Deficit Vitamina B 12

clinical practice
The new engl and journal o f medicine

n engl j med 368;2 nejm.org january 10, 2013
149
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.
An audio version
of this article is
available at
NEJM.org
Vitamin B
12
Deficiency
Sally P. Stabler, M.D.
From the University of Colorado School
of Medicine, Aurora. Address reprint re-
quests to Dr. Stabler at the Division of
Hematology, University of Colorado,
Aurora, CO 80045, or at sally.stabler@
ucdenver.edu.
N Engl J Med 2013;368:149-60.
DOI: 10.1056/NEJMcp1113996
Copyright 2013 Massachusetts Medical Society.
A 57-year-old woman reports increasing symptoms of painful paresthesias in both
legs for the past 18 months. Physical examination reveals impaired position sense
and vibration sense. The serum vitamin B
12
level is 205 pg per milliliter (151.2 pmol
per liter), which is above the lower end of the laboratory reference range. The hemato-
crit is 42%, with a mean corpuscular volume of 96 fl. The serum methylmalonic acid
level is 3600 nmol per liter (normal level, <400), and the serum homocysteine level
49.1 mol per liter (normal level, <14). How should this patient be further evaluated
and treated?
The Clinical Problem
The recognition and treatment of vitamin B
12
deficiency is critical since it is a re-
versible cause of bone marrow failure and demyelinating nervous system disease.
Vitamin B
12
(cobalamin) is synthesized by microorganisms and detected in trace
amounts mostly in foods of animal origin.
1
Uptake in the gastrointestinal tract
depends on intrinsic factor, which is synthesized by the gastric parietal cells, and
on the cubam receptor in the distal ileum.
2
The most frequent cause of severe
vitamin B
12
deficiency is a loss of intrinsic factor due to autoimmune atrophic gas-
tritis,
3
historically called pernicious anemia, even though many patients present
with mainly neurologic manifestations.
4,5
Pathophysiology of Vitamin B
12
Deficiency
Vitamin B
12
is a cofactor for only two enzymes: methionine synthase and L-methyl-
malonylcoenzyme A mutase
6,7
(see Fig. 1 in the Supplementary Appendix, avail-
able with the full text of this article at NEJM.org). The interaction between folate
and B
12
is responsible for the megaloblastic anemia seen in both vitamin deficien-
cies. Dyssynchrony between the maturation of cytoplasm and that of nuclei leads to
macrocytosis, immature nuclei, and hypersegmentation in granulocytes
6
in the
peripheral blood (Fig. 1A). The hypercellular and dysplastic bone marrow can be
mistaken for signs of acute leukemia (Fig. 1B).
10
The ineffective erythropoiesis re-
sults in intramedullary hemolysis and release of lactate dehydrogenase, features
that are similar to those of microangiopathic hemolytic anemia.
8
Clinical and labo-
ratory findings of megaloblastic anemia in the peripheral blood and bone marrow
are shown in Figure 2.
Vitamin B
12
is necessary for the development and initial myelination of the
central nervous system as well as for the maintenance of its normal function.
Demyelination of the cervical and thoracic dorsal and lateral columns of the spinal
cord, occasional demyelination of cranial and peripheral nerves, and demyelin-
ation of white matter in the brain
5
(i.e., combined-systems disease or subacute
combined degeneration) can occur with vitamin B
12
deficiency (Fig. 2). Pathologi-
The New England Journal of Medicine
Downloaded from nejm.org by MIGUEL ANDRADE on April 19, 2014. For personal use only. No other uses without permission.
Copyright 2013 Massachusetts Medical Society. All rights reserved.
150
cal analysis reveals a spongy degeneration due
to the loss of and swelling of myelin sheaths;
this degeneration is visible on magnetic reso-
nance imaging.
11
For unclear reasons, the sever-
ity of megaloblastic anemia is inversely corre-
lated with the degree of neurologic dysfunction.
4,5
Less common conditions associated with vi-
tamin B
12
deficiency include glossitis, malab-
sorption, infertility, and thrombosis (including
thrombosis at unusual sites such as cerebral ve-
nous sinus thrombosis).
12,13
Thrombosis has been
attributed to the marked hyperhomocysteinemia
seen in severe cases of vitamin B
12
deficiency.
Patients occasionally have hyperpigmentation,
which clears with treatment.
6
Causes of Vitamin B
12
Deficiency
Table 1 and Figure 3 list causes of vitamin B
12

deficiency and recommended management. Per-
nicious anemia is discussed below, since this is
the most common cause of severe vitamin B
12

deficiency worldwide.
Dietary vitamin B
12
deficiency in infants and
children is also discussed because of the in-
creasing recognition of severe abnormalities in
exclusively breast-fed infants of mothers with
vitamin B
12
deficiency.
Pernicious Anemia
Pernicious anemia
1
is an autoimmune gastritis
resulting from the destruction of gastric parietal
cells and the associated lack of intrinsic factor to
bind ingested vitamin B
12
. The immune response
is directed against the gastric H/KATPase,
which accounts for associated achlorhydria.
2,3

Other autoimmune disorders, especially thyroid
disease, type 1 diabetes mellitus, and vitiligo, are
also commonly associated with pernicious ane-
mia. Whether the stomach pathogen Helicobacter
pylori plays a causative role in pernicious anemia
is unclear.
19
Autoimmune gastritis may cause
malabsorption of iron, with clinical iron deficien-
cy developing early in life and eventually progress-
ing to malabsorption of vitamin B
12
.
20
The preva-
lence of pernicious anemia ranges from 50 to
4000 cases per 100,000 persons, depending on
the diagnostic criteria.
1
All age groups are af-
fected, but the median age range in large series
is 70 to 80 years.
21,22
Pernicious anemia is more
common in persons of African or European an-
cestry (4.3% and 4.0% prevalence among older
adults, respectively) than in those of Asian ances-
try.
1,21
Milder forms of atrophic gastritis with
hypochlorhydria and an inability to release di-
etary protein-bound vitamin B
12
affect up to 20%
of older adults.
19,23,24
Dietary Deficiency in Infancy and Childhood
The infant of a mother with vitamin B
12
defi-
ciency may be born with the deficiency or it may
occur if he or she is exclusively breast-fed,
15,16

usually between 4 and 6 months of age. Typical
manifestations of vitamin B
12
deficiency in chil-
dren include failure of brain development and
overall growth and development, developmental
regression, hypotonia, feeding difficulties, leth-
argy, tremors, hyperirritability, and coma (Fig.
2).
15,16
Brain imaging may reveal atrophy and
delayed myelination. Anemia may be present.
Vitamin B
12
replacement results in rapid im-
provement in responsiveness, and many infants
recover fully. However, the longer the period of
deficiency, the more likely that there will be
permanent disabilities. Mothers of infants with
key Clinical points
vitamin b
12
deficiency
Vitamin B
12
deficiency causes reversible megaloblastic anemia, demyelinating neurologic disease, or both.
Autoimmune gastritis (pernicious anemia) is the most common cause of severe deficiency.
Methodologic problems may compromise the sensitivity and specificity of current vitamin B
12
assays.
Measurement of methylmalonic acid, homocysteine, or both is used to confirm vitamin B
12
deficiency in untreated patients;
an elevated level of methylmalonic acid is more sensitive and specific for the diagnosis.
For patients with pernicious anemia or malabsorption, lifelong vitamin B
12
therapy is indicated.
High-dose oral vitamin B
12
tablets (1000 to 2000 g) taken daily are as effective as intramuscular monthly injections in
correcting blood and neurologic abnormalities.
clinical practice
151
vitamin B
12
deficiency often have unrecognized
pernicious anemia, but alternatively, they may
have a history of gastric bypass surgery, the
short-gut syndrome, or a long-term vegetarian or
vegan diet.
16
Tandem mass spectrometry, used
in neonatal screening programs in all 50 states,
may detect nutritional B
12
deficiency owing to
an increase in propionyl carnitine, but direct
measurement of methylmalonic acid has higher
sensitivity.
25
Other causes of B
12
deficiency in
children, such as ileal resections, the Imerslund
Grsbeck syndrome, inflammatory bowel disease,
and pernicious anemia, are listed in Table 1.
18
Strategies and Evidence
Evaluation
Both the clinical recognition of vitamin B
12
defi-
ciency and confirmation of the diagnosis by
means of testing can be difficult. An approach to
testing is shown in Table 2.
The patients history may include symptoms
of anemia, underlying disorders causing malab-
sorption, and neurologic symptoms. The most
common neurologic symptoms are symmetric
paresthesias or numbness and gait problems.
4,5
The physical examination may reveal pallor, ede-
ma, pigmentary changes in the skin, jaundice, or
neurologic defects such as impaired vibration
sense, impaired position and cutaneous sensa-
tion, ataxia, and weakness (Fig. 2).
Bone marrow biopsy and aspiration are not
necessary for the diagnosis of megaloblastic
anemia and may be misleading in cases of severe
pancytopenia with hypercellularity, increased
erythroblasts, and even cytogenetic abnormali-
ties, confusing the diagnosis with acute leuke-
mia.
8-10
Imaging of the spinal cord is not indi-
cated in patients with recognized vitamin B
12
deficiency, but in cases of severe myelopathy that
are not initially recognized as the result of vita-
min B
12
deficiency, there is characteristic hyper-
intensity on T
2
-weighted imaging, described as
an inverted V-shaped pattern in the cervical and
thoracic spinal cord.
11
Vitamin B
12
Assay
The first test performed to confirm the diagnosis
of vitamin B
12
deficiency is generally measure-
ment of the serum vitamin B
12
level. Although
an extremely low level (<100 pg per milliliter
[<73.8 pmol per liter]) is usually associated with
clinical deficiency, such low levels are infre-
quently observed. Both false negative and false
positive values are common (occurring in up to
50% of tests) with the use of the laboratory-
reported lower limit of the normal range as a
cutoff point for deficiency.
4,24,26
The high rate of
false negative and false positive results may be
A
B
Figure 1. Peripheral-Blood Cells and Bone Marrow
Specimen Obtained from a Patient with Vitamin B
12

