percent of adults in the United States took a supplement containing B12 (Moss et al., 1989). Although no UL can be set for B12, an exposure assessment is provided here for possible future use. Based on data from the Third National Health and Nutrition Examination Survey (see Appendix H), the highest median intake of B12 from diet and supplements for any life stage and gender group was for males aged 31 through 50 years: 17 µg/ day. The highest reported intake at the ninety-fifth percentile was 37 µg/day for pregnant females aged 14 through 55 years. Risk Characterization On the basis of the review of data involving high-dose intakes of B12, there appear to be essentially no risks of adverse effects to the general population even at the current ninety-fifth percentile of intake noted above. Furthermore, there appear to be no risks associated with intakes of supplemental B12 that are more than two orders of magnitude higher than the ninety-fifth percentile of intake. Although there are extensive data showing no adverse effects associated with high intakes of supplemental B12, the studies in which such intakes were reported were not designed to assess adverse effects.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline RESEARCH RECOMMENDATIONS FOR VITAMIN B12 High-Priority Recommendations Priority should be given to three topics of research related to vitamin B12: The prevalence of B12 deficiency as diagnosed by biochemical, neurological, or hematological abnormalities (e.g., methylmalonic acid and holotranscobalamin II). Improved, economical, and sensitive methods to detect B12 malabsorption and deficiency before adverse neurological and hematological changes occur. Effective methods to reduce the risk of suboptimal B12 status resulting from B12 malabsorption or vegetarian diets. For elderly persons with food-bound malabsorption, research is needed on the form and amount of B12 that can normalize and maintain B12 stores. For vegetarians, information is needed about the absorption of B12 from dairy products, algae, and fortified food products. Other Research Areas Two additional topics also merit attention: The feasibility and potential benefits and adverse effects of fortification of cereal grain foods with B12, considering stability, identity of any degradation products, and bioavailability for normal individuals and those who malabsorb protein-bound B12. The contribution of bacterial overgrowth to elevated serum methylmalonic acid. REFERENCES Adams JF. 1962. The measurement of the total assayable vitamin B12 the body. In: Heinrich HC, ed. Vitamin B12 und Intrinsic Faktor. Stuttgart, Germany: Ferdinand Enke. Pp. 397–403. Adams JF. 1970. Correlation of serum and urine vitamin B12. Br Med J 1:138–139. Adams JF, Tankel HI, MacEwan F. 1970. Estimation of the total body vitamin B12 in the live subject. Clin Sci 39:107–113. Adams JF, Ross SK, Mervyn RL, Boddy K, King P. 1971. Absorption of cyanocobalamin, coenzyme B12, methylcobalamin, and hydroxocobalamin at different dose levels. Scand J Gastroenterol 6:249–252. Adams JF, Boddy K, Douglas AS. 1972. Interrelation of serum vitamin B12, total body vitamin B12, peripheral blood morphology and the nature of erythropoiesis. Br J Haematol 23:297–305.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Carmel R, Sinow RM, Karnaze DS. 1987. Atypical cobalamin deficiency. Subtle biochemical evidence of deficiency is commonly demonstrable in patients without megaloblastic anemia and is often associated with protein-bound cobalamin malabsorption. J Lab Clin Med 109:454–463. Carmel R, Sinow RM, Siegel ME, Samloff IM. 1988. Food cobalamin malabsorption occurs frequently in patients with unexplained low serum cobalamin levels. Arch Intern Med 148:1715–1719. Carmel R, Green R, Jacobsen DW, Qian GD. 1996. Neutrophil nuclear segmentation in mild cobalamin deficiency: Relation to metabolic tests of cobalamin status and observations on ethnic differences