11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

Official reprint from UpToDate®

www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Treatment of vitamin B12 and folate deficiencies

Authors: Robert T Means, Jr, MD, Kathleen M Fairfield, MD, DrPH
Section Editor: William C Mentzer, MD
Deputy Editors: Jennifer S Tirnauer, MD, Lisa Kunins, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2019. | This topic last updated: Sep 27, 2019.

INTRODUCTION

This topic reviews the treatment of vitamin B12 and folate deficiencies, including the route and duration of
therapy, monitoring, and expected hematologic and neurologic response.

Separate topic reviews discuss the clinical manifestations, diagnosis, causes, and pathophysiology of these
deficiencies:

● Clinical presentation and diagnosis – (See "Clinical manifestations and diagnosis of vitamin B12 and
folate deficiency".)
● Causes and pathophysiology – (See "Causes and pathophysiology of vitamin B12 and folate
deficiencies".)

GENERAL PRINCIPLES OF TREATMENT

All individuals with documented vitamin B12 and/or folate deficiency should be treated, unless there is a strong
reason not to do so (eg, palliative care setting or patient refusal). A number of general principles apply to both
vitamin B12 and folate deficiency. These are outlined below and in a 2014 guideline on the diagnosis and
treatment of vitamin B12 and folate deficiency from the British Committee for Standards in Haematology [1].

Urgency of correction — Most individuals with vitamin B12 or folate deficiency present asymptomatically with
an incidental laboratory finding or with the slow development of symptoms. Repletion of the deficient vitamin can
be instituted over a period of weeks in these instances. However, in certain cases it may be prudent to intervene
more urgently:

● Symptomatic anemia or neurologic or neuropsychiatric findings, due to the risk of adverse events and
irreversibility of neurologic deficits
● Pregnancy, as the developing fetus may be affected
● Neonates and infants, whose development may be impacted

In these cases, more urgent correction of the deficiency and more intensive monitoring are indicated. However,
there is no evidence of benefit from using a higher dose. Consultation with a specialist may be appropriate if
there is a question about the cause of the symptoms or the deficiency.

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 1/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

In extremely rare cases of severe deficiency with hemodynamic compromise due to severe anemia, blood
transfusion may be given [2,3]. Vitamin B12 and/or folic acid should also be administered as appropriate, but
these cannot be relied on for emergency therapy because improvements in red blood cell production take
several days to take effect. (See "Red blood cell transfusion in infants and children: Indications" and "Indications
and hemoglobin thresholds for red blood cell transfusion in the adult".)

Route of administration — Vitamin B12 and folic acid can be administered orally or parenterally. For vitamin
B12, formulations are available for intramuscular/deep subcutaneous injection and oral, sublingual, and nasal
administration. For folic acid, formulations are available for intravenous, intramuscular, and subcutaneous use,
as well as oral ingestion.

● Symptomatic patients – Initial parenteral administration (vitamin B12 or folic acid) is suggested for those
who have severe symptomatic anemia or any neurologic findings associated with deficiency. If appropriate,
these individuals can be switched to oral therapy after symptoms resolve. (See 'Treatment of vitamin B12
deficiency' below and 'Treatment of folate deficiency' below.)

● Impaired absorption – Parenteral vitamin B12 replacement is often used for those who do not have the
capacity to absorb oral replacement (eg, pernicious anemia, intestinal blind loop). The parenteral route is
usually well-tolerated, and medication adherence is assured. However, high-dose oral (or sublingual) vitamin
B12 therapy can also be effective for those with impaired absorption, provided that the dose is sufficient,
medication adherence is good, and a response is documented [1,2]. Evidence showing equivalence of
parenteral and high-dose oral therapy is presented below. (See 'Treatment of vitamin B12 deficiency' below.)

We generally do not use the intranasal formulations because of their variable absorption and higher cost;
these formulations may also cause rhinorrhea. Over-the-counter preparations of vitamin B12 designated as
"timed release" should be avoided [4].

● Dietary deficiency – Oral replacement (vitamin B12 or folic acid) is appropriate for those whose deficiency
is due to reduced dietary intake and who have the capacity to ingest and absorb oral supplements.

Individuals treated with parenteral vitamin B12 can be taught to self-administer the injections, often with good
results, minimal to no pain, and lower costs than office-based injection [3].

Available therapeutic preparations — The following formulations are available:

● Vitamin B12 (also called cobalamin) is available as cyanocobalamin, which contains a cyanide (CN) group
introduced during chemical synthesis and hydroxocobalamin. Cyanocobalamin is predominantly used in the
United States and hydroxocobalamin is predominantly used in Europe; both are effective in treating vitamin
B12 deficiency [5]. Of note, pharmacokinetics differ between these formulations, and as a result,
maintenance doses of cyanocobalamin are administered monthly; maintenance hydroxocobalamin is
administered less frequently (once every two to three months) [1,2].

● Folic acid is also called vitamin B9 and is the synthetic form of the vitamin, whereas folate is the form found
naturally in food. Folinic acid (also called leucovorin) is a naturally occurring form of reduced folate that is
primarily used to prevent toxicities of methotrexate; it is more expensive, and while it is effective for treating
folate deficiency, it not typically used for folate repletion in patients without a specific indication.

Other terms used for the physiologic forms of vitamin B12 and folate are presented separately. (See "Clinical
manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Terminology'.)

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 2/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

Duration of therapy — The duration of therapy depends on whether the initial cause of the deficiency persists.
Lifelong replacement is necessary for individuals with a condition that is not reversed (eg, gastric bypass surgery,
autoantibodies to intrinsic factor [pernicious anemia]). If the cause of the deficiency can be treated or eliminated
(eg, excessively restrictive diet, drug-induced deficiency, reversible cause of malabsorption), supplementation
can be discontinued after the deficiency is corrected.

Need for additional testing — Individuals with dietary deficiency of vitamin B12 and folate require education to
ensure that their diet and/or supplements contain sufficient vitamin levels but do not require additional testing.
The following additional testing may be appropriate once the diagnosis of vitamin B12 and/or folate deficiency
has been established:

● For individuals for whom the cause of deficiency is not clear, additional testing to determine the cause is
almost always indicated. This evaluation is presented separately. (See "Clinical manifestations and
diagnosis of vitamin B12 and folate deficiency", section on 'Post-diagnostic testing'.)

