Joseph L. Lasky III, MD, FAAP; Moran Gotesman, MD; and Eduard H. Panosyan, MD
An 18-month-old girl is brought to the office with a 3-day history of cough, rhinorrhea, low-grade fever, mild scleral icterus, and pallor. During her first week after birth, she had hyperbilirubinemia of unknown etiology that required phototherapy. Her family history is significant for mild anemia in her father; the cause of his condition is unknown. A paternal aunt and grandfather had cholecystectomies while in their 30s.
On physical examination, the girl is tachycardic and tachypneic (no respiratory distress) with scleral icterus and pallor. Her spleen is palpable 3 cm below the mid-costal margin. The remainder of her examination is normal.
1. What hemoglobin and hematocrit values are associated with anemia?
2. What are the presenting signs and symptoms of children with anemia?
3. What is the appropriate initial evaluation of children with anemia?
4. What emergency situations in children who present with anemia should be recognized by the primary pediatrician?
5. When should a child with anemia be referred to a hematologist?
6. How is the family history relevant in the evaluation of anemia?
Anemia is caused by a reduction in hemoglobin concentration or red blood cell (RBC) count, with resulting decreased oxygen-carrying capacity of blood. Anemia is defined as a hemoglobin or hematocrit value that is less than 2 standard deviations below the mean for age and sex. With this statistical definition, 2.5% of the healthy population can be categorized as having anemia. These values vary throughout infancy and childhood as hematopoiesis evolves from fetal to adult type, and it is important to reference normal age- and sex-related values when interpreting a hemoglobin or hematocrit result (Table 98.1). Additionally, racial variation exists, with black children having lower average hemoglobin values than white children. Cardiopulmonary status should also be considered, because children with cyanotic heart disease or chronic respiratory insufficiency typically have hemoglobin values higher than the normal range and may be functionally anemic when the hemoglobin value falls, even if it is within the lower range of normal.
Iron deficiency is the most common cause of anemia in childhood, occurring most frequently during late infancy through the first few years of age and again during adolescence. This prevalence pattern corresponds to periods of rapid growth and, when combined with poor dietary intake, can predispose to iron deficiency. Other contributing factors to iron deficiency include preterm birth, blood loss (most commonly menstrual or gastrointestinal [GI]), and GI conditions associated with decreased iron absorption.
Other epidemiologic factors that contribute to anemia are presented in Box 98.1. Anemias with a genetic etiology, including hemoglobinopathies (eg, sickle cell disease, thalassemias), RBC enzyme deficiencies (eg, glucose-6-phosphate dehydrogenase [G6PD], pyruvate kinase), and RBC membrane disorders (eg, hereditary spherocytosis), are commonly diagnosed in childhood. The highest incidence of sickle cell disease, thalassemia, and G6PD deficiency is in individuals of African, Mediterranean, and Southeast Asian descent within the “malaria belt” near the equator, likely reflecting an evolutionary advantage against malaria. Dietary factors can cause impaired hematopoiesis, as in iron, folate, or vitamin B12 deficiency. Ingestion of oxidants (eg, fava beans, medications) can trigger hemolysis in persons with G6PD deficiency. Ingestion of toxins, such as lead, can also result in impaired hematopoiesis. Lead poisoning occurs more commonly in children who live in cities and older housing. In an otherwise healthy child, viral infections can cause a pure red cell aplasia (eg, transient erythroblastopenia of childhood), an autoimmune hemolytic anemia, or an aplastic anemia. Children with congenital hemolytic anemias are at risk for hemolytic and aplastic crises associated with infectious illnesses.
