MEGALOBLASTIC ANEMIAS

MEGALOBLASTIC ANEMIAS

The RBCs  are larger than normal

finely dispersed nuclear chromatin

an asynchrony between maturation of nucleus and cytoplasm,

Megaloblastic morphology  in children result from a deficiency of folic acid, of vitamin B12, or of both.

Both substances are cofactors required in the synthesis of nucleoproteins, and deficiencies result in defective synthesis of DNA  RNA and protein.

In the peripheral blood, red cells are large (increased mean corpuscular volume, MCV)

hypersegmented neutrophils

giant platelets

In the marrow, megaloblastic red cell may appear well hemoglobinized but retains an immature nucleus

Giant metamyelocytes and bands  also seen in the marrow.

Folic Acid Deficiencies

MEGALOBLASTIC ANEMIA OF INFANCY

Folates are abundant in  green vegetables, fruits, and animal organs (liver, kidney). Folic acid is absorbed throughout the small intestine

Surgical removal or disorders of the small intestine may lead to folate deficiency. There is an active enterohepatic circulation.

Dietary deficiency is usually compounded by rapid growth or infection, which may increase folic acid requirements.

normal adult daily requirement is about 100 microgram/24 hr, which rises to 350 microgram/24 hr in pregnancy. The requirements on a weight basis are higher in the pediatric age range in comparison to adults due to the increased needs of growth. The needs are also increased with accelerated tissue turnover, as in hemolytic anemia. Human and cow's milks provide adequate amounts of folic acid. Goat's milk and powered milk is deficient

CLINICAL MANIFESTATIONS.

 Mild megaloblastic anemia seen in very low birthweight infants, and routine folic acid supplementation is advised. Megaloblastic anemia - incidence at 4–7 mo of age, - earlier than iron deficiency anemia, although the two may be present together in infants with poor nutrition

clinical features of anemia

irritable

fail to gain weight

chronic diarrhea

Hemorrhages due to thrombocytopenia -in advanced cases.

Folic acid deficiency may accompany kwashiorkor, marasmus.

LABORATORY FINDINGS.

RBC- macrocytic (MCV >100 fl).

Reticulocyte count -- low

nucleated RBCs are of megaloblastic

Neutropenia and thrombocytopenia present, in long-standing deficiencies. The neutrophils are large, with hypersegmented nuclei

Normal serum folic acid levels are 5–20 ng/mL

deficiency is accompanied by levels less than 3 ng/mL.

Levels of iron and vitamin B12 in serum are usually normal

Serum activity of lactic acid dehydrogenase (LDH) is elevated.

The bone marrow is hypercellular because of erythroid hyperplasia.

Megaloblastic changes are prominent

Large, abnormal neutrophilic forms (giant metamyelocytes) with cytoplasmic vacuolization are seen, and hypersegmentation of the nuclei of megakaryocytes.

TREATMENT.

folic acid - orally - - in a dose of 1–5 mg/24 hr.

1 microgram/24 hr of cyanocobalamin parenterally for suspected vitamin B12 deficiency. Reticulocyte response is seen. within 72 hr,

Blood transfusions are indicated - when the anemia is severe or the child is very ill. Folic acid therapy should be continued for 3–4 wk.

MEGALOBLASTIC ANEMIA OF PREGNANCY

Folate requirements increase markedly during pregnancy. Decreases in serum and RBC folate levels occur at term and may be aggravated by infection. Folate supplementation, 1 mg/24 hr, - during the last trimester. Mothers with folate deficiency may have babies with normal folate stores due to selective transfer of folate to the fetus via placental folate receptors.

FOLIC ACID DEFICIENCY IN MALABSORPTION SYNDROMES

Diffuse inflammatory or degenerative disease of the intestine

CONGENITAL FOLATE MALABSORPTION

An autosomal recessive defect

FOLIC ACID DEFICIENCY ASSOCIATED WITH ANTICONVULSANTS AND OTHER DRUGS

phenytoin, primidone, phenobarbital

Absorption of folic acid is impaired by anticonvulsant drugs, but there is also increased utilization of folate. Megaloblastic anemia also seen in users of oral contraceptives

Methotrexate binds to dihydrofolate reductase and prevents the formation of tetrahydrofolate, the active form.

Pyrimethamine, used in the therapy of toxoplasmosis, and trimethoprim, used for treatment of a variety of infections, may induce folic acid deficiency and, occasionally, megaloblastic anemia. Therapy with folinic acid (5-formyl-tetrahydrofolate) is beneficial.

