Bleeding Infant- Megaloblastic Anemia

Jan 16th - 31st 2001 Bleeding Infant

- Megaloblastic Anemia (Please wait for the content to download)

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Query Asked

A five-month-old male child presented with spontaneous bleeding from posterior of the neck. Child was full term normal vaginal delivery at home by Dai to a primigravida mother and mother did not attend any antenatal check up.
On examination patient is malnourished, pale, show few petechial, ecchymotic rash over face and extremities. CVS and Respiratory system are normal. Per abdo liver is 3.5 cm and spleen is not palpable.

Updates (Based on Responses)
Baseline hematological parameters received are Hb of 8.4 g%, TLC of 4,400, ESR of 28 mm, Platelet count of 16,000, N₂₃L₇₂E₂M₃. Child was taking feeds normally during this period. There is no history of loose motions in the recent past. Child is not icteric but his serum bilirubin is 2.1 gm%. There is no history of jaundice in the child. No history of bleeding from any site due to i/m injection before this. PT (at admission) of the child is Test - 13.4 sec, Control - 13.6 sec. PTTK (at admission) of the child is Test - 28.3 sec, Control - 24.8 sec. There is no history suggestive of obvious skin lesion like hemangioma. Blood culture and CRP of child received are negative. White string is drain, lesion got the secondary infection. Complete hemogram report from automated counter is Hb - 8.6 g%, TLC 4,100, Total RBC count 2.38 x 10⁶ /µl, Hematocrit - 22.4 %, MCV - 110.4, MCH - 32.6, MCHC - 32.4, Platelet count - 20,000. Peripheral smear shows - Leucopenia and thrombocytopenia. Red cells show moderate anisopoikilocytosis with presence of macrocytes, macroovalocytes and few microcytes. Occasional red cells shows Howell Jolly body and basophilic stippling. Corrected retic count is 2.4%. N₃₃L₆₅E₁M₁. Bone marrow shows - smears are hypercellular with erythroid hyperplasia. Erythroid series show megaloblastic changes in approximately 60% cells. Myeloid series show normal maturation with presence of giant and bizarre metamyelocytes and stab cells. Megakaryocytes are normal in number but are seen with decreased platelet budding. No abnormal cell / parasite seen. N₁₈L₀₄E₀M₀₂Stab₁₁Meta₁₀Myelo₂₆, Iron 2+, M:E ratio 2.0:1. Hemogram done on mother show Hb - 10.7 g%, TLC - 8,000, Normal Differential count, Platelet - 2,10,000, MCV - 104.3 fl. Serum cobalamin and folate levels done on mother and chld shows- Cobalamin_child - 23 pg/ml, Folate_child - 9.5 ng/dl. Cobalamin_mother - 76 pg/ml, Folate_mother - 13.6 ng/dl.

