Megaloblastic Anemias

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Megaloblastic Anemias

• Dr. M. Waseem Ashraf
• PGT Pediatrics
• BBH, Rawalpindi

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Anemia

• Anemia is defined as a reduction of the red blood
  cell (RBC) volume or hemoglobin concentration
  below the range of values occurring in healthy
  persons.

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Megaloblastic Anemias

• Megaloblastic anemia is a subset of macrocytic
  anemias in which maturation phase of
  erythropoiesis in bone marrow is abnormal,
  resulting in erythroid precursors that are
  enlarged (MCV gt 100fL) and show failure of
  nuclear maturation (megaloblasts).

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Causes of Megaloblastic Anemias

• Vitamin B12 Deficiency
• Folate Deficiency
• Other causes
• Orotic acid uria
• Thiamine responsive megaloblastic anemia
• Arsenic poisoning
• Nitrous oxide inhalation
• Chemotherapy

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Causes of B12 Deficiency

• Inadequate dietary intake
• Very rare, only in strict vegetarians (vegans)
• Failure of absorption due to intrinsic factor
  deficiency
• Pernicious anemia
• Total and subtotal gastrectomy
• Terminal ileal disease
• Crohns disease
• Strictures and fistulas that bypass terminal
  ileum
• Surgical removal of terminal ileum

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Causes of B12 Deficiency

• Competition for vitamin B12 by intestinal
  pathogens
• Bacterial overgrowth (blind loop Syndrome)
• Diphyllobothrium latum infestation (fish tape
  worm)
• Congenital deficiency of transcobalamine II

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Causes of Folate Deficiency

• Folate deficincy diet
• Alcoholism
• Poverty
• Failure of absorption
• Tropical sprue
• Other malabsorptive states
• Increased Demand
• Pregnancy
• Infancy
• States of increased DNA Synthesis
• Malignant neoplasms
• Erythroid hyperplasia in congenital hemolytic
  anemia

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Causes of Folate Deficiency

• Anti Folate drugs
• Anti cancer as methotrexate
• Anti convulsants as hydantoin

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Patho-physiology

• Megaloblastic anemias result from conditions in
  which nucleic acid synthesis is abnormal, as in
  vitamin B12 and Folate deficiency.
• Vitamin B12 and Folic acid play role as cofactors
  in the conversion of deoxyuridine to deoxy
  thymidine, an essential step in the synthesis of
  DNA.

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Red Cell Changes

• When DNA synthesis is abnormal, erythropoiesis
  changes from normoblastic to megaloblastic.
• Megaloblasts differ from normoblasts in that they
  are larger and show delayed nuclear maturation
  but normal cytoplasmic hemoglobinization,
  (nuclear cytoplasmic asynchrony).
• The late megaloblast shows a primitive nucleus
  and a fully hemoglobinized cytoplasm in contrast
  to late normoblast which has a pyknotic nucleus.

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Red Cell Changes

• Delayed maturation leads to accumulation of
  erythrocyte precursor cells. The bone marrow is
  hypercellular and contains large number of early
  megaloblasts.
• As a result of intra-medullary hemolysis or
  ineffective erythropoeisis, many megaloblasts
  undergo destruction in the bone marrow before
  maturation, aggravating the anemia and producing
  mild elevation in serum bilirubin and lactate
  dehydrogenase.
• The peripheral blood smear shows macrocytosis,
  anisocytosis and poikilocytosis. Oval forms
  (macro-ovalocytes) are prominent and Howel-Jolly
  bodies, consisting of nuclear debris are
  occasionally seen.

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Neutrophil changes

• Neutrophil precursors in the bone marrow show
  marked enlagement,, Giant Metamyelcytes are
  characteristic.
• On peripheral film, neutrophils show
  Hypersegmented nuclei with many cells showing
  more than 5 lobes.

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Neutrophil changes
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Changes in other cells

• Cells having high rate of turnover are effected
  more

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Changes in other cells

• Cells show enlargement and nuclear abnormalities.
• Cervical smears may show changes similar to those
  of dysplasia.

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Features of Folate Deficiency

• Mild mageloblastic anemia has been seen in very
  low birth weight infants and folate
  supplementation is advised.
• Peak incidence in 4-7 months of age.
• Clinical features include weakness, pallor,
  fatigue, irritbility, inadequate weight gianand
  chronic diarrhea.
• Hemorrhages from thronbocytopenia may occur in
  advanced caess.
• It may accompany kwashiorkor. Marasmus or sprue.

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Lab Findings

• Macrocytic anemia MCV gt 100fL
• Reticulocytopenia
• Anisocytosis and poikilocytosis
• Nuclested RBCs with megaloblastic morphology
• Neutropenia with thrombocytopenia
• Large Hypersegmented neutrophils

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Lab Findings

• Low serum folate levels, lt3ng/dL (5-20ng/dL)
• Low RBC folate levelRaised serum LDH
• Hypercellular bone marrow with megaloblastic
  change nad giant metamyelocytes.

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Treatment

• Oral or parentral folic acid 0.5-1mg/day
• 3-4 weeks

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Clinical Features of B12 Deficiency

• Non specific symptoms like weakness, fatigue,
  failure to thrive, irritability, pallor,
  glossitis, vomiting, diarrhea.
• Neurological symptoms include paresthesias,
  sensory deficits, hypotonia, seizyres,
  developmental delay, developmental regression,
  neuropsychiatric changes.
• Neurological symptoms can occur in the absence
  ofhematological abnormalities.

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Lab Findings

• Hematological findings ar similar to that of
  folate deficience
• Decreased serum folate levels
• Raised serum methyl malonic acid and
  homocysteeine levels
• Serum iron and folate levels are normal or raised.

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• Inj. Vitamin B12 mg
• Daily for 14 days (in case of neurological
  disease)
• Weekly for 4 weeks
• Monthly for life long

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Summary

• Deficiency of folate or B12
• Macrocytic anemias with or with out other
  cytopenias
• Slowly developing anemia, usually well
  compensated
• Response to therapy rapid and dramatic
• Treatment necessary to avoid other complications
• Anemia is secondary to other disease process