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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1191-1198
Effective Treatment of Cobalamin Deficiency With Oral
Cobalamin
By
Antoinette M. Kuzminski,
Eric J. Del Giacco,
Robert H. Allen,
Sally P. Stabler, and
John Lindenbaum
From the Division of General Internal Medicine, Bassett Healthcare,
Cooperstown, NY; the Division of Hematology, Department of Medicine,
University of Colorado Health Sciences Center, Denver, CO; and the
Department of Medicine, Columbia University College of Physicians and
Surgeons, New York, NY.
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ABSTRACT |
Because cobalamin deficiency is routinely treated with parenteral
cobalamin, we investigated the efficacy of oral therapy. We randomly
assigned 38 newly diagnosed cobalamin deficient patients to receive
cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90 or 2 mg orally on a daily basis for 120 days.
Therapeutic effectiveness was evaluated by measuring hematologic and
neurologic improvement and changes in serum levels of cobalamin
(normal, 200 to 900 pg/mL) methylmalonic acid (normal, 73 to 271 nmol/L), and homocysteine (normal, 5.1 to 13.9 µmol/L). Five patients
were subsequently found to have folate deficiency, which left 18 evaluable patients in the oral group and 15 in the parenteral group.
Correction of hematologic and neurologic abnormalities was prompt and
indistinguishable between the 2 groups. The mean pretreatment values
for serum cobalamin, methylmalonic acid, and homocysteine were,
respectively, 93 pg/mL, 3,850 nmol/L, and 37.2 µmol/L in the oral
group and 95 pg/mL, 3,630 nmol/L, and 40.0 µmol/L in the parenteral
therapy group. After 4 months of therapy, the respective mean values
were 1,005 pg/mL, 169 nmol/L, and 10.6 µmol/L in the oral group and
325 pg/mL, 265 nmol/L, and 12.2 µmol/L in the parenteral group. The
higher serum cobalamin and lower serum methylmalonic acid levels at 4 months posttreatment in the oral group versus the parenteral group were
significant, with P < .0005 and P < .05, respectively. In cobalamin deficiency, 2 mg of cyanocobalamin
administered orally on a daily basis was as effective as 1 mg
administered intramuscularly on a monthly basis and may be superior.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
THE DAILY REQUIREMENT for cobalamin
(vitamin B12) is 1 to 2 µg. Such tiny doses of the
vitamin are quite efficiently (~60%) absorbed bound to intrinsic
factor via a specific ileal transport system.1 Patients
with pernicious anemia and other intestinal disorders develop cobalamin
deficiency, because they cannot absorb the small amounts of cobalamin
in food via this mechanism. It is stated in textbooks2-4
and widely believed by physicians that such patients cannot reliably
absorb oral cobalamin and require frequent, usually monthly,
intramuscular injections for life. Indeed, in a recent survey of 245 Minnesota internists, more than 90% believed that such patients cannot
absorb sufficient quantities of vitamin B12 when it is
administered orally and 94% were unaware that any effective oral
cobalamin preparations were available.5
However, in the 1950s and 1960s, several investigators6-11
provided evidence for an additional pathway for cobalamin absorption that does not require intrinsic factor or the presence of an intact ileum.8,11-19 If very large doses of cyanocobalamin, in the
range of 100 to 100,000 µg, are administered to patients with
pernicious anemia, approximately 1% of the dose is absorbed, so that
enough can be administered by mouth to easily exceed the daily
requirement. Excellent hematologic responses were also documented in 91 of 91 patients with pernicious anemia who had received 300 to 2,000 µg or more of oral cyanocobalamin daily.8,11-19 Severe
neurological involvement was also reported to respond to large oral
doses.16,17,19 Finally, when patients with pernicious
anemia were placed on daily oral maintenance doses of 1,000 µg, no
hematologic or neurologic relapses occurred and serum cobalamin
concentrations remained normal.10-12,20
However, oral treatment with the vitamin has never been the subject of
a controlled study. Therefore, we conducted a randomized, controlled
trial of oral versus parenteral cyanocobalamin therapy in patients with
cobalamin deficiency. In addition to assessing hematologic and
neurologic responses and changes in serum cobalamin levels, we measured
changes in serum methylmalonic acid and total homocysteine levels, two
metabolic indicators of cobalamin deficiency that are more sensitive
than serum vitamin concentrations.21-23
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MATERIALS AND METHODS |
Selection of patients.
