What are the causes of macrocytic anemia with normal vitamin B12 (B12) levels?

Causes of Macrocytic Anemia with Normal B12 Levels

When B12 is normal, the primary causes to investigate are folate deficiency, medications (especially hydroxyurea, methotrexate, azathioprine), alcohol use, hypothyroidism, liver disease, myelodysplastic syndrome, and hemolysis/hemorrhage. 1, 2

Initial Diagnostic Algorithm

Step 1: Obtain Reticulocyte Count

• A reticulocyte count differentiates production versus destruction causes 1, 2
• Elevated reticulocyte count suggests hemolysis or recent hemorrhage as the cause 1, 2
• Normal or low reticulocyte count indicates impaired bone marrow production, requiring further workup for vitamin deficiencies, medications, hypothyroidism, or myelodysplastic syndrome 1, 2

Step 2: Check Folate Status

• Measure both serum folate (<10 nmol/L or <4.4 μg/L indicates deficiency) and RBC folate (<305 nmol/L or <140 mg/L indicates deficiency) 1
• After excluding B12 deficiency, treat folate deficiency with oral folic acid 5 mg daily for a minimum of 4 months 3, 1
• Critical caveat: Folate supplementation can mask B12 deficiency and precipitate subacute combined degeneration of the spinal cord, so always exclude B12 deficiency first 3, 1, 4

Step 3: Evaluate for Non-Megaloblastic Causes

Medication Review:

• Hydroxyurea, methotrexate, azathioprine, diphenytoin, and other immunosuppressants commonly cause macrocytosis 3, 1, 2
• Consider discontinuation of causative agents when clinically appropriate 1

Thyroid Function:

• Check TSH and free T4, as hypothyroidism is a common cause of macrocytic anemia 1, 2
• Treat underlying thyroid disorder with thyroid hormone replacement 1

Alcohol Use:

• Chronic alcohol use causes macrocytosis directly and impairs B12 absorption 1, 5
• Alcoholism is one of the most common causes of macrocytic anemia in adults 5

Liver Disease:

• Check liver function tests, as liver dysfunction is a frequent cause of macrocytosis 3, 5

Step 4: Assess for Hemolysis or Blood Loss

• If reticulocyte count is elevated, check haptoglobin, LDH, indirect bilirubin, and Coombs test 3, 2
• Perform stool guaiac and consider endoscopy if hemorrhage is suspected 3

Step 5: Consider Myelodysplastic Syndrome

• If initial workup is inconclusive, bone marrow examination should be performed to evaluate for myelodysplastic syndromes or other primary bone marrow disorders 1, 2
• MDS commonly affects the elderly and should be suspected with concurrent leukopenia or thrombocytopenia 6

Important Clinical Caveats

Hidden B12 Deficiency:

• Despite normal serum B12 levels, functional B12 deficiency can exist 2
• If clinical suspicion remains high (neurological symptoms, unexplained macrocytosis), measure methylmalonic acid (>271 nmol/L confirms deficiency) and homocysteine levels 1, 2
• Approximately one-third of B12 deficiency cases present without macrocytic anemia, particularly when neurological symptoms predominate 3

Mixed Deficiency States:

• Check red cell distribution width (RDW), as an elevated RDW can identify coexisting iron deficiency that may mask macrocytosis by normalizing the MCV 1, 2
• In inflammatory conditions, ferritin may be falsely elevated despite concurrent iron deficiency; check transferrin saturation and RDW 1

Multiple Causes Can Coexist:

• Remember that multiple causes of macrocytosis frequently coexist, particularly in patients with chronic conditions 2
• The most common causes in adults are alcoholism, liver disease, hemolysis/bleeding, hypothyroidism, vitamin deficiencies, chemotherapy/drugs, and myelodysplasia 5

Monitoring Response to Treatment

• An increase in hemoglobin of at least 2 g/dL within 4 weeks of treatment indicates an acceptable response 1
• Repeat complete blood counts to monitor therapeutic response 1