Deficiency.
In Panel A, a peripheral-blood smear shows oval macro-
cytes as well as fragmented, misshapen cells and an
immature megaloblastic nucleated red cell (arrow).
The variation in red-cell size and shape could lead to a
misdiagnosis of microangiopathic hemolytic anemia
instead of megaloblastic anemia.
8,9
The mean corpuscu-
lar volume was in the normal range, but an extremely
high red-cell distribution width suggested macrocytosis
combined with microcytic fragmented cells. In Panel B,
a bone marrow aspirate shows megaloblastic features.
Large erythroblasts and other red-cell precursors are
characterized by an open, immature nuclear chromatin
pattern. There is dyssynchrony between the maturation
of cytoplasm and that of nuclei in later red-cell and
granulocyte precursors. A giant band is present. Sev-
eral red-cell precursors have dysplastic nuclei (arrows),
with nuclear fragments (arrowhead) that are compati-
ble with cellular apoptosis and resulting intramedullary
hemolysis. (Photographs courtesy of John W. Ryder,
M.D., Department of Pathology, University of Colorado
School of Medicine.)
152
Brain
Altered mental status
Cognitive defects
Megaloblastic madness: depression,
mania, irritability, paranoia,
delusions, lability
Optic atrophy, anosmia, loss of taste,
glossitis
Infertility
Bone marrow
Hypercellular, increased erythroid
precursors
Open, immature nuclear chromatin
Dyssynchrony between maturation of
cytoplasm and nuclei
Giant bands, metamyelocytes
Karyorrhexis, dysplasia
Abnormal results on flow cytometry
and cytogenetic analysis
Spinal cord
Myelopathy
Spongy degeneration
Paresthesias
Loss of proprioception: vibration,
position, ataxic gait, limb weakness;
spasticity (hyperreflexia); positive
Romberg sign; Lhermittes sign;
segmental cutaneous sensory level
Autonomic nervous system
Postural hypotension
Incontinence
Impotence
Peripheral nervous system
Cutaneous sensory loss
Hyporeflexia
Symmetric weakness
Paresthesias
Abnormalities in infants and children
Developmental delay or regression,
permanent disability
Does not smile
Feeding difficulties
Hypotonia, lethargy, coma
Hyperirritability, convulsions, tremors,
myoclonus
Microcephaly
Choreoathetoid movements
Peripheral blood
Macrocytic red cells, macroovalocytes
Anisocytosis, fragmented forms
Hypersegmented neutrophils, 1% with
six lobes or 5% with 5 lobes
Leukopenia, possible immature white
cells
Thrombocytopenia
Pancytopenia
Elevated lactate dehydrogenase level
(extremes possible)
Elevated indirect bilirubin and
aspartate aminotransferase levels
Decreased haptoglobin level
Elevated levels of methylmalonic acid,
homocysteine, or both
clinical practice
153
due to the fact that only 20% of the total mea-
sured vitamin B
12
is on the cellular delivery pro-
tein, transcobalamin; the remainder is bound to
haptocorrin, a protein of unknown function.
27

Most laboratories now perform automated assays
of vitamin B
12
on platforms used for many other
analytes. There is often poor agreement when
samples are assayed by different laboratories or
with the use of different methods.
31-34
Because
intrinsic factor is used as the assay-binding pro-
tein, antiintrinsic factor antibodies (which are
common in pernicious anemia) must be removed
chemically from the sample, which has proved to
be problematic in the automated assays.
33,34
Re-
cent studies show normal values
34
or falsely high
values
33
of vitamin B
12
in many patients with per-
nicious anemia. New assays of holotranscobala-
min (to measure the vitamin B
12
saturation of
transcobalamin) provide a modest improvement
in specificity over that provided by assays of total
serum vitamin B
12
, but they have not been clini-
cally validated
27-29
and are not yet available com-
mercially in the United States.
Given the limitations of available assays, cli-
nicians should not use a laboratorys reported
lower limit of the normal range to rule out the
diagnosis of vitamin B
12
deficiency in patients
with compatible clinical abnormalities. Clinicians
should also recognize that vitamin B
12
values are
frequently low in patients without other meta-
bolic or clinical evidence of vitamin B
12
deficiency
(i.e., megaloblastic anemia or myelopathy).
Measurement of Serum Methylmalonic Acid
and Total Homocysteine
Measurement of methylmalonic acid, total ho-
mocysteine, or both is useful in making the diag-
nosis of vitamin B
12
deficiency in patients who
have not received treatment.
4,22,24,26,33,35,36
The
levels of both methylmalonic acid and total ho-
mocysteine are markedly elevated in the vast ma-
jority (>98%) of patients with clinical B
12
defi-
ciency (Fig. 4),
7,22
including those who have only
neurologic manifestations of deficiency (i.e., no
anemia).
4,22
Elevated levels of methylmalonic acid and total
homocysteine decrease immediately after treat-
ment, and the levels can be remeasured to docu-
ment adequate vitamin B
12
replacement. Levels of
these metabolites are normal in up to 50% of
patients with low vitamin B
12
levels who have no
hematologic or neurologic response to replacement
therapy, indicating that the low values are false
positive results.
26
Given the limitations of vitamin
B
12
assays in confirming the diagnosis of B
12

deficiency,
31,34
it may be prudent to measure meth-
ylmalonic acid, total homocysteine, or both in pa-
tients with compatible clinical findings or pro-
vide empirical treatment with the use of defined
end points to document a clinical response.
An elevated level of methylmalonic acid is rea-
sonably specific for vitamin B
12
deficiency, and the
level always decreases with vitamin B
12
thera-
py.
24,36
Modest increases (to 300 to 700 nmol per
liter) occur with renal failure.
36,37
However,
nearly all patients with megaloblastic anemia or
myelopathy have levels of methylmalonic acid
that are higher than 500 nmol per liter, and 86%
have levels that are higher than 1000 nmol per
liter (Fig. 3). The level of serum total homocys-
teine is less specific, since it is also elevated in
folate deficiency,
22,35
classic homocystinuria, and
renal failure.
Tests to Determine the Cause of Vitamin B
12

Deficiency
If the patient consumes sufficient amounts of vi-
tamin B
12
and has clinically confirmed B
12
defi-
ciency, then malabsorption must be present.
Testing for pernicious anemia is described in
Table 2. A positive test for antiintrinsic factor or
antiparietal-cell antibodies is indicative of per-
nicious anemia; surveillance for autoimmune
thyroid disease is reasonable in patients with
positive antibody tests. Chronic atrophic gastritis
can be diagnosed on the basis of an elevated fast-
ing serum gastrin level and a low level of serum
pepsinogen I.
3,19
Some experts recommend en-
doscopy to confirm gastritis and rule out gastric
carcinoid and other gastric cancers, since pa-
tients with pernicious anemia are at increased
risk for such cancers.
3
The Schilling test of radioactive vitamin B
12

Figure 2 (facing page). Clinical and Laboratory Findings
in Vitamin B
12
Deficiency.
The spectrum of disease associated with vitamin B
12

deficiency is wide, from asymptomatic to life-threatening
pancytopenia or myelopathy. An increase in the mean
red-cell volume or distribution width or a mean volume
that is higher than expected for the patients age, pre-
sumed iron status (either high or low iron levels), and
the presence of thalassemia are important determinants
of macrocytosis, rather than an absolute value above the
reference range. Cerebral symptoms are usually accom-
panied by paresthesias and signs of myelopathy or
neuropathy.
5
154
T
a
b
l
e

1
.

