Chapter 103: Anemia

• The mean hemoglobin concentration for normal newborns is 18 g/dL, after which it falls to a nadir of 11 g/dL (mean concentration) at 2 to 3 months of life. Although mean hemoglobin concentrations in children continue to vary somewhat by age, 11 g/dL defines the lower limits of normal for the prepubertal patient population.

• Anemias are most easily classified based on red blood cell (RBC) size and degree of bone marrow activity. The size of RBCs is measured as mean corpuscular volume (MCV), with the lower limit of normal for the MCV equaling 70 plus the age in years; bone marrow activity is reflected by the reticulocyte count.

• The most common cause of microcytic anemia in childhood is iron deficiency, usually due to excess intake of cow's milk.

• Thalassemias are inherited defects resulting in the inability to synthesize sufficient quantities of various globin chains of the hemoglobin molecule. Thalassemia trait produces marked microcytosis out of proportion to the degree of anemia.

• If the reticulocyte count is high in the presence of a normocytic anemia, blood loss or a hemolytic process must be considered.

• A low reticulocyte count in the face of significant anemia indicates bone marrow underproduction. If the abnormality is isolated to the RBC line, the primary considerations are transient erythroblastopenia of childhood (TEC) or an aplastic crisis complicating an underlying hemolytic anemia.

• Thrombocytopenia or white blood cell (WBC) abnormalities associated with normocytic anemia and poor reticulocyte response suggests a marrow infiltrative process such as leukemia or acquired aplastic anemia.

• Macrocytic anemia is uncommon in pediatric patients. Folate and vitamin B₁₂ deficiencies are rare in otherwise healthy children.

Hemoglobin values are high at birth and slowly fall to a nadir at 2 to 3 months of age. This nadir is deeper and occurs at a younger age in premature infants. Although mean hemoglobin concentrations in children continue to vary somewhat by age, 11 g/dL plus 0.1 times the age in years defines the lower limits of normal for the prepubertal patient population. After puberty, normative data for adult populations apply and gender differences become apparent.

Patients with mild anemia are usually asymptomatic, and the anemia is most commonly discovered on a routine complete blood count (CBC). Even children with moderate-to-severe anemia may be asymptomatic if the problem develops slowly, compensating well for even severely low hemoglobin levels. When the hemoglobin becomes low enough to produce symptoms, patients may present with fatigue, irritability, or shortness of breath on exertion. Physical examination may reveal pallor, tachycardia, jaundice, and systolic ejection murmur owing to an increased cardiac output. With a rapid drop in hemoglobin, the child may develop dizziness, orthostatic hypotension, or high-output cardiac failure.

Important history to obtain when evaluating anemia includes the patient's diet, prior blood counts, and prior episodes of jaundice. A family history of anemia, splenectomy, jaundice, or gallstones might suggest a hemoglobinopathy or a hereditary membrane disorder. Knowledge of any chronic disorders such as kidney disease, cardiovascular disease, or underlying inflammatory processes is necessary. Physical examination should assess for signs of jaundice, lymphadenopathy, or splenomegaly.

Laboratory evaluation of anemia should begin with a CBC, reticulocyte count, and review of the peripheral blood smear. Further diagnostic evaluation, if needed, is determined by the results of these tests. Causes of anemia are most easily classified based on RBC size (microcytic, normocytic, or macrocytic) and degree of bone marrow activity. The size of RBCs is measured as the MCV, the normal values of which vary with age. The lower limit of normal for the MCV equals 70 plus the age in years up to the normal adult low of 80. Bone marrow activity is reflected by the reticulocyte count. Table 103-1 summarizes the basic interpretation of a screening CBC for the cause for anemia. Table 103-2 reviews the interpretation of the peripheral smear examination of RBC morphology to help determine the cause of anemia.

The most common cause of microcytic anemia in children is iron deficiency. Thalassemia, anemia of inflammation, hemoglobin C disease, hemoglobin E disease, and sideroblastic anemia may also lead to microcytic anemia. Table 103-3 reviews a method for sorting out the common causes of microcytic anemia.

Iron Deficiency

Risk factors for iron deficiency anemia include age between 6 months and 2 years, lack of use of iron-fortified formulas, early introduction of cow's milk into the diet, excess intake of milk, and low socioeconomic status. Whole cow's milk is deficient in bioavailable iron but rich in calories. Excess milk intake produces iron deficiency by its inherent lack of bioavailable iron, by reducing appetite and intake of iron-rich foods, and leading to occult gastrointestinal bleeding from the effect of unmodified cow's milk proteins on gastrointestinal mucosa.¹ During fetal life, most of the total body iron is absorbed during the last trimester, so premature infants are at greater risk for iron-deficiency anemia. They deplete their reduced iron stores early and have an even greater need than full-term infants for iron supplementation.

