Nonmegaloblastic

Overview of Non-Megaloblastic Macrocytic Anemias

• Definition: Macrocytic anemias (MCV > 100 fL) that are not caused by vitamin B12 or folate deficiency. In other words, they are not megaloblastic anemias. The macrocytosis is due to other mechanisms affecting RBC size.
• Key Feature: Macrocytosis (large RBCs), without the typical morphological changes seen in megaloblastic anemia (i.e., no hypersegmented neutrophils or oval macrocytes). Bone marrow examination (if performed) will not show megaloblasts.
• Common Causes:
  • Alcoholism
  • Liver Disease
  • Hypothyroidism
  • Myelodysplastic Syndromes (MDS)
  • Reticulocytosis
  • Medications

Pathophysiology

The exact mechanisms leading to macrocytosis in these anemias are complex and may vary depending on the underlying cause. Some common mechanisms include:

• Altered Lipid Metabolism:
  • Alcohol and liver disease can disrupt lipid metabolism, leading to increased cholesterol deposition in the RBC membrane
  • This increases the surface area of the RBC membrane, resulting in a larger cell size (macrocytosis)
• Accelerated Erythropoiesis:
  • In conditions with increased red blood cell turnover (e.g., hemolysis, acute blood loss), there is an increased number of reticulocytes in the peripheral blood
  • Reticulocytes are larger than mature RBCs, so a high reticulocyte count can increase the MCV, leading to macrocytosis
• Membrane Abnormalities:
  • Hypothyroidism can alter RBC membrane composition, leading to increased cell size
• Clonal Hematopoiesis:
  • In myelodysplastic syndromes (MDS), abnormal stem cells in the bone marrow produce dysplastic blood cells, including macrocytes

Etiology and Associated Conditions

• Alcoholism:
  • Most common cause of non-megaloblastic macrocytosis
  • Alcohol can directly affect RBC membrane lipids and also lead to folate deficiency (contributing to a mixed picture)
• Liver Disease:
  • Altered lipid metabolism and increased cholesterol deposition in RBC membranes
  • Also, can be associated with spur cell anemia (acanthocytes)
• Hypothyroidism:
  • Decreased thyroid hormone affects RBC membrane composition and slows down erythropoiesis
• Myelodysplastic Syndromes (MDS):
  • Clonal hematopoietic stem cell disorders with dysplastic changes in one or more cell lines
  • Macrocytosis may be present due to abnormal maturation of erythroid precursors
• Reticulocytosis:
  • Increased number of reticulocytes in response to hemolysis or blood loss
  • Reticulocytes are larger than mature RBCs, increasing the MCV
• Medications:
  • Hydroxyurea: Interferes with DNA synthesis
  • Azathioprine and other immunosuppressants: Can disrupt cell division
  • Antiretroviral drugs (e.g., zidovudine): Can cause macrocytosis, especially in patients with HIV

Clinical Manifestations

• Symptoms of Anemia (if present):
  • Fatigue
  • Weakness
  • Pallor (pale skin)
  • Shortness of breath
  • Dizziness
• Other Symptoms Depend on the Underlying Cause:
  • Alcoholism: Liver disease, neuropathy, cognitive impairment
  • Liver disease: Jaundice, edema, ascites, coagulopathy
  • Hypothyroidism: Fatigue, weight gain, constipation, dry skin, cold intolerance
  • Myelodysplastic Syndromes (MDS): Infections, bleeding, fatigue