A rare cause -

CONGENITAL DIHYDROFOLATE REDUCTASE DEFICIENCY

Vitamin B 12 (Cobalamin) Deficiency

Vitamin B12 is derived from cobalamin in food, mainly animal sources, secondary to production by microorganisms. Humans cannot synthesize vitamin B12. The cobalamins are released in the acidity of the stomach and combine there with R proteins and intrinsic factor (IF), traverse the duodenum, where pancreatic proteases break down the R proteins, and are absorbed in the distal ileum via specific receptors for IF-cobalamin. In addition, some vitamin B12 from large doses may diffuse through mucosa in the intestine and mouth. In plasma, vitamin B12 is bound to transcobalamin (TC) II

cobalamin is important in the transfer of methyl groups and DNA synthesis.

Vitamin B12 deficiency may result from

            inadequate intake

            surgery involving the stomach or terminal ileum

            lack of secretion of intrinsic factor by the stomach

            consumption or inhibition of the B12-intrinsic factor complex

            abnormalities involving the receptor sites in the terminal ileum

            abnormalities of TCII.

Because vitamin B12 is present in many foods, dietary deficiency is rare

Vitamin B12 deficiency is not commonly seen in kwashiorkor or infantile marasmus.

JUVENILE PERNICIOUS ANEMIA

This rare autosomal recessive disorder results from an inability to secrete gastric intrinsic factor or secretion of a functionally abnormal IF. It differs from the typical disease in adults in that the stomach secretes acid normally and is histologically normal.

CLINICAL MANIFESTATIONS.

9 mo to 11 yr of age. During this interval stores of vitamin B12 acquired in utero is used.

As the anemia becomes severe, weakness, irritability, anorexia, and listlessness occur. The tongue is smooth, red, and painful.

Neurologic manifestations include ataxia, paresthesias, hyporeflexia, Babinski responses, clonus, and coma.

LABORATORY FINDINGS.

RBC - macrocytic, with prominent macro-ovalocytosis of the RBCs

The neutrophils may be large and hypersegmented.

In advanced cases neutropenia and thrombocytopenia, simulating aplastic anemia or leukemia

Serum vitamin B12 levels are <100 pg/mL.

Concentrations of serum iron and serum folic acid are normal or elevated.

Serum LDH activity is increased.

Moderate elevations 2–3 mg/dL of serum bilirubin levels

Excessive excretion of methylmalonic acid in the urine (normal amount, 0–3.5 mg/24 hr) is a reliable and sensitive index of vitamin B12 deficiency.

Gastric acidity may be reduced initially but returns to normal when vitamin B12 therapy is instituted.

Absorption of vitamin B12 is usually assessed by the Schilling test. When a normal person ingests a small amount of vitamin B12 into which 57Co has been incorporated, the radioactive vitamin combines with the IF in stomach secretions and passes to the terminal ileum, where absorption occurs. Because the absorbed vitamin is bound to TCII and incorporated into tissues, little or none is normally excreted in the urine. If a large dose (1 mg) of nonradioactive vitamin B12 is injected parenterally after 2 hr ("flushing dose"), 10–30% of the previously absorbed radioactive vitamin appears in the urine in 24 hr. Children with pernicious anemia usually excrete 2% or less under these conditions. To confirm that absence of IF is the basis of the B12 malabsorption, 30 mg of IF is given with a second dose of radioactive vitamin B12. Normal amounts of radioactive vitamin should now be absorbed and flushed out in the urine. On the other hand, when vitamin B12 malabsorption results from absence of ileal receptor sites or other intestinal causes, no improvement in absorption is seen with intrinsic factor.

The Schilling test result remains abnormal in pernicious anemia, even when therapy has completely reversed the hematologic and neurologic manifestations of the disease.

TREATMENT. - - parenteral administration of vitamin B12 (1 mg), à  reticulocytosis in 2–4 days

The physiologic requirement for vitamin B12 is 1–5 m{mu}g/24 hr, and hematologic responses have been observed with these small doses

If there is neurologic involvement, 1 mg should be injected intramuscularly daily for at least 2 wk.

Maintenance therapy is necessary throughout the patient's life; monthly intramuscular administration of 1 mg of vitamin B12 is sufficient.

TRANSCOBALAMIN DEFICIENCY

Transcobalamin II is the principal physiologic transport vehicle for vitamin B12. The role of TCII in B12 transport is similar to that of transferrin (Tf) for iron; specific receptors for TCII and Tf exist on cells needing vitamin B12 or iron. A congenital deficiency is inherited as an autosomal recessive condition, with failure to absorb and transport vitamin B12. Severe megaloblastic anemia occurs in early infancy. Therapy requires massive parenteral doses of vitamin B12.

VITAMIN B12 MALABSORPTION DUE TO INTESTINAL CAUSES

Surgical resection of the terminal ileum

inflammatory diseases such as regional enteritis

neonatal necrotizing enterocolitis

tuberculosis of intestine-- impair absorption of vitamin B12.