● Individuals with pernicious anemia appear to have an increased risk of gastrointestinal malignancy and may
have a higher prevalence of autoimmune disorders. We suggest increased surveillance and have a lower
threshold for evaluating gastrointestinal or other symptoms in these individuals. (See 'Additional
considerations for pernicious anemia (PA)' below.)

Adverse effects/overdose — Vitamin B12 and folate are water-soluble vitamins that are excreted when stores
are adequate. Rare cases of hypersensitivity or acneiform eruptions with vitamin B12 have been reported [1,2];
we have not seen these in our practice. Reports of serious adverse effects from administration or intake of
greater-than-recommended doses have not been observed. However, associations have been reported between
high folic acid intake and cancer risk, and between preconception folate supplementation higher than 1 mg/d and
incidence of developmental delay in newborns [6,7]. While association does not prove causation, in the absence
of a clinical indication it is prudent to avoid folate or B12 supplementation at levels significantly greater than the
recommended daily allowance. (See "Vitamin supplementation in disease prevention", section on 'Toxicity at high
doses'.)

We also do not advocate routine administration of vitamin B12 or folic acid supplements to groups of individuals
without documented deficiency who eat a varied diet. This practice is likely to incur excess costs and burdens
and could potentially mask underlying disorders. An exception is women who may become pregnant, for whom
routine folic acid supplementation is used to reduce the risk of neural tube defects. (See "Folic acid
supplementation in pregnancy".)

Certain populations are treated with routine supplementation due to their high risk of deficiency. (See 'Prevention
of vitamin B12 deficiency' below and 'Prevention of folate deficiency' below.)

VITAMIN B12

Prevention of vitamin B12 deficiency — Specific interventions to prevent vitamin B12 deficiency are
unnecessary in the vast majority of individuals who consume a varied diet. However, certain settings are
associated with an increased risk of deficiency:

● Vegan or vegetarian diet – Vitamin B12 is present in many animal-based foods but not in plant-derived
foods. Some vitamin B12 may be ingested from soil present on plants or from milk or eggs. However,
individuals who consume a vegan or strict vegetarian diet generally should take supplemental vitamin B12 to

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 3/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

ensure adequate stores. This is especially important in women who are pregnant or may become pregnant
since the developing fetus also requires adequate vitamin B12. Other nonvegetarian diets, such as the
Mediterranean diet, may not contain sufficient vitamin B12 in some cases [8,9]. Daily requirements and
recommended intake are discussed in more detail separately. (See "Vegetarian diets for children", section
on 'Vitamin B12' and "Healthy diet in adults", section on 'Micronutrients'.)

● Gastric or bariatric surgery – Many individuals who have had bariatric or other gastric surgery (eg,
subtotal gastrectomy for ulcer disease) will develop clinically significant vitamin B12 deficiency because they
have insufficient levels of intrinsic factor, which is produced by gastric parietal cells. Supplementation can be
provided by many routes, as listed in the table (table 1) and discussed separately. (See "Bariatric surgery:
Postoperative nutritional management".)

● Disorders of the small intestine – Disorders of the small intestine may be associated with vitamin B12
deficiency, depending on their chronicity and severity, because the vitamin B12-intrinsic factor complex is
absorbed in the distal ileum. Typically, individuals with these conditions are monitored periodically for vitamin
B12 deficiency rather than given routine supplementation. (See "Clinical manifestations and diagnosis of
vitamin B12 and folate deficiency", section on 'Vitamin B12 level (serum)'.)

● Neonates born to vitamin B12-deficient mothers – Infants born to mothers with vitamin B12 deficiency
are at risk for being born deficient and/or of becoming deficient if exclusively breastfed [10-13]. The best
means of preventing neonatal deficiency is to ensure that the mother is vitamin B12 replete during the
pregnancy and breastfeeding. If the neonate is discovered to be vitamin B12-deficient at birth, rapid
correction is indicated. (See "Overview of acquired peripheral neuropathies in children", section on 'Vitamin
B12 (cobalamin) deficiency'.)

● Nitrous oxide exposure – Individuals with prolonged or high-dose exposure to nitrous oxide (N2O) gas,
either as an inhalant anesthetic or as a drug of abuse, can develop rapid onset of vitamin B12 deficiency,
especially if their baseline levels of vitamin B12 are borderline. This occurs because N2O chemically
inactivates the vitamin B12-derived methylcobalamin molecule at the active site of methionine synthase [14].
This can lead to rapid neuropsychiatric deterioration and/or other complications.

In individuals with known vitamin B12 or folate deficiency undergoing anesthesia with N2O, we suggest close
monitoring with a complete blood count (CBC) perioperatively, along with evaluation of macrocytosis and/or
anemia as rapidly as is feasible to avoid this complication. (See "Causes and pathophysiology of vitamin
B12 and folate deficiencies", section on 'Nitrous oxide'.)

As noted above, oral supplementation is likely to be appropriate in these individuals. (See 'Route of
administration' above.)

Aging is not always associated with an increased risk for vitamin B12 deficiency. However, some older
individuals, particularly those with little dietary variation, may be near the threshold for deficiency and may be at
increased risk if they have gastric dysfunction or regularly use histamine-2 receptor antagonists or proton pump
inhibitors, which reduce gastric acid needed for optimal vitamin B12 absorption [14].

Additional discussion of pathophysiology and other less common conditions that predispose to vitamin B12
deficiency are discussed separately. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

Treatment of vitamin B12 deficiency — Vitamin B12 is available in several formulations and can be
administered by several routes, including intramuscular, deep subcutaneous, oral, or sublingual. (See 'Route of
administration' above.)
https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 4/19
11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

● Parenteral – The typical dose for children is 50 to 100 mcg parenterally once per week until the deficiency is
corrected and then once per month (cyanocobalamin) or once every other month (hydroxocobalamin); oral
doses in children are not well established [15]. The typical dose for adults is 1000 mcg parenterally once per
week until the deficiency is corrected and then once per month (cyanocobalamin) or once every other month
(hydroxocobalamin).

● Oral – In adults with normal absorption, oral dosing is equally effective at a dose of 1000 mcg orally once
per day. For individuals with impaired absorption of vitamin B12, therapy with very high oral doses of oral
vitamin B12 (eg, 1000 to 2000 mcg daily) will be effective as long as the dose is high enough to provide
absorption via a mechanism that does not require intrinsic factor or a functioning terminal ileum (ie, passive
diffusion/mass action) [14,16-18].

