Increasing Cost Sensitivity in the Diagnostic Evaluation of Microcytic Anemia

ABSTRACT:Microcytic anemia is prevalent in the primary care setting. It is typically caused by iron deficiency, thalassemia trait, or anemia of chronic disease. Establishing a correct etiology while minimizing resources is important to guide management and avoid excess cost burden on patients and society. This article outlines an algorithm that can potentially lead to significant cost savings per diagnosis of microcytic anemia. 

Microcytic anemia is typically the result of iron deficiency, thalassemia, or anemia of chronic disease (ACD).^1,2 The World Health Organization estimates that 15% to 20% of the world’s population are iron deficient³ and 20% carry a thalassemia trait.⁴ Finding the cause of anemia to reverse, prevent progression, and/or appropriately treat the anemia is important for symptomatic as well as asymptomatic anemia cases, which are more frequently encountered in the outpatient setting. 

For women of child-bearing age, iron deficiency anemia (IDA) must be distinguished from thalassemia carriers as the former requires treatment⁵ and the latter may have repercussions for prenatal counseling.⁶ In the middle-aged and elderly, IDA may be the first sign of occult malignancy.^3,7 Distinguishing thalassemia carriers and ACD from IDA is important to avoid therapeutic harm that may be associated with iron supplementation.⁸ 

Establishing an etiology for anemia may require use of several diagnostic tests—from a complete blood count (CBC) to bone marrow biopsy. Although clinicians generally have poor knowledge of diagnostic costs,⁹ it has been shown that raising their awareness of laboratory prices decreases the number of tests ordered.¹⁰ An estimated $75 to $100 billion is wasted annually due to provider inefficiency which includes overutilization of laboratory testing.¹¹ Furthermore, recent insurance trends toward high-deductible healthcare plans often require greater out-of-pocket payments,¹² which in turn shifts more of the cost burden to patients. 

Part of the American College of Physicians High Value Care initiative is to help physicians provide the best possible care to their patients while simultaneously reducing unnecessary costs.¹³ This article aims to create a diagnostic algorithm to help guide physicians determine the etiology of microcytic anemia using an evidence-based and cost-effective method. 

Methodology

A meta-analysis from published literature on microcytic anemia published from 2000 to 2014 (search terms include iron-deficiency anemia, thalassemia, and anemia of chronic disease) was used to establish the evidence base used for diagnosis of microcytic anemia and costs of associated tests. Less common causes, such as sideroblastic anemia and lead poisoning, were not included due to their low frequency. Articles that used a diagnostic approach to microcytic anemia and that included evidence behind commonly ordered laboratory tests were included. 

Note: None of the literature identified on microcytic anemia examined cost-effectiveness. Current procedural terminology codes for diagnostic tests and Medicare’s 2014 clinical laboratory fee schedule (CLFS) was used to estimate the cost of each test, except the alpha globulin gene testing, for which we used gap-fill allowance reimbursement estimates from 2013 as laboratory fee schedule data was unavailable at the time of publishing. 

The Results

The diagnostic algorithm constructed that considers both evidence and cost in the workup for microcytic anemia is shown in the Figure. 

The ferritin level is used to screen for IDA. If IDA is suspected clinically and/or ferritin is <30 ng/mL, the patient should receive iron supplementation with monitoring of hemoglobin. Possible underlying causes should be explored if clinically indicated. If the hemoglobin level improves within the expected time of within 4 weeks, treatment should be continued. If it does not improve, then other causes such as poor compliance or ongoing blood loss should be considered. 

If ACD is clinically suspected and ferritin is >70 ng/mL, treatment should be aimed at the underlying cause. However, if ferritin is between 30 ng/mL and 70 ng/mL, C-reactive protein (CRP) should be checked. If CRP is elevated, inflammation is present and ferritin may be elevated as it is an acute phase reactant; therefore, treating for concomitant iron deficiency and monitoring hemoglobin may be considered. 

If thalassemia is suspected and diagnosis confirmation is desirable, an electrophoresis should be obtained. If this shows hemoglobin A2 (HbA2) >3.5% then beta-thalassemia carrier is likely. If the electrophoresis is normal, alpha-thalassemia, and other less common hemoglobinopathies are still possible and may require genetic testing to be eliminated. 

The estimated costs of the diagnostic tests are shown in Tables 1 and 2. 

