large before division. Additional causes of megaloblastic anemia include medications that interfere with DNA synthesis or with the absorption or metabolism of Vitamin B12 or folate such as methotrexate, sulfasalazine, metformin, anticonvulsant medications (e.g., valproic acid or phenytoin), certain antibiotics (e.g., trimethoprim/sulfamethoxazole), antiretroviral medications, cholestyramine, triamterene, and nitrous oxide. Non-Megaloblastic anemias Red cell membrane disorders producing codocytes Other disorders which cause macrocytosis without DNA replication problems (i.e., non-megaloblastic macrocytic anemias), are disorders associated with increased red cell membrane surface area, such as pathologies of the liver and spleen which produce codocytes or "target cells" which have a central collection of hemoglobin surrounded by a pallor (a thin area) then followed by a thicker collection of hemoglobin at the rim of the cell. Alcohol Round macrocytes which are not codocytes are produced in chronic alcoholism (which produces a mild macrocytosis even in the absence of vitamin deficiency), apparently as a direct toxic effect of alcohol specifically on the bone marrow. Excessive alcohol consumption is one of the most common causes of macrocytosis and non-megaloblastic macrocytic anemia. Association with rapid red cell turnover and reticulocytosis Mild macrocytosis is a common finding associated with rapid blood restoration or production, since in general, "fresh" or newly produced red cells (reticulocytes) are larger than the mean (average) size, due to slow shrinkage of normal cells over a normal red cell circulating lifetime. Thus, chronic obstructive pulmonary disease (COPD), in which red cells are rapidly produced in response to low oxygen levels in the blood, often produces mild macrocytosis. The macrocytosis associated with COPD is also attributed to excess cell water secondary to carbon dioxide retention. Also, rapid blood replacement from the marrow after a traumatic blood loss, or rapid red blood cell turnover from rapid hemolysis (G6PD deficiency), also often produces mild macrocytosis in the associated anemia. Diagnosis Several tests can help to elucidate the underlying cause of a person's macrocytic anemia. A peripheral blood smear is often recommended as a first step in the evaluation to determine if the macrocytic anemia has megaloblastic features since the causes of megaloblastic and non-megaloblastic macrocytic anemia differ and making this distinction can narrow the list of differential diagnoses. For non-megaloblastic macrocytic anemias, a reticulocyte count may be helpful. Non-megaloblastic macrocytic anemias with a low reticulocyte count (indicating a poor bone marrow response to the anemia) suggest liver disease (e.g., cirrhosis), hypothyroidism, toxic effects of alcohol on the