The clinical presentation of anemia depends on the age of the child, severity and cause of the anemia, and rapidity of onset (Box 98.2). Typically, anemia is detected on routine screening or as part of an evaluation for an acute illness in a child who is asymptomatic and has no significant physical findings. Children with gradual onset of anemia may be relatively asymptomatic, because time has allowed for compensatory mechanisms, such as plasma volume expansion and increased cardiac contractility, to take place. With severe anemia, easy fatigability and exercise intolerance can develop, and pallor, fatigue, headache, dizziness, and irritability may occur. Pallor, tachycardia, tachypnea, edema, and, in severe cases, outright congestive heart failure (CHF) may be noted on examination. Children with an abrupt drop in hemoglobin from blood loss or hemolysis present more acutely with signs of tachycardia, tachypnea, and possible hypotension and shock. If the anemia is caused by acute hemolysis, accompanying jaundice, icterus, and dark urine may be seen.
Reprinted with permission from Brugnara C, Oski FA, Nathan DG. Diagnostic approach to the anemic patient. In: Orkin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 7th ed. Philadelphia, PA: Saunders Elsevier; 2009:456.
Box 98.1. Epidemiologic Factors Related to Anemia
•Autosomal-dominant: hereditary spherocytosis
•Autosomal-recessive: most Embden-Meyerhof pathway enzyme deficiencies (eg, pyruvate kinase deficiency), most hemoglobinopathies (eg, sickle cell disease, β-thalassemia)
•X-linked: G6PD deficiency
•Northern European: hereditary spherocytosis, pyruvate kinase deficiency
•Mediterranean (ie, Italian, Greek, North African): β-thalassemia, G6PD deficiency
•African: sickle cell disease, hemoglobin C, hemoglobin D, G6PD deficiency, α-thalassemia trait, hereditary elliptocytosis
•Southeast Asian: α-thalassemia, hemoglobin E, G6PD deficiency
•Poor dietary intake (ie, iron, folate, or vitamin B12 deficiency)
— Iron (excessive cow’s milk intake)
— Folate (excessive goat’s milk intake)
— Vitamin B12 (vegan diet)
•Poor gastrointestinal absorption
— Iron, absorbed in duodenum (small bowel disease)
— Folate, absorbed in duodenum and jejunum (small bowel disease)
— Vitamin B12, absorbed in terminal ileum (surgical resection, pernicious anemia, small bowel disease)
•Ingestion of oxidants (medications such as sulfa drugs, fava beans in G6PD deficiency)
•Living near highways: increased incidence of lead poisoning
•Poverty: associated with pica and lead poisoning
•Malaria: heterozygous form of sickle cell disease, thalassemia, G6PD-deficiency confer protection
•Viral infections: transient erythroblastopenia of childhood, autoimmune hemolytic anemias, hemolytic crisis in patients with congenital hemolytic anemias
•Parvovirus: aplastic crisis in patients with hemolytic anemias
•Viral hepatitis: aplastic anemia
Abbreviation: G6PD, glucose-6-phosphate dehydrogenase.
Box 98.2. Diagnosis of Anemia in Children
•Congestive heart failure
Erythrocytes develop from pluripotent stem cells within the bone marrow under the influence of various hematopoietic growth factors. Erythropoietin is the primary growth factor regulating RBC production and is produced primarily by renal interstitial peritubular cells. The primary function of the erythrocyte is the delivery of oxygen to tissues for aerobic metabolism, and hemoglobin is the main intracellular protein of the erythrocyte. Hemoglobin consists of 4 polypeptide subunits, each containing an active heme group that is capable of binding to an oxygen molecule. A normal erythrocyte has a life span of approximately 120 days and is subsequently removed from circulation as it passes through the reticuloendothelial system. Under steady state conditions, the daily 1% loss of aged erythrocytes is compensated by a normal active erythropoiesis. It is also important to note that red cell loss is greater (1.5%) and life span is shorter (90 days) during the late fetal and early neonatal period. Anemia occurs when an imbalance exists between erythrocyte production and destruction. It can arise from conditions resulting in decreased production, increased destruction (ie, hemolysis), or blood loss. Deficient production may be caused by nutrient deficiency (ie, iron, folate, vitamin B12), bone marrow failure (acquired or inherited), or bone marrow infiltration (eg, malignancy). Increased destruction of erythrocytes can occur as a consequence of disorders intrinsic to the erythrocyte (eg, hemoglobinopathy, enzymopathy, membranopathy) or extrinsic factors (immune or nonimmune etiologies).