Laboratory Findings

• Complete Blood Count (CBC):
  • Hemoglobin (HGB): Decreased (anemia)
  • Hematocrit (HCT): Decreased
  • Red Blood Cell Count (RBC): Decreased
  • Mean Corpuscular Volume (MCV): Increased (macrocytic) > 100 fL
  • Mean Corpuscular Hemoglobin (MCH): Increased
  • Mean Corpuscular Hemoglobin Concentration (MCHC): Normal
  • Red Cell Distribution Width (RDW): Normal or Increased
  • White Blood Cell Count (WBC): May be normal, decreased (leukopenia), or increased (leukocytosis), depending on the cause
  • Platelet Count: May be normal, decreased (thrombocytopenia), or increased (thrombocytosis), depending on the cause
• Peripheral Blood Smear:
  • Macrocytes: Large RBCs, typically round (not oval)
  • Anisocytosis (variation in RBC size) and poikilocytosis (variation in RBC shape) may be present, but are not as prominent as in megaloblastic anemias
  • Absence of hypersegmented neutrophils and absence of oval macrocytes (helps to rule out megaloblastic anemia)
  • Other findings may be present, depending on the underlying cause:
    • Acanthocytes (spur cells) in liver disease
    • Target cells
    • Schistocytes (in some cases of MDS)
• Reticulocyte Count:
  • May be low, normal, or elevated, depending on the underlying cause
• Vitamin B12 and Folate Levels:
  • Normal (rules out megaloblastic anemia)
• Liver Function Tests (LFTs):
  • Elevated in liver disease
• Thyroid Function Tests (TFTs):
  • Abnormal in hypothyroidism (low T4, high TSH)
• Bone Marrow Aspiration and Biopsy:
  • Cellularity: Variable (can be normocellular, hypercellular, or hypocellular)
  • Maturation: May show dysplastic changes in one or more cell lines (MDS)
  • Absence of megaloblasts
  • Cytogenetic Analysis: To detect chromosomal abnormalities in MDS
• Other Tests:
  • Reticulocyte count
  • Liver and thyroid test panels

Differential Diagnosis

• Megaloblastic Anemias:
  • Vitamin B12 deficiency
  • Folate deficiency
  • Distinguished by hypersegmented neutrophils, oval macrocytes on peripheral smear, and abnormal B12/folate studies
• Hemolytic Anemias:
  • May cause macrocytosis due to increased reticulocytes
  • Elevated reticulocyte count, elevated bilirubin and LDH, decreased haptoglobin
• Cold Agglutinin Disease:
  • Agglutinated red blood cells can falsely elevate MCV
• Medication Side Effects

Treatment and Management

• Treat the Underlying Cause: This is the most important aspect of management

  • Alcoholism:
    • Alcohol cessation
    • Nutritional support (thiamine, folate, multivitamin)
  • Liver Disease:
    • Management of underlying liver disease (e.g., antiviral therapy for hepatitis, abstinence from alcohol)
    • Supportive care (e.g., diuretics for ascites)
  • Hypothyroidism:
    • Thyroid hormone replacement therapy (levothyroxine)
  • Myelodysplastic Syndromes (MDS):
    • Supportive care (transfusions, growth factors)
    • Hypomethylating agents (azacitidine, decitabine)
    • Lenalidomide (for MDS with deletion 5q)
    • Hematopoietic Stem Cell Transplantation (HSCT)
  • Medications:
    • Discontinue offending medications (if possible)

• Supportive Care:

  • Folic acid supplementation
    • Although folate deficiency is not the primary cause of non-megaloblastic macrocytosis, folate supplementation may improve RBC production and overall hematopoiesis. This is controversial, and should be undertaken only when there is a concern that there is a folate deficiency in addition to another condition
  • Blood transfusions:
    • To manage severe anemia

Key Laboratory Findings

• Complete Blood Count (CBC):
  • Macrocytosis (high MCV)
  • Normal MCHC
  • Normal or increased RDW
• Peripheral Blood Smear:
  • Macrocytes (round, not oval)
  • No hypersegmented neutrophils
• Vitamin B12 and Folate Levels:
  • Normal
• Other Tests:
  • Elevated liver function tests (LFTs) in liver disease
  • Abnormal thyroid function tests (TFTs) in hypothyroidism

Key Terms

• Non-Megaloblastic Macrocytic Anemia: Macrocytic anemia not caused by vitamin B12 or folate deficiency
• Macrocytosis: Large red blood cells (MCV > 100 fL)
• Myelodysplastic Syndromes (MDS): Clonal hematopoietic stem cell disorders with ineffective hematopoiesis
• Reticulocytosis: Increased number of reticulocytes in the blood
• Acanthocytes (Spur Cells): RBCs with irregular, spiky projections seen in liver disease
• Hypersegmented Neutrophils: Neutrophils with 5 or more lobes (seen in megaloblastic anemia, not non-megaloblastic)
• Megaloblasts: Abnormal erythroid precursors with delayed nuclear maturation (seen in megaloblastic anemia, not non-megaloblastic)