August 2006: 373–378Brief Critical Review

What is an Adequate Dose of Oral Vitamin B12 in Older People withPoor Vitamin B12 Status?Sohyun Park, PhD, and Mary Ann Johnson, PhD

The prevalence of vitamin B12 deficiency increases inthe elderly, mainly because atrophic gastritis de-creases the production of the acid and digestive en-zymes needed to cleave protein-bound vitamin B12

from the natural chemical form of vitamin B12 foundin meat, poultry, fish, and dairy foods. Depending onthe biochemical criterion that is used, 5% to morethan 20% of older adults have marginal or frankvitamin B12 deficiency. Adults over 50 years of ageshould meet the Recommended Dietary Allowance byconsuming vitamin B12 in the crystalline form, whichdoes not require gastric acid or enzymes for initialdigestion. A recent clinical trial suggests that an oraldose of 500 �g/d of crystalline vitamin B12 is neededto reverse biochemical signs of vitamin B12 deficiencyin older adults.© 2006 International Life Sciences Institute

doi: 10.1301/nr.2006.aug.373–378

Key words: elderly, vitamin B12

FUNCTIONS OF VITAMIN B12

Poor vitamin B12 status is associated with neurolog-ical problems,1-4 hematological disorders,1,2 and otherhealth-related conditions, including poor cognition andAlzheimer’s disease,5-7 depression,8 hearing loss,9-11

cancer,12 and poor bone health.13-16 There are no ran-domized, controlled trials to document the association ofvitamin B12 deficiency with most of these conditions.However, Martin et al.17 reported that the cognitivedysfunction associated with vitamin B12 deficiency wasreversible within 1 year of onset but not after that time.Vitamin B12 deficiency is associated with high homocys-

teine (Hcy), which may be a causal factor in vasculardisease and dementia.1,2,4 High serum or plasma totalhomocysteine (tHcy) is also associated with dementiaand other cognitive disorders.5,7,18 In the FraminghamStudy, elevated serum tHcy (�14 �mol/L) doubled therisk of dementia during a 16-year follow-up period.18

The attributable population risk for the development ofdementia was 16% for tHcy and 21% for the APOE-4allele. Currently, evidence is limited that supplements ofvitamin B12 or other B vitamins directly benefit dementiaor cognition, except when established vitamin deficien-cies are corrected in the early stages.5,7,17

Vitamin B12 is required for two mammalian en-zymes.1,2,4 First, vitamin B12 is a cofactor for methioninesynthase, which facilitates the methyl transfer frommethyltetrahydrofolate to Hcy to form methionine andtetrahydrofolate. Vitamin B12 deficiency is associatedwith decreased activity of methionine synthase, whichleads to increases in Hcy that can be measured in se-rum.1,2,4 Elevated serum Hcy is associated with lowintake or status of folate, vitamin B6, and B12, as well asother genetic, physiological, and behavioral fac-tors.4,19,20 Second, L-methylmalonyl-CoA mutase cata-lyzes the conversion of L-methylmalonyl-CoA to succi-nyl-CoA. Vitamin B12 deficiency is also associated withdecreases in the activity of L-methylmalonyl-CoA mu-tase, which leads to increases in methylmalonic acid(MMA) that can be measured in serum.1,2,4 Confoundingfactors in using these metabolites to assess vitamin B12

status are: both are increased when renal function is poor,Hcy is influenced by other dietary factors includingfolate and vitamin B6, and MMA can reflect bacterialmetabolism of the intestinal microflora.1,2

DEFINING VITAMIN B12 STATUS: DEFICIENT,MARGINAL OR PRECLINICAL, ANDADEQUATE

The most widely used markers of vitamin B12 statusare serum and plasma vitamin B12 followed by MMA.Because poor renal function elevates MMA, it has beensuggested that other metabolites, such as 2-methylcitrate,be used along with this marker.21 There are three types

Drs. Park and Johnson are with the Department ofFoods and Nutrition, The University of Georgia, Ath-ens, Georgia.

