Anemia in childhood

Prof. Dénes Molnár Dept. Pediatr.

Objectives

• Review the different causes of anemia • Develop an approach to the diagnosis of anemia • Discuss the diagnosis and management of iron deficiency anemia • Go over other common causes of anemia in childhood

The Red Blood Cell

• Life span: 120 days – preterm babies 60-90 days in term & 35-50 days in • Production – Regulated by epo (other hemopoietic factors. Colony- stimulating factors, interleukins, thrombopoietin are not mentioned here) • Produced by kidneys in response to low O2 – Epo stimulates marrow to make RBC precursors – Needs iron, B12, folate, and amino acid • Destruction – When old or damaged, taken up by spleen

The RBC

• Membrane • Enzymes • Hemoglobin – Heme (4 heme groups per Hb molecule) • Mediates binding of O2 by Hb – Globin • Protein that surrounds and protects heme molecule • 2 alpha and 2 beta genes (adult Hb)

A few definitions

• Hb – Concentration of RBC Hb in whole blood • Ht (%) – Fractional volume of whole blood occupied by RBC • MCV – Mean value of volume of individual RBC • Microcytic, macrocytic, normocytic • MCHC – Calculated value (Hb/Ht) • Low MCHC indicates hypochromia

A few definitions (cont’d)

• RDW ( Red Cell Distribution Width) – Variability of RBC sizes; normal range 11-15 • Ferritin – Storage form of iron • 1 ng of ferritin: 10 mg of iron stores • Transferrin – Transports iron through plasma • Reticulocytes – Young RBC

Causes of anemia

• Decreased production • Increased destruction • Blood loss

Decreased production

• Defective heme synthesis – Iron deficiency, anemia of chronic disease, lead poisoning • Defective globin synthesis – Alpha and beta thalassemia • Defective DNA synthesis – Nutrient deficiencies (B12, folate) • Impaired epo production – Renal disease

Decreased production (cont’d)

• Marrow failure – Aplastic anemia •

congenital

Fanconi anemia is an autosomal recessive disorder affecting all bone marrow elements and associated with cardiac, renal, and limb malformations as well as dermal pigmentary changes.

(congenital) • acquired – Red cell aplasia • Congenital (Diamond-Blackfan) • Acquired (Transient erythroblastopenia of childhood) • Marrow replacement – Malignancy, myelofibrosis

Increased destruction

• Extracellular – Antibody mediated – Microangiopathic; HUS, DIC – Drugs, toxins – Hypersplenism

Increased destruction

• Intracellular – RBC membrane defects • HS (hereditary spherocytosis, stomatocytosis [For as yet unknown reasons, the cells take on an abnormal shape, resembling a mouth or 'stoma‘]), HE (hereditary eliptocytosis) – Enzyme defects • PK (pyruvate kinase), G6PD – Hemglobinopathies • Sickle cell, thalassemia

Blood loss

• Acute hemorrhage • Chronic blood loss

Anemia

• Definition – Hb concentration > 2 SD below mean for population • Normal values vary with age

Changes by age

Age Newborn 2 wks 3 months 6m – 6 yrs 7-12 yrs Hb (g/l) Hct (%) MCV (fl) lowest Reticuloc ytes (%) 5 168 (137-210) 55 (45-65) 110 165 (130-200) 50 (42-66) 1 120 (95-145) 36 (31-41) 1 120 (105-140) 37 (33-42) 70-74 130 (110-160) 38 (34-40) 76-80 1 1

Physiologic Anemia of Infancy

• Drop in Hb around 3 months of age • Pathophysiology – At birth, O2 sat rises sharply • 65% in utero, nearly 100% when comes out – Decrease in epo production – Fetal RBC have shorter survival time (60 days)

• History

Diagnosing anemia

• Physical exam • Investigations

History

• Maternal history – Anemia during pregnancy – Pregnancy and delivery • Family history – Ethnicity – Anemia – Jaundice, gallstones, cholecystectomy – Transfusion history – Splenomegaly

History

• Patient’s history – Jaundice at birth – Diet history – Medications – Recent infection – Chronic disease – Bruising, bleeding – Pica

Physical exam

General appearance – Pallor, jaundice, bruising • Head and neck – Pale mucous membranes and conjunctiva – Angular stomatitis – Adenopathy • Cardiac – Tachycardia, heart failure if severe – Heart murmur • Abdomen – Organomegaly

Investigations

• Most often incidental finding • CBC and smear – Hb, WBC, plt – MCV • Reticulocyte count • Depending on suspected process – Ferritin and iron studies, folate and B12, LDH, bili, Coombs, osmotic fragility, sickle screen, electrophoresis, bone marrow aspiration, renal function, liver function, etc

Morphological classification

• Cell volume – Microcytic – Macrocytic – Normocytic

Microcytic anemia

• Low MCV • Small cells • Etiologies – Iron-deficiency – Thalassemia – Chronic disease – Lead poisoning

Macrocytic anemia

• High MCV • Big cells • Etiologies – Folic acid and B12 deficiency – Hypothyroidism – Chronic liver disease – Aplastic anemias

