Approach to a child with anemia.

Viraj.

Overview.

• Importance.• Introduction.• Definition.• Physiology.• Approach.• Summary.

Importance.

• Anaemia is a common and often complex finding throughout childhood.

• May contribute to excess cardiovascular or respiratory work (Cohen, 1996).

• About 42% of pregnant women and 47% of children <5 yr of age in developing countries are anemic. (nelson)

• Worldwide, anaemia in adults is responsible for lost productivity, premature deaths, and perinatal complications (Centers for Disease Control, 2002)

and poor growth, developmental delays, and increased susceptibility to infection in children (Lesperance et al., 2002).

• Timely screening coupled with appropriate diagnostic testing will afford the most optimal identification and management of childhood anaemia.

RBC-The important players

• Hemoglobin– Reversibly binds and transports 02 from lungs to

tissues.– 4 globin chains & iron.

RBC-The important players

• Iron– Key element in the production of hemoglobin– Absorption is poor

• Transferrin– Iron transporter

• Ferritin– Iron binder, measure of iron stores, *also acute

phase reactant.*

Definition.

• Anaemia refers to red blood cell (RBC) mass, amount of hemoglobin, and/or volume of packed RBCs less than normal, determined either as a hematocrit or hemoglobin concentration > 2 standard deviations below the normal mean for age (Abshire, 2001; Cohen, 1996; Korones & Cohen, 1997; Walters & Abelson, 1996).

• Infants less than 2 months of age have not yet established steady state values for hemoglobin or hematocrit, hence reference ranges for normal are extensive.

• Children with chronic pulmonary or cardiac disease experience symptoms traditionally suggestive of anaemia at hemoglobin and hematocrit levels above reference cut-offs (Segel, Hirsh, & Feig, 2002a).

• Anaemia may be mild, moderate, or severe in nature.

• Mild anaemia: hemoglobin 9.5-11 g/dl, is often asymptomatic and frequently escapes detection.

• Moderate anaemia: hemoglobin 8-9.5 g/dl, may present with other symptoms and warrants timely management to prevent long-term complications.

• Severe anaemia: hemoglobin < 8 g/dl, will warrant investigation and prompt management.

Mechanisms of anemia.

• Anaemia conceptually reflects an imbalance between RBC production and destruction and may be due to one of three mechanisms. – Excess RBC loss, as occurs with hemorrhage, may create

anaemia as RBCs are depleted in addition to loss of intravascular volume.

– Excess or premature RBC destruction, such as from hemolysis, may create anaemia as RBCs are lost from circulation prior to their normal turnover.

– A third mechanism, insufficient RBC production, may create anaemia either from lack of stimulation of production or lack of RBC precursor availability (Cohen, 1996; Hermiston & Mentzer, 2002; Ioli, 2002).

Burr cells

Target cells

Spur cells

Spherocytes

Heinz body haemolytic anemia.

Bite cells

Basophilic stippling and tear drop cells

Polychromatophilia

Sickle cell

Schistocytes

Tear drop cell

Howell jolly bodies

DIFFERENCES IN THE EVALUATION OF ANEMIA BETWEEN PEDIATRIC AND ADULT PATIENTS.

• The normal ranges for red blood cell parameters are significantly different in infants and children and do not reach adult levels until adolescence.

• Thus, the determination of whether anemia is present or not must be made in an age-appropriate context.

• On identification of anemia, the likelihood of certain diagnostic entities is different in infants, children, and adults.

• In infants and children, anemia often represents a nutritional deficiency or a primary hematologic process, whereas in adults anemia more commonly is an indicator of systemic disease or malignancy.

APPROACH TO ANAEMIA

• There are 3 different approaches that can be taken in determining the cause of anaemia in a particular child:• 1. Pathophysiological approach.

• 2. “Scenario approach.”

• 3. Approach based on “Morphologic classification.”

• Pathophysiologic classification – Is best suited for relating disease processes to

potential treatment.

– In addition, anemia resulting from deficiency states occurs in a significant proportion of patients with normal indices.

• Morphologic classification – subdivides anemia into

• Macrocytic anemia, • Normocytic anemia, and • Microcytic hypochromic anemia.