Patients were recruited from 4 ambulatory care centers that are part of
the Bassett Healthcare network in central New York State. All patients
who had serum cobalamin concentrations less than 160 pg/mL as measured
in the Bassett Healthcare clinical laboratory between January 1993 and
September 1996 were potential subjects. Of 138 such patients, 87 were
excluded for one of the following reasons: location outside the
immediate geographic area of Bassett Hospital; incapacity to give
informed consent; refusal to participate; and associated
life-threatening illness. Additional criteria for participation
included confirmation of the low serum cobalamin level in another
specimen and an elevation of serum methylmalonic acid, total
homocysteine, or of both metabolites greater than 3 standard deviations
(SD) above the mean in normal controls. As a result, another 13 patients were excluded (6 because of a normal repeat serum cobalamin
and 7 in whom neither serum metabolite was elevated). The remaining 38 patients were randomized (Statistical Analysis System; SAS Institute,
Cary, NC) to receive oral or parenteral therapy with cyanocobalamin.
After completion of the trial, 5 were judged to have primary folate
deficiency rather than of cobalamin (see Results) and were excluded
from the final analysis. The remaining 33 patients, who were considered to be truly deficient in cobalamin, form the main subject of this report.
Study protocol.
Patients were interviewed and examined by one of the investigators
before and after the 4-month treatment period. Informed written consent
was obtained. Before and after 1, 2, and 4 months of therapy, serum
specimens were obtained before the daily oral dose or before the
intramuscular treatment, with the exception of 3 patients early in the
study in whom serum was taken (due to error) within minutes of an
injection, on a total of 7 occasions (4 at 1 month, 2 at 2 months, and
1 at 4 months). These 7 specimens were excluded from analysis of serum
cobalamin in the parenteral group, but were judged valid for serum
metabolite concentrations. Serum was not available at the 2-month visit
from 1 patient (no. 3). In patient no. 2, folic acid (400 µg/day by
mouth) was administered in addition to oral cobalamin between the
second and fourth month. The study was approved by the review boards of
the Mary Imogene Bassett Hospital and Columbia-Presbyterian Medical
Center.
Therapeutic regimens.
Patients were randomized to receive 2,000 µg of oral
cyanocobalamin (two 1,000 µg tablets; Nature's Bounty, Bohemia, NY)
administered with breakfast daily for 4 months or 1,000 µg of
cyanocobalamin intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and
90. A research nurse administered the injections and monitored
compliance.
Laboratory methods.
Serum cobalamin and folate concentrations were determined by
radioassays using purified intrinsic factor and milk binder
(Simultrac-S; Becton Dickinson Laboratories, Orangeburg, NY). Serum
anti-intrinsic factor antibodies and unsaturated serum
cobalamin-binding capacity were measured using a coated-charcoal
assay.24 Serum methylmalonic acid and total homocysteine
were measured using capillary gas chromatography-mass
spectrometry.25 Serum pepsinogen I levels were determined
by a double antibody radioimmunoassay (Sorin Biomedical Diagnostics,
Incstar Corp, Steelwater, MN) as was serum gastrin (Becton Dickinson
Laboratories).
Statistical analysis.
Standard methods, including the Students' t-test and the
 2 test with Yates' correction for
continuity26 were used.
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RESULTS |
Characteristics of patients.
Eighteen cobalamin-deficient patients were randomized to oral
cyanocobalamin (Tables 1 and
2) and 15 to intramuscular
treatment (Tables 3 and
4). A majority in both groups were elderly
women. All were white except for 1 Latina patient. All but 1 or 2 patients in each group were outpatients and most were not anemic. In 1 patient (no. 4), the serum creatinine was increased (1.7 mg/dL). In 2 anemic patients in the parenteral group (Table 3), iron deficiency
appeared to contribute to the anemia. The erythrocyte mean cell volume
(MCV) was elevated (>100 fL) in 7 and 8 patients, respectively, in the 2 groups. Four patients in each group had mild to
moderate neurologic symptoms consistent with cobalamin deficiency.
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Table 1.
Pretreatment Clinical and Hematologic Findings and
Responses to 4 Months of Therapy in Patients Randomized to Oral
Cyanocobalamin
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Table 2.
Serum Vitamin and Metabolite Concentrations Before and
After 4 Months of Therapy in Patients Randomized to Oral
Cyanocobalamin
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Table 3.
Pretreatment Clinical and Hematologic Findings and
Responses to 4 Months of Therapy in Patients Randomized to
Parenteral Cyanocobalamin
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Table 4.
