Primary Causes of Macrocytic Anemia
Macrocytic anemia is primarily caused by vitamin B12 deficiency, folate deficiency, alcoholism, liver disease, medications, myelodysplastic syndrome, and hypothyroidism. 1, 2
Classification of Macrocytic Anemia
Macrocytic anemia (defined as mean corpuscular volume >100 fL) can be classified into two main categories:
1. Megaloblastic Macrocytic Anemia
- Vitamin B12 deficiency - most common cause of megaloblastic anemia 2
- Folate deficiency 2
- Drug-induced impairment of DNA synthesis 3
2. Non-megaloblastic Macrocytic Anemia
- Alcoholism 4
- Liver dysfunction 3
- Hypothyroidism 2
- Myelodysplastic syndrome (MDS) 3
- Reticulocytosis (physiologic response to acute anemia) 2
Detailed Causes of Macrocytic Anemia
Vitamin B12 Deficiency
- Inadequate dietary intake (vegetarian/vegan diets)
- Impaired absorption:
- Pernicious anemia (autoimmune gastritis)
- Gastrectomy
- Ileal disease or resection
- Pancreatic insufficiency
Folate Deficiency
- Inadequate dietary intake
- Increased requirements (pregnancy, hemolytic anemia)
- Malabsorption syndromes
- Medications (anticonvulsants, methotrexate) 5
- Alcoholism
Medication-Induced
- Anticonvulsants (phenytoin, primidone, barbiturates) 5
- Chemotherapeutic agents
- Methotrexate (folate antagonist) 5
- Nitrofurantoin 5
- Antibiotics (tetracycline can cause false low folate levels) 5
Alcohol-Related
- Direct toxic effect on bone marrow
- Associated nutritional deficiencies
- Liver disease
Liver Disease
- Altered membrane lipid composition of RBCs
- Increased cholesterol content in RBC membranes
Myelodysplastic Syndrome
- Clonal stem cell disorder
- Ineffective hematopoiesis
- More common in elderly patients 3
Hypothyroidism
- Reduced bone marrow activity
- Decreased oxygen consumption
Diagnostic Approach
Laboratory evaluation:
- Complete Blood Count (CBC) with peripheral blood smear
- Serum vitamin B12 and folate levels
- Reticulocyte count
- Liver function tests
- Thyroid function tests
- Consider bone marrow examination if MDS suspected 3
Peripheral blood smear findings:
- Megaloblastic anemia: macro-ovalocytes and hypersegmented neutrophils 4
- Non-megaloblastic anemia: macrocytes without hypersegmentation
Important Clinical Considerations
Pitfalls to Avoid
- Misdiagnosis risk: Folic acid in doses above 0.1 mg daily may mask vitamin B12 deficiency by correcting hematologic abnormalities while allowing neurologic complications to progress 5
- Thrombotic thrombocytopenic purpura (TTP) mimicry: Combined vitamin B12 and folate deficiency can present with microangiopathic hemolytic anemia and thrombocytopenia, mimicking TTP 6
- Incomplete evaluation: Relying solely on MCV without investigating underlying causes 1
- Drug interactions: Folic acid may antagonize anticonvulsant action of phenytoin, potentially requiring dose adjustments 5
Special Considerations
- Elderly patients with macrocytosis and cytopenias should be evaluated for MDS 3
- Pregnant women have increased folate requirements and may develop deficiency more readily 1
- Patients with chronic alcoholism may have multiple contributing factors (direct toxicity, nutritional deficiencies, liver disease)
By understanding these causes and following a systematic diagnostic approach, clinicians can effectively identify and manage the underlying etiology of macrocytic anemia.