An overgrowth of intestinal bacteria within diverticula or duplications of the small intestine may cause vitamin B12 deficiency

the fish tapeworm Diphyllobothrium latum infests the upper small intestine.

Rare Megaloblastic Anemias

Oroticaciduria

thiamine-responsive and thiamine-dependent megaloblastic

IRON DEFICIENCY ANEMIA

The body of the newborn infant contains about 0.5 g of iron, whereas the adult content is estimated at 5 g. To make up for this discrepancy, an average of 0.8 mg of iron must be absorbed each day during the first 15 yr of life.

1 mg of iron must be absorbed each day.

Iron is absorbed in the proximal small intestine

absorption of dietary iron is assumed to be about 10%, a diet containing 8–10 mg of iron is necessary for optimal nutrition

Iron is absorbed two to three times more efficiently from human milk than from cow's milk, perhaps due in part to differences in calcium content.

Breast-fed infants may, therefore, require less iron from other foods.

Adolescents are also susceptible to iron deficiency because of high requirements due to the growth spurt, dietary deficiencies, and menstrual blood loss.

ETIOLOGY.

Low birthweight

unusual perinatal hemorrhage

The high hemoglobin concentration of the newborn falls during the first 2–3 mo of life

In low-birthweight infants or those with perinatal blood loss, stored iron may be depleted earlier, and dietary sources become of paramount importance. Anemia caused solely by inadequate dietary iron is unusual before 4–6 mo but becomes common at 9–24 mo of age.

The usual dietary pattern observed in infants with iron deficiency anemia is the consumption of large amounts of cow's milk and of foods not supplemented with iron.

Blood loss must be considered a possible cause in every case of iron deficiency anemia, particularly in the older child. Chronic iron deficiency anemia from occult bleeding may be caused by a lesion of the gastrointestinal tract, such as a peptic ulcer, Meckel diverticulum, a polyp or hemangioma, or by inflammatory bowel disease. In some areas hookworm infestation is an important cause of iron deficiency.

Chronic diarrhea may be associated with considerable blood loss.

CLINICAL MANIFESTATIONS.

Pallor is the most important clue to iron deficiency.

In mild to moderate iron deficiency (hemoglobin levels of 6–10 g/dL) compensatory mechanisms, including increased levels of 2,3-diphosphoglycerate (2,3-DPG) and a shift of the oxygen dissociation curve, may be so effective that few symptoms of anemia are noted,

There may be increased irritability.

Pagophagia, the desire to ingest unusual substances such as ice or dirt, may be present

Ingestion of lead-containing substances may lead to concomitant plumbism.

When the hemoglobin level falls below 5 g/dL, irritability and anorexia are prominent.

Tachycardia and cardiac dilatation occur, and systolic murmurs are often present.

The spleen is enlarged to palpation in 10–15% of patients (enlarged spleen is a rare finding in iron deficiency --- if in anemia spleen is palpable think of hemolytic anemia first.)

 In long-standing cases, widening of the diploë of the skull similar to that seen in congenital hemolytic anemias may occur.

The child with iron deficiency anemia may be obese or may be underweight, with other evidence of poor nutrition.

The irritability and anorexia characteristic of advanced cases may reflect deficiency in tissue iron, because with iron therapy striking improvement in behavior frequently occurs before significant hematologic improvement.

Iron deficiency may have effects on neurologic and intellectual function.

Iron deficiency anemia, and even iron deficiency without significant anemia, affect attention span, alertness, and learning of both infants and adolescents

Monoamine oxidase (MAO), an iron-dependent enzyme, plays a crucial role in neurochemical reactions in the central nervous system. Iron deficiency produces decreases in the activities of enzymes such as catalase and cytochromes. Catalase and peroxidase contain iron

LABORATORY FINDINGS.

First, the tissue iron stores represented by bone marrow hemosiderin disappear.

The level of serum ferritin, an iron-storage protein, -- accurate estimate of body iron stores in the absence of inflammatory disease.—ferritin is an acute inflammatory reactant.

Next, there is a decrease in serum iron

the iron-binding capacity of the serum increases,

and the percent saturation falls below normal

When the availability of iron becomes rate limiting for hemoglobin synthesis - free erythrocyte protoporphyrins (FEP) level increases.

As the deficiency progresses, the red blood cells (RBCs) become smaller than normal and their hemoglobin content decreases.

The morphologic characteristics of RBCs are best quantified by the determination of mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV).

RBCs become deformed and mis-shapen and present characteristic microcytosis, hypochromia, poikilocytosis, and increased red cell distribution width (RDW)- aniso- poikilo- cytosis

reticulocyte count may be normal or moderately elevated

Nucleated RBCs may be seen in the peripheral blood.

