Health Concerns

Hemochromatosis

Emerging Therapies

The evolution of the therapeutic treatment for iron overload has been slow. Almost a hundred years passed between the first description of hemochromatosis in 1889 and the establishment of phlebotomy as a treatment; only recently have more precise metabolic and genetic mechanisms of iron overload been elucidated (Pietrangelo 2010).

Iron chelating agent development. There appears to be increasing interest in the development of safer iron chelators with enhanced iron-clearing activity (Zhou 2011). High molecular weight derivatives of desferoxamine, attached to natural or synthetic fibers, retain the iron-binding activity of the classic drug, while offering reduced toxicity and longer time in circulation, thus overcoming some of the shortcomings of desferoxamine alone (Zhou 2011). A new oral chelator (FBS0701) is currently in clinical trials. It has an activity similar to the FDA approved desferasirox, but with a significantly better safety profile (especially for kidney function) (Neufeld 2012). Restoring iron regulatory function through the administration of transferrin, hepcidin, or modified hepcidin molecules (minihepcidin) is also being explored as a potential therapy (Preza 2011; Fleming 2012).

Erythrocytapheresis. Erythrocytapheresis, selective removal of red blood cells from blood while preserving blood volume, has been investigated as an alternative to conventional phlebotomy (Rombout-Sestrienkova 2012). Erythrocytapheresis can remove more red blood cells per procedure (achieving desired reductions in serum ferritin in fewer procedures), with no significant differences in cost, quality of life, or frequency of adverse events (Rombout-Sestrienkova 2012). However, it may demonstrate some of the same drawbacks as phlebotomy (e.g., lowering hepcidin levels).

Bone marrow transplantation and novel stem cell therapies. Understanding genetic iron regulatory mechanisms may allow practitioners another therapeutic direction to address iron overload. Restoration of functional iron regulatory genes in patients with hereditary iron dysregulation may prove a viable treatment. Bone marrow transplantation has already proven to be an effective approach for treating young patients with β-thalassemia. In a survey of 115 transplant procedure patients between 1983 and 2006, 89% (103) survived to an average 15 year follow up, with 96% (99) of those survivors no longer requiring blood transfusions (Di Bartolomeo 2008). Stem cells from bone marrow may also be used to reconstitute iron regulation elsewhere in the body. When type I hemochromatotic mice (containing 2 mutant copies of the HFE gene) were transplanted with bone marrow from healthy donor mice, donor stem cells were detected in the liver (constituting 11% of total liver cells) and intestine after 6 months. In both cases, the stem cells had transformed (differentiated) into cell types appropriate for those organs (liver hepatocytes and intestinal myofibroblasts), partially restored the expression of iron regulatory genes (including HFE), and reduced iron content in these tissues compared to control animals (Morán-Jiménez 2008).