in neutrophil segmentation. Am J Clin Pathol 106:57–63. Casterline JE, Allen LH, Ruel MT. 1997. Vitamin B-12 deficiency is very prevalent in lactating Guatemalan women and their infants at three months postpartum. J Nutr 127:1966–1972. Chanarin I. 1969. The Megaloblastic Anaemias, 1st ed. Oxford: Blackwell Scientific. Chanarin I. 1979. The Megaloblastic Anaemias, 2nd ed. Oxford: Blackwell Scientific. Chanarin I. 1990. The Megaloblastic Anaemias, 3rd ed. Boston: Blackwell Scientific. Dagnelie PC, van Staveren WA, Hautvast JG. 1991. Stunting and nutrient deficiences in children on alternative diets. Acta Pediatr Scand Suppl 374:111–118. Darby WJ, Bridgforth EB, Le Brocquy J, Clark SL, De Oliviera JD, Kevany J, McGanity WJ, Perez C. 1958. Vitamin B12 requirement of adult man. Am J Med 25: 726–732. Day PL, Payne LD, Dinning JS. 1950. Procarcinogenic effect of vitamin B12 on p-dimethylaminoazobenzene-fed rats. Proc Soc Exp Biol Med 74:854–857. Doi K, Matsuura M, Kawara A, Tanaka T, Baba S. 1983. Influence of dietary fiber (konjac mannan) on absorption of vitamin B12 and vitamin E . Tohoku J Exp Med 141:677–681. Donangelo CM, Trugo NM, Koury JC, Barreto Silva MI, Freitas LA, Feldheim W, Barth C. 1989. Iron, zinc, folate and vitamin B12 nutritional status and milk composition of low-income Brazilian mothers. Eur J Clin Nutr 43:253–266. Doscherholmen A, Hagen PS. 1957. A dual mechanism of vitamin B12 plasma absorption. J Clin Invest 36:1551–1557. Doscherholmen A, McMahon J, Ripley D. 1975. Vitamin B12 absorption from eggs. Proc Soc Exp Biol Med 149:987–990. Doscherholmen A, McMahon J, Ripley D. 1978. Vitamin B12 assimilation from chicken meat. Am J Clin Nutr 31:825–830. Doscherholmen A, McMahon J, Economon P. 1981. Vitamin B12 absorption from fish. Proc Soc Exp Biol Med 167:480–484. Doscherholmen A, Silvis S, McMahon J. 1983. Dual isotope Schilling test for measuring absorption of food-bound and free vitamin B12 simultaneously. Am J Clin Pathol 80:490–495. Draper A, Lewis J, Malhotra N, Wheeler E. 1993. The energy and nutrient intakes of different types of vegetarian: A case for supplements? Br J Nutr 69:3–19. Dugois P, Amblard P, Imbert R, Bignicourt B. 1969. Acne caused by vitamin B12. Lyon Med 221:1165–1167. Dupre A, Albarel N, Bonafe JL, Christol B, Lassere J. 1979. Vitamin B12-induced acnes. Cutis 24:210–211. El Kholty S, Gueant JL, Bressler L, Djalali M, Boissel P, Gerard P, Nicolas JP. 1991. Portal and biliary phases of enterohepatic circulation of corrinoids in humans. Gastroenterology 101:1399–1408.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Fernandes-Costa F, Metz J. 1982. Levels of transcobalamins I, II, and III during pregnancy and in cord blood. Am J Clin Nutr 35:87–94. Fernandes-Costa F, van Tonder S, Metz J. 1985. A sex difference in serum cobalamin and transcobalamin levels. Am J Clin Nutr 41:784–786. Ford JE, Hutner SH. 1955. Role of vitamin B12 in the metabolism of micro-organisms. Vitam Horm 13:101–136. Foulds WS. 1968. Hydroxocobalamin in the treatment of Leber’s hereditary optic atrophy. Lancet 1:896–897. Foulds WS. 1969a. Cyanide induced optic neuropathy. Ophthalmologica 158:350– 358. Foulds WS. 1969b. The optic neuropathy of pernicious anemia. Arch Ophthalmol 82:427–432. Foulds WS. 1970. The investigation and therapy of the toxic amblyopias. Trans Ophthalmol Soc UK 90:739–763. Fréry N, Huel G, Leroy M, Moreau T, Savard R, Blot P, Lellouch J. 1992. Vitamin B12 among parturients and their newborns and its relationship with birth-weight. Eur J Obstet Gynecol Reprod Biol 45:155–163. Gambon RC, Lentze MJ, Rossi E. 1986. Megaloblastic anaemia in one of monozygous twins breast fed by their vegetarian mother. Eur J Pediatr 145:570–571. Garry PJ, Goodwin JS, Hunt WC. 1984. Folate and vitamin B12 status in a healthy elderly population. J Am Geriatr Soc 32:719–726. Georgadze GE. 1960. Effect of vitamin B1 and B12 on induction of malignant growths in hamsters. Vopr