Highlights & Basics
- Vitamin B12 (cobalamin) deficiency classically presents with megaloblastic anemia, but can also present with neurologic and neuropsychiatric complaints.
- Older people, patients with chronic malabsorption, patients with a history of gastric resection or bypass, and those taking certain medications (metformin, proton-pump inhibitors) are at risk.
- Early diagnosis is critical in preventing and halting the progression of neurologic disorders such as peripheral neuropathy, subacute combined degeneration of the spinal cord, and dementia.
- Methylmalonic acid and homocysteine levels may help to diagnose vitamin B12 deficiency at an early, asymptomatic state.
- Cause of vitamin B12 deficiency should be searched for once a diagnosis is confirmed.
- Treatment with high-dose oral vitamin B12 therapy may be as effective as intramuscular vitamin B12 therapy.
Quick Reference
History & Exam
Key Factors
old age
history of gastric surgery (gastrectomy, or bypass for obesity)
Other Factors
paresthesias
vegan and strict vegetarian diet
chronic gastrointestinal disease (e.g., Crohn disease or celiac disease)
medication (proton-pump inhibitors, H2 receptor antagonists, metformin, anticonvulsants)
ataxia
decreased vibration sense
positive Romberg test
pallor
petechiae
glossitis
angular cheilitis
cognitive impairment
Diagnostics Tests
1st Tests to Order
CBC
peripheral blood smear
serum vitamin B12
reticulocyte count
Other Tests to consider
methylmalonic acid (MMA)
homocysteine
holotranscobalamin (hTC)
anti-intrinsic factor antibody (anti-IFAB)
antiparietal cell (APC) antibody
serum gastrin (fasting)
Treatment Options
acute
symptomatic
severe symptoms
mild to moderate symptoms
asymptomatic or borderline deficiency
patients aged >65 years with poor diet
vegan or strict vegetarian diet
with chronic gastrointestinal illness
after bariatric surgery
Definition
Vignette
Common Vignette
Other Presentations
Epidemiology
Etiology
- Decreased dietary intake
- Diminished gastric breakdown of vitamin B12 from food
- Malabsorption from the gastrointestinal tract.
- Vegans and strict vegetarians
- History of gastric or intestinal surgery
- History of atrophic gastritis
- Pernicious anemia, in which autoimmune destruction of the parietal cells (which produce intrinsic factor) leads to reduced vitamin B12 absorption from the gastrointestinal tract
- Gastric malabsorption.
- Crohn disease
- Celiac disease
- Bacterial overgrowth syndromes.
Pathophysiology
Diagnostic Approach
At-risk groups
Symptoms and signs
Initial diagnostic testing
- Probable vitamin B12 deficiency: <200 picograms/mL
- Possible vitamin B12 deficiency: 201 to 350 picograms/mL
- Unlikely vitamin B12 deficiency: >350 picograms/mL.
Clinical assessment of deficiency severity
- Mild to moderate hematologic manifestations: usually asymptomatic with normal hematocrit and an MCV that is at the upper limit of the normal range or mildly elevated.
- Severe neurologic manifestations: subacute combined spinal degeneration, dementia, or cognitive impairment. Subacute combined spinal degeneration is progressive neurologic degeneration of the posterior and lateral columns of the spinal cord; patients present with ataxia, decreased vibration sense, muscle weakness, and hyperreflexia.
- Severe hematological manifestations: pancytopenia and marked symptomatic anemia.
Confirmatory diagnostic testing: serum vitamin B12 <200 picograms/mL
Confirmatory diagnostic testing: serum vitamin B12 201 to 350 picograms/mL
Confirmatory diagnostic testing: serum vitamin B12 >350 picograms/mL
Determining the underlying cause of vitamin B12 deficiency
Risk Factors
History & Exam
Tests
Differential Diagnosis
Folic acid (vitamin B9) deficiency
Differentiating Signs/Symptoms
- Generally does not present with neurologic symptoms. Rare in the present era of folic acid fortification in the US.
Differentiating Tests
- Serum folate levels are low.
