Albertine Donker

General Discussion 319 9 might argue that infants are born with sufficient iron stores at birth to overcome the first months of infancy, also in case of an IRIDA due to a pathogenic TMPRSS6 defect. However, in IRIDA patients, iron stores are often sufficient irrespective of age. The main problem is the maldistribution of iron since the high hepcidin levels favor entrapment of iron inside the macrophages. This mechanism plays an even more important role in early life because of the relatively short life span and consequently high turnover of fetal Hb. The occurrence of sufficient iron stores at birth does therefore not sufficiently explain the apparent absence of complaints during the first postnatal months of an IRIDA patient. Interestingly, studies in suckling mice suggest that enterocyte ferroportin is hypo-responsive to hepcidin during infancy. 85 Other mice studies indicate that in the fetus and infant DMT1 and ferroportin are expressed in all areas of the small intestines and colon, in contrast to the situation in adults in whom iron absorption predominantly occurs in the duodenum. 86 These studies indicate that both the sensitivity of ferroportin to degradation by hepcidin and the surface area available to absorb iron are age-dependent, possibly explaining the onset of IRIDA symptoms only a couple of months after birth in the majority of patients. According to our observations and those of others (reviewed in 1 ), in most patients, especially in whom a bi-allelic TMPRSS6 defect is found, the signs and symptoms of IRIDA, including iron deficiency anemia that is not responsive to oral iron and only partially responsive to parenteral iron, typically persist into early adulthood. Afterwards, the phenotype becomes milder in many IRIDA patients, with declining requirements for (parenteral) iron treatment. One might hypothesize that iron needs of the erythroblasts and/or other iron-demanding tissues decrease with decline of growth in adults. Another explanation might be the increasing TSAT/hepcidin ratio during childhood, as we observed in our reference values study on serum hepcidin values ( Chapter 7 4 ), indicating a changing set point of systemic iron homeostasis, with an increased tendency to absorb and release iron into the circulation with advancing age. As a first step, our own observations regarding this typical course need confirmation, underpinning the importance of longitudinally following IRIDA patients due to TMPRSS6 defects and collecting clinical, biochemical and genetic data in national and international biobanks, as proposed in this chapter.