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Subnormal Vitamin B12 Concentrations and Anaemia in Older Persons

current evidence suggests that the outcomes of studies in patients with severe vitamin B12 deficiency should not be extrapolated to patients with subnormal vitamin B12 concentrations in the general population. In the Leiden 85-plus Study, a population- based prospective follow-up study of 85-year-old individuals in Leiden, The Netherlands, we showed that low vitamin B12 concentrations (<150pmol/l) in 85-year-old subjects are not associated with the presence of anaemia at 85 years of age. The prevalence of anaemia in those with low vitamin B12 concentrations was 29%, and 25% in those with normal vitamin B12 concentrations (p=0.48). There were no differences in haemoglobin concentrations between subjects with low vitamin B12 concentrations and those with normal vitamin B12 concentrations (p=0.59). Also, participants with low vitamin B12 concentrations did not have a higher risk of developing anaemia from age 85 onwards (see Figure 1). Adjustment for possible confounders did not change our results.46

Although the biological role of vitamin B12 in haematopoiesis is well-defined,38,43–45

Interestingly, our study did not appear the first to cast doubt on the relationship between subnormal vitamin B12 concentrations and anaemia in older individuals. We performed a systematic review to evaluate the association between subnormal vitamin B12 concentrations and anaemia in older people in the published literature (reprinted with permission by BioMed Central).47

All published cross-

sectional and longitudinal observational studies in older individuals (mean or median age ≥60 years) on the association between vitamin B12 and anaemia were considered for inclusion in this review. In addition, we considered all randomised controlled trials (RCTs) where subjects 60 years of age and over were treated with vitamin B12 (any dose and any form of administration) and were compared with subjects who were given a placebo. We used pre-defined clinical queries (both sensitive and specific) for aetiology and treatment as provided in PubMed (January 1949–October 2009) and EMBASE (January 1980–October 2009) using relevant Medical Subject Headings (MeSH) and free text words for vitamin B12 and anaemia.

Twenty-one cross-sectional observational studies with a total number of 16,185 participants were included. The studies showed inconsistent results in terms of the association between subnormal vitamin B12 concentrations or vitamin B12 deficiency and anaemia in older subjects. In three out of 21 studies, an association between subnormal vitamin B12 and anaemia was found.48–50

For seven of 21 studies, the

presence of an association was not clear because conflicting findings in terms of the presence of an association were reported.51–57


studies did not find an association between subnormal vitamin B12 and anaemia.58–68

Even in studies that had defined vitamin B12 deficiency using the lowest cut-off points for serum vitamin B12 levels,51,53,55

in which the strongest associations were to be expected, the presence of an association between vitamin B12 deficiency and anaemia was not clear, because conflicting findings regarding the presence of an association were reported. Similar inconsistencies were found with respect to the association between subnormal vitamin B12 concentrations and mean corpuscular volume (MCV).

In our population-based sample of 85-year-old subjects, low vitamin B12 concentrations were not associated with an increased risk of having anaemia at baseline (prevalent anaemia) or developing anaemia during follow-up (incident anaemia).

Our own study appeared to be the only longitudinal study on the effect of low vitamin B12 concentrations (<150pmol/l) on developing anaemia.46


Figure 1: The Effect of Vitamin B12 Deficiency (<150pmol/l) on Anaemia During Follow-up in Subjects without Anaemia at 85 Years of Age






0 85 86 87 88 Age (years) Normal vitamin B12 levels (n=265) Vitamin B12 deficiency (n=48)

n=313, hazard ratio 0.85, 95% confidence interval 0.43–1.65.46 Reprinted with permission. Archives of Internal Medicine, 2008;168(20):2241. Copyright © 2008, American Medical Association. All rights reserved.

We found three randomised placebo-controlled trials with a total number of 210 participants that met the criteria for intervention studies for inclusion in our review.69–71

These three trials included

patients with low or subnormal vitamin B12 concentrations at the start of the study. The first trial, by Hughes et al., included a random sample of 39 persons aged ≥65 years registered at general practices in a town in Wales, UK, who were treated for four weeks with intramuscular hydroxocobalamin or placebo. Haemoglobin was measured after five weeks.69

The second trial, by Hvas et al., included

140 persons in Aarhus, Denmark, with elevated methylmalonic acid concentrations (median age 75 years in the treatment group and 74 years in the placebo group), who received weekly intramuscular injections of cyanocobalamin or placebo for one month. Haemoglobin was measured after three months (13 weeks).70

In the third trial, by

Seal et al., 31 persons in two geriatric hospitals in Melbourne, Australia, (mean age ≥78 years) received two doses of oral cyanocobalamin daily or placebo for four weeks.71

Owing to clinical heterogeneity (differences in methods of administration, dose of vitamin B12, outcome measures and treatment follow-up time), we did not combine the results in a meta- analysis. However, all three RCTs, which were regarded as high quality, showed no beneficial effects of vitamin B12 administration on haemoglobin concentrations, MCV, cognitive function and neurological symptoms.69–71

Neither was there any therapeutic effect in participants who were anaemic.70

Taking these findings into account, one may conclude that strong evidence of a positive association between subnormal vitamin B12 concentrations and anaemia in older persons in the general population is lacking.

137 89 90

Cumulative incidence of anaemia (%)

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