Review Articles

Vitamin B-12 deficiency in the elderly: current dilemmas1’2

Sally P Stabler, John Lindenbaum, and Robert H Allen

ABSTRACT Vitamin B-l2 deficiency is present in up to 15% folate (17). Thus, there are new questions regarding the diag-
of the elderly population as documented by elevated methylma- nosis and treatment of vitamin B-12 deficiency in elderly
lonic acid with or without elevated total homocysteine concentra- subjects. We address the relative specificity and sensitivity of
tions in combination with low or low-normal vitamin B- 12 con- the metabolites and vitamin concentrations, the causal role of
centrations. Clinical signs and symptoms of vitamin B-12 vitamin B-l2 deficiency in hyperhomocysteinemia, the clinical
deficiency are insensitive in elderly subjects and comorbidity in manifestations of vitamin B-12 deficiency, and treatment op-
these subjects makes responses to therapy difficult to interpret. tions in the elderly.
Many elderly subjects with hyperhomocysteinemia have undiag-
nosed vitamin B-l2 deficiency with elevated serum methylmalonic

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acid concentrations. Therefore, such elderly subjects should not ELEVATED SERUM MMA AND HOMOCYSTEINE IN
receive folic acid supplementation before their vitamin B-l2 status CLINICAL VITAMIN B-12 OR FOLATE DEFICIENCY
is diagnosed. Oral vitamin B-12 supplementation may be effective
Vitamin B- 12 is a known cofactor for two reactions in higher
in lowering serum methylmalonic acid values in the elderly. How-
animals (Figure 1 and Figure 2). In the first reaction,
ever, the dose of vitamin B-l2 in most common multivitamin
L-methylmalonyl-C0A is converted to succinyl-CoA by an
preparations is too low for this purpose. Research efforts should
adenosylcobalamin-dependent enzyme, L-methylmalonyl-C0A
be directed toward determining practical methods for diagnosing
mutase (1 8). When methylmalonyl-CoA concentrations in-
and treating vitamin B-l2 deficiency in the millions of elderly
crease, a specific hydrolase cleaves the D-isomer to MMA (19).
subjects with undiagnosed deficiency. Am J Clin Nutr 1997;
The second reaction is the methylation of homocysteine by
66:741-9.
methionine synthase utilizing a methyl group from N5-methyl-
tetrahydrofolate and methylcobalamin as a cofactor (20). Al-
KEY WORDS Methylmalonic acid, cobalamin, homocys-
ternatively, homocysteine is condensed with serine to form
teine, folate, dementia, elderly, vitamin B-12
cystathionine, in a reaction dependent on pyridoxal 5’-phos-
phate (21). Cystathionine can be further cleaved to a-ketobu-
INTRODUCTION tyrate and cysteine (21). MMA concentrations increase to ex-
tremely high levels in clinical vitamin B- 12 deficiency (22-28)
Several recent developments make it necessary to reexamine and with inborn errors of cobalamin or mutase metabolism
strategies for diagnosing and treating vitamin B-12 (cobalamin) (18). Both clinical vitamin B-l2 and clinical folate deficiencies
deficiency in the large numbers of elderly subjects with undi- result in elevated concentrations of tHcy, termed hyperhomo-
agnosed deficiency. The first development was the realization cysteinemia (28-32). tHcy is also occasionally elevated in
that serum vitamin B-12 concentrations have limited sensitivity subjects with vitamin B-6 deficiency (33, 34). Both tHcy and
and specificity in the elderly. In many cases, both the low and MMA concentrations increase in renal insufficiency (24, 3 1,
low-normal serum vitamin B- 12 concentrations found fre- 35-38). tHcy concentrations are usually correlated with serum
quently in elderly subjects are accompanied by elevations in creatinine, age, male sex, and total cysteine concentrations
the vitamin B-l2-dependent metabolites methylmalonic acid (39, 40).
(MMA), total homocysteine (tHcy), or both (1-7). In fact, 50% During the past decade it became possible to determine the
of those with elevated concentrations of metabolites have a sensitivity and specificity of serum vitamin B-12 and folate
serum vitamin B- 1 2 concentration above the conventional cut- concentrations as well as to identify the clinical syndromes
off of 2 SD below the mean in a normal population (1, 2). associated with various vitamin deficiencies when sensitive
Elevated MMA and tHcy concentrations respond to therapy and specific assays for serum and urine MMA and tHcy be-
with vitamin B-l2, given either alone or in combination with
other vitamins (1, 4, 5, 8).
I From the Departments of Medicine and Biochemistry, Division of
A second development is the growing body of evidence that
Hematology, University of Colorado Health Sciences Center, Denver, and
elevations of homocysteine, regardless of cause, are associated
Columbia University College of Physicians and Surgeons, New York.
with vascular disease; thus, homocysteine-lowering regimens
2 Address reprint requests to SP Stabler, University of Colorado Health
are currently being developed (9-16). A third important devel- Sciences Center, 4200 East Ninth Avenue, Campus Box B-l70, Denver,
opment is the federally mandated food folate-fortification pro- CO 80220. E-mail: jonesjo@jove.UCHSC.edu.
gram; by January 1998, potentially millions of vitamin B-12- Received April 9, 1997.
deficient elderly subjects will be exposed to increased dietary Accepted for publication June 19, 1997.