Intranasal administration is generally not used. Transdermal forms of vitamin B12 are available over the counter,
but this route of administration has not been validated clinically in the setting of vitamin B12 deficiency and
should not be relied upon for treatment.

Evidence regarding the relative efficacy of parenteral versus high-dose oral vitamin B12 comes from small
randomized trials and observational studies.

● A 2018 Cochrane review that included three small trials (153 participants in total) comparing oral versus
intravenous vitamin B12 in individuals with vitamin B12 deficiency suggested that both routes were effective
in raising vitamin B12 levels [19].

● A 2006 systematic review found data from two randomized trials (108 participants) that compared oral
versus intramuscular vitamin B12 and found that oral vitamin B12 at these doses was equivalent to or better
than intramuscular vitamin B12 for raising serum vitamin B12 levels, correcting anemia, and in one case,
resolving neuropsychiatric findings [20-22].

The following describes common approaches to treating patients with different causes of vitamin B12 deficiency:

● Pernicious anemia – Pernicious anemia (PA; vitamin B12 deficiency due to autoantibodies that inhibit
vitamin B12 absorption (see "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency",
section on 'Terminology')) is a potentially lifelong condition that prevents vitamin B12 absorption and thus is
usually treated with parenteral vitamin B12, which is typically administered by intramuscular or deep
subcutaneous injection at an initial dose of 1000 mcg (1 mg) once per week for four weeks, followed by
1000 mcg once per month. These doses have been found to be effective in observational studies [22,23].
Therapy is continued indefinitely. As noted above, high-dose oral vitamin B12 (1000 to 2000 mcg [1 to 2 mg]
daily) is also an option, provided there are no acute symptoms of anemia or neurologic complications and
adherence is assured.

● Altered gastrointestinal anatomy – Alterations in gastrointestinal anatomy that affect production of intrinsic
factor or absorption of the intrinsic factor-vitamin B12 complex include bariatric surgery, gastrectomy, ileal
loop syndrome, and others. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

If the alteration is permanent, then indefinite treatment with parenteral vitamin B12 is usually appropriate. If
the alteration is reversed, then therapy may be discontinued, although it is reasonable to check the vitamin
B12 level several months after stopping therapy. We often check the level three or four times during the first
year off of therapy. (See 'Intensity of and duration of monitoring' below.)

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 5/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

● Dietary deficiency – Individuals with diets that lack vitamin B12 (eg, vegans, vegetarians, infants
exclusively breastfed by vitamin B12-deficient mothers) are expected to have normal absorption via the oral
route and can be treated with oral supplements that provide the recommended amount. (See "Vitamin
supplementation in disease prevention", section on 'Vitamin B12 (cobalamin)'.)

● Concerning symptoms – Some individuals with symptomatic anemia, neurologic or neuropsychiatric

findings, or pregnancy (in which the developing fetus may be deprived of vitamin B12) may benefit from
more aggressive repletion. For these symptomatic patients or those with greater urgency for correction, we
suggest initial administration of parenteral vitamin B12 since this ensures rapid absorption and compliance.
However, data are limited as to whether correction of the deficiency occurs more rapidly or long-term
complications are reduced with parenteral versus oral therapy, as discussed below. These individuals may
be treated with 1000 mcg of vitamin B12 every other day initially for approximately two weeks, followed by
administration once monthly (cyanocobalamin) or once every two to three months (hydroxocobalamin) [1].
Once the initial deficiency has been corrected, it would be reasonable to switch to oral administration if the
patient preferred the oral route, as long as individuals with impaired absorption are given high enough doses
to ensure adequate serum levels.

● Lack of access to parenteral administration or patient preference – Some individuals may not have
access to parenteral vitamin B12, particularly those residing in resource-limited settings, and some
individuals may prefer to use an oral or sublingual vitamin B12 preparation. In these cases, it is reasonable
to use the formulation that is available or that the patient prefers, as long as the dose is appropriate.
Sublingual vitamin B12 replacement has not been studied extensively, but data from small studies suggest
that therapy is effective as long as the dose is sufficient [2,24,25]. We often check vitamin B12 levels three
to four times during the first year of therapy. Some experts will give the initial dose parenterally to ensure
absorption [14].

● Possible issues with medication adherence – Some individuals may have more difficulty adhering to daily
oral medication. In these cases, monthly vitamin B12 injections ensures adequate adherence.

The typical response and our approach to monitoring are discussed below. (See 'Assessing and monitoring
response to treatment' below.)

Additional considerations for pernicious anemia (PA) — In addition to lifelong treatment of vitamin B12
deficiency (see 'Treatment of vitamin B12 deficiency' above), individuals with PA may require additional
evaluations and/or a lower threshold for evaluating symptoms of related conditions:

● Gastrointestinal malignancy – PA is associated with an increased risk of gastrointestinal malignancy

(carcinoma, carcinoid tumors) for which screening may be appropriate [26]. In a 2013 systematic review that
included 27 studies on the association of PA with gastric cancer, the pooled incidence rate for gastric cancer
was 0.27 percent per patient-year; the relative risk compared with individuals without PA was 6.8 (95% CI
2.6-18.1) [27]. A 2015 population-based case control study of older individuals (ages 66 to 69 years) in the
United States found increased odds ratios (ORs) for gastric adenocarcinoma (OR 2.2, 95% CI 1.9-2.5);
gastric carcinoid (OR 11.4, 95% CI 8.9-14.7); small intestinal cancer (OR 1.6, 95% CI 1.3-2.0); and some
non-gastrointestinal malignancies [28]. The association of PA with gastrointestinal malignancies outside the
stomach (eg, colon) is less clear [29,30].

A 1995 American Society of Gastrointestinal Endoscopy guideline has recommended that individuals with
PA should undergo upper gastrointestinal endoscopy soon after PA diagnosis and/or if they develop
gastrointestinal symptoms [31]. This is consistent with our practice. However, a support-group-based survey
https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 6/19
11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

of patients with PA found that only approximately one-fourth had undergone endoscopic screening [32].
There are insufficient data to support routine surveillance with upper endoscopy following an initial screening
in the absence of symptoms or to alter the patient's schedule for colon cancer screening based on the
diagnosis of PA.