– The main advantages of this classification are that the classification is simple, is based on readily available red cell indices (MCV and MCHC), and forces the physician to consider the most important types of curable anemia: vitamin B12 , folic acid, and iron-deficiency anemias.

– Such practical considerations have led to wide acceptance of this classification.

Approach.

• History,• Physical examination.• Complete blood cell count, • Reticulocyte count, • Peripheral blood smear.

History.

• Age : • Newborn: Hemorrhage, Hemolysis, Infections,

Impaired red cell production.• Infants & children : Iron deficiency anemia, Vit.B12

deficiency, hemolytic anemias.• Adolescent, menstruating & pregnant teens : Iron

deficiency.• Sex : Male : G-6 PD deficiency.• Race : • Tribes : Sickle cell anemia, • Sindhi,punjabi,gujarati : Thalassemia.

• Family history : congenital anemias, hemolytic anemias.• (1)X-linked: G6PD def. • (2)Autosomal dominant: Spherocytosis.

• (3)Autosomal recessive: Sickle cell anemia ,

Fanconi anemia. • (4)Family member with early age of

cholecystectomy/ splenectomy. • (5)Ethnicity: Thalassemia; G6PD def.

• H/o gallstones , recurrent jaundice : Hemolytic anemias.

• Family history of anemia, requirement for blood transfusions and demise of children: Thalassemia major.

• H/o Pica, chronic diarrhea, prior surgery, acute and prolonged infections, liver and renal diseases.

• H/o tingling sensation , history suggestive of neuropathy : Vit B 12 deficiency.

Diagnostic Approach-History• Diarrhea: – Malabsorption of VitB12/E/Fe. – Inflammatory bowel disease and anemia of chronic disease

with or without blood loss. – Milk protein intolerance induced blood loss – Intestinal resection : Vit B12 def

• Infection:– Giardia : iron malabsorption – Intestinal bacterial overgrowth: Vit.B12 def – EBV, CMV, Parvovirus : BM suppression – Mycoplasma, Malaria : Hemolysis – Hepatitis : aplastic anemia – Endocarditis, HIV

Diagnostic Approach-History• Nutrition:– (1)Cows milk diet : iron def. – (2)Strict vegetarian : Vit B12 def. – (3)Goats milk: Folate def. – (4)Pica: Plumbism, Iron def. – (5) Cholestasis, malabsorption : Vit.E def

• Drugs: – (1)G6PD:oxidants(sulfa, primaquine, henna) – (2)Immune mediated Hemolysis (penicillin) – (3)Bone marrow suppression (chemotherapy) – (4) Phenytoin increase folate requirement

Physical examination.

• Fever - acute infection, intravascular disease, collagen vascular disease.

• Jaundice suggests Hemolysis.• Petechia & Purpura—bleeding tendency.• Hypertension & edema - renal disease.• Hepatosplenomegaly and lymphadenopathy —

infiltrative disease. • Growth failure or poor wt. gain — Anemia of chronic

disease or organ failure.• Examine stool for blood; urine for hemoglobinuria.

Physical Findings in Anemia• Skin:• Hyper pigmentation, café au lait spots - Fanconi

anemia • Jaundice - Hemolysis • Petechia & Purpura - BMinfiltration, autoimmune

Hemolysis & thrombocytopenia • Erythematous rash- Parvovirus , E.B.Virus • Butterfly rash - SLE; • Vitiligo – Vit B12 def.

• Head : • Frontal bossing - Thalassemia major • Microcephaly - Fanconi anemia

Physical Findings in Anemia– Eyes: • Microphthalmia - Fanconi anemia • Retinopathy - Sickle cell disease • Optic atrophy - Osteopetrosis • KF ring - Wilson disease

– Ears: • Deafness - Osteopetrosis

– Mouth: • Glossitis-B12 def. , iron def • Angular stomatitis - Iron def • Pigmentation - Peutz Jeghers syndrome • Telangiectasia - Osler Weber Rendu syndrome

Physical Findings in Anemia

• Chest: • Cardiac murmur-Endocarditis, prosthetic valve

Hemolysis.• Abdomen: • Hepatomegaly - Hemolysis, infiltrative tumor,

chronic disease, hemangioma, cholecystitis.

• Splenomegaly - Hemolysis, sickle cell disease, Thalassemia, malaria, EBvirus, portal hypertension.

