Iron Deficiency

Iron Imbalance in Children, Part 1: Identification and Treatment of Iron Deficiency

Germaine L. Defendi, MD, MS

ABSTRACT: This article, the first of a 2-part series on iron imbalance in pediatric patients, focuses on iron deficiency. It discusses the pathophysiology of iron metabolism, how the body effectively absorbs iron in its heme and nonheme forms, the body’s cellular response to iron depletion, the causes of and diagnostic clues to iron deficiency anemia, and supplementation treatments for iron deficiency in children. Part 2 of this series will focus on iron overload.


Iron is an essential mineral and nutrient in the human body. It is vital for the normal function of bodily processes by which cells generate energy. Too little or too much iron compromises the body’s metabolic and physiologic functions. Inadequate iron in the diet is a nutritional problem for billions of people worldwide.1 Iron is not a product of bodily resources and therefore must be absorbed through the gastrointestinal (GI) pathway as a dietary source.

Millions of people in the United States have anemia due to their inadequate iron stores.2 In 2007, this nutritional deficiency affected 2.4 million U.S. children.3 Iron deficiency in childhood has been linked to lasting cognitive impairment.3 

Conversely, too high a bodily iron load also is a health concern. The concept that either too little or too much of an essential nutrient can be harmful seems especially true of iron.


The human body tightly regulates the absorption and recycling of iron. Iron is such an essential element for life that no physiologic mechanism exists in the body for iron excretion.

At baseline, the body of a healthy adult maintains 3 to 5 g of iron. Approximately 66% of iron stores are found in 2 proteins: hemoglobin and myoglobin. These proteins utilize iron to help accept, carry, and release oxygen throughout the body. Of the remaining iron load, 25% to 30% is stored in the body as ferritin or hemosiderin, with the majority as ferritin. Ferritin, an intracellular protein, releases iron in a controlled manner based on bodily need. Measurement of serum ferritin indicates the body’s iron status and is a useful tool for diagnosing iron imbalance. Low ferritin values reflect depleted iron stores. High ferritin values can signal iron overload, hepatic trauma (from the release of ferritin stored in the liver), an inflammatory condition (as a nonspecific acute-phase reactant response), or a malignancy. Hemosiderin, an insoluble iron-storage complex, is a “transformed” ferritin that is composed primarily of ferritin that has been partially digested by autophagosomes.4

The remaining iron store, approximately 6%, is found in oxidizing-reducing enzymatic reactions of cellular metabolism (eg, flavin enzymes, oxidative phosphorylation in mitochondria), and in reactions producing amino acids, hormones, and neurotransmitters.4,5


The body’s goal is to conserve iron, and physiologic pathways exist to absorb and utilize this mineral. Intestinal mucosal cells of the duodenum and upper jejunum enable maximal absorption of digested iron-containing sources. Initially, mucosal ferritin absorbs iron from the GI tract and stores it in the mucosal cells. When the body requires iron, mucosal ferritin transports it to another protein, mucosal transferrin. Mucosal transferrin, in turn, transfers plasma iron to the transport glycoprotein transferrin. Iron is then transported to the bone marrow for erythropoiesis and to muscle cells for myoglobin. The iron storage pool is in the liver, spleen, bone marrow, and skeletal muscle in the forms of ferritin-bound iron and hemosiderin.4 Hemosiderin is a poor source of replenishing diminished iron stores.

Hepcidin is the iron-regulatory hormone that controls the dietary absorption, storage, and tissue distribution of iron. It decreases iron transfer to blood plasma in 3 ways: from the duodenum; from macrophages involved in recycling senescent erythrocytes; and from iron-storing hepatocytes. Feedback control of hepcidin is regulated by plasma and hepatic iron concentrations and by erythropoietic demand for iron.6

Red blood cell (RBC) destruction occurs in the liver and spleen; iron is recovered from these damaged cells. The iron is packed into transferrin and stored as ferritin-bound iron in the liver. Thus, hepatic tissue serves as the body’s primary physiologic pool of iron. Hepatic ferritin recycles needed iron back to the bone marrow, muscle fibers, and cells. With an increased iron pool, some ferritin is changed into hemosiderin.4

