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Z. Ioav Cabantchik, William Breuer and Eitan Fibach Hadassah-Hebrew University Medical Centre, Jerusalem, Israel PATHOPHYSIOLOGY OF IRON OVERLOAD Symposium 6, 11th International Conference on Thalassaemia & Haemoglobinopathies Iron overload is a pathophysiological condition of excessive systemic iron accumulation, characterized by the appearance of redox-active iron forms in extracellular fluids and toxic levels of iron in specific tissues and cell types. Among the various pathologies leading to iron overload are impaired functioning of humoral factors (hepcidin), mutations in genes of cell iron metabolism (HFE, ferroportin, hemojuvelin), or a combination of these together with the massive intake of iron via repeated transfusions (thalassemia). In hereditary haemochromatosis and transfusion-dependent anaemias, the continual influx iron into the circulation ultimately surpasses the transferriniron-binding-capacity of plasma, leading to the formation of labile plasma iron (LPI) (a labile component of non-transferrin-bound iron=NTBI). This form of iron may gain access to cells opportunistically, via pathways for uptake of other metals (possibly calcium channels) or adsorptive endocytosis, leading to increased levels of cytosolic labile (redox-active) cell iron (LCI). The participation of LCI in generating reactive oxygen species is a key factor leading to compromised functional integrity of key organs such as the liver, heart and endocrine tissues. The goal of iron chelation are to confer protection from constantly re-emerging LPI and relief from tissue iron overload by removing accumulated cell iron while avoiding overchelation and damage to essential functions. In chronic iron overload, it might take months to safety reduce body iron levels, because at any given time only a small proportion of body iron is labile (LPI or LCI) and hence chelatable. Systematic monitoring of labile iron forms appearing in body fluids (LPI) and/or in circulating cells (LCI) of iron overloaded patients has provided an analytical platform for assessing the adequacy of chelation treatment and the screening of chelation efficiency in clinical and experimental settings. Supported by the Israel Science Foundation via the Israel Academy of Sciences, Novartis Pharma (Switzerland), and Apopharma (Canada).