Megaloblastic Anemias

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Chapter 448 Megaloblastic Anemias

Megaloblastic anemia is a macrocytic anemia characterized by ineffective erythropoiesis, a kinetic term that describes active erythropoiesis associated with premature cell death and decreased red blood cell (RBC) output from the bone marrow. The RBCs are larger than normal at every developmental stage, and maturational asynchrony between the nucleus and cytoplasm of erythrocytes is present. The delayed nuclear development becomes increasingly evident as cell divisions proceed. Myeloid and platelet precursors are also affected, and giant metamyelocytes and neutrophil bands are often present in the bone marrow. There is usually an associated thrombocytopenia and leukopenia. The peripheral blood smear is notable for large, often oval, RBCs, with increased mean corpuscular volume (MCV). Neutrophils are characteristically hypersegmented, with many having >5 lobes. Almost all cases of childhood megaloblastic anemia result from folic acid or vitamin B12 deficiency; rarely, they may be caused by inborn errors of metabolism. Because folate and vitamin B12 are both required for the manufacture of nucleoproteins, deficiencies result in defective DNA and, to a lesser extent, RNA and protein synthesis. Megaloblastic anemias resulting from malnutrition are relatively uncommon in the USA but are important worldwide (Chapters 1 and 43).

448.1 Folic Acid Deficiency

Folic acid, or pteroylglutamic acid, consists of pteroic acid conjugated to glutamic acid. Biologically active folates are derived from folic acid and serve as one-carbon donors and acceptors in many biosynthetic pathways. As such, they are essential for DNA replication and cellular proliferation. Like other mammals, humans cannot synthesize folate and depend on dietary sources, including green vegetables, fruits, and animal organs (e.g., liver, kidney). Folates are heat labile and water soluble, and consequently boiling or heating folate sources leads to decreased amounts of vitamin. Naturally occurring folates are in a polyglutamated form that is less-efficiently absorbed than the monoglutamate species (i.e., folic acid). Dietary folate polyglutamates are hydrolyzed to simple folates that are absorbed primarily in the proximal small intestine by a specific carrier-mediated system. There is an active enterohepatic circulation. Folic acid is not biologically active and is reduced by dihydrofolate reductase to tetrahydrofolate, which is transported into tissue cells and polyglutamated. Because body stores of folate are limited, megaloblastic anemia will occur after 2-3 mo on a folate-free diet.


Folic acid deficiency can occur as a consequence of inadequate folate intake, decreased folate absorption, or acquired and congenital disorders of folate metabolism.

Laboratory Findings

The anemia is macrocytic (mean corpuscular volume >100 fL). Variations in RBC shape and size are common (see Fig. 441-2). The reticulocyte count is low, and nucleated RBCs demonstrating megaloblastic morphology often are seen in the blood. Neutropenia and thrombocytopenia may rarely be present, particularly in patients with long-standing and severe deficiencies. The neutrophils are large, some with hypersegmented nuclei. Normal serum folic acid levels are 5-20 ng/mL; with deficiency, levels are <3 ng/mL. Levels of RBC folate are a better indicator of chronic deficiency. The normal RBC folate level is 150-600 ng/mL of packed cells. Levels of iron and vitamin B12

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