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The megaloblastic anemias are a group of disorders characterized by the presence of distinctive morphologic appearances of the developing red cells in the bone marrow. The marrow is usually cellular and the anemia is based on ineffective erythropoiesis. The cause is usually a deficiency of either cobalamin (vitamin B12) or folate, but megaloblastic anemia may occur because of genetic or acquired abnormalities that affect the metabolism of these vitamins or because of defects in DNA synthesis not related to cobalamin or folate (Table 105–1). Cobalamin and folate absorption and metabolism are described next, followed by the biochemical basis, clinical and laboratory features, causes, and treatment of megaloblastic anemia.

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Table 105–1 Causes of Megaloblastic Anemia 
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Cobalamin (vitamin B12) exists in a number of different chemical forms. All have a cobalt atom at the center of a corrin ring. In nature, the vitamin is mainly in the 2-deoxyadenosyl (ado) form, which is located in mitochondria. It is the cofactor for the enzyme methylmalonyl coenzyme A (CoA) mutase. The other major natural cobalamin is methylcobalamin, the form in human plasma and in cell cytoplasm. It is the cofactor for methionine synthase. There are also minor amounts of hydroxocobalamin to which methyl- and adocobalamin are converted rapidly by exposure to light.

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Dietary Sources and Requirements

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Cobalamin is synthesized solely by microorganisms. Ruminants obtain cobalamin from the foregut, but the only source for humans is food of animal origin, e.g., meat, fish, and dairy products. Vegetables, fruits, and other foods of nonanimal origin are free from cobalamin unless they are contaminated by bacteria. A normal Western diet contains 5–30 μg of cobalamin daily. Adult daily losses (mainly in the urine and feces) are 1–3 μg (∼0.1% of body stores), and as the body does not have the ability to degrade cobalamin, daily requirements are also about 1–3 μg. Body stores are of the order of 2–3 mg, sufficient for 3–4 years if supplies are completely cut off.

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Absorption

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Two mechanisms exist for cobalamin absorption. One is passive, occurring equally through buccal, duodenal, and ileal mucosa; it is rapid but extremely inefficient, with <1% of an oral dose being absorbed by this process. The normal physiologic mechanism is active; it occurs through the ileum and is efficient for small (a few micrograms) oral doses of cobalamin, and it is mediated by gastric intrinsic factor (IF). Dietary cobalamin is released from protein complexes by enzymes in the stomach, duodenum, and jejunum; it combines rapidly with a salivary glycoprotein that belongs to the family of cobalamin-binding proteins known as haptocorrins (HCs). In the intestine, the haptocorrin is digested by pancreatic trypsin and the cobalamin is transferred to IF.

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IF (gene at chromosome 11q13 coding for 9 exons) ...

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