Megaloblastic Anemia

Diagnosis

Indications for Testing

• Anemia with macrocytosis

Laboratory Testing

• CBC
  • Blood smear – may view macro ovalocytes, anisocytosis, and hypersegmented nuclei in white blood cells 
  • Hemoglobin and hematocrit – if anemia not present, evaluate for nonmegaloblastic causes of macrocytosis
• Reticulocyte count – usually low; if elevated, proceed with hemolytic evaluation
• B₁₂ and folate levels – use to differentiate single and combined defect
  •  Folate levels
    • Low folate suggests folate deficiency
    • Serum RBC folate – acceptable alternative test to serum folate testing
    • Suggest concurrent testing with B₁₂
  • B12 levels
    • B₁₂ <100 pg/mL – B₁₂ deficiency confirmed; consider evaluation for pernicious anemia
    • B₁₂ 100-400 pg/mL – order methylmalonic acid (MMA) 
      • If MMA elevated – B₁₂ deficiency likely; consider pernicious anemia
      • If MMA normal – not pernicious anemia
    • B₁₂ >400 pg/mL – B₁₂ deficiency unlikely; folate deficiency likely
      • If clinical suspicion of B₁₂ deficiency remains – order MMA and check homocysteine levels
        • If MMA and homocysteine elevated – B₁₂ deficiency confirmed
  • Normal B₁₂ and folate levels – consider bone marrow biopsy
• Parietal cell antibody (PCA) and intrinsic factor (IF)-blocking antibody testing (see Megaloblastic Anemia Testing algorithm)
  • PCA is not as helpful as IF-blocking test because of lack of specificity
  • IF positive – pernicious anemia confirmed
  • IF negative – order PCA
    • PCA positive – pernicious anemia confirmed
    • PCA negative – order gastrin (serum)
      • Gastrin <100 pg/mL – not pernicious anemia
      • Gastrin >100 pg/mL – pernicious anemia (indirect confirmation)

Differential Diagnosis

• Nonmegaloblastic etiologies
  • Alcoholism
  • Medication-induced macrocytosis
  • Liver disease-associated macrocytosis
  • Hypothyroidism
  • Infiltrative disorders of the bone marrow
  • Nitrous oxide abuse
  • Splenectomy-induced macrocytosis
• Megaloblastic etiologies
  • See information in Clinical Background

Clinical Background

Megaloblastic anemias are a group of macrocytic anemias in which the bone marrow shows megaloblastic erythropoieses.

Epidemiology

• Prevalence – macrocytosis occurs in 2-4% of the population
• Age – usually occurs in older adults

Definitions

• Anemia
  • Men – HgB <13 g/dL 
  • Women – HgB <12 g/dL 
• Macrocytosis – mean corpuscular volume >100 fL

Etiology

• Vitamin B₁₂ (cobalamin) deficiency
  • Malabsorption
    • Absence of intrinsic factor (IF)
  • Achlorhydria 
    • Most common in the elderly and patients on acid suppression
  • Postgastrectomy syndrome
  • Intestinal stasis due to anatomic lesions
  • Ileal abnormalities  
    • Tropical sprue
    • Inherited B₁₂ disorders
• Folic acid deficiency
  • Malabsorption, inadequate intake
  • Drugs (anticonvulsants, 5-fluorouracil, methotrexate)
  • Metabolic disorders
  • Inherited disorders of folate
• Combined deficiencies of folic acid and cobalamin are not uncommon

Clinical Presentation

• Symptoms
  • Often based on the presence of anemia
  • Pale skin, anorexia, sore tongue, numbness, paresthesias
  • >50% present without anemia and have few symptoms
• Pernicious anemia – most common cause of B₁₂ deficiency
  • Absence of IF
    • Autoimmune destruction of parietal cell antibodies (PCA) is most common etiology
    • 80% have PCA; ≥50% have IF-blocking antibodies
  • Most common in patients of northern European descent
  • Increased incidence in patients with other autoimmune diseases such as Graves disease, vitiligo, hypoparathyroidism, Addison disease, Hashimoto disease

Treatment

• Oral – folate replacement
• Parenteral or intranasal – B₁₂ replacement (B₁₂ cannot be replaced orally)
  • In pernicious anemia, lifelong replacement is necessary

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Vitamin B12 0070150 Method: Quantitative Chemiluminescent Immunoassay	Preferred test is B12 reflex to MMA
Folate, Serum 0070070 Method: Quantitative Chemiluminescent Immunoassay	Preferred test is B12 & folate panel
Vitamin B12 Binding Capacity 0070260 Method: Quantitative Radioimmunoassay

Diagnostic Algorithm

  Megaloblastic Anemia Testing Algorithm