● Other autoimmune disorders – There may be higher prevalence of other autoimmune disorders in
individuals with PA, although there is very little high-quality evidence regarding such a risk. We do not
specifically test for these conditions in the absence of symptoms, but we ensure that age-appropriate
preventive care is performed and maintain a low threshold for considering autoimmune causes of symptoms
and evaluating as appropriate. (See "Preventive care in adults: Recommendations" and "Evidence-based
approach to prevention".)

Individuals without documented vitamin B12 deficiency — With the exception of the preventive use of
vitamin B12 in certain populations (see 'Prevention of vitamin B12 deficiency' above), we do not advocate routine
administration of vitamin B12 to individuals without documented deficiency. We are aware that injections of
vitamin B12 are used in the absence of deficiency by some practitioners. There are no data to support this
practice, and it represents low-value care. Despite our skepticism, some experts have advocated possible
supplementation in healthy adults [3].

FOLATE

Prevention of folate deficiency — Folate deficiency has become uncommon in individuals residing in countries
that provide routine fortification of grains and cereals with folic acid. However, individuals with the following
conditions may be at increased risk of developing folate deficiency:

● Gastrointestinal disorders that prevent absorption of dietary folates in the duodenum (eg, bariatric surgery)
● Severe malnutrition, restrictive diets, or reduced oral intake
● Chronic excessive alcohol use, which may be associated with chronic malnutrition and increased metabolic
needs
● Reduced intake of green leafy vegetables if residing in a country where cereals and grains are not routinely
supplemented with folic acid
● Chronic hemolytic anemia with increased red blood cell turnover
● Other conditions associated with high cellular turnover such as severe eczema

In these cases, oral folic acid at a dose of 1 mg daily is typically sufficient to prevent deficiency from developing.

Folate is also required during early embryogenesis for neural tube formation, and routine folic acid
supplementation is used during pregnancy to reduce the risk of neural tube defects. This subject is discussed in
detail separately. (See "Folic acid supplementation in pregnancy".)

Goat milk is low in folate, and infants fed exclusively goat milk may not receive adequate folic acid [33,34]. Some
powdered goat milk is supplemented with folic acid but use of a commercial infant formula is preferable. (See
"Dietary recommendations for toddlers, preschool, and school-age children".)

Antimetabolites such as methotrexate act by reducing intracellular folates and cause a predictable megaloblastic
anemia. In many cases, when these drugs are used to treat nonmalignant conditions, a source of folate is
provided (eg, folic acid, folinic acid). Disease-specific prescribing information should be followed. Folinic acid
(leucovorin) rescue after high-dose methotrexate for acute lymphoblastic leukemia and other hematologic

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 7/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

malignancies is discussed separately. (See "Major side effects of low-dose methotrexate" and "Therapeutic use
and toxicity of high-dose methotrexate".)

Additional discussion of pathophysiology and other less common conditions that predispose to folate deficiency
are discussed separately. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies".)

Treatment of folate deficiency — Folate deficiency is typically treated with oral folic acid (1 to 5 mg daily) [1].
This dose is usually sufficient even if malabsorption is present, because it is considerably in excess of the 200
mcg (0.2 mg) recommended dietary allowance (table 2). (See "Vitamin supplementation in disease prevention",
section on 'Folic acid'.)

For those with a reversible cause of deficiency, therapy is generally given for one to four months or until there is
laboratory evidence of hematologic recovery. For those with a chronic cause of folate deficiency, therapy may be
given indefinitely.

Intravenous folic acid may be appropriate in certain settings, such as individuals who are unable to take an oral
medication (eg, due to vomiting or obtundation) or those who have severe or symptomatic anemia due to folate
deficiency and hence have a more urgent need for rapid correction.

It is important to be aware that administration of folic acid can partially reverse some of the hematologic
abnormalities associated with vitamin B12 deficiency; however, the neurologic manifestations of vitamin B12
deficiency are not treated by folic acid. Thus, administration of folic acid to an individual with vitamin B12
deficiency can potentially mask untreated vitamin B12 deficiency or even worsen the neurologic complications
(the latter for reasons that are not entirely clear) [35]. Because of this, testing for (and treatment of) vitamin B12
deficiency may be appropriate in certain patients being treated with folic acid:

● Test for vitamin B12 deficiency in individuals with suspected folate deficiency, those with folate deficiency
whose anemia and/or macrocytosis does not resolve with folic acid treatment, and/or those who develop
new neurologic symptoms upon treatment with folic acid.

● Administer vitamin B12 to individuals with megaloblastic anemia who are being treated with folic acid before
results of vitamin B12 testing are available.

● Administer vitamin B12 to individuals with folate deficiency who develop neurologic symptoms after
treatment with folic acid. Ideally, testing for vitamin B12 deficiency is also sent, but administration of vitamin
B12 should not be delayed while awaiting the results.

Some experts advocate repeat testing for vitamin B12 deficiency in patients receiving long-term folic acid,
especially if hematologic (eg, macrocytic anemia, increasing levels of serum lactate dehydrogenase) and/or
neurologic worsening occur [36].

Individuals without documented folate deficiency — With the exception of the preventive use of folic acid in
certain populations (see 'Prevention of folate deficiency' above), we do not advocate routine administration of
folic acid to individuals without documented deficiency.

The use (or avoidance) of folic acid supplementation to individuals without folate deficiency to reduce the risks of
cancer and heart disease are discussed separately. (See "Vitamin supplementation in disease prevention",
section on 'Folic acid'.)

ASSESSING AND MONITORING RESPONSE TO TREATMENT

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 8/19
11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

Typical response — A hematologic response to vitamin B12 and/or folic acid should occur within a predictable
timeframe as below, provided that the bone marrow is functioning normally and there are no other causes of
anemia.

The following laboratory changes are seen [2,3]:

● Markers of hemolysis (eg, lactate dehydrogenase [LDH] and indirect bilirubin) decline within the first one to
two days.
● Evidence of new red blood cell production (increases in the reticulocyte count) occurs within three to four
days.
● Anemia (low hemoglobin and hematocrit) starts to improve at approximately one to two weeks and
normalizes within four to eight weeks.
● Some individuals can develop hypokalemia during the initial week of treatment as there is marked potassium
uptake during production of new blood cells, but this is unlikely to be clinically significant [2].
● Hypersegmented neutrophils disappear within approximately two weeks (10 to 14 days).
● Leukopenia and/or thrombocytopenia resolve within two to four weeks (if they were present).
● Serum folate and/or vitamin B12 levels increase into the normal range.