The differential diagnosis of anemia can be determined by considering the underlying mechanism of anemia, whether decreased production, increased destruction, or blood loss, and the size of the erythrocyte (ie, mean corpuscular volume [MCV]). The differential diagnosis of anemia based on pathophysiology and erythrocyte size can be found in Table 98.2 and Box 98.3. In determining the cause of anemia, the reticulocyte count is the most useful test in ascertaining whether the anemia is caused by decreased production or increased destruction. A reduced reticulocyte count indicates decreased marrow production, whereas an elevated reticulocyte count is strongly suggestive of hemolysis. Anemia based on erythrocyte size can be classified as microcytic (low MCV), normocytic (normal MCV), or macrocytic (high MCV). Microcytic anemias reflect a defect in hemoglobin synthesis and are most commonly the result of iron deficiency, thalassemia, lead poisoning, and chronic disease. Macrocytic anemias reflect a relative decrease in DNA synthesis during impaired erythropoiesis and are usually of nutritional origin (ie, vitamin B12 or folate deficiency). The many other causes of anemia commonly fall into the normocytic category and can be further divided based on the reticulocyte count. Etiology and erythrocyte size, the 2 systems for classification of anemia, are not mutually exclusive—simultaneous application of these systems enables the pediatrician to make a primary diagnosis of anemia and determine its probable causes.
Abbreviations: ANA, antinuclear antibodies; DIC, disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; Hb, hemoglobin; HUS, hemolytic uremic syndrome; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; RBC, red blood cell; RDW, red cell distribution width; TSH, thyroid-stimulating hormone; WBC, white blood cell. Derived from Lanzkowsky P. Manual of Pediatric Hematology-Oncology. New York, NY: Churchill Livingstone; 1989:2–3.
Box 98.3. Differential Diagnosis of Childhood Anemias Based on Red Blood Cell Size
Hypochromic, Microcytic Anemia (Low MCV)
•Iron deficiency anemia
•Anemia of inflammation or chronic disease
Normochromic, Normocytic Anemia (Normal MCV)
•High reticulocyte count
— Intrinsic red cell disorders
•Hemoglobinopathies (hemoglobin SS disease)
•Enzymopathies (G6PD, PK)
— Extrinsic red cell disorders
•Nonimmune (thrombotic thrombocytopenic purpura [eg, hemolytic uremic syndrome])
•Low reticulocyte count
— Pure red cell aplasia (congenital hypoplastic anemia, TEC)
— Pancytopenia (marrow failure or infiltration)
Macrocytic Anemia (Increased MCV)
•Vitamin B12 deficiency
•Congenital hypoplastic anemia
Abbreviations: G6PD, glucose-6-phosphate dehydrogenase; HS, hereditary spherocytosis; MCV, mean corpuscular volume; PK, pyruvate kinase; SS, 2 sickle β-globin genes; TEC, transient erythroblastopenia of childhood.
Iron deficiency is the most frequent cause of microcytic anemia in childhood and occurs as a result of inadequate intake and increased requirements resulting from growth, blood loss, and malabsorption of iron. As iron deficiency evolves, depletion of iron stores occurs first, followed by iron-deficient erythropoiesis without anemia, finally resulting in iron deficiency anemia. The combination of rapid growth and inadequate iron intake is responsible for the common occurrence of iron deficiency anemia in toddlers and adolescents. Many young newborns and infants are spared because of adequate iron stores acquired in utero and the ingestion of iron-fortified formulas. Exclusively breastfed newborns and infants may require supplemental iron before 6 months of age and should be evaluated for anemia. Preterm newborns are the exception, because they have lower baseline iron stores. (Much of the iron stores are acquired by the fetus in the third trimester.) As iron stores become depleted during late infancy and cow’s milk is introduced into the diet, the ever-growing older infant/toddler becomes at risk for iron deficiency. Excessive intake of cow’s milk during the first few years after birth predisposes to iron deficiency because cow’s milk has minimal bioavailable iron (<1 mg/L). Large intake of cow’s milk results in early satiety and prevents adequate intake of other iron-containing foods. Iron deficiency is often further compounded by trace amounts of GI blood loss resulting from GI mucosal damage or cow’s milk allergy enteropathy. Adolescents, particularly menstruating females, are also prone to iron deficiency because of the pubertal growth spurt and suboptimal dietary habits. In young infants and children older than 3 years, purely dietary iron deficiency is uncommon, and an evaluation for blood loss or malabsorption is warranted. Blood loss can occur as hematochezia or melena (eg, inflammatory bowel disease, diarrhea, Meckel diverticulum, polyp, ulcer), menorrhagia, epistaxis, hematuria, or rarely as pulmonary bleeding (eg, pulmonary hemosiderosis). Iron is absorbed primarily in the duodenum, and several dietary factors (eg, coffee, tea) as well as primary intestinal disorders can impair absorption (ie, celiac disease).
