What causes macrocytic anemia?

Causes of Macrocytic Anemia

Macrocytic anemia is most commonly caused by vitamin B12 deficiency, folate deficiency, alcoholism, liver disease, medications, and myelodysplastic syndrome. 1, 2

Classification of Macrocytic Anemias

Macrocytic anemias (MCV >100 fL) can be divided into two main categories:

1. Megaloblastic Macrocytic Anemias

• Vitamin B12 (Cobalamin) Deficiency

  • Pernicious anemia (autoimmune destruction of intrinsic factor)
  • Malabsorption syndromes
  • Strict vegetarian diet with no animal products
  • Gastric or ileal resection
  • Medications interfering with absorption

• Folate Deficiency

  • Inadequate dietary intake
  • Increased requirements (pregnancy, hemolysis)
  • Malabsorption
  • Medications (methotrexate, anticonvulsants)

2. Non-Megaloblastic Macrocytic Anemias

• Liver Disease

  • Alcoholic liver disease
  • Cirrhosis
  • Hepatitis

• Alcoholism (independent of liver disease)

• Medications

  • Chemotherapy drugs
  • Antiretrovirals
  • Hydroxyurea
  • Azathioprine and other immunosuppressants

• Endocrine Disorders

  • Hypothyroidism

• Hematologic Disorders

  • Myelodysplastic syndrome (MDS)
  • Aplastic anemia
  • Acute leukemia

• Other Causes

  • Reticulocytosis (in response to hemolysis or blood loss)
  • Rare inherited disorders of DNA synthesis

Diagnostic Approach

The diagnostic approach to macrocytic anemia should include:

1. Complete Blood Count with MCV

   • MCV >100 fL confirms macrocytosis 1
   • Evaluate other cell lines (leukocytes, platelets)

2. Reticulocyte Count

   • Low/normal: suggests decreased production
   • High: suggests hemolysis or blood loss 1

3. Peripheral Blood Smear

   • Megaloblastic changes: hypersegmented neutrophils, macro-ovalocytes
   • Non-megaloblastic: target cells, round macrocytes

4. Vitamin Levels

   • Serum B12 levels
   • Serum folate and RBC folate levels

5. Additional Testing Based on Clinical Suspicion

   • Liver function tests
   • Thyroid function tests
   • Alcohol use assessment
   • Bone marrow examination (if MDS suspected)

Key Clinical Considerations

Vitamin B12 Deficiency

• May present with neurological symptoms (paresthesias, ataxia, dementia)
• Treatment: Intramuscular vitamin B12 injections (hydroxocobalamin 1mg)
• For neurological involvement: hydroxocobalamin 1mg IM on alternate days until no further improvement 1
• Without neurological involvement: hydroxocobalamin 1mg IM three times weekly for 2 weeks, then 1mg every 2-3 months for life 1

Folate Deficiency

• Often coexists with B12 deficiency
• IMPORTANT: Never treat folate deficiency before ruling out B12 deficiency, as folate supplementation can mask B12 deficiency while allowing neurological damage to progress 1, 3
• Treatment: Oral folic acid 5mg daily for at least 4 months 1

Alcohol-Related Macrocytic Anemia

• Often multifactorial (direct toxic effect on bone marrow, nutritional deficiencies)
• Treatment includes alcohol cessation and nutritional supplementation

Medication-Induced Macrocytic Anemia

• Consider medication review and possible discontinuation of offending agents
• Common culprits: chemotherapy, anticonvulsants, methotrexate

Myelodysplastic Syndrome

• More common in elderly patients
• Often presents with pancytopenia
• Requires bone marrow examination for diagnosis

Common Pitfalls to Avoid

1. Failing to rule out vitamin B12 deficiency before treating with folate - This can mask the hematologic manifestations of B12 deficiency while allowing neurological damage to progress 3

2. Missing concurrent iron deficiency - Mixed deficiency states can result in a normal MCV despite macrocytic and microcytic processes occurring simultaneously

3. Overlooking medication effects - Many commonly prescribed medications can cause macrocytosis

4. Assuming all macrocytic anemias are due to vitamin deficiencies - Consider myelodysplastic syndrome, especially in elderly patients with unexplained cytopenias

5. Neglecting to investigate the underlying cause - For example, not evaluating for malabsorption or pernicious anemia in B12 deficiency cases

By systematically evaluating patients with macrocytic anemia and identifying the specific cause, appropriate treatment can be initiated to address both the anemia and its underlying etiology.