Iron deficiency anemia develops slowly and patients rarely present with acute symptoms. Even with drastically reduced hemoglobin levels, patients are usually well compensated and hemodynamically stable. The diagnosis is usually made on the basis of the history, with CBC results showing anemia and significant microcytosis. The reticulocyte count should not be low or “normal”, when it should be elevated in response to the level of anemia. Thrombocytosis is common in iron deficiency anemia, but thrombocytopenia may also be seen. If necessary, further diagnostic testing will reveal a reduced serum iron, an elevated total iron binding capacity (TIBC), and a reduced ferritin level. Ferritin, however, is an acute-phase reactant and in the face of infection or inflammation may be elevated despite the presence of iron deficiency anemia. A trial of iron therapy is both diagnostic and therapeutic. Ferrous sulfate is administered in an amount sufficient to provide 4 to 6 mg/kg of elemental iron per day. Therapy is continued until the hemoglobin and MCV have normalized and iron stores are replete, which often takes several months. Multivitamins with iron, do not provide adequate amounts of iron to correct iron deficiency. An increase in the reticulocyte count is typically seen in a matter of days, and the hemoglobin level increases in 1 to 2 weeks. Identification and elimination of the cause of the iron deficiency is also necessary and is usually accomplished with appropriate dietary counseling.

Thalassemia

Thalassemias are inherited defects resulting in the absence or decreased production of normal hemoglobin, leading to a microcytic anemia. The condition is most common in people of Mediterranean, Southeast Asian, and African ancestry and is the most common single-gene disease worldwide.² In general the disease is classified by the number of abnormal globin genes. The heterozygous form of thalassemia is often referred to as thalassemia trait. Thalassemia trait produces marked microcytosis out of proportion to the degree of anemia. There is typically a high total RBC count and narrow red cell distribution width (RDW), which helps differentiate thalassemia trait from iron deficiency anemia. Unlike iron deficiency, the reticulocyte count in thalassemia should be normal or slightly elevated.

α-Thalassemia results from a decreased production of α-globin because of a deletion or mutation in one or more of the four α-globin genes. Patients will have a normal hemoglobin electrophoresis outside of the newborn period (when hemoglobin Barts may be detected). The silent carrier state results from a defect in a single gene and patients have no anemia and normal-appearing red cells. α-thalassemia trait refers to a defect in two genes, resulting in mild microcytic anemia. Hemoglobin H disease occurs when there is only one normal α-globin gene. These patients have moderate anemia in the 8 to 10 g/dL range but may have increased hemolysis with stress or infection. A defect in all four α-globin genes results in α-thalassemia major, a condition leading to severe fetal complications.

β-Thalassemia results from a decreased production of β-globin because of a mutation or deletion in one or more of the two β-globin genes. In β-thalassemia trait, the hemoglobin concentration is often 2 to 3 g/dL below normal values. A hemoglobin electrophoresis will demonstrate an elevated A₂ component and in some cases an elevated level of fetal hemoglobin (Hgb F). In β-thalassemia intermedia, patients maintain a hemoglobin level of 6 to 8 g/dL and do not require chronic transfusion. β-thalassemia major produces severe hemolytic anemia with marked microcytosis and reticulocytosis. It usually presents within the first year of life. Pallor, jaundice, and hepatosplenomegaly are often present. Because patients require lifelong transfusion therapy, the use of uncrossmatched blood is avoided, except in the most dire circumstances. The major side effect of long-term transfusion therapy is iron overload, which adversely affects multiple organs, especially the liver and heart.

Lead Poisoning

Although microcytic anemia may be seen in children with lead poisoning, the anemia is actually owing to iron deficiency. Lead poisoning must be considered in the child with microcytic anemia. Iron deficiency leads to pica and the ingestion of lead. Iron deficiency also increases absorption of lead from the gastrointestinal tract.³

Although normocytic anemia is less common than microcytic anemia, the differential diagnosis in childhood is extensive (Table 103-4). The primary determinant in establishing a differential is whether the anemia is owing to decreased production, increased destruction, or blood loss. Most diagnosis may be made based on history, reticulocyte count, and review of RBC morphology.⁴

Normocytic Anemia With High Reticulocyte Count

If the reticulocyte count is high in the presence of a normocytic anemia, blood loss must be considered. If there is no evidence of blood loss, a hemolytic anemia is likely. The workup for a patient with hemolytic anemia includes a Coombs or direct antiglobulin test (DAT) to determine whether the hemolytic anemia is immunologic in nature. Immune hemolytic anemia may be the result of a drug reaction, infection, collagen vascular disorder, or malignancy, but commonly no etiology is determined.

Patients often present acutely with severe anemia, pallor, jaundice, and hemoglobinuria. Transfusions may be necessary with severe symptomatic anemia but may be difficult owing to the circulating antibody causing “incompatibility” in vitro and rapid destruction of transfused RBCs in vivo. Immunosuppression with corticosteroid is frequently adequate to diminish RBC destruction, so that the patient's brisk reticulocytosis can repair the anemia. In severe or refractory cases, plasmapheresis or IVIG may be necessary.

