Iron-Chelating Therapy

Posted by • January 14th, 2011

The latest article in the Clinical Therapeutics review series, “Iron-Chelating Therapy for Transfusional Iron Overload,” comes from Dr. Gary Brittenham at the Columbia University Medical Center.

Because humans lack any effective means to excrete excess iron, repeated transfusions over time inexorably produce the clinical problem of iron overload. In patients with thalassemia who undergo transfusion from infancy, iron-induced liver disease and endocrine disorders develop during childhood and are almost inevitably followed in adolescence by death from iron-induced cardiomyopathy unless preemptive chelation is introduced.

Clinical Pearls

How does iron accumulation lead to organ dysfunction?

Non-transferrin-bound iron is a heterogeneous assortment of iron complexes that appear to be the major mediators of extrahepatic tissue damage in transfusional iron overload. Non-transferrin-bound plasma iron enters specific cells, particularly hepatocytes, cardiomyocytes, anterior pituitary cells, and pancreatic beta-cells. In these cells, iron accumulation leads to the generation of reactive oxygen species, resulting in cellular dysfunction, apoptosis, and necrosis.

How are the available iron chelators administered?

Deferoxamine is administered subcutaneously or intravenously, usually with a portable pump, for 8 to 10 hours each day, 5 to 7 days per week. Subcutaneous administration is preferred except in patients with severe cardiac iron  deposition, for whom continuous intravenous deferoxamine therapy is recommended. The synthetic chelator deferasirox is well absorbed from the gastrointestinal tract and thus can be administered orally. A third iron chelator, the synthetic oral agent deferiprone is not approved for use in the United States or Canada.

Table 1. Iron-Chelating Agents in Clinical Use.

Morning Report Questions

Q: When should iron-chelating therapy be initiated?

A: Ideally, iron-chelating therapy should be initiated prophylactically, before clinically significant iron accumulation has occurred. Treatment should begin when patients have received 10 to 20 red-cell transfusions. Patients who have already undergone repeated transfusion without sufficient chelation can also be successfully treated, but they may require more intensive regimens.

Q: What is the clinical benefit of iron-chelating therapy?

A: Only one small, randomized trial has compared chelation plus deferoxamine with no therapy; this trial enrolled 20 children with (beta)-thalassemia. After a mean of 5.8 years of treatment with intramuscular deferoxamine, the liver iron concentration was 25.9 mg per gram of liver tissue (dry weight) in the deferoxamine group and 42.2 mg per gram in the control group. At 14 years, one death had occurred in the deferoxamine group and six deaths had occurred in the control group.

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