Am J Clin Nutr 1997:66:741-9. Printed in USA. © 1997 American Society for Clinical Nutrition 741
742 STABLER ET AL

Valine
Isoleucine
Methionine
COOH
Threonine
Odd chain fatty acids SH-CoA + HC-CH3
Thyrnine COOH urine
Cholesterol
Biotin METHYLMALONIC ACID
ATP COOH
Mg2

H2C-CH

CO-S-CoA
+ HC03
Propionyl-CoA
Carboxylase
HC-CH3

CO-S-CoA
I
rboxyIic
Acid
Cycle

COOH
)
PROPIONYL-C0A D-METHYLMALONYL-CoA COOH Adenosylcobalamin

HC-CH _______________
4
CH2
L-Methylmalonyl-C0A
Cl1
CO-S-CoA
Mutase
4.
CO-S-CoA
L-METHYLMALONYL-.CoA SUCCINYL’-COA

*CH

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1420 iiie Synthase HC-COOH
C-000H 4

HOC-COOH
HC-COOH
HC-COOH
OXALOACETIC ACID
2-METHYLCITRIC ACID

FIGURE 1. The vitamin B-l2 (adenosylcobalamin)-dependent conversion of L-methylmalonyl-C0A to succinyl-CoA is shown (18). D-Methylmalonyl-
CoA can be cleaved to methylmalonic acid by a specific hydrolase (19). Propionyl-CoA can be condensed with oxaloacetic acid by citrate synthase to form
2-methylcitric acid (20).

came available. It was shown that MMA concentrations are Several other metabolites, although less sensitive than MMA
elevated in nearly every patient with hematologic or neurologic and tHcy, are also elevated in severe clinical vitamin B-12 and
abnormalities due to cobalamin deficiency and that MMA folate deficiencies. Cystathionine and 2-methylcitrate are fre-
concentrations respond to vitamin therapy (24-28, 41). It was quently elevated in vitamin B-12-deficient patients (48, 49).
also shown that in inadequately treated patients with known Serum cystathionine and N-methylglycine (sarcosine) are fre-
pernicious anemia (those not receiving an adequate number of quently elevated in folate-deficient subjects (48, 50). Serum
vitamin B-l2 injections), MMA concentrations were most cystathionine concentrations were found to be increased in
commonly the first indicator to become abnormal (42). At least subjects with drug-induced vitamin B-6 deficiency (34), espe-
5% of subjects with classic, clinically defined vitamin B-12 cially after a methionine load. Both cystathionine and 2-meth-
deficiency have serum vitamin B- 12 values above conventional ylcitric acid are more sensitive to poor renal function than are
cutoffs (42). Serum tHcy was also found to be elevated in MMA and tHcy (48, 49), and can thus suggest this diagnosis in
> 90% of subjects with clinical vitamin B-l2 deficiency or subjects with borderline serum creatinine values.
with megaloblastic anemia resulting from folate deficiency
(28). tHcy is slightly less sensitive than MMA concentrations
and there are a few vitamin B-12-deficient patients with tHcy HIGH PREVALENCE OF ELEVATED MMA AND tHcy
elevations only (28). Response to therapy is specific and can be IN THE ELDERLY
used diagnostically because folic acid treatment does not cor-
rect elevated MMA or tHcy in vitamin B-l2 deficient patients Because the diagnostic utility of serum MMA and tHcy
and vice versa (43). Folate-deficient subjects do not have values was first shown in subjects with severe vitamin B- 12
elevated MMA concentrations unless they have renal failure or deficiency due to classically defined pernicious anemia (ie,
volume depletion (28). A significant number of vitamin B-12- positive for antibodies to intrinsic factor or a positive stage 1
deficient patients who have marked elevations of MMA and Schilling test), it became possible to study elderly populations
tHcy have neurologic abnormalities that respond to vitamin to determine whether their high prevalence of low vitamin
B-12, despite the absence of megaloblastic anemia (44). There B-l2 concentrations had metabolic or clinical significance. The
is an inverse relation between the severity of the neurologic combination of elevated MMA with low or low-normal serum
disease and that of the hematologic disease (45). Comparisons vitamin B-12 concentrations, with or without elevated tHcy,
of metabolite concentrations with vitamin B- 12 concentrations was found in 5-15% of elderly populations (1-4, 7, 51). Only
and clinical syndromes showed that serum vitamin B-12 is a few of these subjects had proven pernicious anemia (1 2, 5, ,

