Megaloblastic

Overview of Megaloblastic Anemias

Definition: A group of macrocytic anemias characterized by impaired DNA synthesis, resulting in abnormal maturation of hematopoietic cells in the bone marrow and distinctive morphological changes in red blood cells
Hallmark: The presence of megaloblasts (large, abnormal erythroid precursors) in the bone marrow and macrocytes (large red blood cells) in the peripheral blood. Hypersegmented neutrophils (neutrophils with 5 or more lobes) are also a characteristic finding
Cause: Primarily caused by deficiencies of vitamin B12 (cobalamin) or folate (folic acid), which are essential for DNA synthesis
Key Feature: Ineffective erythropoiesis (premature destruction of abnormal RBC precursors in the bone marrow)

Etiology

Vitamin B12 Deficiency:
- Pernicious Anemia: Autoimmune destruction of parietal cells in the stomach, leading to decreased production of intrinsic factor (IF). IF is required for vitamin B12 absorption in the ileum.
- Malabsorption Syndromes:
  - Gastrectomy: Removal of the stomach, leading to decreased IF production
  - Ileal Resection or Disease (e.g., Crohn’s disease): Impairs vitamin B12 absorption
  - Bacterial Overgrowth in the Small Intestine: Bacteria compete with the host for vitamin B12
  - Pancreatic Insufficiency: Decreased release of pancreatic proteases needed to release vitamin B12 from binding proteins
- Dietary Deficiency:
  - Rare, but can occur in strict vegetarians (vegans) who do not supplement with vitamin B12
- Other Causes:
  - Fish tapeworm (Diphyllobothrium latum) infection: The tapeworm absorbs vitamin B12 in the intestine
  - Certain Medications (e.g., metformin, proton pump inhibitors)
Folate Deficiency:
- Inadequate Dietary Intake:
  - Most common cause of folate deficiency
  - Occurs in individuals with poor diets, alcoholism, or fad diets
- Increased Folate Requirements:
  - Pregnancy: Folate requirements increase to support fetal development
  - Hemolytic Anemia: Increased erythropoiesis increases folate demand
  - Malignancies: Rapidly dividing cells require more folate
- Malabsorption:
  - Celiac disease
  - Inflammatory bowel disease
- Medications:
  - Methotrexate: Inhibits dihydrofolate reductase (DHFR), an enzyme required for folate metabolism
  - Trimethoprim: Also inhibits DHFR
  - Phenytoin: Can interfere with folate absorption
- Alcohol Abuse:
  - Impairs folate absorption and utilization

Pathophysiology

Impaired DNA Synthesis:
- Vitamin B12 and folate are essential for the synthesis of thymidine, a nucleotide required for DNA synthesis
- Vitamin B12 acts as a cofactor for methionine synthase, which converts homocysteine to methionine. Methionine is needed for the synthesis of tetrahydrofolate (THF), the active form of folate
- Folate, in the form of tetrahydrofolate (THF), is required for several steps in DNA synthesis, including the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP)
- Deficiency of either vitamin B12 or folate leads to impaired DNA synthesis
Megaloblastic Changes:
- Impaired DNA synthesis affects rapidly dividing cells, particularly hematopoietic cells in the bone marrow
- Megaloblasts: Abnormal, large erythroid precursors with delayed nuclear maturation and asynchronous development of the nucleus and cytoplasm
  - Nuclear maturation is delayed due to impaired DNA synthesis
  - Cytoplasmic maturation proceeds normally (RNA and protein synthesis are not affected), resulting in a large cell with a relatively immature nucleus
- Dysplasia: Megaloblastic changes also occur in myeloid and megakaryocytic cell lines, leading to abnormal granulocytes (e.g., hypersegmented neutrophils) and platelets
Ineffective Hematopoiesis:
- Megaloblastic changes and DNA damage lead to increased apoptosis (programmed cell death) of hematopoietic precursors in the bone marrow
- Results in decreased production of mature RBCs, WBCs, and platelets, leading to cytopenias
Neurological Manifestations (Vitamin B12 Deficiency):
- Vitamin B12 is required for the maintenance of myelin, the protective sheath around nerve fibers
- B12 deficiency can cause demyelination of the spinal cord and peripheral nerves, leading to neurological symptoms

Clinical Manifestations

Symptoms of Anemia:
- Fatigue
- Weakness
- Pallor (pale skin)
- Shortness of breath
- Dizziness
Gastrointestinal Symptoms:
- Glossitis (sore, red tongue)
- Loss of appetite
- Diarrhea
Neurological Symptoms (Vitamin B12 Deficiency):
- Peripheral neuropathy (numbness, tingling, and burning sensations in the hands and feet)
- Loss of balance
- Difficulty walking
- Memory loss, confusion, or dementia
- Depression
- Optic neuropathy (vision problems)
Physical Examination Findings:
- Pallor
- Glossitis (smooth, beefy-red tongue)
- Neurological abnormalities:
  - Decreased vibratory sense and proprioception
  - Impaired reflexes
  - Positive Romberg sign (loss of balance when standing with eyes closed)

