Childhood Anemia ,2011Haileyesus Adam

Introduction

Anemia • Defined as a reduction in the hemoglobin concentration, hematocrit, or number of

red blood cells (RBC) per cubic millimeter

• Results whenever the homeostatic balance between cell Production(effective erythropoiesis) and loss is disrupted

Differentiation during hematopoiesis

Physiologic classification of anemia

The major childhood anemias are classified according to physiologic disturbance

A. Disorders of effective red cell productionB. Disorders of increased red cell destruction or

loss

Disorders of effective red cell production

1. Marrow failurea. Aplastic anemiaCongenitalAcquiredb. Pure red cell aplasiaCongenital: Diamond–Blackfan SyndromeAcquired: transient erythroblastopenia of childhood

Disorders of effective red cell production

c. Marrow replacementMalignanciesOsteopetrosisMyelofibrosisChronic renal diseaseVitamin D deficiencyInfectionTuberculosisd. Pancreatic insufficiency-marrow hypoplasia syndrome

Disorders of effective red cell production

2. Impaired erythropoietin productiona. Chronic renal diseaseb. Hypothyroidism, hypopituitarismc. Chronic inflammationd. Protein malnutritione. Hemoglobin mutants with decreased affinity

for oxygen

Disorders of effective red cell production

3. Abnormalities of cytoplasmic maturationa. Iron deficiencyb. Thalassemia syndromesc. Sideroblastic anemiasd. Lead poisoning

Disorders of effective red cell production

4. Abnormalities of nuclear maturationa. Vitamin B12 deficiencyb. Folic acid deficiencyc. Thiamine-responsive megaloblastic anemiad. Hereditary abnormalities in folate metabolism

5. Primary dyserythropoieitc anemias6. Erythropoietic protoporphyria7. Refractory sideroblastic anemia

Disorders of increased red cell destruction or loss

1. Defects of hemoglobina. Structural mutants (eg. HbSS, HbSC)b. Diminished globin production (eg.

Thalassemias)2. Defects of the red cell membrane3. Defects of red cell metabolism4. Antibody-mediated

Disorders of increased red cell destruction or loss

5. Mechanical injury to the erythrocytea. Hemolytic uremic syndromeb. Thrombotic thrombocytopenic purpurac. Disseminated intravascular coagulation6. Thermal injury to the erythrocyte7. Oxidant-induced red cell injury

Disorders of increased red cell destruction or loss

8. Paroxysmal nocturnal hemoglobinuria9. Plasma-lipid-induced abnormalities of the red

cell membrane10. Acute/Chronic blood loss11. Hypersplenism

Evaluation of the anemic child

The first step• Make sure a child is truly anemic The second step• Developing a differential diagnosis– History, physical examination, CBC and the

peripheral blood smear (PBS)

Normal hematologic values by age

Evaluation of the anemic childStep 1 : Determine the child is anemic using the Hb/HctStep 2: Evaluate the Red Cell Indices• Mean corpuscular volume (MCV)

– The lower limit for the MCV(<10 years) approximately 70 fL + age in years– The upper limit fo(>0.5 years) is 84 + 0.6 fL per year until the upper limit of 96 fL– Enables classification of anemia

• microcytic• normocytic or• macrocytic.

• The red cell volume distribution width (RDW)– reflects the variability in cell size – used as a measure of anisocytosis

• The use of the RDW and the total RBC count to aid in further differentiating between specific etiologies of microcytic, normocytic, and macrocytic anemia is discussed below

Evaluation of the anemic child

3.Asess the white blood cell (WBC) and platelet counts• Simple anemia Vs pancytopenia • A leukoerythroblastic blood picture

– normal bone marrow is replaced by tumor or other diseases• Elevated WBC and/or platelet count

– most often due to reactive processes• infection is the most common cause• iron deficiency anemia• autoimmune disorders• inflammatory bowel diseases• hemolytic anemia• vitamin E deficiency

4.Microscopic examination of the PBS

A.Assess the size, color, and shape of the red cells

• Macrocytic,Normocytic,Microcytic• Central pallor:Excessive(Hypochromia) , Absence (spherocytosis)• Polychromasia with large cells (reticulocytosis)• Distinctive abnormalities in shape

– red cell membrane disorders (eg spherocytosis, stomatocytosis, or elliptocytosis) – hemoglobinopathies (eg sickle cell disease, thalassemia).