often nonspecific with a low predictive value (41, 46, 47). 52); the rest may have various degrees of food vitamin B-l2
Normal concentrations of MMA and tHcy in subjects with low malabsorption due to atrophic gastritis (5, 52) or intestinal
vitamin B-l2 concentrations rules out significant clinical defi- pathology. Few of these subjects were found to have classic
ciency (41). megaloblastic anemia, and comorbidity made interpretation of
 VITAMIN B-l2 DEFICIENCY IN THE ELDERLY 743

CH3 H
N-CHfCOOH N-CH2-COOH
H H

IN-METHYLGLYCINE I ethYI5
sferase

Multiple
H CH3 H
I Transferases
Adenosyl-S-CH2-CH2-C-COOH -S-CH2- CH2--COOH
NH2 NH2

IS-ADENOSYLHOMOCYSTEINEI IS-ADENOSYLMETHIONINE I

Hydrolase Methionine
Adenosyltransferase

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‘Adenoslne ICH3-Cb11
FAD
H Methionine Synthase H
CH2-S-CH2-CH2-f!-COOH
NH2 15CH2ThF1 NH2

IHOMOCYSTEINE I DNAA” IMETHIONINEj

RNA
Serine Pathways
Cystathionine
-synthase
Pyndoxal
Phosphate

H sphate
Pyrldoxal
S-CHfCH2-f-COOH
NH
7-Cystathionase H
HS-CH2-(-COOH
CH2-C-COOH + CH3-CH2-C-COOH
NH2 NH2 0
NH3 FCYSTEINE1
ICYSTATHIONINE I Ia-KETOBUTYRATEJ
fl#{231}NH2

Transaminase(s)
1

H
CHCH2-f-COOH
NH2

kL-AM4OBUTYRAj
FIGURE 2. The pathway of methionine metabolism is shown. Homocysteine can be methylated to form methionine utilizing N5-methyltetrahydrofolate
(5-CH3-THF) and methylcobalamin (CH3-Cbl) (20). Homocysteine can be condensed with serine to form cystathionine, which can be further cleaved to
a-ketobutyrate and cysteine (21). N-Methylglycine is formed by the methylation of glycine in an S-adenosylmethionine-dependent reaction (22). The
S-adenosylhomocysteine resulting from demethylation is then cleaved to form homocysteine, which completes a cycle of transmethylation (21).

neurologic abnormalities difficult (1, 2, 7, 52). Perhaps most or <200 pg/mL) (1-4, 7). In an evaluation of 548 subjects
surprising was that there were almost as many subjects with from the Framingham Heart Study cohort, a cutoff of 260
elevated MMA or tHcy among those with serum vitamin B-l2 pmol/L (350 pg/mL) for serum vitamin B-l2 was much better
concentrations in the low-normal range as there were among able to separate subjects with elevations of MMA from those
those with concentrations in the low range (ie, < 150 pmol/L, with normal MMA concentrations (2).
744 STABLER ET AL

ARE ELEVATED CONCENTRATIONS OF MMA AND tHcy in addition to serum vitamin B-l2, unequivocal vitamin
tHcy DETRIMENTAL IN THE ELDERLY? B-l2 deficiency can be shown in subjects with mild or corn-
pletely absent hernatologic abnormalities (44).
Elevations of serum MMA in elderly subjects in screening
We do not know what percentage of vitamin B-l2-deficient
studies range from concentrations just above a 2-SD cutoff
patients have anemia because there are no data from large
(> 27 1 nmol/L) (1, 2) to the high concentrations frequently
general population studies that could be used to correlate MMA
seen in subjects with severe clinical vitamin B-12 deficiency
values with hernatologic variables. It is possible that only a
(28). It is possible that a normal range for MMA determined in
minority of the patients with severe biochemical vitamin B-l2
younger populations is not valid for elderly subjects. This is
deficiency ever develop megaloblastic anemia. Evidence sup-
unlikely, however, because the elevated concentrations seen in
the elderly decrease readily into the normal range when the porting this view can be found in an interesting series of studies
subjects receive parenteral vitamin B-l2 therapy (1, 4, 8, 52, published in the Netherlands on infants and young children
53). Only in an occasional subject with renal failure do MMA who had been weaned to a macrobiotic diet that did not contain
concentrations fail to fall into the normal range with vitamin significant amounts of vitamin B-12 (55-57). These subjects
B-12 therapy. In one study by Rasmussen et al (54), MMA had severe vitamin B-12 deficiency on the basis of high con-
concentrations did not decrease when 252 normal subjects were centrations of serum MMA and tHcy (57), but had only subtle
treated with high-dose oral vitamin B-l2 for 2 wk unless the hernatologic abnormalities (55). Despite rapid growth status
subjects had a baseline concentration > 240 nmol/L. Thus, it and coexistent iron deficiency, the subjects did not have the
appears that elevations of MMA that decrease with vitamin severe anemia that might have been expected. They did, how-
B-l2 therapy actually document enzymatic deficiency, because ever, have developmental and growth abnormalities. The in-

