Drug-Induced Megaloblastic Anemia.

More than 50 years ago, Victor Herbert first described the concept that defective nucleoprotein synthesis, attributable to various causes, results in the development of megaloblastic anemia.1 Megaloblastic anemia is characterized by the presence of a hypercellular marrow with large, abnormal hematopoietic progenitor cells with a characteristic finely stippled, lacy nuclear chromatin pattern. These abnormal progenitor cells, or megaloblasts, were first described by Paul Ehrlich in 1880. Leukopenia and thrombocytopenia are frequently present. Although the marrow is hypercellular, many of the cells die within it in a process called ineffective erythropoiesis. Megaloblastosis usually results from a deficiency of vitamin B12 (cobalamin) or folic acid, or a deficiency in their metabolism; however, any interference with the synthesis of purines, pyrimidines, or protein may result in megaloblastosis.2 Megaloblastic maturation is the morphologic result of any biochemical defect that causes a slowing of DNA synthesis. The hallmark of this megaloblastosis is nuclear-cytoplasmic dissociation; the nucleus remains immature in appearance while the cytoplasm matures more normally. This dissociation, which is the result of DNA synthesis that is retarded relative to normal RNA and protein synthesis, is manifested in the marrow and other proliferating tissues in the body by large cells containing a large nucleus with a diffuse and immature-appearing chromatin content, surrounded by normal-appearing cytoplasm.3 However, a high mean corpuscular volume does not necessarily imply a diagnosis of megaloblastic anemia. A high mean corpuscular volume is noted also in cases of alcohol abuse, hypothyroidism, aplastic anemia, myelodysplasia, and any condition in which the reticulocyte count is considerably elevated (such as in hemolytic anemia); it may also be a congenital finding. Since it was first described in 1849 by Thomas Addison,4 megaloblastic anemia has been attributed to both congenital (uncommon) and acquired (common) problems. It is most frequently related to vitamin B12 deficiency due to defective absorption, folic acid deficiency due to malnutrition, or both. However, because of the correction of most of the dietary causes of vitamin B12 and folate deficiency, druginduced megaloblastic anemia has become a more prominent cause of megaloblastic anemia. The drugs that may cause this condition are commonly used in clinical practice, and their effects on DNA synthesis pathways may be underappreciated (Table 1). A number of biochemical processes in DNA synthesis are vulnerable to inhibition by drugs, but among the most important of these is the new synthesis of thymidine. Figure 1 shows the structure of nucleotides and their associated terminology. Thymidine is a component of DNA but not RNA, and it is present in cells in rate-limiting amounts. The other nucleotides tend to be present in excess. Thymidine can be salvaged from the turnover of DNA, but the main source is the addition of a methyl group to the 5-position of the pyrimidine ring to convert From George Washington University and the Washington DC Veterans Affairs Medical Center, Washington, DC (C.S.H.). Address reprint requests to Dr. Hesdorffer at the Department of Medicine, Washington DC Veterans Affairs Medical Center, 50 Irving St. NW, Washington, DC 20422 or at charles . hesdorffer@ va . gov.