C
a
u
s
e
s

a
n
d

T
r
e
a
t
m
e
n
t

o
f

V
i
t
a
m
i
n

B
1
2

D
e
f
i
c
i
e
n
c
y
.
C
a
u
s
e
T
r
e
a
t
m
e
n
t
F
o
l
l
o
w
-
u
p
S
e
v
e
r
e

m
a
l
a
b
s
o
r
p
t
i
o
n
P
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a

(
a
u
t
o
i
m
m
u
n
e

g
a
s
t
r
i
t
i
s
)
I
n
t
r
a
m
u
s
c
u
l
a
r

c
y
a
n
o
c
o
b
a
l
a
m
i
n

a
t

a

d
o
s
e

o
f

1
0
0
0

g

a
d
m
i
n
i
s
t
e
r
e
d

i
n
t
r
a
m
u
s
c
u
l
a
r
l
y

d
a
i
l
y

o
r

e
v
e
r
y

o
t
h
e
r

d
a
y

f
o
r

1

w
k
,

t
h
e
n

w
e
e
k
l
y

f
o
r

4

t
o

8

w
k
,

a
n
d

t
h
e
n

m
o
n
t
h
l
y

f
o
r

l
i
f
e
,

o
r

o
r
a
l

c
y
a
n
o
c
o
b
a
l
a
-
m
i
n

a
t

a

d
a
i
l
y

d
o
s
e

o
f

1
0
0
0

t
o

2
0
0
0

g

f
o
r

l
i
f
e
*
A
d
m
i
n
i
s
t
e
r

i
r
o
n

a
n
d

f
o
l
a
t
e

r
e
p
l
a
c
e
m
e
n
t

a
s

n
e
e
d
e
d

f
o
r

f
u
l
l

h
e
m
o
-
g
l
o
b
i
n

r
e
s
p
o
n
s
e
,

e
s
p
e
c
i
a
l
l
y

i
n

p
a
t
i
e
n
t
s

w
i
t
h

i
n
t
e
s
t
i
n
a
l

d
i
s
-
e
a
s
e
;

p
e
r
f
o
r
m

s
u
r
v
e
i
l
l
a
n
c
e

f
o
r

o
t
h
e
r

a
u
t
o
i
m
m
u
n
e

c
o
n
d
i
-
t
i
o
n
s
,

e
s
p
e
c
i
a
l
l
y

t
h
y
r
o
i
d

d
i
s
e
a
s
e

i
n

p
a
t
i
e
n
t
s

w
i
t
h

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
;

p
e
r
f
o
r
m

u
p
p
e
r

e
n
d
o
s
c
o
p
y

i
n

p
a
t
i
e
n
t
s

w
i
t
h

s
y
m
p
-
t
o
m
s

o
f

g
a
s
t
r
i
c

c
a
n
c
e
r

o
r

i
r
o
n

d
e
f
i
c
i
e
n
c
y
T
o
t
a
l

o
r

p
a
r
t
i
a
l

g
a
s
t
r
e
c
t
o
m
y
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
G
a
s
t
r
i
c

b
y
p
a
s
s

o
r

o
t
h
e
r

b
a
r
i
a
t
r
i
c

s
u
r
g
e
r
y
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
I
l
e
a
l

r
e
s
e
c
t
i
o
n

o
r

o
r
g
a
n

r
e
c
o
n
s
t
r
u
c
t
i
v
e

s
u
r
g
e
r
y

(
i
l
e
a
l

c
o
n
d
u
i
t

d
i
v
e
r
s
i
o
n

a
n
d

i
l
e
o
c
y
s
t
o
-
p
l
a
s
t
y
)
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
I
n
f
l
a
m
m
a
t
o
r
y

b
o
w
e
l

d
i
s
e
a
s
e
,

t
r
o
p
i
c
a
l

s
p
r
u
e
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
I
m
e
r
s
l
u
n
d
G
r
s
b
e
c
k

a
n
d

o
t
h
e
r

s
y
n
d
r
o
m
e
s
S
a
m
e

a
s

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
G
e
n
e
t
i
c

c
o
u
n
s
e
l
i
n
g

t
o

d
e
t
e
c
t

v
i
t
a
m
i
n

B
1
2

d
e
f
i
c
i
e
n
c
y

i
n

f
a
m
i
l
y

m
e
m
b
e
r
s
M
i
l
d

m
a
l
a
b
s
o
r
p
t
i
o
n
P
r
o
t
e
i
n
-
b
o
u
n
d

v
i
t
a
m
i
n

B
1
2

m
a
l
a
b
s
o
r
p
t
i
o
n
O
r
a
l

c
y
a
n
o
c
o
b
a
l
a
m
i
n

a
t

a

d
o
s
e

o
f

5
0
0

t
o

1
0
0
0

g

d
a
i
l
y

o
r

i
n
t
r
a
-
m
u
s
c
u
l
a
r

c
y
a
n
o
c
o
b
a
l
a
m
i
n

a
t

a

d
o
s
e

o
f

1
0
0
0

g

d
a
i
l
y

o
r

e
v
e
r
y

o
t
h
e
r

d
a
y

f
o
r

1

w
k
,

t
h
e
n

w
e
e
k
l
y

f
o
r

4

t
o

8

w
k
,

a
n
d

t
h
e
n

m
o
n
t
h
l
y

f
o
r

l
i
f
e
P
e
r
f
o
r
m

t
e
s
t
s

f
o
r

i
r
o
n

d
e
f
i
c
i
e
n
c
y
,

a
n
e
m
i
a

o
f

c
h
r
o
n
i
c

k
i
d
n
e
y

d
i
s
-
e
a
s
e
,

a
n
d

a
n
e
m
i
a

o
f

c
h
r
o
n
i
c

i
n
f
l
a
m
m
a
t
i
o
n
;

t
h
e
s
e

c
o
n
d
i
t
i
o
n
s

c
o
e
x
i
s
t

f
r
e
q
u
e
n
t
l
y

i
n

o
l
d
e
r

a
d
u
l
t
s
,

m
a
y

l
i
m
i
t

t
h
e

r
e
s
p
o
n
s
e

t
o

t
r
e
a
t
m
e
n
t
,

a
n
d

m
a
y

r
e
q
u
i
r
e

f
u
r
t
h
e
r

t
r
e
a
t
m
e
n
t
M
i
l
d

a
t
r
o
p
h
i
c

g
a
s
t
r
i
t
i
s
S
a
m
e

a
s

f
o
r

p
r
o
t
e
i
n
-
b
o
u
n
d

v
i
t
a
m
i
n

B
1
2

m
a
l
a
b
s
o
r
p
t
i
o
n
S
a
m
e

a
s

f
o
r

p
r
o
t
e
i
n
-
b
o
u
n
d

v
i
t
a
m
i
n

B
1
2

m
a
l
a
b
s
o
r
p
t
i
o
n
U
s
e

o
f

m
e
t
f
o
r
m
i
n
1
4
S
a
m
e

a
s

f
o
r

p
r
o
t
e
i
n
-
b
o
u
n
d

v
i
t
a
m
i
n

B
1
2

m
a
l
a
b
s
o
r
p
t
i
o
n
S
a
m
e

a
s

f
o
r

p
r
o
t
e
i
n
-
b
o
u
n
d

v
i
t
a
m
i
n

B
1
2

m
a
l
a
b
s
o
r
p
t
i
o
n
U
s
e

o
f

d
r
u
g
s

t
h
a
t

b
l
o
c
k

s
t
o
m
a
c
h

a
c
i
d
S
a
m
e

a
s

f
o
r

p
r
o
t
e
i
n
-
b
o
u
n
d

v
i
t
a
m
i
n

B
1
2

m
a
l
a
b
s
o
r
p
t
i
o
n
S
a
m
e

a
s

f
o
r

p
r
o
t
e
i
n
-
b
o
u
n
d

v
i
t
a
m
i
n

B
1
2

m
a
l
a
b
s
o
r
p
t
i
o
n
D
i
e
t
a
r
y

d
e
f
i
c
i
e
n
c
y
A
d
u
l
t
s
V
e
g
a
n

o
r

v
e
g
e
t
a
r
i
a
n

d
i
e
t
,

o
r

d
i
e
t

l
o
w

i
n

m
e
a
t

a
n
d

d
a
i
r
y

p
r
o
d
u
c
t
s
S
u
p
p
l
e
m
e
n
t
s

c
o
n
t
a
i
n
i
n
g

>
2

g

o
f

v
i
t
a
m
i
n

B
1
2

o
r

f
o
o
d
s

f
o
r
t
i
f
i
e
d

w
i
t
h

v
i
t
a
m
i
n

B
1
2
P
e
r
f
o
r
m

t
e
s
t
s

f
o
r

i
r
o
n

d
e
f
i
c
i
e
n
c
y
,

w
h
i
c
h

i
s

v
e
r
y

c
o
m
m
o
n
I
n
f
a
n
t
s
B
r
e
a
s
t
-
f
e
e
d
i
n
g

i
n

i
n
f
a
n
t
s

w
i
t
h

v
i
t
a
m
i
n

B
1
2
d
e
f
i
c
i
e
n
t

m
o
t
h
e
r
s
1
5
,
1
6
I
n
t
r
a
m
u
s
c
u
l
a
r

c
y
a
n
o
c
o
b
a
l
a
m
i
n

a
t

a

d
o
s
e

o
f

2
5
0

t
o

1
0
0
0

g

d
a
i
l
y
,

t
h
e
n

w
e
e
k
l
y

u
n
t
i
l

p
a
t
i
e
n
t

r
e
c
o
v
e
r
s
;

t
r
e
a
t
m
e
n
t

o
f

m
o
t
h
e
r

t
o

e
n
r
i
c
h

b
r
e
a
s
t

m
i
l
k
;

