IRON DEFICIENCY ANEMIA

IRON DEFICIENCY ANEMIA

Current Diagnosis

Symptoms

•   Fatigue

•   Poor exercise tolerance

•   Weakness

•   Irritability

•   Poor concentration

•   Dry mouth

•   Headache

•   Pica

Signs

•   Pallor

•   Systolic heart murmur if anemia is present

•   Atrophy of lingual papillae

•   Koilonychia

•   Chlorosis

Laboratory Findings

•   Decreased iron seen on bone marrow aspirate (gold standard)

•   Low serum ferritin (diagnostic)

•   Low serum iron level

•   High serum iron-binding capacity

•   Low serum hemoglobin

•   Low mean corpuscular hemoglobin

•   Low mean corpuscular volume

•   Variations in size and shape of red blood cells

Current Therapy

Oral Replacement

• Ferrous sulfate (or other equivalent iron preparation) 325 mg three times daily.

• Add ascorbic acid tablet 500 mg with each iron tablet to increase iron absorption.

• Consider enteric-coated tablets to decrease gastrointestinal problems associated with oral iron therapy.

Parenteral Replacement

• If oral therapy is not tolerated, parental preparations including iron dextran, iron sucrose, or ferric gluconate may be used.

Unstable Patient

• If the patient is hemodynamically unstable due to anemia, consider blood transfusion.

Treatment Endpoint

• Iron deficiency has been corrected if the serum ferritin is 50 ng/mL or more.

Epidemiology

Iron is necessary for production of erythrocytes and the normal functioning of several iron-containing cellular enzymes. Iron deficiency is defined as the decrease of total iron stores in the body. Iron deficiency anemia results when iron deficiency is severe enough to decrease erythropoiesis. The most common cause of iron deficiency in the U.S. adult population is blood loss. The most common sources of blood loss are menstrual and gastrointestinal. Other causes of iron deficiency include inadequate intake during high-demand states such as pregnancy, early childhood, or erythropoietin therapy. A diet low in iron-rich foods (vegetarian or vegan) can lead to iron deficiency.

Gastrointestinal diseases including Crohn’s disease, sprue, and postgastrectomy states can decrease iron absorption from the gastrointestinal tract, resulting in iron deficiency. Chronic inflammatory states can lead to decreased use of available iron stores, leading to symptoms of iron deficiency.

Iron deficiency is the most common micronutrient deficiency in the world. Iron deficiency affects approximately 2% to 5% of children and adolescents in the United States and 4% of the U.S. adult population, including 20% of women of childbearing age, 50% of pregnant women, and 2% of men.

Risk Factors

Risk factors for iron deficiency include age, socioeconomic status, sex, diet, disease, and medical treatment. Infants, children, and adolescents are at risk, especially during periods of rapid growth. Low socioeconomic status, including minority population group and low income, increase the risk for iron deficiency. Risk is increased in women during the childbearing years and during pregnancy and breastfeeding. Diets low in iron-rich foods, including vegan and vegetarian diets, increase the risk.

Any illness or therapy that leads to decreased absorption of iron or loss of blood also increases the risk. Gastrointestinal diseases causing blood loss or decreased iron absorption can lead to iron deficiency.

Antacids cause decreased iron absorption and nonsteroidal antiinflammatory drugs (NSAIDs) cause gastrointestinal blood loss. Erythropoietin therapy depletes iron stores because of increased hematopoiesis. Frequent phlebotomy, including repetitive blood donation or treatment for polycythemia or hemochromatosis, decreases iron stores.

Pathophysiology

Total body iron stores for men are approximately 3.5 g and for women are about 2.5 g. More than 70% of body iron is found in hemoglobin, and the remainder is contained in myoglobin, tissue enzymes, and storage or transport proteins. Iron absorption takes place almost exclusively in the duodenum and upper jejunum. In a non–iron- deficient state, only about 6% to 10% of iron from food is absorbed (1 mg of 15 mg/day of dietary iron). Factors that increase iron absorption from the gut include ingestion of heme (meat) iron, iron- deficient states, and coadministration of vitamin C (ascorbic acid).

Factors that decrease iron absorption include ingestion of certain foods including vegetable fiber phytates, tea tannates, bran, and medications including tetracyclines and antacids.

Iron deficiency develops in stages. During the early stage, iron needs exceed iron intake and body iron stores are depleted, causing an increase in absorption of dietary iron. As this process continues, erythropoiesis is impaired, leading to iron deficiency anemia, and dysfunction of iron-containing cellular enzymes can occur. This enzyme dysfunction can contribute to the fatigue and loss of stamina seen in patients with iron deficiency anemia. Iron deficiency during childhood can result in deficiencies in growth and cognitive function.

Prevention

Prevention of iron deficiency is focused on providing supplemental dietary iron to populations at risk for iron deficiency. Current recommendations include elemental iron supplementation (1 mg/kg/d) for breast-fed infants after 6 months of age and iron supplementation of infant formula (12 mg/L elemental iron) for formula-fed infants. Iron-enriched cereals should be among the first solid foods offered to infants. Whole cow’s milk should be avoided during the first year of life to decrease the possibility of occult gastrointestinal bleeding. Supplemental iron should be taken during pregnancy and breast-feeding.

Clinical Manifestations

Patients with iron deficiency may be asymptomatic. The presence of symptoms and signs of iron deficiency depend on the degree of deficiency, the time course of the development of iron deficiency, and the overall physiologic state of the patient. Common symptoms of iron deficiency include fatigue, weakness, irritability, poor concentration, exercise intolerance, dry mouth, and headache. Severe iron deficiency can cause pica, a craving to eat substances such as ice, dirt, clay, or paint. Signs of iron deficiency include pallor and a systolic heart murmur if anemia is present, alopecia, atrophy of lingual papillae, koilonychias, and chlorosis.

