In the healthy body, there is a balance between iron intake and iron loss. Plasma iron levels are regulated by the hepcidin/ferroportin system. Disturbances in the hepcidin/ferroportin regulatory system cause diseases associated with iron deficiency or iron overload.
In certain diseases, excess iron may result from increased absorption (primary iron storage disease) or from repeated blood transfusions (secondary iron storage disease). Too much iron cannot be compensated by active excretion (e.g. via urine). As a result, the transport and storage capacity for iron is exceeded, and free iron is formed in the blood (NTBI). Some of the NTBI can be converted into labile iron. Redox-reactive labile iron can cross cell membranes in an uncontrolled manner without active transport. If labile iron accumulates in the cells, the antioxidant mechanisms of the cells are overwhelmed and reactive oxygen species (ROS) are subsequently formed. These ROS damage macromolecules such as proteins, DNA and lipids, and consequently organelles such as lysosomes and mitochondria. The damage at the molecular and cellular levels can eventually lead to organ dysfunction. Iron overload thus has a toxic effect in that excess iron is present in an unbound form and causes severe oxidative stress.
Diseases such as hereditary hemochromatosis and chronic transfusion-related anemias such as thalassemias show that iron overload can have multiple consequences (e.g., on the heart, liver, or other organs).
Since the organism has no physiological mechanisms to excrete excess iron, the excess iron must be bound by chelating agents. Chelators form a complex with iron that is excreted biliterally. In this way, iron chelators reduce the amount of labile iron into the normal range and subsequently reduce oxidative stress and its subsequent damage to organs. Maintenance of protection against oxidative stress can only be achieved by continuous iron chelation.
Gattermann N et al. Dtsch Arztebl Int 2021; 118: 847-56; DOI: 10.3238/arztebl.m2021.0290
Onkopedia Guidelines. Beta Thalassämie. DGHO Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie e.V. (Accessed: October 2019).