The causes of cobalamin deficiency are listed in Table 6-1. The vast majority of affected individuals have some type of gastrointestinal malabsorption. In the United States and in other areas with temperate climate, most patients have either pernicious anemia or food cobalamin malabsorption.
TABLE 6-1Causes of Cobalamin Deficiency ||Download (.pdf) TABLE 6-1 Causes of Cobalamin Deficiency
Intrinsic factor deficiency
Food cobalamin malabsorption-common
Disease of distal ileum: sprue, ileitis, resection
Competition from parasites
Bacteria: "blind loop"; intestinal diverticulum
Much less common:
Inadequate dietary intake
Pernicious anemia is an autoimmune disorder that destroys the parietal cells in the gastric mucosa. These cells are the site of both intrinsic factor production and the pumping of protons into the gastric lumen. A gastric biopsy may reveal an infiltrate of lymphocytes and plasma cells in the lamina propria. With time, the mucosa atrophies, and the gastric wall becomes thin. Some studies have suggested that the autoimmune attack on gastric parietal cells is a consequence of inflammation induced by Helicobacter pylori infection. As shown in Figure 6-1, the absence of intrinsic factor prevents cobalamin from being absorbed in the distal ileum. Normally, 2 to 3 mg of cobalamin is stored in the liver. With loss of intrinsic factor, cobalamin can no longer be absorbed; after 2 to 5 years, the stores in the liver are exhausted, and the patient is at risk of developing severe deficiency.
An even more common cause of cobalamin deficiency is malabsorption due to the absence of gastric acid that is necessary for the transfer of cobalamin in food to haptocorrin (Fig. 6-1). The prevalence of gastric achlorhydria increases sharply with age, affecting 40% of individuals over age 80. Cobalamin deficiency is also encountered among younger individuals following long-term administration of proton pump inhibitors for treatment of various disorders of the upper gastrointestinal tract. Because intrinsic factor is present, the impairment in cobalamin absorption is less marked than in pernicious anemia. Accordingly, the deficiency takes longer to develop and is usually less severe.
Because intrinsic factor is produced only in the stomach, it follows that total gastrectomy will lead to malabsorption of cobalamin. By the same token, surgical resection of the terminal ileum, where cobalamin is absorbed, has the same effect. However, these surgeries are seldom performed and are therefore uncommon causes of cobalamin deficiency. In contrast, deficiency of both cobalamin and folate is often encountered in certain parts of the world near the equator including Puerto Rico and Haiti, owing to a chronic malabsorption condition known as tropical sprue. The cause of this disorder is unclear, but the fact that patients respond to antibiotic therapy offers a clue to pathogenesis. Other chronic inflammatory diseases of the ileum such as regional enteritis (e.g., Crohn disease) also can lead to cobalamin malabsorption. Deficiency of cobalamin also may arise because of competition from organisms within the gastrointestinal tract. Anatomical stasis due to diverticula, stricture, or surgically created "blind loops" can lead to overgrowth of bacteria that usurp cobalamin-intrinsic factor complexes that are en route to the ileum. In Scandinavia, infestation with the fish tapeworm results in a similar parasitic confiscation of cobalamin.
Two other rare causes of cobalamin deficiency deserve mention. Individuals who are strict vegans and ingest no animal products at all (including dairy products) may, over a protracted time period, become deficient. In contrast, acute cobalamin deficiency is occasionally encountered in individuals following prolonged exposure to the anesthetic agent nitrous oxide, which can combine chemically with cobalamin and abolish its biological activity.
Hematologic-common: Anemia > ↓ WBC, ↓ Plts
Gastrointestinal-rare: Glossitis, malabsorbtion
Neurologic-common: Neuropathy > spinal disease > dementia
Patients with cobalamin deficiency come to medical attention because of anemia and/or neurological symptoms. They tend to be elderly. Those with pernicious anemia may have other autoimmune manifestations such as vitiligo or antibody-mediated endocrinopathies. The onset of the anemia is insidious, with symptoms and signs no different than those seen in other causes of chronic anemia. The anemia is often severe. It is not unusual for a patient with cobalamin deficiency to present with a hemoglobin level as low as 5 g/dL. In addition to pallor, a patient's skin may have a lemon tinge, and there may be slight scleral icterus, owing to increased levels of bilirubin in the plasma arising from destruction of erythroid cells in the bone marrow (ineffective erythropoiesis).
