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  • Macrocytic anemia.

  • Megaloblastic blood smear (macro-ovalocytes and hypersegmented neutrophils).

  • Low serum vitamin B12 level.


Vitamin B12 belongs to the family of cobalamins and serves as a cofactor for two important reactions in humans (eFigure 13–7). As methylcobalamin, it is a cofactor for methionine synthetase in the conversion of homocysteine to methionine, and as adenosylcobalamin for the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA. These enzymatic steps are critical for annealing Okazaki fragments during DNA synthesis, particularly in erythroid progenitor cells. Vitamin B12 comes from the diet and is present in all foods of animal origin. The daily absorption of vitamin B12 is 5 mcg.

eFigure 13–7.

Role of cobalamin (vitamin B12) and folic acid in nucleic acid and myelin metabolism. Lack of either cobalamin or folic acid retards DNA synthesis (A), and lack of cobalamin leads to loss of folic acid, which cannot be held intracellularly unless polyglutamated. Lack of cobalamin also leads to abnormal myelin synthesis, probably via a deficiency in methionine production (B).

After being ingested, vitamin B12 is bound to intrinsic factor, a protein secreted by gastric parietal cells in an acid environment. Other cobalamin-binding proteins (called R factors) compete with intrinsic factor for vitamin B12. Vitamin B12 bound to R factors cannot be absorbed. The vitamin B12–intrinsic factor complex travels through the intestine and is absorbed in the terminal ileum by cells with specific receptors for the complex. It is then transported through plasma and stored in the liver. Three plasma transport proteins have been identified. Transcobalamins I and III (differing only in carbohydrate structure) are secreted by white blood cells. Although approximately 90% of plasma vitamin B12 circulates bound to transcobalamins I and III, only transcobalamin II is capable of transporting vitamin B12 into cells.

The liver contains 2–5 mg of stored vitamin B12. Since daily utilization is 3–5 mcg, the body usually has sufficient stores of vitamin B12 so that it takes more than 3 years for vitamin B12 deficiency to occur if all intake or absorption immediately ceases.

Since vitamin B12 is present in foods of animal origin, dietary vitamin B12 deficiency is extremely rare but is seen in vegans—strict vegetarians who avoid all dairy products, meat, and fish (Table 13–6). Pernicious anemia is an autoimmune illness whereby autoantibodies destroy gastric parietal cells (that produce intrinsic factor) and cause atrophic gastritis or bind to and neutralize intrinsic factor, or both. Abdominal surgery may lead to vitamin B12 deficiency in several ways. Gastrectomy will eliminate the site of intrinsic factor production; blind loop syndrome will cause competition for vitamin B12 by bacterial overgrowth in the lumen of the intestine; ...

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