What is Megaloblastic Anemia

The term megaloblastic describes the characteristic appearance of the red cell precursors in the bone marrow. Megaloblastic anemias are caused by impaired DNA synthesis.

The term megaloblastic describes the characteristic appearance of the red cell precursors in the bone marrow. Megaloblastic anemias are caused by impaired DNA synthesis. Because the MCV is elevated (>100 fL), megaloblastic anemias are classified as macrocytic anemias. Because of perturbed DNA synthesis, the nucleus and cytoplasm mature at different rates, giving rise to cells with large, immatureappearing nuclei and a normal cytoplasm. This is referred to as nuclear-cytoplasmic asynchrony.

There are numerous causes of megaloblastic anemia, but by far the most common are folate deficiency, cobalamin (vitamin B12) deficiency, and certain drugs. Any disorder or condition leading to a deficiency of one or both of these nutrients, or that interferes with DNA synthesis, can precipitate a megaloblastic anemia.

Pathogenesis

Folate is a cofactor for the enzyme that converts deoxyuridine monophosphate to deoxythymidine monophosphate. The products undergo additional phosphorylation reactions, producing the deoxytriphosphate compounds (deoxythymidine triphosphate [dTTP], deoxyuridine triphosphate [dUTP]). When dTTP is deficient, dUTP is incorporated into DNA. The cell attempts to correct the base substitution, however, in the absence of dTTP, DNA fragmentation and cell death ensue.

Cobalamin is a required cofactor for the enzymes involved in producing bioactive folate. Therefore, it is believed that cobalamin deficiency leads to megaloblastic anemia by engendering a deficiency of usable folate (the methylfolate trap hypothesis).

Physiology

For normal adults, the daily requirement of folate is 50 ug. Foods rich in folate include green vegetables and fruits. The average daily American diet contains 400 to 600 ug of folate. Because some of the dietary folate may not be readily absorbed, the recommended daily allowance of folate is 0.4 mg. The total folate content in the average adult is approximately 5 mg. Therefore, when folate intake is deficient, megaloblastic anemia develops over a period of many months (>4 months). Folate requirements are increased when cell turnover or cell synthetic rates rise; examples: hemolytic anemias, alcoholism, pregnancy, and lactation (6-fold increase). Folate is absorbed mostly in the proximal jejunum; therefore, clinical conditions that induce injury at this site may impair folate absorption (sprue).

Cobalamin is synthesized from specific microorganisms. The dietary sources of cobalamin include meat, liver, seafood, and dairy products. Individuals not consuming these products must receive a cobalamin supplement to prevent deficiency. The average Western diet contains up to 30 ug of cobalamin per day, but only between 1 to 5 ug is absorbed. The average adult’s total body cobalamin content is 2 to 5 mg. Because the average daily losses of cobalamin amount to less than 0.1% of the body pool, it may take years to develop cobalamin deficiency even with complete abstinence. The recommended daily allowance of cobalamin for adults is 5 ug.

The absorption of cobalamin requires intrinsic factor, a glycoprotein synthesized and secreted by the parietal cells of the stomach. Additionally, gastric secretions contain R proteins, which bind cobalamin. Cobalamin in the diet is released via digestive enzymes in the stomach. Once free, the cobalamin is bound by R proteins in the stomach, and the cobalamin-R complexes are then degraded by pancreatic enzymes in the duodenum. The free cobalamin is then bound by intrinsic factor, and the intrinsic factor-cobalamin complex interacts with the intrinsic factor receptor, cubilin, and is subsequently absorbed. The terminal ileum has the highest density of cubilin.

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Norma MacLennan
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Posted on Dec 22, 2011