Onkol 6:54–58. Grasbeck T, Nyberg W, Reizenstein P. 1958. Biliary and fecal vitamin B12 excretion in man. An isotope study. Proc Soc Exp Biol Med 97:780–784. Green R, Kinsella LJ. 1995. Current concepts in the diagnosis of cobalamin deficiency. Neurology 45:1435–1440. Green R, Jacobsen DW, Van Tonder SV, Kew MC, Metz J. 1982. Absorption of biliary cobalamin in baboons following total gastrectomy. J Lab Clin Med 100:771–777. Gueant JL, Champigneulle B, Gaucher P, Nicolas JP. 1990. Malabsorption of vitamin B12 in pancreatic insufficiency of the adult and of the child. Pancreas 5:559–567. Hall CA, Finkler AE. 1966. Function of transcobalamin II: A B12 binding protein in human plasma. Proc Soc Exp Biol Med 123:55–58. Hansen HA, Weinfeld A. 1962. Metabolic effects and diagnostic value of small doses of folic acid and B12 in megaloblastic anemias. Acta Med Scand 172:427– 443. Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. 1991. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore) 70:229–245. Heinrich HC. 1964. Metabolic basis of the diagnosis and therapy of vitamin B12 deficiency. Semin Hematol 1:199–249. Hellegers A, Okuda K, Nesbitt RE Jr, Smith DW, Chow BF. 1957. Vitamin B12 absorption in pregnancy and in the newborn. Am J Clin Nutr 5:327–331. Herbert V, Jacob E, Wong KT, Scott J, Pfeffer RD. 1978. Low serum vitamin B12 levels in patients receiving ascorbic acid in megadoses: Studies concerning the effect of ascorbate on radioisotope vitamin B12 assay. Am J Clin Nutr 31:253– 258. Herzlich B, Herbert V. 1988. Depletion of serum holotranscobalamin II. An early sign of negative vitamin B12 balance. Lab Invest 58:332–337.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Heyssel RM, Bozian RC, Darby WJ, Bell MC. 1966. Vitamin B12 turnover in man. The assimilation of vitamin B12 from natural foodstuff by man and estimates of minimal daily requirements. Am J Clin Nutr 18:176–184. Hoey H, Linnell JC, Oberholzer VG, Laurance BM. 1982. Vitamin B12 deficiency in a breastfed infant of a mother with pernicious anaemia. J R Soc Med 75:656– 658. Houston GA, Files JC, Morrison FS. 1985. Race, age, and pernicious anemia. South Med J 78:69–70. Hsing AW, Hansson L-E, McLaughlin JK, Nyren O, Blot WJ, Ekbom A, Faumeni JF. 1993. Pernicious anemia and subsequent cancer: A population-based cohort study. Cancer 71:745–750. Hurwitz A, Brady DA, Schaal SE, Samloff IM, Dedon J, Ruhl CE. 1997. Gastric acidity in older adults. J Am Med Assoc 278:659–662. Isaacs R, Friedman A. 1938. Standards for maximum reticulocyte percentage after intramuscular liver therapy in pernicious anemia. Am J Med Sci 196:718–719. Isaacs R, Bethell FH, Riddle MC, Friedman A. 1938. Standards for red blood cell increase after liver and stomach therapy in pernicious anemia. JAMA 111:2291. Jadhav M, Webb JK, Vaishnava S, Baker SJ. 1962. Vitamin B12 deficiency in Indian infants. Lancet 1962:903–907. Jathar VS, Inamdar-Deshmukh AB, Rege DV, Satoskar RS. 1975. Vitamin B12 and vegetarianism in India. Acta Haematol 53:90–97. Johnsen R, Bernersen B, Straume B, Forde OH, Bostad L, Burhol PG. 1991. Prevalences of endoscopic and histological findings in subjects with and without dyspepsia. Br Med J 302:749–752. Johnson PR Jr, Roloff JS. 1982. Vitamin B12 deficiency in an infant strictly breastfed by a mother with latent pernicious anemia. J Pediatr 100:917–919. Jones BP, Broomhead AF, Kwan YL, Grace CS. 1987. Incidence and clinical significance of protein-bound vitamin B12 malabsorption. EUT J Haematol 38:131– 136. Joosten E, Pelemans W, Devos P, Lesaffre E, Goossens W, Criel A, Verhaeghe R. 1993. Cobalamin absorption and serum homocysteine and methylmalonic acid in elderly subjects with low serum cobalamin. Eur J Haematol 51:25–30. Joosten E, Lesaffre E, Riezler R. 1996. Are different reference intervals for methylmalonic acid and total homocysteine necessary in elderly people? Eur J Haematol 57:222–226. Kalnev VR, Rachkus I, Kanopkaite