Although cobalamin deficiency can impair proliferation of mucosal cells in the gastrointestinal tract, this seldom causes symptoms. Some patients develop a sore, beefy red, smooth tongue (glossitis) due to atrophy of the papillae (Fig. 6-7). Cobalamin deficiency can also cause blunting of the mucosal villi in the small intestine and mild malabsorption. These findings are normalized by treatment.
Atrophic glossitis in a patient with pernicious anemia. The smooth surfaces on the periphery of the tongue reflect loss of papillae.
Neurological manifestations are an important and sometimes overlooked consequence of cobalamin deficiency. They are generally associated with severe anemia. However, patients may present with significant neurological findings without anemia or even macrocytosis. Most patients complain of numbness or tingling, generally in the legs. Less often patients develop ataxia and loss of proprioception as a result of damage to the posterior columns of the spinal cord. They also may have muscle weakness and spasticity as a result of damage to the lateral columns (Fig. 6-8). Dementia may be observed in patients with severe cobalamin deficiency. As a rule of thumb, any patient who presents with neurological manifestations of peripheral neuropathy, ataxia, or dementia should be evaluated for cobalamin deficiency, even in the absence of concurrent anemia or macrocytosis.
Spinal cord section showing demyelination of the posterior and lateral columns (arrows) in a patient with pernicious anemia.
The hematologic features of the megaloblastic anemias are described earlier and do not distinguish in any way between cobalamin and folate deficiency. Demonstration of a low serum cobalamin level is a useful initial step in establishing a diagnosis. However, if the result is at the lower end of the normal range, cobalamin deficiency can be verified by an elevation in the serum levels of methylmalonate and homocysteine, which are the substrates for the respective adenosylcobalamin and methylcobalamin reactions (Fig. 6-3). Once cobalamin deficiency is documented, its cause should be investigated. About half of patients with pernicious anemia will have antibodies in the serum against intrinsic factor. Gastric achlorhydria will be found in all those with either pernicious anemia or food cobalamin malabsorption. If stomach acid is present, it is likely that the patient has either bacterial overgrowth or malabsorption in the terminal ileum.
In all patients with cobalamin deficiency, replacement therapy results in complete cure of the hematologic abnormalities, unless there is a second process that independently suppresses erythropoiesis. Unfortunately, therapy is much less effective in reversing the neurological complications. It is important to establish a diagnosis prior to instituting a treatment plan because the administration of folate to a cobalamin-deficient patient will partially correct the anemia but (for unknown reasons) may exacerbate the neurological manifestations.
Patients with severe anemia are at risk of becoming hypokalemic immediately following initiation of therapy, owing to the anabolic burst of orderly cell division. Moreover, these patients, particularly the elderly, may be at the brink of cardiac decompensation. Therefore, sudden expansion of blood volume should be carefully avoided. Typically, these patients mount a brisk hematologic recovery, and red cell transfusions should be avoided unless the patient evinces symptoms or signs of ischemic damage to vital organs such as the brain or heart.
Because the vast majority of cobalamin deficiency is due to malabsorption, replacement therapy is given parenterally. Regular injections of cobalamin (initially weekly, then monthly) are effective in keeping patients in hematologic remission. A typical response following the initiation of treatment is shown in Figure 6-9. A rapid rise in the reticulocyte count, peaking at about day 7, is followed by a slower but steady rise in hemoglobin and hematocrit concentrations, accompanied by a decline in the MCV to normal. Oral administration of cobalamin can be equally effective when given in doses high enough to penetrate the intestinal mucosal barrier by mass action. However, because many patients (particularly the elderly) fail to take their medications regularly, most physicians favor parenteral administration.
Response of a patient with pernicious anemia to cobalamin therapy. Note the brisk reticulocyte response during the first week of therapy and the subsequent rise in hemoglobin (Hb) and red cell count (RBC). Note also the shift in the ratio of (Hb) to RBC, reflecting the gradual reduction in mean cell volume during therapy.