Can a vitamin B12 (B12) deficiency cause leukopenia (low white blood cell count)?

Can Vitamin B12 Deficiency Cause Leukopenia?

Yes, vitamin B12 deficiency can definitively cause leukopenia (low white blood cell count) through impaired DNA synthesis affecting all hematopoietic cell lines, including white blood cells. 1, 2, 3

Mechanism of Leukopenia in B12 Deficiency

Vitamin B12 deficiency impairs DNA synthesis through disruption of one-carbon metabolism, leading to disordered DNA replication and maturation arrest in rapidly dividing bone marrow cells. 4 This affects all blood cell lines, causing:

• Pancytopenia (low RBCs, WBCs, and platelets) rather than isolated cytopenias 1, 3
• Neutropenia and/or leukopenia with dysgranulopoiesis (abnormal neutrophil development) 2
• Hypersegmented neutrophils (>5 lobes) as a characteristic finding on peripheral smear 4, 3

The functional interdependence between B12 and folate creates a "folate trap" where B12 deficiency leads to functional folate deficiency, compounding the DNA synthesis impairment. 4

Hematologic Presentation

B12 deficiency causes extensive hematologic alterations that can be profound enough to mimic acute leukemia or myelodysplastic syndromes: 1, 5

• Macrocytosis (MCV >100 fL) with megaloblastic changes 6, 3
• Hypercellular bone marrow with blastic differentiation that can be mistaken for leukemia 1, 5
• Elevated LDH from ineffective hematopoiesis and hemolysis 3
• Megaloblastic neutrophils and monocytes with nuclear-cytoplasmic asynchrony on bone marrow examination 2

Critical Diagnostic Pitfall

The dysplastic changes in B12 deficiency can be so severe that patients are misdiagnosed with acute myeloid leukemia or myelodysplastic syndrome, leading to consideration of unnecessary chemotherapy. 1, 5 Multiple case reports document patients referred for induction chemotherapy who were ultimately found to have simple B12 deficiency with complete resolution after parenteral B12 supplementation. 1, 5

Diagnostic Approach for Pancytopenia

When evaluating pancytopenia or isolated leukopenia, B12 deficiency must be excluded before pursuing more aggressive diagnoses: 6, 3

1. Check serum B12 level as part of initial workup for any unexplained cytopenia 6, 7
2. Review peripheral smear for hypersegmented neutrophils (≥5 lobes), macroovalocytes, and teardrop cells 3
3. Measure methylmalonic acid (MMA) if B12 is indeterminate (180-350 pg/mL) to confirm functional deficiency 7
4. Check reticulocyte count - will be low despite anemia, indicating decreased RBC production 6
5. Measure LDH and indirect bilirubin - often markedly elevated from ineffective hematopoiesis 3

For B12 levels <150 pmol/L (<203 pg/mL), deficiency is confirmed and treatment should begin immediately. 7 For borderline results (180-350 pg/mL), MMA testing detects an additional 5-10% of patients with functional deficiency who would otherwise be missed. 7

Treatment Response

Parenteral vitamin B12 supplementation results in rapid normalization of blood counts and bone marrow morphology, confirming the diagnosis retrospectively. 1, 5, 3 This reversibility distinguishes B12 deficiency from true myelodysplastic syndromes or leukemia, which do not respond to vitamin supplementation.

The standard treatment is 1000 mcg intramuscularly for patients with severe hematologic manifestations, though oral supplementation (1000-2000 mcg daily) is equally effective for most patients without severe neurologic symptoms. 7

Populations at Higher Risk

Screen for B12 deficiency in patients with cytopenias who have: 7, 8

• Age >60-75 years (18.1% have metabolic deficiency) 7
• Metformin use >4 months 7
• PPI or H2 blocker use >12 months 7
• Vegetarian/vegan diet 7
• History of gastric/ileal resection (especially >20 cm of ileum) 7
• Autoimmune conditions (pernicious anemia, atrophic gastritis) 7