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Iron deficiency in absence of anemia and blood count changes is a common disorder. Since iron is an essential cofactor not only of hemoglobin and myoglobin but also of numerous enzymes fundamental for many biological processes, it is understandable that the spectrum of iron deficiency related symptoms may be complex, severe and difficult to associate with iron deficiency. This often leads to significant diagnostic delays and a multitude of misleading diagnoses and treatments. Therefore, considering a diagnosis of iron deficiency without anemia requires a high degree of alertness. The second step in the diagnostic process, following consideration of the possibility of iron deficiency, is a careful history that covers all potential causes of deficient iron stores since the patient’s birth and beyond combined by the appropriate investigations. The ferritin concentration is key for ascertaining the diagnosis. A ferritin concentration of less than 30 µg/L in a symptomatic individual means iron deficiency, but the patient may be iron deficient with much higher ferritin concentrations. Simultaneous determination of C-reactive protein with ferritin is practically useless. The treating physician should be familiar with the complexity of ferritin determinations and the interpretation of the results. The mainstay of treatment is oral iron but a considerable proportion of patients are intolerant or insufficiently responsive to oral iron and require intravenous iron therapy. The longer the duration of the iron deficiency, the more complicated the treatment and the patient’s recovery may become. For some patients, iron deficiency seems to be a chronic disorder requiring management exceeding 5 years. In 1–5% of patients, particularly those with a duration of iron deficiency in absence of anemia of more than 15–25 years, the restoration of iron stores does not lead to clinical recovery within 5 years of follow-up. Iron deficiency without anemia has a high impact on the well-being and quality of life of the affected individuals and impacts significantly also on society, since the challenges in recognition, diagnosis and treatment of the condition generate costs probably in excess of 100 million euros/5 million inhabitants.
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