Hematology and Oncology

Classifications and Symptoms

Anemia is the most common abnormality of RBCs, and it is identified as a decrease in hemoglobin level. At any given age, anemia is defined practically as a value greater than 2 standard deviations, below the mean ( Table 12.1 ). However, physiologically, anemia is best defined as a hemoglobin level that is too low to meet tissue oxygen demands. Recognition that a child’s hemoglobin level is abnormal requires knowledge of age, gender, and race-related normal values. Anemia occurs as a result of one of the following: (1) decreased bone marrow production of RBCs, and reticulocytes ( Fig. 12.3 ), (2) increased destruction of mature RBCs peripherally or as precursors in the bone marrow, or (3) loss of RBCs (hemorrhage). In some situations, a combination of these factors can occur.

Physical examination of the anemic child may reveal pallor, although in the fair-skinned or dark-skinned child, it may be easily missed, unless palmar creases or conjunctivae are also examined thoroughly ( Fig. 12.4 ). Vital signs may be normal, but tachycardia may be present. Severe anemia from any cause may elicit symptoms of fatigue; decreased appetite; headache; and, in extreme cases, shock, congestive heart failure, or even stroke.

Iron Deficiency

The most common anemia encountered in pediatrics is microcytic anemia, due to iron deficiency. A lack of iron leads to failure of hemoglobin production. Iron deficiency, however, is only a laboratory finding, not a diagnosis. The causes of iron deficiency must be elucidated through a careful history and physical examination. Although poor nutrition is the most common cause, other causes such as hemorrhage or malabsorption must also be considered. Because the normal full-term infant has adequate iron reserve to accommodate the increasing RBC mass through the first 5 months of life, iron deficiency is usually not seen until the second half of the first year of life. It is detected most often in the 10- to 18-month-old child who ingests large volumes of cow’s milk. Whole cow’s milk not only is deficient in dietary iron but often leads to enteropathy with occult gastrointestinal blood loss, exacerbating the child’s iron-deficient status. A second peak of iron deficiency anemia is seen during adolescence in girls, due to nutrition and loss of RBCs.

Affected children may manifest a peculiar physical finding termed koilonychia, or “spooning” of fingernails and toenails ( Fig. 12.5 ). Glossitis also may be observed in iron deficiency. The RBCs of iron deficiency anemia are microcytic and hypochromic. The number of platelets often is increased (particularly when an enteropathic condition is present), although it may be normal or even decreased. In severe iron deficiency anemia, anisocytosis and poikilocytosis may be prominent. Nonspecific abnormalities of RBC morphology (such as the presence of micro-ovalocytes or basophilic stippling) may also occur. Bizarre RBC shapes are due to a three-dimensional change in structure when viewed in a two-dimensional plane of the light microscope. When viewed in two dimensions, the cells appear ovoid. Fig. 12.6 shows a peripheral blood smear of a child with iron deficiency anemia.

The history and physical examination, blood count, and review of the peripheral blood smear may be sufficient for diagnosis in many instances of hypochromic, microcytic anemia. If the evaluation before obtaining a more specific test strongly suggests iron deficiency, a therapeutic trial of iron may be a reasonable approach. However, additional laboratory studies are often indicated. Importantly, normal values of ferritin, serum iron, total iron binding capacity (TIBC), and transferrin saturation demonstrate age-related variation. Serum iron and TIBC alone may not give an accurate perspective of total body iron stores, as they are relatively short-term measures, and are affected by recent intake. Ferritin is a superior measure of long-term iron stores, but it also is an acute-phase reactant and may be elevated into the low normal range in a child with a concurrent inflammatory process. However, if ferritin is low, it is diagnostic of iron deficiency.

The coexistence of iron deficiency and lead intoxication is well documented; though in practice, an increased lead level more commonly is secondary to pica in children with iron deficiency, and it is not the cause of anemia. Pica is the ingestion of non-food items, such as chalk, carpet fibers, or other debris. In primary lead intoxication, nonhematologic manifestations, particularly neurologic complications, appear long before an anemia develops. Significant radiographic changes are also seen in primary lead intoxication ( Fig. 12.7 ). When they do occur, hematologic abnormalities of lead intoxication such as basophilic stippling ( Fig. 12.8 ) are a direct result of the effect of lead on several cellular enzymes involved in heme production. Lead inhibits these enzyme systems, impairing iron use and globin synthesis.

