What iron overload?
Iron overload, also known as hemochromatosis or iron overload disorder, is a condition characterized by excessive accumulation of iron in the body. Iron overload can occur due to various reasons, including increased dietary intake of iron, genetic disorders affecting iron metabolism, or chronic transfusion therapy.
There are two main types of iron overload:
- Primary Hemochromatosis: This type of iron overload is primarily caused by genetic mutations that affect iron metabolism. The most common form of primary hemochromatosis is hereditary hemochromatosis (HH), which is typically inherited in an autosomal recessive pattern. Mutations in genes such as HFE, HJV, HAMP, and TFR2 can lead to impaired regulation of iron absorption and excessive iron accumulation in tissues, particularly in the liver, pancreas, heart, and other organs. Without proper treatment, primary hemochromatosis can lead to organ damage, cirrhosis, diabetes, heart failure, and other complications.
- Secondary Iron Overload: This type of iron overload occurs secondary to other medical conditions or treatments that increase iron absorption or deposition in the body. Secondary iron overload can result from chronic liver disease (such as alcoholic liver disease or nonalcoholic fatty liver disease), chronic transfusion therapy for conditions such as thalassemia or sickle cell disease, or excessive dietary intake of iron supplements. In these cases, iron overload develops as a consequence of underlying medical conditions or treatments rather than genetic predisposition.
What is the relationship between iron overload and oxidative stress?
The relationship between iron overload and oxidative stress is tightly linked, as excessive accumulation of iron in the body can lead to increased production of reactive oxygen species (ROS) and oxidative damage. Several mechanisms contribute to the generation of oxidative stress in the context of iron overload:
- Fenton Reaction: Iron overload provides a surplus of iron ions in the body, which can catalyze the Fenton reaction. In the Fenton reaction, iron reacts with hydrogen peroxide (H2O2) to produce highly reactive hydroxyl radicals (•OH). Hydroxyl radicals are potent oxidizing agents that can damage cellular components, including lipids, proteins, and DNA, leading to oxidative stress and tissue injury.
- Haber-Weiss Reaction: In addition to the Fenton reaction, iron can also participate in the Haber-Weiss reaction, which involves the conversion of superoxide anions (O2•−) to hydrogen peroxide in the presence of iron ions. Hydrogen peroxide generated through the Haber-Weiss reaction can further contribute to oxidative stress by promoting the formation of hydroxyl radicals via the Fenton reaction.
- Mitochondrial Dysfunction: Excess iron accumulation in mitochondria can impair mitochondrial function and disrupt oxidative metabolism, leading to increased production of ROS within the mitochondria. Mitochondria are a major source of ROS production in cells, and mitochondrial dysfunction can exacerbate oxidative stress and cellular damage in the context of iron overload.
- Inflammatory Response: Iron overload can trigger an inflammatory response, characterized by the activation of immune cells and the release of pro-inflammatory cytokines. Inflammatory processes generate ROS as byproducts of immune cell activation and respiratory burst reactions. Excessive ROS production during inflammation overwhelms antioxidant defenses and leads to oxidative stress, further propagating inflammation and tissue injury.
- Lipid Peroxidation: ROS generated in the presence of excess iron can react with polyunsaturated fatty acids in cell membranes, leading to lipid peroxidation. Lipid peroxidation results in the formation of reactive lipid peroxides and other cytotoxic products, which can disrupt membrane integrity and function, exacerbating oxidative stress and cellular damage.
Overall, iron overload promotes oxidative stress through multiple mechanisms, including the Fenton and Haber-Weiss reactions, mitochondrial dysfunction, inflammation, and lipid peroxidation.