Iron Deficiency Anemia

Iron deficiency anemia develops when body stores of iron drop too low to support normal red blood cell (RBC) production. Inadequate dietary iron, impaired iron absorption, bleeding, or loss of body iron in the urine may be the cause. Iron equilibrium in the body normally is regulated carefully to ensure that sufficient iron is absorbed in order to compensate for body losses of iron (see the image below).

The total body iron in a 70-kg man is about 4 g. This is maintained by a balance between absorption and body losses. Although the body only absorbs 1 mg daily to maintain equilibrium, the internal requirement for iron is greater (20-25 mg). An erythrocyte has a lifespan of 120 days so that 0.8% of red blood cells are destroyed and replaced each day. A man with 5 L of blood volume has 2.5 g of iron incorporated into the hemoglobin, with a daily turnover of 20 mg for hemoglobin synthesis and degradation and another 5 mg for other requirements. Most of this iron passes through the plasma for reutilization. Iron in excess of these requirements is deposited in body stores as ferritin or hemosiderin.

Essential update: ACP releases new recommendations for iron deficiency anemia

The American College of Physicians (ACP) recently released the following treatment guidelines for adult patients with anemia and iron deficiency^[1] :

• A restrictive red blood cell transfusion strategy is recommended for hospitalized patients with coronary heart disease, with the trigger hemoglobin threshold lowered to 7-8 g/dL (recommendation: weak; quality of evidence: low)
• Erythropoiesis-stimulating agents are not recommended for patients with mild to moderate anemia and either congestive heart failure or coronary heart disease (recommendation: strong; quality of evidence: moderate)

History

Although iron deficiency anemia is a laboratory diagnosis, a carefully obtained history can facilitate its recognition. The history can also be useful in establishing the etiology of the anemia and, perhaps, in estimating its duration.

Iron deficiency in the absence of anemia is asymptomatic. One half of patients with moderate iron deficiency anemia develop pagophagia. Usually, they crave ice to suck or chew. Occasionally, patients are seen who prefer cold celery or other cold vegetables in lieu of ice. Leg cramps, which occur on climbing stairs, also are common in patients deficient in iron.

Often, patients can identify a distinct point in time when these symptoms first occurred, providing an estimate of the duration of the iron deficiency.

Fatigue and diminished capability to perform hard labor are attributed to the lack of circulating hemoglobin; however, they occur out of proportion to the degree of anemia and probably are due to a depletion of proteins that require iron as a part of their structure.

Increasing evidence suggests that deficiency or dysfunction of nonhemoglobin proteins has deleterious effects. These include muscle dysfunction, pagophagia, dysphagia with esophageal webbing, poor scholastic performance, altered resistance to infection, and altered behavior.

Dietary history

A dietary history is important. Vegetarians are more likely to develop iron deficiency, unless their diet is supplemented with iron. National programs of dietary iron supplementation are initiated in many portions of the world where meat is sparse in the diet and iron deficiency anemia is prevalent. Unfortunately, affluent nations also supplement iron in foodstuffs and vitamins without recognizing the potential contribution of iron to free radical formation and the prevalence of genetic iron overloading disorders.

Elderly patients who are in poor economic circumstances and do not wish to seek aid may try to survive on a “tea and toast” diet. They may also be hesitant to share this dietary information. This group is far more likely to develop protein-calorie malnutrition before they develop iron deficiency anemia.

A fundamental concept is that after age 1 year, dietary deficiency alone is not sufficient to cause clinically significant iron deficiency, so a source of blood loss should always be sought as part of the management of a patient with iron deficiency anemia. Infants and toddlers are the primary risk groups for dietary iron deficiency anemia. Neonates who double their birthweight are a special risk group. Also see Pediatric Acute Anemia and Pediatric Chronic Anemia.

Pica is not a cause of iron deficiency anemia; pica is a symptom of iron deficiency anemia. It is the link between iron deficiency anemia and lead poisoning, which is why iron deficiency anemia should always be sought when a child is diagnosed with lead poisoning. Hippocrates recognized clay eating; however, modern physicians often do not recognize it unless the patient and family are specifically queried. Both substances decrease the absorption of dietary iron. Clay eating occurs worldwide in all races, though it is more common in Asia Minor. Starch eating is a habit in females of African heritage, and it often is started in pregnancy as a treatment for morning sickness.

