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.