• Kidney anomaly - pelvic/absent kidney.

Physical Findings in Anemia

• Extremities :• Absent thumb-Fanconi anemia • Spoon nails-Iron deficiency • Dystrophic nails- Dyskeratosis congenita

• CNS : • Irritable, apathy - Iron def. • Peripheral neuropathy - lead poisoning • Ataxia, post. Column signs - Vit B12def • Stroke - Sickle cell anemia

• Short stature : Fanconi anemia, Malnutrition.

• Pallor : nail beds, oral mucous membranes and conjunctivae.

• Observing skin pallor and palmar creases is insufficient in children as the skin creases do not show pigmentation. (O.P.GHAI)

Mean Corpuscular Volume

• The average volume of the red blood cells is a useful red cell index that is used in classification of anemias and may provide insights into Pathophysiology of red cell disorders.

• Usually measured directly with automated instruments but may also be calculated from the erythrocyte count and the Hct by means of the following formula.

Red Cell Distribution Width.

• The RDW is a red cell measurement that quantitates red cell volume heterogeneity that is provided by the more modern automated hematology analyzers and reflects the range of red cell sizes measured within a sample.

• RDW has been proposed to be useful in early classification of anemias because it becomes abnormal earlier in nutritional deficiency anemias than any of the other red cell parameters, especially in cases of iron deficiency anemia.

• RDW is particularly useful when characterizing microcytic anemias, particularly distinguishing between iron deficiency anemia (high RDW, normal to low MCV) and uncomplicated heterozygous Thalassemia (normal RDW, low MCV).

• RDW is useful as a method for initial characterization of anemia, particularly microcytic anemias, although other tests are usually required to confirm the diagnosis.

• RDW is also useful in identifying red cell fragmentation, agglutination, or dimorphic cell populations (including patients who have had transfusions or have been recently treated for a nutritional deficiency)

Automated Reticulocyte Counts.

• Determination of the numbers of reticulocytes or immature, nonnucleated red blood cells that contain RNA provides useful information about the bone marrow's capacity to synthesize and release red cells in response to a physiologic challenge, such as anemia.

• In the past, reticulocyte counts were performed manually using supravital staining with methylene blue.

• Reticulocytes will stain precipitated RNA that appears as a dark blue meshwork or granules (at least two per cell) allowing reticulocytes to be identified and enumerated by manual counting methods

• Normal values for reticulocytes in adults are 0.5 to 1.5%, although they may be 2.5 to 6.5% in newborns (falling to adult levels by the second week of life).

• Because there are relatively low numbers of reticulocytes, the CV for reticulocyte counting is relatively large (10 to 20%).

• To increase accuracy of reticulocyte counting, alternative methods using flow cytometry and staining with acridine orange or thioflavin allow for many more cells to be analyzed, thereby increasing accuracy and precision of counts.

Reticulocyte Production Index.

• RPI corrects the retics for the degree of anemia• RPI indicates whether bone marrow is responding

appropriately to anemia• RPI= Retic x Hb (o) x 0.5 divided by Hb (n)• RPI > 3 increased production (Hemolysis or blood

loss)• RPI < 2 decreased production or ineffective

production for the degree of anemia• Reticulocytopenia—acute onset of anemia,

antibody mediated destruction, BMdisease.

AETIOLOGY

• (1) Inadequate response RPI < 2– A. Hypochromic microcyctic– B. Normochromic Normocytic– C. Macrocytic

• (2)Adequate response RPI > 3 – R/O blood loss---Includes Hemolytic disorders

Corrected reticulocyte count.• Corrected reticulocyte count = patient reticulocyte

count patient hematocrit / normal hematocrit.• High reticulocyte count :

– Hemolysis,– Hemorrhage,– Splenic sequestration,– Sepsis,– Recovery from vitamin or iron deficiency.

• Low reticulocyte count : – Congenital or acquired, – Aplastic/hypoplastic anemia.– Transient erythroblstopenia of childhood,– Pure red cell aplasia,– BM infiltration

Pathophysiological approach.

• Based on pathophysiology, anemias are divided into – Anemia due to acute hemorrhage,

– Anemia due to hypo proliferation,

– Anemia due to Hemolysis.

APPROACH TO HYPOPROLIFERATIVE ANEMIA IN THE CHILD.