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): Increased (anisocytosis)
- White Blood Cell Count (WBC): May be decreased (leukopenia)
- Platelet Count: May be decreased (thrombocytopenia)
Peripheral Blood Smear:
- Macrocytes (large RBCs): Often oval in shape
- Anisocytosis (variation in RBC size) and poikilocytosis (variation in RBC shape)
- Hypersegmented neutrophils: Neutrophils with 5 or more lobes
- Howell-Jolly bodies: Nuclear remnants in RBCs
- Basophilic stippling: Ribosomal RNA precipitates in RBCs
Reticulocyte Count:
- Low (inappropriately low for the degree of anemia)
Bone Marrow Aspiration and Biopsy:
- Hypercellular marrow with erythroid hyperplasia
- Megaloblasts: Large, abnormal erythroid precursors with delayed nuclear maturation
- Dysplastic changes in myeloid and megakaryocytic cell lines
Vitamin B12 and Folate Levels:
- Serum Vitamin B12: Decreased in vitamin B12 deficiency
- Red Blood Cell Folate: Decreased in folate deficiency
Other Tests:
- Serum Methylmalonic Acid (MMA): Elevated in vitamin B12 deficiency
- Serum Homocysteine: Elevated in both vitamin B12 and folate deficiency
- Antibodies to Intrinsic Factor (IF): Present in pernicious anemia
- Parietal Cell Antibodies: May be present in pernicious anemia
- Schilling Test: (Historically used to assess vitamin B12 absorption, but now rarely performed)
Other Potential Lab Results:
- Elevated Iron
- Elevated Lactate Dehydrogenase
- Elevated Bilirubin

Differential Diagnosis

Non-Megaloblastic Macrocytic Anemias:
- Alcoholism
- Liver disease
- Hypothyroidism
- Myelodysplastic syndromes (MDS)
- Reticulocytosis (increased reticulocytes can falsely elevate MCV)
- Medications (e.g., hydroxyurea)
Other Causes of Anemia:
- Iron deficiency anemia
- Anemia of chronic disease
- Thalassemia
- Aplastic anemia
Neurological Disorders:
- Multiple sclerosis
- Peripheral neuropathy from other causes

Treatment and Management

Vitamin B12 Deficiency:
- Vitamin B12 Injections:
  - Cyanocobalamin or hydroxocobalamin
  - Administered intramuscularly or subcutaneously
  - Initial treatment: Daily injections for 1-2 weeks, followed by monthly maintenance injections for life
  - Oral Vitamin B12:
    - High-dose oral vitamin B12 may be effective for patients without severe malabsorption
- Treatment of Underlying Cause:
  - Address the cause of malabsorption (e.g., treat bacterial overgrowth, discontinue offending medications)
- Monitoring:
  - Monitor hemoglobin and reticulocyte count to assess response to treatment
  - Neurological symptoms may take several months to improve
Folate Deficiency:
- Oral Folic Acid Supplementation:
  - Typically 1-5 mg daily
  - Treatment is usually effective in restoring normal folate levels and resolving anemia
- Dietary Modifications:
  - Increase intake of folate-rich foods (e.g., leafy green vegetables, citrus fruits, beans)
- Avoid Alcohol Abuse
- Treatment of Underlying Cause:
  - Address malabsorption or discontinue offending medications
General Management:
- Monitor complete blood counts to assess response to therapy
- Address any neurological complications of vitamin B12 deficiency
- Genetic counseling (for inherited causes of malabsorption)

Key Laboratory Findings

Complete Blood Count (CBC):
- Macrocytic anemia (high MCV)
- Possible leukopenia and thrombocytopenia
Peripheral Blood Smear:
- Oval macrocytes
- Hypersegmented neutrophils
Reticulocyte Count:
- Low
Vitamin B12 and Folate Levels:
- Low serum vitamin B12 and/or red blood cell folate
Serum Methylmalonic Acid (MMA):
- Elevated in vitamin B12 deficiency
Serum Homocysteine:
- Elevated in both vitamin B12 and folate deficiency

Key Terms

Megaloblastic Anemia: Macrocytic anemia due to impaired DNA synthesis
Megaloblast: Abnormal, large erythroid precursor in the bone marrow
Macrocytosis: Presence of large red blood cells (MCV > 100 fL)
Hypersegmented Neutrophil: Neutrophil with 5 or more lobes
Vitamin B12 (Cobalamin): Essential vitamin for DNA synthesis and neurological function
Folate (Folic Acid): Essential vitamin for DNA synthesis
Intrinsic Factor (IF): Protein produced by parietal cells in the stomach, required for vitamin B12 absorption
Schilling Test: (Historical) Test to assess vitamin B12 absorption
Methylmalonic Acid (MMA): Metabolite elevated in vitamin B12 deficiency
Homocysteine: Amino acid elevated in both vitamin B12 and folate deficiency
Pernicious Anemia: Autoimmune destruction of parietal cells, leading to vitamin B12 deficiency

Macrocytic

Nonmegaloblastic