What causes macrocytosis?

Causes of Macrocytosis

Macrocytosis (MCV >100 fL) is most commonly caused by vitamin B12 deficiency, folate deficiency, medications (particularly methotrexate, azathioprine, and hydroxyurea), and alcohol use. 1, 2

Megaloblastic Causes (DNA Synthesis Defects)

Vitamin B12 Deficiency

• Pernicious anemia from autoimmune destruction of gastric parietal cells is a primary cause 2
• Ileal resection >30 cm leads to B12 malabsorption since the distal ileum is the absorption site 2
• Active inflammatory bowel disease with ileal involvement impairs B12 absorption 3
• Results in megaloblastic changes with macro-ovalocytes and hypersegmented neutrophils on peripheral smear 1, 4

Folate Deficiency

• Low dietary intake, particularly in alcoholics and malnourished patients 1, 5
• Malabsorption from jejunal inflammatory bowel disease 2
• Sulfasalazine blocks folate absorption in the intestine 2, 3
• Excess utilization from mucosal inflammation in IBD 3
• Produces identical megaloblastic morphology to B12 deficiency 1, 5

Non-Megaloblastic Causes

Medications

• Methotrexate inhibits dihydrofolate reductase, blocking conversion to tetrahydrofolic acid and causing macrocytosis through impaired DNA synthesis 2, 3
• Thiopurines (azathioprine, 6-mercaptopurine) cause direct myelosuppression rather than vitamin deficiency 2, 3
• Hydroxyurea is a well-established cause of drug-induced macrocytosis 1
• Zidovudine has become a frequent cause in HIV populations 6

Alcohol and Liver Disease

• Alcoholism is one of the most common causes, producing non-megaloblastic macrocytosis 1, 4, 7
• Chronic liver disease of any etiology causes macrocytosis 1, 7

Other Non-Megaloblastic Causes

• Hypothyroidism produces macrocytosis through decreased erythropoiesis 1, 7
• Reticulocytosis from hemolysis or hemorrhage causes macrocytosis because immature reticulocytes are larger cells 2, 3
• Myelodysplastic syndrome and primary bone marrow disorders 1, 7
• Erythropoietin therapy shifts immature reticulocytes into circulation 2

Critical Diagnostic Pitfalls

Mixed Deficiencies Mask Each Other

• Concurrent iron deficiency with B12 or folate deficiency produces falsely normal MCV as microcytosis and macrocytosis cancel out 2
• Elevated red cell distribution width (RDW) suggests a mixed picture when MCV appears normal 2
• Mean corpuscular hemoglobin (MCH) is more sensitive than MCV for detecting iron deficiency in this scenario 2
• In inflammatory conditions like IBD, ferritin <50 μg/L may still indicate iron deficiency despite inflammation 2

Folate Supplementation Danger

• Never give folic acid before excluding B12 deficiency 2, 3
• Folate supplementation masks B12 depletion and can precipitate subacute combined degeneration of the spinal cord, causing irreversible neurological damage 1, 2, 3
• This is because folate can correct the macrocytosis but allows neurological deterioration to progress 1

Diagnostic Approach

Initial Testing

• Peripheral blood smear to distinguish megaloblastic (macro-ovalocytes, hypersegmented neutrophils) from non-megaloblastic morphology 1, 4
• Reticulocyte count differentiates production defects (low/normal) from hemolysis/hemorrhage (elevated) 1, 3
• Vitamin B12 and folate levels are essential first-line tests 1, 4, 8

Additional Testing Based on Initial Results

• If megaloblastic: vitamin B12 and folate levels, consider Schilling test for B12 malabsorption 9
• If non-megaloblastic with low reticulocyte count: thyroid function tests, liver function tests, medication review 1, 7
• If non-megaloblastic with high reticulocyte count: evaluate for hemolysis or hemorrhage 1, 9