Please address all correspondence to: Dr. MaryAnn Johnson, Department of Foods and Nutrition, TheUniversity of Georgia, Dawson Hall, Athens, GA 30602;Phone: 706-542-2292; Fax: 706-542-5059; E-mail:mjohnson@fcs.uga.edu.

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(I, II, and III) of vitamin B12-binding proteins in plasma,called transcobalamins (TC).2 TC II binds to a smallfraction (7% to 20%) of plasma vitamin B12 and forms acomplex called holotranscoablamin II (holoTC II).2 Ho-loTC II is released into the portal circulation and is latertransported into cells.2,22 HoloTC II is a reasonablemarker for assessing vitamin B12 status1,2,23: higher ho-loTC II indicates better vitamin B12 status.22 Megalo-blastic anemia is not a reliable sign of vitamin B12

status24,25 because it is not always present in people withvitamin B12 deficiency.23

Generally, serum vitamin B12 concentrations under150 to 160 pmol/L indicate frank vitamin B12 deficien-cy,2 but there is no widely accepted biochemical cutofffor marginal or preclinical vitamin B12 deficiency or forvitamin B12 adequacy.2,21,23 Use of both serum vitaminB12 and MMA may improve the differential diagnosis ofvitamin B12 deficiency. Although there is some contro-versy, information from several sources suggests thatmarginal status might be defined as a serum vitamin B12

above 160 pmol/L and below 222 to 258 pmol/L (300 to350 pg/mL), along with MMA concentrations over 270or 370 nmol/L (�2 and �3 standard deviations [SDs],respectively, above the values in young controls).26-31

The age-adjusted geometric mean concentration ofMMA was 137 nmol/L in The National Health andNutrition Examination Survey (NHANES) 1999-2000.32

There are concerns that raising the lower limit of normalserum vitamin B12 will falsely classify many vitamin B12

adequate people as deficient.23 Others question the use ofincreased MMA as the only marker for the diagnosis ofvitamin B12 deficiency.33 However, Pennypacker et al.28

reported that in older adults from geriatric outpatientclinics with serum vitamin B12 concentrations under 222pmol/L and no previous history of vitamin B12 defi-ciency, the prevalence of elevated serum MMA (�3 SDsabove the mean for normal) was similar among thosewith serum vitamin B12 concentrations of 75 to 148pmol/L and 148 to 222 pmol/L. Lindenbaum et al.27

found that in the Framingham elderly population, serumMMA and tHcy concentrations were similarly elevatedamong those with serum vitamin B12 concentrations of74 to 147 pmol/L and 148 to 258 pmol/L. Together, thesestudies suggest that a combination of serum vitamin B12

(above 160 pmol/L and below 222 to 258 pmol/L) andMMA (�270 or 370 nmol/L) rather than either indexalone may be useful for the assessment of marginal orpreclinical vitamin B12 status. Additional research isneeded to identify the concentrations of serum vitaminB12 and MMA that are associated with specific biochem-ical, clinical, and physiological measures of frank vita-min B12 deficiency as well as marginal or preclinicaldeficiency.

PREVALENCE OF VITAMIN B12 DEFICIENCY

Depending on the biochemical criterion that is used(vitamin B12 and/or MMA) 5% to more than 20% ofolder adults are deficient in vitamin B12.1,2,25,34 Riskfactors for deficiency include low animal protein intake,no crystalline vitamin B12 from supplements or fortifiedfoods, malabsorption associated with atrophic gastritis orHelicobacter pylori infection, pancreatic or intestinalpathology, and gastric acid-reducing medica-tions.1,2,25,34-36 The prevalence of vitamin B12 deficiencyincreases with advanced age, mainly because atrophicgastritis decreases the production of the acid and diges-tive enzymes needed to cleave protein-bound vitaminB12 from the natural chemical form of vitamin B12 foundin meat, poultry, fish, and dairy foods.1,2,4 Loss of in-trinsic factor (pernicious anemia), gastrectomy, and ilealdisease/resection are less common causes of vitamin B12

deficiency. People over 50 years of age should consumethe RDA for vitamin B12 in the crystalline form (i.e.,fortified foods or dietary supplements), which does notrequire gastric acid or enzymes for initial digestion.1,37

