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Researchers at the University of Utah School of Medicine (Salt Lake City) and colleagues at the University of California, Los Angeles, may have found a way to make it easier to diagnose anemia related to chronic illness, as well as diseases of iron overload.

According to the researchers, iron balance in the body is regulated by the interaction between a liver-produced hormone called hepcidin and the iron transporting receptor ferroportin. Hepcidin binds to ferroportin resulting in decreased export of iron out of cells. An excess of hepcidin in the blood can cause anemia and a deficiency of hepcidin causes a build-up of iron that is damaging to body organs.

Both anemia and iron overload have various causes, so it is often difficult to distinguish among those causes.

"It is hard to diagnose the anemia of chronic disease," said the study's senior author, Jerry Kaplan, PhD, University of Utah professor of pathology and assistant VP for research at the University of Utah Health Sciences. "Having an assay for hepcidin would make it much easier and it would also help in diagnosing iron overload diseases."

The research is published in the August issue of Cell Metabolism.

The researchers say they have identified the hepcidin-binding domain (HBD), the specific site where hepcidin binds to ferroportin. By placing a synthetic version of that binding site on agarose beads, the researchers developed a rapid, sensitive test, called the HBD assay, for measuring the concentration of active hepcidin in the blood.

According to the researchers, the ability to detect and measure hepcidin has important implications for the diagnosis of anemias and iron overload disorders related to hepcidin. Anemia is a deficiency of the oxygen-carrying molecules inside red blood cells, which can be caused by iron deficiency, vitamin B12 or folate deficiency, or chronic illnesses. Anemia of chronic disease, or anemia of inflammation, is thought to be related to abnormally high levels of hepcidin, the researchers noted.

The most common human disorder of iron overload is hereditary hemochromatosis, which leads to abnormal accumulation of iron in the liver, heart, skin, and other organs. The researchers said that some types of hereditary hemochromatosis are associated with inappropriately low levels of hepcidin in the blood.

The HBD assay developed by Kaplan and his colleagues detects biologically active hepcidin. The test is designed to readily detect variations in hepcidin levels in the blood due to mutations in genes that are known to affect hepcidin levels, as well as mutations in other genes involved in iron metabolism. It can also measure hepcidin concentration in response to inflammation, according to the study.

The researchers said the new test would help doctors distinguish anemias and diseases of iron metabolism that arise from abnormalities in hepcidin from those that have other causes.

Hepcidin was first reported for its role in the body's defense against bacterial and fungal infections. Current scientific evidence, however, suggests that hepcidin's primary role in the body is to regulate iron balance, the researchers said.

Kaplan and his colleagues found that even very small changes to the composition of the HBD had significant effects on the ability of the binding site to bind hepcidin. They also discovered that hepcidin's ability to bind to the HBD decreases at temperatures below the normal human body temperature of 37 degrees Celsius due to structural changes in the hepcidin molecule at lower temperatures. This change in structure also affected the ability of hepcidin to bind to bacteria. This raised questions about the effect of low temperatures on iron metabolism and antibacterial activity.

The hepcidin-binding domain of fish is nearly identical to the human HBD. The researchers looked at hepcidin in fish such as the brown trout from the Middle Provo River, which routinely live in very cold waters. Most mammals have only one hepcidin gene, but fish have multiple hepcidin genes that encode hepcidin molecules of different lengths. In the study, Kaplan and his colleagues found that the fish hepcidin, which is the same length as human hepcidin, was able to bind to the HBD at temperatures as low as 4-degrees Celsius but had very little antibacterial activity at both 4 degrees Celsius and 37 degrees Celsius. According to the study, this discovery provides insight into the evolution of hepcidin among vertebrates. Human hepcidin has both iron- and bacteria-related activities, while fish hepcidin genes evolved to separate these functions.

Due to the similarity of the HBD among vertebrates, Kaplan said the test could be used to measure hepcidin in the blood of all vertebrates.

According to the National Heart, Lung, and Blood Institute, women and people with chronic diseases are at greater risk for anemia. Usually, the first test used to diagnose anemia is a complete blood count (CBC), which tells a number of things about a persons blood including the hemoglobin level and the hematocrit level, which measures how much of the blood is made up of red blood cells.

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