• Presence of inclusions – basophilic stippling (as seen in thalassemia, lead poisoning)

• Nucleated red blood cells – Normal only in the newborn– indicative of a stressed marrow

Microscopic examination of the PBS

B.The number and morphology of WBCs and platelet– Toxic granulation suggests an acute inflammatory

state – hypersegmented neutrophils are characteristic of

vitamin B12 and folate deficiency

History and physical examination

• Helpful in further defining the cause of anemia• Components of the history

– Patient history– Maternal history :in anemic infants from birth to six months of age– Family history : in any anemic child

• Consider the relative frequency of the various causes of anemia with age – iron deficiency anemia

• before 6 months:Prematurity, neonatal blood loss, maternal anemia• school age chidren: ongoing blood loss, malabsorption, or a very poor

diet – in the neonatal period include recent blood loss, isoimmunization, congenital

infection, or the initial manifestation of a congenital hemolytic anemia– b-chain hemoglobinopathies such as sickle cell disease or b-thalassemia from

3 to 6 months of age – a-chain hemoglobinopathies are evident during fetal life and at birth

The history of the anemic child Maternal History

a. Pregnancy/delivery complications b. Drug ingestion c. Pica, nonfood product ingestion d. Anemic during pregnancy

Family History

a.Ethinicity b. Anemia c. Jaundice d. Splenomegallye. Gallstones f. Bleeding disordersg. Cancer h. Transfusions

The history of the anemic child

3. Patient Historya. Hyperbilirubinemiab. Prematurityc. Diet history Type/quantity of milkd. Medicationse. Activity levelf. Acute or recent infectiong. Evidence of chronic infection/diseaseh. Evidence of endocrinopathyi. Evidence of liver diseasej. Easy bruising/blood loss

Physical examination

• Tachycardia suggests an acute process • A normal heart rate suggests a more chronic process• Jaundice points to a hemolytic process• Splenomegally

– inherited hemolytic anemia– Malignancy– acute infection– hypersplenism

• Petechiae indicate multiple cell lineages are involved Additional characteristic clinical signs are discussed below

Refining the DDx of anemia

Selection of further diagnostic tests Microcytic anemia• Reflect a quantitative defect in the production

of hemoglobin during erythrocyte maturation – a defect in heme synthesis • inadequate quantity of substrate • an inability to use substrate

– to a defect in globin synthesis (due to an inherited hemoglobinopathy)

Microcytic anemia• Differential diagnosis :

– iron deficiency– lead poisoning,– anemia of inflammation, or– thalassemia (or other more rare hemoglobinopathies)– Sideroblastic anemias also cause microcytosis but are rare in children

• Iron deficiency anemia– is the most common – age of the patient and diet history raise the index of suspicion for the

diagnosis• Peak prevalence occurs during late infancy and early childhood• A second peak of iron deficiency is seen during adolescence In these populations

– a therapeutic trial of oral iron is an appropriate initial diagnostic test

Iron content of foodstuffs

Factors affecting iron absorption of nonheme iron from thegastrointestinal tract

Microcytic anemiaFurther laboratory analysis should be pursued in children• who do not have a history suspicious for iron deficiency anemia, • who have severe anemia or atypical hematologic findings, • who are less than age 6 months or more than age 18 months, or • who do not respond to an initial trial of iron therapy Clues from the initial CBC to direct further testing:• The erythrocyte count

– elevated (usually to >5 million/uL) in the child with thalassemia trait – depressed in the child with iron deficiency.

