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Iron Deficiency Anemia

(Anemia of Chronic Blood Loss; Chlorosis)

by Alan E. Lichtin, MD

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 levels with high serum total iron binding capacity. If the diagnosis is made, occult blood loss is suspected. Treatment involves iron replacement and treatment of the cause of blood loss.

Pathophysiology

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, lower androgen levels, and dearth of stored iron because of iron loss due to menses and pregnancy. The distribution of body iron in an average man is Hb, 2100 mg; ferritin, 700 mg (in cells and plasma); hemosiderin, 300 mg (in cells); myoglobin, 200 mg; tissue (heme and nonheme) enzymes, 150 mg; and transport-iron compartment, 3 mg.

Iron absorption

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 transport and usage

Iron from intestinal mucosal cells 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 storage and recycling

Iron not used for erythropoiesis is transferred by transferrin, an iron-transporting protein, to the storage pool; iron is stored in 2 forms, ferritin and hemosiderin. The most important is ferritin (a heterogeneous 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 level 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 bone 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.


Iron deficiency

Deficiency develops in stages. In the first stage, iron requirement exceeds intake, causing progressive depletion of bone marrow iron stores. As stores decrease, absorption of dietary iron increases in compensation. During later stages, deficiency impairs RBC synthesis, ultimately causing anemia.

Severe and prolonged iron deficiency also may cause dysfunction of iron-containing cellular enzymes.


Etiology

Because iron is poorly absorbed, dietary iron barely meets the daily requirement for most people. Even so, people 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, or decreased intake readily causes 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 Overview of Hemolytic Anemia) when the amount of iron released during hemolysis exceeds the haptoglobin-binding capacity. Vitamin C deficiency can contribute to iron deficiency anemia by causing 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 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.

Symptoms and Signs

Most symptoms of iron deficiency are due to anemia. Such symptoms include fatigue, loss of stamina, shortness of breath, weakness, dizziness, and pallor. Fatigue also may result from dysfunction of iron-containing cellular enzymes.

In addition to the usual manifestations of anemia, some uncommon symptoms occur in severe iron deficiency. Patients 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 (Plummer-Vinson syndrome).

Diagnosis

  • CBC, serum iron, iron-binding capacity, and serum ferritin

  • Rarely bone marrow examination

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 measured 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 level is low in iron deficiency and in many chronic diseases and is elevated in hemolytic disorders and in iron-overload syndromes (see Overview of 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 transferrin receptor levels reflect 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 with increased erythropoiesis.

Serum ferritin levels 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 ng/mL in men and 49 ng/mL in women. Low levels (< 12 ng/mL) are specific for iron deficiency. However, ferritin is an acute-phase reactant, and levels increase in inflammatory and neoplastic disorders, so 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).

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.

Stages of iron deficiency

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 level 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 level 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 level 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 epistaxis or GU bleeding is underestimated by the patient and requires evaluation in patients with normal GI study results.

Other microcytic anemias

Iron deficiency anemia must be differentiated from other microcytic anemias (see Table: Differential Diagnosis of Microcytic Anemia Due to Decreased RBC Production). If tests exclude iron deficiency in patients 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 Hb A 2 ), and genetic testing (eg, for α-thalassemia) may help distinguish these entities.

Differential Diagnosis of Microcytic Anemia Due to Decreased RBC Production

Diagnostic Criteria

Iron Deficiency

Iron-Transport Deficiency

Sideroblastic Iron Utilization

Iron Reutilization

Peripheral smear

Microcytosis (M) vs hypochromia (H)

M > H

M > H

M > H , may be normocytic

M > H

Polychromatophilic targeted cells

Absent

Absent

Present

Absent

Stippled RBCs

Absent

Absent

Present

Absent

RBCs

RBC distribution width (RDW)

Normal

Serum iron

Serum iron: iron-binding capacity

:

:

:Normal

:

% Saturation of transferrin

< 10

0

> 50

> 10

Serum ferritin

(Normal, 30–300 ng/mL)

< 12 ng/mL

No data available

> 400 ng/mL

30–400 ng/mL

Bone marrow

RBC:granulocyte ratio (normal, 1:3–1:5)

1:1–1:2

1:1–1:2

1:1–5:1

1:1–1:2

Marrow iron

Absent

Present

Present

Ringed sideroblasts

Absent

Absent

Present

Absent

>= more common than;= increased; = decreased.

Treatment

  • Oral supplemental iron

  • Rarely parenteral iron

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 once/day or bid. Larger doses are largely unabsorbed but increase adverse effects especially. 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 correction of 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 cancer, insufficient iron intake, or, very rarely, malabsorption of oral iron.

Key Points

  • Iron deficiency anemia is usually caused by blood loss (eg, GI, menstrual) but may be due to hemolysis or increased demand for iron (eg, in pregnancy, lactation, periods of rapid growth in children).

  • Differentiate iron deficiency anemia from other microcytic anemias (eg, anemia of chronic disease, hemoglobinopathies, congenital RBC membrane abnormalities).

  • Measure serum iron, iron-binding capacity, and serum ferritin levels.

  • Iron deficiency typically causes low serum iron, high iron-binding capacity, and low serum ferritin levels.

  • Always seek a cause of iron deficiency, even when anemia is mild.

  • Oral iron supplements are usually adequate; reserve use of parenteral iron for hematologists because of risks of adverse effects (eg, anaphylactoid reactions, serum sickness, thrombophlebitis).

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