Iron Deficiency Anemia

Iron deficiency anemia (IDA) is an anemia caused by low iron stores in the body; it accounts for approximately half of all anemia cases.   IDA may result from low dietary iron intake, blood loss, increased physiologic demand (eg, periods of rapid growth), or the use of certain medications, among other causes.  Initial testing for IDA typically includes an assessment of hemoglobin (Hb), hematocrit (Hct), and red blood cell (RBC) indices such as mean corpuscular volume (MCV), followed by serum ferritin (SF) if Hb levels are 2 standard deviations below normal for age and sex. Total iron binding capacity (TIBC), transferrin saturation (Tsat), and other tests may also be helpful for diagnosis if anemia of chronic disease/anemia of inflammation (ACD/AI) is a possibility. Treatment for IDA depends on the cause of anemia, but generally begins with oral supplemental iron. Hb, Hct, RBC indices, SF, and other tests may be used to monitor the effectiveness of treatment.

Quick Answers for Clinicians

What are special considerations for iron deficiency anemia testing in young children?

Anemia is estimated to occur in 0.9-4.4% of American children, and has been linked to adverse neurodevelopmental consequences and increased risk of lead poisoning.  Although the U.S. Preventive Services Task Force finds insufficient evidence to support universal screening for iron deficiency anemia (IDA) in children 6-24 months of age,  the American Academy of Pediatrics recommends universal screening at 1 year of age, including assessment of hemoglobin (Hb) and risk factors for IDA. If Hb levels are <11 g/dL at 1 year, further evaluation is recommended, including measurement of serum ferritin (SF) and C-reactive protein (CRP) levels, followed by oral iron supplementation. In cases of mild anemia, Hb can be retested 1 month after treatment initiation to confirm the diagnosis and effectiveness of oral iron. 

What are special considerations for iron deficiency anemia testing in pregnancy?

During pregnancy, the body exhibits an increased iron requirement of approximately 1 g. Due to this increased need for iron, anemia (defined as hemoglobin [Hb] <11 g/dL in the first trimester, <10.5 g/dL in the second trimester, and <11 g/dL in the third trimester) is observed more frequently in pregnant women than in the general population. Iron deficiency anemia (IDA) during pregnancy has been associated with adverse maternal-fetal consequences, including abnormal fetal heart beat and fetal cerebral vasodilation.  Although the U.S. Preventive Services Task Force finds insufficient evidence for universal iron screening and supplementation during pregnancy,  the American College of Obstetricians and Gynecologists recommends that all pregnant women should be screened for anemia, and that patients with anemia should be treated with oral iron in addition to prenatal vitamins. 

What is the recommended approach to patients with iron deficiency anemia who do not respond to iron therapy?

Patients with iron deficiency anemia (IDA) that is refractory to iron therapy may have anemia with a mixed etiology (eg, anemia of chronic disease/anemia of inflammation with concomitant IDA). Consider evaluation for additional causes of anemia. Patients not responding to iron therapy should also be evaluated for medication noncompliance, and an alternative route of supplementary iron administration (eg, parenteral or intravenous) could be considered. In extremely rare cases, consider evaluation for iron-refractory iron-deficiency anemia (IRIDA), a rare hereditary form of IDA responsible for <1% of cases.  IRIDA has been linked to mutations in the TMPRSS6 gene.  If it will affect clinical decision making, a suspected TMPRSS6 mutation can be confirmed by genetic testing.

When should a blood smear be ordered in the diagnosis and/or management of iron deficiency anemia?

Although a blood smear is not necessary for a diagnosis of iron deficiency anemia (IDA), it may be helpful for evaluating other forms of anemia or confirming suspicions of IDA. For example, IDA may present similarly to anemia of chronic disease/anemia of inflammation. In IDA, a peripheral blood smear will reveal anisocytosis and poikilocytosis, whereas these characteristics are not observed in anemia of chronic disease/inflammation.  Peripheral blood smears are not routinely used in monitoring.