SI. 1977. Influence of methylcobalamin and cyanocobalamin on the neoplastic process in rats. Prikl Biochim Mikrobiol 13:677. Kano Y, Sakamoto S, Miura Y, Takaku F. 1985. Disorders of cobalamin metabolism. Crit Rev Oncol Hematol 3:1–34. Karnaze DS, Carmel R. 1990. Neurologic and evoked potential abnormalities in subtle cobalamin deficiency states, including deficiency without anemia and with normal absorption of free cobalamin. Arch Neurol 47:1008–1012. Kato N, Narita Y, Kamohara S. 1959. Liver vitamin B12 levels in chronic liver diseases. J Vitam 5:134–140. Krasinski SD, Russell RM, Samloff IM, Jacob RA, Dallal GE, McGandy RB, Hartz SC. 1986. Fundic atrophic gastritis in an elderly population: Effect on hemoglobin and several serum nutritional indicators. J Am Geriatr Soc 34:800–806. Kuhne T, Bubi R, Baumgartner R. 1991. Maternal vegan diet causing a serious infantile neurological disorder due to vitamin B12 deficiency. Eur J Pediatr 150:205–208.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, Marcell PD, Stabler SP, Allen RH. 1988. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 318:1720–1728. Lindenbaum J, Savage DG, Stabler SP, Allen RH. 1990. Diagnosis of cobalamin deficiency: 2. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 34:99–107. Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH. 1994. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr 60:2–11. Linnell JC, Smith AD, Smith CL, Wilson J, Matthews DM. 1968. Effects of smoking on metabolism and excretion of vitamin B12. Br Med J 2:215–216. Loria A, Vaz-Pinto A, Arroyo P, Ramirez-Mateos C, Sanchez-Medal L. 1977. Nutritional anemia. 6. Fetal hepatic storage of metabolites in the second half of pregnancy. J Pediatr 91:569–573. Low-Beer TS, McCarthy CF, Austad WI, Brzechwa-Ajdukiewicz A, Read AE. 1968. Serum vitamin B12 levels and vitamin B12 binding capacity in pregnant and non-pregnant Europeans and West Indians. Br Med J 4:160–161. Luhby AL, Cooperman JM, Donnenfeld AM, Herrero JM, Teller DN, Wenig JB. 1958. Observations on transfer of vitamin B12 from mother to fetus and newborn. Am J Dis Child 96:532–533. Mangiarotti G, Canavese C, Salomone M, Thea A, Pacitti A, Gaido M, Calitri V, Pelizza D, Canavero W, Vercellone A. 1986. Hypervitaminosis B12 in maintenance hemodialysis patients receiving massive supplementation of vitamin B12. Int J Artif Organs 9:417–420. Martin DC, Francis J, Protetch J, Huff J. 1992. Time dependency of cognitive recovery with cobalamin replacement: Report of a pilot study. J Am Geriatr Soc 40:168–172. McEvoy AW, Fenwick JD, Boddy K, James OF. 1982. Vitamin B12 absorption from the gut does not decline with age in normal elderly humans. Age Ageing 11:180– 183. Metz J, Hart D, Harpending HC. 1971. Iron, folate, and vitamin B12 nutrition in a hunter-gatherer people: A study of the Kung Bushmen. Am J Clin Nutr 24:229– 242. Miller DR, Specker BL, Ho L, Norman EJ. 1991. Vitamin B-12 status in a macrobiotic community. Am J Clin Nutr 53:524–529. Miller A, Furlong D, Burrows BA, Slingerland DW. 1992. Bound vitamin B12 absorption in patients with low serum B12 levels. Am J Hematol 40:63–166. Moelby L, Rasmussen K, Jensen MK, Pedersen KO. 1990. The relationship between clinically confirmed cobalamin deficiency and serum methylmalonic acid. J Intern Med 228:373–378. Mollin DL, Ross GI. 1952. The vitamin B12 concentrations of serum and urine of normals and of patients with megaloblastic anaemias and other diseases. J Clin Pathol 5:129–139. Moss AJ, Levy AS, Kim I, Park YK. 1989. Use of Vitamin and Mineral Supplements in the United States: Current Users, Types of Products, and Nutrients. Advance Data, Vital and Health Statistics of the National Center for Health Statistics, No. 174. Hyattsville, MD: National Center for Health Statistics. Muir M, Landon M. 1985. Endogenous origin of microbiologically-inactive cobalamins (cobalamin analogues) in the human fetus. Br J Haematol 61:303–306.