o
r
a
l

s
u
p
p
l
e
m
e
n
t
a
t
i
o
n

w
i
t
h

1

t
o

2

g

o
f

v
i
t
a
m
i
n

B
1
2

d
a
i
l
y

o
r

v
i
t
a
m
i
n

B
1
2
e
n
r
i
c
h
e
d

f
o
r
m
u
l
a

o
r

f
o
o
d
C
o
n
f
i
r
m

m
e
t
a
b
o
l
i
c

r
e
s
p
o
n
s
e

i
n

i
n
f
a
n
t
s

o
r

r
e
f
e
r

p
a
r
e
n
t
s

t
o

g
e
n
e
t
-
i
c
s

s
p
e
c
i
a
l
i
s
t

f
o
r

e
v
a
l
u
a
t
i
o
n
;

p
r
o
v
i
d
e

n
u
t
r
i
t
i
o
n
a
l

c
o
u
n
s
e
l
i
n
g

f
o
r

m
o
t
h
e
r
s
clinical practice
155
absorption is no longer available. A potential
replacement absorption test is under develop-
ment wherein the increase in vitamin B
12
satura-
tion of holotranscobalamin is measured after
several days of oral B
12
loading,
39
but this re-
quires further study.
Treatment of Vitamin B
12
Deficiency
The daily requirement of vitamin B
12
has been set
at 2.4 g,
40,41
but higher amounts 4 to 7 g
per day which are common in persons who eat
meat or take a daily multivitamin, are associated
with lower methylmalonic acid values.
42
Healthy
older adults should consider taking supplemental
crystalline vitamin B
12
as recommended by the
Food and Nutrition Board.
41
However, most pa-
tients with clinical vitamin B
12
deficiency have
malabsorption and will require parenteral or high-
dose oral replacement. Adequate supplementa-
tion results in resolution of megaloblastic anemia
and resolution of or improvement in myelopathy.
Injected Vitamin B
12

There are many recommended schedules for in-
jections of vitamin B
12
(called cyanocobalamin in
the United States and hydroxocobalamin in Eu-
rope).
6,23
About 10% of the injected dose (100 of
1000 g) is retained. Patients with severe abnor-
malities should receive injections of 1000 g at
least several times per week for 1 to 2 weeks,
then weekly until clear improvement is shown,
followed by monthly injections. Hematologic re-
sponse is rapid, with an increase in the reticulo-
cyte count in 1 week and correction of megalo-
blastic anemia in 6 to 8 weeks. Patients with
severe anemia and cardiac symptoms should be
treated with transfusion and diuretic agents, and
electrolytes should be monitored. Neurologic
symptoms may worsen transiently and then sub-
side over weeks to months.
5
The severity and du-
ration of the neurologic abnormalities before
treatment influence the eventual degree of recov-
ery.
4,5
Treatment of pernicious anemia is lifelong.
In patients in whom vitamin B
12
supplementa-
tion is discontinued after clinical recovery, neu-
rologic symptoms recur within as short a period
as 6 months, and megaloblastic anemia recurs in
several years.
6
High-Dose Oral Treatment
High-dose oral treatment is effective and is increas-
ingly popular. A study performed 45 years ago
C
h
i
l
d
r
e
n
D
i
s
e
a
s
e
s

s
i
m
i
l
a
r

t
o

t
h
o
s
e

c
a
u
s
i
n
g

m
a
l
a
b
-
s
o
r
p
t
i
o
n

i
n

a
d
u
l
t
s
1
0
0

g

o
f

i
n
t
r
a
m
u
s
c
u
l
a
r

v
i
t
a
m
i
n

B
1
2

m
o
n
t
h
l
y

o
r

h
i
g
h
-
d
o
s
e

o
r
a
l

v
i
t
a
m
i
n

B
1
2

d
a
i
l
y

i
n

y
o
u
n
g
e
r

c
h
i
l
d
r
e
n
;

t
r
e
a
t
m
e
n
t

a
s

p
e
r

a
d
u
l
t
s

i
n

o
l
d
e
r

c
h
i
l
d
r
e
n
C
o
n
f
i
r
m

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a

o
r

c
o
n
g
e
n
i
t
a
l

m
a
l
a
b
s
o
r
p
t
i
o
n
R
e
c
r
e
a
t
i
o
n
a
l

o
r

o
c
c
u
p
a
t
i
o
n
a
l

a
b
u
s
e

o
f

n
i
t
r
o
u
s

o
x
i
d
e
I
n
t
r
a
m
u
s
c
u
l
a
r

c
y
a
n
o
c
o
b
a
l
a
m
i
n

a
t

a

d
o
s
e

o
f

1
0
0
0

g

a
d
m
i
n
i
s
-
t
e
r
e
d

o
n

t
h
e

s
a
m
e

s
c
h
e
d
u
l
e

a
s

t
h
a
t

f
o
r

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a

a
b
o
v
e

a
n
d

f
o
r

l
i
f
e

i
f

u
n
d
e
r
l
y
i
n
g

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a

i
s

p
r
e
s
e
n
t
E
v
a
l
u
a
t
e

f
o
r

v
i
t
a
m
i
n

B
1
2

m
a
l
a
b
s
o
r
p
t
i
o
n
;

p
r
o
v
i
d
e

a
d
d
i
c
t
i
o
n

c
o
u
n
-
s
e
l
i
n
g
N
i
t
r
o
u
s

o
x
i
d
e

a
n
e
s
t
h
e
s
i
a

i
n

o
c
c
u
l
t

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
1
7
*

I
n
t
r
a
m
u
s
c
u
l
a
r

h
y
d
r
o
x
o
c
o
b
a
l
a
m
i
n

c
a
n

b
e

s
u
b
s
t
i
t
u
t
e
d

f
o
r

i
n
t
r
a
m
u
s
c
u
l
a
r

c
y
a
n
o
c
o
b
a
l
a
m
i
n
,

b
u
t

d
o
c
u
m
e
n
t

t
h
e

l
o
n
g
-
t
e
r
m

r
e
s
p
o
n
s
e

i
f

i
t

i
s

a
d
m
i
n
i
s
t
e
r
e
d

a
t

3
-
m
o
n
t
h

i
n
t
e
r
v
a
l
s
.

E
x
p
e
r
t
s

a
r
e

n
o
t

i
n

a
g
r
e
e
m
e
n
t

a
b
o
u
t

t
h
e

n
e
c
e
s
s
i
t
y

o
r

f
r
e
q
u
e
n
c
y

o
f

r
o
u
t
i
n
e

u
p
p
e
r

e
n
d
o
s
c
o
p
y

i
n

p
a
t
i
e
n
t
s

w
i
t
h

p
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
.

H
o
w
e
v
e
r
,

s
y
m
p
t
o
m
s

s
u
g
g
e
s
t
i
v
e

o
f

g
a
s
t
r
i
c

c
a
r
c
i
n
o
m
a
,

u
n
-
e
x
p
l
a
i
n
e
d

i
r
o
n

d
e
f
i
c
i
e
n
c
y
,

a
n
d

p
r
o
v
e
n

g
a
s
t
r
o
i
n
t
e
s
t
i
n
a
l

b
l
o
o
d

l
o
s
s

s
h
o
u
l
d

p
r
o
m
p
t

a

f
u
l
l

i
n
v
e
s
t
i
g
a
t
i
o
n
.

C
o
n
g
e
n
i
t
a
l

m
a
l
a
b
s
o
r
p
t
i
o
n

o
f

v
i
t
a
m
i
n

B
1
2

r
e
s
u
l
t
s

f
r
o
m

m
u
t
a
t
i
o
n
s

o
f

t
h
e

i
l
e
a
l

c
u
b
a
m

r
e
c
e
p
t
o
r
,

c
u
b
i
l
i
n
,

o
r

a
m
n
i
o
n
l
e
s
s

(
a
s

i
n

t
h
e

I
m
e
r
s
l
u
n
d
G
r
s
b
e
c
k

s
y
n
d
r
o
m
e
)

a
n
d

f
r
o
m

m
u
t
a
t
i
o
n
s

i
n

g
a
s
t
r
i
c

i
n
t
r
i
n
s
i
c

f
a
c
t
o
r
.

T
h
e
s
e

s
y
n
d
r
o
m
e
s

a
r
e

u
s
u
a
l
l
y

m
a
n
i
f
e
s
t
e
d

i
n

i
n
f
a
n
c
y

a
n
d

e
a
r
l
y

c
h
i
l
d
h
o
o
d
,

a
l
t
h
o
u
g
h

s
t
u
d
i
e
s

h
a
v
e

s
h
o
w
n

a

d
e
l
a
y

i
n

o
n
s
e
t

e
v
e
n

i
n
t
o

a
d
o
l
e
s
c
e
n
c
e
.
1
8

N
i
t
r
o
u
s

o
x
i
d
e

i
n
a
c
t
i
v
a
t
e
s

t
h
e

v
i
t
a
m
i
n

B
1
2
d
e
p
e
n
d
e
n
t

e
n
z
y
m
e

m
e
t
h
i
o
n
i
n
e

s
y
n
t
h
a
s
e

a
n
d

c
a
u
s
e
s

f
o
r
m
a
t
i
o
n

o
f

v
i
t
a
m
i
n

B
1
2

a
n
a
l
o
g
u
e
s

a
n
d

g
r
a
d
u
a
l

t
i
s
s
u
e

d
e
p
l
e
t
i
o
n

o
f

v
i
t
a
m
i
n

B
1
2
.
156
Figure 3. The Normal Mechanisms and Defects of Absorption of Vitamin B
12
.
The vitamin B
12
(Cbl) released from food protein by peptic action is bound to haptocorrin (HC) in the stomach and
travels to the duodenum, where pancreatic proteases digest the HC, releasing Cbl to bind to intrinsic factor (IF).
The IF-Cbl complex binds to a specific receptor in the distal ileum (the cubam receptor) and is internalized, eventu-
ally released from lysosomes, and transported into the blood. Both HC and transcobalamin (TC) bind Cbl in the cir-
culation, although the latter is the cellular delivery protein. Adapted from Stabler.
6
clinical practice
157
T
a
b
l
e

2
.