- Be aware that low serum folate can result in falsely low vitamin B12 levels.
- Treat with folic acid and retest.
Myelodysplastic syndrome (MDS)
Differentiating Signs/Symptoms
- Presents with macrocytic anemia and is difficult to differentiate from vitamin B12 deficiency initially.
- MDS is a group of disorders characterized by a clonal chromosomal abnormality, ineffective and dysplastic hematopoiesis resulting in ≥1 cytopenias, and a varying predilection to develop acute myeloid leukemia.
- These disorders can arise primarily without any precipitating event or may be related to previous treatment with either chemotherapy or radiation.
Differentiating Tests
- CBC in MDS shows normochromic or macrocytic red cells; about 40% of patients have neutropenia, and >30% have thrombocytopenia. Morphologic abnormalities include oval macrocytic red cells and granulocytes with the pseudo-Pelger-Huet anomaly (hypogranular and hypolobulated granulocytes).
- Bone marrow histopathology in MDS demonstrates dysplasia in a proportion of undifferentiated myeloblasts.
- Prussian blue iron staining of bone marrow aspirate can show ringed sideroblasts (abnormal erythroid precursor cells that have granules around the nucleus).
Alcoholic liver disease
Differentiating Signs/Symptoms
- May present with macrocytic anemia and nutritional deficiencies. History should reveal alcohol use.
Differentiating Tests
- Elevated liver enzymes.
- Liver biopsy histopathology shows fatty change, inflammation, and variable amounts of fibrosis leading to cirrhosis in severe, chronic alcoholic liver disease.
Hypothyroidism
Differentiating Signs/Symptoms
- May present with macrocytic anemia.
- May show signs of muscle and joint pain, weakness in the extremities, and fatigue; delayed relaxation of deep tendon reflexes strongly suggests hypothyroidism.
Differentiating Tests
- Elevated thyroid-stimulating hormone, decreased T3 and T4, and elevated creatine kinase.
Peripheral neuropathy
Differentiating Signs/Symptoms
- Compression neuropathies, and neuropathies due to diabetes or thyroid disease, may be difficult to differentiate from neurologic symptoms of vitamin B12 deficiency.
Differentiating Tests
- Nerve conduction studies and electromyogram are helpful in confirming and characterizing neuropathy; that is, demyelinating, axonal, polyneuropathy, mononeuropathy multiplex, radiculopathy, or plexopathy.
- Treatment with vitamin B12 may improve symptoms, but neuropathy may be irreversible.
Diabetic neuropathy
Differentiating Signs/Symptoms
- Paresthesia is a common feature and may occur in the extremities as a result of neuropathy in those with prolonged undiagnosed diabetes. Other types of neuropathy may be present in diabetes, including autonomic neuropathy.
Differentiating Tests
- Elevated fasting glucose or HbA1c.
- Antiglutamic acid decarboxylase antibodies, islet cell antibodies, and insulin autoantibodies are present in 85% of patients with type 1 diabetes at the time of diagnosis, but may disappear within a few years.
Differentiating Signs/Symptoms
- Macrocytosis due to certain medications, including hydroxyurea, methotrexate, zidovudine, azathioprine, capecitabine, and cladribine.
Differentiating Tests
- Usually a clinical diagnosis. Serum drug levels may confirm the association.
Dementia
Differentiating Signs/Symptoms
- Characterized by cognitive (memory) changes, psychiatric symptoms, personality changes, problem behaviors, and changes in day-to-day functioning.
- May be due to multiple different factors that are clinically indistinguishable from vitamin B12 deficiency.
Differentiating Tests
- A mental state exam or neuropsychiatric testing should be conducted if the diagnosis is uncertain.
- Vitamin B12 testing is normal.
Depression
Differentiating Signs/Symptoms
- Characterized by persistent low mood causing varying levels of social, cognitive, occupational, and physical dysfunction.[78]
Differentiating Tests
- Vitamin B12 testing is normal.
