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Iron deficiency
is the most common cause of anemia and usually results from blood
loss. Symptoms are usually nonspecific. RBCs tend to be microcytic
and hypochromic, and iron stores are low as shown by low serum ferritin
and low serum iron with high serum transferrin. If the diagnosis
is made, occult blood loss is suspected. Treatment involves iron
replacement and treatment of blood loss.
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 body size, lower androgen levels, and the dearth of stored iron in women because of iron loss with menses and pregnancy. The distribution of body iron in an average man is Hb, 2100 mg; myoglobin, 200 mg; tissue (heme and nonheme) enzymes, 150 mg; and transport-iron compartment, 3 mg. Iron is stored in cells and plasma as ferritin (700 mg) and in cells as hemosiderin (300 mg).
Iron is absorbed in the duodenum and upper jejunum. Absorption of iron is determined by the type of iron molecule and by what other substances are ingested. Iron absorption is best when food contains heme iron (meat). Dietary nonheme iron must be reduced to the ferrous state and released from food binders by gastric secretions. Nonheme iron absorption is reduced by other food items (eg, vegetable fiber phytates and polyphenols; tea tannates, including phosphoproteins; bran) and certain antibiotics (eg, tetracycline ). Ascorbic acid is the only common food element known to increase nonheme iron absorption.
The average American diet, which contains 6 mg of elemental iron/kcal of food, is adequate for iron homeostasis. Of about 15 mg/day of dietary iron, adults absorb only 1 mg, which is the approximate amount lost daily by cell desquamation from the skin and intestines. In iron depletion, absorption increases, although the exact signaling mechanism is not known; however, absorption rarely increases to > 6 mg/day unless supplemental iron is added. Children have a greater need for iron and appear to absorb more to meet this need.
Iron from the intestinal mucosal cell is transferred to transferrin, an iron-transport protein synthesized in the liver; transferrin can transport iron from cells (intestinal, macrophages) to specific receptors on erythroblasts, placental cells, and liver cells. For heme synthesis, transferrin transports iron to the erythroblast mitochondria, which insert the iron into protoporphyrin for it to become heme. Transferrin (plasma half-life, 8 days) is extruded for reutilization. Synthesis of transferrin increases with iron deficiency but decreases with any type of chronic disease.
Iron not used for erythropoiesis is transferred by transferrin to the storage pool, which has 2 forms. The most important is ferritin (a heterogenous group of proteins surrounding an iron core), which is a soluble and active storage fraction located in the liver (in hepatocytes), bone marrow, and spleen (in macrophages); in RBCs; and in serum. Iron stored in ferritin is readily available for any body requirement. Circulating (serum) ferritin concentration parallels the size of the body stores (1 ng/mL = 8 mg of iron in the storage pool). The 2nd storage pool of iron is in hemosiderin, which is relatively insoluble and is stored primarily in the liver (in Kupffer cells) and in the marrow (in macrophages).
Because iron absorption is so limited, the body recycles and conserves iron. Transferrin grasps and recycles available iron from aging RBCs undergoing phagocytosis by mononuclear phagocytes. This mechanism provides about 97% of the daily iron needed (about 25 mg of iron). With aging, iron stores tend to increase because iron elimination is slow.
Etiology
Because iron is poorly absorbed, most people barely meet the daily requirement. Thus, even modest losses, increased requirements, or decreased intake readily produces iron deficiency.
Blood loss is almost always the cause. In men, the most frequent cause is chronic occult bleeding, usually from the GI tract. In premenopausal women, cumulative menstrual blood loss (mean, 0.5 mg iron/day) is a common cause. Another possible cause of blood loss in men and women is chronic intravascular hemolysis (see Anemias Caused by Hemolysis) if the amount of iron released during hemolysis exceeds the haptoglobin-binding capacity. Vitamin C deficiency can contribute to iron deficiency anemia by producing capillary fragility, hemolysis, and bleeding.
Increased iron requirement 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 Pregnancy Complicated by Disease: Anemia in Pregnancy) despite the absence of menses. Lactation also increases the iron requirement (mean, 0.4 mg/day).
Decreased iron absorption can result from gastrectomy and upper small-bowel malabsorption syndromes. Rarely, absorption is decreased by dietary deprivation from undernutrition and certain forms of pica (eg, starch, clay, ice).
Pathophysiology,
Symptoms, and Signs
Deficiency develops in stages. In the 1st stage, iron requirement exceeds intake, causing progressive depletion of bone marrow iron stores. As stores decrease, compensatory increase in absorption of dietary iron occurs. During later stages, deficiency is severe enough to impair RBC synthesis. Ultimately, anemia results in symptoms and signs.
Iron deficiency, if severe and prolonged, may cause dysfunction of iron-containing cellular enzymes. This dysfunction may contribute to fatigue and loss of stamina via mechanisms independent of the anemia itself.
In addition to the usual manifestations of anemia, some uncommon symptoms occur in severe iron deficiency; a patient may have pica, an abnormal craving to eat substances (eg, ice, dirt, paint). Other symptoms of severe deficiency include glossitis, cheilosis, concave nails (koilonychia), and, rarely, dysphagia caused by a postcricoid esophageal web.
Diagnosis
Iron deficiency anemia is suspected in patients with chronic blood loss or microcytic anemia, particularly if pica is present. In such patients, CBC, serum iron and iron-binding capacity, and serum ferritin are obtained.
