The Evaluation of Iron Deficiency and Iron Overload

Abstract

Background: In the western world, 10-15% of women of child-bearing age suffer from iron-deficiency anemia. Iron overload due to chronic treatment with blood transfusions or hereditary hemochromatosis is much rarer.

Methods: This review is based on pertinent publications retrieved by a selective search on the pathophysiology, clinical features, and diagnostic evaluation of iron deficiency and iron overload.

Results: The main causes of iron deficiency are malnutrition and blood loss. Its differential diagnosis includes iron-refractory iron deficiency anemia (IRIDA), a rare congenital disease in which the hepcidin level is pathologically elevated, as well as the more common anemia of chronic disease (anemia of chronic inflammation), in which increased amounts of hepcidin are formed under the influence of interleukin-6 and enteric iron uptake is blocked as a result. Iron overload comes about through long-term transfusion treatment or a congenital disturbance of iron metabolism (hemochromatosis). Its diagnostic evaluation is based on clinical and laboratory findings, imaging studies, and specific mutation analyses.

Conclusion: Our improving understanding of the molecular pathophysiology of iron metabolism aids in the evaluation of iron deficiency and iron overload and may in future enable treatment not just with iron supplementation or iron chelation, but also with targeted pharmacological modulation of the hepcidin regulatory system.

Figure 1

Regulation of systemic iron metabolism The amount of available iron (center and right), inflammatory factors (left), the iron required for erythropoiesis (right), and hormones and growth factors control hepcidin expression. Replete iron stores increase the amount of the cytokine BMP6 (bone morphogenetic protein 6), which together with the coreceptor hemojuvelin (HJV) activates the BMP/SMAD signaling pathway. Hepcidin induces the degradation of ferroportin, thus reducing the release of iron from duodenal enterocytes and macrophages of the reticuloendothelial system. In inflammation-related functional iron deficiency, hepcidin expression is increased via the JAK2-STAT3 signaling pathway. As a consequence of iron deficiency anemia, the kidney produces erythropoietin, which increases erythropoiesis. Erythroid progenitor cells continue to produce erythroferron, which inhibits the BMP/SMAD pathway and hepcidin. EPO, erythropoietin; ERFE, erythroferron; FPN, ferroportin; HFE, high Fe (iron); IL6, interleukin 6; JAK, Janus kinase; STAT, signal transducers and activators of transcription; SMAD, small-body-size mothers against decapentaplegic homolog 1; TFR2, transferrin receptor 2; TSAT, transferrin saturation.

Figure 2

Diagnostic algorithm for patients with suspected iron-deficiency anemia ACD, anemia of chronic disease; CRP, C-reactive protein; MCV, mean corpuscular volume; sTfR, soluble transferrin receptor; n, normal

Figure 3

Measuring mean liver iron concentration using magnetic resonance imaging A patient with severe iron overload. As can be seen, the iron is unevenly distributed in the liver, so measuring iron by means of invasive liver biopsy can give unrepresentative findings..