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the values cannot be manipulated in normal subjects. In the vestigators did not provide information on the folate intake of
same study, high-dose oral folate (10 mg/d) caused a marked these subjects, but it is possible there was a masking of anemia
decrease in serum tHcy even in subjects with tHcy concentra- by high dietary folate, which could be present in a totally
tions below the mean (54). The fact that tHcy can be driven to vegetarian diet (56).
very low concentrations by large amounts of oral folic acid Severe enzymatic vitamin B- 12 deficiency can exist in sub-
suggests that this decrease cannot always be used as evidence
jects without frank megaloblastic anemia (44). Data from five
for tissue deficiency, in contrast with the serum MMA concen- patients studied recently at the University of Colorado Health
tration response to vitamin B-l2 treatment.
Sciences Center are shown in Table 1. Patients 1 and 2 were
It is possible that the elevations of MMA and tHcy found in
selected because they had among the highest MMA values
screening studies in the elderly are of no clinical importance
measured in samples sent from the clinics of the University of
because associated vitamin B- 12-deficient megaloblastic ane-
Colorado Health Sciences Center. In these subjects, MMA
mia is rare in such surveys. Elevations of tHcy, regardless of
concentrations were extremely high despite normal or almost
cause, may be associated with increased vascular disease (10,
normal complete blood counts. Patient 2 had donated two units
1 1), although there have been no intervention studies to prove
any benefit in lowering such concentrations. There has been a of blood for later autologous postoperative transfusion in the
historical bias to consider vitamin B-l2 deficiency as synony- weeks before the blood count shown in the table. Patient 4 is
mous with megaloblastic anemia, extending even to the desig- interesting because she had a normal vitamin B-12 concentra-
nation of the severe malabsorption disorder due to lack of tion but an MMA value as high as that of patient 3, whose
intrinsic factor as “pernicious anemia”. Until recently the spe- vitamin B- 12 concentration was clearly low. Without anemia
cific diagnosis of deficiency depended mainly on the vitamin and with a normal vitamin B-12 value, many clinicians would
B- 12 concentration, and the purely or mostly neurologic pre- assume that patient 4 had normal vitamin B-l2 status. How-
sentations of vitamin B- 12 deficiency were considered rare. ever, MMA and tHcy concentrations were elevated in this
However, with the confirmatory evidence of elevated MMA or patient but were not representative of values seen in patients

TABLE 1
Laboratory data from five patients deficient in vitamin B-l2’

Patient Age Sex MMA Hcy MCV Hct Serum B-12 Serum folate

y nmol/L ,mzoLIL JL pmol/L nmol/L

12 47 F 74300 43.8 98 0.41 33 ND
2 64 M 68600 76.1 110 0.38 < 12 ND
34 83 F 12600 92.4 95 0.47 48 17
44 93 F 11 300 22.5 92 0.46 170 26
54 99 F 6 200 40.9 93 0.35 30 17
Normal
range - - 73-271 5-16.2 80-100 0.40-0.50 (F); 150-590 4-45
0.42-0.52 (M)
1 MMA, methylmalonic acid; Hcy, homocysteine; MCV, mean corpuscular volume; Hct, hematocrit; ND, not done.
2 Severe paresthesias documented in the medical record for several years.