The differential diagnosis for nonimmune hemolytic anemia includes micro and macroangiopathic destruction, membrane disorders, metabolic abnormalities, and hemoglobinopathies. Sickle cell anemia is discussed in detail in Chapter 104.

Microangiopathic RBC destruction can occur with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome. The peripheral smear will demonstrate schistocytes, burr cells, and other RBC fragments.

Hereditary spherocytosis (HS)⁵ and elliptocytosis (HE) result from inherited mutations in a variety of proteins making up the red cell membrane. The incidence of HS is estimated at 1 in 5000 in the United States. Most cases are inherited in an autosomal dominant pattern, making family history important in the diagnosis. However, up to 25% of cases may arise in patients with no family history.^4,5 Hemolytic anemia occurs due to splenic destruction of abnormally shaped RBCs. The disease often presents as jaundice and anemia in infancy. The degree of anemia varies widelyt is often consistent within affected family members. Laboratory studies reveal anemia, reticulocytosis, and hyperbilirubinemia. The diagnosis is made by reviewing the peripheral smear and possibly family history; osmotic fragility studies are confirmatory. The major hematologic crisis is aplastic anemia, which is usually secondary to a parvovirus infection. Patients may also have an increased rate of hemolysis with stress or infection. Splenectomy is curative and is considered in patients with severe hemolysis leading to frequent transfusion or hospitalization. Spherocytes may be seen in the peripheral smear of conditions other than HS, including neonates with ABO incompatibility, patients with clostridial sepsis, severe burns, and spider, bee, or snake bites.

Inherited metabolic disorders, such as pyruvate kinase and glucose-6-phosphate dehydrogenase (G6PD) deficiencies, also cause chronic hemolysis. There are multiple variants of G6PD deficiency, with varying degrees of severity. The A-variant is seen in approximately 10% of African American males and becomes symptomatic only after a significant challenge from a drug or infection. Enzyme levels are higher in young cells, so normal levels of G6PD may be obtained when assayed from G6PD-deficient patients during periods of brisk reticulocytosis. The assay may have to be repeated when the acute hemolysis has passed. Treatment involves blood transfusion with severe anemia and counseling regarding avoidance of oxidant stressors.

Normocytic Anemia With Low Reticulocyte Counts

A low reticulocyte count in the face of significant anemia indicates bone marrow underproduction. If the abnormality is isolated to the RBC line, the primary considerations are TEC and an aplastic crisis complicating an underlying hemolytic anemia.

TEC is an acquired pure RBC aplasia; WBC and platelet counts are normal. It typically affects children between 1 and 4 years of age. There is seasonal clustering and an associated history of preceding viral illness, but no causative viral agent has been identified. Supportive therapy is usually sufficient as patients are typically hemodynamically stable and recover spontaneously over several weeks. Transfusion may be necessary in symptomatic patients. Steroids have not been shown to speed recovery.

Other entities in the differential of normocytic anemia with low-to-normal reticulocyte counts and no abnormalities of other cell lines include anemia of chronic disease, inflammatory processes, and decreased erythropoietin from renal insufficiency. Anemia of chronic disease (ACOD) occurs in patients with acute or chronic immune activation, resulting in disorder of iron hemostasis and blunted erythropoietin response.⁶ ACOD is usually a mild normocytic, normochromic anemia, but may be microcytic in long-standing cases, making it difficult to differentiate from iron deficiency (see Table 103-1). Diamond–Blackfan anemia is a congenital RBC aplasia that usually presents in the first year of life with severe anemia. The age of onset of anemia may help to differentiate Diamond–Blackfan from TEC. Occasionally, other congenital abnormalities are associated, such as cleft palate, skeletal anomalies, and congenital heart disease.

Thrombocytopenia or WBC abnormalities associated with normocytic anemia and poor reticulocyte response suggests marrow infiltration or acquired aplastic anemia. Marrow infiltration is most commonly due to leukemia. Leukemic blasts may be apparent in the peripheral blood. Atypical lymphocytes from Epstein–Barr virus or other viral infections can appear similar to lymphoblasts. Lymphoma and other tumors with potential to metastasize to the bone marrow may also cause failure of production, with resultant decreases in multiple cell lines.

Acquired aplastic anemia in the absence of an underlying hemolytic anemia has been associated with drugs and infections. Often no etiology is determined. The prognosis is quite poor and bone marrow transplantation is often required. Blood transfusion is performed judiciously for patients who are candidates for bone marrow transplantation because of the risk of sensitization.

Macrocytic anemia is relatively uncommon in pediatric patients. Aplastic anemia or leukemia, although usually causing normocytic anemia, can result in macrocytosis. Because of the large size of reticulocytes, marked reticulocytosis can lead to a high MCV although mature RBCs may be of a normal size. Folate and vitamin B₁₂ deficiencies can result in megaloblastic anemia. These are rare in otherwise healthy children but should be considered in children with underlying gastrointestinal pathology. Goat's milk contains little folate, and infants maintained on this alone may develop macrocytic anemia. Some drugs, notably AZT (zidobudine), can cause macrocytosis.