The CAP Today monthly Q & A column allows readers to submit their pathology-related questions for reply by appropriate medical consultants. April’s Q & A column features a response from Jennifer Oliveira, M.D., Division of Hematopathology, Co-Director, Metabolic, Hematology Laboratory, at Mayo Clinic in Rochester, Minnesota, regarding recommendations for microcytosis cases with high RBC count but without anemia.
Q. We review peripheral blood smears and sometimes provide recommendations. For microcytic anemia with high red blood cell (RBC) count, iron study and hemoglobin electrophoresis are suggested to rule out hemoglobinopathy. But for cases of microcytosis with high RBC count but without anemia, should we give the same recommendation as for an anemic patient?
A. I find microcytosis to be a fascinating and sometimes oversimplified issue. As the question suggests, the differential diagnosis for microcytic anemia versus microcytosis without anemia contains overlapping entities. An increase in RBC count relative to the hemoglobin level can be used as a factor to consider; in combination with microcytosis and a relatively normal red cell distribution width, these are traditionally termed “thalassemic indices.” Typically, when iron deficiency is the cause of microcytosis, the RBC count is decreased proportionately to the hemoglobin and hematocrit. When thalassemia is present, there may be an increased or at least a relatively increased (greater than three times the Hgb level) RBC count in relation to the hemoglobin and hematocrit. Many hemoglobin disorders result in microcytic anemia. In addition, a number of them are associated with normal hemoglobin levels and the only indication is the microcytosis and possibly an increased RBC count. In these situations, the recommendation to exclude a hemoglobinopathy or thalassemia is appropriate because many common alpha and beta thalassemias, as well as other hemoglobin conditions such as large beta globin cluster deletions (hereditary persistence of fetal hemoglobin, delta beta thalassemia, epsilon gamma delta beta thalassemia) and hemoglobin variants (Hb E, Hb C, compensated unstable variants), can be present. Additional causes of microcytosis with normal hemoglobin levels include polycythemic conditions (polycythemia vera, congenital erythrocytosis mutations, and high oxygen affinity hemoglobin variants) with coincident iron deficiency.
Many polycythemic patients undergo therapeutic chronic phlebotomy to control the elevated hemoglobin levels through iatrogenic iron deficiency. In polycythemia, iron deficiency counterbalances the abnormally increased RBC production, and the opposing conditions result in a targeted (usually normal) hemoglobin level with increased RBC count, although the RDW can be variably elevated, likely due to the introduction of reticulocytes.
In summary, for patients with increased RBC count and microcytosis but normal hemoglobin values, the differential diagnosis most commonly includes a hemoglobin disorder or a polycythemic disorder with coincident iron deficiency. Even in the absence of anemia, the proper evaluation of unexplained microcytosis is often clinically useful. A definitive identification of a hemoglobin disorder is required for genetic counseling purposes, and discouraging unnecessary chronic iron supplementation is important in thalassemia patients because they are prone to iron overload.