3 Several years of neurologic complaints with severe myelopathy, upper and lower extremity weakness, personality change, and positive Lhermitte sign.
4 These three subjects were the most vitamin B- 12-deficient subjects in a cohort (n 1 83) of nursing home patients.
 VITAMIN B-l2 DEFICIENCY IN THE ELDERLY 745

with inborn errors of cobalamin metabolism. Thus, these ele- Because both vitamin B-12 deficiency and Alzheimer dis-
vations probably represent vitamin B-12 deficiency. ease and other dementias are common in the elderly popula-
Megaloblastic anemia was found to be rare in two elderly tion, it seems likely that many subjects will have combinations
cohorts with a 12% prevalence of vitamin B-l2 deficiency of disorders. It would take an astute clinician to determine what
(1, 2). Mean corpuscular volume was high (100.6 and 100.5 fL) percentage of cognitive dysfunction in a specific individual
in only two of the seven most vitamin B-l2-deficient subjects could be attributed to only vitamin B-12 deficiency. Thus, it
whose MMA values ranged from 2200 to 6820 nmolIL. A seems prudent to aggressively diagnose and treat vitamin B- 12
minor degree of anemia (hematocrit 0.36) was present in deficiency. Similarly, painful paresthesias are common in dia-
four of the same subjects (1, 2). betes mellitus, spinal disorders, and atherosclerotic peripheral
Comorbidity complicates the recognition of the clinical man- vascular disease but the same elderly patients who have these
ifestations of vitamin B-12 deficiency in the elderly. Diabetes disorders may also have vitamin B-12 deficiency. Although it
mellitus, peripheral vascular disease, osteoarthritis, spinal ste- would be desirable to treat vitamin B-l2 deficiency, it is likely
nosis, Alzheimer disease, and other dementias are common in that the clinical response to treatment will be variable. The
the elderly and can cause paresthesias, sensory loss, gait dis- duration of prior symptoms was a major predictor of response
in a study of well-defined patients with vitamin B-12 defi-
turbances, neuropathy, other leg pain syndromes, and cognitive
loss. Several studies have addressed the prevalence of vitamin ciency the nervous
of system (45). It is likely that diagnosis
B-l2 deficiency in dementia syndromes (1, 52, 58-64), partic- would be delayed more in elderly subjects with multiple causes
ularly Alzheimer disease, and have also studied the benefits of for similar neurologic symptoms than in younger, healthier
treatment (1 52, 62-64).
, One study suggested that delay in patients and that the elderly subjects would thus be less likely
to respond even if most of their signs and symptoms were

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vitamin B- 1 2 treatment may have been associated with lack of
response of cognitive abnormalities (63). In another study, actually due to vitamin B- 12 deficiency. To answer some of the
questions we have outlined about the sensitivity and specificity
dementia did not appear to be related to vitamin B-l2 defi-
of the clinical manifestations of vitamin B-l2 deficiency, the
ciency and treatment did not benefit dementia (64), although
prevalence of megaloblastic anemia and neurologic symptoms
the concentration of serum vitamin B-12 used to divide the
compatible with vitamin B-12 deficiency should be determined
subjects (1 10 pmollL, or 150 pg/rnL) was too low; deficient
in a large population survey such as the National Health and
subjects would have been present in both the low and the
Nutrition Examination Survey (65) in subjects found to have
normal groups. In a Netherlands cohort with dementia, only
elevated serum MMA concentrations.
one patient of 19 treated with parenteral vitamin B-12 re-
sponded with improved cognitive functioning (62). Because
vitamin B-12 deficiency was defined only as a vitamin B-l2
concentration < 150 pmollL (< 200 pg/mL) (62), however, the VITAMIN B-12 DEFICIENCY IS A MAJOR CAUSE OF
problem of false positives was not addressed. HYPERHOMOCYSTEINEMIA IN THE ELDERLY
MMA or tHcy concentrations have been measured in elderly
There is mounting evidence that elevated homocysteine may
patients with dementia or other neurologic or psychiatric ab-
be an independent risk factor for atherosclerotic and thrombotic
normalities in several studies. The mean vitamin B- 12 concen-
vascular disease (10, 1 1 ), although there are no intervention
tration was lower and the mean MMA concentration higher in
studies proving this hypothesis. The underlying high preva-
a group of elderly patients from Denmark with Alzheimer
lence of elevated MMA concentrations and vitamin B-l2 de-
dementia compared with patients with other dementias, pa-
ficiency in elderly populations has largely been overlooked in
tients with other mental disorders, or control subjects (60). The
vascular disease studies despite mean ages of 55-60 y in many
patients with Alzheimer dementia did not have the typical of the cohorts. We found that 60-66% of elderly subjects with
neurologic features of vitamin B- 12 deficiency and only one elevated tHcy concentrations also had elevated MMA concen-
had macrocytosis. In a cohort referred to a psychogeriatric trations (66). These elevated MMA concentrations in associa-
department in Sweden, there was no difference in the mean tion with hyperhomocysteinemia indicate subjects with vitamin
concentration of tHcy in demented compared with nonde- B-l2 deficiency only, probable combined vitamin B-l2 and
mented seniors (61). Macrocytic anemia was rare in the sub- folate deficiency, or renal insufficiency. Comparing serum
jects with low vitamin B- 12 concentrations. Despite the fact vitamin B- 1 2 and folate concentrations is often not useful
that there was no correlation of tHcy with dementia, most diagnostically because 33% of elderly subjects have low or
subjects with vitamin B-12 < 150 pmol/L (< 200 pg/mL) had low-normal concentrations of both and another ‘33% have
elevated tHcy, as did a significant number of subjects with normal concentrations of both (61 ). MMA was elevated in 66%
vitamin B-l2 concentrations < 200 pmollL (< 270 pg/mL) of the Framingham subjects with serum folate concentrations
(61). In another investigation, a battery of metabolic, vitamin < 1 1 nmol/L (< 5 ng/mL) as well as tHcy > 16.2 .amol/L (2,
B-l2 absorption, neuropsychologic, and electrophysiologic 66). MMA and tHcy concentrations are correlated in the el-
tests were evaluated in 13 elderly subjects with dementia and derly so that if hyperhomocysteinemic seniors are targeted for
low serum vitamin B- 1 2 concentrations before and after treat- folate treatment, then undiagnosed vitamin B-12-deficient sub-
ment (52). Abnormalities in MMA, tHcy, results of the de- jects will invariably be treated also (5 1 , 66).
oxyuridine suppressive test, hemoglobin, mean corpuscular Few studies of elderly subjects with vascular disease have
volume, neuropathy signs and symptoms, electroencephalo- addressed the problem of the high prevalence of undiagnosed
grams, and visual evoked and somatosensory potentials im- vitamin B-l2 deficiency and the lack of sensitivity and speci-
proved in most of the subjects. However, results on neuropsy- ficity of the serum vitamin B- 12 concentration. Recent publi-
chologic tests improved for only one demented patient (52). cations addressing the serious methodologic problems associ-
746 STABLER ET AL