Iron loss occurs through sweating, menstruation, and shedding of mucosal and dermal epithelial cells. Intestinal mucosal cells are replaced every 4 to 6 days. When intestinal mucosal cells are shed and excreted in stool, some iron is lost.7


The amount of dietary iron absorbed by the body depends on its food source. Less than 10% of iron is absorbed from a nutritionally balanced diet.8,9 Iron occurs in 2 dietary forms, heme and nonheme. Heme iron is found primarily in animal flesh such as meats, poultry, and fish. This iron originates from the blood and heme-containing proteins in meat and cell mitochondria. Some heme iron also is found in plant cell mitochondria. Nonheme iron is found in both plant and animal sources.10

Heme iron is well absorbed and thus is a significant contributor to the body’s iron stores. It is absorbed through the GI tract at a relatively constant rate. Typically, the intestinal absorption of nonheme iron is less than that of heme iron, with the amount absorbed influenced by dietary factors and the current bodily store. Persons with severe iron deficiency absorb heme and nonheme iron more efficiently and are more responsive to dietary enhancing factors than persons with an established healthy iron pool. In a balanced physiologic state, 1 to 2 mg of iron are absorbed and excreted each day.8

The Institute of Medicine has established a daily estimated average requirement for iron, expressed as mg/d. These iron requirements are listed in table format and vary with age, gender, and pregnancy and lactation.9 Sources of dietary heme and nonheme iron are listed in Table 1.2,10-14


Iron is absorbed in the proximal small intestine (ie, the duodenum and upper jejunum). Meat, fish, and poultry contain highly bioavailable heme iron. MFP factor (an acronym for meat, fish, and poultry) is a peptide present in animal flesh that promotes the absorption of iron from nonheme-containing foods when heme and nonheme dietary sources are ingested together. Vitamin C (ascorbic acid) present in citrus fruits also enhances nonheme iron absorption from foods when consumed concurrently.15 Vitamin C captures ferric iron (trivalent state, Fe3+) from nonheme sources and reduces it to ferrous iron (divalent state, Fe2+), the ionic iron form required for GI absorption.9,16 Other enhancing factors for nonheme iron absorption include dietary citric acid and lactic acid.17

Some dietary elements bind with nonheme iron and thereby inhibit absorption. These include phytates (antioxidant compounds found in whole-grain products, legumes, and nuts), EDTA in food additives, and calcium and phosphorus found in milk and antacids. Medications that increase gastric pH (eg, antacids, histamine H2-receptor antagonists, proton-pump inhibitors) reduce iron absorption; thus, oral iron supplements should be taken either 2 hours before or 4 hours after ingesting antacids or acid reducers.16 Tannic acid (tannin) found in coffee and tea also inhibits iron absorption.Quinolone and tetracycline antibiotics impede iron absorption, as well.15,18


Increased RBC loss or decreased RBC production can cause an overall decrease in RBC mass below a critical level. Iron depletion due to the overutilization of the body’s iron stores without adequate replacement leads to iron-deficient erythropoiesis and, ultimately, iron deficiency anemia. Anemia is defined practically as a hemoglobin (Hgb) level that is less than 2 standard deviations below the average Hgb value for age. Physiologically, anemia is best explained as an Hgb level that is too low to meet the body’s tissue oxygen needs.19

Three levels of anemia are defined based on serum Hgb values: mild (Hgb > 10 g/dL), moderate (Hgb 7-10 g/dL), and severe (Hgb < 7 g/dL).20 An anemic state progresses as iron stores are depleted before iron deficiency erythropoiesis arises: iron depletion (due to reduced iron stores in tissue over time), early-onset iron deficiency anemia (depleted iron stores with maintenance of normal RBC morphology), and late-onset iron deficiency anemia (depleted iron stores with change in RBC morphology, notably microcytic and hypochromic RBCs).15

Four general categories identify the causes of iron deficiency: increased iron requirements, increased iron loss, decreased iron in the diet, and decreased iron absorption.

