Albertine Donker

Chapter 9 322 resulting in iron release by the RES and iron accumulation in the parenchymal cells, as the hepatocytes. While parenchymal iron overload may result in liver cirrhosis and hepatocellular carcinoma, this form of iron loading is considered more harmful than RES iron loading. 96-98 However, increased levels of RES iron may impair the cytotoxic response of themacrophage against pathogens and promote the survival of intracellular microbes as Salmonella, Mycobacteria and Legionalla. 99-101 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, although the evidence is not unambigious. 102,103 For these reasons, caution should be exercised when using chronic intravenous iron in IRIDA patients, in our opinion. Sincemacrophages in the human body are predominantly located in the spleen and to a lesser extent in the liver, we suggest that the application of MRI of both the liver and spleen might be helpful inmonitoring iron loading of the RES in IRIDA patients in the future. 104-106 Wewould expect more IO in the spleen than in the liver in these patients, while we anticipate the opposite in patients with mainly parenchymal iron loading due to for example hereditary hemochromatosis. The feasibility of this approach still needs exploration. A potential technical constraint might be the sensitivity of the current MRI scans to discern (minor) differences of iron loading between the liver and the spleen. Noteworthy, others and we observed that some IRIDA patients to a certain extent respond to prolonged oral iron supplementation, with or without the addition of vitamin C, despite a severe TMPRSS6 genotype. 2,3,107 Of note, this chronic oral iron supplements might result in unabsorbed iron entering the colon, causing unwanted side effects on the intestinal host-microbiota interface, 108,109 although in the future this problem might be overcome by the administration of liposomal iron or nano- compound iron, both new generations of oral iron with a high gastrointestinal absorption and bioavailability. 110-115 The benefits of these types or oral iron need further exploration in IRIDA patients. Taking into account the possible side effects of both parenteral en enteral iron supplementation, clinical studies are warranted in IRIDA patients, assessing the benefits of iron administration on Hb but also on exercise tolerance and thyroid function, against the possible side effects regarding infections with intracellular pathogens, atherosclerosis, or dysbiosis of the gut microbiota, dependent on the route of administration and dosing scheme.