Differentiating Signs/Symptoms
- Patients present with symptoms of anemia and vitamin B12 deficiency. They may also have fever and complain of gastric pain or discomfort. Common features include tiredness, dyspnea, paresthesias, sore red tongue, diarrhea, and mild jaundice.
Differentiating Tests
- Once vitamin B12 deficiency is confirmed, testing for anti-intrinsic factor antibody (anti-IFAB) can determine whether PA is the cause. It is only 50% sensitive, but highly specific for PA.[2] Testing for anti-IFAB should be done before initiating vitamin B12 replacement therapy because high vitamin B12 levels may lead to false positive results.[70] [71]
- Antiparietal cell (APC) antibody can, in conjunction with other tests, help to determine whether PA is the cause. It is highly sensitive (85%), but has low specificity for PA. APC antibodies may be elevated in atrophic gastritis.[2]
- Once a patient is given intrinsic factor and vitamin B12 level is normal, gastrin levels will normalize.
Crohn disease
Differentiating Signs/Symptoms
- Crohn disease can affect any part of the gastrointestinal tract, and symptoms may be extremely variable.
- Increased risk for B12 deficiency occurs with ileectomy >20 cm.[47]
Differentiating Tests
- The classic findings on histologic exam include involvement of all layers of the bowel wall by granulomas, ulcerations, and acute and chronic inflammation.
Celiac disease
Differentiating Signs/Symptoms
- Patients present with unexplained gastrointestinal symptoms, chronic diarrhea, unexplained iron deficiency anemia, vitamin D deficiency, or a skin rash consistent with dermatitis herpetiformis.
- Other situations include failure to thrive, short stature, recurrent severe aphthous stomatitis, recurrent spontaneous abortion, and infertility.
Differentiating Tests
- Immunoglobulin A antigliadin and antiendomysial antibodies.
- Small-bowel histology is the most specific and sensitive test, showing villous atrophy and mucosal inflammation with hyperplastic changes to crypts.
- Iron deficiency anemia is the most common clinical presentation in adults.
- Folate (and less commonly vitamin B12) deficiency may lead to macrocytic anemia.
Peptic ulcer disease from Helicobacter pylori infection
Differentiating Signs/Symptoms
- H pylori is a gram-negative, microaerophile bacterium that inhabits the stomach and duodenum. It causes a chronic low-level atrophic gastritis and is strongly linked to the development of duodenal and gastric ulcers and stomach cancer.
- Over 80% of people infected with the bacterium are asymptomatic.
Differentiating Tests
- The carbon urea breath test is positive.
- The most reliable method for detecting H pylori infection is endoscopic biopsy. Histopathology shows gastric atrophy, inflammation, and bacterial organisms on special stains.
Chronic pancreatitis
Differentiating Signs/Symptoms
- History of gallstone disease or alcohol misuse.
- Characterized by recurrent or persistent abdominal pain and progressive injury to the pancreas and surrounding structures, resulting in scarring and loss of function.
Differentiating Tests
- Ultrasound or CT imaging of the abdomen may reveal fibrosis and calcification of the pancreas.
- Evaluation of pancreatic enzymes is the most sensitive and specific test for diagnosing mild to moderate pancreatic insufficiency or chronic pancreatitis, but it is available in only a few centers. Pancreatic juice is collected with a gastroduodenal tube during exogenous hormone stimulation with cholecystokinin and/or secretin.
- Helps differentiate pancreatic from nonpancreatic types of malabsorption.
Differentiating Signs/Symptoms
- History may show conditions that alter intestinal anatomy, motility, and gastric acid secretion. These include use of proton-pump inhibitors and anatomic disturbances in the bowel, including fistulae, diverticula, and blind loops created after surgery.
Differentiating Tests
- The definitive investigation requires culture of jejunal fluid that grows >10⁵ bacteria/mL.
- Hydrogen breath testing may show malabsorption but is not very sensitive or specific for bacterial overgrowth.
- A trial of treatment with antibiotics for 1 week may give the diagnosis.