Increased iron requirements arise with rapid growth periods as seen in infancy, childhood, and adolescence. Pregnancy and lactation also increase iron needs.

Increased iron loss is related to blood loss from menorrhagia, metrorrhagia, acute bleeding due to trauma, chronic and/or occult blood loss from disease, malignancy, or vascular malformations, or frequent blood donations (≥ 2 units/y for women, ≥ 3 units/y for men).15 A fecal occult blood test can help diagnose intestinal bleeding as the source of iron loss.

Decreased iron in the diet reflects inadequate consumption of bioavailable iron sources. Children who are at high risk include premature infants; infants primarily fed cow’s milk before the age of 12 months; exclusively breastfed infants younger than 6 months of age who are not fed iron-fortified cereals or another dietary source of iron; formula-fed infants who do not receive standard iron-fortified formulas8;and children aged 1 to 5 years who drink more than 24 oz (three 8-oz bottles) of cow’s milk, goat’s milk, or soy milk daily. Excess milk consumption decreases a child’s interest in eating other foods with better iron content, such as meats and iron-fortified cereals. Other children at increased risk for an iron-deficient diet are those on restricted diets and those undergoing growth spurts without proper nutritional options.

Decreased iron absorption can be due to concurrent dietary intake of foods or medications that increase gastric pH.Optimal iron absorption requires the acidic environment of the duodenum andupperjejunum. Alkaline conditions in these tissues hamper iron absorption.15 The inability to adequately absorb iron also is linked to reduced GI surface absorption area from surgical interventions (eg, partial gastrectomy). Patients diagnosed with inflammatory bowel disease (eg, Crohn disease), celiac disease, autoimmune disorders, and lead toxicity also have shown decreased iron absorption.15,20


Patients with a low iron pool can remain asymptomatic despite laboratory values that indicate iron deficiency anemia. Presenting signs and symptoms are related to decreased oxygen delivery to the body’s tissues. Clinical signs of iron deficiency are pallor, pale conjunctivae, tachycardia, systolic ejection murmur, hair loss, and glossitis. Koilonychia (“spooning” of the fingernails and/or toenails) and an appetite for nonnutritive items such as ice, soil, clay, or paper (pica), have been described in patients with a longstanding anemic state. Symptoms include irritability, chronic fatigue or generalized weakness, headache, a “whooshing” heartbeat sound in the ears, shortness of breath, and chest pain with activity.15,19

Table 2 summarizes the signs and symptoms of iron deficiency anemia.3,19,21


After a medical history and thorough physical examination, diagnostic clarity for iron deficiency is based on serum laboratory test values. Initial tests should include a complete blood count with RBC indexes, platelet count, and reticulocyte count. Microscopic examination of a peripheral blood smear shows small (microcytic), oval-shaped RBCs with pale centers (hypochromic). More specific iron studies are ferritin level, iron level, red cell distribution width (RDW), total iron-binding capacity (TIBC), and transferrin level. The serum value for iron saturation is calculated using iron level and TIBC results.

In addition, iron deficiency and lead toxicity (also a microcytosis) can occur concurrently. A serum lead level test and a free erythrocyte protoporphyrin (FEP) test help determine whether lead toxicity is a concern.19,20

Test results of patients with iron deficiency anemia reflect the following values: low Hgb (< 2 standard deviations below average for age); microcytosis and hypochromic RBCs on peripheral blood smear; low mean corpuscular volume; low white blood cell count; low or (more often) high platelet count; low reticulocyte count (characteristic of hypoproliferative anemias); low ferritin level; low iron level; low iron transferrin saturation; high RDW (reflects microcytic RBCs mixed with normocytic RBCs)12,15; high transferrin level; high TIBC; and high FEP level.


Treatment modalities for restoring body iron stores are administered orally, intravenously, or intramuscularly.

