After absorption, the body handles vitamin B12 very efficiently. It is stored in the liver, which normally contains reserves sufficient to support bodily needs for 5 to 20 years. Because of these large liver stores, clinical presentations of vitamin B12 deficiency typically follow years of unrecognized malabsorption.
The most frequent cause vitamin B12 deficiency is pernicious anemia, which is believed to result from an autoimmune attack on the gastric mucosa that suppresses the production of intrinsic factor. Histologically, there is a chronic atrophic gastritis marked by a loss of parietal cells, a prominent infiltrate of lymphocytes and plasma cells, and megaloblastic changes in mucosal cells similar to those found in erythroid precursors. The serum of most affected patients contains several types of autoantibodies that block the binding of vitamin B12 to intrinsic factor or prevent binding of the intrinsic factor–vitamin B12 complex to cubilin. Autoantibodies are of diagnostic use, but they are not thought to be the primary cause of the gastric pathology; rather, it seems that an autoreactive T cell response initiates gastric mucosal injury and triggers the formation of autoantibodies. When the mass of intrinsic factor-secreting cells falls below a threshold (and reserves of stored vitamin B12 are depleted), anemia develops.
Other causes of vitamin B12 malabsorption include gastrectomy (leading to loss of intrinsic factor–producing cells), ileal resection (resulting in loss of intrinsic factor–B12 complex–absorbing cells), and disorders that disrupt the function of the distal ileum (such as Crohn disease, tropical sprue, and Whipple disease). Particularly in older persons, gastric atrophy and achlorhydria may interfere with the production of acid and pepsin, which are needed to release the vitamin B12 from its bound form in food.
The metabolic defects responsible for the anemia of vitamin B12 deficiency are intertwined with folate metabolism. Vitamin B12 is required for recycling tetrahydrofolate, which, as described previously, is the form of folate that is needed for DNA synthesis. In keeping with this relationship, the anemia of vitamin B12 deficiency is reversed with the administration of folate.
By contrast, folate administration does not prevent and may in fact worsen certain neurologic symptoms that are specific to vitamin B12 deficiency. The main neurologic lesions associated with vitamin B12 deficiency are demyelination of the posterior and lateral columns of the spinal cord, sometimes beginning in the peripheral nerves. In time, axonal degeneration may supervene. The severity of the neurologic manifestations is not related to the degree of anemia. Indeed, neurologic disease may occur in the absence of overt megaloblastic anemia.
Clinical Features. The manifestations of vitamin B12 deficiency are nonspecific. As with all anemias, findings include pallor, easy fatigability, and, in severe cases, dyspnea and even congestive heart failure. The increased destruction of erythroid progenitors because of ineffective erythropoiesis may give rise to mild jaundice, and megaloblastic changes in the oropharyngeal epithelium may produce a beefy red tongue. The spinal cord disease begins with symmetric numbness, tingling, and burning in the feet or hands, followed by unsteadiness of gait and loss of position sense, particularly in the toes. Although the anemia responds dramatically to parenteral vitamin B12, the neurologic manifestations often fail to resolve. As discussed in Chapter 15, patients with pernicious anemia have an increased risk for the development of gastric carcinoma.
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