Iron Deficiency Anemia

Iron is distributed in active metabolic and storage pools. Total body iron is about 3.5 g in healthy men and 2.5 g in women; the difference relates to women's smaller body size and dearth of stored iron because of iron loss due to menses. The distribution of body iron is

Because nonheme iron is poorly absorbed, dietary iron barely meets the daily requirement for most people. Even so, men who eat a typical Western diet are unlikely to become iron deficient solely as a result of dietary deficiency. However, even modest losses, increased requirements, iatrogenic phlebotomy, or decreased caloric intake can contribute to iron deficiency.

Blood loss is the major cause of iron deficiency. In men and postmenopausal women, the most frequent cause is chronic occult bleeding, usually from the gastrointestinal tract (eg, due to peptic ulcer disease Peptic Ulcer Disease A peptic ulcer is an erosion in a segment of the gastrointestinal mucosa, typically in the stomach (gastric ulcer) or the first few centimeters of the duodenum (duodenal ulcer), that penetrates... read more , malignancy, hemorrhoids, or vascular ectasias Vascular Gastrointestinal Lesions Several distinct congenital or acquired syndromes involve abnormal mucosal or submucosal blood vessels in the gastrointestinal tract. These vessels may cause recurrent bleeding, which is rarely... read more ). In premenopausal women, cumulative menstrual blood loss (mean, 0.5 mg iron/day) is a common cause. Intestinal bleeding due to hookworm infection Symptoms and Signs Ancylostomiasis is infection with the hookworm Ancylostoma duodenale or Necator americanus. Symptoms include rash at the site of larval entry and sometimes abdominal pain or other... read more is a common cause in developing countries. Less common causes include urinary blood loss, recurrent pulmonary hemorrhage (see Diffuse Alveolar Hemorrhage Diffuse Alveolar Hemorrhage Diffuse alveolar hemorrhage is persistent or recurrent pulmonary hemorrhage. There are numerous causes, but autoimmune disorders are most common. Most patients present with dyspnea, cough, hemoptysis... read more ) and chronic intravascular Myelodysplastic Syndrome (MDS) The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular... read more or traumatic (exercise-induced) hemolysis when the amount of iron released during hemolysis exceeds the plasma haptoglobin-binding capacity.

Increased iron requirements may contribute to iron deficiency. From birth to age 2 and during adolescence, when rapid growth requires a large iron intake, dietary iron often is inadequate. During pregnancy, the fetal iron requirement increases the maternal iron requirement (mean, 0.5 to 0.8 mg/day—see Anemia in Pregnancy Anemia in Pregnancy Normally during pregnancy, erythroid hyperplasia of the marrow occurs, and red blood cell (RBC) mass increases. However, a disproportionate increase in plasma volume results in hemodilution... read more ) despite the absence of menses. Lactation also increases the iron requirement (mean, 0.4 mg/day).

Decreased iron absorption can result from gastrectomy or malabsorption syndromes Overview of Malabsorption Malabsorption is inadequate assimilation of dietary substances due to defects in digestion, absorption, or transport. Malabsorption can affect macronutrients (eg, proteins, carbohydrates, fats)... read more such as celiac disease Celiac Disease Celiac disease is an immunologically mediated disease in genetically susceptible people caused by intolerance to gluten, resulting in mucosal inflammation and villous atrophy, which causes malabsorption... read more , atrophic gastritis Autoimmune Metaplastic Atrophic Gastritis Autoimmune metaplastic atrophic gastritis is an inherited autoimmune disease that attacks parietal cells, resulting in hypochlorhydria and decreased production of intrinsic factor. Consequences... read more , Helicobacter pylori infection Helicobacter pylori Infection Helicobacter pylori is a common gastric pathogen that causes gastritis, peptic ulcer disease, gastric adenocarcinoma, and low-grade gastric lymphoma. Infection may be asymptomatic or... read more , achlorhydria, short bowel syndrome Short Bowel Syndrome Short bowel syndrome is malabsorption resulting from extensive resection of the small bowel (usually more than two thirds the length of the small intestine). Symptoms depend on the length and... read more , and rarely IRIDA Iron-transport deficiency anemia In myelodysplastic syndrome, anemia is commonly prominent. The anemia is usually normocytic or macrocytic, and a dimorphic (large and small) population of circulating cells can be present. ... read more (iron-refractory iron deficiency anemia). Rarely, absorption is decreased by dietary deprivation due to undernutrition.

Most symptoms of iron deficiency are due to anemia. Such symptoms include fatigue, loss of stamina, shortness of breath, weakness, dizziness, and pallor. Another common symptom is restless leg syndrome Periodic Limb Movement Disorder (PLMD) and Restless Legs Syndrome (RLS) Periodic limb movement disorder (PLMD) and restless legs syndrome (RLS) are characterized by abnormal motions of and, for RLS, usually sensations in the lower or upper extremities, which may... read more (RLS), which is an unpleasant urge to move the legs during periods of inactivity.

In addition to the usual manifestations of anemia, some uncommon symptoms occur in severe iron deficiency. Patients may have pica Pica Pica is persistent eating of nonnutritive, nonfood material for ≥1 month when it is developmentally inappropriate (eg, pica is not diagnosed in children < 2 years) and when it is not part... read more , an abnormal craving to eat nonfood substances (eg, ice, dirt, paint, starch, ashes). Other symptoms of severe deficiency include glossitis, cheilosis, and concave nails (koilonychia).