Neuropsychiatric improvement after treatment of vitamin B12 deficiency often occurs over a longer period of time
(eg, starting within approximately three months and continuing to improve for as long as one year). Some experts
report transient worsening of neurologic symptoms before improvement [3]. However, some neurologic findings
may be irreversible, especially if they have been present for a long time before the deficiency was corrected [37].
In a 1991 series involving 121 individuals with vitamin B12 deficiency with neurologic findings, all had some
neurologic improvement, to a degree that was inversely related to the extent and duration of disease [38].
Neurologic recovery was complete in 57 (47 percent), and only 7 (6 percent) had residual long-term moderate to
severe neurologic disability.

Neurologic findings may recur more rapidly than hematologic findings in individuals with pernicious anemia who
have been treated, recovered, and then discontinued vitamin B12 supplementation (eg, neurologic findings may
return within six months, whereas megaloblastic anemia may take years to recur) [3].

Intensity of and duration of monitoring — The intensity of monitoring for hematologic and/or neurologic
improvement depends on the severity of symptoms and other considerations. As examples:

● For a person with concerning neurologic or neuropsychiatric findings or symptoms related to cytopenias (eg,
shortness of breath from anemia, bleeding with thrombocytopenia), we monitor more aggressively so that
we may intervene if the response is not occurring. This might involve daily testing of the complete blood
count (CBC) for hospitalized patients and testing the vitamin B12 or folate level in one to two days.

● For a pregnant woman with vitamin B12 or folate deficiency, concerns about fetal deficiency may warrant
more rapid testing (eg, within a few days) to ensure that the vitamin has been absorbed. The urgency of
correction is also greater during pregnancy. (See 'Urgency of correction' above.)

● An individual with an incidental finding of deficiency presenting as mild macrocytosis and/or mild anemia
could have a repeat CBC and measurement of the deficient vitamin (eg, vitamin B12 and/or folate level,
methylmalonic acid [MMA] and/or homocysteine if appropriate) at two to four weeks.

If the individual is receiving oral therapy and there is concern about adequate absorption, it may be
appropriate to monitor these parameters more frequently until it is clear that improvement is occurring.

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=sea… 9/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

Additional testing may be required if the individual reports lack of response (or worsening) in the expected time
frame. This may include earlier testing of the CBC, vitamin B12 or folate level, or metabolites (MMA and
homocysteine) and/or testing for other causes of anemia or neuropsychiatric findings. (See "Clinical
manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Differential diagnosis'.)

Monitoring should continue until a complete response has been documented. For those with a cause of
deficiency that is known to have been eliminated, subsequent testing may not be necessary. However, it may be
prudent to reevaluate the CBC and/or vitamin B12 or folate level within 3 to 12 months after stopping therapy.

Approach to lack of response — A delayed or incomplete response suggests that the vitamin was not taken or
was not absorbed, or that the original diagnosis was inaccurate or incomplete. In cases in which the expected
response is not seen, the following is appropriate:

● Verify that the correct vitamin was taken.

● Switch from oral to parenteral therapy if there are concerns about absorption (eg, possible pernicious
anemia incorrectly diagnosed as dietary lack of vitamin B12) or adherence. (See 'Available therapeutic
preparations' above.)

● Repeat the diagnostic testing. (See "Clinical manifestations and diagnosis of vitamin B12 and folate
deficiency".)

● Perform additional testing for other causes of anemia or other findings (eg, test for concomitant iron or
copper deficiency, infection, hypothyroidism, and/or a myelodysplastic syndrome). The specific testing
depends on the characteristics of the anemia and the patient history and examination. (See "Approach to the
child with anemia" and "Approach to the adult with anemia" and "Anemia in the older adult".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics
patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the
four or five key questions a patient might have about a given condition. These articles are best for patients who
want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education
pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are comfortable with some medical
jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Vitamin B12 deficiency and folate (folic acid) deficiency (The Basics)"
and "Patient education: Pernicious anemia (The Basics)" and "Patient education: How to plan and prepare
for a healthy pregnancy (The Basics)" and "Patient education: Epilepsy and pregnancy (The Basics)" and
"Patient education: Nutrition before and during pregnancy (The Basics)" and "Patient education: Vitamin
supplements (The Basics)")

● Beyond the Basics topics (see "Patient education: Inflammatory bowel disease and pregnancy (Beyond the
Basics)" and "Patient education: Nausea and vomiting of pregnancy (Beyond the Basics)")

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 10/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

SUMMARY AND RECOMMENDATIONS

● All individuals with documented vitamin B12 and/or folate deficiency should be treated. There are several
available formulations and possible routes of administration. The choice among these, as well as other
considerations (duration of therapy, additional testing) depend on the underlying cause of the deficiency and
urgency with which it needs to be corrected. (See 'General principles of treatment' above.)

● Individuals at risk for vitamin B12 deficiency (eg, vegan or strict vegetarian diet, gastric or bariatric surgery)
should receive oral vitamin B12 supplements. (See 'Prevention of vitamin B12 deficiency' above.)

● Vitamin B12 deficiency may be treated with oral or parenteral vitamin B12.

• For patients with vitamin B12 deficiency who have concerning symptoms (eg, severe or symptomatic
anemia, neuropsychiatric findings), we suggest parenteral rather than oral vitamin B12 (Grade 2C). This
ensures rapid absorption and compliance, although improvements in anemia and neuropsychiatric
findings may be equivalent with oral administration. (See 'Treatment of vitamin B12 deficiency' above.)

• The dose is 1000 mcg by deep subcutaneous or intramuscular injection once weekly for one month
followed by 1000 mcg once per month.

• Oral (or sublingual) vitamin B12 are effective alternatives if adherence is not a concern. If oral vitamin
B12 is used in individuals with impaired absorption, the dose is 1000 to 2000 mcg daily.

• Pernicious anemia (PA) and other chronic causes of deficiency are treated indefinitely. Individuals with
PA are at increased risk for gastrointestinal malignancy. We perform a one-time upper gastrointestinal
endoscopy soon after PA diagnosis and/or if the individual develops gastrointestinal symptoms. (See
'Additional considerations for pernicious anemia (PA)' above.)

