What causes macrocytic anemia (large red blood cell anemia)?

From the Guidelines

Macrocytic anemia is primarily caused by vitamin B12 deficiency and folate deficiency. The most common causes of megaloblastic, macrocytic anemia are vitamin B12 and folate deficiency, as stated in the British Obesity and Metabolic Surgery Society guidelines 1. These deficiencies can lead to impaired DNA synthesis in developing red blood cells, resulting in larger-than-normal cells (macrocytes) that function poorly and have shortened lifespans. Some key points to consider are:

• Vitamin B12 deficiency can result from inadequate dietary intake, malabsorption conditions, or gastrointestinal surgeries
• Folate deficiency typically stems from poor nutrition, alcoholism, or increased requirements during pregnancy
• Other causes of macrocytic anemia include alcoholism, liver disease, and certain medications that disrupt DNA synthesis, such as methotrexate and phenytoin Treatment of vitamin B12 deficiency involves hydroxocobalamin 1 mg intramuscularly administered on alternate days until there is no further improvement, then hydroxocobalamin 1 mg intramuscularly administered every 2 months 1. For folic acid deficiency, oral folic acid 5 mg daily should be given for a minimum of 4 months, but only after excluding vitamin B12 deficiency 1. It is essential to treat vitamin B12 deficiency immediately and address the underlying cause of the deficiency to prevent long-term complications and improve quality of life.

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. While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy

Causes of macrocytic anemia include:

• Folic acid deficiency, which impairs thymidylate synthesis and leads to defective DNA synthesis
• Certain medications, such as phenytoin, which can cause macrocytosis and megaloblastic anemia, usually responsive to folic acid therapy 2 3

From the Research

Causes of Macrocytic Anemia

• Macrocytic anemia is generally classified into megaloblastic or nonmegaloblastic anemia 4, 5
• Megaloblastic anemia is caused by deficiency or impaired utilization of vitamin B12 and/or folate 4, 5, 6, 7, 8
• Nonmegaloblastic macrocytic anemia is caused by various diseases such as:
  • Myelodysplastic syndrome (MDS) 4, 5
  • Liver dysfunction 4, 5
  • Alcoholism 4, 5
  • Hypothyroidism 4, 5
  • Certain drugs 4
  • Inherited disorders of DNA synthesis 4
• Macrocytosis can also result from the release of reticulocytes in the normal physiologic response to acute anemia 5

Relationship Between Vitamin B12, Folate, and Macrocytic Anemia

• Vitamin B12 and folate deficiencies may result in macrocytic anemia 6, 7, 8
• However, anemia and macrocytosis should not be used to predict folate or B12 deficiencies 6
• Measurement of folate and B12 should be considered when evaluating treatment refractoriness 6
• Current guidelines recommend that vitamin B12, folate, homocysteine, and methylmalonic acid assays should be assessed concurrently due to their close relationship in metabolism 7