Differential diagnosis of macrocytosis. The first branchpoint is the reticulocyte count. Since reticulocytes are larger than mature red blood cells, increased numbers of reticulocytes can cause macrocytosis. If reticulocytes are not increased, there is a tendency to split the causes into megaloblastic vs. non-megaloblastic. However, the definition of megaloblastic varies between authors. In some cases, it is defined as nuclear-cytoplasmic asynchrony in erythroid precursors (and/or the presence of hypersegmented neutrophils on the peripheral smear). Elsewhere it is defined more loosely as impaired DNA synthesis. Vitamin B12 and folate deficiency are unequivocally megaloblastic in nature. However, some medications can impair DNA synthesis without resulting in classic morphological changes, and it is not clear whether or not they should be included in the megaloblastic category. On the non-megaloblastic side, it is important to distinguish between spurious macrocytosis (lab artifact) and real macrocytosis. Spurious causes of macrocytosis are usually identified and corrected by the hematology lab before being reported to the clinician. Causes of true macrocytosis are highly varied.
Despite extensive work up, about 20% of cases of macrocytosis remain undiagnosed.
About 50% of cases of macrocytosis occur without anemia.