Normocytic Anemia

• Normal MCV • Production, destruction or loss • Must look at reticulocyte count – Young RBC – Determines adequacy of bone marrow response

Normocytic anemia

• High retic count – Blood loss – Hemolysis • Low retic or normal count – Aplastic anemia – Leukemia – Chronic disease – TEC – Congenital hypoplastic syndromes

Anemia in children

• Iron deficiency – Most common • Transient erythroblastopenia of childhood (TEC) • Hemoglobinopathies – Sickle cell disease – Thalassemia

Iron deficiency anemia

• Epidemiology – Most common heme abnormality of childhood – Most common nutritional deficiency worldwide – 500 million to 2 billion people are iron deficient according to WHO • 80% of world’s population

Iron metabolism

• Body iron content: 2 to 6 g (2 g in adult female, 6 g in adult male) – 1.5-2 g in Hb – 0.5-1 g bound to enzymes, transferrin (protein that carries iron), in storage form (hemosiderin and ferritin) – The rest in myoglobin –

At birth,

most term infants have 75 mg of elemental iron per kilogram of body weight, found primarily as hemoglobin (75%), but also as storage (15%) and tissue protein iron (10%).

• Most iron is recycled • Gut absorption depends on: – Epo production – Body iron stores – Bioavailability of dietary iron

Food sources

• Bioavailability factors – Fish, poultry, meat • Iron 30% bioavailable – Vegetables • Iron 10% bioavailable • Absorbtion factors – Vitamin C increases absorbtion – Phytates (bran, oats, rye, fiber) and tea decrease absorbtion

Iron requirement

• The estimated iron requirement of the term infant is 1 mg/kg per day. • Because more than 80% of the iron is accreted during the third trimester of gestation, infants born before term must accrete more iron postnatally. Thus, the requirements for preterm infants range from 2 mg/kg per day (bwt. 1500 and 2500 g) to 4 mg/kg per day (bwt. < 1500 g). • Preterm infants who receive erythropoietin appear to need at least 6 mg/kg per day of iron.

Iron absorbtion

• Generally 10% of dietrary iron is absobed • Greater than 50% of iron from human milk is absorbed compared with typically less than 12% of iron from cow milk-derived formula

Who is at risk?

• Babies – Newborn body contains 75mg/kg – Infants triple blood volume in 1 st year – Each kg gain requires increase of 35 to 45 mg body iron – Term babies usually iron replete for 5-6 months, then need iron-fortified foods • Iron recycled in first 2 to 3 months – Pre term at greater risk

Who is at risk?

• Toddlers – Too much cow’s milk!!!

• Maximum 16 oz/day • Interferes with absorption from other food • Colitis • Decreased appetite for food • Teenagers – Increased requirement due to growth spurt – Menstrual loss

Causes of iron deficiency

• Newborn factors – LBW, perinatal hemorrhage, prematurity • Dietary deficiencies – Insufficient intake, poor iron bioavailability • Early cow’s milk exposure – Excessive cow’s milk intake • Blood loss • Iron deficiency itself!

– Blunting of intestinal villi leads to increased blood loss

Lab findings

• • • • • Bone marrow hemosiderin first disappears  – Most reliable indicator of tissue stores RDW earliest sign on blood work    Ferritin Iron, Hb  TIBC • Smear – microcytosis and hypochromia • Retic normal or moderately increased – Insufficient response

Long-term consequences

• Has been linked to ADHD and breath-holding spells – Although not well substantiated • Exercise intolerance – Study done in teenagers • Neurological impairment – More school difficulties, especially math and memory skills • Increases lead absorption – Leading to more cognitive abnormalities

Screening

• 9 mos of age if high risk – Recommanded by Canadian Task force • High risk – Pre-term / LBW baby – High prevalence in community – Low SES – Special health needs • Consider screening – Toddlers with poor diets – Teenagers

Prevention

• Breast fed infant – > 2 servings of iron-fortified cereals at 6 months • Formula-fed infant – Iron-fortified formula • Pre-term breast fed infant – Iron 1 to 2 mg/kg at 1-2 mos, until 6-12 mos • No cow’s milk until 12 months • Limit cow’s milk intake in toddlers – < 500 cc from 1 to 5 yrs

Treatment

• Diet modification – Decrease cow’s milk – Increase iron-rich foods • Iron therapy – 4 to 6 mg/kg of elemental iron • Increased absorption with Vit C

Treatment, cont’d

• Parenteral iron – 2-3% anaphylaxis – No advantage • PRBC transfusion – RARELY necessary – Only if hemodynamically unstable – 3 to 5 cc/kg at a time, watch for CHF

Response to therapy

• 12-24 hours – Intracellular replaced – Subjective improvement – Increased appetite • 36-48 hours – Bone marrow response – Erythroid hyperplasia • 48 to 72 hours – Retics increased, peak at around 5 to 7 days

Response to therapy (cont’d)

• 4 to 30 days – Increased Hemoglobin • 1 to 3 months – Repletion of iron stores • Treat for a total of at least 3 months

Treatment failure

• Poor compliance – 10% GI side effects – Poor taste • Ongoing blood loss • Wrong diagnosis

Characteristics of anemias

Parameter s MCV Apl. Anemia Hgb conc RBC Hgb conc Rets Se Bil Folate, B12 def.

