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Editorial |
1 Children’s Hospital Boston, Department of Laboratory Medicine, 300 Longwood Ave., Boston, MA 02115
aFax 617-713-4347, E-mail carlo.brugnara{at}tch.harvard.edu
In this issue of the Journal, Thomas and Thomas (1) provide a novel approach to the diagnosis of iron-deficient states. Traditionally, iron deficiency studies have used various biochemical indicators of iron metabolism to establish the absence or presence of biochemical iron deficiency and to assess the performance of a potentially novel biochemical or hematologic marker. Biochemical indicators have included serum iron, serum transferrin, transferrin saturation, serum ferritin, and serum circulating transferrin receptor (TfR) as well as various ratios of these variables. Hematologic indices that have been used to establish the presence of iron deficiency anemia have included, in addition to hemoglobin (Hb) or hematocrit (Hct), abnormal erythrocytes or reticulocyte indices that identify the presence of hypochromic and microcytic cells. Additional variables that have been investigated include zinc protoporphyrin and erythrocyte ferritin. Studies on the diagnosis of iron-deficient states have been complicated by the absence of a clear reference method to detect biochemical iron deficiency. Iron staining of bone marrow biopsy is widely quoted as a gold standard, but the invasive nature of this procedure severely limits its use. A less invasive standard for iron deficiency is based on the hematologic response to iron replacement therapy: an increase of the reticulocyte count or reticulocyte index after oral or intravenous iron replacement therapy reveals the presence of iron deficiency.
The use of biochemical markers to diagnose iron-deficient states is problematic in clinical conditions such as the anemia of chronic disease (ACD). When a disturbed iron metabolism is associated with acute or chronic phase inflammatory responses, serum ferritin and transferrin concentrations are affected and not informative. Biochemical markers are also less effective in diagnosing functional iron deficiency, a transient discrepancy between iron supply and utilization that is mostly seen in individuals treated with recombinant human erythropoietin (r-HuEPO).
In their report, Thomas and Thomas (1) approach the diagnosis of ACD and functional iron deficiency by determining two hematologic gold standard factors for iron deficiency: the presence of hypochromic erythrocytes (HYPO) and a reduced hemoglobin content of reticulocytes (CHr). Various biochemical markers are then assessed based on this "hematologic" definition of iron-deficient states. Several important findings emerge from this report:
5 mg/L). In patients with ACD, cutoff values for ferritin are <100 µg/L in men and <20 µg/L in women, compared with cutoff values of <20 µg/L and <10 µg/L in the absence of inflammation, respectively. The serum TfR-ferritin index is the best biochemical marker of functional iron deficiency, with a cutoff value of 1.5 in the absence of ACD and 0.8 in its presence. The study by Thomas and Thomas (1) convincingly demonstrates that biochemical markers are relatively insensitive in diagnosing functional iron deficiency. In addition, the dual role of serum TfR as both a marker of iron-deficient erythropoiesis and a marker of erythroid bone marrow mass (2)(3) limits its power to identify functional iron deficiency in conditions of hypoproliferative erythropoiesis. It is likely that at early stages of iron deficiency, before the development of anemia, the impaired iron supply to the erythron produces transient bouts of iron-deficient erythropoiesis, which lead to a shift in the distribution of CHr to lower values and to the appearance of hypochromic cells. These changes are then followed by the development of frank microcytosis and hypochromia and are therefore helpful in identifying early stages of iron deficiency, especially in conditions where biochemical markers are not informative.
Classical iron deficiency associated with chronic blood loss and/or poor dietary iron intake does not represent a particular challenge for the laboratory and clinicians. The combination of hypochromic microcytic anemia and biochemical signs of iron deficiency (low iron, low transferrin saturation, and low ferritin) associated with a clinical history of chronic blood loss and/or poor iron intake represents a common scenario in a primary care setting. Chronic blood loss is mostly associated with chronic noninfectious gastrointestinal bleeding or menometrorrhagia in the developed world and chronic parasitic infections in developing countries. However, several clinical scenarios have emerged that provide new challenges to assess the balance between iron availability and erythropoietic iron requirements.