Indications for Testing

Patients who present with anemia (Hb levels at least 2 standard deviations below the mean for age and sex) should be tested for iron deficiency.

Criteria for Diagnosis

The suggested diagnostic criteria for IDA are confirmed evidence of anemia and laboratory evidence of low iron stores. 

Laboratory Testing

Initial Evaluation

The first recommended step in the evaluation of suspected IDA is a CBC, including an assessment of Hct, Hb, RBC count, platelet count, and white blood cell count,    as well as a peripheral smear review to evaluate RBC morphology. RBC indices (including RBC distribution width [RDW]) from a CBC are particularly important for the initial evaluation of IDA. IDA is a microcytic anemia, but up to 40% of patients with IDA exhibit normocytic RBCs; thus, patients with anemia and an MCV of <95 fL should be tested for IDA.  For patients with low Hb and an MCV ≥95 fL, consider testing for other types of anemia (see Anemia and Anemia Testing Algorithm).

Diagnosis

Red Blood Cell Distribution Width

RDW, obtained from a CBC, will guide further testing. If RDW is high, iron studies (ferritin/iron and iron binding capacity) should be ordered. If RDW is normal, evaluate RBC count (from the CBC). In the case of an elevated RBC count, consider testing to distinguish between thalassemia and early iron deficiency. If the RBC count is low, consider evaluation for ACD/AI.

Ferritin/Iron and Iron Binding Capacity

SF and TIBC (which includes calculation of transferrin saturation) are the first-line tests to evaluate iron stores and can differentiate between IDA and other forms of microcytic anemia.   Both IDA and ACD/AI exhibit low ferritin and low transferrin saturation. TIBC, however, is increased in severe IDA (although it may be normal in mild IDA), while it is decreased in ACD/AI.   Iron levels vary throughout the day, so it is important to test iron during the morning, when iron levels are at their peak. 

Hemoglobin A2 Quantification

An elevated RBC count with a reduced MCV raises clinical suspicion for thalassemia. HbA2 quantitation is suggested to distinguish between early iron deficiency and thalassemia (see Thalassemia topic). An elevated HbA2 level suggests possible thalassemia.

Additional Testing

In certain cases, iron studies and HbA2 may be insufficient to evaluate a microcytic anemia.

Soluble Transferrin Receptor Test

Soluble transferrin receptor levels can be used to test for iron deficiency when other tests are nondiagnostic.  Soluble transferrin receptor levels are increased in iron deficiency and are not affected by inflammation.  It is important that soluble transferrin receptor test results be interpreted in the context of other iron status test results. 

Erythrocyte Protoporphyrin Test

Erythrocyte protoporphyrin testing may be useful to distinguish between thalassemia minor and other causes of hypochromic microcytic anemia. Erythrocyte protoporphyrin levels are elevated in patients with iron deficiency, anemia of chronic disease, and sideroblastic anemia, but not in patients with thalassemia minor or other anemias associated with atypical heme synthesis. 

Bone Marrow Biopsy

If IDA is not indicated by any of the above tests, but suspicion of IDA persists, a bone marrow biopsy may be considered to assess bone marrow iron levels. Although bone marrow biopsy is invasive, it remains the gold standard test for IDA. If bone marrow iron levels are low, the patient may be diagnosed with IDA; if not, additional testing may be required (see Anemia and Anemia Testing Algorithm).

Responsiveness to Oral Iron Treatment

An increase in Hb of 1 g/dL after 1 month of oral iron treatment confirms the diagnosis of IDA and indicates responsiveness to treatment.  In patients who do not respond to oral iron supplementation, additional evaluation may be considered.

Screening

IDA is estimated to occur in <3% of the general United States population. No screening recommendation exists for asymptomatic adults.   Although the U.S. Preventive Services Task Force finds insufficient evidence to recommend IDA screening during pregnancy,  the American College of Obstetrics and Gynecology recommends universal Hb screening for pregnant women at an initial visit, and additional evaluation as appropriate.  