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DRI Dietary Reference Intakes: For Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline Narayanan MN, Dawson DW, Lewis MJ. 1991. Dietary deficiency of vitamin B12 is associated with low serum cobalamin levels in non-vegetarians. Eur J Haematol 47:115–118. Naurath HJ, Joosten E, Riezler R, Stabler SP, Allen RH, Lindenbaum J. 1995. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet 346:85–89. Nilsson-Ehle H, Jagenburg R, Landahl S, Lindstedt G, Swolin B, Westin J. 1986. Cyanocobalamin absorption in the elderly: Results for healthy subjects and for subjects with low serum cobalamin concentration. Clin Chem 32:1368–1371. Norman EJ, Morrison JA. 1993. Screening elderly populations for cobalamin (vitamin B12) deficiency using the urinary methylmalonic acid assay by gas chromatography mass spectrometry. Am J Med 94:589–594. Ostryanina AD. 1971. Effect of vitamin B12 on the induction of tumors in mouse skin. Patol Fiziol Eksperim Terapiya 15:48–53. Pennypacker LC, Allen RH, Kelly JP, Matthews LM, Grigsby J, Kaye K, Lindenbaum J, Stabler SP. 1992. High prevalence of cobalamin deficiency in elderly out-patients. J Am Geriatr Soc 40:1197–1204. Puissant A, Vanbremeersch F, Monfort J, Lamberton J-N. 1967. A new iatrogenic dermatosis: Acne caused by vitamin B12. Bull Soc Fr Dermatol Syphiligr 74:813– 815. Quinn K, Basu TK. 1996. Folate and vitamin B12 status of the elderly. Eur J Clin Nutr 50:340–342. Rauma AL, Torronen R, Hanninen O, Mykkanen H. 1995. Vitamin B-12 status of long-term adherents of a strict uncooked vegan diet (“living food diet”) is compromised. J Nutr 125:2511–2515. Reizenstein P. 1959. Excretion of non-labeled vitamin B12 in man. Acta Med Scand 165:313–320. Reizenstein P, Ek G, Matthews CM. 1966. Vitamin B12 kinetics in man. Implications on total-body B12 determinations, human requirements, and normal and pathological cellular B12 uptake. Phys Med Biol 11:295–306. Robertson JA, Gallagher ND. 1983. Increased intestinal uptake of cobalamin in pregnancy does not require synthesis of new receptors. Biochim Biophys Acta 757:145–150. Rogers AE. 1975. Variable effects of a lipotrobe-deficient, high-fat diet on chemical carcinogens in rats. Cancer Res 35:2469–2474. Rosenberg LE, Fenton WA. 1989. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease, 6th ed. New York: McGraw-Hill. Pp. 821–844. Rosner F, Schreiber ZA. 1972. Serum vitamin B12 and vitamin B12 binding capacity in chronic myelogenous leukemia and other disorders. Am J Med Sci 263:473– 480. Russell RM. 1992. Vitamin B12. In: Hartz SC, Russell RM, Rosenberg IH, eds. Nutrition in the Elderly. The Boston Nutritional Status Survey. London: Smith-Gordon. Pp. 141–145. Sahyoun NR, Otradovec CL, Hartz SC, Jacob RA, Peters H, Russell RM, McGandy RB. 1988. Dietary intakes and biochemical indicators of nutritional status in an elderly, institutionalized population. Am J Clin Nutr 47:524–533. Savage D, Gangaidzo I, Lindenbaum J. 1994a. Vitamin B12 deficiency is the primary cause of megaloblastic anemia in Zimbabwe. Br J Haematol 86:844–850.

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