Zollinger-Ellison syndrome
Differentiating Signs/Symptoms
- A condition caused by a gastrin-secreting tumor that causes hypersecretion of gastric acid leading to ulcer disease. It most commonly presents with abdominal pain, diarrhea, and gastroesophageal reflux. Less common presentations include weight loss, gastrointestinal bleeding, nausea, and vomiting.
Differentiating Tests
- Elevated level of fasting serum gastrin in the absence of achlorhydria, and either a positive secretion test or histologically demonstrated neuroendocrine tumor.
Tropical sprue
Differentiating Signs/Symptoms
- Believed to be initiated or sustained by an undefined infection.
- Presents with symptoms and signs of malabsorption, stomach pain, diarrhea, and bloating.
- The relapse rate is substantial in treated patients who remain in, or return to, endemic areas in the tropics.
Differentiating Tests
- Endoscopy and small bowel biopsy reveals progressive villus atrophy in the small intestine similar to celiac disease.
- Therapeutic trial with tetracyclines for 6 months normalizes mucosal structure in the small intestine.
Fish tapeworm (Diphyllobothrium latum)
Differentiating Signs/Symptoms
- Fish tapeworm is native to Scandinavia, western Russia, and the Baltic states. Now present in North America, especially the Pacific Northwest.
- Infection arises following eating raw fish or fish products.
- Patients present with symptoms of malnutrition including anemia.
Differentiating Tests
- Fish tapeworm eggs appear in the feces 5 to 6 weeks after infection, and fecal exam may confirm the diagnosis.
HIV infection
Differentiating Signs/Symptoms
- Malnutrition is common in HIV disease, particularly in resource-poor areas. A cycle of opportunistic infection causing loss of weight and poor appetite, together with diarrhea and malabsorption, contributes to malnutrition.
Differentiating Tests
- Enzyme-linked immunosorbent assay (ELISA) testing should be ordered when HIV testing is indicated. False-negatives may occur during window period immediately after infection and before antibodies to HIV have developed. A positive result should be confirmed with a Western blot or second ELISA. The window period can be reduced to 2-4 weeks by using fourth-generation tests that detect IgM and IgG antibodies to HIV and p24 antigen.[79] CDC: HIV - laboratory tests
Alpha-thalassemia
Differentiating Signs/Symptoms
- An inherited autosomal recessive blood disease.
- Vitamin B12 requirement is increased in alpha-thalassemia; vitamin B12 deficiency may be the presenting feature. Patients present with anemia, hepatosplenomegaly, leg ulcers, and bone pain. This disease is more common in Mediterranean countries, Asia, the Middle East, and South America.
Differentiating Tests
- CBC and peripheral smear show microcytosis, erythrocytosis, hypochromia, and mild anemia.
- A diagnosis can be made by a combination of family studies and the ruling out of both iron deficiency anemia and beta-thalassemia trait.
- A definitive diagnosis can be made by DNA sequencing of the alpha-globin chain.
Multiple sclerosis
Differentiating Signs/Symptoms
- Neurologic manifestations of vitamin B12 deficiency can mimic clinical symptoms of multiple sclerosis. However, in almost all cases of multiple sclerosis there are also brain lesions.
- Variable presentation: multiple episodes separated by space (i.e., neurologic symptoms result from lesions in different central nervous system sites) and time. Symptoms include progressive limb weakness, gait difficulty, ataxia, loss of balance, and paroxysmal vertigo.
Differentiating Tests
- Brain MRI typically shows areas of demyelination.
- Cerebrospinal fluid (CSF) exam shows elevated IgG and oligoclonal banding.
Syphilis (tabes dorsalis)
Differentiating Signs/Symptoms
- History of syphilis infection or sexually transmitted infection.
- Neurologic symptoms of tabes dorsalis and subacute combined spinal degeneration may be similar.
Differentiating Tests
- The Venereal Disease Research Laboratory (VDRL) reaction test alone cannot always be depended on in differential diagnosis.
- CSF exam is required to diagnose neurosyphilis.
- CSF VDRL reactivity test is specific but not sensitive for neurosyphilis.