L
a
b
o
r
a
t
o
r
y

T
e
s
t
i
n
g

i
n

V
i
t
a
m
i
n

B
1
2

D
e
f
i
c
i
e
n
c
y
.
*
T
e
s
t
S
e
n
s
i
t
i
v
i
t
y
S
p
e
c
i
f
i
c
i
t
y
C
o
m
m
e
n
t
s
M
e
a
s
u
r
e
m
e
n
t

t
o

d
e
t
e
c
t

d
e
f
i
c
i
e
n
c
y
S
e
r
u
m

v
i
t
a
m
i
n

B
1
2

<
2
0
0

p
g
/
m
l

o
r

l
a
b
o
-
r
a
t
o
r
y

c
u
t
o
f
f

l
e
v
e
l
6
5
9
5
%

f
o
r

p
r
o
v
e
n

c
l
i
n
i
c
a
l

d
e
f
i
c
i
e
n
c
y
;

5
0
%

f
o
r

d
e
t
e
c
t
i
n
g

e
l
e
v
a
t
e
d

l
e
v
e
l

o
f

m
e
t
h
y
l
m
a
-
l
o
n
i
c

a
c
i
d
5
0
6
0
%

f
o
r

c
l
i
n
i
c
a
l

r
e
s
p
o
n
s
e
;

8
0
%

f
o
r

d
e
-
t
e
c
t
i
n
g

e
l
e
v
a
t
e
d

l
e
v
e
l

o
f

m
e
t
h
y
l
m
a
l
o
n
i
c

a
c
i
d
C
u
r
r
e
n
t

v
i
t
a
m
i
n

B
1
2

a
s
s
a
y
s

a
r
e

e
s
p
e
c
i
a
l
l
y

p
r
o
b
l
e
m
a
t
i
c

i
n

p
a
t
i
e
n
t
s

w
i
t
h

a
n
t
i
i
n
t
r
i
n
s
i
c

f
a
c
t
o
r

a
n
t
i
b
o
d
i
e
s
S
e
r
u
m

v
i
t
a
m
i
n

B
1
2

<
3
5
0

p
g
/
m
l
9
0
%
2
5
%

f
o
r

d
e
t
e
c
t
i
n
g

e
l
e
v
a
t
e
d

l
e
v
e
l

o
f

m
e
t
h
y
l
-
m
a
l
o
n
i
c

a
c
i
d
H
o
l
o
t
r
a
n
s
c
o
b
a
l
a
m
i
n

<
2
0

t
o

4
5

p
m
o
l
/

l
i
t
e
r
I
n
s
u
f
f
i
c
i
e
n
t

d
a
t
a

o
n

s
e
n
s
i
t
i
v
i
t
y

f
o
r

c
l
i
n
i
c
a
l

d
e
-
f
i
c
i
e
n
c
y
;

4
6
8
9
%

f
o
r

d
e
t
e
c
t
i
n
g

e
l
e
v
a
t
e
d

l
e
v
e
l

o
f

m
e
t
h
y
l
m
a
l
o
n
i
c

a
c
i
d
I
n
s
u
f
f
i
c
i
e
n
t

d
a
t
a

o
n

s
p
e
c
i
f
i
c
i
t
y

f
o
r

c
l
i
n
i
c
a
l

d
e
-
f
i
c
i
e
n
c
y
;

2
8
9
6
%

f
o
r

d
e
t
e
c
t
i
n
g

e
l
e
v
a
t
e
d

l
e
v
e
l

o
f

m
e
t
h
y
l
m
a
l
o
n
i
c

a
c
i
d
L
e
v
e
l
s

o
f

h
o
l
o
t
r
a
n
s
c
o
b
a
l
a
m
i
n

i
n
c
r
e
a
s
e

i
n

r
e
-
n
a
l

f
a
i
l
u
r
e
;

s
u
p
e
r
i
o
r

t
o

m
e
a
s
u
r
e
m
e
n
t

o
f

t
o
t
a
l

v
i
t
a
m
i
n

B
1
2

i
n

p
r
e
g
n
a
n
c
y
,

w
h
e
n

t
h
e

t
o
t
a
l

l
e
v
e
l

d
e
c
r
e
a
s
e
s
S
e
r
u
m

m
e
t
h
y
l
m
a
l
o
n
i
c

a
c
i
d

>
4
0
0

n
m
o
l
/
l
i
t
e
r
9
8
%

f
o
r

c
l
i
n
i
c
a
l

d
e
f
i
c
i
e
n
c
y
P
o
o
r

s
p
e
c
i
f
i
c
i
t
y

f
o
r

c
l
i
n
i
c
a
l

r
e
s
p
o
n
s
e

i
n

p
a
t
i
e
n
t
s

w
i
t
h

m
o
d
e
s
t

e
l
e
v
a
t
i
o
n

o
f

l
e
v
e
l

o
f

m
e
t
h
y
l
-
m
a
l
o
n
i
c

a
c
i
d

(
3
0
0
1
0
0
0

n
m
o
l
/
l
i
t
e
r
)
R
e
n
a
l

f
a
i
l
u
r
e

a
n
d

v
o
l
u
m
e

d
e
p
l
e
t
i
o
n

m
a
y

i
n
-
c
r
e
a
s
e

l
e
v
e
l

o
f

s
e
r
u
m

m
e
t
h
y
l
m
a
l
o
n
i
c

a
c
i
d
,

b
u
t

r
a
r
e
l
y

t
o

>
1
0
0
0

n
m
o
l
/
l
i
t
e
r
S
e
r
u
m

o
r

p
l
a
s
m
a

t
o
t
a
l

h
o
m
o
c
y
s
t
e
i
n
e

>
2
1

m
o
l
/
l
i
t
e
r
9
6
%

f
o
r

c
l
i
n
i
c
a
l

d
e
f
i
c
i
e
n
c
y
H
o
m
o
c
y
s
t
e
i
n
e

l
e
v
e
l

a
l
s
o

i
n
c
r
e
a
s
e
d

i
n

c
l
i
n
i
c
a
l

f
o
l
a
t
e

d
e
f
i
c
i
e
n
c
y

a
n
d

r
e
n
a
l

i
n
s
u
f
f
i
c
i
e
n
c
y
T
e
s
t

t
o

d
e
t
e
r
m
i
n
e

c
a
u
s
e

o
f

d
e
f
i
c
i
e
n
c
y
P
e
r
n
i
c
i
o
u
s

a
n
e
m
i
a
A
n
t
i
i
n
t
r
i
n
s
i
c

f
a
c
t
o
r

a
n
t
i
b
o
d
i
e
s
5
0
%
1
0
0
%
M
u
s
t

b
e

t
e
s
t
e
d

>
7

d
a
y
s

a
f
t
e
r

v
i
t
a
m
i
n

B
1
2

i
n
-
j
e
c
t
i
o
n

t
o

p
r
e
v
e
n
t

f
a
l
s
e

p
o
s
i
t
i
v
e

r
e
s
u
l
t
A
n
t
i
p
a
r
i
e
t
a
l
-
c
e
l
l

a
n
t
i
b
o
d
i
e
s
8
0
%
5
0
1
0
0
%
A
t
r
o
p
h
i
c

b
o
d
y

g
a
s
t
r
i
t
i
s

(
a
n
t
r
a
l

s
p
a
r
i
n
g
)
*
*
F
a
s
t
i
n
g

h
i
g
h

s
e
r
u
m

g
a
s
t
r
i
n

l
e
v
e
l

(
>
1
0
0

p
m
o
l
/
l
i
t
e
r
)
8
5
%
L
o
w

l
e
v
e
l

o
f

s
e
r
u
m

p
e
p
s
i
n
o
g
e
n

I

(
<
3
0

g
/
l
i
t
e
r
)
9
0
%
E
n
d
o
s
c
o
p
y

w
i
t
h

p
e
n
t
a
g
a
s
t
r
i
n
-
f
a
s
t

h
y
p
o
c
h
l
o
r
h
y
d
r
i
a
1
0
0
%
R
a
r
e
l
y

p
e
r
f
o
r
m
e
d
M
a
l
a
b
s
o
r
p
t
i
o
n

o
f

v
i
t
a
m
i
n

B
1
2
V
i
t
a
m
i
n

B
1
2

a
b
s
o
r
p
t
i
o
n

t
e
s
t
S
c
h
i
l
l
i
n
g

t
e
s
t

n
o

l
o
n
g
e
r

a
v
a
i
l
a
b
l
e
I
n
c
r
e
a
s
e

i
n

s
e
r
u
m

h
o
l
o
t
r
a
n
s
c
o
b
a
l
a
m
i
n

l
e
v
e
l

a
f
t
e
r

o
r
a
l

l
o
a
d
i
n
g
U
n
k
n
o
w
n
U
n
k
n
o
w
n
P
r
o
m
i
s
i
n
g

p
r
e
c
l
i
n
i
c
a
l

d
a
t
a
,

b
u
t

s
t
i
l
l

e
x
p
e
r
i
-
m
e
n
t
a
l
*

T
o

c
o
n
v
e
r
t

t
h
e

v
a
l
u
e
s

f
o
r

v
i
t
a
m
i
n

B
1
2

t
o

p
i
c
o
m
o
l
e
s

p
e
r

l
i
t
e
r
,

m
u
l
t
i
p
l
y

b
y

0
.
7
3
7
8
.

