Key site in iron metabolism aids in diagnosing anemia of chronic disease

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Key site in iron metabolism aids in diagnosing anemia of chronic

disease

Public release date: 5-Aug-2008

EurekAlert - Washington,DC*

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University of Utah Health Sciences

http://www.eurekalert.org/pub_releases/2008-08/uouh-ksi080108.php

Rapid test for hepcidin can also help to distinguish causes of iron

overload

SALT LAKE CITY – University of Utah School of Medicine researchers

have developed a new tool that facilitates diagnosis of anemia

related to chronic illness, as well as diseases of iron overload.

The results of a study detailing the new tool are published in the

August 2008 issue of the journal Cell Metabolism, a publication of

Cell Press.

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 result in anemia and a deficiency of hepcidin causes a

build-up of iron that is damaging to body organs.

Since both anemia and iron overload have various causes, it is often

difficult to distinguish among those causes. " It is hard to diagnose

the anemia of chronic disease, " said senior author Jerry Kaplan,

Ph.D., University of Utah professor of pathology and assistant vice

president 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. "

Identification of the Hepcidin-Binding Domain

In the study, Kaplan and researchers from the University of Utah and

University of California, Los Angeles report that 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.

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

a form of anemia that is thought to be related to abnormally high

levels of hepcidin.

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. 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. This assay can 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. This novel test

would allow doctors to 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.

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°C 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.

Evolutionary Insight

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 this 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°C but had very little

antibacterial activity at both 4°C and 37°C. 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 hepcidin binding site among

vertebrates, the usefulness of the novel HBD assay described in this

study is not limited to humans. " The assay can be used to easily

measure hepcidin in the blood of all vertebrates, " says Kaplan.