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Vitamin B 12

by Larry E. Johnson, MD, PhD

Cobalamin is a general term for compounds with biologic vitamin B 12 activity. These compounds are involved in nucleic acid metabolism, methyl transfer, and myelin synthesis and repair. They are necessary for the formation of normal RBCs.

Food-bound vitamin B 12 is released in the stomach’s acid environment and is bound to R protein (haptocorrin). Pancreatic enzymes cleave this B 12 complex (B 12 -R protein) in the small intestine. After cleavage, intrinsic factor, secreted by parietal cells in the gastric mucosa, binds with vitamin B 12 . Intrinsic factor is required for absorption of vitamin B 12 , which takes place in the terminal ileum.

Vitamin B 12 in plasma is bound to transcobalamins I and II. Transcobalamin II is responsible for delivering vitamin B 12 to tissues. The liver stores large amounts of vitamin B 12 . Enterohepatic reabsorption helps retain vitamin B 12 . Liver vitamin B 12 stores can normally sustain physiologic needs for 3 to 5 yr if B 12 intake stops (eg, in people who become vegans) and for months to 1 yr if enterohepatic reabsorption capacity is absent.

Large amounts of vitamin B 12 seem to be nontoxic but are not recommended for regular use (ie, as a general tonic).

Vitamin B 12 Deficiency

Dietary vitamin B 12 deficiency usually results from inadequate absorption, but deficiency can develop in vegans who do not take vitamin supplements. Deficiency causes megaloblastic anemia, damage to the white matter of the spinal cord and brain, and peripheral neuropathy. Diagnosis is usually made by measuring serum vitamin B 12 levels. The Schilling test helps determine etiology. Treatment consists of oral or parenteral vitamin B 12 . Folate (folic acid) should not be used instead of vitamin B 12 because folate may alleviate the anemia but allow neurologic deficits to progress.


Inadequate vitamin B 12 intake is possible in vegans but is otherwise unlikely. Breastfed babies of vegan mothers may develop vitamin B 12 deficiency by age 4 to 6 mo because in these babies, liver stores (which are normally extensive in other babies) are limited and their rapid growth rate results in high demand.

Inadequate vitamin B 12 absorption is the most common cause of deficiency (see Table: Causes of Vitamin B 12 Deficiency and Symptoms and Signs). In the elderly, inadequate absorption most commonly results from decreased acid secretion. In such cases, crystalline vitamin B 12 (such as that available in vitamin supplements) can be absorbed, but food-bound vitamin B 12 is not liberated and absorbed normally. Inadequate absorption may occur in blind loop syndrome (with overgrowth of bacteria) or fish tapeworm infestation; in these cases, bacteria or parasites use ingested vitamin B 12 so that less is available for absorption. Vitamin B 12 absorption may be inadequate if ileal absorptive sites are destroyed by inflammatory bowel disease or are surgically removed. Less common causes of inadequate vitamin B 12 absorption include chronic pancreatitis, gastric surgery, malabsorption syndromes, AIDS, use of certain drugs (eg, antacids, metformin), repeated exposure to nitrous oxide, and a genetic disorder causing malabsorption in the ileum (Imerslund-Graesbeck syndrome).

Less commonly, decreased utilization or use of certain drugs causes vitamin B 12 deficiency (see Table: Causes of Vitamin B 12 Deficiency).

Pernicious anemia is often used synonymously with vitamin B 12 deficiency. However, pernicious anemia specifically refers to anemia resulting from vitamin B 12 deficiency caused by an autoimmune metaplastic atrophic gastritis with loss of intrinsic factor (see Autoimmune Metaplastic Atrophic Gastritis). Patients with classic pernicious anemia, most commonly younger adults, are at increased risk of stomach and other GI cancers.

Causes of Vitamin B 12 Deficiency



Inadequate diet

Vegan diet

Breastfeeding of infants by vegan mothers

Fad diets

Impaired absorption

Lack of intrinsic factor (due to autoimmune metaplastic atrophic gastritis, destruction of gastric mucosa, gastric surgery, or gastric bypass surgery)

Intrinsic factor inhibition

Decreased acid secretion

Small-bowel disorders (eg, inflammatory bowel disease, celiac disease, cancer, biliary or pancreatic disorders)

Competition for vitamin B 12 (in fish tapeworm infestation or blind loop syndrome)


Inadequate utilization

Enzyme deficiencies

Liver disorders

Transport protein abnormality




Nitrous oxide (repeated exposure)

Symptoms and Signs

Anemia usually develops insidiously. It is often more severe than its symptoms indicate because its slow evolution allows physiologic adaptation. Occasionally, splenomegaly and hepatomegaly occur. Various GI symptoms, including weight loss and poorly localized abdominal pain, may occur. Glossitis, usually described as burning of the tongue, is uncommon.

Neurologic symptoms develop independently from and often without hematologic abnormalities.

Subacute combined degeneration refers to degenerative changes in the nervous system due to vitamin B 12 deficiency; they affect mostly brain and spinal cord white matter. Demyelinating or axonal peripheral neuropathies can occur.

In early stages, decreased position and vibratory sensation in the extremities is accompanied by mild to moderate weakness and hyporeflexia. In later stages, spasticity, extensor plantar responses, greater loss of position and vibratory sensation in the lower extremities, and ataxia emerge. These deficits may develop in a stocking-glove distribution. Tactile, pain, and temperature sensations are usually spared but may be difficult to assess in the elderly.