• The RDW – high in iron deficiency – normal in thalassemia trait

• Indices such as the MCV/RBC ratio: A value– < 13 favors thalassemia trait – >14 points to iron deficiency

Microcytic anemia

The reticulocyte count• Is the most valuable tool for further narrowing of the differential diagnosis• Reflects the rate at which new red cells are being produced• The reticulocyte response will not be evident until three to five days after

the onset of the event• Maximal reticulocytosis is seen seven to 10 days after the onset of

hemolysis• The absolute reticulocyte count or reticulocyte index more accurately

reflects the rate oferythropoiesis– Reticulocyte percentage X the RBC count \100– Normally reticulocyte count is 50,000 to 100,000/mm3– Depressed in iron deficiency anemia, lead poisoning, and anemia of acute or

chronic inflammation– Elevated in a-b-thalassemia,

Microcytic anemiaAdditional tests should be ordered on the basis of clinical suspicion• Ferritin• Free erythrocyte protoporphyrin (FEP)• Serum iron• Iron binding capacity • A lead level should be obtained to rule out lead toxicity in young children

with suspected or confirmed iron deficiency anemia• To look for ongoing blood loss

– Urinalysis and stool guaiac and for parasites like hook worm

Microcytic anemia• An erythrocyte sedimentation rate (ESR), while non-specific,can help

confirm anemia of inflammation• Hb electrophoresis if there is

– a strong clinical suspicion of a hemoglobinopathy – an elevated reticulocyte count– elevated serum lactate dehydrogenase and total and indirect bilirubin

Macrocytic anemia

The first step in evaluating macrocytic anemia is to determine if the elevated MCV is due to increased reticulocytosis

• Reticulocytosis is suggested when – PBS will reveal large, polychromatic reticulocytes in a

background of normocytic, normochromic cells– Elevated RDW – Evidences for its cause(acute red cell loss ) are present• Hemorrhage: Physical examination• Hemolysis: serum bilirubin, LDH, and/or a positive Coombs’ test• Hypersplenism: Physical examination

Macrocytic anemia

Due to a relative decrease in DNA synthesis during erythropoiesis

• Folate and/or vitamin B12 deficieny • Ineffective erythropoiesis or marrow failure• Liver disease and hypothyroidism

Differentiate between these etiologies:PBS• showing oval macrocytes, hypersegmented PMN leukocytes, and

sometimes giant platelets suggest folate or vitamin B12 deficiency • The absence of hypersegmented PMNs and round macrocytes are more

consistent with myelodysplasia and bone marrow failure

Macrocytic anemia

Folate DeficiencyDietary• The common dietary sources of folate are green leafy vegetables• Breast milk and infant formulas provide adequate folate• Folate deficiency can be found in infants and children who primarily consume

goat’s milk

Other causes of folate deficiency include • Malabsorption, • Increased utilization of folate as in chronic hemolytic anemia• Genetic or acquired impairment of folate metabolism• Drugs that impair folate metabolism

– antimetabolites (methotrexate and mercaptupurine)– anticonvulsants phenytoin (Dilantin), – antibiotics (trimethoprimsulfa)

Macrocytic anemia

Vitamin B12 Deficiencies • nutritional deficiency of vitamin B12 is extremely rare except in

strict vegans• deficiency is due to malabsorption

– Terminal Ileum resection– Pernicious anemia – inherited disorders of transport or metabolism of vitamin B12

Glossitis and evidence of mucosal atrophy (indigestion, anorexia, diarrhea) suggest nutritional deficiency

Neurologic disorders paresthesias, ataxia, and spastic weakness of the legs greater than the arms point to vitaminn B12 deficiency

Macrocytic anemia

Ineffective erythropoiesis or marrow failure

Constitutional• Physical examination – The typical facies of DBA or Fanconi’s anemia

• A low reticulocyte count

Macrocytic anemia

Additional Tests• Methylmalonic acid: vitamin B12 • Homocysteine: folate deficiency• Empiric therapy with vitamin B12 and folate • Liver disease and hypothyroidism screening • A bone marrow biopsy and aspirate are indicated

Normocytic anemia

Normocytic Anemia with pancytopenia • suggests ineffective hematopoeisis affecting all cell lineages• bone marrow biopsy and aspirate are indicated to rule out

– severe aplastic anemia– leukemia – infiltration by metastatic malignant cells– myelodysplastic syndromes– evidence of a storage disease (eg, Gaucher’s disease)

• a hypercellular marrow in the presence of pancytopenia indicates peripheral sequestration or destruction – Hypersplenism is the most common cause

Normocytic anemia

Normocytic Anemia without pancytopenia – assess the bone marrow response to the anemia :