ated with assaying serum and red blood cell folate only confuse amounts of folate (5 mg) did not correct the hyperhomocys-
these issues further (67, 68). Serum vitamin B-l2 was not teinemia in 30% of treated subjects who may also have had
measured in subjects with rnyocardial infarction in the Physi- mild renal insufficiency (14). Subjects with vascular disease
cian’ s Health Study although the advanced age (40-84 y) of and hyperhornocysteinemia generally have higher serum cre-
some participants would have placed them at risk for vitamin atinine compared with control subjects (14, 16) and the benefit
B-l2 deficiency (12, 69). This was a serious omission because of smaller increases in folate intake has not been studied
serum folate and pyridoxal 5’-phosphate concentrations were extensively in patients with renal insufficiency. Serum tHcy
not significantly lower in the case subjects, although there were also remains high despite large daily folic acid supplements in
more case than control subjects with tHcy values above the subjects with frank renal failure (73). A high mean dietary
95th percentile (69). In subjects from the Framingham Heart intake of folate (300 p.g) did not eliminate hyperhomocysteine-
Study cohort, the prevalence of extracranial carotid stenosis mia in a recently studied elderly cohort (5 1 ) because all of the
was increased when tHcy was in the top quartile, which was subjects with tHcy > 16.2 pmol/L also had elevated serum
correlated directly with plasma folate and pyridoxal 5’-phos- MMA as a result of vitamin B-l2 deficiency or renal impair-
phate and inversely with folate intake (15). However, a sub- ment. At this point there are not enough data to speculate
group of this cohort was found to have a high prevalence of whether small increases in dietary folate will significantly
elevated MMA concentrations in combination with tHcy (2, lower tHcy concentrations in the elderly.
66). Vitamin B-l2 deficiency probably played a greater role in
the hyperhomocysteinemia in these subjects than was fully
appreciated when only vitamin intake and serum vitamin con-
WHAT DOSE OF ORAL VITAMIN B-12 WILL
centrations were analyzed. At this point we do not know the