Medicinal iron. The dose of medicinal iron required to treat patients with iron deficiency is higher than the dose found in daily multivitamin supplements. Oral preparations treat iron deficiency until it is corrected and the body’s iron stores have been replenished. For infants and children, the daily dose range of elemental iron for iron deficiency anemia is 4 to 6 mg/kg/d. Adults with iron deficiency require 150 to 200 mg/d of elemental iron, equivalent to 2 to 5 mg of iron/kg/d.16,20

Prescribed iron supplements require patients to follow a daily regimen for several months to adequately replace their depleted iron pool. Positive iron absorption responses are reflected by improvements in the reticulocyte count (within 3-10 days, average 7 days) and an increase in Hgb values (2-4 weeks after initiation). Oral treatment should be continued for 3 to 6 months,20 along with scheduled continuity of care. Patients should take iron supplements between meals, either 2 hours before or 1 hour after a meal, to maximize potential absorption.22

Iron supplement preparations contain different amounts of elemental iron based on the iron salt used. The divalent ferrous form (Fe2+) is used: ferrous sulfate, ferrous gluconate, and ferrous fumarate. No particular salt or formulation (eg, liquid, tablet) is preferred. Enteric-coated tablets may have better tolerance and therefore foster better patient adherence. The availability of various formulations of iron supplements prepared with different iron salts can make proper dosage confusing. To prevent misuse, patients and caregivers must be educated that elemental iron concentrations vary with iron salt preparation.

Patients’ poor tolerance of a particular iron preparation due to adverse effects can prompt a change to another iron salt formulation. Reported adverse effects of medicinal iron supplements are abdominal discomfort, nausea, vomiting, diarrhea, constipation, and darker stools.16,22

Ferrous sulfate supplements frequently are prescribed for iron deficiency anemia. For young children, ferrous sulfate iron drops and elixir preparations are available. A ferrous sulfate supplement prescribed for older pediatric patients and adults is 1 tablet (325 mg) 3 times a day.16 Each tablet contains 65 mg of elemental iron. Three tablets contain 195 mg of elemental iron, within the recommended daily dose of elemental iron for adults and children older than 12 years of age.

Table 3 lists iron salt supplements available over-the-counter or by prescription.23 Table 4 reviews the daily doses of elemental iron in all age groups.16,22


Intravenous or intramuscular iron. IV or IM iron supplementation is indicated to treat iron deficiency anemia in the following groups15,20: patients who cannot absorb iron well through the GI tract; patients who have severe iron deficiency and/or chronic blood loss; patients who are receiving supplemental erythropoietin (eg, hemodialysis patients); and patients who cannot tolerate oral medicinal iron.

For IV administration, consultation with a hematologist is recommended. IV iron is available as iron dextran, iron sucrose, and sodium ferric gluconate preparations.IV iron dextran is dosed at 50 mg/mL. Low-molecular-weight iron dextran is preferred in order to minimize the possible occurrence of severe allergic reactions. An initial test dose of 10 to 25 mg (0.5 mL) should be given, followed by a 30- to 60-minute observation period, before the infusion is continued. Anaphylaxis and hypotension often are associated with iron dextran preparations. Urticaria, pruritus, myalgia, and arthralgia are other potential adverse effects.16,20

Blood transfusions. RBC transfusions are used to treat patients with severe iron deficiency anemia who are actively bleeding or who have cardiovascular instability. Guidance from the hematology team is recommended. Inpatient hospital admission with following of proper transfusion protocol is required. The benefits and risks of receiving blood products must be discussed thoroughly with the patient and/or the patient’s caregiver before initiating this procedure. 

Transfusions temporize symptoms by quickly replacing RBCs, but this treatment approach does not correct a patient’s iron deficiency. Long-term outpatient treatment entails a daily oral iron supplement to replenish and stabilize the body’s iron stores.24


Iron has an essential role in sustaining the body’s balance. Too little iron creates an unhealthy imbalance in which metabolic and physiologic function are significantly compromised. Given iron’s vital role, it is important to understand how to identify and treat iron depletion and deficiency. Early identification of iron depletion should prompt a diagnostic investigation and therapeutic assessment. To reduce incidence of this hematologic condition, patients and caregivers should be educated about its underlying causes and the roles of dietary iron and medicinal iron supplements.

Germaine L. Defendi, MD, MS, is an associate clinical professor of pediatrics at Olive View–UCLA Medical Center in Sylmar, California.


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