- CSF fluorescent treponemal antibody absorption reactivity test is sensitive but not specific for neurosyphilis.
Criteria
- Probable vitamin B12 deficiency: <200 picograms/mL
- Possible vitamin B12 deficiency: 201 to 350 picograms/mL
- Unlikely vitamin B12 deficiency: >350 picograms/mL.
Screening
Treatment Approach
Vitamin B12 therapy options
Patients presenting with severe symptoms
Patients with mild to moderate symptoms
Asymptomatic or borderline deficiency in high-risk patients
Pregnancy and breast-feeding
Monitoring response to treatment
Maintenance therapy
Treatment Options
symptomatic
severe symptoms
parenteral cyanocobalamin or hydroxocobalamin
Primary Options
cyanocobalamin (vitamin B12)
1000 micrograms intramuscularly/subcutaneously once daily for 1-2 weeks, followed by 1000 micrograms once weekly for 1 month
- hydroxocobalamin
1000 micrograms intramuscularly three times weekly for 2 weeks, followed by 1000 micrograms once every 3 months
- hydroxocobalamin
Comments
- Patients with severe hematologic (pancytopenia and marked symptomatic anemia) or neurologic (subacute combined spinal degeneration, dementia, or cognitive impairment) symptoms of vitamin B12 deficiency require hospital admission and acute and urgent treatment.[90]
- An acute regimen of parenteral cyanocobalamin is given daily for 1 to 2 weeks, and then once a week for up to 1 month, until significant reticulocytosis is seen in the marrow.[91]
- Brisk bone marrow reticulocytosis can be measured in 1-2 weeks as a response to treatment. Other markers of deficiency, including methylmalonic acid, homocysteine, and mean corpuscular volume, should normalize in 8 weeks with adequate treatment.
- In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.
referral to neurologist and/or hematologist
Comments
- Patients with severe neurologic symptoms may require neurologic and psychogeriatric referral and evaluation while commencing the acute parenteral treatment regimen. In some cases, neurologic symptoms may be irreversible despite serum vitamin B12 levels returning to normal.
- Patients with symptomatic anemia and pancytopenia require hospital admission and hematologic specialist referral.
- Pregnant women should be managed in consultation with their obstetrician.
blood transfusion ± low-dose diuretic
Primary Options
- bumetanide
0.5 to 2 mg orally/intravenously once or twice daily initially, increase according to response, maximum 10 mg/day
- bumetanide
Comments
- Patients with symptomatic anemia and pancytopenia require hospital admission and hematologic specialist referral and, rarely, may require red blood cell (RBC) transfusion.
- If there are signs of congestive cardiac failure, cardiac monitoring is advised and packed RBCs should be given together with low-dose diuretic therapy.
- Diuretics should generally be avoided in pregnancy unless the benefits outweigh the risks, and only under specialist guidance.
oral folic acid
Primary Options
folic acid (vitamin B9)
1 mg orally once daily
Comments
- Folate supplementation can help reverse the hematologic abnormalities.
lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin
Primary Options
cyanocobalamin (vitamin B12)
1000 micrograms orally once daily
Secondary Options
cyanocobalamin (vitamin B12)
1000 micrograms intramuscularly/subcutaneously once monthly
- hydroxocobalamin
1000 micrograms intramuscularly once every 3 months
- hydroxocobalamin
Comments
- Most patients identified with vitamin B12 deficiency require lifelong maintenance therapy with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin.
- Oral cyanocobalamin is generally well tolerated for maintenance therapy. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to oral therapy. It may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[98]
- Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[99] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[100] [101] [102]
- Absorption can be maximized by administration on an empty stomach.
- A response with daily oral cyanocobalamin should be seen within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.
- In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.
mild to moderate symptoms
oral or parenteral cyanocobalamin or parenteral hydroxocobalamin
Primary Options
cyanocobalamin (vitamin B12)
1000 micrograms orally once daily; 1000 micrograms intramuscularly/subcutaneously once monthly
- hydroxocobalamin
1000 micrograms intramuscularly once every 3 months
- hydroxocobalamin
Comments
- Treatment of patients with mild to moderate symptoms of vitamin B12 deficiency (e.g., mild anemia, dysesthesia/paresthesias, polyneuropathy, depression) is with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin, depending on clinician preference.