Iron and iron-binding capacity (or transferrin) are usually both tested, because their relationship is important. Various tests exist; the range of normal values relates to the test used. In general, normal serum iron is 75 to 150 μg/dL (13 to 27 μmol/L) for men and 60 to 140 μg/dL (11 to 25 μmol/L) for women; total iron-binding capacity is 250 to 450 μg/dL (45 to 81 μmol/L). Serum iron concentration is low in iron deficiency and in many chronic diseases and is elevated in hemolytic disorders and in iron-overload syndromes (see Iron Overload). Patients taking oral iron may have normal serum iron despite a deficiency; in such circumstances, a valid test requires cessation of iron therapy for 24 to 48 h. The iron-binding capacity increases in iron deficiency.
Serum ferritin concentrations closely correlate with total body iron stores. The range of normal in most laboratories is 30 to 300 ng/mL, and the mean is 88 in men and 49 in women. Low concentrations (< 12 ng/mL) are specific for iron deficiency. However, ferritin may also be elevated in cases of liver injury (eg, hepatitis) and in some tumors (especially acute leukemia, Hodgkin lymphoma, and GI tract tumors).
Serum transferrin receptor reflects the amount of RBC precursors available for active proliferation; levels are sensitive and specific. The range of normal is 3.0 to 8.5 μg/mL. Levels increase in early iron deficiency and when erythropoiesis increases.
The most sensitive and specific criterion for iron-deficient erythropoiesis, however, is absent marrow stores of iron, although a bone marrow examination is rarely needed.
Iron deficiency anemia must be differentiated from other microcytic anemias (see Table 1: Anemias Caused by Deficient Erythropoiesis: Differential Diagnosis of Microcytic Anemia Due to Decreased RBC Production ). If tests exclude iron deficiency in a patient with microcytic anemia, then anemia of chronic disease, structural Hb abnormalities (eg, hemoglobinopathies), and congenital RBC membrane abnormalities are considered. Clinical features, Hb studies (eg, Hb electrophoresis and HbA2), and genetic testing (eg, α-thalassemia) may help distinguish these entities.
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Table 1
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Differential Diagnosis
of Microcytic Anemia
Due to Decreased RBC Production
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Diagnostic Criteria
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Iron Deficiency
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Iron- Transport Deficiency
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Sideroblastic Iron Utilization
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Iron Reutilization
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Peripheral blood
Microcytosis (M) vs hypochromia (H)
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M > H
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M > H
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M > H , may be normocytic
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M > H
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Polychromatophilic targeted cells
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Absent
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Absent
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Present
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Absent
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Stippled RBCs
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Absent
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Absent
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Present
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Absent
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RBC distribution width (RDW)
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↑
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↑
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↑
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Normal
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Serum iron
Serum iron: iron-binding capacity
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↓:↑
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↓:↓
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↑:Normal
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↓:↓
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% Saturation of transferrin
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< 10
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0
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> 50
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> 10
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Serum ferritin
(normal, 30–300 ng/mL)
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< 12
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No data available
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> 400
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30–400
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Bone marrow
RBC:granulocyte ratio (normal, 1:3–1:5)
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1:1–1:2
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1:1–1:2
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1:1–5:1
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1:1–1:2
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Marrow iron
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Absent
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Present
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↑
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Present
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Ringed sideroblasts
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Absent
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Absent
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Present
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Absent
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↑ = increased; ↓ = decreased.
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Laboratory test results help stage iron deficiency anemia. Stage 1 is characterized by decreased bone marrow iron stores; Hb and serum iron remain normal, but serum ferritin concentration falls to < 20 ng/mL. The compensatory increase in iron absorption causes an increase in iron-binding capacity (transferrin level). During stage 2, erythropoiesis is impaired. Although the transferrin level is increased, the serum iron concentration decreases; transferrin saturation decreases. Erythropoiesis is impaired when serum iron falls to < 50 μg/dL (< 9 μmol/L) and transferrin saturation to < 16%. The serum ferritin receptor concentration rises (> 8.5 mg/L). During stage 3, anemia with normal-appearing RBCs and indices develops. During stage 4, microcytosis and then hypochromia develop. During stage 5, iron deficiency affects tissues, resulting in symptoms and signs.
Diagnosis of iron deficiency anemia prompts consideration of its cause, usually bleeding. Patients with obvious blood loss (eg, women with menorrhagia) may require no further testing. Men and postmenopausal women without obvious blood loss should undergo evaluation of the GI tract, because anemia may be the only indication of an occult GI cancer. Rarely, chronic epistasis or GU bleeding is underestimated by the patient and requires evaluation in patients with normal GI study results.
Treatment
Iron therapy without pursuit of the cause is poor practice; the bleeding site should be sought even in cases of mild anemia.
Iron can be provided by various iron salts (eg, ferrous sulfate , gluconate, fumarate) or saccharated iron po 30 min 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 1 or 2 times/day. Larger doses are largely unabsorbed but increase adverse effects, especially constipation. 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 the same therapeutic response as oral iron but can cause adverse effects, such as anaphylactoid reactions, serum sickness, thrombophlebitis, and pain. It 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). The dose of parenteral iron is determined by a hematologist. Oral or parenteral iron therapy should continue for ≥ 6 mo after correcting Hb 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 wk but then rises 0.7 to 1 g/wk until near normal, at which time rate of increase tapers. Anemia should be corrected within 2 mo. A subnormal response suggests continued hemorrhage, underlying infection or malignancy, insufficient intake of iron, or, very rarely, malabsorption of oral iron.
Last full review/revision November 2005
Content last modified November 2005
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