The basic cause of megaloblastic anemias is impaired DNA synthesis (delayed mito-ses) without impairment of RNA synthesis; this produces a nuclear-cytoplasmic asynchrony that affects all rapidly proliferating cell lines, including cells of the bone marrow, gastrointestinal tract, and gynecologic system. The erythrocytes are the most obvious rapidly proliferating cells that exhibit these changes, and specifically show megaloblastic maturation, with megaloblasts in bone marrow forming macro-ovalocytes in peripheral blood. Autohemolysis of the affected megaloblasts in bone marrow (ineffective erythropoiesis) will cause increased bilirubin and increased lac-tate dehydrogenase (LDH). White blood cell changes include giant metamyelocytes in bone marrow and hypersegmented neutrophils (>5 lobes) in peripheral blood. Note that platelets are not increased in size.
· Dietary deficiency is rare because B12 is stored in the liver and it takes years to develop dietary deficiency; it is usually seen only in strict vegetarians (diet with no animal protein, milk, or eggs).
· Decreased absorption of vitamin B12 is more common and may be caused by decreased intrinsic factor associated with gastrectomy or pernicious anemia (an autoimmune gastritis); pancreatic insufficiency (pancreatic proteases nor-mally break down B12-R complexes in duodenum); or intestinal malabsorption due to parasites (fish tapeworm [Diphyllobothrium latum]), bacteria (blind-loop syndrome), or Crohn’s disease of the ileum.
· Clinically, B12 deficiency causes weakness due to anemia (megaloblastic ane-mia) and sore (“beefy”) tongue due to generalized epithelial atrophy. Unlike folate deficiency, vitamin B12 deficiency can also cause the central nervous system effects of subacute combined degeneration of the spinal cord, char-acterized by demyelination of the posterior and lateral columns of the spinal cord; the posterior (sensory) tract damage causes loss of vibratory and position sense, while the lateral cord damage involves dorsal spinocerebellar tracts (arm and leg dystaxia) and corticospinal tracts (spastic paralysis).
· Lab tests show low serum B12, increased serum homocysteine, and increased methylmalonic acid in urine. Treatment is intramuscular vitamin B12, which will cause increased reticulocytes in about 5 days.
Megaloblastic anemia due to folate deficiency can be caused by multiple processes:
· Decreased intake in chronic alcoholics and the elderly
· Decreased absorption in the upper small intestine
· Increased requirement for folate during pregnancy and infancy
· Folate antagonists, e.g., methotrexate
Clinically, folate deficiency produces megaloblastic anemia without neurologic dis-ease symptoms. Lab tests show low serum folate levels and increased serum homo-cysteine. Treatment is folate replacement.