- In patients treated with oral cyanocobalamin, a response should be seen within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.
- In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.
lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin
Primary Options
cyanocobalamin (vitamin B12)
1000 micrograms orally once daily
Secondary Options
cyanocobalamin (vitamin B12)
1000 micrograms intramuscularly/subcutaneously once monthly
- hydroxocobalamin
1000 micrograms intramuscularly once every 3 months
- hydroxocobalamin
Comments
- Most patients identified with vitamin B12 deficiency require lifelong maintenance therapy with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin.
- Oral cyanocobalamin is generally well tolerated for maintenance therapy. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to oral therapy. It may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[98]
- Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[99] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[100] [101] [102]
- Absorption can be maximized by administration on an empty stomach.
- A response with daily oral cyanocobalamin should be seen within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.
- In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.
asymptomatic or borderline deficiency
patients aged >65 years with poor diet
dietary supplementation + multivitamins
Comments
- Low serum vitamin B12 (<200 picograms/mL) may not be associated with symptoms. But dietary advice on the importance of eating animal-derived foods (such as meat, fish, eggs, and milk), and taking multivitamin supplements, is recommended as first-line treatment in this group.
- Combined diet and multivitamins should meet the recommended dietary allowance of 2.4 micrograms/day.[58]
lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin
Primary Options
cyanocobalamin (vitamin B12)
1000 micrograms orally once daily
Secondary Options
cyanocobalamin (vitamin B12)
1000 micrograms intramuscularly/subcutaneously once monthly
- hydroxocobalamin
1000 micrograms intramuscularly once every 3 months
- hydroxocobalamin
Comments
- If diet and multivitamin supplements do not help, or if the diet cannot be improved, cyanocobalamin treatment is advised.
- Most patients identified with vitamin B12 deficiency require lifelong maintenance therapy with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin.
- Oral cyanocobalamin is generally well tolerated for maintenance therapy. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to high-dose oral therapy. It may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[98]
- Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[99] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[100] [101] [102]
- Absorption can be maximized by administration on an empty stomach.
- A response with daily oral cyanocobalamin should be seen within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.
- In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.
vegan or strict vegetarian diet
dietary supplementation + multivitamins
Comments
- Pregnant and breast-feeding women who have a strict vegetarian or vegan diet should be counseled about adequate intake of vitamin B12 and supplementation.[103] Breast-feeding women who adhere to a vegan diet will only provide adequate vitamin B12 for her infant if the mother satisfies vitamin B12 requirements through supplementation.[97]
lifelong oral or parenteral cyanocobalamin or parenteral hydroxocobalamin
Primary Options
cyanocobalamin (vitamin B12)
1000 micrograms orally once daily
Secondary Options
cyanocobalamin (vitamin B12)
1000 micrograms intramuscularly/subcutaneously once monthly
- hydroxocobalamin
1000 micrograms intramuscularly once every 3 months
- hydroxocobalamin
Comments
- Lifelong maintenance treatment with once-daily oral cyanocobalamin or once-monthly parenteral cyanocobalamin is advised.
- Oral cyanocobalamin is generally well tolerated for maintenance therapy. Parenteral cyanocobalamin is often reserved for those who cannot take daily pills or have documented failure to oral therapy. It may also be considered when there are concerns about adherence to oral vitamin B12 replacement therapy.[98]
- Some clinicians may attempt to lower the effective dose of maintenance oral cyanocobalamin. Periodic monitoring after replacement may be able to identify patients who may maintain serum levels with oral doses <1000 micrograms/day.[99] However, absorption may be variable, and some patients may experience less than maximal clinical and laboratory response with oral cyanocobalamin doses <1000 micrograms/day.[100] [101] [102]
- Absorption can be maximized by administration on an empty stomach.