APPROACH TO HEMOLYTIC ANEMIA IN THE CHILD.

Approach to a child with anemia(scenario approach) Anemia (Hb less than normal level) - No lymph nodes - No hepatosplenomegaly - No petechiae or ecchymosis

----- Nutritional iron deficiency or megaloblastic ----- Pure red cell aplasia ----- Thalassemia trait ----- Lead poisoning ----- Renal disease

Anemia (Hb less than normal level) - No lymph nodes - No hepatosplenomegaly - With petechiae and ecchymosis

----- Aplastic anemia ----- Bleeding disorder ----- Coagulation disorder ----- ITP ----- DIC

Anemia (Hb less than normal level) With hepatosplenomegaly

----- Thalassemia ----- Liver disorders

Anemia (Hb less than normal level) With petechiae, lymphadenopathy and

hepatosplenomegaly --- Leukamia --- Infections --- DIC

Morphological approach.

• Anemias may be morphologically categorized on the basis of RBC size (mean corpuscular volume [MCV]), and microscopic appearance.

• They can be classified as microcytic, normocytic, or macrocytic based on whether the MCV is low, normal, or high, respectively.

• RBC size also changes with age, and normal developmental changes in MCV should be recognized before a designation is made.

Microcytes Macrocytes

Normocytes

Reticulocyte count

Normal or reduced Increased

Low serum ironLow ferritin

Increased TIBC

Iron deficiency

Low serum ironNormal or high ferritin

Normal or low TIBC

Raised ESR,CRPInflammatory

disease

Anemia of chronic disease

Normal serum ironNormal TIBC

Normal ferritin

Hemoglobin electrophoresis

Hemoglobinopathies

Peripheral smear for RBC morphology,

Tests for hemolysis(bilirubin,LDH,haptoglobin)

Hemoglobin electrophoresis

Increased serum ironLow TIBC

Increased ferritin

Sideroblastic anemia

Approach to Microcytic anemia

Approach to Normocytic anemiaReticulocyte count

IncreasedNormal or reduced

Positive tests for Hemolysis

Yes No

Hemolytic anemia

Hemorrhage Recovery from nutritional

deficiency, sepsis.

Serum iron

Low

Anemia of chronic disease

Early iron deficiency

Normal or high

BM biopsy

Screen for renal,hepatic,endocrine

disease

negative Positive

Anemia of renal, hepatic, endocrine

disease

Infiltrative disease (leukemia, metastasis, myelofibrosis)

Aplastic anemia, pure red cell aplasia,Myelodysplastic syndrome

Cong. Dyserythropoetic anemia

Approach to Macrocytic anemia

Peripheral smear shows hyper segmented neutrophils and macro- ovalocytes.

Yes NoLikely megaloblastic anemia

Likely non megaloblastic anemia

BM Examination to confirm megaloblastic anemia and vit

B12/folic acid levels or response to vit B12 /folic acid therapy

Megaloblastic marrow and

anemia improves

Continue vit B12/folate Treat underlying cause

Non megaloblastic marrow or no improvement

Investigate for Drug induced, e.g. phenytoin,

Cyanotic heart disease,Down syndrome,Hypothyroidism

Deficiency: transcobalamin II, IF

Reticulocyte count

Increased

Hemolysis,hemorrhage

Decreased

Hypothyroidism,Liver disease

If negative do BM forAplastic anemia,Red cell aplasia,

MDS, Sideroblastic anemia

What to do?

• Brief clinical history.• Physical findings.• 1st line : Hemoglobin, hematocrit, MCV,

retic.count, peripheral smear.• 2nd line : Iron studies, evidence of Hemolysis,

electrophoresis.• 3rd line : bone marrow.

Summary.

• Anaemia is a common and often complex finding throughout childhood.

• Iron is a Key element in the production of hemoglobin with poor absorption.

• Infants less than 2 months of age have not yet established steady state values.

• The determination of whether anemia is present or not must be made in an age-appropriate context.

• Morphologic classification is widely accepted.

• A systematic approach is the key to diagnosis.

References

• Nelson’s textbook. 17th edition.• Hoffman’s hematology.• William’s hematology. 7th edition.• Wintrobe’s hematology. • O.P.Ghai.

Thanks.