Using the Hemoglobin Content of Reticulocytes (RET-He) to Evaluate Anemia in Patients With Cancer

Ellinor I. B. Peerschke, PhD; Melissa S. Pessin, MD, PhD; Peter Maslak, MD


Am J Clin Pathol. 2014;142(4):506-512. 

In This Article

Abstract and Introduction


Objectives Evaluation of anemia, particularly iron deficiency, in patients with cancer is difficult. This study examined using the hemoglobin content of reticulocytes (RET-He) to rule out iron deficiency, as defined by serum iron studies (transferrin saturation <20%, serum iron <40 μg/dL, and ferritin <100 ng/mL), in an unselected cancer patient population.

Methods Patients were entered into the study based on the existence of concurrent laboratory test requests for CBC and serum iron studies.

Results Using a threshold of 32 pg/cell, RET-He ruled out iron deficiency with a negative predictive value (NPV) of 98.5% and 100%, respectively, in the study population (n = 209) and in a subpopulation of patients with low reticulocyte counts (n = 19). In comparison, the NPV of traditional CBC parameters (hemoglobin, <11 g/dL; mean corpuscular volume, <80 fL) was only 88.5%.

Conclusions: These results support the use of RET-He in the evaluation of iron deficiency in a cancer care setting.


Advanced reticulocyte indices, such as the cellular hemoglobin content of reticulocytes, designated CHr and RET-He, are reportable parameters on Siemens ADVIA 2120 (Siemens, Tarrytown, NY) and Sysmex XE and XN series automated hematology analyzers (Sysmex, Lincolnshire, IL),[1] respectively, without additional blood requirements or technical intervention. Good agreement between CHr and RET-He measurements has been reported.[2–4] These indices correlate with iron-deficient erythropoiesis and are useful markers of iron deficiency in infants and children,[5] adult blood donors,[6] geriatric patients,[7,8] pregnant women,[9] and patients with chronic kidney disease undergoing hemodialysis.[3,4,8,10,11] In addition, the hemoglobin content of reticulocytes is a useful tool for monitoring patients' response to iron replacement therapy[12,13] and detecting iron-restricted erythropoiesis in patients receiving erythropoietin therapy.[14–18] However, little is known about the utility of RET-He in the evaluation of complex anemias in malignancy.

Although iron deficiency is the leading cause of anemia worldwide, the anemia of chronic disease is more common among patients with malignancies. In contrast to iron deficiency anemia caused by inadequate iron stores, the anemia of chronic disease is associated with decreased iron availability despite abundant stores.[19–21] The hemoglobin content of reticulocytes may assist in differentiating between these forms of anemia[22,23] and shows a lower degree of within-patient variability than ferritin or other serum indicators of iron status.[24]

In the current outpatient cancer care setting, assessing iron deficiency requires additional biochemical tests, results of which are not available in real time. Iron deficiency anemia may be inferred from limited information provided by automated CBC and reticulocyte analysis, including hemoglobin (Hb), hematocrit, and RBC indices. However, measures of mature erythrocyte indices (mean corpuscular volume [MCV], mean corpuscular hemoglobin, and RBC distribution width) cannot detect early iron-deficient erythropoiesis due to the slow turnover of erythrocytes (~120 days) in circulation.[25]

In contrast, the hemoglobin content of reticulocytes reflects the recent functional availability of iron[12,26–29] for erythropoiesis, and results are available in real time as part of automated reticulocyte analysis. The measurement is not affected by physiologic interferences, except in cases of thalassemia[30] and macrocytosis/megaloblastosis.[31] The present study, therefore, investigated RET-He, reported by the Sysmex XE 2100, as a tool to rapidly rule out iron deficiency, defined by results of serum iron studies in an outpatient oncology setting. Iron deficiency is associated with significant morbidity in oncology patients and is readily treated. Thus, the ability to assess iron deficiency, as part of automated CBC/reticulocyte analysis, may significantly enhance patient management, particularly in an outpatient setting. Since the etiology of anemia in patients with cancer is complex, involving cytopenias secondary to chemotherapy, bone marrow failure, chronic disease/inflammation, and/or iron deficiency, the goal of the present study was to establish an RET-He cutoff that could rapidly rule out iron deficiency. The data suggest that RET-He, at a threshold of 32 pg/cell, may be an important discriminator to rule out iron deficiency anemia in patients with cancer.