Although the U.S. Preventive Services Task Force also finds insufficient evidence to recommend IDA screening in children, the American Academy of Pediatrics recommends universal Hb and risk factor screening for children at 1 year of age.  If anemia (Hb <11 g/dL) is detected, additional screening, including SF and C-reactive protein (CRP), is recommended. Bright Futures (an initiative of the American Academy of Pediatrics) recommends regular anemia risk assessments or screenings, as appropriate, through 21 years of age. 

Monitoring

In adults, IDA often results from chronic blood loss due to gastrointestinal or genitourinary bleeding (eg, menorrhagia). Identification and treatment of the source of bleeding are the first steps in the resolution of IDA related to blood loss; supplemental iron can then be provided to replenish iron stores. IDA related to decreased intake or absorption can also be treated with supplemental iron.  In all patients receiving supplemental iron, an assessment of iron stores can be performed if Hb, Hct, and other RBC indices fail to respond to therapy as expected. 

Oral Supplementation

Patients without comorbidities on oral iron therapy should have Hb and RBC indices retested at 1 month to confirm the diagnosis of IDA and to evaluate the effectiveness of treatment.  Thereafter, evaluation of Hb and iron stores is recommended every 3 months for the first year and once thereafter if Hb and RBC indices remain normal. 

Parenteral Supplementation

Patients on parenteral iron should have iron stores evaluated at 3 months following initiation of parenteral therapy and every 6 months thereafter until the cessation of therapy. 

Patient Populations Requiring Special Consideration

Patients considering gastric bypass should be evaluated for IDA prior to surgery. Following surgery, patients who have had gastric bypass or another bariatric surgery are at increased risk for IDA due to reduced absorption of dietary iron. Evaluation of iron stores via SF and Tsat is recommended every 3 months following surgery for the first year. A complete iron workup to assess serum iron and iron stores is recommended every year following surgery.  See the ARUP Consult Gastric Bypass topic for more information.

A complex inflammatory state exists in patients with chronic kidney disease, leading to challenges in iron homeostasis. Patients with chronic kidney disease should be tested for IDA every 3 months, or more often if receiving hemodialysis, intravenous iron, or an erythropoietin stimulating agent. Due to the increase in SF observed with inflammation, testing should include RBC indices and an assessment of iron stores using both Tsat and SF. 

Anemia of inflammation is the most common complication of inflammatory bowel disease (IBD). Anemia is particularly complex in IBD, as IBD is a chronic inflammatory condition that also leads to problems with iron absorption, resulting in concomitant IDA. Furthermore, patients with IBD may also suffer from vitamin deficiencies, leading to simultaneous megaloblastic anemia. The European Crohn’s and Colitis Organization recommends assessing all patients with IBD for anemia with a CBC along with SF and CRP tests. Patients with mild IBD or IBD in remission should be tested every 6-12 months; patients with active disease should be tested every 3 months. Additionally, serum vitamin B12 and folate should be tested at least once per year. A full workup, including CBC, reticulocyte count, SF, Tsat, and CRP should be performed any time anemia is observed, and if needed, serum B12, folic acid, haptoglobin, reticulocyte hemoglobin, lactate dehydrogenase, soluble transferrin receptor, creatinine, and urea should be tested to identify the cause of anemia. 

ARUP Laboratory Tests

Initial Evaluation

Identify presence of anemia; establish morphology indices; monitor effectiveness of treatment

Assess erythropoiesis in hematologic conditions

Diagnosis

Aid in the diagnosis of iron deficiency anemia; monitor effectiveness of treatment

Evaluate for thalassemia

Additional Testing

Aid in the diagnosis of IDA

Medical Experts

Contributor

Pearson

Lauren N. Pearson, DO, MPH
Assistant Professor of Clinical Pathology, University of Utah
Laboratory Director for ARUP at University of Utah Health and Huntsman Cancer Institute
Laboratory Director, South Jordan and Sugarhouse Health Center Clinical Laboratories

References

Resources from the ARUP Institute for Clinical and Experimental Pathology®