The most definitive measure of iron status is a bone-marrow aspirate stained for iron; if iron is absent the patient has completely depleted iron stores and is considered to be iron deficient. Bone marrow aspiration, frequently referred to as the "gold standard" for evaluation of iron status, is not routinely done for assessment of iron status, because it is invasive, expensive, time-consuming and painful. Instead, the diagnostic assessment of iron status is based on measurements of the three pools of iron (Worwood, 1994) (see Basics of Iron Metabolism).
The major metabolic pool, RBC heme iron, is measured as blood hemoglobin (Hb) concentration. If Hb is normal, the subject is not iron deficient. Iron stores may vary from excessive to absent; a normal Hb tells only that the amount of iron is sufficient for the conserved re-utilization for RBC production. If Hb is low, iron deficiency is one of many possibilities.
The storage pool is measured by the concentration of serum ferritin, which is roughly proportional to the total stores of iron (Worwood, 1994). Ferritin below the normal range indicates depletion of iron stores and possible iron deficiency (Table 1). In a healthy subject, low serum ferritin (<10 - 20 ug/L) correlates well with iron deficiency, but ferritin is an acute-phase protein that is markedly elevated in response to inflammation. In patients with chronic disease, the ferritin concentration for diagnosis of iron deficiency is elevated to a variable extent, making decisions about what is "low" very difficult (Baer et al., 1990). Ferritin cut-offs of 30 - 70 ug/L have been recommended for chronic disease patients (Nelson et al., 1978; Porter et al., 1994), and ferritin as high as 220 ug/L has been reported in a patient with chronic disease who was almost certainly iron deficient (North et al., in press).
The transit pool is measured directly as serum iron (SI) and transferrin. Transferrin is usually measured as Total Iron Binding Capacity (TIBC), the amount of protein-bound iron after addition of a saturating amount of iron to serum (transferrin is effectively the only iron-binding component of serum) (Worwood, 1994). SI tends to be low in iron deficiency (but also in inflammatory conditions). TIBC tends to be elevated in iron deficiency, presumably a compensatory mechanism (but it is lower in inflammatory conditions). The percent saturation of transferrin, the ratio SI/TIBC, also decreases in iron deficiency.
For an otherwise healthy patient, some combination of these parameters is adequate for assessing iron status. A special circumstance arises, however, with patients who have a "chronic" disease, for this purpose defined as an inflammatory, infectious or malignant disease. These patients have a high frequency of anemia of complex etiology; it is referred to as anemia of chronic disease (ACD). ACD has blood-cell characteristics similar to those of iron-deficiency anemia (IDA), so a differential diagnosis requires an assessment of iron status (see Differentiation of ACD & IDA).
The complication is that inflammatory conditions directly affect the parameters of iron status (Table 1). A new parameter, independent of inflammatory conditions, is required. Serum soluble transferrin receptor (sTfR) increases in iron deficiency and is unaffected by chronic disease (see sTfR & the Diagnosis of Irons Deficiency, and R&D Systems Serum sTfR Assay is Comparable to Marrow Aspirate Iron Stain).
Serum sTfR thus appears to be an excellent addition to the traditional tests of iron status. It has, in fact, been shown to be comparable to marrow aspiration, the gold standard, in evaluating patients for iron deficiency. It is mechanistically and, in analysis of clinical data, statistically inde pendent of the other tests. An elevated level of sTfR reflects cells' needs for more iron, or functional iron deficiency.
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