Anemia of Inflammation

Inflammatory diseases, such as chronic infection, inflammatory bowel disease, or rheumatologic conditions, may lead to microcytic anemia. Although the symptoms of the child’s primary illness usually clarify the diagnosis, there are occasionally cases in which a chronic subclinical infection (particularly of the urinary tract) may go undiagnosed. Clinical factors often can make this diagnosis, although one laboratory study that may be of value is the serum ferritin determination. Ferritin is decreased in iron deficiency, whereas in chronic inflammatory states, it is usually elevated. Also, though serum iron can be low in both iron deficiency and anemia of chronic disease, TIBC is increased in iron deficiency and decreased in anemia of chronic disease. These changes are felt to be due to the upregulation of the enzyme hepcidin, which redirects total body iron to storage pools rather than RBC production.

Megaloblastic Anemia

Although the etiology of macrocytic anemias varies, common morphologic abnormalities of erythropoietic cells exist. In the bone marrow, the hallmark is the megaloblast, a nucleated RBC with a lacy chromatin pattern and asynchrony of maturation between cytoplasm and nucleus. The morphologic alterations are a direct result of decreased nuclear protein deoxyribonucleic acid (DNA) synthesis compared with cytoplasmic protein synthesis, which stems from a relative decrease in the factors needed in DNA replication, namely folate and cobalamin (vitamin B ₁₂ ). Laboratory diagnosis requires the measurement of folate and vitamin B ₁₂ levels in the serum and RBCs. Glossitis ( Fig. 12.9 ) or angular stomatitis, commonly seen in vitamin B ₁₂ deficiency, can be helpful during physical findings in the diagnostic process.

On the peripheral blood smear, the RBCs are large, and display a great deal of variation in their shapes ( Fig. 12.10 ). These macrocytic cells are generally normochromic. In addition, actively dividing marrow cells may become involved in the pathologic process. Neutrophils are the second most likely cells to display morphologic abnormalities. These cells become large and show pathognomonic hypersegmentation of the nucleus ( Fig. 12.11 ). Neutropenia is common. The more severe and prolonged megaloblastic anemias ultimately may lead to moderate thrombocytopenia, with large, bizarre platelets on the peripheral blood smear. Megaloblastic changes in each cell line are shown in Fig. 12.12 .

Because a healthy diet is unlikely to lead to folate or vitamin B ₁₂ deficiency, a low level of either should raise questions of altered bioavailability or unusual diet. Goat milk is folate deficient, and an infant on a goat milk diet may become folate depleted over time. Various drugs that decrease folate absorption (phenytoin) or interfere with folate metabolism (methotrexate) may also lead to megaloblastic changes. A pathologic condition of the gastrointestinal tract may cause malabsorption of folate or vitamin B ₁₂ . This condition may be iatrogenic if a portion of the intestines is removed for medical reasons. Pernicious anemia is a specific cause, due to deficiency in intrinsic factor, which is required for vitamin B ₁₂ absorption. Elevated levels of vitamin B ₁₂ are generally not indicative of a problem in children, though there are exceptions.

Acquired Pure Red Cell Aplasia

Acquired forms of pediatric pure red cell aplasias (PRCAs) are rare, although well recognized. Transient erythroblastopenia of childhood (TEC) occurs in 1- to 4-year-old children and appears 2 weeks to 2 months after a respiratory or gastrointestinal illness. Fortunately, TEC is transient and self-limited. It has been noted that the RBCs in congenital PRCA have fetal characteristics, but the RBCs of TEC have age-appropriate characteristics ( Table 12.2 ). The cause of TEC remains obscure. TEC may occur after many different viral infections and most likely represents an altered immunity from the infection that affects erythropoiesis. Treatment is supportive and determined by the degree of symptoms. Non–TEC-acquired PRCA is rare in pediatrics, although these can result from infectious suppression of marrow precursors.

Hemolytic Anemias

Hemolytic anemias are defined by the premature destruction of RBCs. This can occur by mechanical, infectious, enzymatic, or immune-mediated mechanisms. Symptoms and severity vary not only among individuals, but also between diagnoses. Jaundice, especially scleral icterus, splenomegaly, and dark urine are common presentations during hemolytic episodes. Although all hemolytic anemias may have acute exacerbations, some also feature in more chronic phases of red cell breakdown. The history of individual patients, laboratory studies, and blood cell morphology are important factors in making the accurate diagnosis. Some of the most common morphologic features are described in Box 12.1 . Treatments can vary, and splenectomy may be a consideration. However, splenectomy in children is fraught with infectious, vascular, and thrombotic complications.