What are the causes of macrocytic anemia (large red blood cell anemia)?

From the Guidelines

Macrocytic anemia should be treated based on the underlying cause, with vitamin B12 deficiency treated with hydroxocobalamin 1 mg intramuscularly administered on alternate days until there is no further improvement, then hydroxocobalamin 1 mg intramuscularly administered every 2 months, as recommended by the most recent guidelines 1. The most common causes of macrocytic anemia include vitamin B12 deficiency, folate deficiency, alcoholism, liver disease, and certain medications.

• Vitamin B12 deficiency is a common cause of macrocytic anemia, and treatment should be initiated immediately, especially if there is possible neurological involvement, with hydroxocobalamin 1 mg intramuscularly administered on alternate days until there is no further improvement, then hydroxocobalamin 1 mg intramuscularly administered every 2 months 1.
• Folate deficiency may also cause macrocytic anemia, and treatment with oral folic acid 5 mg daily for a minimum of 4 months is recommended, after excluding vitamin B12 deficiency 1.
• Other causes of macrocytic anemia, such as alcoholism, liver disease, and certain medications, should be managed accordingly, with abstinence from alcohol, management of the underlying liver disease, and adjustment of medications as needed. Diagnosis of macrocytic anemia typically involves a complete blood count showing elevated mean corpuscular volume (MCV >100 fL), peripheral blood smear examination, and specific tests for B12 and folate levels, as well as additional testing such as methylmalonic acid and homocysteine levels, which are elevated in B12 deficiency 1. Prompt treatment of macrocytic anemia is important to prevent irreversible neurological damage in the case of vitamin B12 deficiency, and to reduce the risk of neural tube defects in the developing fetus in the case of folate deficiency during pregnancy. The classification of anemia based on mean corpuscular volume (MCV) and reticulocytes can help guide diagnosis and treatment, with macrocytic anemia characterized by an MCV >100 fL and normal or low reticulocytes, and may be caused by vitamin B12 or folate deficiency, among other causes 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 by less commonly inherited disorders of DNA synthesis 3.

Causes and Diagnosis of Macrocytic Anemia

• Vitamin B12 deficiency is the most common cause for megaloblastic anemia, although folate deficiency also can contribute 4.
• Nonmegaloblastic anemia entails normal DNA synthesis and typically is caused by chronic liver dysfunction, hypothyroidism, alcohol use disorder, or myelodysplastic disorders 4.
• The three most common causes of macrocytosis--vitamin B12 or folate deficiency, liver disease, and reticulocytosis--usually can 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, and it should be ordered in conjunction with serum and red cell folate determinations 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.
• Anemia and macrocytosis should not be used to predict folate or B12 deficiencies, or refractoriness to antidepressants, and measurement of folate and B12 should be considered when evaluating treatment refractoriness 6.

Relationship between Folate, Vitamin B-12, and Macrocytic Anemia

• Low vitamin B-12 status is associated with anemia, macrocytosis, and cognitive impairment in older Americans 7.
• In seniors with low vitamin B-12 status, high serum folate is associated with anemia and cognitive impairment, while high serum folate is associated with protection against cognitive impairment when vitamin B-12 status is normal 7.