Approximately 10% to 30% of older adults have malab-sorption of protein-bound vitamin B12, and about 1% to2% lack the intrinsic factor (the causal factor in perni-cious anemia) that is required for active uptake of vita-min B12 in the small intestine.2,25

ORAL CRYSTALLINE VITAMIN B12

SUPPLEMENTATION

Vitamin B12 is generally considered nontoxic andhas no Tolerable Upper Intake Level (UL).1 The RDAfor younger adults 19 to 50 years of age (2.4 �g/d) maynot be sufficient for most older adults (51 years andolder) with atrophic gastritis if vitamin B12 sources aremeat, poultry, fish, and dairy foods.1 Therefore, althoughthe same amount of vitamin B12 is recommended forolder and younger adults (2.4 �g/d), crystalline vitaminB12 is recommended for older adults.1 This RDA wasderived by a factorial method that extrapolated from theamount of intramuscular vitamin B12 required to reversethe hematological signs of vitamin B12 deficiency inpatients with pernicious anemia.1 The RDA of 2.4 �g/dfor the general population 51 years and older1,37 can bemet with multivitamin or B-vitamin supplements or for-tified breakfast cereals that contain at least 25% to 100%of the Daily Value (6 �g) of vitamin B12. Consumptionof crystalline vitamin B12 in the range of about 1 to 50�g/d was associated with higher serum vitamin B12

and/or lower MMA concentrations in observational stud-ies of community-dwelling older people.35,36,38

High oral doses of crystalline vitamin B12 (2000�g/d) for several weeks can correct frank vitamin B12

deficiency (e.g., serum vitamin B12 � 130 pmol/L and

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MMA � 271 nmol/L) and may be somewhat moreeffective than intramuscular therapy,25,39 which has dis-advantages such as pain and cost. Large oral doses areeffective even in those with pernicious anemia, becauseabout 1% of orally administered vitamin B12 is passivelyabsorbed without the need for intrinsic factor.25,39 Thelowest oral doses of crystalline vitamin B12 that cancorrect frank or marginal deficiency are not yet clear.However, a recent study from the Netherlands has ad-dressed this question in elderly subjects. Eussen et al.40

have suggested that older adults with biochemical evi-dence of frank or marginal vitamin B12 deficiency need500 �g/d crystalline vitamin B12 to correct vitamin B12

deficiency.

CYANOCOBALAMIN SUPPLEMENTATION OFVITAMIN B12-DEFICIENT ELDERLY

Eussen et al.40 conducted a randomized, double-blind, parallel, dose-finding study in the Netherlands.Free-living adults 70 years of age and older (N � 120)were randomly assigned to one of five different doses (3,112, 270, 553, and 860 �g/d) of oral vitamin B12 (cya-nocobalamin) supplements for 16 weeks. Participantswith self-reported anemia, surgery or diseases of thestomach or small intestine, or any life-threatening dis-eases were excluded from the study. However, partici-pants were not screened for pernicious anemia or atro-phic gastritis. All participants had normal renal function(serum creatinine concentrations � 120 �mol/L), andvitamin B12 deficiency was defined as serum vitamin B12

concentrations of 100 to 300 pmol/L and plasma MMAconcentrations of � 260 nmol/L. Blood samples werecollected 4 times (screening, randomization or baseline,8 weeks after supplementation, and 16 weeks after sup-plementation). The primary study outcome was plasmaMMA. Plasma tHcy concentrations, plasma holoTC con-centrations, and serum vitamin B12 concentrations weredefined as secondary study outcomes. Hematologicalvariables included hemoglobin, hematocrit, mean cellvolume, and hypersegmentation of neutrophils.