Diagnosis

The gold standard for diagnosis of iron deficiency is the demonstration of decreased iron available for erythropoiesis on a bone marrow aspiration sample. The wide availability of reliable serum iron markers makes bone marrow sampling for diagnosis of iron deficiency unnecessary in most cases. A low serum iron is characteristic of both iron deficiency and anemia of chronic disease. Serum total iron binding capacity is decreased in iron deficiency and elevated in anemia of chronic disease. Serum iron and total iron binding capacity are often ordered together. Many authorities think serum ferritin determination is the most useful laboratory test for iron deficiency. Ferritin levels reflect the quantity of iron stored in the reticuloendothelial system. A low serum ferritin level is diagnostic of iron deficiency. Serum ferritin levels can be falsely elevated in the presence of inflammation.

The diagnosis of iron deficiency anemia requires a decline in serum hemoglobin to less than 13 g/dL in men or 12 g/dL in women along with a decreased mean corpuscular volume and mean corpuscular hemoglobin and the presence of iron deficiency. Other findings in iron deficiency anemia include variation in erythrocyte shape and size (poikilocytosis and anisocytosis) and elevation in the coefficient of red blood cell distribution width (RDW).

Because gastrointestinal blood loss is a common cause of iron deficiency anemia, patients who present with iron deficiency anemia should be considered for appropriate screening for gastrointestinal conditions, including malignancies.

Differential Diagnosis

The differential diagnosis of iron deficiency includes causes of fatigue and exercise intolerance such as hypothyroidism, electrolyte disturbances due to diuretic therapy, left ventricular dysfunction, chronic lung disease, malignancies, or liver disease.

Anemia of chronic disease can mimic iron deficiency anemia.

Differentiating characteristics of the two types of anemia can be found in Table 1.

Table 1

Difference between Iron Deficiency Anemia and Anemia of Chronic Illness

 

Test                                                               Iron Deficiency Anemia Anemia of Chronic Illness
Serum iron Low Low
Ferritin Low Increased
Red cell morphology Variable Normal
C-reactive protein Normal Increased

Treatment

Iron may be replaced via oral or intravenous routes. The most cost- effective oral iron preparation is a non–enteric-coated ferrous sulfate tablet. The most common oral iron replacement regimen consists of one 325 mg ferrous sulfate tablet (Feosol) by mouth three times daily. Each 325 mg ferrous sulfate tablet contains 65 mg of elemental iron.

Other iron salts, ferrous gluconate (Fergon) and ferrous fumarate (Ferro-Sequels) are available for oral replacement. The absorption of oral iron is enhanced by taking the pills on an empty stomach or with an ascorbic acid tablet (500 mg). Because of the gastric distress often caused by oral iron replacement, most practitioners prescribe enteric- coated iron tablets.

Patients who cannot take or cannot tolerate oral iron can be treated with intravenous iron preparations, iron dextran (InFeD), iron sucrose (Venofer),1 ferric gluconate (Ferrlecit)1, or ferumoxytol (Feraheme).

Because of the pain associated with the injection and other problems, intramuscular iron is seldom used.

Patients who are severely anemic and hemodynamically unstable may be candidates for blood transfusion. To determine the total dose of iron needed to correct the deficiency, the total iron deficit (depleted stores plus the deficit in red cell hemoglobin iron) should be calculated before beginning therapy. Because the most common cause of iron deficiency is blood loss, the management of iron deficiency should include identification of the source and cause of blood loss.

Monitoring

The earliest marker for successful iron replacement is an increase in the reticulocyte count, which occurs within 5 to 10 days of initiation of iron replacement. A hemoglobin increase of 2 g/dL is considered an appropriate response to oral iron replacement. Complete blood counts should be obtained at 1 month and 2 months after beginning replacement therapy. Iron deficiency should be corrected after 2 months of replacement therapy. Treatment of iron deficiency should continue until the serum ferritin reaches a level of 50 ng/mL. Darkening of stools after 2 or 3 days of starting oral iron replacement is a reliable marker of compliance.

Complications

If properly treated, iron deficiency has few complications in adults. Untreated iron deficiency in infants and small children can lead to cognitive development and growth deficits. Treating iron deficiency without identifying the source and cause of blood loss could result in delay or failure to diagnose gastrointestinal malignancies or other serious clinical problems.

References

1.     Anderson G.J., Frazer D.M., Mclaren G.D. Iron absorption and metabolism. Curr Opin Gastroenterol. 2009;25:129–135.

2.    Beers M.H., Porter R.S., Jones T.V., et al. Anemias caused by deficient erythropoiesis. In: Merck Manual of Diagnosis and Therapy. ed 18th Whitehouse Station, NJ: Merck Research Laboratories; 2006.

3.     Clark S.F. Iron deficiency anemia: Diagnosis and management. Curr Opin Gastroenterol. 2009;26:122–128.

4.    Clark S.F. Iron deficiency anemia. Nutr Clin Pract. 2008;23:128– 141.

5.     Cook J.D. Diagnosis and management of iron deficiency anaemia. Best Pract Res Clin Haematol. 2005;18:319–332.

6.      Oski F.A. The nonhematologic manifestations of iron deficiency. A J Di Child. 1979;133:315–322.

1  Not FDA approved for this  indication

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