Introduction
The term megaloblastic anemia (MA) is used to describe a macrocytic anemia that is associated with a characteristic change-the megaloblastic change in the erythroid precursors in the bone marrow. This megaloblastic erythroid precursor is typically described as a cell which is large and whose nuclear instruction is arrested or delayed while nuclear maturation is arrested or delayed while cytoplasmic maturation proceeds normally - the difference due to defect in DNA synthesis and not much alteration in the synthesis of RNA and other proteins. The typically described in erythroid precursors, the changes are evident in all rapidly proliferating cells of the body. The cause of MA is true deficiency of B₁₂, folate or both at cellular level and in more than 95% cases. The deficiency is due to nutritional causes or due to malabsorption. In children the disease is more common in infancy and pre-school age groups.
Is MA increasing?
Iron deficiency is the commonest cause of nutritional anemia the world over irrespective of age, gender or geographical area. However MA also contributes significantly at least among poor population of developing countries. In the studies quoting incidence of various types of nutritional anemias different methods have been used - some reporting macrocytosis on PS, others megaloblastosis in the bone marrow, still other defining cases on serum levels of nutrients. Still there is some suggestion that in pediatric population incidence of MA is on the rise. Incidence as low as 2% was reported (Ghai et al). Though earlier studies reported macrocytic anemia in 16-20% cases. Sharma et al (1985) reported 24% MA in malnourished children; while in a more recent study (Gomber et al 1998) approx. 40% preschool children with nutritional anemia had low serum levels of B₁₂ and / or folate.
B₁₂ Vs Folate: Deficiency of which micronutrient is more common?
Most available studies on MA have included all cases-adults as well as children. In the literature during sixties and seventies folate deficiency was reported 2-5 times more common than B₁₂ deficiency. In infants and preschool children B₁₂ deficiency was more commonly deserved. More recent literature on the subject-late eighties and nineties clearly shows that deficiency of B₁₂ is 4-5 times more common than folate deficiency. This trend is seen in both - pediatric patients and adults. Prolonged exclusive breast feeding by malnourished anemic mothers is an important factor in the etiology of B₁₂ deficiency in infants and young children. Children of such mothers are born with poor B₁₂ stores and they receive very little B₁₂ through breast milk due to deficiency in mothers. The literature from other developing countries e.g. Mexico, Zimbabwe, Pakistan also reports similar higher incidence of B₁₂ deficiency.
Clinical features: Is anemia the only problem?
In addition to pallor of various shades there are certain clinical features which are particularly common or seen exclusively in cases with MA. Developmental retardation or regression is an important finding. These children are normally apathetic, not interested in surroundings and have hypotomia. Hyperpigmentation of knukles, terminal phalanges, dorsum of hand etc is frequently seen (20-80% cases). Tremors are described in 5-15% cases-the infantile tremor syndrome of mogaloblastic anemia, hypotonia, developmental regression and tremors. Some of the cases of MA may clinically mimic cases of acute leukemia and aplastic anemia as hepatosplenomegaly (due to extramedullary hemopoiesis) of varying severity and cutaneous and other bleeding manifestations are described in 25-30% cases.
Hematological findings:
What is more in addition to anemia ? Diagnosis of MA is suggested by presence of macrocytosis on PS. Presence of hypersegmented neutrophils also supports the diagnosis. Some cases may have Circulating red cell precursors showing megaloblastic changes. Reticulocyte count is usually decreased. MCV is found to be increased (>90 fl.) What is more striking on peripheral blood examination is presence of thrombocytopenia, leucopenia and neutropenia. Thrombocytopenia is described in 50-80% cases with many of them having precariously low platelet counts. Neutropenia has been reported in 20-50% cases. Thus many cases (upto 50% in some cases) of MA may have pancytopenia - a finding which might lead to misdiagnosis of aplastic anemia (or acute leukemia if hepatosplenanegaly is also present). In some series on pancytopenia it has been observed that MA is more frequent etiological diagnosis than aplastic anemia or leukemia. The diagnosis of MA is confirmed on bone marrow examination that shows trilineal hyperplasia with megaloblastic change typically in the erythroid precursors. Deoxyuridine (DU) suppression test and FIGLU tests are required only if bone marrow does not reveal megaloblastosis. Reduced serum levels of B₁₂ and folate will make the etiological diagnosis. It has been shown that serum and urinary methylmalonic acid (MMA) are increased in B₁₂ deficiency and not in folate deficiency states.
Treatment.
Apparently, replacing the deficient substance should be the treatment but in practical situations serum levels are usually not available hence combination therapy is employed. Daily dose of 1mg of folic acid is more than adequate though larger doses are safe. The dose schedule if B₁₂ Therapeutic response can be obtained with a dose of 0.2 µg/kg for 2 days, but usually a 1000 µg dose is recommended which may be continued for the first 7 days. In our experience and other studies, use of this high dose has resulted in hyperexitability and tremors in some patients. Smaller dose i.e. 100-250 µg by initially given daily for a week and then less frequently may be an alternative. Traditional recommendation for assessing response to therapy is to look for reticulocytosis. However, with the availability of electronic cell counter a fall in MCV can be used. Fall in MCV by 5-10 fl over 1-2 weeks can be expected with good therapeutic response. Platelet count and neutrophil count tend to improve quickly. Infact some patients may develop thrombocytosis.

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