History of hemorrhage

Two thirds of body iron is present in circulating red blood cells as hemoglobin. Each gram of hemoglobin contains 3.47 mg of iron; thus, each mL of blood lost from the body (hemoglobin 15 g/dL) results in a loss of 0.5 mg of iron.

Bleeding is the most common cause of iron deficiency, either from parasitic infection (hookworm) or other causes of blood loss. With bleeding from most orifices (hematuria, hematemesis, hemoptysis), patients will present before they develop chronic iron deficiency anemia; however, gastrointestinal bleeding may go unrecognized. Patients often do not understand the significance of a melanotic stool.

Excessive menstrual losses may be overlooked. Unless menstrual flow changes, patients typically do not seek medical attention for menorrhagia. If the clinician asks, these patients generally report that their menses are normal. Because of the marked differences among women with regard to menstrual blood loss (10-250 mL per menses), query the patient about a specific history of clots, cramps, and the use of multiple tampons and pads

Signs and symptoms

Patients with iron deficiency anemia may report the following:

• Fatigue and diminished capability to perform hard labor
• Leg cramps on climbing stairs
• Craving ice (in some cases, cold celery or other cold vegetables) to suck or chew
• Poor scholastic performance
• Cold intolerance
• Reduced resistance to infection
• Altered behavior (eg, attention deficit disorder)
• Dysphagia with solid foods (from esophageal webbing)
• Worsened symptoms of comorbid cardiac or pulmonary disease

Findings on physical examination may include the following:

• Impaired growth in infants
• Pallor of the mucous membranes (a nonspecific finding)
• Spoon-shaped nails (koilonychia)
• A glossy tongue, with atrophy of the lingual papillae
• Fissures at the corners of the mouth (angular stomatitis)
• Splenomegaly (in severe, persistent, untreated cases)
• Pseudotumor cerebri (a rare finding in severe cases)

Diagnosis

Useful tests include the following:

• Complete blood count
• Peripheral blood smear
• Serum iron, total iron-binding capacity (TIBC), and serum ferritin
• Evaluation for hemosiderinuria, hemoglobinuria, and pulmonary hemosiderosis
• Hemoglobin electrophoresis and measurement of hemoglobin A2 and fetal hemoglobin
• Reticulocyte hemoglobin content

Tests useful for establishing the etiology of iron deficiency anemia and excluding or establishing a diagnosis of another microcytic anemia include the following:

• Stool testing
• Incubated osmotic fragility testing
• Measurement of lead in tissue
• Bone marrow aspiration

CBC results in iron deficiency anemia include the following:

• Low mean corpuscular volume (MCV)
• Low mean corpuscular hemoglobin concentration (MCHC)
• Elevated platelet count (>450,000/µL) in many cases
• Normal or elevated white blood cell count

Peripheral smear results in iron deficiency anemia are as follows:

• RBCs are microcytic and hypochromic in chronic cases
• Platelets usually are increased
• In contrast to thalassemia, target cells are usually not present, and anisocytosis and poikilocytosis are not marked
• In contrast to hemoglobin C disorders, intraerythrocytic crystals are not seen

Results of iron studies are as follows:

• Low serum iron and ferritin levels with an elevated TIBC are diagnostic of iron deficiency
• A normal serum ferritin can be seen in patients who are deficient in iron and have coexistent diseases (eg, hepatitis or anemia of chronic disorders)

Other Laboratory Tests

Stool testing

Testing stool for the presence of hemoglobin is useful in establishing gastrointestinal (GI) bleeding as the etiology of iron deficiency anemia. Usually, chemical testing that detects more than 20 mL of blood loss daily from the upper GI tract is employed. More sensitive tests are available; however, they produce a high incidence of false-positive results in people who eat meat. Severe iron deficiency anemia can occur in patients with a persistent loss of less than 20 mL/d.

To detect blood loss, the patient can be placed on a strict vegetarian diet for 3-5 days and the stool can be tested for hemoglobin with a benzidine method, or red blood cells (RBCs) can be radiolabeled with radiochromium and retransfused. Stools are collected, and the radioactivity is quantified in a gamma-detector and compared to the radioactivity in a measured quantity of the patient’s blood. An immunologic method of detecting human species-specific hemoglobin in stool is under development and could increase specificity and sensitivity.

