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.'"
One of the novelties of this paper is the point that iron absorption is regulated by three factors: the degree of impaired red-blood-cell production called ineffective erythropoiesis, the degree of organ iron overload, and the expression of Fpn1 and Hamp1. In this study, Dr. Rivella's team found that the impaired red-blood-cell production that occurs in beta-thalassemia lowers Hamp1 expression, reducing hepcidin activity and thereby boosting iron uptake. This was true for mice engineered to have the more severe (major) form of beta-thalassemia, and also for young mice with the milder (intermedia) form of the disease.
"However, as mice with beta-thalassemia intermedia got older, another gene began to play a key role in iron overload," Dr. Rivella says. "That gene was Fpn1, which controls the expression of another important molecule, ferroportin."
Ferroportin is the key molecular transporter for iron absorbed from food via the intestine. "Contrary to what happens in major disease, we found that Hamp1 expression actually rises in adult mice with beta-thalassemia intermedia," Dr. Rivella says. "But that doesn't mean iron absorption falls. Why? Because a rise in Hamp1 is accompanied by a concurrent rise in Fpn1 expression."
That's a whole new paradigm for chronic iron overload in patients with the intermedia form of the beta-thalassemia, the researchers say. "It appears that even though Hamp1 is trying to shut down iron absorption in the gut, a spike in Fpn1 expression is boosting levels of ferroportin, the iron transporter. So the net result is the same: rising iron uptake," Dr. Rivella says.
The finding may be heartening to those treating the disease, however.
"It shows that if we keep doing what we are doing -- modulating hepcidin levels in blood -- we can still manipulate this relationship to get iron absorption under control in both the major and intermedia forms of the illness," Dr. Rivella says. "That's great news."
This study received funding from the Carlo and Micol Schejola Foundation, the Cooley's Anemia Foundation, the Children's Cancer and Blood Foundation, the U.S. National Institutes of Health, the Associazione per la Lotta alla Talassemia di Rovigo (AVLT), Associazione Regionale Sarda per la Lotta Contro la Talassemia e per l'Assistenza dei Talassemici, the Roche Foundation for Anemia Research, and the American Portuguese Biomedical Fund.