● Individuals at risk for folate deficiency (eg, malnutrition, chronic alcohol use, chronic hemolytic anemia)
should receive folic acid supplementation (typical dose, 1 mg orally per day). We do not advocate routine
folic acid supplementation for the general population. Folic acid supplementation in pregnancy is discussed
separately. (See 'Prevention of folate deficiency' above and 'Individuals without documented folate
deficiency' above and "Folic acid supplementation in pregnancy".)

● Folate deficiency is typically treated with oral folic acid (1 to 5 mg daily). Therapy is generally given for one
to four months or until there is laboratory evidence of hematologic recovery, or indefinitely for those with a
chronic cause of folate deficiency. Intravenous folic acid may be appropriate for individuals who are unable
to take an oral medication or those who require more urgent correction. Testing and/or treatment for vitamin
B12 deficiency may be appropriate for some patients. (See 'Treatment of folate deficiency' above.)

● The typical response to correction of vitamin B12 and/or folate deficiency includes an initial reticulocytosis
over one to two weeks followed by resolution of anemia in four to eight weeks. Resolution of
neuropsychiatric changes in those with vitamin B12 deficiency may take longer and may be incomplete,
especially in those with more severe and/or longstanding deficits. Monitoring for a response to therapy
should be tailored to the patient's symptoms and other factors (eg, more intensive monitoring in pregnant
women). If the expected response does not occur, additional testing for other causes of the patient's findings
may be indicated. (See 'Assessing and monitoring response to treatment' above.)

● Causes of vitamin B12 and folate deficiency and our approach to diagnostic testing are discussed in detail in
separate topic reviews. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies" and
https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 11/19
11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

"Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

ACKNOWLEDGMENT

We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at
UpToDate gratefully acknowledge Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-
Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Devalia V, Hamilton MS, Molloy AM, British Committee for Standards in Haematology. Guidelines for the
diagnosis and treatment of cobalamin and folate disorders. Br J Haematol 2014; 166:496.

2. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood 2008; 112:2214.

3. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med 2013; 368:149.

4. Solomon LR. Oral vitamin B12 therapy: a cautionary note. Blood 2004; 103:2863.

5. Sugrue A. Author's reply to Charkin. BMJ 2014; 349:g5391.

6. Kim YI. Folate and cancer: a tale of Dr. Jekyll and Mr. Hyde? Am J Clin Nutr 2018; 107:139.

7. Valera-Gran D, Navarrete-Muñoz EM, Garcia de la Hera M, et al. Effect of maternal high dosages of folic
acid supplements on neurocognitive development in children at 4-5 y of age: the prospective birth cohort
Infancia y Medio Ambiente (INMA) study. Am J Clin Nutr 2017; 106:878.

8. Balcı YI, Ergin A, Karabulut A, et al. Serum vitamin B12 and folate concentrations and the effect of the
Mediterranean diet on vulnerable populations. Pediatr Hematol Oncol 2014; 31:62.

9. Carmel R, Mallidi PV, Vinarskiy S, et al. Hyperhomocysteinemia and cobalamin deficiency in young Asian
Indians in the United States. Am J Hematol 2002; 70:107.

10. Antony AC. Vegetarianism and vitamin B-12 (cobalamin) deficiency. Am J Clin Nutr 2003; 78:3.

11. Centers for Disease Control and Prevention (CDC). Neurologic impairment in children associated with
maternal dietary deficiency of cobalamin--Georgia, 2001. MMWR Morb Mortal Wkly Rep 2003; 52:61.

12. Grattan-Smith PJ, Wilcken B, Procopis PG, Wise GA. The neurological syndrome of infantile cobalamin
deficiency: developmental regression and involuntary movements. Mov Disord 1997; 12:39.

13. Renault F, Verstichel P, Ploussard JP, Costil J. Neuropathy in two cobalamin-deficient breast-fed infants of
vegetarian mothers. Muscle Nerve 1999; 22:252.

14. Green R. Vitamin B12 deficiency from the perspective of a practicing hematologist. Blood 2017.

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 12/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

15. Carmel R, Watkins D, Rosenblatt DS. Megaloblastic anemia. In: Nathan and Oski's hematology and oncolo
gy of infancy and childhood, 8th ed, Orkin SH, Fisher DE, Ginsburg D, et al (Eds), Elsevier Saunders, Phila
delphia 2015. Vol 1, p.308.

16. Hathcock JN, Troendle GJ. Oral cobalamin for treatment of pernicious anemia? JAMA 1991; 265:96.

17. Eussen SJ, de Groot LC, Clarke R, et al. Oral cyanocobalamin supplementation in older people with
vitamin B12 deficiency: a dose-finding trial. Arch Intern Med 2005; 165:1167.

18. Rajan S, Wallace JI, Brodkin KI, et al. Response of elevated methylmalonic acid to three dose levels of oral
cobalamin in older adults. J Am Geriatr Soc 2002; 50:1789.

19. Wang H, Li L, Qin LL, et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.
Cochrane Database Syst Rev 2018; 3:CD004655.

20. Kuzminski AM, Del Giacco EJ, Allen RH, et al. Effective treatment of cobalamin deficiency with oral
cobalamin. Blood 1998; 92:1191.

21. Bolaman Z, Kadikoylu G, Yukselen V, et al. Oral versus intramuscular cobalamin treatment in megaloblastic
anemia: a single-center, prospective, randomized, open-label study. Clin Ther 2003; 25:3124.

22. Butler CC, Vidal-Alaball J, Cannings-John R, et al. Oral vitamin B12 versus intramuscular vitamin B12 for
vitamin B12 deficiency: a systematic review of randomized controlled trials. Fam Pract 2006; 23:279.

23. Glass GB, Skeggs HR, Lee DH. Hydroxocobalamin. V. Prolonged maintenance of high vitamin B12 blood
levels following a short course of hydroxocobalamin injections. Blood 1966; 27:234.

24. Delpre G, Stark P, Niv Y. Sublingual therapy for cobalamin deficiency as an alternative to oral and
parenteral cobalamin supplementation. Lancet 1999; 354:740.

25. Slot WB, Merkus FW, Van Deventer SJ, Tytgat GN. Normalization of plasma vitamin B12 concentration by
intranasal hydroxocobalamin in vitamin B12-deficient patients. Gastroenterology 1997; 113:430.

26. Hsing AW, Hansson LE, McLaughlin JK, et al. Pernicious anemia and subsequent cancer. A population-
based cohort study. Cancer 1993; 71:745.

