IRON DEFICIENCY ANEMIA

Essentials of Diagnosis

Serum ferritin < 12 mcg/L.

Caused by bleeding in adults unless proved otherwise.

Responds to iron therapy.
General Considerations
Iron deficiency is the most common cause of anemia worldwide. The causes are listed in Table 13–3. Aside from circulating red blood cells, the major location of iron in the body is the storage pool as ferritin or as hemosiderin and in macrophages.

Table 13–3. Causes of iron deficiency.

Deficient diet
Decreased absorption
Increased requirements
Pregnancy
Lactation
Blood loss
Gastrointestinal
Menstrual
Blood donation
Hemoglobinuria
Iron sequestration
Pulmonary hemosiderosis

The average American diet contains 10–15 mg of iron per day. About 10% of this amount is absorbed. Absorption occurs in the stomach, duodenum, and upper jejunum. Dietary iron present as heme is efficiently absorbed (10–20%) but nonheme iron less so (1–5%), largely because of interference by phosphates, tannins, and other food constituents. Small amounts of iron—approximately 1 mg/d—are normally lost through exfoliation of skin and mucosal cells. There is no physiologic mechanism for increasing normal body iron losses.
Menstrual blood loss in women plays a major role in iron metabolism. The average monthly menstrual blood loss is approximately 50 mL, or about 0.7 mg/d. However, menstrual blood loss may be five times the average. To maintain adequate iron stores, women with heavy menstrual losses must absorb 3–4 mg of iron from the diet each day. This strains the upper limit of what may reasonably be absorbed, and women with menorrhagia of this degree will almost always become iron deficient without iron supplementation.
In general, iron metabolism is balanced between absorption of 1 mg/d and loss of 1 mg/d. Pregnancy may also upset the iron balance, since requirements increase to 2–5 mg of iron per day during pregnancy and lactation. Normal dietary iron cannot supply these requirements, and medicinal iron is needed during pregnancy and lactation. Repeated pregnancy (especially with breast-feeding) may cause iron deficiency if increased requirements are not met with supplemental medicinal iron. Decreased iron absorption can on very rare occasions cause iron deficiency and usually occurs after gastric surgery, though concomitant bleeding is frequent.
By far the most important cause of iron deficiency anemia is blood loss, especially gastrointestinal blood loss. Chronic aspirin use may cause it even without a documented structural lesion. Iron deficiency demands a search for a source of gastrointestinal bleeding if other sites of blood loss (menorrhagia, other uterine bleeding, and repeated blood donations) are excluded.
Chronic hemoglobinuria may lead to iron deficiency since iron is lost in the urine; traumatic hemolysis due to a prosthetic cardiac valve and other causes of intravascular hemolysis (eg, paroxysmal nocturnal hemoglobinuria) should also be considered. Frequent blood donors may also be at risk for iron deficiency.
Clinical Findings
SYMPTOMS AND SIGNS
As a rule, the only symptoms of iron deficiency anemia are those of the anemia itself (easy fatigability, tachycardia, palpitations and tachypnea on exertion). Severe deficiency causes skin and mucosal changes, including a smooth tongue, brittle nails, and cheilosis. Dysphagia because of the formation of esophageal webs (Plummer–Vinson syndrome) also occurs. Many iron-deficient patients develop pica, craving for specific foods (ice chips, etc) often not rich in iron.
LABORATORY FINDINGS
Iron deficiency develops in stages. The first is depletion of iron stores. At this point, there is anemia and no change in red blood cell size. The serum ferritin will become abnormally low. A ferritin value less than 30 mcg/L is a highly reliable indicator of iron deficiency. The serum total iron-binding capacity (TIBC) rises. Bone marrow biopsy for evaluation of iron stores is now rarely performed because of intraobserver variation in its interpretation.
After iron stores have been depleted, red blood cell formation will continue with deficient supplies of iron. Serum iron values decline to less than 30 mcg/dL and transferrin saturation to less than 15%.
In the early stages, the MCV remains normal. Subsequently, the MCV falls and the blood smear shows hypochromic microcytic cells (see blood smear). With further progression, anisocytosis (variations in red blood cell size) and poikilocytosis (variation in shape of red cells) develop. Severe iron deficiency will produce a bizarre peripheral blood smear, with severely hypochromic cells, target cells, hypochromic pencil-shaped cells, and occasionally small numbers of nucleated red blood cells. The platelet count is commonly increased.