Median age of the participants was 80 years (range,70 to 94). Participants were highly compliant with takingthe supplements (mean compliance: 98%). At baseline,median plasma MMA was 330 nmol/L (range 230 to5160 nmol/L, but the percentage under 260 nmol/L wasnot reported), plasma tHcy was 14.5 �mol/L (range 7.8to 114.0 �mol/L), plasma holoTC was 47 pmol/L (range8 to 121 pmol/L), and serum vitamin B12 was 208pmol/L (range 113 to 362 pmol/L). After 16 weeks oforal vitamin B12 supplementation, the percentage ofparticipants with MMA concentrations below 260nmol/L (considered adequate vitamin B12 status) rangedfrom 21% in those supplemented with 3 �g/d to 76% in

those supplemented with 860 �g/d (Figure 1). Propor-tional decreases in MMA concentrations were not sig-nificantly different between those supplemented with553 �g/d and those supplemented with 860 �g/d. PlasmatHcy concentrations decreased as oral supplementationdose increased and continued to decrease with 860 �g/d.Proportional increases in serum vitamin B12 and plasmaholoTC were observed in response to increasing doses ofvitamin B12. Nonlinear regression analyses and curve-fitting procedures were used to identify the lowest oraldose required to achieve maximal reduction in MMA andelevation in holoTC. These dose-finding curves sug-gested that 830 �g/d would provide 80% of the maxi-mum decrease in MMA, and 449 �g/d would provide80% of the maximum increase in holoTC. Unlike theMMA dose-finding curves, the tHcy dose-finding curvedid not stabilize. The authors concluded that a daily doseof 500 �g was the lowest dose of vitamin B12 that wouldnormalize biochemical markers in an elderly populationwith mild vitamin B12 deficiency, leading to a maximumdecrease in MMA and a maximum increase in holoTCconcentrations.40

There are some limitations to this study. The rangesof serum vitamin B12 and plasma MMA included bothmarginally and frankly deficient individuals. The preva-lence of pernicious anemia, atrophic gastritis, and neu-rologic and hematologic signs of vitamin B12 deficiencywere not assessed. It was not always clear when theinvestigators were using the analyzed vitamin B12 con-tent for analyses. Different conclusions as to the amountof vitamin B12 needed to maximally lower MMA couldbe drawn according to how the data were analyzed andinterpreted. Since tHcy continued to decrease with in-creasing doses of vitamin B12, perhaps higher amounts of

0

10

20

30

40

50

60

70

80

3 µg 112 µg 270 µg 553 µg 860 µg

Daily Oral Vitamin B12 Supplementation

Ad

eq

ua

te V

ita

min

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2 S

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Figure 1. Percentage of participants considered vitamin B12

adequate, with methylmalonic acid concentrations below 260nmol/L, after 16 weeks of daily vitamin B12 supplementation.Data are from Eussen et al., 2005.40

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vitamin B12 and/or co-administration with folic acid areneeded to maximally lower tHcy. The participants’ folatestatus was not optimal, with plasma folate ranging from1.1 to 18.8 nmol/L, where serum folate � 6.8 nmol/L isconsidered folate deficiency41 and older adults (�60years) in the US have geometric mean serum folate in thepost-folate fortification era of 39.4 nmol/L according toNHANES 1999-2000.32 Strengths of the study includednormal renal function in the participants, multiple bio-chemical indices of vitamin B12 status, high compliancewith taking the supplements, and use of the analyzedvitamin B12 content of the supplements for data analyses.

