How common is vitamin B-12 deficiency?

1–3
Lindsay H Allen

ABSTRACT 221 pmol/L. The gold-standard indicator is elevated serum (or

In considering the vitamin B-12 fortification of flour, it is important less commonly, urinary) methylmalonic acid (MMA). Recently,
to know who is at risk of vitamin B-12 deficiency and whether those a cutoff of .210 nmol/L has been proposed, ie, the 95th per-
individuals would benefit from flour fortification. This article reviews centile for vitamin B-12–replete participants with normal renal
current knowledge of the prevalence and causes of vitamin B-12 de- function in the National Health and Nutrition Examination
ficiency and considers whether fortification would improve the status Survey in the United States (1). The limitations of MMA as an
of deficient subgroups of the population. In large surveys in the indicator include the cost of analysis, the need for mass spec-

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United States and the United Kingdom, ’6% of those aged 60 y trometry, and, especially in developing countries, the possibility
are vitamin B-12 deficient (plasma vitamin B-12 , 148 pmol/L), with of concentrations being increased by bacterial overgrowth. Al-
the prevalence of deficiency increasing with age. Closer to 20% though vitamin B-12 deficiency is the major cause of elevated
have marginal status (plasma vitamin B-12: 148–221 pmol/L) plasma total homocysteine (tHcy) in folate-replete populations
in later life. In developing countries, deficiency is much more such as in the US elderly after the folic acid fortification of flour
common, starting in early life and persisting across the life span. (2), in other locations deficiencies of folate, riboflavin, and vi-
Inadequate intake, due to low consumption of animal-source tamin B-6 must be ruled out because these too will increase
foods, is the main cause of low serum vitamin B-12 in younger tHcy. However, if vitamin B-12 supplementation or fortification
adults and likely the main cause in poor populations worldwide; in of a population group lowers tHcy, this can be used as an in-
most studies, serum vitamin B-12 concentration is correlated with dicator of improved status (3). Megaloblastic anemia does not
intake of this vitamin. In older persons, food-bound cobalamin usually result from chronic, marginal depletion of the vitamin
malabsorption becomes the predominant cause of deficiency, at
caused by low dietary intake (4) but occurs more commonly in
least in part due to gastric atrophy, but it is likely that most elderly
pernicious anemia and severe vitamin B-12 deficiency (serum
can absorb the vitamin from fortified food. Fortification of flour
vitamin B-12 , 120–150 pmol/L).
with vitamin B-12 is likely to improve the status of most persons
with low stores of this vitamin. However, intervention studies are
still needed to assess efficacy and functional benefits of increasing PREVALENCE OF DEFICIENCY IN SURVEYS
intake of the amounts likely to be consumed in flour, including in
elderly persons with varying degrees of gastric atrophy. Am J Serum vitamin B-12 concentrations in the US population were
Clin Nutr 2009;89(suppl):693S–6S. reported in the National Health and Nutrition Examination
Surveys from 1999 to 2002 (1, 5). The prevalence of deficiency
(serum vitamin B-12 , 148 pmol/L) varied by age group and
affected 3% of those aged 20–39 y, ’4% of those aged 40–59
INTRODUCTION y, and ’6% of persons aged 70 y. Deficiency was present in
Vitamin B-12 deficiency and depletion are common in ,1% of children and adolescents but was 3% in children aged
wealthier countries, particularly among the elderly, and are most ,4 y (the youngest age group reported). Marginal depletion
prevalent in poorer populations around the world. This prevalence (serum vitamin B-12: 148–221 pmol/L) was more common and
was underestimated in the past for several reasons, including the occurred in ’14–16% of those aged 20–59 y and .20% of
erroneous belief that deficiency is unlikely except in strict those .60 y. Plasma MMA concentrations were markedly
vegetarians or patients with pernicious anemia, and that it usually higher after age 60 y. Of .1600 elderly (age 60 y) California
takes ’20 y for stores of the vitamin to become depleted. This Hispanics in the Sacramento Area Latino Study on Aging
article reviews the prevalence of deficiency and its underlying
1
causes, which is relevant to assessing the potential benefits of From the US Department of Agriculture, ARS Western Human Nutrition
fortifying flour with this vitamin. Research Center, University of California, Davis, Davis, CA.
2
Presented at the symposium ‘‘Is It Time for Mandatory Vitamin B-12
Fortification in Flour?’’ held at Experimental Biology 2008, San Diego, CA,
DIAGNOSIS OF DEFICIENCY 8 April 2008.
3
Reprints not available. Address correspondence to LH Allen, USDA,
A diagnosis of vitamin B-12 deficiency is usually made on the ARS Western Human Nutrition Research Center, 430 West Health Sciences
basis of serum or plasma vitamin B-12 concentration, with de- Drive, University of California, Davis, Davis, CA 95616. E-mail: lindsay.
ficiency currently defined as a concentration , 148 pmol/L (200 allen@ars.usda.gov.
pg/mL) and marginal status defined as a concentration of 148– First published online December 30, 2008; doi: 10.3945/ajcn.2008.26947A.