Serum Vitamin and Metabolite Concentrations Before and
After 4 Months of Therapy in Patients Randomized to Parenteral
Cyanocobalamin
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All patients had a low serum cobalamin; 2 in each group had a decreased
serum folate (Tables 2 and 4). Serum methylmalonic acid was greater
than 3 SD above the mean in normal controls in all except no. 33 in the
parenteral group. Serum total homocysteine was greater than 3 SD above
the normal mean in 10 and 12 patients, respectively, in the oral and
parenteral groups. The 2 groups did not differ significantly in mean
age, pretreatment hematocrit, MCV, serum cobalamin, folate,
methylmalonic acid, or total homocysteine.
Etiology of cobalamin deficiency.
Seven patients (Tables 1 and 3) had serum antibodies to intrinsic
factor, establishing the diagnosis of pernicious anemia. In 4, there
was a history of gastric or ileal surgery. Fourteen patients, 7 in each
group, were felt to have severe chronic atrophic gastritis (which could
cause either intrinsic factor deficiency or food-cobalamin
malabsorption)27,28 using a combination of serum pepsinogen
and gastrin concentrations29-31 (see footnote to Table 1).
Three had poor dietary animal protein intake and 3 were taking agents
reported to cause food cobalamin malabsorption.32,33
Hematologic and neurologic responses.
Hematologic and neurologic responses to cyanocobalamin are shown in
Tables 1 and 3 and are summarized in Table
5. They are similar to those observed in a larger study that used only parenteral cobalamin.34 In approximately one half of the
patients in each group, a major decrease in MCV occurred. The mean
decrease after 4 months of treatment was highly significant in each
group (P < .005). Substantial increments in hematocrit
attributable to cobalamin therapy were seen in a minority of both
groups, most strikingly in patients no. 2 and 3 on oral cyanocobalamin.
Four patients on each treatment experienced dramatic improvement of neurologic complaints. Improvement in mental status, gait, or vibration
sense was documented in 2 and 3 patients, respectively, after oral and
parenteral therapy.
Serum cobalamin concentrations.
The most striking difference between the two groups was in the behavior
of the serum cobalamin level (Fig 1 and
Tables 2 and 4). In patients receiving oral cyanocobalamin, serum
cobalamin values continued to increase throughout the 4-month treatment period. In contrast, following a substantial increase after 1 month of
intramuscular therapy, the mean serum cobalamin in the parenteral group
decreased at 2 months and remained essentially the same at 4 months.
Serum cobalamin levels were significantly higher in the oral than the
parenteral group at 2 months (643 ± 328 v 306 ± 118 pg/mL; P < .001). The difference was more than threefold at 4 months (1,005 ± 595 v 325 ± 165 pg/mL;
P < .0005). The 95% confidence intervals for the 4-month
serum cobalamin concentrations were 708 to 1,300 pg/mL in the oral
group and 230 to 420 pg/mL in the parenteral group.
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| Fig 1.
Mean serum cobalamin levels before and during 4 months of
therapy with cyanocobalamin. Bars indicate ± 1 SEM. At 2 and 4 months, mean serum cobalamin concentrations were significantly higher with oral therapy (P < .001 and P < .0005, respectively).
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In patients receiving oral therapy, all serum cobalamin concentrations
were obtained more than 24 hours after the last oral dose. All of the
cobalamin in serum was found to be bound to protein by coated-charcoal
assay.
In the parenteral group, the serum specimen at 1 month was obtained 9 days after the last of a series of six 1,000 µg injections; the
subsequent 2- and 4-month samples were collected 1 month after the most
recent 1,000 µg maintenance injection. The serum cobalamin concentration was normal (>200 pg/mL) in all subjects in the oral group at 1, 2, and 4 months and in all in the parenteral group at 1 month. However, the serum cobalamin was again low at 2 and 4 months in
3 and 4 patients receiving intramuscular therapy, respectively. At 4 months, the serum value was greater than 300 pg/mL in only one half of
the parenteral group compared with all of those receiving oral
cyanocobalamin (Tables 2, 4, and 5; P < .001).
Serum metabolite levels.
Elevated serum methylmalonic acid concentrations
(Fig 2) decreased to less than 3 SD above
the mean for normal controls during therapy in every patient except no.