A
v
a
i
l
a
b
l
e

a
s
s
a
y
s

a
r
e

l
a
r
g
e
l
y

c
h
e
m
i
l
u
m
i
n
e
s
c
e
n
t

m
i
c
r
o
p
a
r
t
i
c
l
e

i
m
m
u
n
o
a
s
s
a
y
s

p
e
r
f
o
r
m
e
d

w
i
t
h

t
h
e

u
s
e

o
f

a
u
t
o
m
a
t
e
d

a
n
a
l
y
z
e
r
s

t
h
a
t

i
n

g
e
n
e
r
a
l

s
h
o
w

h
i
g
h
e
r

v
a
l
u
e
s

t
h
a
n

t
h
e

r
a
d
i
o
d
i
l
u
t
i
o
n

a
n
d

m
i
c
r
o
b
i
o
l
o
g
i
c

a
s
s
a
y
s

u
s
e
d

i
n

p
a
s
t

s
t
u
d
i
e
s

o
f

c
l
i
n
i
c
a
l
l
y

c
o
n
f
i
r
m
e
d

d
e
f
i
c
i
e
n
c
y
.
4
,
2
2
,
2
4
,
2
6

T
h
u
s
,

t
h
e
s
e

t
e
s
t
s

a
r
e

l
i
k
e
l
y

t
o

h
a
v
e

l
o
w
e
r

s
e
n
s
i
t
i
v
i
t
i
e
s

a
n
d

s
p
e
c
i
f
i
c
i
t
i
e
s

t
h
a
n

t
h
e

o
l
d
e
r

a
s
s
a
y
s
.

T
h
e

h
o
l
o
t
r
a
n
s
c
o
b
a
l
a
m
i
n

a
s
s
a
y

h
a
s

b
e
e
n

s
t
u
d
i
e
d

w
i
d
e
l
y

i
n

E
u
r
o
p
e
2
7
-
3
0

b
u
t

i
s

n
o
t

y
e
t

c
o
m
m
e
r
c
i
a
l
l
y

a
v
a
i
l
a
b
l
e

i
n

t
h
e

U
n
i
t
e
d

S
t
a
t
e
s
.

T
h
e

a
p
p
r
o
p
r
i
a
t
e

l
o
w
e
r

e
n
d

o
f

t
h
e

r
e
f
e
r
e
n
c
e

r
a
n
g
e

i
s

s
t
i
l
l

u
n
d
e
r

d
e
b
a
t
e
.
3
3

T
h
e

v
a
l
u
e
s

f
o
r

s
e
n
s
i
t
i
v
i
t
y

a
n
d

s
p
e
c
i
f
i
c
i
t
y

a
r
e

r
e
v
i
e
w
e
d

i
n

H
e
i
l

e
t

a
l
.
2
9

U
r
i
n
a
r
y

m
e
t
h
y
l
m
a
l
o
n
i
c

a
c
i
d

h
a
s

n
o
t

b
e
e
n

e
x
t
e
n
s
i
v
e
l
y

s
t
u
d
i
e
d
,

b
u
t

v
a
l
u
e
s

g
r
e
a
t
e
r

t
h
a
n

2
.
5

m
o
l

p
e
r

m
i
l
l
i
m
o
l
e

o
f

c
r
e
a
t
i
n
i
n
e

s
u
g
g
e
s
t

d
e
f
i
c
i
e
n
c
y
.

E
l
e
v
a
t
e
d

l
e
v
e
l
s

o
f

m
e
t
h
y
l
m
a
l
o
n
i
c

a
c
i
d

f
a
l
l

w
i
t
h

v
i
t
a
m
i
n

B
1
2

t
h
e
r
a
p
y
,

b
u
t

a
n

a
s
s
o
c
i
a
t
e
d

c
l
i
n
i
c
a
l

r
e
s
p
o
n
s
e

i
s

h
i
g
h
l
y

v
a
r
i
a
b
l
e
,

d
e
p
e
n
d
i
n
g

l
a
r
g
e
l
y

o
n

t
h
e

p
r
e
s
e
n
c
e

o
f

v
i
t
a
m
i
n

B
1
2
r
e
l
a
t
e
d

d
i
s
e
a
s
e
.

E
v
i
d
e
n
c
e

o
f

a

c
a
u
s
a
l

p
a
t
h
o
l
o
g
i
c

p
r
o
c
e
s
s

d
o
e
s

n
o
t

c
o
n
f
i
r
m

c
o
e
x
i
s
t
i
n
g

B
1
2

d
e
f
i
c
i
e
n
c
y
,

s
i
n
c
e

u
n
d
e
r
l
y
i
n
g

g
a
s
t
r
o
i
n
t
e
s
t
i
n
a
l

d
i
s
e
a
s
e

m
a
y

p
r
e
d
a
t
e

t
h
e

d
e
f
i
c
i
e
n
c
y

b
y

m
a
n
y

y
e
a
r
s
.
*
*

T
h
e

r
e
l
a
t
i
o
n
s
h
i
p

b
e
t
w
e
e
n

a
t
r
o
p
h
i
c

b
o
d
y

g
a
s
t
r
i
t
i
s

(
a
u
t
o
i
m
m
u
n
e

g
a
s
t
r
i
t
i
s
)

a
n
d

i
n
f
e
c
t
i
o
n

w
i
t
h

H
e
l
i
c
o
b
a
c
t
e
r

p
y
l
o
r
i

i
s

v
a
r
i
a
b
l
e
.

A
n
t
r
a
l

s
p
a
r
i
n
g

i
s

a

t
y
p
e

o
f

a
t
r
o
p
h
i
c

b
o
d
y

g
a
s
t
r
i
t
i
s

i
n

w
h
i
c
h

t
h
e

c
e
l
l
s

i
n

t
h
e

a
n
t
r
u
m

c
a
n

p
r
o
d
u
c
e

h
i
g
h

l
e
v
e
l
s

o
f

g
a
s
t
r
i
n
.