Some patients are also irritable and mildly depressed. Paranoia (megaloblastic madness), delirium, confusion, and, at times, postural hypotension may occur in advanced cases. The confusion may be difficult to differentiate from age-related dementias, such as Alzheimer disease.


  • CBC and vitamin B 12 and folate levels

  • Sometimes methylmalonic acid levels or Schilling test

It is important to remember that severe neurologic disease may occur without anemia or macrocytosis.

Diagnosis is based on CBC and vitamin B 12 and folate levels. CBC usually detects megaloblastic anemia. Tissue deficiency and macrocytic indexes may precede the development of anemia. A vitamin B 12 level < 200 pg/mL (< 145 pmol/L) indicates vitamin B 12 deficiency. The folate level is measured because vitamin B 12 deficiency must be differentiated from folate deficiency as a cause of megaloblastic anemia; folate supplementation can mask vitamin B 12 deficiency and may alleviate megaloblastic anemia but allow the neurologic deficits to progress or even accelerate.

When clinical judgment suggests vitamin B 12 deficiency but the vitamin B 12 level is low-normal (200 to 350 pg/mL [145 to 260 pmol/L]) or hematologic indexes are normal, other tests can be done. Measuring serum methylmalonic acid (MMA) levels may be useful. An elevated MMA level supports vitamin B 12 deficiency but may be due to renal failure. MMA levels can also be used to monitor the response to treatment. MMA levels remain normal in folate deficiency; homocysteine levels may be elevated with either vitamin B 12 or folate deficiency. Less commonly, holotranscobalamin II (transcobalamin II–B 12 complex) content is measured; when holotranscobalamin II is < 40 pg/mL (< 30 pmol/L), vitamin B 12 is deficient.

After deficiency is diagnosed, additional tests may be indicated for younger adults but usually not for the elderly. Unless dietary vitamin B 12 is obviously inadequate, serum gastrin levels or autoantibodies to intrinsic factor may be measured; sensitivity and specificity of these tests may be poor.

Schilling test

The Schilling test is useful only if diagnosing intrinsic factor deficiency is important, as in classic pernicious anemia. This test is not necessary for most elderly patients. The Schilling test measures absorption of free radiolabeled vitamin B 12 . Radiolabeled vitamin B 12 is given orally, followed in 1 to 6 h by 1000 μg (1 mg) of parenteral vitamin B 12 , which reduces uptake of radiolabeled vitamin B 12 by the liver. Absorbed radiolabeled vitamin B 12 is excreted in urine, which is collected for 24 h. The amount excreted is measured, and the percentage of total radiolabeled vitamin B 12 is determined. If absorption is normal, ≥ 9% of the dose given appears in the urine. Reduced urinary excretion (< 5% if kidney function is normal) indicates inadequate vitamin B 12 absorption. Improved absorption with the subsequent addition of intrinsic factor to radiolabeled vitamin B 12 confirms the diagnosis of pernicious anemia.

The test is often difficult to do or interpret because of incomplete urine collection or renal insufficiency. In addition, because the Schilling test does not measure absorption of protein-bound vitamin B 12 , the test does not detect defective liberation of vitamin B 12 from foods, which is common among the elderly. The Schilling test repletes vitamin B 12 and can mask deficiency, so it should be done only after all other diagnostic tests and therapeutic trials.

If malabsorption is identified, the Schilling test can be repeated after a 2-wk trial of an oral antibiotic. If antibiotic therapy corrects malabsorption, the likely cause is intestinal overgrowth of bacteria (eg, blind-loop syndrome).


  • Supplemental vitamin B 12

Vitamin B 12 1000 to 2000 μg po can be given once/day to patients who do not have severe deficiency or neurologic symptoms or signs. A nasal gel preparation of vitamin B 12 is available at a higher price. Large oral doses can be absorbed by mass action, even when intrinsic factor is absent. If the MMA level (sometimes used to monitor treatment) does not decrease, patients may not be taking vitamin B 12 .

For more severe deficiency, vitamin B 12 1 mg IM is usually given 1 to 4 times/wk for several weeks until hematologic abnormalities are corrected; then it is given once/mo.

Although hematologic abnormalities are usually corrected within 6 wk (reticulocyte count should improve within 1 wk), resolution of neurologic symptoms may take much longer. Neurologic symptoms that persist for months or years become irreversible. In most elderly people with vitamin B 12 deficiency and dementia, cognition does not improve after treatment. Vitamin B 12 treatment must be continued for life unless the pathophysiologic mechanism for the deficiency is corrected.

Infants of vegan mothers should receive supplemental vitamin B 12 from birth.

Key Points

  • Common causes of vitamin B 12 deficiency include inadequate dietary amounts (eg, in vegans), impaired absorption, age-related decreased acid secretion, and autoimmune metaplastic atrophic gastritis (which causes pernicious anemia).

  • The deficiency commonly causes megaloblastic anemia, loss of position and vibration sensation (which occurs early and progresses), and, when advanced, paranoia, delirium, and confusion.

  • Do a CBC and measure vitamin B 12 and folate levels.

  • Do a Schilling test in young and middle-aged adults with the deficiency.

  • Treat with supplemental vitamin B 12 .

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