Incubated osmotic fragility

Incubated osmotic fragility is useful. Microspherocytosis may produce a low-normal or slightly abnormal MCV; however, the MCHC usually is elevated rather than decreased, and the peripheral smear shows a lack of central pallor rather than hypochromia. Spherocytosis can normally be separated from iron deficiency anemia by peripheral blood smear.

Tissue lead concentrations

Measure tissue lead concentrations. Chronic lead poisoning may produce a mild microcytosis. The anemia probably is related to the anemia of chronic disorders. The incidence of lead poisoning is greater in individuals who are iron deficient than in healthy subjects because increased absorption of lead occurs in individuals who are iron deficient. Paint in old houses has been a source of lead poisoning in children and painters.

Bone marrow aspiration

A bone marrow aspirate can be diagnostic of iron deficiency. The absence of stainable iron in a bone marrow aspirate that contains spicules and a simultaneous control specimen containing stainable iron permit establishment of a diagnosis of iron deficiency without other laboratory tests.

A bone marrow aspirate stained for iron (Perls stain) can be diagnostic of iron deficiency, provided that spicules are present in the smear and that a control specimen containing iron is performed at the same time. Although this test has largely been displaced in the diagnosis of iron deficiency by serum iron, TIBC, and serum ferritin testing, the absence of stainable iron in a bone marrow aspirate is the criterion standard for the diagnosis of iron deficiency.

This test is diagnostic in identifying the sideroblastic anemias by showing ringed sideroblasts in the aspirate stained with Perls stain. Occasionally, it is useful in separating patients with the anemia of chronic disorders or alpha-thalassemia from patients with iron deficiency, and it is useful in identifying patients with both iron deficiency and the anemia of chronic disorders.

Diagnostic Considerations

Other conditions to be considered include the following:

• Anemia of chronic disorders
• Hemoglobin CC disease
• Hemoglobin DD disease
• Lead poisoning
• Microcytic anemias
• Autoimmune hemolytic anemia
• Hemoglobin S-beta thalassemia

Management

Treatment of iron deficiency anemia consists of correcting the underlying etiology and replenishing iron stores. Iron therapy is as follows:

• Oral ferrous iron salts are the most economical and effective form
• Ferrous sulfate is the most commonly used iron salt
• Better absorption and lower morbidity have been claimed for other iron salts
• Toxicity is generally proportional to the amount of iron available for absorption
• Reserve parenteral iron for patients who are either unable to absorb oral iron or who have increasing anemia despite adequate doses of oral iron
• Reserve transfusion of packed RBCs for patients who are experiencing significant acute bleeding or are in danger of hypoxia and/or coronary insufficiency

Complications

Iron deficiency anemia diminishes work performance by forcing muscles to depend on anaerobic metabolism to a greater extent than they do in healthy individuals. This change is believed to be attributable to deficiency in iron-containing respiratory enzymes rather than to anemia.

Severe anemia due to any cause may produce hypoxemia and enhance the occurrence of coronary insufficiency and myocardial ischemia. Likewise, it can worsen the pulmonary status of patients with chronic pulmonary disease.

Defects in structure and function of epithelial tissues may be observed in iron deficiency. Fingernails may become brittle or longitudinally ridged, with the development of koilonychia (spoon-shaped nails). The tongue may show atrophy of the lingual papillae and develop a glossy appearance. Angular stomatitis may occur with fissures at the corners of the mouth.

Dysphagia may occur with solid foods, with webbing of the mucosa at the junction of the hypopharynx and the esophagus (Plummer-Vinson syndrome); this has been associated with squamous cell carcinoma of the cricoid area. Atrophic gastritis occurs in iron deficiency with progressive loss of acid secretion, pepsin, and intrinsic factor and development of an antibody to gastric parietal cells. Small intestinal villi become blunted.

Cold intolerance develops in one fifth of patients with chronic iron deficiency anemia and is manifested by vasomotor disturbances, neurologic pain, or numbness and tingling.

Rarely, severe iron deficiency anemia is associated with papilledema, increased intracranial pressure, and the clinical picture of pseudotumor cerebri. These manifestations are corrected with iron therapy.

