Etiology

Most iron in neonates is in circulating hemoglobin. As the relatively high hemoglobin concentration of the newborn infant falls during the first 2-3 mo of life, considerable iron is reclaimed and stored. These reclaimed stores usually are sufficient for blood formation in the first 6-9 mo of life in term infants. Stores are depleted sooner in low-birthweight infants or infants with perinatal blood loss because their iron stores are smaller. Delayed clamping of the umbilical cord can improve iron status and reduce the risk of iron deficiency. Dietary sources of iron are especially important in these infants. In term infants, anemia caused solely by inadequate dietary iron usually occurs at 9-24 mo of age and is relatively uncommon thereafter. The usual dietary pattern observed in infants and toddlers with nutritional iron-deficiency anemia in developed countries is excessive consumption of bovine milk (low iron content, blood loss from milk protein colitis) in a child who is often overweight. Worldwide, undernutrition is usually responsible for iron deficiency.

Blood loss must be considered as a possible cause in every case of iron-deficiency anemia, particularly in older children. Chronic iron-deficiency anemia from occult bleeding may be caused by a lesion of the gastrointestinal (GI) tract, such as peptic ulcer, Meckel diverticulum, polyp, hemangioma, or inflammatory bowel disease. Infants can have chronic intestinal blood loss induced by exposure to a heat-labile protein in whole bovine milk. This GI reaction is not related to enzymatic abnormalities in the mucosa, such as lactase deficiency, or to a typical milk allergy. Involved infants characteristically develop anemia that is more severe and occurs earlier than would be expected simply from an inadequate intake of iron. The ongoing loss of blood in the stools can be prevented either by breast-feeding or by delaying the introduction of whole bovine milk in the 1st year of life and then limiting the quantity of whole bovine milk to <24 oz/24 hr. Unrecognized blood loss also can be associated with chronic diarrhea and rarely with pulmonary hemosiderosis. In developing countries, infections with hookworm, Trichuris trichiura, Plasmodium, and Helicobacter pylori often contribute to iron deficiency.

About 2% of adolescent girls have iron-deficiency anemia, due in large part to their adolescent growth spurt and menstrual blood loss. The highest risk of iron deficiency is among teenagers who are or have been pregnant; >30% of these girls have iron-deficiency anemia.

Clinical Manifestations

Most children with iron deficiency are asymptomatic and are identified by recommended laboratory screening at 12 months of age or sooner if at high risk. Pallor is the most important clinical sign of iron deficiency but is not usually visible until the hemoglobin falls to 7-8 g/dL. It is most readily noted as pallor of the palms, palmar creases, nail beds, or conjunctivae. Parents often fail to note the pallor because of the typical slow drop over time. Often a visiting friend or relative is the first to notice. In mild to moderate iron deficiency (i.e., hemoglobin levels of 6-10 g/dL), compensatory mechanisms, including increased levels of 2,3-diphosphoglycerate (2,3-DPG) and a shift of the oxygen dissociation curve, may be so effective that few symptoms of anemia aside from mild irritability are noted. When the hemoglobin level falls to <5 g/dL, irritability, anorexia, and lethargy develop, and systolic flow murmurs are often heard. As the hemoglobin continues to fall, tachycardia and high output cardiac failure can occur.

Iron deficiency has nonhematologic systemic effects. The most concerning effects in infants and adolescents are impaired intellectual and motor functions that can occur early in iron deficiency before anemia develops. There is evidence that these changes might not be completely reversible after treatment with iron, increasing the importance of prevention. Pica, the desire to ingest non-nutritive substances, and pagophagia, the desire to ingest ice, are other systemic symptoms of iron deficiency. The pica can result in the ingestion of lead-containing substances and result in concomitant plumbism (Chapter 702).

Laboratory Findings

In progressive iron deficiency, a sequence of biochemical and hematologic events occurs (Tables 449-1 and 449-2). Clinically, iron deficiency anemia is not difficult to diagnose. First, tissue iron stores are depleted. This depletion is reflected by reduced serum ferritin, an iron-storage protein, which provides an estimate of body iron stores in the absence of inflammatory disease. Next, serum iron levels decrease, the iron-binding capacity of the serum (serum transferrin) increases, and the transferrin saturation falls below normal. As iron stores decrease, iron becomes unavailable to complex with protoporphyrin to form heme. Free erythrocyte protoporphyrins (FEPs) accumulate, and hemoglobin synthesis is impaired. At this point, iron deficiency progresses to iron-deficiency anemia. With less available hemoglobin in each cell, the red cells become smaller. This morphologic characteristic is best quantified by the decrease in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Developmental changes in MCV require the use of age-related standards for diagnosis of microcytosis (see Table 441-1). Increased variation in cell size occurs as normocytic red cells are replaced by microcytic ones; this variation is quantified by an elevated RBC distribution width (RDW). The red cell count (RBC) also decreases. The reticulocyte percentage may be normal or moderately elevated, but absolute reticulocyte counts indicate an insufficient response to the degree of anemia. The blood smear reveals hypochromic, microcytic red cells with substantial variation in cell size. Elliptocytic or cigar-shaped red cells are often seen (Fig. 449-1). Detection of increased transferrin receptor and decreased reticulocyte hemoglobin concentration provides supporting diagnostic information when these studies are available.