27. Vannella L, Lahner E, Osborn J, et al. Systematic review: gastric cancer incidence in pernicious anaemia.
Aliment Pharmacol Ther 2013; 37:375.

28. Murphy G, Dawsey SM, Engels EA, et al. Cancer Risk After Pernicious Anemia in the US Elderly
Population. Clin Gastroenterol Hepatol 2015; 13:2282.

29. Talley NJ, Chute CG, Larson DE, et al. Risk for colorectal adenocarcinoma in pernicious anemia. A
population-based cohort study. Ann Intern Med 1989; 111:738.

30. Boursi B, Mamtani R, Haynes K, Yang YX. Pernicious anemia and colorectal cancer risk - A nested case-
control study. Dig Liver Dis 2016; 48:1386.

31. Minoli G, Prada A, Gambetta G, et al. The ASGE guidelines for the appropriate use of upper
gastrointestinal endoscopy in an open access system. Gastrointest Endosc 1995; 42:387.

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 13/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

32. Pritchard DM, Hooper M. Letter: gastric cancer and pernicious anaemia--only a minority of UK pernicious
anaemia patients have had a gastroscopy. Aliment Pharmacol Ther 2016; 43:1106.

33. Turck D. Cow's milk and goat's milk. World Rev Nutr Diet 2013; 108:56.

34. Alférez MJ, Rivas E, Díaz-Castro J, et al. Folic acid supplemented goat milk has beneficial effects on
hepatic physiology, haematological status and antioxidant defence during chronic Fe repletion. J Dairy Res
2015; 82:86.

35. Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with
increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci U S A 2007;
104:19995.

36. Dhar M, Bellevue R, Carmel R. Pernicious anemia with neuropsychiatric dysfunction in a patient with sickle
cell anemia treated with folate supplementation. N Engl J Med 2003; 348:2204.

37. Vasconcelos OM, Poehm EH, McCarter RJ, et al. Potential outcome factors in subacute combined
degeneration: review of observational studies. J Gen Intern Med 2006; 21:1063.

38. Healton EB, Savage DG, Brust JC, et al. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore)
1991; 70:229.

Topic 7154 Version 54.0

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 14/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

GRAPHICS

Micronutrient management after bariatric surgery [1]

Preoperative Postoperative Symptoms of

RDA [2] Supplementation Repletion
prevalence prevalence deficiency

Vitamin Up to 17% [3] 8 to 11% after Early signs: Men: 900 LAGB: 5000 IU daily Without corneal
A [1,3] RYGB Night blindness mcg (3000 RYGB or SG: 5000 to changes: 10,000
70% after BPD/DS Bitot's spots IU) 10,000 IU daily to 25,000 IU daily
Women: orally until clinical
Hyperkeratinization BPD/DS: 10,000 IU
700 mcg improvement (1 to
of skin daily
(2300 IU) 2 weeks)
Loss of taste
With corneal
Advanced signs: changes: 50,000
to 100,000 IU
Corneal damage
daily IM for 3
Blindness
days, followed by
50,000 IU daily IM
for 2 weeks

Vitamin D 25 to 68% 25 to 80% Hypocalcemia, tetany, General: 3000 IU D3 daily from 3000 to 6000 IU of
tingling, cramping, 600 IU all sources to maintain D3 daily
metabolic bone disease, Pregnancy, a 25(OH)D level of (preferred), or
muscle pain lactation, >30 ng/mL 50,000 IU of D2 1
or over 71 to 3 times per
years of week
age: 800
IU

Vitamin E 2.2% Uncommon Neuromuscular disorders General: Adults and adolescents 90 to 300 mg (100
and hemolysis 15 mg 14 or older: 15 mg to 400 IU) daily
(22.4 IU) (22.4 IU) daily
Lactation: Lactation: 19 mg (28.4
19 mg IU) daily
(28.4 IU)

Vitamin K Uncommon Uncommon Impaired coagulation 90 to 120 LAGB, RYGB, or SG: Acute
mcg 90 to 120 mcg daily malabsorption: 10
BPD/DS: 300 mcg mg of parenteral
daily vitamin K
Chronic
malabsorption: 1
to 2 mg per day
orally or 1 to 2 mg
per week
parenterally

Vitamin B1 16 to 29% 1 to 49% Numbness, tingling in 1.5 mg >12 mg daily, Oral: 100 mg
(Thiamine) extremities, gait ataxia, preferably 50 to 100 three times daily
edema, vomiting, mg daily from a B- until symptoms
confusion complex supplement resolve
Wernicke-Korsakoff With IV hydration, 100 Intravenous: 200
syndrome: mg of thiamine should mg three times
Encephalopathy be added to the daily to 500 mg
Ataxia solution (should not once or twice daily
contain glucose if for 3 to 5 days,
Oculomotor
Wernicke followed by 250
dysfunction
encephalopathy is mg daily for 3 to 5
Confabulation
suspected) days, and
Impaired memory
subsequent oral
Impaired learning maintenance (100
mg daily)
Beriberi: indefinitely
Neuropathy Intramuscular:
Pain 250 mg daily for 3
Paresthesia to 5 days, or 100
Loss of reflexes to 250 mg
monthly

Vitamin 0 to 18% 33% after RYGB; 4 Macrocytic 2.4 mcg Oral dose of 350 to 1000 to 2000 mcg
B12 to 20% after SG (megaloblastic) anemia, 500 mcg daily, or 1000 daily until the level
mild pancytopenia, is normalized, then

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 15/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate
neuropsychiatric findings mcg IM or SQ monthly, resume
(eg, depression, or by nasal spray maintenance dose
neuropathy)

Folate 0 to 54% Up to 65% after Macrocytic 400 mcg General: 400 to 800 1000 mcg daily
RYGB; 18% after (megaloblastic) anemia, mcg daily until the level is
SG mild pancytopenia, Women of childbearing normalized, then
neural tube defects age: 800 to 1000 mcg resume
daily maintenance dose

Should not exceed 1

mg per day

Iron 0 to 58% LAGB 14%, SG Anemia Men ages Males, post- Oral: 150 to 300
<18%, RYGB 20 to Pica 19 and menopausal women, mg 2 to 3 times a
55%, BPD 13 to older and and patients without day
Impaired learning
62%, DS 8 to 50% women history of anemia: 18 Parenteral iron for
ages 51 mg of iron from a those who do not
and older: multivitamin respond to oral
8 mg per Menstruating women supplementation
day and men or women
Women who have undergone
between RYGB, SG, or BPD/DS:
the ages >45 to 60 mg of
of 19 to elemental iron daily
50: 18 mg from all sources*
per day