Iron deficiency anemia is suspected in patients with chronic blood loss or microcytic anemia, particularly if pica is present. In such patients, a CBC, serum iron and iron-binding capacity, and serum ferritin and reticulocyte count are obtained (see table Typical Serum Values for Iron, Iron-Binding Capacity, Ferritin, and Transferrin Saturation Typical Normal Serum Values for Iron, Iron-Binding Capacity,Ferritin, and Transferrin Saturation ).

Iron and iron-binding capacity (and transferrin saturation) are measured because their relationship is important. Various tests exist; the range of normal values relates to the test used and varies from laboratory to laboratory. In general, normal serum iron is 75 to 150 mcg/dL (13 to 27 micromol/L) for men and 60 to 140 mcg/dL (11 to 25 micromol/L) for women; total iron-binding capacity is 250 to 450 mcg/dL (45 to 81 micromol/L) and transferrin saturation is 20 to 50%. Serum iron level is low in iron deficiency and in many chronic diseases and is elevated in hemolytic disorders Overview of Hemolytic Anemia At the end of their normal life span (about 120 days), red blood cells (RBCs) are removed from the circulation. Hemolysis is defined as premature destruction and hence a shortened RBC life span... read more and in iron-overload syndromes Overview of Iron Overload Typical adults lose about 1 mg iron (Fe) per day in shed epidermal and gastrointestinal cells; menstruating females lose on average an additional 0.5 to 1 mg/day from menses. This iron loss... read more . The iron-binding capacity increases in iron deficiency, while the transferrin saturation decreases.

Serum ferritin levels closely correlate with total body iron stores. The range of normal in most laboratories is 30 to 300 ng/mL (67.4 to 674.1 pmol/L), and the mean is 88 ng/mL (197.7 pmol/L) in men and 49 ng/mL (110.1 pmol/L) in women. Low levels (< 12 ng/mL [27 pmol/L]) are specific for iron deficiency. However, ferritin is an acute-phase reactant, and levels increase in inflammatory and infectious disorders (eg, hepatitis Overview of Acute Viral Hepatitis Acute viral hepatitis is diffuse liver inflammation caused by specific hepatotropic viruses that have diverse modes of transmission and epidemiologies. A nonspecific viral prodrome is followed... read more ), and neoplastic disorders (especially acute leukemia Overview of Leukemia Leukemia is a malignant condition involving the excess production of immature or abnormal leukocytes, which eventually suppresses the production of normal blood cells and results in symptoms... read more , Hodgkin lymphoma Hodgkin Lymphoma Hodgkin lymphoma is a localized or disseminated malignant proliferation of cells of the lymphoreticular system, primarily involving lymph node tissue, spleen, liver, and bone marrow. Symptoms... read more , and gastrointestinal tract tumors). In these disorders, a serum ferritin level up to 100 ng/mL remains compatible with iron deficiency.

The reticulocyte count is low in iron deficiency. The peripheral smear generally reveals hypochromic red cells with significant anisopoikilocytosis, which is reflected in a high red cell distribution width (RDW).

The most sensitive and specific criterion for iron-deficient erythropoiesis is absent bone marrow stores of iron, although a bone marrow examination is rarely needed.

Iron therapy without pursuit of the cause is poor practice; a bleeding site should be sought even in cases of mild anemia.

Oral iron can be provided by various iron salts (eg, ferrous sulfate, ferrous gluconate, ferrous fumarate) or saccharated iron given 30 minutes before meals (food or antacids may reduce absorption). A typical initial dose is 60 mg of elemental iron (eg, as 325 mg of ferrous sulfate) given once a day or every other day (1 Treatment reference Iron deficiency is the most common cause of anemia and usually results from blood loss; malabsorption, such as with celiac disease, is a much less common cause. Symptoms are usually nonspecific... read more ). Larger doses are largely unabsorbed due to increased hepcidin production but increase adverse effects, especially constipation or other GI upset. Ascorbic acid either as a pill (500 mg) or as orange juice when taken with iron enhances iron absorption without increasing gastric distress.

Parenteral iron causes a more rapid therapeutic response than oral iron does but can cause adverse effects, most commonly allergic reactions or infusion reactions (eg, fever, arthralgias, myalgias). Severe anaphylactoid reactions Anaphylactoid reactions Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more that were more common in the past were mostly caused by high molecular weight iron dextran, which is no longer available. Parenteral iron is reserved for patients who do not tolerate or who will not take oral iron or for patients who steadily lose large amounts of blood because of capillary or vascular disorders (eg, hereditary hemorrhagic telangiectasia Hereditary Hemorrhagic Telangiectasia Hereditary hemorrhagic telangiectasia is a hereditary disorder of vascular malformation transmitted as an autosomal dominant trait affecting men and women. (See also Overview of Vascular Bleeding... read more ). The dose of parenteral iron is determined by a hematologist.

Oral or parenteral iron therapy should continue for ≥ 6 months after correction of hemoglobin levels to replenish tissue stores.

The response to treatment is assessed by serial Hb measurements until normal RBC values are achieved. Hb rises little for 2 weeks but then rises 0.7 to 1 g/week until near normal, at which time the rate of increase tapers. Anemia should be corrected within 2 months. A subnormal response suggests continued hemorrhage, underlying infection or cancer, insufficient iron intake, or malabsorption of oral iron. If the symptoms of anemia, such as fatigue, weakness, and shortness of breath, do not abate following resolution of the anemia, an alternative cause should be sought.