The use of r-HuEPO has quickly led to the understanding that an adequate iron supply is critical to obtaining a therapeutic response (4). Functional iron deficiency (or iron-restricted erythropoiesis) is seen in healthy individuals with apparently normal iron stores. The marked increase in erythropoietic activity induced by r-HuEPO is of a magnitude to transiently deplete otherwise normal body iron stores and lead to the production of reticulocytes and erythrocytes that are indistinguishable from those produced in frank iron-deficiency anemia (5)(6). The issue of functional iron deficiency has received a great deal of attention by clinicians treating patients on chronic renal dialysis. It is well known that in many of these patients biochemical markers for iron are noninformative: frequently, serum ferritin concentrations >500–600 µg/L are seen in patients who are markedly iron deficient and respond to iron therapy. Recent studies have shown that the Hb content of reticulocytes is valuable in identifying functional iron-deficient states (7)(8) as well as determining when iron therapy is needed (9). Proper management of iron and r-HuEPO therapy in these patients could produce substantial savings, by reducing inappropriate use of iron and r-HuEPO, and better quality of care, by avoiding exposure to unnecessary therapies and/or uninformative laboratory tests. The recent study by Fishbane et al. (9) demonstrated how an alternative approach based on hematologic indices can lead to substantial optimization of intravenous iron therapy.
Another area that has very recently produced important new information for our understanding of basic iron metabolism and erythrocyte pathophysiology is that of the illicit use of r-HuEPO or similar drugs for blood doping of competitive athletes. The use of r-HuEPO or EPO-like products to increase the Hct/Hb and, thus, the performance of competitive athletes has received a great deal of attention in the 2000 and 2002 Olympic Games. Work by Parisotto et al. (10) has demonstrated that a combination of biochemical and hematologic markers is highly effective in identifying recent (within 72 h) illicit use of R-HuEPO. In a simulated r-HuEPO doping setting, the unique combination (ON model) of high Hct (or Hb) with increased reticulocyte Hct (a product of reticulocyte count and reticulocyte mean corpuscular volume), high serum EPO, increased serum TfR, and an increased percentage of hypochromic cells correctly identified individuals who recently used this drug. In addition, substantial evidence exists on the capability of identifying past use of r-HuEPO, based on the unique combination of high Hct (or Hb), suppressed erythropoiesis (low reticulocyte count), and reduced endogenous serum EPO (OFF model) (10)(11). The combination of hematologic and biochemical markers achieved more substantial power in detecting illicit use of erythropoietic stimulators than did use of any of these markers alone. The combination of biochemical and hematologic markers is expected to be helpful in screening and possibly confirming abuse of any substance that acts like EPO. This should deter abuse of the new forms of EPO that are now becoming available (11).
We should not forget that, although great progress has been made in the prevention of iron deficiency in children, iron deficiency is still the leading cause of anemia in children. In the US alone, 700 000 toddlers 1–2 years of age are iron deficient, and 240 000 toddlers have iron-deficiency anemia (12). Iron deficiency (with or without anemia) has been associated with impaired cognitive development, indicating a crucial role of iron in promoting normal brain development (13). The anemia of young infants can be reversed with iron supplementation, but the observed alteration in cognitive performance may not be fully correctable (14). Thus, early recognition of iron deficiency, even before the development of anemia, is crucial to prevent impaired intellectual development. The biochemical markers that are commonly used in adults have shown poor performance in infants and young children, whereas use of reticulocyte markers has shown some promise (15).
The work of Thomas and Thomas (1) provides a useful new approach to the diagnosis of iron-deficient states. However, the limited availability of HYPO and CHr determinations, which are currently provided by only one class of instruments, poses a serious limitation to a wider use of these markers. Additional work is also needed to define the best strategy for identifying iron-deficient states in individuals with ß- or 
-thalassemia trait, in whom HYPO and CHr are abnormal, and in individuals with macrocytic/megaloblastic erythropoiesis, such as that associated with chemotherapy of various malignancies, where CHr is abnormally increased.
Footnotes
1 Dr. Brugnara has a Children’s Hospital-approved consulting agreement with Bayer Diagnostics (Tarrytown, NY). He has received honoraria from Bayer Diagnostics for scientific presentations and editorial work. 
References
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