Zinc 24 to 28% 70% after Growth retardation, Women: 8 BPD/DS: 16 to 22 mg Optimal repletion
overall; 9 to 74% BPD/DS, 40% delayed sexual maturity, mg (200% RDA) dose unknown
seeking BPD/DS after RYGB, 19% impotence, impaired Men: 11 RYGB: 8 to 22 mg Overdose can be
after SG, 34% immune function mg (100 to 200% RDA) associated with
after LAGB toxicity or copper
SG or LAGB: 8 to 11
mg (100% RDA) deficiency

Maintain a ratio of 8 to
15 mg of zinc per 1 mg
of copper

Copper 68% in women 90% after Anemia, neutropenia, 900 mcg BPD/DS or RYGB: 2 Mild-to-moderate
seeking BPD BPD/DS, 10 to ataxia mg daily (200% RDA) deficiency: 3 to 8
20% after RYGB SG or LAGB: 1 mg mg copper orally
daily (100% RDA) until levels
normalize
Maintain a ratio of 8 to
15 mg of zinc per 1 mg Severe deficiency:
of copper 2 to 4 mg
intravenous copper
for 6 days or until
symptoms resolve

Selenium 2% 14 to 22% after Skeletal muscle 55 mcg Unknown but likely 2 mcg/kg/day in
RYGB and BPD/DS dysfunction and higher than 100 patients who
cardiomyopathy, mood mcg/day [4] develop
disorder, impaired cardiomyopathy [5]
immune function,
macrocytosis

Calcium 1 to 10% [6] 3.6% after Bone disease, secondary 1000 to RYGB, SG, or LAGB: RYGB, SG, or
bariatric surgery hyperparathyroidism 1200 mg 1200 to 1500 mg daily LAGB: 1200 to
(1.9% after RYGB, in divided doses 1500 mg daily in
9.3% after SG, BPD/DS: 1800 to 2400 divided doses
and 10% after mg daily in divided BPD/DS: 1800 to
BPD/DS) doses 2400 mg daily in
divided doses

RDA: Recommended Daily Allowance; RYGB: Roux-en-Y gastric bypass; BPD/DS: biliopancreatic diversion with duodenal switch; IU:
international unit; LAGB: laparoscopic adjustable gastric band; SG: sleeve gastrectomy; IM: intramuscular; IV: intravenous; SQ:
subcutaneous.

References:
1. Parrott J, Frank L, Rabena R, et al. American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for
the Surgical Weight Loss Patient 2016 Update: Micronutrients. Surg Obes Relat Dis 2017; 13:727.
2. U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020 Dietary Guidelines for Americans,
8th Edition, December 2015. Available at: http://health.gov/dietaryguidelines/2015/guidelines/ (Accessed on July 27, 2017).
3. Stein J, Stier C, Raab H, Weiner R. Review article: The nutritional and pharmacological consequences of obesity surgery. Aliment
Pharmacol Ther 2014; 40:582.

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 16/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate
4. Institute of Medicine (U.S.). Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin
E, Selenium, and Carotenoids, National Academy Press, Washington DC 2000.
5. Al-Matary A, Hussain M, Ali J. Selenium: a brief review and a case report of selenium responsive cardiomyopathy. BMC Pediatr 2013;
13:39.
6. Shah M, Sharma A, Wermers RA, et al. Hypocalcemia after bariatric surgery: Prevalence and associated risk factors. Obes Surg 2017.

Graphic 114101 Version 2.0

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 17/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

Dietary Reference Intakes (DRIs): Recommended dietary allowances and adequate intakes of
several vitamins

Female Male
Source Child Female Male Female Male
14 to 14 to
of goal* 1 to 3 4 to 8 4 to 8 9 to 13 9 to 13
18 18

Vitamins

Vitamin A, mg RAE RDA 300 400 400 600 600 700 900

Vitamin E, mg AT RDA 6 7 7 11 11 15 15

Vitamin D, RDA 600 600 600 600 600 600 600

international units

Vitamin C, mg RDA 15 25 25 45 45 65 75

Thiamin, mg RDA 0.5 0.6 0.6 0.9 0.9 1 1.2

Riboflavin, mg RDA 0.5 0.6 0.6 0.9 0.9 1 1.3

Niacin, mg RDA 6 8 8 12 12 14 16

Vitamin B6, mg RDA 0.5 0.6 0.6 1 1 1.2 1.3

Vitamin B12, mcg RDA 0.9 1.2 1.2 1.8 1.8 2.4 2.4

Choline, mg AI 200 250 250 375 375 400 550

Vitamin K, mcg AI 30 55 55 60 60 75 75

Folate, mcg DFE RDA 150 200 200 300 300 400 400

RAE: retinol activity equivalents; RDA: recommended dietary allowance; AT: alpha-tocopherol; AI: adequate intake; DFE: dietary folate
equivalents.
* 14 g fiber per 1000 kcal = basis for AI for fiber.

References:
1. Institute of Medicine. Dietary Reference Intakes: The essential guide to nutrient requirements. Washington (DC): The National
Academies Press, 2006.
2. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): The National Academies Press, 2010.
Reproduced from: U.S. Department of Health and Human Services and U.S. Department of Agriculture. 2015–2020 Dietary Guidelines for
Americans, 8th Edition, December 2015. Available at: http://health.gov/dietaryguidelines/2015/guidelines/ (Accessed on January 13, 2016).

Graphic 106207 Version 2.0

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 18/19

11/10/2019 Treatment of vitamin B12 and folate deficiencies - UpToDate

Contributor Disclosures
Robert T Means, Jr, MD Nothing to disclose Kathleen M Fairfield, MD, DrPH Nothing to disclose William C Mentzer,
MD Equity Ownership/Stock Options: Johnson & Johnson [Anemia (Erythropoietin)]. Jennifer S Tirnauer, MD Nothing to
disclose Lisa Kunins, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by
vetting through a multi-level review process, and through requirements for references to be provided to support the content.
Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

https://www-uptodate-com.uchile.idm.oclc.org/contents/treatment-of-vitamin-b12-and-folate-deficiencies/print?search=vitamina b12&source=se… 19/19