Pathogenesis and management of iron toxicity in thalassemia.
In thalassemia major, iron overload is the joint outcome of multiple blood transfusions and an inappropriately increased iron absorption associated with ineffective erythropoiesis. Threshold values for iron toxicity are a liver iron concentration exceeding 440 mmoles/g dry weight, serum ferritin >2500 ng/mL, DFO urinary iron excretion >20 mg/day, and transferrin saturation >75%. The outpouring of catabolic iron that exceeds the iron-carrying capacity of transferrin results in the emergence of non-transferrin-bound iron (NTBI). NTBI is cleared preferentially by the liver and myocardium at a rate exceeding 200 times that of transferrin iron. NTBI catalyzes the formation of free radicals, resulting in oxidative stress and damage to mitochondria, lysosomes, lipid membranes, proteins, and DNA. The long-term consequences of iron toxicity, including cirrhosis, myocardiopathy, and endocrine disorders, are preventable and mostly reversible by effective iron chelation therapy. Recent technologic advances in the documentation of organ-specific siderosis and the improved efficiency of iron chelating programs resulted in a spectacular improvement in the prevention of iron-induced end-organ failure and improved survival in thalassemic patients.
Hershko
Chaim
C
Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel. hershko@szmc.org.il
D001565:Benzoates / Q000737:chemistry / Q000627:therapeutic use; D000077588:Deferasirox; D000077543:Deferiprone; D003676:Deferoxamine / Q000737:chemistry / Q000627:therapeutic use; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000633:toxicity; D007502:Iron Chelating Agents / Q000737:chemistry / Q000627:therapeutic use*; D019190:Iron Overload / Q000097:blood / Q000188:drug therapy* / Q000209:etiology*; D008958:Models, Molecular; D011728:Pyridones / Q000737:chemistry / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013789:Thalassemia / Q000097:blood / Q000150:complications*; D014168:Transferrin / Q000378:metabolism; D065227:Transfusion Reaction; D014230:Triazoles / Q000737:chemistry / Q000627:therapeutic use
D001565:Benzoates; D007502:Iron Chelating Agents; D011728:Pyridones; D017382:Reactive Oxygen Species; D014168:Transferrin; D014230:Triazoles; D000077543:Deferiprone; D007501:Iron; D003676:Deferoxamine; D000077588:Deferasirox