Discussion 

Based on evidence in the literature, we were able to create an algorithm for the initial diagnostic workup of microcytic anemia (Figure), which totals $55.27 for recommended tests outlined in Table 1. Our diagnostic approach relies largely on clinical judgment as the most valuable tool; patient history, physical exam, and clinician experience are crucial components as well. The particular laboratory tests used were selected based on cost, availability, and evidence. 

Note: The prices of tests set by Medicare’s national limits were used as a cost equivalent and do not always reflect the actual charge, especially to patients. For instance, a hemoglobin level under the CLFS is estimated at $3.23 versus $16 for the uninsured patient. Avoiding unnecessary testing and associated costs maximizes patient care.

CBC

Anemia is typically diagnosed with a CBC. However, keep in mind that this test may need to be repeated for confirmation as 5% of the population without the disease has been shown to have an abnormal CBC.² The cost of a CBC is $8.83 whereas a hemoglobin and hematocrit (H/H) costs $3.23. Therefore, we recommend using a H/H test for confirmation. It is important to consider that hemoglobin values vary by sex and ethnicity, and appropriate reference ranges should be used.^14,15 

MCV

Traditionally, anemia is categorized into subtypes based on mean corpuscular volume (MCV): normocytic (MCV 80-100 fL), microcytic (MCV <80 fL), and macrocytic (MCV >100 fL).¹ This approach is useful but has some limitations. First, the accuracy of MCV is affected by the time from blood draw to analysis; long transits to the laboratory or a few days in storage may cause inaccurate results.^16,17 Second, MCV changes slowly so it cannot be used to diagnose early iron deficiency, for example, nor is it useful for monitoring therapy in the acute setting.¹⁷ Third, there is significant overlap between the causes of microcytic and normocytic anemia.⁶ For instance, in IDA, microcytosis is not a sensitive finding so an MCV value of 95 could still be suggestive when otherwise considering diagnosis of IDA.¹⁶ Conversely, a lower MCV is associated with a greater likelihood of IDA. For instance, an MCV <70 has a likelihood ratio (LR) of 12.5, while an MCV >90 has an LR of 0.29.⁵ Thus, microcytosis is not sensitive for diagnosing IDA; however, the smaller the MCV the greater the likelihood of IDA. 

Serum Ferritin

After diagnosing microcytic anemia, obtain a serum ferritin. Ferritin is the main iron storage protein in the body and plays a critical role in iron homeostasis.¹⁸ The cost of a serum ferritin test is $18.59. Consider taking this measurement first because the presence of IDA can affect the result of other tests (and hence confound interpretation).² 

Ferritin is highly specific in diagnosing IDA¹⁹; IDA is the most common cause of microcytic anemia.¹⁴ A cut-off point of <30 ng/mL is used to diagnose IDA in noninflammatory states.¹⁹ If ferritin is <30 ng/mL, IDA is likely and the patient should be treated as stated below. The lower the ferritin, the more likely the patient is to have IDA.⁷ For example, a ferritin <15 ng/mL typically indicates absent iron stores²⁰ and has an LR of 51 in diagnosing IDA, versus a ferritin of 35 to 44 ng/mL which has an LR of 1.8.⁷ 

It is important to note that a ferritin cut-off of <30 ng/mL is not sensitive for diagnosing IDA,^7,16,19 and iron deficiency may be suspected based on other grounds (eg, heavy menses). If IDA is suspected, a trial treatment of iron is recommended. Remember to recheck H/H after several weeks of therapy to monitor for improvement, which is typically an increase of hemoglobin 1 g/dL every 2 to 3 weeks.⁵ 

If anemia does not improve, consider ongoing blood loss, poor compliance, and other possible causes of anemia. Note: We do not recommend checking traditional indices—such as iron, transferrin, or total iron binding capacity (TIBC)—as they are affected by numerous physiological and pathological processes and have low specificity in diagnosing IDA.^15-17,19,21 Furthermore, the cost of these tests is $38.18 (Table 2) and they do not contribute much useful information. We do not recommend a bone marrow biopsy, traditionally considered the gold standard⁷ when suspecting IDA as this is invasive and expensive at $433.47 per test, typically associated with complications,¹⁷ and may be inaccurate.²²

ACD

ACD is typically associated with normocytic anemia, but can cause microcytic anemia in some cases. In ACD, ferritin levels are normal or increased due to the acute phase nature of ferritin in inflammation, along with increased storage of iron within the reticuloendothelial system.²⁰ Traditionally, the upper limit of normal is 70 ng/mL for diagnosing IDA in ACD¹⁸ and IDA is unlikely in the presence of a persistently normal or elevated ferritin.² Treatment for ACD is geared toward treating the underlying cause. 

