Vitamin B12 (cobalamin) deficiency is associated with neurologic, psychiatric, hematologic, and possibly cardiovascular aberrations. In most cases, vitamin B12 deficiency is caused by an acquired defect in absorption of this nutrient from the gut.

Classically, vitamin B12 deficiency (pernicious anemia) is caused by autoimmune damage to the acid-producing cells-called parietal cells-in the stomach; this autoimmune condition becomes more common as people age. However, anything that impairs parietal cell function can contribute to poor absorption of cobalamin.

Mechanisms of Vitamin B12 (Cobalamin) Absorption

Under normal conditions, the acidic environment of the stomach promotes the separation of cobalamin from food. In addition to producing acid, parietal cells also excrete intrinsic factor, a protein that binds to vitamin B12 and greatly facilitates its absorption in the lower part of the small intestine.

A second, less efficient mechanism of absorption involves the transport of free vitamin B12 across the intestinal wall, after which it binds to transcobolamin II, a transport protein that carries vitamin B12 throughout the body. Only 1% of a large oral dose is absorbed in this manner. (Elia M. Oral or parenteral therapy for B12 deficiency. Lancet 1998;352:1721-2)

Problems Associated with Vitamin B12 Deficiency

In humans, only two enzymatic reactions are dependent upon vitamin B12:

  1. The conversion of methylmalonic acid to succinyl-CoA, where vitamin B12 acts as a cofactor. B12 deficiency leads to increased levels of methylmalonic acid and relatively lower levels of succinyl-CoA.
  2. The conversion of homocysteine to methionine, where both vitamin B12 and folate serve as cofactors. Deficiencies of either vitamin may lead to increased homocysteine levels; homocysteine is an inflammatory molecule that contributes to atherosclerosis.

Due to the ubiquitous nature of these processes in cellular metabolism, vitamin B12 deficiency manifests in the following abnormalities:


  • Megaloblastic (large cells) anemia
  • Pancytopenia (a lack of production of all blood cell lines: white blood cells, red corpuscles, and platelets)


  • Paresthesias (abnormal sensations)
  • Peripheral neuropathy (loss of motor, sensory, or positional function in distal nerve distributions)
  • Combined systems disease (damage to nerve tracts in the spinal cord that leads to difficulty with walking, spasticity in the lower extremities, a loss of positional sense, and vibratory sensations in the feet and legs)


  • Irritability
  • Personality change
  • Dementia (typically mild)
  • Depression
  • Psychosis


  • Potentially increased incidence of heart attack and stroke

(From Oh R and Brown D. Vitamin B12 deficiency. Am Fam Phys. 2003;67[5]:679-86)

Diagnosis of Vitamin B12 Deficiency

  • Measurement of serum vitamin B12 levels and examination of peripheral blood smears are inaccurate methods of diagnosing vitamin B12 deficiency; serum levels do not correlate well with total body stores of vitamin B12, and patients sometimes develop neuropsychiatric symptoms before hematologic manifestations appear.
  • Measurements of metabolites of cobalamin-driven enzymatic pathways are earlier and more sensitive indicators of a person's vitamin B12 status. Thus, individuals with high homocysteine or methylmalonic acid levels should be suspected of being vitamin B12 deficient.
  • Although an elevated methymalonic acid level is more specific than a high homocysteine level for cobalamin deficiency, kidney disease can elevate levels of methylmalonic acid in spite of normal vitamin B12 levels. Therefore, elevations of methylmalonic acid alone should be interpreted with caution.
  • Furthermore, an elevated homocysteine level can be due to either vitamin B12 or folate deficiency. In addition to monitoring serum B12, methylmalonic acid, and homocysteine levels, folic acid levels should probably also be routinely checked.

Causes of Vitamin B12 Deficiency

Once vitamin B12 deficiency is diagnosed, underlying causes can be sought:

  • Although autoimmune damage to parietal cells-usually diagnosed by the presence of antibodies to intrinsic factor and parietal cells-remains the most common cause of cobalamin deficiency, the widespread use of acid-blocking medications for ulcer or reflux treatment may be an increasingly common contributor. (Marcuard S, et al. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med. 1994;120:211-15 and Termanini B, et al. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. Am J Med. 1998;104:422-30)
  • Because the typical Western diet contains adequate amounts of vitamin B12-and since the body can store a two- to five-year supply-nutritional deficiency is rare in developed countries. However, alcoholics, elderly persons who eat restricted diets, and strict vegans are at risk.
  • Other causes of malabsorption, including Crohn's disease, celiac disease, atrophic gastritis, tapeworm infestation, and gastrectomy surgery are sometimes causative.
  • Rarely, hereditary defects in transport-protein synthesis can lead to vitamin B12 deficiency.

How is Vitamin B12 Deficiency Treated?

Injections with vitamin B12 have traditionally been physicians' treatment of choice for deficiency states. However, it has been known since 1968 that large oral doses of vitamin B12 (1,000 to 2,000 mcg daily) are safe, effective for reversing the deficiency, and well-tolerated by patients.

Vitamin B12 deficiency can go undetected until symptoms develop; with the increasing use of acid-blocking medications, more individuals may be at risk than was previously recognized.

The copyright of the article Vitamin B12 and Pernicious Anemia in Vitamins & Minerals is owned by Stephen Allen Christensen.