Albertine Donker

Chapter 9 324 CONCLUDING REMARKS AND SUMMARY OF FUTURE PERSPECTIVES Unexplained microcytic anemias might be caused by defects in genes involved in iron metabolism or heme synthesis. An important message of this thesis is that these genetic anemias need attention from both clinicians and researchers. Awareness among clinicians for these rare, heterogeneous disorders will result in a timely diagnosis, thereby avoiding unnecessary long diagnostic processes and allowing the initiation of adequate treatment modalities. Hopefully this will ultimately result in the prevention of both (severe) iron deficiency but also iron loading and its possibly life-long sequelae. As explained in this thesis, this iron loading concerns two different patterns, which might overlap. First, low hepcidin expression followed by increased intestinal iron absorption and iron release by the macrophages results in parenchymal iron excess. Second, hepcidin overexpression with subsequent iron entrapment in the macrophages, particularly after the administration of parenteral iron, leads to RES iron excess. The first mentioned pathophysiologic mechanism is thought to play a role in XLSA, underpinning the importance of a prompt diagnosis in order to prevent severe complications as liver cirrhosis or hepatocellular carcinoma. The second mentioned pathophysiologic mechanism is an important factor in the development of iron loading of the macrophages in IRIDA patients, especially after the administration of intravenous iron supplementation. Noteworthy, there are, although not equivocal, concerns about the association between RES iron loading and atherosclerosis. The results of the retrospective and observational studies in this thesis provide clinicians with essential information and practical clinical tools, which facilitate the diagnostic and therapeutic process regarding both children and adults with microcytic anemias due to a genetic disorder of iron metabolism or heme synthesis. However, lots of work needs to be done, both on the preclinical and clinical level, as we discussed in this chapter and as we will summarize in the next paragraphs. First, collaboration on the national and international level by expanding networks and biobanks is an important precondition because of the rarity of the disorders addressed in this thesis. Accompanying ethical, legal and social issues that nowadays hamper the process of biobanking need to be addressed urgently in our opinion. A second prerequisite is the establishment of standardized serum hepcidin