A. Inappropriately low reticulocyte count – acute or chronic inflammation – Generally, the Hb is greater than 8, RBC morphology

is normal, serum ferritin and ESR are elevated – clinical history points to a likely cause of

inflammation – Monitor patients for resolution of the anemia,

which can take 1 to 3 months

Normocytic anemia

B. Normocytic anemia without Pancytopenia and elevated reticulocyte count

• suggests premature disappearance of RBCs due to blood loss or hemolysis

• The source of blood loss may be overt or occult– Repeated guaiac tests are indicated– More uncommon sources of hemorrhage include

beneath the scalp, intrabdominal,urinary tract, and pulmonary hemorrhage

Normocytic anemia

Hemolysis • It may be

– acute or chronic,– congenital or acquired, – intrinsic or extrinsic to the RBC

• the clinical signs and laboratory findings in hemolysis depend on both the rate and site of red cell destruction

• Hyperbilirubinemia• An increase in plasma hemoglobin, a decrease in serum

haptoglobin, and the presence of hemoglobinuria suggest intravascular hemolysis

Hemolytic AnemiasCongenital hemolytic anemias • Disorders of the red cell membrane

– (eg hereditary spherocytosis, stomatocytosis, or elliptocytosis),• Hemoglobinopathies

– (eg, hemoglobin SS)• Red cell enzyme deficiencies

– (eg glucose-6- phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency)

• A family history positive for anemia, splenomegaly, jaundice, and/or gallstones supports the DX

• Ethnic background can also be helpful

Congenital Hemolytic AnemiasHereditary spherocytosis • most common in whites• An elevated MCHC and spherocytes on the PBS supports this diagnosis\• An MCHC greater than 35.4 coupled with an RDW >14 is almost always

diagnostic• The osmotic fragility test or ektacytometry are confirmatoryG6PD deficiency• is most common in those of African or Mediterranean descent• often present with acute hemolysis after an infection or after

encountering an oxidant stress• Signs of acute intravascular hemolysis with tachycardia, jaundice, and

hemoglobinuria• The PBS reveals schistocytes and spherocytes initially

Acquired hemolytic anemias Immune-mediated or Non Immune-mediatedImmune mediated : Antibody-mediated hemolytic anemia • Causes

– part of a more generalized autoimmune process (such as lupus) – after exposure to a drug– in children it is most often a self-limited disease following a viral illness

• confirmed by a positive direct and indirect Coombs’ testNon Immune-mediated • secondary to factors that cause mechanical damage to the red cells :

toxins mechanical or abnormal heart valves, fibrin strands in DIC or HUS

• usually intravascular and associated with red cell fragments on the PBS

Summary

• Anemia is a sign of disease and not a final diagnosis• The clinician’s goal is to define the underlying cause• The anemia may be due to decreased production or increased

destruction or loss of red blood cells• Integration of the results of the initial CBC, particularly the RBC

indices, the peripheral blood smear, the history and the physical examination can help organize the focus of further evaluations and, ultimately, minimize the number of tests needed to make a firm diagnosis

• In our situation ,always consider the coexistence of malnutrition and chronic bacterial infection or parasitic disease like malaria,hookworm and schistosomiasis

• The study of hematologic disorders in children in developing countries poses• problems that are not encountered in wealthier societies. In particular, the clinical• courses of these conditions are often modified by, whereas many of the common• infectious disorders of the developing countries give rise to their own complex• hematologic manifestations.• Apart from their intrinsic interest and global importance, because of the• massive movements of refugee populations and the ease of international travel, it• is vital that pediatricians in wealthier countries have some appreciation of the• complexities of hematologic disorders in the developing world. A more extensive• review of this rapidly developing field has been published recently [1]. Here, the• authors summarize a few of the more important issues in this field.• Anemia• The extremely complex issue of the prevalence and etiology of anemia in• developing countries is the subject of several reviews [1–4]. Because of differences• in methodology and design it is often difficult to compare the results of• surveys for anemia in particular populations. In many populations, particularly if• preschool children are included, the prevalence of anemia is extremely high, in• some cases reaching almost 100% of the population.• It is particularly difficult to assess the relative importance of different causes of• anemia in developing countries. Many surveys focus on only a single mechanism,• and it is clear that to obtain a true picture of the prevalence and causes of anemi