Led by researchers at Weill Cornell Medical College in New York City, an international group of scientists has pinpointed a specific genetic relationship as the cause of dangerous iron overload in persons with a form of the inherited blood disease, beta-thalassemia.
"Iron overload remains the biggest threat to the health of patients with thalassemia," says the study's senior author Dr. Stefano Rivella, assistant professor of genetic medicine in pediatrics at Weill Cornell Medical College. "Our discovery that ferroportin levels play a role in the problem could lead to better treatment."
"We discovered that proteins controlling iron intake -- such as hepcidin (Hamp1), a key signaler of body iron levels and controller of ferroportin (Fpn1), an iron-transporting molecule active in the gut -- are out of balance in the milder form of the disease, beta-thalassemia intermedia. In this paradigm, the body allows too much iron to enter the body through the intestine, boosting iron to unhealthy levels," continues Dr. Rivella.
The team also uncovered important, unsuspected differences in the distribution of iron in tissues between beta-thalassemia intermedia and the more serious form of the disease, called beta-thalassemia major.
The findings are being published today (Feb. 13) in the online edition of Blood.
Beta-thalassemia is one of the most common inherited forms of chronic anemia, with incidence highest in Southeast Asia, the Middle East and Africa. The U.S. National Institutes of Health estimates that approximately 1,000 Americans have beta-thalassemia.
The disease is caused by mutations in the beta-globin gene, which governs the production of hemoglobin.
"Almost 200 different mutations can occur in the beta-globin gene, so the severity of the illness varies widely," Dr. Rivella explains. "Some patients with the milder intermedia form of the disease may not need regular blood transfusions, but patients with beta-thalassemia must have them to sustain life. The iron loading in thalassemia depends on the volume of blood transfused and the amount accumulated from gut absorption. Gut absorption is particularly important in thalassemia intermedia, where no, or irregular, transfusions are given. In thalassemia major, increased absorption is inversely proportional to the mean post-transfusional hemoglobin."
Too much iron comes with a price, however: iron overload of the body's tissues.
"In fact, this excess of iron is the cause of many serious complications and can even prove fatal. Some of the organs mot severely affected are the liver, the heart and the endocrine glands -- leading to liver fibrosis, cirrhosis and cancer; heart failure; growth impairment; diabetes; and osteoporosis," Dr. Rivella says. For that reason, patients must undergo chelation therapy, a treatment aimed at draining excess iron from tissues.
For years, people assumed that the iron overload seen in beta-thalassemia was due to transfusions alone. But experts began to notice that even patients with beta-thalassemia intermedia, who did not undergo transfusions, had higher-than-average iron stores. (In fact, studies in patients with the intermedia form of the disease found that they had rates of iron uptake in the gut that were three to four times normal.)
"Obviously, there is also something about the disease itself that encourages excessive iron uptake," according to lead researcher Sara Gardenghi, a post-doctoral fellow in Dr. Rivella's lab.
To help unravel that mystery, Weill Cornell researchers, including Dr. Patricia J. Giardina and Dr. Robert W. Grady -- along with colleagues at Oporto University in Portugal, Tel-Aviv University and the Hebrew University in Israel, and Children's Hospital and Harvard Medical School in Boston -- investigated iron overload, using sophisticated, genetically engineered mouse models of beta-thalassemia. The first-ever mouse model for beta-thalassemia major was, in fact, developed by Dr. Rivella when he worked at Memorial Sloan-Kettering Cancer Center in Dr. Michel Sadelain's laboratory.
"Our prior studies had already revealed that Hamp1 -- a gene regulating expression of a signaling molecule called hepcidin -- had a role to play in boosting iron levels in beta-thalassemia," Dr. Rivella says. "Essentially, hepcidin is a ‘sensor' molecule present in the blood that tells the intestine, ‘OK, we've had enough iron today, it's time to slow absorption.'"