The thalassemias are a heterogeneous group of inherited anemias that are characterized by impaired or absent synthesis of the or β chains that make up the normal adult hemoglobin tetramer. Beta-thalassemias are caused by a decrease in the production of β-globin chains. Anemia observed in the severe forms of β-thalassemia occurs as a result of ineffective erythropoiesis. This is because of the instability of excess chains, which precipitate and cause oxidative damage to the cell membrane, resulting in premature destruction of the erythrocyte within the bone marrow. Erythrocytes that do survive in circulation have a shortened life span because of increased hemolysis. Severe forms (ie, compound heterozygous or homozygous state) are classified as β-thalassemia intermedia or β-thalassemia major depending on the clinical presentation and degree of anemia. Individuals with β-thalassemia major develop a severe anemia during the first year after birth because decreasing levels of fetal hemoglobin ( 2γ2) cannot be replaced by normal adult hemoglobin ( 2β2). Hemoglobin values fall to the range of 3 to 4 g/dL, and regular transfusions are required. Individuals with β-thalassemia intermedia usually present later in life and do not require early intervention with blood transfusions. In these patients, hemoglobin values are in the 7 to 8 g/dL range, and individuals may be intermittently transfusion dependent. Individuals with β-thalassemia trait (ie, β-thalassemia minor), the heterozygous form, have a mild microcytic anemia with a hemoglobin that is approximately 2 g/dL below the normal mean for age. Clinically it is an asymptomatic anemia; however, it is of diagnostic relevance in that it must be distinguished from iron deficiency anemia, which may be a concomitant problem.
The -thalassemias are caused by a decrease in the production of chains and typically are milder than β-thalassemias. This is because the excess of β chains that occurs in -thalassemia is more stable, resulting in less membrane damage and intramedullary erythrocyte destruction. Humans have 4 -globin genes. Individuals with a deletion of 1 -globin gene are silent carriers and are asymptomatic, with a normal hemoglobin value and MCV. Individuals with the 2-gene deletion have -thalassemia trait and have a very mild microcytic anemia that is asymptomatic. Three-gene deletion causes hemoglobin H disease, a moderate chronic hemolytic anemia that may be intermittently transfusion-dependent. This occurs primarily in individuals of Southeast Asian descent. Four-gene deletion causes hydrops fetalis, an almost universally fatal condition that essentially results in fetal CHF and intrauterine demise.
Although lead inhibits heme synthesis and red cell function on many levels, microcytic anemia is a late finding of lead intoxication. Iron deficiency and lead poisoning often occur together, and the relationship between the two is complex. Pica is a risk factor for lead ingestion. In the presence of lead, iron uptake by the erythrocyte is diminished and iron deficiency increases lead retention and toxicity. Intestinal absorption and uptake of lead by red cells is decreased in the presence of iron. Additionally, iron deficiency and lead poisoning both tend to occur in individuals of lower socioeconomic status, and both are exacerbated by concomitant nutritional deficiencies.