Fe def.

Hemolysis Blood loss

When to call pediatric hematologist

• Neutropenia and /or thrombocytopenia • Significant adenopathy/organomegaly • Suspected hemolysis • Hemodynamic compromise and/or HCT < 20% • Suspected thalassemia major or sickle cell dis • Failure to respond to therapeutic iron trial

Hereditary spherocytosis

• Prevalence: 1/5000 • Etiology: Autosomal dominant, 25% have no previous family history • Most common molecular defects: spectrin, ankyrin

Clinical manifestations

• Hyperbilirubinemia in the neonate • Some children stay symptomeless until adulthood, others have recurrent hemolytic crisis • After infancy the spleen is enlarged • Gallstone • Icterus

• Transfusion • Splenectomy

Treatment

Diamond-Blackfan anemia

•

Diamond-Blackfan anemia Blackfan –Diamond anemia

(DBA), also known as and

Inherited erythroblastopenia

, is a congenital erythroid aplasia that usually presents in infancy . DBA patients have low red blood cell counts ( anemia ). The rest of their blood cells (the platelets and the white blood cells ) are normal. This is in contrast to

Schwachman-Diamond syndrome

, in which the bone marrow defect results primarily in neutropenia , and

Fanconi anemia

, where all cell lines are affected resulting in pancytopenia .

Clinical picture

• Diamond-Blackfan anemia is characterized by anemia (low red blood cell counts) with decreased erythroid in the bone marrow . This usually develops during the neonatal period. About 47% of affected individuals also have a variety of congenital craniofacial abnormalities, including malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate . Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing malignancies leukemia and other

Diagnosis

• Typically, a diagnosis of DBA is made through a simple blood count and a bone marrow biopsy .

• A diagnosis of DBA is made on the basis of anemia, low reticulocyte (immature red blood cells) counts, and diminished erythroid precursors in bone marrow. Features that support a diagnosis of DBA include the presence of congenital abnormalities, macrocytosis , elevated fetal hemoglobin , and elevated adenosine deaminase levels in red blood cells.

• Most patients are diagnosed in the first two years of life. However, some mildly affected individuals only receive attention after a more severely affected family member is identified.

• About 20-25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.(19q13.2)

Treatment

• Corticosteroid • Transfusion • Bown marrow transplantation

Transient erythroblastopenia of childhood (TEC)

• Acquired erythroid bone marrow failure – Unknown etiology • 18 mos to 2 yrs • Often follows viral illness • Child otherwise healthy • Resolves spontaneously – Weeks to months

TEC

• Lab findings – Normocytic anemia (Hb 50-70, sometimes as low as 20) – Low retic count – No evidence of hemolysis – Other cell lines unaffected • Treatment – Supportive – Transfusion if symptomatic

Hemoglobinopathies

• Thalassemia – Decreased or absence of production of one or more globin chains • Alpha, beta, and variants • Sickle cell disease – Structural defect of beta-globin chain

Thalassemia

• Epidemiology – Prevalent in certain populations • Africa, Middle East, Asia, and Mediterranean population • Pathogenesis – Decreased or absent synthesis of one or more globin chains • Imbalance in number of chains – Precipitation of unstable Hb • Hemolysis occurs

Alpha-Thalassemia

• Common in Asian and black populations • Phenotype depends on number of deletions – 1-gene deletion • Silent carrier, no anemia – 2-gene deletion (trait) • Mild hypochromic, microcytic anemia – 3-gene deletion (Hemoglobin H) • Severe anemia • Hb Bart (gamma globin tetramers) – 4-gene deletion • Incompatible with life • Hb Bart

Beta-thalassemia

• Mediterranean or Southeast Asian origin • Phenotype depends on number and type of mutations – Minor • Microcytic anemia – Intermedia • Moderate to severe anemia – Major • Severe anemia, transfusion dependant

Diagnosis

• Family history, ethnic origin • CBC – Microcytic anemia • Normal or increased ferritin • Hb electrophoresis – Decreased HbA, increased HbF – Abnormal Hemoglobins • Gene studies

Treatment

• Alpha trait – None – Counseling • Severe anemia – Transfusion – Watch for iron overload – Chelation therapy – Splenectomy

Sickle Cell Disease

• Defect of beta-globin chain – Amino acid substitution (valine for glutamine) • Prevalent in certain populations – African, Caribbean, Middle Eastern, Indian, Mediterranean populations Hb susceptible to deoxygenation, acidosis, temperature, dehydration – RBC distorted into sickle shape – Results in tissue ischemia and infarction – Shortened RBC survival

Sickle Cell Disease

• Manifestations (only in disease, not if trait) – Bony crisis – Chest crisis – Strokes – Splenic sequestration – Aplastic anemia • Susceptibility to infections; autosplenectomize – Encapsulated organisms • Need penicillin prophylaxis

Treatment

• Pain control – NSAIDs, opiates • Hydration • Antibiotics if febrile • Transfusions • Exchange transfusions • Hydroxyurea