T
h
e
r
e

i
s

m
a
l
a
b
s
o
r
p
t
i
o
n

i
f

c
l
i
n
i
c
a
l
l
y

p
r
o
v
e
n

v
i
t
a
m
i
n

B
1
2

d
e
f
i
c
i
e
n
c
y

i
s

p
r
e
s
e
n
t

i
n

a

p
a
t
i
e
n
t

w
h
o

e
a
t
s

m
e
a
t
,

r
e
c
e
i
v
e
s

m
u
l
t
i
v
i
t
a
m
i
n

t
h
e
r
a
p
y
,

o
r

b
o
t
h
.
158
showed that 0.5 to 4% of radioactively labeled
oral vitamin B
12
can be absorbed by passive dif-
fusion in both normal controls and patients with
pernicious anemia.
43
Thus, oral doses of 1000 g
deliver 5 to 40 g, even if taken with food.
A randomized trial that compared an oral
dose of 2000 g daily with parenteral therapy
(seven injections of 1000 g of cyanocobalamin
over a period of 1 month, followed by monthly
injections) in patients with pernicious anemia,
atrophic gastritis, or a history of ileal resection
showed similar reductions in the mean corpus-
cular volume and increases in the hematocrit at
4 months in both groups.
38
All participants
(four in each group) with paresthesias, ataxia, or
memory loss had resolution or improved with
treatment. However, levels of methylmalonic
acid after treatment were significantly lower
with daily oral treatment (169 nmol per liter, vs.
265 nmol per liter with parenteral treatment)
and vitamin B
12
levels were significantly higher
(1005 pg per milliliter vs. 325 pg per milliliter
[741.5 vs. 239.8 pmol per liter]). A more recent
trial with a similar design involving a proprie-
tary oral vitamin B
12
preparation also revealed
significantly lower levels of methylmalonic acid
in the oral-treatment group at the 3-month follow-
up.
30
In a randomized trial comparing oral with
intramuscular vitamin B
12
(1000-g doses, daily
for 10 days, then weekly for 4 weeks, and month-
ly thereafter), the two groups had similar im-
provements in hematologic abnormalities and
vitamin B
12
levels at 90 days.
44
Case series of
patients treated with oral vitamin B
12
have
yielded variable results; elevated levels of meth-
ylmalonic acid, homocysteine, or both were re-
ported in about half of patients with malabsorp-
tion who were treated with twice-weekly oral
doses of 1000 g,
45
whereas normal homocyste-
ine levels were reported in patients treated with
1500 g daily after gastrectomy.
46
Data are lack-
ing from long-term studies to assess whether
oral treatment is effective when doses are ad-
ministered less frequently than daily. Studies
involving older adults, many of whom had
chronic atrophic gastritis, showed that 60% re-
quired large oral doses (>500 g daily) to correct
elevated levels of methylmalonic acid.
47,48
Proponents of parenteral therapy state that
compliance and monitoring are better in patients
who receive this form of therapy because they
have frequent contact with health care providers,
whereas proponents of oral therapy maintain
that compliance will be improved in patients
who receive oral therapy because of convenience,
comfort, and decreased expense. High-dose vita-
min B
12
tablets (500 to 1500 g) are available in
the United States without a prescription. Self-
administered injections are also easily taught,
economical, and in my experience, effective. Pa-
tients should be informed of the pros and cons
of oral versus parenteral therapy, and regardless
of the form of treatment, those with pernicious
anemia or malabsorption should be reminded of
the need for lifelong replacement.
Areas of Uncertainty
Vitamin B
12
deficiency is the major cause of hy-
perhomocysteinemia in countries with folate-
fortified food, such as the United States and
S
e
r
u
m

M
e
t
h
y
l
m
a
l
o
n
i
c

A
c
i
d

(
n
m
o
l
/
l
i
t
e
r
)
300,000
100,000
10,000
5,000
1,000
500
50,000
100
10 50 100 0 150 200 250 300 350 400 450
Serum Total Homocysteine (mol/liter)

Figure 4. Serum Methylmalonic Acid and Total Homocysteine Concentrations
in 491 Episodes of Vitamin B
12
Deficiency.
The data shown have been combined from studies performed over a period
of 25 years.
4,6,22,24,26,35,37,38
Most of the patients with clinically confirmed
vitamin B
12
deficiency had documented pernicious anemia and a proven re-
sponse to vitamin B
12
therapy. Open circles indicate episodes in patients
with a hematocrit lower than 38%, and solid circles indicate episodes in
those with a hematocrit of 38% or higher. Patients without anemia had
neurologic manifestations of vitamin B
12
deficiency and similar values of
methylmalonic acid and total homocysteine. The axis for serum methylmalo-
nic acid is plotted on a log scale. The dashed lines indicate values that are
3 SD above the mean for healthy blood donors: 376 nmol per liter for meth-
ylmalonic acid and 21.3 mol per liter for total homocysteine. The level of
methylmalonic acid was greater than 500 nmol per liter in 98% of the pa-
tients and greater than 1000 nmol per liter in 86%. Adapted from Stabler.
7
clinical practice
159
Canada. Epidemiologic studies show significant
associations between elevated homocysteine lev-
els and vascular disease and thrombosis. How-
ever, large randomized trials of combined high-
dose vitamin B therapy in patients with vascular
disease have shown no reduction in vascular
events.
49
Vitamin B
12
status should be evaluated
in patients with hyperhomocysteinemia before
folic acid treatment is initiated.
The potential role of mild vitamin B
12
defi-
ciency in cognitive decline with aging remains
uncertain. Epidemiologic studies indicate an in-
verse association between vitamin B
12
supplemen-
tation and neurodegenerative disease, but results
of randomized trials have been largely negative.
50
Besides oral tablets, vitamin B is available in
sublingual preparations, oral sprays, nasal gels
or sprays, and transdermal patches. Data on the
absorption and efficacy of these alternative prep-
arations are lacking.
Guidelines
Nutritional guidelines for vitamin B
12
intake are
published by the Food and Nutrition Board,
41

and nutritional guidelines for vegetarians are
published by the American Dietetic Association.
40

