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Iron Overload
Iron overload is an excess of systemic iron, leading to its progressive accumulation in vital organs (e.g., liver, heart, pancreas, and endocrine organs). When untreated, iron overload increases the risk of liver cirrhosis, heart failure, diabetes mellitus, osteoporosis, hypogonadism, and neurodegenerative symptoms. These potentially fatal complications are preventable by iron depletion therapies.
Iron overload results from pathologically increased intestinal iron absorption or as a side effect of clinical interventions (i.e., recurrent red blood cell [RBC] transfusions and parenteral iron administration to treat anemia).
200 billion RBCs are produced every day requiring ample iron to maintain adequate erythropoiesis. Iron transported in the circulation is mostly used for hemoglobin (Hb) synthesis in RBCs. Iron supply to the bone marrow is largely maintained by iron recycling in reticuloendothelial macrophages, which engulf senescent RBCs, releasing iron back into circulation. Small amounts of iron are absorbed by duodenal enterocytes to replace ordinary iron losses. When iron absorption is uncontrolled or parenteral iron is supplied, a significant iron accumulation may occur, leading to parenchymal iron deposition and overload.
Pathophysiology
Iron overload can be primary, when genetically inherited as disorders of enhanced iron absorption (e.g., hereditary hemochromatosis [HH]), or secondary, when acquired through the administration of recurrent RBC transfusions (e.g., β-thalassemia major). Thus, patients with HH continually absorb iron, despite excess iron stores. Transfusion-requiring β-thalassemia major patients often receive up to 4 RBC units per month and may accumulate 10 g of iron per year, threefold more than total normal body content in a healthy 70-kg male. These two conditions both lead to pathological tissue iron overload.
Because no physiological mechanism exists for active iron excretion in humans, iron absorption and recycling are tightly regulated to maintain iron homeostasis ( Fig. 72.1 ). The peptide hormone hepcidin orchestrates systemic iron flux by binding to the iron exporter ferroportin on the surface of iron-releasing cells (macrophages and enterocytes), blocking cellular iron release into the circulation. Therefore, inherited and acquired disorders that prevent normal hepcidin production result in iron overload.
Hepcidin production is regulated by multiple and opposing signals. (1) Elevated iron stores and inflammation (IL-1, IL-6, activin-B) induce hepcidin to prevent iron overload and deprive invading microorganisms of growth-essential iron, respectively. (2) Conversely, erythropoietic demand and hypoxia suppress hepcidin production, enabling further iron supply for Hb synthesis. Recently, erythroferrone has been identified as a key erythropoietin-responsive erythroid regulator of hepcidin. Additional factors, including GDF15, may also be important.
Insufficiently elevated hepcidin is implicated as a cause of primary and secondary iron overload. Primary iron overload diseases (i.e., HH) result from mutations in hepcidin or its regulators (HFE, HJV, TfR2), leading to insufficient hepcidin production, inappropriately high iron absorption, and iron overload. Secondary iron overload diseases (e.g., transfusion-dependent β-thalassemia major and myelodysplastic syndrome) result in iron overload predominantly from excess iron acquisition through repeated RBC transfusions.
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