Albertine Donker

General Introduction 33 1 to improve the anemia. To our knowledge, no guidelines are available addressing the route of iron administration, the optimal dose and dosing intervals, taking into account the benefits and possible side effects of oral versus parenteral iron. On one hand, oral iron supplements may result in unabsorbed iron entering the colon causing unwanted side effects on the intestinal host-microbiota interface. 124,125 On the other hand, excess of iron due to parenteral iron treatment will result in iron accumulation in the macrophages of especially the liver and the spleen because of the inappropriately high serum hepcidin levels. This predominantly RES iron storage is also characteristic for patients with loss of function variants in SLC40A1 encoding FPN, 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 are associated with iron accumulation in the parenchymal cells, as the hepatocytes, which may result in liver cirrhosis and hepatocellular carcinoma. Therefore, parenchymal iron loading is considered more harmful than RES iron loading. 126-128 However, accumulation in the RES iron has implications for multiple aspects of macrophage antimicrobial activity. At one hand intracellular iron can be used to support the activity of hemoproteins that exert cytotoxic effects on pathogens. On the other hand, intracellular iron down-regulates the transcription of NOS that is required as a toxic defense against infectious microorganisms. 14,129 Therefore, one might argue that increased levels of RES iron may impair the cytotoxic response of the macrophage against pathogens and promote the survival of intracellular microbes as Salmonellla, Mycobacteria and Legionalla. 88 Moreover, recent data suggest that iron loading of the RES might exacerbate the progression of atherosclerosis by inducing inflammation and enhancing the glycolysis inside the macrophages. 130 Until now, no data exist on these possible side effects of parenteral iron treatment in IRIDA patients but restraint use of intravenous iron supplementation seems justified because of the above-mentioned possible risks of intracellular infections and progression of atherosclerosis. X-linked sideroblastic anemia due to ALAS2 defects might result in severe systemic iron loading even in un-transfused patients XLSA is the most common inherited form of sideroblastic anemia (SA) and is associated with several mutations in the erythroid specific ALAS2 gene, which is the first and rate limiting step of heme biosynthesis. 54,131-133 Also defects in an