Megaloblastic Anemias Dr. M. Waseem Ashraf PGT Pediatrics BBH, Rawalpindi

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.

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 > 100fL) and show failure of nuclear maturation (megaloblasts).

Causes of Megaloblastic Anemias Vitamin B12 Deficiency Folate Deficiency Other causes – Orotic acid uria – Thiamine responsive megaloblastic anemia – Arsenic poisoning – Nitrous oxide inhalation – Chemotherapy

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 – Crohn’s disease – Strictures and fistulas that bypass terminal ileum – Surgical removal of terminal ileum

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

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

Causes of Folate Deficiency Anti Folate drugs – Anti cancer as methotrexate – Anti convulsants as hydantoin

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.

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.

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.

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.

Neutrophil changes

Changes in other cells Cells having high rate of turnover are effected more

Changes in other cells Cells show enlargement and nuclear abnormalities. Cervical smears may show changes similar to those of dysplasia.

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.

Lab Findings Macrocytic anemia MCV > 100fL Reticulocytopenia Anisocytosis and poikilocytosis Nuclested RBCs with megaloblastic morphology Neutropenia with thrombocytopenia Large Hypersegmented neutrophils

Lab Findings Low serum folate levels, <3ng/dL (5-20ng/dL) Low RBC folate levelRaised serum LDH Hypercellular bone marrow with megaloblastic change nad giant metamyelocytes.

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

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.

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.

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

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