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CORRECT DEFICIENCY IN THE ELDERLY?
age at which the prevalence of elevated MMA and vitamin
B- 12 deficiency starts to sharply increase. However, in one Vitamin B-l2 is readily available in foods of animal origin
study MMA was elevated in 44% of hyperhomocysteinemic and is extensively stored and conserved via the enterohepatic
subjects (mean age: 58 y) with hyperlipidemia (14). In the circulation (74). There are multiple causes of vitamin B-12
Boston Heart Study, patients with a mean age of 58 y who had deficiency in the elderly, including true pernicious anemia,
sustained a myocardial infarction were also found to have both atrophic gastritis causing food vitamin B-12 malabsorption,
higher MMA and higher tHcy concentrations (70). and previous gastric or other intestinal surgery (5, 52). The
This high prevalence of vitamin B-l2 deficiency in older traditional treatment of pernicious anemia in the United States
subjects with hyperhomocysteinemia raises several practical is injections of vitamin B-12. However, several studies in
issues in designing intervention studies that would use folic subjects with pernicious anemia showed that oral doses of
acid treatment to lower tHcy in vascular disease patients. 300-1000 j.ag are effective in raising serum vitamin B-12 con-
Megaloblastic anemia may remit when a vitamin B-12-defi- centrations and preventing clinical abnormalities (75-77). It is
cient subject receives a large dose of folic acid, a phenomenon likely that similar doses of vitamin B-12 would be effective in
termed “masking of anemia.” The neurologic signs and symp- elderly subjects with less complete malabsorption.
toms of untreated vitamin B- 1 2 deficiency can progress in such A major gap in our knowledge is the lowest quantity of oral
patients, however. There are few data available for determining vitamin B- 12 that would correct elevated MMA concentrations
a “safe” concentration of folate supplementation (7 1), although in either all or most elderly subjects, including those with renal
1 mg is widely touted. The recognition that neurologic and insufficiency. The mean serum vitamin B- 12 concentration
hematologic severity are inversely related and that a significant rose from 100 pmoIIL (146 pg/mL) to 270 prnol/L (37 1 pg/mL)
subset ( 10-30%) of vitamin B- 12-deficient subjects initially in elderly subjects in a geriatric ward in Belgium who received
present with neurologic symptoms further confuses the issues an oral solution containing 100 p.g vitamin B-l2/d for 30 d
(44, 45). It would be inappropriate in intervention studies to (78). The serum vitamin B- 12 concentration was normalized in
screen out those elderly subjects with elevated MMA in addi- 88% of the patients studied after 1 mo. Neither MMA nor tHcy
tion to elevated tHcy values because the remaining group was measured in these subjects, but the marked rise in the
would not be representative of the general population at risk for serum vitamin B-l2 concentration suggests that the dose was
vascular disease. Also, the question must be raised as to effective. Standard multivitamin pills available in the United
whether it is ethical to treat known vitamin B-l2-deficient States contain a much lower dose of vitamin B-12 than used in
subjects with a placebo. However, if vitamin B-l2 is given to this study, usually < 10 p.g. In the Framingham cohort, mul-
both placebo and intervention groups to satisfy ethical consid- tivitamin use resulted in a lower prevalence of vitamin B-12
erations, it is likely that the high tHcy concentrations due to deficiency and elevated MMA and tHcy, but did not eliminate
vitamin B-12 deficiency will decrease significantly. Vitamin the risk (2). A similar decrease in mean tHcy and MMA was
B-12 deficiency can also develop during long-term studies in a found in multivitamin supplement users in an elderly New
late middle-aged population. Mexico cohort (51). However, the most vitamin B-l2-deficient
Similar issues are raised by the food folate-fortification subject, with a serum MMA concentration of 1300 nmol/L and
program now being implemented. Although the program is tHcy concentration of 21.3 .amolIL, was taking a multivitamin
designed to prevent neural tube defects, some authors have containing 6 ag vitamin B-12 and 400 ag folic acid (51). It
speculated that increasing dietary folate will lower tHcy and seems likely that an adequate oral vitamin B-12 supplementa-
possibly improve vascular health (11, 72). Oral folic acid in tion amount for most elderly subjects would be > 6 but < 300
large doses of 10 mg/d will decrease tHcy concentrations in p.g/d.
virtually every normal subject and in some subjects with un- A further unanswered question is whether the vitamin B- 12
clear vitamin B-l2 and folate status (54). In contrast, lower added to breakfast cereals, liquid nutritional supplements, and
 VITAMIN B-12 DEFICIENCY IN THE ELDERLY 747

other highly processed foods is more bioavailable than the 5. Joosten E, Pelemons W, Devos P. et al. Cobalamin absorption and
vitamin B-l2 naturally protein-bound in animal foods. Another serum homocysteine and MMA in elderly subjects with low serum