- A response with daily oral cyanocobalamin should be seen within 8 weeks. If serum vitamin B12 does not significantly rise after this time, clinicians should switch to parenteral cyanocobalamin (if not already used) or consider other causes.
- In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.
with chronic gastrointestinal illness
parenteral cyanocobalamin or hydroxocobalamin
Primary Options
cyanocobalamin (vitamin B12)
1000 micrograms intramuscularly/subcutaneously once monthly
- hydroxocobalamin
1000 micrograms intramuscularly once every 3 months
- hydroxocobalamin
Comments
- In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.
after bariatric surgery
oral, parenteral, or intranasal cyanocobalamin or parenteral hydroxocobalamin
Primary Options
cyanocobalamin (vitamin B12)
350-1000 micrograms orally once daily; or 1000 micrograms intramuscularly/subcutaneously once monthly; or 3000 micrograms intramuscularly/subcutaneously every 6 months; or 500 micrograms intranasally once weekly
- hydroxocobalamin
1000 micrograms intramuscularly once every 3 months
- hydroxocobalamin
Comments
- Patients who have had bariatric surgery may not be able to adequately maintain serum vitamin B12 levels with multivitamins; therefore, oral, parenteral, or intranasal cyanocobalamin should be given.[74] [95] An oral multivitamin supplement optimized for bariatric surgery has shown potential benefit in reducing vitamin deficiencies following Roux-en-Y gastric bypass surgery, but the evidence is limited.[96]
- In Europe, hydroxocobalamin is more commonly used than cyanocobalamin. Hydroxocobalamin is retained longer in the body than cyanocobalamin, but superiority to cyanocobalamin has not been established in clinical trials.
Prevention
Primary Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
Megaloblastic anemia
Subacute combined spinal degeneration
Other neurologic disease
Monitoring
Complications
Citations
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Snow CF. Laboratory diagnosis of vitamin B12 and folate deficiency: a guide for the primary care physician. Arch Intern Med. 1999 Jun 28;159(12):1289-98.[Abstract][Full Text]
Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013 Jan 10;368(2):149-60.[Abstract]
National Institutes of Health, Office of Dietary Supplements. Dietary supplement fact sheet: vitamin B12. 2022 [internet publication].[Full Text]
Guidelines and Protocols Advisory Committee, British Columbia. Cobalamin (vitamin B12) and folate deficiency. Jan 2023 [internet publication].[Full Text]
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Key Articles
Other Online Resources
Referenced Articles
Guidelines
Diagnostic
Summary
Recommends B12 test in clinically symptomatic patients with specific features of B12 deficiency.Published by
Guidelines and Protocols Advisory Committee, British Columbia
Published
2023
Summary
A comprehensive overview of the diagnostic approach for cobalamin and folate disorders.Published by
British Society for Haematology
Published
2014
Treatment
Summary
Lists sources of vitamin B12 and recommended dietary allowances.Published by
Office of Dietary Supplements, National Institutes of Health
Published
2022
Summary
Guidance to help the individual choose a healthy diet.Published by
US Department of Health and Human Services; US Department of Agriculture
Published
2020
Summary
Recommendations regarding testing and treatment for vitamin B12 deficiency in patients who have had bariatric surgery.Published by
American Association of Clinical Endocrinologists; Obesity Society; American Society for Metabolic & Bariatric Surgery
Published
2019
Summary
Addresses the management of cobalamin (vitamin B12) deficiency in adults.Published by
Guidelines and Protocols Advisory Committee, British Columbia
Published
2023
Summary
Consensus guidance on provision of micronutrients, including vitamin B12, and monitoring during nutritional support.Published by
European Society for Clinical Nutrition and Metabolism
Published
2022
Summary
Dietetic recommendations for patients with inflammatory bowel disease.Published by
European Society for Clinical Nutrition and Metabolism
Published
2020
Summary
Evidence-based approach to the management of vitamin B12 and folate deficiency.Published by
British Society for Haematology
Published
2014
Summary
Recommendations for B12 intake by life stage and gender.Published by
Australian Government National Health and Medical Research Council and New Zealand Ministry for Health
Published
2017