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Discovery
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Christoph Eberle

Not Every Blood Donation is Voluntary

A rare form of excessive iron storage caused by pathogenic mutations can wreak havoc with red blood cell formation

Hoping to cure various diseases, ancient physicians often resorted to bloodletting. It was as easy as essential in their practice to treat the sick and stemmed from the belief of balancing the body’s humours to regain health. Though in many cases it was without the desired outcome, a few patients could only be helped by occasional bloodletting to prevent their condition from worsening. Worldwide around 200 cases are now described in the medical literature, in which ferroportin disease (FD) has been diagnosed.

Also known as type 4 hereditary hemochromatosis (HH), ferroportin disease is a rare form of excessive iron storage caused by various pathogenic mutations in the SLC40A1 gene and inherited in an autosomal dominant pattern. This gene’s product, ferroportin-1 (FPN1), exports nonheme iron to the circulation. Essential to complete red blood cell formation, humans can uptake iron only through nutrition; once absorbed in the intestine, it becomes a precious component for metabolism, and as such most of it gets scavenged from red blood cells that are discarded naturally. To regulate physiological iron levels, hepcidin binds to ferroportin-1, resulting in deposits of this metal in body cells, mostly enterocytes, hepatocytes and macrophages.

Ferroportin-1 coding gene variants detected in patients had been used to classify two disease types, though clinical symptoms can vary greatly complicating differential diagnosis (see figure below.) Either mutant ferroportin-1 loses its iron-transporting capacity linked to the classical type A, or its resistance to hepcidin develops into the non-classical type B, in which iron constantly enters the blood stream.

Ferroportin infographic -- rare disease causes iron deficiency blood letting treatment

 

Accordingly, genetic testing is needed to rule in a suspected diagnosis. If confirmed, those patients get their individual symptoms treated as intervention is warranted. The disease severity depends on the disease type with type B corresponding with more complications. Mild cases may only require long-term monitoring, whereas liver damage from cirrhosis to carcinoma can progress with severe forms. Other symptoms include heart arrhythmias, anemia, joint pain and diabetes. Current treatments reduce potentially toxic serum iron levels either by preventative phlebotomy or by chelating drugs like Deferoxamine, which are also utilized for similar iron overload disorders. Unlike men women depend less on bloodletting due to menstruation.

At present the www.clinicaltrial.gov registry only lists one study investigating an improvement to the differential diagnosis of ferroportin disease; there are no novel therapeutic modalities. Theoretically the latter one may be straightforward to put to the test, given that biomarkers measuring physiological iron storage (ferritin), transport and delivery (ferritin) are well established in the clinic. To correct gene defects causing rare disorders, the drug development industry keeps exploring cutting edge technologies to bring targeted cell and gene therapies. Hope rests on this emerging arsenal to one day make a difference for ferroportin disease patients and for the more than 90% of other known rare disorders that lack cures and awareness still. As with every arsenal may this latest one be utilized wisely.