Anemia of inflammation or chronic disease may occur in children with chronic infections, generalized inflammatory disorders (eg, rheumatoid arthritis), and some cancers. It is characterized by a decrease in serum iron and iron-binding capacity, an increase in ferritin, and the presence of iron in bone marrow macrophages indicating impaired iron mobilization from storage sites. Increased synthesis of hepcidin, an iron regulatory hormone, under the influence of inflammatory cytokines seems to be responsible for the hypo-ferremia observed in anemia of inflammation. Generally, anemia of inflammation is mild and may be microcytic or normocytic.
Folate and vitamin B12 deficiency cause a macrocytic anemia as a result of defective erythroid precursor nuclear maturation and megaloblastic changes in the bone marrow. Folate is absorbed in the duodenum and jejunum and is widely available in meats, green leafy vegetables, and cereals. Because of the ubiquity of folate, dietary deficiency is uncommon; however, newborns and infants fed exclusively goat’s milk are at risk because of the exceedingly low levels of folate in goat’s milk. Individuals with chronic hemolytic anemias may also become folate-deficient because of high bone marrow activity and increased demand.
Vitamin B12 is available from animal sources and is actively absorbed in the terminal ileum in association with intrinsic factor. Vitamin B12 deficiency can occur in individuals with a strict vegan diet (or in exclusively breastfed newborns and infants of women following a strict vegan diet); however, it usually occurs as a result of malabsorption. Decreased absorption can occur in the setting of pernicious anemia secondary to decreased intrinsic factor, surgical resection (ie, following necrotizing enterocolitis), and GI disease.
Other causes of macrocytic anemias include congenital hypoplastic anemias, myelodysplastic syndromes, chemotherapeutic agents (eg, methotrexate), and hypothyroidism.
Normocytic anemias can be classified as hemolytic (ie, associated with a reticulocytosis) or hypoplastic (eg, reticulocytopenia). Hemolytic anemias can be further divided into disorders that are intrinsic or extrinsic to the RBC. Intrinsic RBC disorders include hemoglobinopathies, enzymopathies, and membranopathies.
Sickle cell disease is the most common hemoglobinopathy worldwide and is concentrated in individuals of African or mixed African descent. Inheritance of 2 sickle β-globin genes (ie, hemoglobin SS) is the most common form; however, other significant sickle syndromes include hemoglobin SC, Sβ+ thalassemia, and Sβ° thalassemia. Hemolytic anemia and painful vasoocclusive episodes are the hallmarks of sickle cell disease. The anemia is generally well tolerated, with hemoglobin values ranging from 6.5 to 8.5 g/dL with an associated reticulocytosis (5%–15%). The 2 most common hematologic complications in sickle cell disease are aplastic crises and splenic sequestration, both of which can cause an acute drop in hemoglobin. Aplastic crises typically are the result of infection with parvovirus, which temporarily causes the complete cessation of red cell production. Splenic sequestration occurs most commonly in infants and young children with sickle cell disease, often in association with a viral illness. Large amounts of blood can be quickly trapped in the spleen, causing hypovolemia, shock, and massive splenomegaly. See Selected References for further information on and excellent reviews of this multisystem disorder.
Glucose-6-phosphate dehydrogenase deficiency, the most common RBC enzyme deficiency, is an X-linked recessive hereditary disease that renders the red cell susceptible to oxidant stress and hemolysis. Several variants have been defined; however, the most common variants are those associated with acute intermittent hemolytic anemias with exposure to oxidant stresses (eg, fava beans, medications). Variants associated with chronic hemolytic anemias are very rare.
Pyruvate kinase deficiency is the most common red cell enzyme defect and causes a chronic congenital hemolytic anemia. The degree of hemolysis is variable, ranging from a mild, fully compensated hemolytic process without anemia to a transfusion-dependent anemia. Individuals with severe hemolysis may be chronically jaundiced and may develop the clinical complications of chronic hemolytic states (eg, gallstones, transient aplastic crises in association with infections, folate deficiency, and infrequently, skin ulcers). Hereditary spherocytosis is the most common red cell membra-nopathy and is characterized by the presence of spherical-shaped erythrocytes on the peripheral blood smear. Increased membrane fragility caused by defects in proteins of the red cell membrane (ie, spectrin, ankyrin, band 3, protein 4.2) results in membrane vesiculation and membrane loss and the assumption of a spheroidal shape. Hemolysis occurs when these spherocytes are then trapped within the spleen. Clinically, the degree of hemolysis varies from mild anemia to severe transfusion dependence. Complications of a chronic hemolytic state, such as gallstones, aplastic crises, and folate deficiency, also may be observed.