4 (Table 2), in whom the serum creatinine was elevated. During oral
treatment, the serum methylmalonic acid decreased progressively over 4 months (Fig 2). In contrast, in the parenteral group, the nadir in the
serum concentration was usually reached at 1 month, with a subsequent modest rebound (Fig 2), so that the levels were significantly higher at
2 and 4 months than at 1 month in those receiving intramuscular injections (P < .001 and P < .05, respectively).
The methylmalonic acid value in patients no. 20 and 25, which had been
less than 3 SD above the mean for normal controls at 30 days, was
elevated by 4 months (Table 4); serum cobalamin concentrations had
decreased to low to borderline values in these 2 patients. Mean
concentrations of the metabolite (Fig 2) did not differ significantly
between the 2 treatment groups except at 4 months, when the value was higher in those receiving injections (P < .05).
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| Fig 2.
Mean serum methylmalonic acid concentrations before and
during 4 months of therapy with oral or parenteral cyanocobalamin. Bars
indicate ± SEM. At 4 months, methylmalonic acid concentrations were
signficantly lower with oral therapy (P < .05).
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Elevated serum total homocysteine concentrations decreased to normal in
most patients in both groups (Tables 2 and 4), decreasing progressively
over 4 months of oral therapy, in contrast to a more pronounced
decrease during the first month of injections (Fig 3). However, in a minority of patients
in both groups, the response of this metabolite was not optimal. At 4 months, serum homocysteine remained greater than 3 SD above the mean
for normal controls in patients no. 11 and 17 of the oral group and in
patients no. 27 and 28 receiving intramuscular therapy (Tables 2 and
4). All of these patients had achieved normal serum cobalamin and methylmalonic acid concentrations. Each gave a history consistent with
markedly decreased dietary folate intake associated with depression,
dementia, or alcoholism; in all except patient no. 11, the serum folate
was low or low normal. It was not possible to undertake a subsequent
trial of folic acid therapy in these patients. However, in a patient
with pernicious anemia as well as severe anorexia and depression, a
continued increase of serum homocysteine after 2 months of oral
cobalamin therapy responded to folic acid (patient no. 2 in Table 2 as
indicated in a footnote to Table 2).
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| Fig 3.
Mean serum total homocysteine concentrations before and
during cyanocobalamin therapy administered by mouth ( ) or by
injection (---). Bars indicate 1 standard error above or below
mean. The number of patients at each point is the same as in Fig 2.
Normal range indicates 2 SD above and below the mean in normal
controls. Mean values did not differ significantly between the 2 groups at any time point.
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Patients with primary folate deficiency.
After completion of the trial, 5 patients were considered to have
primary deficiency of folate rather than cobalamin and were excluded
from the analysis. At entry, each of them had low levels of both
cobalamin and folate; homocysteine values (but not those of
methylmalonic acid) were greater than 3 SD above the normal mean. None
had evidence of underlying atrophic gastritis. Four of the five gave a
history of depression, alcoholism, or malnutrition. During parenteral
or oral therapy, cobalamin levels became normal in all 5 patients, but
there were no hematologic responses. Homocysteine concentrations did
not normalize at 4 months (and actually increased during treatment in
4). In 1 of them who was available for subsequent study, the serum
homocysteine had increased from 28.1 µmol/L before therapy to 65.2 µmol/L after parenteral cyanocobalamin, at which time the serum
folate remained low at 1.8 ng/mL. After a 4-week course of 1 mg of
daily oral folic acid, the serum homocysteine concentration decreased
to 10.0 µmol/L as the serum folate concentration increased to 27.4 ng/mL.
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DISCUSSION |
This randomized controlled trial of oral versus intramuscular
cyanocobalamin in the treatment of well-documented cobalamin deficiency
demonstrated that oral and parenteral therapy were equally effective in
producing excellent hematologic and neurologic remissions, as well as
robust initial metabolic responses. Furthermore, an oral regimen of
2,000 µg per day resulted in serum cobalamin concentrations that were
more than 3 times greater than those obtained with a standard
parenteral schedule35 of nine 1,000 µg injections
administered over a 4-month period (Fig 1). Furthermore, the absorption
of the oral preparation was good in every patient, so that at 4 months
18 of 18 receiving oral therapy versus only 7 of 14 receiving
injections achieved serum cobalamin levels greater than 300 pg/mL, a
value below which metabolic evidence of cobalamin deficiency is
frequently demonstrated, especially in the elderly.23,36 Indeed, the lower vitamin concentrations in the parenteral group were
associated with slightly but significantly higher values for
methylmalonic acid, a metabolite that is frequently abnormal before
serum cobalamin levels become subnormal as deficiency of the vitamin
develops.21 The clinical importance of maintaining normal
serum cobalamin and metabolite levels is unclear; however, it is
reasonable to use a therapeutic preparation with the greatest overall
bioavailability, particularly if it enjoys high patient acceptability.