If ferritin is <70 ng/mL, one should consider concomitant IDA and a CRP should be checked. We recommend checking a CRP as opposed to erythrocyte sedimentation rate (ESR) as CRP is more specific for inflammation,²³ is not affected by age, has a less controversial reference range,²⁴ and the cost difference is not substantial ($7.06 for CRP versus $4.84 for ESR). If CRP is high, then inflammation is likely²⁵ and a trial of iron therapy should be considered with monitoring for improvement in hemoglobin with an H/H. 

Of note, some patients may not respond to oral iron and may require intravenous iron.¹⁷ If CRP is low and ferritin is >30 ng/mL without reason to suspect concomitant IDA, therapy should be geared toward the underlying cause with consideration for alternative causes.

Additional Tests

Other laboratory tests may help to distinguish between IDA and ACD, including reticulocyte hemoglobin, percent hypochromic cells, and soluble transferrin receptor.²⁶ These are not included in our algorithm due to their limited availability,¹⁹ which makes them impractical. In addition, the soluble transferrin receptor is costly at $49.89, and has low specificity⁷ and variable reference ranges.²⁷ 

Thalassemia 

A thalassemia carrier should be suspected in cases of lifelong anemia.² Prior to screening for thalassemia, make sure that IDA does not coexist as this can mask typical findings seen on electrophoresis.¹⁴ If the diagnosis is suspected based on a relatively high red blood count in relation to hemoglobin in an ancestral-prone patient without child-bearing concerns, it may not be necessary to pursue confirmatory testing. In addition, using the red blood cell distribution width (RDW) may assist in distinguishing thalassemia trait from iron deficiency anemia, as RDW is more commonly normal in the former, and elevated in the latter,²⁸ however it is limited by its relatively low sensitivity and specificity.²⁹ 

However, when the diagnosis needs to be established, the first step is hemoglobin electrophoresis which costs $17.56.¹⁴ Electrophoresis is typically abnormal in beta-thalassemia trait, which can be strongly considered when the HbA2 is >3.5%,^6,30 whereas it is typically normal in alpha-thalassemia carriers.² 

If electrophoresis is normal, an evaluation of the alpha globulin gene for common deletions or variants can be carried out as a screening test for alpha-thalassemia. The cost of this $183.22; due to the expense, is only recommended if testing will change management. It should be noted that in patients of Southeast Asians and African American descent where alpha-thalassemia is more common, genetic testing might be more highly indicated.

Additional steps of diagnosis vary depending on the individual lab, but may include chromatography, capillary electrophoresis, and DNA studies.^6,31,32 These costs vary widely between laboratories. Consider referral to a geneticist prior to DNA testing. 

A cost-effective and an evidence-based approach is needed to maximize patient care in the diagnosis of microcytic anemia. The basic tests of CBC, ferritin, hemoglobin electrophoresis, and CRP cost a total of $55.27 and can be used in a stepwise fashion to establish the etiology of microcytic anemia in most cases. Avoiding nonspecific tests including iron, TIBC, and transferrin would save a total of $38.13. 

Further, avoiding expensive tests such as soluble transferrin receptor, which has low specificity with variable reference ranges, would save an additional $49.89. Bone marrow biopsy is invasive, rarely indicated, and avoiding this would cut costs by $433.47. Repeating tests, such as electrophoresis, if the patient is iron deficient should be avoided and would save $17.56. 

If every test we excluded were performed to diagnose microcytic anemia, the cost would total $521.54 whereas our recommended approach would cost a maximum of $55.27, or a savings of $466.27 per diagnosis. This algorithm relies heavily on clinical judgment and follows a stepwise approach to minimize cost while maximizing patient care.

Danielle L. Heidemann, MD, specializes in internal medicine at the Henry Ford Hospital in Detroit, MI.

Kimberly Baker-Genaw, MD, is the director of medical education and the vice chair for education in the department of internal medicine at Henry Ford
Hospital in Detroit, MI.

Nicholas A. Joseph, MD, is a PGY-3 internal medicine resident at Henry Ford Hospital in Detroit, MI, with plans to subspecialize in geriatrics.

Philip Kuriakose, MD, is the chief in the section of hematology, division of hematology/oncology at Henry Ford Hospital in Detroit, MI.

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