White blood cell counts are normal.

Thrombocytosis- may occur or,

in a few cases, thrombocytopenia. The mechanisms of these platelet abnormalities are not clear. They appear to be a direct consequence of iron deficiency, perhaps with associated gastrointestinal blood loss or associated folate deficiency, and they return to normal with iron therapy and dietary change.

The bone marrow is hypercellular, with erythroid hyperplasia.

The normoblasts may have scanty, fragmented cytoplasm with poor hemoglobinization.

Leukocytes and megakaryocytes are normal.

Hemosiderin cannot be demonstrated in marrow specimens by Prussian blue staining.

In about a third of cases occult blood can be detected in the stools.

DIFFERENTIAL DIAGNOSIS

Iron deficiency must be differentiated from other hypochromic microcytic anemias.

In lead poisoning associated with iron deficiency, the red cells are morphologically similar, but coarse basophilic stippling of the RBCs, an artifact of drying the slide, is frequently prominent. Elevations of blood lead, free erythrocyte protophyrin, and urinary coproporphyrin levels are seen

beta-thalassemia trait resemble those of iron deficiency

and RDW is usually normal or only slightly elevated.

Alpha-Thalassemia trait - diagnosis requires direct identification of DNA defects or difficult globin synthesis studies after the newborn period. The diagnosis can be assumed when a case of familial hypochromic microcytic anemia with normal levels of Hb A2 and Hb F, and normal hemoglobin electrophoresis, is refractory to iron therapy. In the newborn period infants with the alpha-thalassemia trait have 3–10% Barts and the MCV is decreased

Thalassemia major- - erythroblastosis and hemolytic component

Hb H disease, a form of alpha -thalassemia with hypochromia and microcytosis, has  hemolytic component due to instability of the beta-chain tetramers resulting from a deficiency of alpha globin.

chronic inflammation and infection, the RBC morphology - usually normochromic, may be microcytic, but in these conditions both the serum iron level and iron-binding ability are reduced, and serum ferritin levels are normal or elevated.

Elevations of FEP level are not specific to iron deficiency and are observed in patients with lead poisoning, chronic hemolytic anemia, the anemia associated with chronic disorders, and some of the porphyrias.

TREATMENT.

Oral administration of simple ferrous salts (sulfate, gluconate, fumarate) provides inexpensive and satisfactory therapy.

There is no evidence that addition of any trace metal, vitamin, or other hematinic substance increases the response to simple ferrous salts. All iron tonics are just the same

Be familiar with an inexpensive preparation of one of the simple ferrous compounds.

The therapeutic dose should be calculated in terms of elemental iron; ferrous sulfate is 20% elemental iron by weight.

A daily total of 6 mg/kg of elemental iron in three divided doses provides an optimal amount of iron for the stimulated bone marrow to use.

Better absorption may result when medicinal iron is given before meals.

Intolerance to oral iron is rare.

A parenteral iron preparation (iron dextran) is an effective form of iron and is usually safe when given in a properly calculated dose

While adequate iron medication is given the family must be educated about the patient's diet, and the consumption of milk should be limited to a reasonable quantity, preferably 500 mL /24 hr or less.

This reduction has a dual effect: The amount of iron-rich foods is increased, and blood loss from intolerance to cow's milk proteins is prevented. When the re-education of child and parent is not successful, parenteral iron medication may be indicated. Iron deficiency can be prevented in high-risk populations by providing iron-fortified formula or cereals during infancy.

The expected clinical and hematologic responses to iron therapy

Within 72–96 hr after administration of iron to the anemic child, peripheral reticulocytosis is seen.

The height of this response is inversely proportional to the severity of the anemia.

Reticulocytosis is followed by a rise in the hemoglobin level, which may increase as much as 0.5 g/dL/24 hr.

 Iron medication should be continued for 8 wk after blood values are normal.

Failures of iron therapy occur when

            the child does not receive the prescribed medication,

            iron is given in a form that is poorly absorbed,

            there is continuing unrecognized blood loss, such as intestinal or pulmonary loss, or with menstrual periods.

            incorrect diagnosis

Blood transfusion is indicated only when the anemia is very severe or when superimposed infection may interfere with the responseDo not attempt rapid correction of severe anemia by transfusion; the procedure may be dangerous because of associated hypervolemia and cardiac dilatation.

Packed or sedimented red cells should be administered slowly

severely anemic children with hemoglobins under 4 g/dL - given only 2–3 mL/kg of packed cells at any one time (furosemide may also be administered as a diuretic).

In congestive heart failure-modified exchange transfusion - fresh-packed RBCs -, - diuretics followed by slow infusion of packed red cells may suffice.