Causes of Macrocytic Anemia
Classification by Reticulocyte Count
Macrocytic anemia is most effectively classified by reticulocyte count, which immediately distinguishes between production defects (low/normal reticulocytes) and hemolysis or hemorrhage (elevated reticulocytes). 1
Macrocytic Anemia with Low or Normal Reticulocytes
The following conditions impair red blood cell production and present with macrocytosis:
Megaloblastic Causes (Impaired DNA Synthesis)
- Vitamin B12 deficiency is the single most common cause of megaloblastic macrocytic anemia, accounting for approximately 78% of megaloblastic cases 2
- Folate deficiency causes megaloblastic anemia through impaired DNA synthesis, occurring with increased requirements (pregnancy, hemolysis, chronic myeloid leukemia) 1
- Combined B12 and folate deficiency occurs in approximately 22% of megaloblastic anemia cases, typically in malabsorption syndromes 2
- Long-term cytostatic medications including hydroxyurea, methotrexate, and azathioprine cause macrocytosis by interfering with DNA synthesis 1, 3
Non-Megaloblastic Causes (Normal DNA Synthesis)
- Myelodysplastic syndrome (MDS) represents approximately 35% of non-megaloblastic macrocytic anemia cases and is particularly important in elderly patients 1, 2
- Hypothyroidism causes macrocytic anemia through reduced erythropoietin production and decreased bone marrow activity 1, 4
- Alcoholism produces isolated macrocytosis (often without anemia initially) through direct toxic effects on erythropoiesis 1, 5
- Liver disease (chronic dysfunction) causes macrocytosis through altered lipid metabolism affecting red cell membranes 1, 6
- Thiamine-responsive megaloblastic anemia syndrome is a very rare inherited disorder 1
Macrocytic Anemia with Elevated Reticulocytes
- Hemolytic anemia produces "false macrocytosis" because reticulocytes are larger than mature red cells and elevate the MCV 1
- Myelodysplastic syndrome with hemolysis can present with both macrocytosis and elevated reticulocytes 1
Key Diagnostic Distinctions
An MCV >110 fL strongly suggests megaloblastic anemia (p=0.0007), making vitamin B12 or folate deficiency the most likely diagnosis. 2 In contrast, modest macrocytosis (MCV 100-110 fL) is more commonly associated with non-megaloblastic causes such as alcoholism, liver disease, or hypothyroidism. 5
Neutrophil hypersegmentation on peripheral blood smear is one of the most sensitive and specific signs of megaloblastic anemia, helping distinguish it from non-megaloblastic causes. 5
Critical Clinical Pitfall
Three important caveats warrant emphasis: First, combined iron deficiency with B12/folate deficiency can mask macrocytosis, presenting with a normal MCV but elevated RDW—this combination is very rare but occurs in malabsorption. 1 Second, patients with megaloblastic marrow who fail to respond to vitamin replacement may have underlying MDS, particularly if elderly (mean age 55 years in one series). 2 Third, primary bone marrow diseases including leukemias and MDS must be considered when pancytopenia accompanies macrocytic anemia. 1
Relative Frequency
In clinical practice, megaloblastic anemia accounts for approximately 38% of all macrocytic anemia cases, with vitamin B12 deficiency being the predominant etiology. 2 Primary bone marrow disorders (particularly MDS) represent 35% of cases, liver diseases 15%, and hemolytic anemia 8%. 2 Macrocytosis is found in approximately 2-4% of laboratory evaluations. 5