Impaired immune function is reported in subjects who are iron deficient, and there are reports that these patients are prone to infection; however, because of the presence of other factors, the current evidence is insufficient to establish that this impairment is directly due to iron deficiency.

Children deficient in iron may exhibit behavioral disturbances. Neurologic development is impaired in infants and scholastic performance is reduced in children of school age. The intelligence quotients (IQs) of schoolchildren deficient in iron are reported to be significantly lower than those of their nonanemic peers. Behavioral disturbances may manifest as an attention deficit disorder. Growth is impaired in infants with iron deficiency. The neurologic damage to an iron-deficient fetus results in permanent neurologic injury and typically does not resolve on its own. Iron repletion stabilizes the patient so that his or her status does not further decline.

A case-control study of 2957 children and adolescents with iron deficiency anemia and 11,828 healthy controls from the Taiwan National Health Insurance Database found that iron deficiency anemia is associated with an increased risk for psychiatric disorders. After adjusting for demographic data and risk factors for iron deficiency anemia, children and adolescents with iron deficiency anemia were at higher risk for the following^{[2, 3]} :

• Unipolar depressive disorder
• Bipolar disorder
• Anxiety disorder
• Autism spectrum disorder
• Attention-deficit/hyperactivity disorder
• Tic disorder
• Delayed development
• Mental retardation

Prevention

Certain populations are at sufficiently high risk for iron deficiency to warrant consideration for prophylactic iron therapy. These include pregnant women, women with menorrhagia,^[11] consumers of a strict vegetarian diet, infants,^[12] adolescent girls, and regular blood donors.

Pregnant women have been given supplemental iron since World War II, often in the form of all-purpose capsules containing vitamins, calcium, and iron. If the patient is anemic (hemoglobin < 11 g/dL), administer the iron at a different time of day than calcium because calcium inhibits iron absorption.

The practice of routinely administering iron to pregnant females in affluent societies has been challenged. Nevertheless, providing prophylactic iron therapy during the last half of pregnancy continues to be advisable, except in settings where careful follow-up for anemia and methods for measurement of serum iron and ferritin are readily available.

Iron supplementation of the diet of infants is advocated. Premature infants require more iron supplementation than term infants. Infants weaned early and fed bovine milk require more iron because the higher concentration of calcium in cow milk inhibits absorption of iron. Usually, infants receive iron from fortified cereal. Additional iron is present in commercial milk formulas.

Iron supplementation in populations living on a largely vegetarian diet is advisable because of the lower bioavailability of inorganic iron than heme iron.

The addition of iron to basic foodstuffs in affluent nations where meat is an important part of the diet is of questionable value and may be harmful. The gene for familial hemochromatosis (HFe gene) is prevalent (8% of the US white population). Excess body iron is postulated to be important in the etiology of coronary artery disease, strokes, certain carcinomas, and neurodegenerative disorders because iron is important in free radical formation.

Consultations

Surgical consultation often is needed for the control of hemorrhage and treatment of the underlying disorder. In the investigation of a source of bleeding, consultation with certain medical specialties may be useful to identify the source of bleeding and to provide control.

Among the medical specialties, gastroenterology is the most frequently sought consultation. Endoscopy has become a highly effective tool in identifying and controlling GI bleeding. If bleeding is brisk, angiographic techniques may be useful in identifying the bleeding site and controlling the hemorrhage. Radioactive technetium labeling of autologous erythrocytes also is used to identify the site of bleeding. Unfortunately, these radiographic techniques do not detect bleeding at rates less than 1 mL/min and may miss lesions that bleed only intermittently.

Long-Term Monitoring

Monitor patients with iron deficiency anemia on an outpatient basis to ensure that there is an adequate response to iron therapy and that iron therapy is continued until after correction of the anemia to replenish body iron stores. Follow-up also may be important to treat any underlying cause of the iron deficiency.

Response to iron therapy can be documented by an increase in reticulocytes 5-10 days after the initiation of iron therapy. The hemoglobin concentration increases by about 1 g/dL weekly until normal values are restored. These responses are blunted in the presence of sustained blood loss or coexistent factors that impair hemoglobin synthesis.

Reference : Medscape