Scientists Discover Novel Cause Of Iron Overload In Thalassemia Disorders
Researchers have discovered a novel cause of iron overload in patients with thalassemia, a genetic blood disorder that causes anemia.
According to the study, thalassemia patients overproduce a protein called GDF15, which suppresses the production of a liver protein, hepcidin, which in turn leads to an increase in the uptake of dietary iron in the gut. This finding has implications for iron metabolism in other diseases, including cancer, and may contribute to the future development of therapies for thalassemia. The study, led by researchers at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH, appears online August 26, 2007, as an Advanced Online Publication in the journal, Nature Medicine.
Thalassemia is an inherited blood disease characterized by the under production of normal hemoglobin, the oxygen-carrying protein in red blood cells. People with severe forms of thalassemia often suffer from anemia, a condition in which the body tissues do not get enough oxygen from the blood, and often require blood transfusions. Blood transfusions contribute to iron overload in people with thalassemia, but these people also suffer from iron overload independent of blood transfusions. Excess iron causes damage to many organs including the heart and liver, and diabetes can develop in severe cases. Patients with thalassemia often require treatment to remove the excess iron to prevent tissue damage.
"The treatment of iron overload in patients with thalassemia is particularly difficult because of their anemia," says Jeffery L. Miller, M.D., chief of the Molecular Genomics and Therapeutics Section of the Molecular Medicine Branch, Division of Intramural Research, NIDDK, and last author of the study. "So we have been searching for the mechanism responsible for iron overload in thalassemia in hopes of finding new therapies for those patients."
Thalassemia patients absorb too much iron from food due to abnormally low levels of a small peptide, called hepcidin, which regulates iron uptake from the gut. People with thalassemia should produce hepcidin at high levels. Instead, these patients have reduced levels of hepcidin. This confounded the authors and led them to ask if the low levels of hepcidin were somehow caused by the underlying problem in thalassemia -abnormal development of red blood cells.
Red blood cells, also called erythrocytes, are filled with hemoglobin, which transports oxygen throughout the body. Erythrocytes circulate in the blood, but they originate in the bone marrow as erythroblasts and go through several stages of differentiation until they finally leave the bone marrow and enter the blood stream as fully-formed erythrocytes. Previous research has shown that people with thalassemia disorders have elevated numbers of erythroblasts in the bone marrow, but have reduced numbers of healthy erythrocytes circulating in the blood. Due to the problems with forming hemoglobin, many erythroblasts never make it into the blood stream as healthy erythrocytes.
"Since erythroblasts need iron to make hemoglobin, we reasoned that the increased number of erythroblasts in thalassemia may send stronger messages to the liver to suppress hepcidin and thereby absorb more iron even in the condition of iron overload,