Albertine Donker

IRIDA: a Heterogeneous Disease 161 4 and dosing intervals of intravenous iron in IRIDA patients. Kitsaki et al 40 investigated hepcidin and other iron parameters in hemodialysis patients, characterized by elevated hepcidin levels 41 treated with intravenous iron. They observed a rapid, small but significant elevation and subsequent decrease to baseline level of serum hepcidin after administration of intravenous iron, as also seen in patient 14 ( Supplemental Table 9 ). This increase of hepcidin inhibits the efflux of iron from the macrophages to the serum, thereby decreasing the amount of iron supply to transferrin and erythroblasts. This suggests that small doses of intravenous iron with short intervals resulting in only slightly elevated hepcidin levels might be superior to large doses with large intervals with regards to increasing the serum levels of ferric- transferrin available for erythropoiesis and minimizing substantial iron sequestration of the reticulo-endothelial system (RES) (and associated elevation of ferritin levels). 40 These observations need confirmation in IRIDA patients. Since IRIDA is a disease with inappropriately high serumhepcidin levels and a low TSAT, excess of iron due to intravenous iron treatment will be stored in the RES of especially the liver and the spleen. This predominantly RES iron storage is also characteristic for patients with loss of function variants in SLC40A1, but differs from observations in patients with hereditary hemochromatosis due to variants in HFE, TfR2, HJV and HAMP and gain of function variants in SLC40A1 that is associated with iron accumulation in the parenchymal cells, such as the hepatocytes, which can be harmful and of more concern than iron stored in the RES. 42-44 However, long-term consequences of intravenous iron treatment on for instance the occurrence of infections and tissue damage have not been established yet in IRIDA patients. Therefore, to stay on the safe side and based on the case report of Cau 39 and on the clinical course of patient 13, we recommend performing a trial of oral iron in combination with vitamin C in IRIDA patients not responsive to oral iron alone, prior to starting parenteral iron supplementation, in order to use the more natural intestinal function of the intestine to prevent toxic iron loading. In addition, since the clinical phenotype of an IRIDA patient might evolve in time from unresponsiveness to partially responsiveness to oral iron, 45,46 we suggest to critically assess whether repeated administration of intravnous iron is required, and to reassess responsiveness to oral iron and vitamin C. Five out of our 21 patients have a Mediterranean origin. In addition, 40 out of 61 bi- allelic and six out of 10 mono-allelic patients described to date are from thalassemia or malaria endemic regions. 3,4,7 It is known that especially β-thalassemia, but also