Iron represents a paradox for living systems by being essential for a wide variety of metabolic processes, but also having the potential to cause deleterious effects. To ensure that there is adequate iron for basal functions but no free iron that could promote formation of reactive oxygen species, iron homeostasis is regulated at both the cellular and systemic level. The hormone hepcidin, is the master regulator of iron absorption and distribution to tissues. Hereditary Hemochromatosis and Iron Refractory Iron Deficiency Anemia are autosomal recessive diseases characterized by inappropriate levels of hepcidin that leads to iron dyshomeostasis. In β-thalassemia, tissue hypoxia and erythropoiesis downregulates the expression of hepcidin leading to secondary iron dyshomeostasis. Chronic anemia and iron overload are the main complications of β-thalassemic patients. β-thalassemia intermedia is clinically heterogeneous. Generally, the mildest form of anemia do not require a steady transfusion treatment. Thalassemia major patients are regularly transfused to improve haemoglobin levels, suppress bone marrow activity and reduce gastrointestinal iron absorption. Redox imbalance and genotoxic damage iron-induced are commonly observed in β thalassaemic patients. Were previously reported that anemia-induced hypoxia is an additional source of oxidative damage that has been underestimated in thalassemia. A better knowledge on the behaviour of iron homeostasis parameters and its relationship with oxidative imbalance and genotoxicity may allow a better understanding of thalassemia, a pathology in which hypoxia, erythropoiesis, iron overload and inflammation coexist. Based on these findings, I aimed herein to investigate, the pathophysiological mechanisms of iron dyshomeostasis in transfused and untransfused thalassaemic patients by assesing hepcidin and co-modulatory factors, such us HIF1α and Glut 1, soluble transferrin receptor (sTFR), soluble hemojuvelin (sHJV), GDF15 and erytroferrone (ERFE); the role of anemia in oxidative and genotoxic damage in regularly transfused thalassaemic patients in relation to blood transfusion regimen and iron chelation therapy to improve the effectiveness of therapeutic management; the genotoxic/cytotoxic effect of thalassemia complications and their drug treatments, in addition to universally know oxidative damage induced by iron overload, in politransfused patients.
|Titolo:||Oxidative damage and iron dyshomeostasis in thalassemic patients|
|Data di pubblicazione:||19-giu-2018|
|Appare nelle tipologie:||Tesi di dottorato|