There are no recommendations from the Ameri-
can Society of Hematology for the diagnosis and
treatment of vitamin B
12
deficiency. The Ameri-
can Academy of Neurology recommends mea-
surements of vitamin B
12
, methylmalonic acid,
and homocysteine in patients with symmetric
polyneuropathy.
51
The American Society for Gas-
trointestinal Endoscopy recommends a single
endoscopic evaluation at the diagnosis of perni-
cious anemia.
52
Conclusions
and Recommendations
The patient in the vignette has neurologic abnor-
malities that are consistent with vitamin B
12
de-
ficiency. Since vitamin B
12
levels may be above
the lower end of the laboratory reference range
even in patients with clinical deficiency, methyl-
malonic acid, total homocysteine, or both should
be measured to document vitamin B
12
deficiency
before treatment is initiated; the elevated levels
in this patient confirm the diagnosis. In the ab-
sence of dietary restriction or a known cause of
malabsorption, further evaluation is warranted
in particular, testing for pernicious anemia
(antiintrinsic factor antibodies). Either paren-
teral vitamin B
12
treatment (8 to 10 loading injec-
tions of 1000 g each, followed by monthly
1000-g injections), or high-dose oral vitamin
B
12
treatment (1000 to 2000 g daily) is an effec-
tive therapy. I would review both options (includ-
ing the possibility of self-injection at home) with
the patient. Effective vitamin replacement will
correct blood counts in 2 months and correct or
improve neurologic signs and symptoms within
6 months.
Dr. Stabler reports holding patents (assigned to the University
of Colorado and Competitive Technologies) on the use of homo-
cysteine, methylmalonic acid, and other metabolites in the diag-
nosis of vitamin B
12
and folate deficiency, but no longer receiv-
ing royalties for these patents. No other potential conflict of
interest relevant to this article was reported.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
References
1. Stabler SP, Allen RH. Vitamin B12 de-
ficiency as a worldwide problem. Annu
Rev Nutr 2004;24:299-326.
2. Nielsen MJ, Rasmussen MR, Andersen
CB, Nex E, Moestrup SK. Vitamin B(12)
transport from food to the bodys cells-a
sophisticated, multistep pathway. Nat Rev
Gastroenterol Hepatol 2012;9:345-54.
3. Toh BH, Chan J, Kyaw T, Alderuccio F.
Cutting edge issues in autoimmune gas-
tritis. Clin Rev Allergy Immunol 2012;
42:269-78.
4. Lindenbaum J, Healton EB, Savage
DG, et al. Neuropsychiatric disorders
caused by cobalamin deficiency in the ab-
sence of anemia or macrocytosis. N Engl J
Med 1988;318:1720-8.
5. Healton EB, Savage DG, Brust JC,
Garrett TJ, Lindenbaum J. Neurologic as-
pects of cobalamin deficiency. Medicine
1991;70:229-45.
6. Stabler SP. Megaloblastic anemias:
pernicious anemia and folate deficiency.
In: Young NS, Gerson SL, High KA, eds.
Clinical hematology. Philadelphia: Mos-
by, 2006:242-51.
7. Stabler SP. Vitamin B12. In: Erdman
JW Jr, MacDonald IA, Zeisel SH, eds. Pres-
ent knowledge in nutrition. 10th ed. New
York: Wiley-Blackwell, 2012:343-58.
8. Dalsania CJ, Khemka V, Shum M, De-
vereux L, Lachant NA. A sheep in wolfs
clothing. Am J Med 2008;121:107-9.
9. Andrs E, Affenberger S, Zimmer J, et
al. Current hematological findings in co-
balamin deficiency: a study of 201 con-
secutive patients with documented co-
balamin deficiency. Clin Lab Haematol
2006;28:50-6.
10. Parmentier S, Meinel J, Oelschlaegel U,
et al. Severe pernicious anemia with dis-
tinct cytogenetic and flow cytometric ab-
errations mimicking myelodysplastic syn-
drome. Ann Hematol 2012;91:1979-81.
11. Pittock SJ, Payne TA, Harper CM. Re-
versible myelopathy in a 34-year-old man
with vitamin B12 deficiency. Mayo Clin
Proc 2002;77:291-4.
12. Remacha AF, Souto JC, Piana JL, et
al. Vitamin B12 deficiency, hyperhomo-
cysteinemia and thrombosis: a case and
control study. Int J Hematol 2011;93:
458-64.
13. Limal N, Scheuermaier K, Tazi Z, Sene
D, Piette JC, Cacoub P. Hyperhomocyste-
inaemia, thrombosis and pernicious anae-
mia. Thromb Haemost 2006;96:233-5.
14. de Jager J, Kooy A, Lehert P, et al. Long
term treatment with metformin in pa-
tients with type 2 diabetes and risk of vi-
tamin B-12 deficiency: randomised pla-
cebo controlled trial. BMJ 2010;340:c2181.
15. Dror DK, Allen LH. Effect of vitamin
160
clinical practice
B12 deficiency on neurodevelopment in
infants: current knowledge and possible
mechanisms. Nutr Rev 2008;66:250-5.
16. Honzik T, Adamovicova M, Smolka V,
Magner M, Hruba E, Zeman J. Clinical pre-
sentation and metabolic consequences in
40 breastfed infants with nutritional vita-
min B12 deficiency what have we
learned? Eur J Paediatr Neurol 2010;14:
488-95.
17. Singer MA, Lazaridis C, Nations SP,
Wolfe GI. Reversible nitrous oxide-induced
myeloneuropathy with pernicious ane-
mia: case report and literature review.
Muscle Nerve 2008;37:125-9.
18. Tanner SM, Sturm AC, Baack EC, Li-
yanarachchi S, de la Chapelle A. Inherited
cobalamin malabsorption: mutations in
three genes reveal functional and ethnic
patterns. Orphanet J Rare Dis 2012;7:56.
19. Lewerin C, Jacobsson S, Lindstedt G,
Nilsson-Ehle H. Serum biomarkers for
atrophic gastritis and antibodies against
Helicobacter pylori in the elderly: implica-
tions for vitamin B12, folic acid and iron
status and response to oral vitamin thera-
py. Scand J Gastroenterol 2008;43:1050-6.
20. Hershko C, Ronson A, Souroujon M,
Maschler I, Heyd J, Patz J. Variable hema-
tologic presentation of autoimmune gas-
tritis: age-related progression from iron
deficiency to cobalamin depletion. Blood
2006;107:1673-9.
21. Wun Chan JC, Yu Liu HS, Sang Kho BC,
et al. Pernicious anemia in Chinese: a study
of 181 patients in a Hong Kong hospital.
Medicine (Baltimore) 2006;85:129-38.
22. Savage DG, Lindenbaum J, Stabler SP,
Allen RH. Sensitivity of serum methylma-
lonic acid and total homocysteine determi-
nations for diagnosing cobalamin and fo-
late deficiencies. Am J Med 1994;96:239-46.
23. Carmel R. How I treat cobalamin (vi-
tamin B12) deficiency. Blood 2008;112:
2214-21.
24. Pennypacker LC, Allen RH, Kelly JP, et
al. High prevalence of cobalamin defi-
ciency in elderly outpatients. J Am Geriatr
Soc 1992;40:1197-204.
25. Sarafoglou K, Rodgers J, Hietala A,
Matern D, Bentler K. Expanded newborn
screening for detection of vitamin B12 de-
ficiency. JAMA 2011;305:1198-200.
26. Stabler SP, Allen RH, Savage DG, Lin-
denbaum J. Clinical spectrum and diag-
nosis of cobalamin deficiency. Blood
1990;76:871-81.
27. Nexo E, Hoffmann-Lcke E. Holo-
transcobalamin, a marker of vitamin B-12
status: analytical aspects and clinical util-
ity. Am J Clin Nutr 2011;94:359S-365S.
28. Schrempf W, Eulitz M, Neumeister V,
et al. Utility of measuring vitamin B12 and
its active fraction, holotranscobalamin, in
neurological vitamin B12 deficiency syn-
dromes. J Neurol 2011;258:393-401.
29. Heil SG, de Jonge R, de Rotte MC, et
al. Screening for metabolic vitamin B12
deficiency by holotranscobalamin in pa-
tients suspected of vitamin B12 deficien-
cy: a multicentre study. Ann Clin Biochem
2012;49:184-9.
30. Castelli MC, Friedman K, Sherry J, et
al. Comparing the efficacy and tolerabili-
ty of a new daily oral vitamin B12 formu-
lation and intermittent intramuscular vi-
tamin B12 in normalizing low cobalamin
levels: a randomized, open-label, parallel-
group study. Clin Ther 2011;33(3):358.e2-
371.e2.
31. Carmel R, Brar S, Agrawal A, Penha
PD. Failure of assay to identify low co-
balamin concentrations. Clin Chem
2000;46:2017-8.
32. Galloway M, Hamilton M. Macrocyto-
sis: pitfalls in testing and summary of
guidance. BMJ 2007;335:884-6.
33. Yang DT, Cook RJ. Spurious eleva-
tions of vitamin B
12
with pernicious ane-
mia. N Engl J Med 2012;366:1742-3.
34. Carmel R, Agrawal YP. Failures of co-
balamin assays in pernicious anemia.
N Engl J Med 2012;367:385-6. [Erratum,
N Engl J Med 2012;367:976.]
35. Stabler SP, Marcell PD, Podell ER, et
al. Elevation of total homocysteine in the
serum of patients with cobalamin or fo-
late deficiency detected by capillary gas
chromatographymass spectrometry. J Clin
Invest 1988;81:466-74.
36. Stabler SP, Marcell PD, Podell ER, Al-
len RH, Lindenbaum J. Assay of methyl-
malonic acid in the serum of patients
with cobalamin deficiency using capillary
gas chromatographymass spectrometry.
J Clin Invest 1986;77:1606-12.
37. Rasmussen K, Vyberg B, Pedersen KO,
Brchner-Mortensen J. Methylmalonic
acid in renal insufficiency: evidence of ac-
cumulation and implications for diagno-
sis of cobalamin deficiency. Clin Chem
1990;36:1523-4.
38. Kuzminski AM, Del Giacco EJ, Allen
RH, Stabler SP, Lindenbaum J. Effective
treatment of cobalamin deficiency with
oral cobalamin. Blood 1998;92:1191-8.
39. Greibe E, Nexo E. Vitamin B12 ab-
sorption judged by measurement of holo-
transcobalamin, active vitamin B12: eval-
uation of a commercially available EIA
kit. Clin Chem Lab Med 2011;49:1883-5.
40. American Dietetic Association, Dieti-
tians of Canada. Position of the American
Dietetic Association and Dietitians of
Canada: vegetarian diets. J Am Diet Assoc
2003;103:748-65.
41. Institute of Medicine Food and Nutri-
tion Board. Dietary reference intakes:
thiamin, riboflavin, niacin, vitamin B6,
folate, vitamin B12, pantothenic acid, bio-
tin and choline. Washington, DC: Nation-
al Academies Press, 1998.
42. Bor MV, von Castel-Roberts KM,
Kauwell GP, et al. Daily intake of 4 to 7 g
dietary vitamin B-12 is associated with
steady concentrations of vitamin B-12
related biomarkers in a healthy young
population. Am J Clin Nutr 2010;91:571-7.
43. Berlin H, Berlin R, Brante G. Oral
treatment of pernicious anemia with high
doses of vitamin B12 without intrinsic
factor. Acta Med Scand 1968;184:247-58.
44. Bolaman Z, Kadikoylu G, Yukselen V,
Yavasoglu I, Baructa S, Senturk T. Oral
versus intramuscular cobalamin treat-
ment in megaloblastic anemia: a single-
center, prospective, randomized open-label
study. Clin Ther 2003;25:3124-34.
45. Bor MV, Cetin M, Ayta S, Altay C,
Ueland PM, Nexo E. Long term biweekly
1 mg oral vitamin B12 ensures normal
hematological parameters, but does not
correct all other markers of vitamin B12
deficiency: a study in patients with inher-
ited vitamin B12 deficiency. Haematolog-
ica 2008;93:1755-8.
46. Kim HI, Hyung WJ, Song KJ, Choi SH,
Kim CB, Noh SH. Oral vitamin B12 re-
placement: an effective treatment for vita-
min B12 deficiency after total gastrecto-
my in gastric cancer patients. Ann Surg
Oncol 2011;18:3711-7.
47. Rajan S, Wallace JI, Brodkin KI,
Beresford SA, Allen RH, Stabler SP. Re-
sponse of elevated methylmalonic acid to
three dose levels of oral cobalamin in
older adults. J Am Geriatr Soc 2002;50:
1789-95.
48. Eussen SJ, de Groot LC, Clarke R, et
al. Oral cyanocobalamin supplementation
in older people with vitamin B12 deficien-
cy: a dose-finding trial. Arch Intern Med
2005;165:1167-72.
49. Yang HT, Lee M, Hong KS, Ovbiagele
B, Saver JL. Efficacy of folic acid supple-
mentation in cardiovascular disease pre-
vention: an updated meta-analysis of ran-
domized controlled trials. Eur J Intern
Med 2012;23:745-54.
50. Nachum-Biala Y, Troen AM. B-vita-
mins for neuroprotection: narrowing the
evidence gap. Biofactors 2012;38:145-50.
51. England JD, Gronseth GS, Franklin G,
et al. Practice parameter: the evaluation of
distal symmetric polyneuropathy: the role
of autonomic testing, nerve biopsy, and
skin biopsy (an evidence-based review)
report of the American Academy of Neu-
rology, the American Association of
Neuromuscular and Electrodiagnostic
Medicine, and the American Academy of
Physical Medicine and Rehabilitation.
PM&R 2009;1:14-22.
52. Hirota WK, Zuckerman MJ, Adler DG,
et al. ASGE guideline: the role of endos-
copy in the surveillance of premalignant
conditions of the upper GI tract. Gastro-
intest Endosc 2006;63:570-80.
Copyright 2013 Massachusetts Medical Society.

Deficit Vitamina B 12

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Deficit Vitamina B 12

Uploaded by

Copyright:

Available Formats

clinical practice

The new engl and journal o f medicine

You might also like