Can folate (Vitamin B9) cause high Mean Corpuscular Volume (MCV)?

Can Folate Cause High MCV?

No, folate deficiency (not excess) is associated with high MCV (macrocytosis), while folate supplementation typically normalizes elevated MCV in deficiency states. 1

Understanding MCV and Macrocytosis

Mean Corpuscular Volume (MCV) is a measurement of the average size of red blood cells. The normal range is typically 80-100 fL. When MCV exceeds 100 fL, this is defined as macrocytosis.

Causes of High MCV (Macrocytosis)

The most common causes of macrocytosis (MCV > 100 fL) include:

1. Vitamin B12 deficiency - Primary cause of megaloblastic macrocytic anemia 1
2. Folate deficiency - Another major cause of megaloblastic macrocytic anemia 1
3. Medications - Including hydroxyurea, diphenytoin, and certain chemotherapeutic agents 1
4. Alcoholism - Can cause non-megaloblastic macrocytosis 1
5. Myelodysplastic syndrome (MDS) - Can present with macrocytosis 1

Folate and MCV Relationship

Folate (vitamin B9) functions as a methyl group donor in one-carbon metabolism. It works in close conjunction with vitamin B12, with considerable functional interdependence 1. When folate levels are insufficient, this leads to:

• Impaired DNA synthesis
• Megaloblastic changes in rapidly dividing cells
• Macrocytosis (elevated MCV)
• Eventually, megaloblastic anemia if left untreated

Key Points About Folate and MCV

• Folate deficiency causes high MCV, not folate excess 1
• Folate supplementation in deficient patients typically normalizes elevated MCV
• Folate deficiency gives rise to macrocytosis, and serum levels should be measured in patients with high MCV 1
• In patients with macrocytosis and elevated MCH (mean corpuscular hemoglobin), low serum folate levels are found in a significant percentage (53%) of cases, even before anemia develops 2

Clinical Implications

When evaluating a patient with high MCV:

1. Check both folate and vitamin B12 levels - Both deficiencies can cause macrocytosis and may coexist 1

2. Consider measuring homocysteine or methylmalonate in doubtful cases:

   • Increased homocysteine indicates tissue deficiency of either B12 or folate
   • Methylmalonate is specific for B12 deficiency 1

3. Important caution: Folate supplementation may mask severe vitamin B12 depletion. It is essential that vitamin B12 deficiency is treated immediately before initiating additional folic acid to avoid precipitating subacute combined degeneration of the spinal cord 1

Diagnostic Approach to High MCV

When encountering a patient with high MCV (>100 fL):

1. Check vitamin B12 and folate levels
2. Consider other causes: alcohol use, medications, liver disease, MDS
3. If folate deficiency is identified, investigate:
   • Dietary intake
   • Malabsorption issues
   • Medication effects (anticonvulsants, sulfasalazine, methotrexate) 1
   • Non-adherence to supplements (in patients who should be taking them)

Treatment Considerations

For folate deficiency causing high MCV:

• Oral folic acid 5 mg daily for a minimum of 4 months 1
• Always rule out vitamin B12 deficiency before treating with folate 1

In summary, folate excess does not cause high MCV; rather, folate deficiency is a major cause of macrocytosis and megaloblastic anemia.