What causes macrocytic anemia?

Causes of Macrocytic Anemia

Macrocytic anemia is primarily caused by vitamin B12 deficiency, folate deficiency, medications, myelodysplastic syndrome, alcoholism, liver dysfunction, and hypothyroidism. 1, 2

Classification of Macrocytic Anemia

Macrocytic anemia can be divided into two main categories:

1. Megaloblastic Macrocytic Anemia

• Results from impaired DNA synthesis in red blood cell precursors 3
• Most common causes:
  • Vitamin B12 deficiency (most frequent cause) 1, 3
  • Folate deficiency 1, 3
  • Medications that interfere with DNA synthesis (methotrexate, hydroxyurea) 1

2. Non-megaloblastic Macrocytic Anemia

• Normal DNA synthesis but abnormal red cell membrane development 3
• Common causes:
  • Alcoholism (most common cause of non-megaloblastic macrocytic anemia) 4, 5
  • Liver disease 4, 5
  • Hypothyroidism 1, 4
  • Myelodysplastic syndrome (MDS) 1, 2
  • Reticulocytosis (due to hemolysis or recent hemorrhage) 1, 5

Diagnostic Approach Based on Reticulocyte Count

Reticulocyte count helps differentiate between various causes of macrocytic anemia:

Low or Normal Reticulocyte Count

• Vitamin B12 deficiency 1, 6
• Folate deficiency 1, 6
• Myelodysplastic syndrome 1, 6
• Medications (azathioprine, methotrexate, hydroxyurea) 6, 1
• Hypothyroidism 1, 4
• Alcoholism 4, 5
• Liver disease 4, 5

Elevated Reticulocyte Count

• Hemolytic anemia 6, 1
• Recent hemorrhage 1, 5
• Vitamin B12 deficiency with concurrent hemolysis 6
• Folate deficiency with concurrent hemolysis 6
• Myelodysplastic syndrome with hemolysis 6

Medication-Induced Macrocytosis

Several medications can cause macrocytic anemia:

• Azathioprine and 6-mercaptopurine 6, 1
• Methotrexate 1, 3
• Hydroxyurea 1, 3
• Chemotherapeutic agents 4

Less Common Causes

• Inherited disorders of DNA synthesis 2
• Thiamine-responsive megaloblastic anemia syndrome (rare) 6
• Pure red cell aplasia 6
• Bone marrow infiltration by cancer (prostate, breast) 6

Clinical Pearls

• When macrocytosis is present, vitamin B12 and folate deficiency should be the first considerations 1
• Neutrophil hypersegmentation is one of the most sensitive and specific signs of megaloblastic anemia 5
• In patients with inflammatory conditions, ferritin levels may be elevated despite iron deficiency, potentially masking concurrent iron deficiency 1
• About 50% of patients with subclinical vitamin B12 deficiency have normal B12 levels; measuring serum methylmalonic acid and homocysteine levels is more sensitive 7
• When MDS is suspected (especially in elderly patients with macrocytic anemia and concurrent leukopenia or thrombocytopenia), hematology consultation is appropriate 2
• A wide red cell distribution width (RDW) can help identify iron deficiency when microcytosis and macrocytosis coexist, neutralizing each other and resulting in a normal MCV 6