Macrocytic Anemia

Aka: Macrocytic Anemia, Megaloblastic Anemia, Megaloblastic Macrocytic Anemia, Non-megaloblastic Macrocytic Anemia

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II. Diagnosis

  1. See Hemoglobin Cutoffs for Anemia
  2. See Hematocrit Cutoffs for Anemia
  3. Macrocytosis
    1. Mean Corpuscular Volume > 100 fl
    2. MCV cutoff varies by age and per reference

III. Pathophysiology

  1. Macrocytosis is further divided based on Peripheral Smear (See below)
    1. Megaloblastic Macrocytic Anemia
    2. Non-megaloblastic Macrocytic Anemia
  2. Megaloblastic Macrocytic Anemia
    1. DNA and RNA synthesis disorder
    2. Affects Bone Marrow erythrocyte precursors
  3. Non-megaloblastic Macrocytic Anemia
    1. Secondary to Reticulocytosis (Reticulocytes are slightly larger than mature Red Blood Cells)
    2. Increased RBC production in response to Hemolysis, Hemorrhage or other red cell loss

IV. Causes: Megaloblastic Macrocytic Anemia

  1. See Medications Affecting Folate Metabolism
  2. Vitamin B12 Deficiency (Pernicious Anemia)
  3. Folate Deficiency (often Alcohol related)
  4. Atrophic Gastritis
  5. Gastrointestinal malabsorption
  6. Nitrous Oxide Abuse
  7. Primary Bone Marrow disorders

V. Causes: Non-megaloblastic Macrocytic Anemia

  1. See Medication Causes of Marrow Toxicity
  2. Alcohol Abuse
  3. Emphysema
  4. Hypothyroidism
  5. Accelerated Erythropoiesis (High Reticulocyte Index)
    1. Hemolytic Anemia
    2. Post-hemorrhagic Anemia
  6. Increased RBC membrane surface area
    1. Obstructive Jaundice
    2. Hepatic disease
    3. Post-splenectomy
  7. Bone Marrow disorders
    1. Myelophthisic Anemia
    2. Myelodysplastic Anemia (Myelodysplastic Syndrome)
    3. Aplastic Anemia
    4. Acquired Sideroblastic Anemia

VI. Causes: Spurious Macrocytosis (False Positive)

  1. Cold Agglutinins
    1. Causes Red Blood Cells to clump and appear larger
  2. Hyperglycemia
    1. Red cells from hemoconcentrated blood swell when diluted for testing
  3. Significant Leukocytosis
    1. Increased sample turbidity results in overestimation of red cell size

VII. Labs

  1. Peripheral Smear: Findings suggestive of Megaloblastic Anemia
    1. Neutrophil Hypersegmentation (>=6 lobes of nuclei)
    2. Megaloblastosis: Oval shaped Macrocytes
    3. Reticulocyte Index <1% (Reticulocytopenia)
      1. See Anemia for causes of Reticulocytosis
      2. By contrast, Reticulocytosis alone increases MCV
    4. Findings sensitive and specific (Early sign)
  2. Reflex studies usually obtained when macrocytosis identified
    1. Serum Vitamin B12
    2. RBC Folate (not Serum Folate which is inaccurate)
    3. Reticulocyte Count
    4. Thyroid Stimulating Hormone (TSH)

VIII. Evaluation: Step 1 - Peripheral Blood Smear

  1. Megaloblastic Anemia Anemia
    1. Go to step 2
  2. Non-megaloblastic Macrocytic Anemia
    1. Consider non-megaloblastic causes listed above
    2. Consider Hemolysis or Hemorrhage (Reticulocyte Count increased)
    3. Consider Alcoholism
    4. Check liver function panel (LFT)
    5. Check Thyroid Stimulating Hormone (TSH)

IX. Evaluation: Step 2 - Reticulocyte Count

  1. Reticulocyte Count less than 2%
    1. Go to step 3
  2. Reticulocyte Count greater than 2%
    1. Evaluate for Hemolytic Anemia

X. Evaluation: Step 3 - Serum Vitamin B12

  1. Vitamin B12 >400 pg/ml
    1. Go to Step 5
  2. Vitamin B12 100-400 pg/ml
    1. Go to Step 4
  3. Vitamin B12 <100 pg/ml
    1. Treat Vitamin B12 Deficiency with Vitamin B12 Replacement

XI. Evaluation: Step 4 - Methylmalonic acid (MMA) and Serum Homocysteine Levels

  1. Normal Methylmalonic acid (MMA)
    1. Increased Homocysteine: Go to Step 5
    2. Normal Homocysteine: Go to Step 6
  2. Increased MMA (with normal or increased Homocysteine)
    1. Treat Vitamin B12 Deficiency with Vitamin B12 Replacement

XII. Evaluation: Step 5 - RBC Folate (not Serum Folate which is inaccurate)

  1. Serum Folic Acid normal
    1. Go to Step 6
  2. Serum Folic Acid low
    1. Treat Folate Deficiency with Folic Acid supplementation

XIII. Evaluation: Step 6 - Nondiagnostic Findings

  1. Consider other causes above
  2. Consider Medication Causes of Macrocytic Anemia
  3. Consider Bone Marrow Biopsy for myeloproliferative disorder evaluation

XIV. References

  1. Brigden (1995) Postgrad Med 97(5):171-86 [PubMed]
  2. Kaferle (2009) Am Fam Physician 79(3): 203-8 [PubMed]
  3. Wang (2016) Am Fam Physician 93(4): 270-8 [PubMed]

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