Fig.

Iron deficiency anemia. (Peripheral blood, 50 x.) Hypochromic and microcytic cells due to iron deficiency. The diameter of the normal red blood cell should be approximately the same as that of the nucleus of a small lymphocyte. This smear shows that most of the red cells are much smaller than the lymphocytes. This patient also has an increased platelet count—a common finding in patients with iron deficiency. (Courtesy of L Damon.)

Differential Diagnosis
Other causes of microcytic anemia include anemia of chronic disease, thalassemia, and sideroblastic anemia. Anemia of chronic disease is characterized by normal or increased iron stores in the bone marrow and a normal or elevated ferritin level; the serum iron is low, often drastically so, and the TIBC is either normal or low. Thalassemia produces a greater degree of microcytosis for any given level of anemia than does iron deficiency. Red blood cell morphology on the peripheral smear is abnormal earlier in the course of thalassemia.
Treatment
The diagnosis of iron deficiency anemia can be made either by the laboratory demonstration an iron-deficient state or evaluating the response to a therapeutic trial of iron replacement.
Since the anemia itself is rarely life-threatening, the most important part of treatment is identification of the cause—especially a source of occult blood loss.
ORAL IRON
Ferrous sulfate, 325 mg three times daily, which provides 180 mg of iron daily of which up to 10 mg is absorbed (though absorption may exceed this amount in cases of severe deficiency), is the preferred therapy. Compliance is improved by introducing the medicine more slowly in a gradually escalating dose with food. Alternatively, in cases of poor tolerance, one pill of ferrous sufate can be taken at bedtime on an empty stomach. It is preferable to prescribe a lower dose of iron or to allow ingestion concurrent with food than to insist on a more rigorous schedule that will not be followed. An appropriate response is a return of the hematocrit level halfway toward normal within 3 weeks with full return to baseline after 2 months. Iron therapy should continue for 3–6 months after restoration of normal hematologic values to replenish iron stores. Failure of response to iron therapy is usually due to noncompliance, although occasional patients may absorb iron poorly. Other reasons for failure to respond include incorrect diagnosis (anemia of chronic disease, thalassemia) and ongoing gastrointestinal blood loss that exceeds the rate of new erythropoiesis.
PARENTERAL IRON
The indications are intolerance to oral iron, refractoriness to oral iron, gastrointestinal disease (usually inflammatory bowel disease) precluding the use of oral iron, and continued blood loss that cannot be corrected. Because of the possibility of anaphylactic reactions, parenteral iron therapy should be used only in cases of persistent anemia after a reasonable course of oral therapy. Until recently, iron dextran had been the only form of parenteral iron available in the United States. Now, sodium ferric gluconate is available and has been shown to result in a lower incidence of severe anaphylaxis. To date, no deaths have been reported with the use of this preparation.
The dose (total 1.5–2 g) may be calculated by estimating the decrease in volume of red blood cell mass and then supplying 1 mg of iron for each milliliter of volume of red blood cells below normal. Approximately 1 g should then be added for storage iron. Total body iron ranges between 2 g and 4 g: approximately 50 mg/kg in men and 35 mg/kg in women. Most (70–95%) of the iron is present in hemoglobin in circulating red blood cells. One milliliter of packed red blood cells (not whole blood) contains approximately 1 mg of iron. In men, red blood cell volume is approximately 30 mL/kg. A 70-kg man will therefore have approximately 2100 mL of packed red blood cells and consequently 2100 mg of iron in his circulating blood. In women, the red cell volume is about 27 mL/kg; a 50-kg woman will thus have 1350 mg of iron circulating in her red blood cells. Thus, a woman whose hemoglobin is 9 g/dL would be treated with a total of 1315 mg of parenteral iron, 315 mg for the increased red blood cell mass and 1000 mg to provide iron stores. The entire dose may be given as an intravenous infusion over 4–6 hours. A test dose of a dilute solution is given first, and the patient should be observed during the entire infusion for anaphylaxis.

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