Am J Clin Nutr 2009;89(suppl):693S–6S. Printed in USA. Ó 2009 American Society for Nutrition 693S
694S ALLEN

(SALSA), 6% had plasma vitamin B-12 in the range of de- it is clear that animal-source or fortified foods affect serum vi-
ficiency and an additional 16% had marginal status, with evi- tamin B-12 across the usual range of daily intake.
dence of further decline in plasma vitamin B-12 with age (6). Plasma vitamin B-12 concentrations plateaued at intakes .10
The prevalence of vitamin B-12 deficiency (serum B-12  150 lg/d in the Framingham Offspring Study. This is consistent with
pmol/L) increased substantially after age 69 y in 3 UK surveys earlier observations by Chanarin (19) who summarized studies
(combined n ¼ 3511); it affected about 1 in 20 people aged that measured vitamin B-12 absorption from radioactively labeled
65–74 y and at least 1 in 10 of those aged 75 y (7, 8). aqueous solutions and foods. Although .70% of the vitamin is
Across studies in Latin America, ’40% of children and adults absorbed when intake is in the range of 0.1–0.5 lg, the ileal re-
had deficient or marginal status (9), including a nationally rep- ceptors for the vitamin B-12–intrinsic factor complex become
resentative sample of women and children in the 1999 Mexican saturated with higher intakes such that absorption falls to ’50%
National Nutrition Survey. The reported prevalence of deficient of a 1-lg dose, 15% of a 10-lg dose, and 3% of a 25–50-lg dose
and marginal values is much higher in African and Asian (Figure 1). The maximum amount that can be absorbed from a 5–
countries, eg, 70% in Kenyan school children (10, 11), 80% in 50-lg single dose is 1.5 lg. Above 25 lg, only 1% of a dose is
Indian preschoolers (12), and 70% in Indian adults (13). absorbed, by passive diffusion, which explains why the relative
increase in serum vitamin B-12 is related to the log of the dose. In
healthy Danish women, serum vitamin B-12 and other vitamin
LOW INTAKE AND RISK OF DEFICIENCY B-12 status indicators appeared to plateau at an intake (from food 1
The 2 main causes of vitamin B-12 deficiency are inadequate supplements) .6 lg/d (20), but in part this is expected because of