Only a few other intervention studies have comparedvarious oral doses of vitamin B12 in older people withpoor vitamin B12 status. In these studies, serum orplasma vitamin B12 was under 221 pmol/L and/or MMAwas over 271 nmol/L, indicating that the participantswere at least marginally deficient; cyanocobalamin wasused as the supplement.39,42,43 Kuzminski et al.39 exam-ined the efficacy of oral vitamin B12 supplementationversus intramuscular vitamin B12 injections in patientswith vitamin B12 deficiency recruited from New Yorkstate (N � 33). Some patients had neurological symp-toms such as memory loss, paresthesias, and ataxia.Patients were randomly assigned to either oral vitaminB12 supplementation (2000 �g/d) for 4 months or to 9intramuscular vitamin B12 injections (1000 �g on days 1,3, 7, 10, 14, 21, 30, 60, and 90). Mean age in the oraltreatment group (N � 18) was 72 � 11; 7 patients hadsevere chronic atrophic gastritis and 5 patients had per-nicious anemia. After 4 months of daily oral supplemen-tation, mean serum vitamin B12 concentrations increasedfrom 68.6 to 740.8 pmol/L, mean serum MMA concen-trations decreased from 3850 to 169 nmol/L, and meanserum tHcy concentrations decreased from 37.2 to 10.6�mol/L. After 4 months of oral supplementation, pa-tients with both atrophic gastritis and pernicious anemiahad similar increases in serum vitamin B12 and decreasesin MMA, but pernicious anemia patients had somewhatlarger decreases in tHcy than did atrophic gastritis pa-tients (mean tHcy at baseline and after supplementationin atrophic gastritis patients was 31 and 8.4 �mol/L,respectively, and in pernicious anemia patients was 70and 11.4 �mol/L, respectively).

Others have shown that short periods of low-dosesupplements of vitamin B12 do not appear to normalizevitamin B12 status in deficient subjects.42,43 For example,Rajan et al.42 conducted a study with older adults re-cruited from Washington state. This study was a sequen-tial, non-randomized intervention study using oral dosesof vitamin B12 (6 weeks for each dose) starting at 25�g/d followed by 100 �g/d and 1000 �g/d in 23 olderadults (� 65 years) with vitamin B12 deficiency (definedas serum vitamin B12 � 221 pmol/L and serum MMA �

271 nmol/L). Daily oral doses of 25 and 100 �g de-creased but did not normalize serum MMA concentra-tions. Seal et al.43 examined 31 older adults from Mel-bourne, Australia (mean age 81.4 years) with vitamin B12

deficiency (defined as serum concentrations of 100 to150 pmol/L) without pernicious anemia. MMA was notassessed. Participants were randomly assigned to receiveone of the following oral supplements for 4 weeks:placebo, 10, or 50 �g/d of vitamin B12. After 4 weeks ofsupplementation, serum vitamin B12 concentrations wereincreased by 11.7%, 40.2%, and 51.7% in the placebo,10 �g/d, and 50 �g/d groups, respectively, comparedwith baseline. Compared with placebo, 50 �g/d but not10 �g/d significantly increased mean serum vitamin B12,but not all individuals who received 50 �g/d vitamin B12

had significant increases in serum vitamin B12. The oraldose of 50 �g/d vitamin B12 was not sufficient tosignificantly lower tHcy concentrations after 4 weeks.However, the small sample size may have limited theability to detect the effects of vitamin B12 supplementsfor some metabolites.

Together, these studies show that low doses ofvitamin B12 (�50 �g/d) for short periods of time do notincrease serum/plasma vitamin B12 to above the margin-ally deficient range of about 260 pmol/L. More than 100�g is needed for at least 8 weeks to decrease MMA toless than 300 nmol/L. Maximum lowering of tHcy to thepostulated beneficial concentration of under 10 �mol/L32

probably will not be achieved with vitamin B12 alone,especially in countries without mandatory folate fortifi-cation (e.g., Australia43 and the Netherlands40). Addi-tional research is needed to determine the amount of oralcrystalline vitamin B12 needed to improve and maintainvitamin B12 status in marginally deficient and franklydeficient older adults with various causes of vitamin B12

deficiency, such as atrophic gastritis, certain medica-tions, and/or pernicious anemia.

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