Causes of Macrocytosis
Macrocytosis (MCV >100 fL) is most commonly caused by vitamin B12 or folate deficiency, alcohol use, medications (particularly thiopurines, methotrexate, and sulfasalazine), liver disease, hypothyroidism, and reticulocytosis from hemolysis or hemorrhage. 1, 2
Megaloblastic Causes (Impaired DNA Synthesis)
Vitamin B12 deficiency is the most common cause of megaloblastic macrocytic anemia, characterized by macro-ovalocytes and hypersegmented neutrophils on peripheral smear 3, 1:
- Malabsorption from ileal disease or resection: Resection of >30 cm of distal ileum (with or without ileocecal valve) causes B12 deficiency; resection <20 cm typically does not 4
- Pernicious anemia: Autoimmune destruction of gastric parietal cells
- Dietary deficiency: Particularly in strict vegans 1
Folate deficiency presents similarly to B12 deficiency with megaloblastic changes 4, 5:
- Inadequate intake: Poor nutrition, alcoholism 1
- Malabsorption: Active inflammatory bowel disease, particularly in jejunal involvement 4
- Increased utilization: Pregnancy, hemolytic anemia, chronic inflammation 4
- Medication-induced malabsorption: Sulfasalazine blocks folate absorption 4
Non-Megaloblastic Causes (Normal DNA Synthesis)
Medication-induced macrocytosis through myelosuppressive activity rather than vitamin deficiency 6:
- Thiopurines: Azathioprine and 6-mercaptopurine cause macrocytosis through direct myelosuppression, not folate interference 4, 6
- Methotrexate: Inhibits dihydrofolate reductase, blocking conversion to tetrahydrofolic acid 4
- Zidovudine: Has become a leading cause of macrocytosis in HIV patients, with MCV often >110 fL 7
Alcohol use disorder is the second most common cause after vitamin deficiencies, producing mild to moderate macrocytosis (MCV rarely >110 fL) with round macrocytes 1, 8, 2:
Chronic liver disease causes uniform, mild macrocytosis with round (not oval) macrocytes 8, 3
Reticulocytosis from hemolysis or recent hemorrhage elevates MCV due to release of large immature red cells 6, 8:
- MCV rarely exceeds 110 fL in pure reticulocytosis 8
- Reticulocyte count is elevated, distinguishing this from other causes 6
Hypothyroidism produces mild macrocytosis through decreased erythropoiesis 1, 2
Primary bone marrow disorders including myelodysplastic syndromes and myeloproliferative disorders 1, 2:
- Consider especially in elderly patients with unexplained persistent macrocytosis and other cytopenias 6
Important Diagnostic Considerations
Mixed deficiencies can mask each other 6:
- Concurrent iron deficiency (microcytosis) with B12/folate deficiency (macrocytosis) may produce falsely normal MCV
- Elevated red cell distribution width (RDW) suggests mixed picture 6
- MCH is more sensitive than MCV for detecting iron deficiency and may reveal iron deficiency even when macrocytosis masks expected microcytosis 6
Inflammatory conditions complicate interpretation 4, 6:
- Ferritin <50 μg/L may still indicate iron deficiency in presence of inflammation, despite macrocytosis 4
- In IBD patients, ferritin up to 100 μg/L may be consistent with iron deficiency 6
Tissue deficiency despite normal serum levels 6:
- Elevated homocysteine reveals tissue deficiency of B12 or folate despite normal serum levels
- Methylmalonic acid is specific for B12 deficiency with better sensitivity than serum B12
Critical Clinical Pitfalls
Never give folic acid before excluding B12 deficiency, as folate supplementation may mask B12 depletion and precipitate subacute combined degeneration of the spinal cord 4
Epoetin therapy itself causes macrocytosis due to shifting of immature (large) reticulocytes into circulation; iron overload is also associated with macrocytosis 4
In IBD patients on sulfasalazine or methotrexate, macrocytosis may be medication effect rather than true vitamin deficiency, but both should be evaluated 4