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dietary intake and, in the elderly, malabsorption of the vitamin the lower efficiency of absorption of the vitamin at higher intakes.
from food. Contrary to popular belief, not only strict vegetarians
(vegans) are at high risk of vitamin B-12 deficiency, and there is
strong evidence that status reflects usual intake across a wide FOOD-BOUND COBALAMIN MALABSORPTION
range. In the United States and Canada, the Estimated Average Malabsorption of vitamin B-12 from food is the main cause of
Requirement is 0.7–2.0 lg/d across the life span, whereas the deficiency in the elderly and explains why depletion occurs with
respective Recommended Dietary Allowance is 0.9–2.4 lg/d. aging. The condition is caused by atrophy of the gastric mucosa
The vitamin is present only in animal-source foods (ASFs) or and the gradual loss of gastric acid, which releases the vitamin
fortified foods. In the large EPIC study in the United Kingdom, from food. In its early stages, gastric inflammation and elevated
intakes increased progressively with ASF intake, averaging 0.4 serum gastrin concentrations are common. In elderly persons in
lg for vegans, 2.6 lg for lactoovovegetarians, 5.0 lg for those the Framingham Offspring Study, 24% of those aged 60–69 y
who also consumed fish, and 7.2 lg for consumers of meat and 37% of those aged 80 y had elevated serum gastrin (21).
(omnivores) (14). Numerous other studies on smaller population Likewise, in the SALSA Study, serum gastrin was elevated in
groups confirmed that both vitamin B-12 intake and serum vi- 48% of the elderly participants with deficient plasma vitamin B-12
tamin B-12 concentrations increase progressively from vegans values, in 23% of those with marginal concentrations, and in 21%
to lactoovovegetarians, to those who consume fish or some meat, of those with normal status; overall, these concentrations were
to omnivores (15–17). inversely correlated with plasma vitamin B-12 (6).
ASF intake may be restricted for cultural or religious reasons Food-bound cobalamin malabsorption is diagnosed when an
and, by many people in the world, because of low income. Food individual has normal absorption of crystalline vitamin B-12
and Agriculture Organization food balance sheets reveal that using a Schilling test, no antibodies to intrinsic factor or other
most of the world’s population consumes ,20% of their energy tests positive for pernicious anemia (which is defined as vitamin
as ASFs, with many countries in Africa consuming ,10%, B-12 malabsorption due to loss of gastric intrinsic factor se-
compared with .20% in wealthier regions and 40% in the United cretion), and no acid-suppressing medications or gastric surgery
States. Predictably, lower intakes are associated with a higher
prevalence of deficient and marginal serum B-12 concentrations;
strong correlations were found in all studies that measured both
vitamin B-12 intake and serum vitamin B-12 (10–17).
Fortified foods, especially ready-to-eat cereals, and supple-
ments can be important sources of vitamin B-12. In the US
Framingham Offspring Study, ’16% of those aged 26–83 y had
serum vitamin B-12 ,185 pmol/L and ’9% had values ,148
pmol/L (18). Mean intake of the vitamin was 9 lg/d. Intake from
all sources was higher in persons with serum vitamin B-12
.185 pmol/L than in those with serum vitamin B-12 ,148
pmol/L, including supplements (1.5 compared with 0.4 lg/d)
and fortified cereals (0.6 compared with 0.3 lg/d). Overall,
plasma vitamin B-12 increased by 45 pmol/L for each doubling
of intake, with response to supplements and cereals similar to
that produced by other foods. In nonconsumers of supplements,
for each doubling of intake, plasma vitamin B-12 was increased
by 24 pmol/L with fortified cereals, 39 pmol/L with dairy FIGURE 1. The efficiency of absorption of a single oral dose of vitamin
products, and only 12 pmol/L with meat, fish, and poultry. Thus, B-12 across a range of intakes. Based on data from reference 19.
 HOW COMMON IS VITAMIN B-12 DEFICIENCY? 695S
but impaired absorption of the vitamin when administered bound crystalline vitamin added as a fortificant to flours, and in fact
to egg or chicken serum (22). Because a normal Schilling test elderly persons are advised to consume a higher proportion of their
also means that intrinsic factor secretion and function are nor- vitamin B-12 intake as fortified foods and supplements. By def-
mal, reabsorption of biliary vitamin B-12 is maintained and inition, diagnosis of food-bound cobalamin malabsorption requires
depletion of the vitamin will progress slowly, over years. Impor- normal absorption of free cobalamin, so a person with this con-
tantly, however, a longitudinal study revealed that serum vitamin dition should be able to absorb crystalline vitamin B-12 added as
B-12 declined between ages 70–81 y in elderly Swedish men, and a fortificant to food or in supplements. However, in a small
for reasons not understood, the decline was most evident in those proportion of elderly persons, gastric atrophy may have progressed
with lower serum values initially (23). It seems reasonable to assume to a stage in which intrinsic factor production is impaired so that
that entering later life with low stores of the vitamin for whatever they cannot absorb the vitamin from any source, including fortified
reason, including low dietary intake, would increase the risk that foods. Although pernicious anemia is clearly most prevalent in the
deficiency would result from chronic food cobalamin malabsorption. elderly, it is still relatively uncommon. A study in California found
The causes of food cobalamin malabsorption are uncertain. that 1.9% of 729 free-living persons aged 60 y had undiagnosed
Carmel (24) summarized data from 9 studies in the United States pernicious anemia defined as an abnormal Schilling test or positive
and found that the condition was present in ’40% of patients antiintrinsic factor antibodies, and that their vitamin B-12 de-
with unexplained low serum vitamin B-12 concentrations. Not pletion was still relatively mild (29). It is possible, although un-
all of those patients were elderly, and some had other risk factors tested, that some elderly persons have a moderate degree of
such as gastric resection. In a subsequent comparison of 43 impairment of crystalline vitamin B-12 absorption but have not