issue is whether dietary animal protein would cause a second- cobalamin. Eur J Haematol 1993;51:25-30.
6. Selhub J, Jacques PF, Wilson PWF, et al. Vitamin status and intake as
ary binding of vitamin B-12, resulting in decreased absorption
primary determinants of homocysteinemia in an elderly population.
of supplemental vitamin B-12. Finally, a recent investigation in
Am J Clin Nutr 1994;60:2-ll.
California suggests that pernicious anemia may affect 2% of
7. Metz J, Bell AH, Flicker L, et al. The significance of subnormal serum
the elderly (79): should supplemental vitamin B-l2 be required vitamin B,2 concentration in older people: a case control study. J Am
to protect individuals with pernicious anemia as well as those Geriatr Soc 1996;44:l355-6l.
with food vitamin B-l2 malabsorption related to atrophic 8. Naurath RI, Joosten E, Riezler R, Stabler SP, Allen RH, Lindenbaum
gastritis? J. Effects of vitamin B12, folate and vitamin B6 supplements in
elderly people with normal serum vitamin concentrations. Lancet
1995;346:85-9.
SUMMARY 9. Ubbink JB, Becker PJ, Vermaak WJH, Delport R. Results of B-
vitamin supplementation study used in a prediction model to define a
Screening studies of elderly cohorts have revealed a high reference range for plasma homocysteine. Clin Chem 1995:41:1033-7.
prevalence (up to 14%) of previously undiagnosed vitamin 10. Ueland PM, Refsum H, Brattstrom L. Plasma homocysteine and car-

B-l2 deficiency manifested by elevations in serum MMA or diovascular disease. In: Francis RBJ, ed. Atherosclerotic cardiovascu-
lar disease, hemostasis, and endothelial function. New York: Marcel
tHcy. These elevated metabolites can be readily corrected with
Dekker Inc, 1992:183-236.
parenteral vitamin B-l2 supplementation. Hyperhomocysteine-
11. Boushey CJ, Beresford SAA, Omenn GS, Motulsky AG. A quantita-
mia in the elderly is usually accompanied by elevated MMA

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tive assessment of plasma homocysteine as a risk factor for vascular
concentrations and often other evidence of vitamin B- 12 defi-
disease: probable benefits of increasing folic acid intakes. JAMA
ciency. However, clear-cut megaloblastic anemia and myelop- l995;274: 1049-57.
athy or neuropathy are rare in elderly vitamin B-12-deficient 12. Stampfer MJ, Malinow MR, Willett WC, et al. Prospective study of
subjects despite often high concentrations of MMA or tHcy. plasma homocyst(e)ine and risk of myocardial infarction in US phy-
The actual prevalence of megaloblastic anemia or neurologic sicians. JAMA 1992;68:877-8l.
disorders in all subjects with vitamin B-l2 deficiency is not 13. Arnesen E, Refsum H, Bonaa KH, Ueland PM, Forde OH, Nordrehaug
known because selection bias favors the presentation of meg- JE. Serum total homocysteine and coronary heart disease. Int J Epi-

aloblastic anemia. Therefore, clinical manifestations cannot be demiol l995;4:704-9.

14. Glueck CJ, Shaw P. Lange JE, Tracy T, Sieve-Smith L, Wang Y.
used as the only screening or treatment guide. Large amounts
Evidence that homocysteine is an independent risk factor for athero-
of oral vitamin B-l2 (100-1000 pg/d) appear to be effective in
sclerosis in hyperlipidemic patients. Am J Cardiol 1995:75:132-6.
increasing serum vitamin B- 12 concentrations, but the small
15. Selhub J, Jacques PF, Boston AG, et al. Association between plasma
quantity of vitamin B-l2 in most multivitamin preparations homocysteine concentrations and extracranial carotid artery stenosis.
(6 pg) is not sufficient to correct elevated MMA concentrations N Engi J Med l995;332:286-9l.
in all elderly subjects. Further investigations need to be di- 16. Robinson K, Mayer ELI, Miller DP, et al. Hyperhomocysteinemia and
rected toward practical methods of screening for and treating low pyridoxal phosphate: independent and reversible risk factors for
vitamin B-12 deficiency in the millions of elderly persons at coronary artery disease. Circulation 1995;92:2825-30.
risk, especially because dietary folic acid will be increased 17. Food standards: amendment of standards of identity for enriched grain

in the near future as a result of the food folate-fortification products to require addition of folic acid. Fed Regist 1996;61 :8781-97.
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Table 1. The authors and the University of Colorado and Columbia acterization of rat liver D-methylmalonyl-coenzyme A hydrolase.
University hold patents relating to the use of methylmalonic acid, homo- J Biol Chem l983;258:l14l5-21.
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vitamin B- 12 and folate deficiency. A company has been formed at the methylictric acid I and II levels in serum, urine and cerebro-
University of Colorado to perform the assays. spinal fluid of patients with cobalamin deficiency. Metabolism
1993:42:978-88.
21. Mudd SH, Levy HL, Skovby F. Disorder of transsulfuration. In:
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