From the Guidelines
Macrocytic anemia should be treated with vitamin B12 supplementation if the deficiency is present, and oral folic acid if folate deficiency is confirmed, after excluding vitamin B12 deficiency, to prevent complications such as permanent neurological damage and worsening anemia. The most common causes of macrocytic anemia are vitamin B12 and folate deficiency, and treatment depends on the underlying cause 1. For vitamin B12 deficiency with possible neurological involvement, hydroxocobalamin 1 mg intramuscularly should be administered on alternate days until there is no further improvement, then hydroxocobalamin 1 mg intramuscularly administered every 2 months 1. For people with vitamin B12 deficiency and no neurological involvement, hydroxocobalamin 1 mg intramuscularly should be administered three times a week for 2 weeks, followed by maintenance treatment with 1 mg intramuscularly every 2–3 months for life 1.
Key Considerations
- Folic acid deficiency may indicate non-adherence with the daily multivitamin and mineral supplement or malabsorption, and some medications, such as anticonvulsants, sulfasalazine, and methotrexate, may affect folic acid levels 1.
- For treatment of folic acid deficiency, oral folic acid 5 mg daily should be given for a minimum of 4 months, after excluding vitamin B12 deficiency 1.
- Laboratory evaluation should include complete blood count, peripheral blood smear, reticulocyte count, vitamin B12 and folate levels, liver function tests, and thyroid function tests.
- Macrocytic anemia often develops gradually, with symptoms including fatigue, weakness, shortness of breath, pale skin, and neurological symptoms in B12 deficiency cases.
Diagnosis and Treatment Approach
- The morphologic approach to evaluating anemia characterizes it based on the mean corpuscular volume (MCV), with macrocytic anemia having an MCV greater than 100 fL, often indicating vitamin B12 or folate deficiency 1.
- The kinetic approach focuses on the underlying mechanism of anemia, distinguishing among the production, destruction, and loss of RBCs, with a reticulocyte count corrected against the degree of anemia providing an indication of the RBC production capacity by the bone marrow 1.
From the FDA Drug Label
Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective deoxyribonucleic acid (DNA) synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. The answer to the question about macrocytic anemia is that folic acid deficiency can lead to macrocytic anemia due to impaired thymidylate synthesis and defective DNA synthesis, resulting in megaloblast formation. Key points include:
- Megaloblastic anemia is associated with folic acid deficiency
- Macrocytic anemia is a type of anemia that can occur due to folic acid deficiency
- Folic acid is necessary for normal erythropoiesis and nucleoprotein synthesis 2
From the Research
Definition and Classification of Macrocytic Anemia
- Macrocytic anemia is defined as a red blood cell (RBC) mean corpuscular volume (MCV) >100 femtoliter (fL) 3.
- It is generally classified into megaloblastic or nonmegaloblastic anemia 3, 4.
- Megaloblastic anemia is caused by deficiency or impaired utilization of vitamin B12 and/or folate, whereas nonmegaloblastic macrocytic anemia is caused by various diseases such as myelodysplastic syndrome (MDS), liver dysfunction, alcoholism, hypothyroidism, certain drugs, and less commonly inherited disorders of DNA synthesis 3.
Causes of Macrocytic Anemia
- Vitamin B12 deficiency is the most common cause of megaloblastic anemia 4.
- Folate deficiency can also contribute to megaloblastic anemia 4.
- Nonmegaloblastic anemia can be caused by chronic liver dysfunction, hypothyroidism, alcohol use disorder, or myelodysplastic disorders 4.
- Macrocytosis can also result from the release of reticulocytes in the normal physiologic response to acute anemia 4.
Diagnosis and Investigation of Macrocytic Anemia
- The three most common causes of macrocytosis -- vitamin B12 or folate deficiency, liver disease, and reticulocytosis -- can usually be differentiated on the basis of red cell indexes and morphologic findings 5.
- Serum vitamin B12 determination remains the best test for unmasking vitamin B12 deficiency 5.
- Serum and red cell folate determinations should be ordered in conjunction with serum vitamin B12 determination in the course of investigating a macrocytic anemia 5.
Treatment and Management of Macrocytic Anemia
- Macrocytic anemias are treated with cause-specific therapies, and it is crucial to differentiate nonmegaloblastic from megaloblastic anemia 3.
- Management of macrocytic anemia is specific to the etiology identified through testing and patient evaluation 4.
- Measurement of folate and B12 should be considered when evaluating treatment refractoriness 6.
Relationship between Macrocytic Anemia and Folate/Vitamin B12 Deficiency
- Anemia and macrocytosis are well-defined expected hematologic findings of vitamin B12 and folate deficiency 7.
- However, some studies have shown that anemia and macrocytosis may not always be associated with subnormal B12 or folate levels 6, 7.
- Determining a hematologic cutoff value may help physicians in clinical practice to identify patients with vitamin B12 or folate deficiency 7.