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normal elderly and 159 elderly persons with low serum co- progressed to pernicious anemia. Some evidence for this was
balamin (22), malabsorption affected primarily those aged 60 y obtained in the SALSA Study in which elderly persons in the
and was not clearly related to markers of gastric function (eg, highest quartile of serum gastrin needed a significantly higher
serum gastrin). Helicobacter pylori infection was present in intake of crystalline vitamin B-12 to achieve the same serum
78% of those with severe malabsorption, in 50% with mild vitamin B-12 concentrations as those in the lowest quartile (21).
malabsorption, and in 44% with normal absorption, but any Testing the ability of the elderly to absorb high doses, eg,
effect of H. pylori was independent of its association with .100 lg, is not useful for answering the question of efficacy of
atrophic gastritis and gastric acid production; H. pylori in- food fortification because ’1% of a high dose will be absorbed
fection is generally accepted as being the main cause of by passive diffusion, independently of gastric function or in-
chronic atrophic gastritis and affects ’50% of those aged 60 trinsic factor. A recent report by the Flour Fortification Initiative
y in industrialized countries and a far greater proportion in recommended that where vitamin B-12 fortification is practiced,
developing countries. Elevated serum gastrin was a significant 2 lg/100 lg of flour should be added (30). The main constraint
predictor of malabsorption but was not elevated in two-thirds on the level of fortification is the cost of the vitamin used in
of those who had malabsorption. Malabsorption was more premixes, not safety or sensory changes in the product. On the
prevalent in Hispanics and blacks, which was not explained by basis of an average flour consumption of ’150 g/d in the United
their higher prevalence of H. pylori infection. States, the relevant question becomes the efficiency of absorp-
The low gastric pH that occurs as a result of gastric atrophy can tion from intakes ’3 lg/d. In the Netherlands, subjects aged 50–
also increase bacterial overgrowth in the upper intestine, which 65 y were assigned randomly to consume bread fortified with 9.6
results in less absorption of protein-bound (but not crystalline) lg vitamin B-12 and 138 lg folic acid daily or unfortified bread
vitamin B-12. A short course of treatment with tetracycline re- for 12 wk (31). Fortification increased serum folate by 45% and
versed protein-bound vitamin B-12 malabsorption in elderly serum vitamin B-12 by 49%, and the proportion of subjects with
persons with atrophic gastritis (25). High doses of H2-receptor serum vitamin B-12 ,133 pmol/L decreased from 8% to 0%.
antagonists (eg, .1000 lg/d cimetidine) or proton pump in- Although the study showed that bread made with vitamin B-12–
hibitors (eg, 20–40 mg/d omeprazole) inhibit food cobalamin fortified flour can increase serum concentrations of the vitamin,
absorption (the latter by 70%) by reducing gastric acid secretion the level of fortification was high and elderly persons with
(26, 27). However there is little evidence that deficiency of vi- baseline serum concentrations ,118 pmol/L (ie, those who may
tamin B-12 will result from short-term use of these medications. have had more severe gastric atrophy and/or preclinical perni-
Gastric bypass or resection can also produce vitamin B-12 de- cious anemia) were excluded. Only one study has measured the
ficiency. The influence of polymorphisms in proteins that effect of low doses on elderly persons (70 y) with serum vi-
transport the vitamin is not well established, but the 776G.C tamin B-12 ,162 pmol/L and defined as having ‘‘food vitamin
polymorphism in transcobalamin, for which 20% of the pop- B-12 malabsorption’’ (32). They were given a daily dose ranging
ulation is homozygous, is associated with higher MMA and from 2.5 to 80 lg in water after breakfast for 30 d. The authors
lower trans cobalamin concentrations (28). concluded that serum vitamin B-12 increased as a linear func-
tion of the log of the dose, and 5.9 lg/d was needed to increase
serum vitamin B-12 by 37 pmol/L (50 pg/mL). There was no
EFFECT OF FOOD-BOUND COBALAMIN MALABSORP- effect on MMA or tHcy. Unfortunately, food cobalamin mal-
TION ON ABSORPTION OF VITAMIN B-12 FROM absorption was defined as a normal Schilling test accompanied
FORTIFIED FOODS by some type of gastric problem or pernicious anemia (2 cases)
In the United States and other industrialized countries, the so malabsorption may or may not have been present; furthermore,
main reason to fortify flour with vitamin B-12 is to improve the the serum vitamin B-12 response was highly variable across the
status of the elderly. It is assumed that most elderly persons with few lower intakes tested, the study was too short to determine an
impaired absorption of the vitamin from food can still absorb the optimal dose, and the dose was not provided in food.
696S ALLEN

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