eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Iron Deficiency Anemia: Differential Diagnoses & Workup

Author: Marcel E Conrad, MD, (Retired) Distinguished Professor of Medicine, University of South Alabama
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Updated: Aug 4, 2009

Differential Diagnoses

Spherocytosis, Hereditary
Thalassemia, Alpha
Thalassemia, Beta

Other Problems to Be Considered

Anemia of chronic disorders
Hemoglobin CC disease
Hemoglobin DD disease
Lead poisoning
Microcytic anemias
Sideroblastic anemias

Workup

Laboratory Studies

• CBC count
  • This documents the severity of the anemia. In chronic iron deficiency anemia, the cellular indices show a microcytic and hypochromic erythropoiesis, ie, both the mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) have values below the normal range for the laboratory performing the test. Reference range values for the MCV and MCHC are 83-97 fL and 32-36 g/dL, respectively.
  • Often, the platelet count is elevated (>450,000/µL). This normalizes following iron therapy.
  • The WBC count is usually within reference ranges (4500-11,000/µL).
  • If the CBC count is obtained after blood loss, the cellular indices do not enter the abnormal range until most of the erythrocytes produced before the bleed are destroyed at the end of their normal lifespan (120 d).
• Peripheral smear
  • Examination of the peripheral smear is an important part of the workup of patients with anemia. Examination of the erythrocytes shows microcytic and hypochromic red blood cells in chronic iron deficiency anemia. The microcytosis is apparent in the smear long before the MCV is decreased after an event producing iron deficiency. Platelets usually are increased in this disorder.
  • Unlike thalassemia, target cells usually are not present, and anisocytosis and poikilocytosis are not marked. It lacks the intraerythrocytic crystals seen in hemoglobin C disorders.
  • Combined folate deficiency and iron deficiency are commonplace in areas of the world with little fresh produce and meat. The peripheral smear reveals a population of macrocytes mixed among the microcytic hypochromic cells. This combination can normalize the MCV.
• Serum iron, total iron-binding capacity (TIBC), and serum ferritin: A low serum iron and ferritin with an elevated TIBC are diagnostic of iron deficiency. While a low serum ferritin is virtually diagnostic of iron deficiency, a normal serum ferritin can be seen in patients who are deficient in iron and have coexistent diseases (hepatitis, anemia of chronic disorders). These test findings are useful in distinguishing iron deficiency anemia from other microcytic anemias (see Image 1).
  

  

  The sequence of events (left to right) that occur with gradual depletion of body stores of iron. Serum ferritin and stainable iron in tissue stores are the most sensitive laboratory indicators of mild iron deficiency and are particularly useful in differentiating iron deficiency from the anemia of chronic disorders. The percentage saturation of transferrin with iron and free erythrocyte protoporphyrin values do not become abnormal until tissue stores are depleted of iron. Subsequently, a decrease in the hemoglobin concentration occurs because iron is unavailable for heme synthesis. Red blood cell indices do not become abnormal for several months after tissue stores are depleted of iron.

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  The sequence of events (left to right) that occur with gradual depletion of body stores of iron. Serum ferritin and stainable iron in tissue stores are the most sensitive laboratory indicators of mild iron deficiency and are particularly useful in differentiating iron deficiency from the anemia of chronic disorders. The percentage saturation of transferrin with iron and free erythrocyte protoporphyrin values do not become abnormal until tissue stores are depleted of iron. Subsequently, a decrease in the hemoglobin concentration occurs because iron is unavailable for heme synthesis. Red blood cell indices do not become abnormal for several months after tissue stores are depleted of iron.

• A bone marrow aspirate can be diagnostic of iron deficiency. The absence of stainable iron in a bone marrow aspirate that contains spicules and a simultaneous control specimen containing stainable iron permit establishment of a diagnosis of iron deficiency without other laboratory tests.
• Other laboratory tests are useful to establish the etiology of iron deficiency anemia and to exclude or establish a diagnosis of 1 of the other microcytic anemias.
  • Testing stool for the presence of hemoglobin is useful in establishing gastrointestinal bleeding as the etiology of iron deficiency anemia. Usually, chemical testing that detects more than 20 mL of blood loss daily from the upper gastrointestinal tract is employed. More sensitive tests are available; however, they produce a high incidence of false-positive results in people who eat meat. Severe iron deficiency anemia can occur in patients with a persistent loss of less than 20 mL/d.
  • To detect blood loss, the patient can be placed on a strict vegetarian diet for 3-5 days and the stool can be tested for hemoglobin using a benzidine method, or red blood cells can be radiolabeled with radiochromium and retransfused. Stools are collected, and the radioactivity is quantified in a gamma-detector and compared to the radioactivity in a measured quantity of the patient's blood. An immunological method of detecting human species-specific hemoglobin in stool is under development and could increase specificity and sensitivity.
• Hemoglobinuria and hemosiderinuria can be detected by laboratory testing as described under Causes. This documents iron deficiency to be due to renal loss of iron and incriminates intravascular hemolysis as the etiology.
• Hemoglobin electrophoresis and measurement of hemoglobin A₂ and fetal hemoglobin are useful in establishing either beta-thalassemia or hemoglobin C or D as the etiology of the microcytic anemia. Unfortunately, simple tests do not exist for alpha-thalassemia in most laboratories, and it is a diagnosis of exclusion.
• Reticulocyte hemoglobin content (CHr) - Mateos Gonzales et al assessed the diagnostic efficiency of commonly used hematologic and biochemical markers, as well as the CHr in the diagnosis of iron deficiency in children, with or without anemia.¹  The investigators identified CHr and iron serum as the only parameters that were independently associated with iron deficiency (P <0.05), and CHr was the strongest predictor of iron deficiency and iron deficiency anemia. Mateos Gonzalez et al concluded that measurement of CHr may be a reliable method to assess deficiencies in tissue iron supply and, in combination with a CBC count, may be an alternative to the traditional biochemical panel for the diagnosis of iron deficiency in children.¹

Other Tests

• Incubated osmotic fragility is useful. Microspherocytosis may produce a low-normal or slightly abnormal MCV; however, the MCHC usually is elevated rather than decreased, and the peripheral smear shows a lack of central pallor rather than hypochromia.
• Measure tissue lead concentrations. Chronic lead poisoning may produce a mild microcytosis. The anemia probably is related to the anemia of chronic disorders. The incidence of lead poisoning is greater in individuals who are iron deficient than in healthy subjects because increased absorption of lead occurs in individuals who are iron deficient. Paint in old houses has been a source of lead poisoning in children and painters.

Procedures

A bone marrow aspirate stained for iron (Perls stain) can be diagnostic of iron deficiency provided spicules are present in the smear and a control specimen containing iron is performed at the same time. While this largely has been displaced in the diagnosis of iron deficiency by performance of serum iron, TIBC, and serum ferritin, the absence of stainable iron in a bone marrow aspirate is the criterion standard for the diagnosis of iron deficiency. It is diagnostic in identifying the sideroblastic anemias by showing ringed sideroblasts in the aspirate stained with Perls stain. Occasionally, it is useful in separating patients with the anemia of chronic disorders or alpha-thalassemia from patients with iron deficiency, and it is useful in identifying patients with both iron deficiency and the anemia of chronic disorders.

Histologic Findings

The absence of stainable iron in body tissues, including the bone marrow and liver, is the most useful histological finding in individuals who are iron deficient. Nonspecific abnormalities of epithelial tissues are reported in iron deficiency. These include gastric atrophy and clubbing of the small intestinal villi. While they suggest that iron deficiency is a pantropic disorder, they have little clinical diagnostic value.

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