Short Takes: DIAGNOSIS

14 Jun

Clinical manifestations of IDA are often vague and nonspecific. Symptoms may include fatigue, weakness, shortness of breath, and headache.The common “gold standard” for the diagnosis of iron deficiency in clinical practice involves the invasive act of obtaining a staining of a bone marrow aspirate. In lieu of obtaining a bone marrow sample, appropriate interpretation of laboratory tests may suffice. This process is germane to the optimal prescribing of iron products. Classic laboratory values in patients with IDA usually reveal micro-cytic, hypochromic anemia with low serum iron levels, high total iron-binding capacity (TIBC), low transferrin saturation, and low serum ferritin levels.

Many prescribers unintentionally overlook other important factors and look only at serum iron levels in anemic patients. Because serum levels are also low in anemia of chronic disease (ACD), for which iron would not be beneficial, they should consider other indices (Table 1). One secondary check involves the TIBC, which tends to be higher in iron-deficiency states and lower in patients with ACD. As a result of this finding and because of the interrelationship between these two parameters, IDA tends to yield transferrin saturation levels of less than 15%.
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The serum ferritin, however, is thought to be the most sensitive and specific single noninvasive test for assessing true iron stores. A ferritin level range of 12 to 30 ng/ml or lower is thought to be a reasonably good diagnostic measure of true IDA. Because ferritin is an acute-phase reactant, however, upward skewing can occur in both acute and chronic inflammatory conditions. This means, of course, that “false-negative” ferritin results are possible with these patients.

Chronic disease states, such as renal or liver failure, human immunodeficiency virus (HIV) infection, sickle cell disease, conditions necessitating repeated blood transfusions, malignancies, and chronic inflammatory disorders, may elevate measured values up to 45 to 100 ng/ml or even as high as 160 ng/ml in iron-deficient patients. In fact, in a study done by Coenen et al., six of 40 patients with chronic inflammatory diseases and ferritin levels above 160 ng/ml had no iron in their bone marrow. This study, however, is considered to be an outlier from the results of most other papers, and an amalgamation of data from numerous other sources indicate that values greater than 200 ng/ml would generally rule out true iron deficiency in these populations. For acute-phase scenarios (e.g., infection, myocardial infarction, and other modes of acute trauma), the ferritin cutoffs are less clear.

Table 1   Fe or Not Fe? That Is the Question—Iron Deficiency versus Chronic Disease: A Contrast in Usual Laboratory Tendencies



Serum Fe


Transferrin Sat.

Iron deficiency anemia






Anemia of chronic disease

WNL to slightly low





WNL to high

Given these limitations, and because iron deficiency is a chronic disorder that is treated with long-term therapy, assessment of iron deficiency and subsequent iron repletion needs is best done when patients are not in the throes of an acute medical event. In fact, several studies show a reasonable correlation between the erythrocyte sedimentation rate (ESR) and ferritin levels. Thus, in both acute and chronic inflammatory states, an elevated ESR suggests that serum ferritin levels might be falsely elevated. Again, if the ferritin result does not correlate well with other clinical and laboratory findings, a bone marrow aspirate can then be considered. cheap cialis canadian pharmacy

When iron therapy is used empirically in patients with less classic “borderline” or “mixed” diagnoses, practitioners can check the reticulocyte count for an early assessment of clinical response. Good responses, which would justify continued therapy, elicit an elevation in the reticulocyte count from a base­line value of less than 2%-3% to 4%-6% during the peak period of one to two weeks after initiation of treatment. In terms of hemoglobin response, an increase of at least 2 g/dl after about three to four weeks is a desirable outcome.

In general, unless patients have an occult blood loss, such as GI microbleeding resulting from nonsteroidal anti-inflammatory drugs (NSAIDs) or diverticula, iron supplementation should not be considered a lifelong necessity. In most patients without a continued underlying blood loss, chronic malab-sorption, or extremely poor dietary status, iron stores should be replete after three to six months of therapy. Ferritin levels reaching at least 50 ng/ml with normalized Wintrobe indices (mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration) should imply full iron storage repletion and, therefore, an appropriate endpoint for iron supplementation.


Ferrous sulfate tablets are the most commonly used formulation for oral iron supplementation. Contrary to popular belief, the therapeutic dose of ferrous sulfate might not be a one-size-fits-all 325 mg three times daily. Small-scale studies in young women with moderate anemia have shown that hemoglobin values can be significantly raised with ferrous sulfate 200 mg when given as infrequently as once per week. In addition, most sources suggest a starting dose of ferrous sulfate, from 300 to 325 mg once daily, to be increased slowly according to the patient’s GI tolerance. A slow titration not only allows for acclimation of the GI tract but also can help practitioners determine a minimum therapeutic dose.

Many patients may demonstrate hematological improvement, with less likelihood of intolerance and noncompliance, when they are taking once-daily or twice-daily iron. Administering iron less frequently can have beneficial effects on adherence and tolerance to therapy and might also reduce problems with drug-drug interactions.

Ideally, oral iron should be taken separately from potentially chelating medications by two to three hours. For example, patients receiving twice-daily (Cipro canadian, Bayer) and ferrous sulfate three times a day would need to take iron five times each day. This schedule reduces the likelihood of these medications being taken properly.


The next time that readers are considering prescribing ferrous sulfate 325 mg three times a day, it is of the utmost importance to remember the three tenets of iron supplementation:

1. The appropriate laboratory tests (including ferritin values) should be completed before patients begin iron therapy.

2. For most patients, iron can be initiated at 325 mg once daily and can be increased to patient tolerability and drug effect.

3. Fewer iron administration times (lower doses) might lead to fewer adverse effects, fewer drug-drug interactions, and better patient compliance and may still improve the patient’s overall condition.