Hemolytic anemias that are caused by factors extrinsic to the red cell can be further classified as immune-mediated or nonimmune. Immune-mediated anemias may be the result of alloantibodies that occur in the setting of neonatal Rh or ABO incompatibility or transfusion reactions. Autoantibodies may occur in association with infection, autoimmune disorders, malignancy, or drugs. In children, autoantibodies (ie, warm immunoglobulin G, cold immunoglobulin M) are often seen in association with a viral illness or mycoplasma infection. Nonimmune hemolytic anemias include thrombotic thrombocytopenic purpura and macroangiopathy anemias caused by a myriad of etiologies, including infections, drugs, toxins, burns, and artificial heart valves.
Anemia resulting from reticulocytopenia can be congenital or acquired and can occur in isolation or in the setting of pancytopenia. Congenital hypoplastic anemia (ie, Diamond-Blackfan anemia) is a ribosomal disorder that causes a congenital pure red cell aplasia that presents early in infancy. The bone marrow typically shows red cell aplasia with a paucity of red cell precursors, and the red cells may be normocytic or macrocytic. Associated congenital anomalies, such as craniofacial anomalies, radial abnormalities, and renal and cardiac defects, occur in approximately 25% of affected individuals. Transient erythroblastopenia of childhood is an acquired anemia resulting from reticulocytopenia that typically occurs following a viral illness. Usual age of presentation is between 2 and 3 years in an otherwise healthy child, and complete recovery is the natural course. Aplastic processes, such as idiopathic aplastic anemia and hereditary Fanconi syndrome, usually present with neutropenia or thrombocytopenia in addition to anemia.
When evaluating an infant or child with anemia, the age, rapidity of symptom onset, MCV, and suspected underlying mechanism of anemia direct the history (Box 98.4). In most instances, it is important to inquire about dietary habits, with particular attention paid to the type and amount of milk ingested per day (number of bottles/ounces). Ingestion of more than 24 ounces of cow’s milk per day should raise suspicion of iron deficiency anemia. Medication use, potential toxin ingestion (eg, lead), or a history of pica should be determined as well. Additionally, potential sources of blood loss (eg, hematochezia, melena, menorrhagia, hematuria, epistaxis, pulmonary) should be addressed. Acute onset of jaundice, icterus, or dark urine is suggestive of hemolysis and should elicit questions about possible triggers (eg, fava beans, medications, illnesses). A personal history of neonatal hyperbilirubinemia or a family history of anemia, gallstones, cholecystectomy, or splenectomy is suggestive of a congenital hemolytic anemia. Acute onset of hemolysis with a viral illness is consistent with an autoimmune hemolytic anemia. Individuals with a marrow failure syndrome often present with a prolonged history of increased fatigue and pallor, with occasional history of previous red cell transfusions prior to diagnosis. In acquired marrow failure states, such as aplastic anemia, the history is occasionally consistent with antecedent hepatitis, a viral syndrome, or, rarely, exposure to toxins (eg, benzene, toluene-containing compounds), or use of oral chloramphenicol, which is commonly available over the counter in Latin America.
Box 98.4. What to Ask
•Does the child eat meat?
•Does the child drink too much milk (>24 oz/day)?
•Has the child had any bleeding recently?
•Has the child had a recent illness?
•Is the child taking any medications?
•Have the child’s eyes appeared yellow?
•Does the child have a family history of anemia, jaundice, gallstones, or splenectomy?
•Did the child or siblings have jaundice at birth requiring phototherapy or exchange transfusion?
•Was the child born preterm, and if so, how early?