Serum homocysteine levels may be elevated in either Cbl or folate
deficiency.22,24 In the absence of an increased serum methylmalonic acid, an isolated increase in serum homocysteine is
usually caused by folate deficiency.22,37 It is of interest that 5 patients entered into the trial were later considered to have
primary folate deficiency. Although serum cobalamin levels were low,
only serum homocysteine was increased and did not respond to 4 months
of parenteral or oral cyanocobalamin (and even increased further in
most of the subjects). Others have reported that serum cobalamin levels
may often be low in patients with folate deficiency in the absence of
defects in cobalamin intake, absorption, or body stores, and have noted
increases in serum cobalamin after folate therapy
alone.38,39 Our findings are consistent with previous
reports that only specific therapy with the vitamin in which the
patient is truly deficient will normalize increased metabolite
levels.40,41
In addition, among the 33 patients reported here who had clear-cut
evidence of true cobalamin deficiency, despite impressive decreases in
serum methylmalonic acid and the achievement of normal to increased
serum cobalamin concentrations (Tables 2 and 4), 5 (3 on oral and 2 on
parenteral therapy) showed only partial serum homocysteine responses.
All gave a history consistent with folate deficiency, although 1 of
them (patient no. 2) also had unequivocal underlying pernicious anemia.
Thus, of 38 patients randomized into the study based on low serum
cobalamin and increased metabolite levels, 10 (26%) were found to have
folate deficiency as well, either primary or in association with lack
of cobalamin.
In summary, in a randomized, controlled trial, large daily oral doses
of cyanocobalamin were found equally effective in producing hematologic
and neurologic responses as a standard parenteral regimen in patients
with cobalamin deficiency and also resulted in clearly superior serum
cobalamin levels after 4 months of treatment. Slightly better control
of metabolic abnormalities was also achieved with the oral preparation.
Our findings, taken together with the extensive and convincing,
although uncontrolled, previous reports in the
literature,8-19,42 strongly support the view that high doses of oral cyanocobalamin can replace intramuscular therapy in most
situations in which the latter is currently administered. Large doses
of cyanocobalamin appear to be nontoxic.43 The costs of
either therapy are low, although the need for a health provider to
administer monthly injections often adds considerable
expense.5,44,45 It has been argued that patients are less
likely to be compliant with oral treatment,41 although
compliance has been reported to be very good.10,42 However,
any maintenance therapy is likely to be associated with neglect,
especially since today cobalamin injections are often administered
outside the physician's office by the patient, a relative, or a
friend. Of a large series of patients with pernicious anemia, 11%
interrupted parenteral therapy and suffered a relapse.46
Oral maintenance therapy has been widely used in Sweden for more than
25 years.5,10,44,47 In a series of 64 Swedish patients
maintained for several years on 1,000 µg/d, none relapsed or had a
low serum cobalamin level.10 The 2,000 µg dose used in
our study might therefore be considered overly generous, although it
may provide an element of safety in view of the wide range of serum
cobalamin concentrations found after 4 months (Table 2). Because the
various preparations of oral cyanocobalamin (as well as parenteral
cobalamin) are not regulated by the FDA, bioavailability may be
unpredictable. Use of oral preparations other than that used in this
study may not yield similar results. Compliance and effectiveness of
cobalamin therapy in individual patients can and should be checked
occasionally by measuring the serum cobalamin level either alone or
together with metabolite levels.
Undoubtedly, parenteral treatment will continue to play a role in the
treatment of cobalamin deficiency, particularly in hospitalized patients; in those with diarrhea, vomiting, or otherwise unable to take
medication by mouth; in the unreliable; and in patients with severe
neurologic involvement. In the initial treatment of the average
outpatient with mild to moderate deficiency or in patients who require
maintenance therapy, oral cyanocobalamin with a preparation of proven
bioavailability should be strongly considered, if not indeed viewed as
the regimen of choice.
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FOOTNOTES |
Submitted February 26, 1998;
accepted April 21, 1998.
Address correspondence to Robert H. Allen, MD, 4200 E 9th Ave, Box
B-170, Denver, CO 80220.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
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Abstract
Introduction
Abstract