Vitamin B12 Deficiency

(Pernicious Anemia)

ByLarry E. Johnson, MD, PhD, University of Arkansas for Medical Sciences
Reviewed/Revised Nov 2022
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Cobalamin is a general term for compounds with biologic vitamin B12 activity. These compounds are involved in nucleic acid metabolism, methyl transfer, and myelin synthesis and repair. They are necessary for the formation of normal red blood cells and normal neural function (see table Sources, Functions, and Effects of Vitamins).

Dietary sources of vitamin B12 include meats (especially beef, pork, and organ meats [eg, liver]), poultry, eggs, fortified cereals, milk and milk products, and seafood such as clams, oysters, mackerel, and salmon. Food-bound vitamin B12 is released in the stomach’s acid environment and is bound to R protein (haptocorrin). Pancreatic enzymes cleave this B12 complex (B12-R protein) in the small intestine. After cleavage, intrinsic factor, secreted by parietal cells in the gastric mucosa, binds with vitamin B12. Intrinsic factor is required for absorption of vitamin B12, which takes place in the terminal ileum.

Vitamin B12 in plasma is bound to transcobalamins I and II. Transcobalamin II is responsible for delivering vitamin B12 to tissues. The liver stores large amounts of vitamin B12. Enterohepatic reabsorption helps retain vitamin B12. Liver vitamin B12 stores can normally sustain physiologic needs for 3 to 5 years if B12 intake stops (eg, in people who become vegans) and for months to 1 year if enterohepatic reabsorption capacity is absent.

Large amounts of vitamin B12 seem to be nontoxic but are not recommended for regular use (ie, as a general tonic).

(See also Overview of Vitamins.)

Etiology of Vitamin B12 Deficiency

Vitamin B12 deficiency can result from

  • Inadequate intake

  • Inadequate absorption

  • Decreased utilization

  • Use of certain drugs

Inadequate vitamin B12 intake is possible in vegans but is otherwise unlikely. Breastfed babies of vegan mothers may develop vitamin B12 deficiency by age 4 to 6 months 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 B12 absorption is the most common cause of deficiency (see table Causes of Vitamin B12 Deficiency). In older people, inadequate absorption most commonly results from decreased acid secretion. In such cases, crystalline vitamin B12 (such as that available in vitamin supplements) can be absorbed, but food-bound vitamin B12 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 B12 so that less is available for absorption.

Vitamin B12 absorption may be inadequate if ileal absorptive sites are destroyed by inflammatory bowel disease or are surgically removed.

Less common causes of inadequate vitamin B12 absorption include chronic pancreatitis, gastric or bariatric surgery, malabsorption syndromes, AIDS

Less commonly, decreased utilization of vitamin B12 or use of certain drugs causes vitamin B12 deficiency (see table Causes of Vitamin B12 Deficiency).

Pernicious anemia is often used synonymously with vitamin B12 deficiency. However, pernicious anemia specifically refers to anemia resulting from vitamin B12 deficiency caused by an autoimmune metaplastic atrophic gastritis with loss of intrinsic factor. Patients with classic pernicious anemia, most commonly younger adults, are at increased risk of stomach and other gastrointestinal cancers.


Symptoms and Signs of Vitamin B12 Deficiency

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 gastrointestinal 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 B12 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 older people.

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.

Diagnosis of Vitamin B12 Deficiency

  • Complete blood count (CBC) and vitamin B12 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 of vitamin B12 deficiency is based on CBC and vitamin B12 and folate levels. CBC usually detects megaloblastic anemia. Tissue deficiency and macrocytic indexes may precede the development of anemia. A vitamin B12 level < 200 pg/mL (< 145 pmol/L) indicates vitamin B12 deficiency. The folate level is measured because vitamin B12 deficiency must be differentiated from folate deficiency as a cause of megaloblastic anemia; folate supplementation can mask vitamin B12 deficiency and may alleviate megaloblastic anemia but allow the neurologic deficits to progress or even accelerate.

When clinical judgment suggests vitamin B12 deficiency but the vitamin B12 level is low-normal (200 to 350 pg/mL [145 to 260 pmol/L]) or hematologic indexes are normal, other tests can be done. They include measuring the following:

  • Serum methylmalonic acid (MMA) levels: An elevated MMA level supports vitamin B12 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: Levels may be elevated with either vitamin B12 or folate deficiency.

  • Less commonly, holotranscobalamin II (transcobalamin II–B12 complex) content: When holotranscobalamin II is < 40 pg/mL (< 30 pmol/L), vitamin B12 is deficient.

After vitamin B12 deficiency is diagnosed, additional tests (eg, Schilling test) may be indicated for younger adults but usually not for older people. Unless dietary vitamin B12 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 older patients. The Schilling test measures absorption of free radiolabeled vitamin B12. Radiolabeled vitamin B12 is given orally, followed in 1 to 6 hours by 1000 mcg (1 mg) of parenteral vitamin B12, which reduces uptake of radiolabeled vitamin B12 by the liver. Absorbed radiolabeled vitamin B12 is excreted in urine, which is collected for 24 hours. The amount excreted is measured, and the percentage of total radiolabeled vitamin B12 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 B12 absorption. Improved absorption with the subsequent addition of intrinsic factor to radiolabeled vitamin B12 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 B12, the test does not detect defective liberation of vitamin B12 from foods, which is common among older people. The Schilling test repletes vitamin B12 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-week trial of an oral antibiotic. If antibiotic therapy corrects malabsorption, the likely cause is intestinal overgrowth of bacteria (eg, blind-loop syndrome).

Treatment of Vitamin B12 Deficiency

  • Supplemental vitamin B12

Vitamin B12 1000 to 2000 mcg orally can be given once a day to patients who do not have severe deficiency or neurologic symptoms or signs. A nasal gel preparation of vitamin B12 is available at a higher price. Large oral doses can be absorbed by mass action, even when intrinsic factor is absent. If the methylmalonic acid (MMA) level (sometimes used to monitor treatment) does not decrease, patients may not be taking vitamin B12.

For more severe deficiency, vitamin B12 1 mg IM is usually given 1 to 4 times a week for several weeks until hematologic abnormalities are corrected; then it is given once a month.

Although hematologic abnormalities are usually corrected within 6 weeks (reticulocyte count should improve within 1 week), resolution of neurologic symptoms may take much longer. Neurologic symptoms that persist for months or years become irreversible. In most older people with vitamin B12 deficiency and dementia, cognition does not improve after treatment.

Vitamin B12 treatment must be continued for life unless the pathophysiologic mechanism for the deficiency is corrected.

Infants of vegan mothers should receive supplemental vitamin B12 from birth.

Key Points

  • Common causes of vitamin B12 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 complete blood count and measure vitamin B12 and folate levels.

  • Do a Schilling test in young and middle-aged adults with vitamin B12 deficiency.

  • Treat with supplemental vitamin B12.

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