Abstract
Iron is essential for life because it is indispensable for several biological reactions, such as oxygen transport, DNA synthesis, and cell proliferation. Over the past few years, our understanding of iron metabolism and its regulation has changed dramatically. New disorders of iron metabolism have emerged, and the role of iron as a cofactor in other disorders has begun to be recognized. The study of genetic conditions such as hemochromatosis and iron-refractory iron deficiency anemia (IRIDA) has provided crucial insights into the molecular mechanisms controlling iron homeostasis. In the future, these advances may be exploited to improve treatment of both genetic and acquired iron disorders. IRIDA is caused by mutations in TMPRSS6, the gene encoding matriptase-2, which downregulates hepcidin expression under conditions of iron deficiency. The typical features of this disorder are hypochromic, microcytic anemia with a very low mean corpuscular volume of erythrocytes, low transferrin saturation, no (or inadequate) response to oral iron, and only a partial response to parenteral iron. In contrast to classic iron deficiency anemia, serum ferritin levels are usually low-normal, and serum or urinary hepcidin levels are inappropriately high for the degree of anemia. Although the number of cases reported thus far in the literature does not exceed 100, this disorder is considered the most common of the “atypical” microcytic anemias. The aim of this review is to share the current knowledge on IRIDA and increase awareness in this field.
Highlights
Iron deficiency anemia (IDA) has been described for centuries
The prevalence of Iron-refractory iron deficiency anemia (IRIDA) seems to be more frequent than predicted and more heterogeneous than previously thought, indicating that the “classical” severe homozygous form may be just one of several forms of the disorder, with some cases of mild microcytic anemia belonging to this disorder
A few points may help in a “classical” IRIDA diagnosis in the clinical practice of hematologists and pediatricians: if present, the familial nature of the disease; the presence of atypical iron parameters not in accordance with classical IDA; and the absence of the expected hematologic response after the use of oral iron
Summary
Iron deficiency anemia (IDA) has been described for centuries. As a very frequent disorder, IDA constitutes a serious public health problem. It usually develops due to low intake of dietary iron; in the presence of hypochromic, microcytic anemia, it is the first underlying cause to be considered. Some inherited conditions with variable clinical characteristics may result in microcytic anemia by causing defective iron metabolism. Iron-refractory iron deficiency anemia (IRIDA; OMIM #206200), which was described only recently, is one such disorder [1]. Iron-refractory iron deficiency anemi develops due to mutations in TMPRSS6, the gene encoding matriptase-2. Its typical mode of inheritance is autosomal recessive, and IRIDA is characterized clinically by hypochromic, microcytic anemia with an inadequate response to oral iron and an only partial response to parenteral iron [1,2]
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