 |
|
Key site in iron metabolism aids in diagnosing anemia of chronic disease
August 06, 2008Rapid 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.
University of Utah Health Sciences
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.
University of Utah Health Sciences
Hepcidin Current Events and Hepcidin News RSSMetabolic insight to illuminate causes of iron imbalance
New insight into key players in iron metabolism has yielded a novel tool for distinguishing among root causes of iron overload or deficiency in humans, the researchers report in the August issue of Cell Metabolism, a publication of Cell Press. While the body needs iron to produce hemoglobin, a substance in red blood cells that enables them to carry oxygen, too much iron can build up and eventually damage organs.
A genetic cause for iron deficiency
The discovery of a gene for a rare form of inherited iron deficiency may provide clues to iron deficiency in the general population - particularly iron deficiency that doesn't respond to iron supplements - and suggests a new treatment approach.
Increased hepcidin expression: A novel oncogenic signalling mechanism
Historically anaemia, which is associated with colorectal cancer, has been attributed to blood loss. Previous studies have elegantly shown that the anti-microbial peptide hepcidin can also induce anaemia as a consequence of infection and or inflammation.
Europe's most common genetic disease is a liver disorder
Much less widely known than the dangerous consequences of iron deficiencies is the fact that too much iron can also cause problems. The exact origin of the genetic iron overload disorder hereditary hemochromatosis [HH] has remained elusive.
MIT uncovers key blood protein
Scientists working in the only lab at MIT doing hematology research have uncovered a protein that plays a key role in the recycling of iron from blood.
Unexpected link between gene in liver and iron overload
A new study in the December Cell Metabolism reveals an unexpected connection between a tumor suppressor gene in the liver and the normally careful control over the amount of iron absorbed from the diet.
Hemochromatosis, Inflammation and Anemia: Researchers Discover a Surprising Link
Patients with inflammatory diseases such as arthritis, chronic infections and some types of cancer, often become anemic - a condition called anemia of chronic disease (ACD). While ACD rarely kills patients, it can make their lives miserable. A discovery at EMBL, in collaboration with researchers at Children's Hospital Boston and Harvard Medical School, now links the gene HFE to ACD. The HFE gene is mutated in patients suffering from the common iron overload disease hemochromatosis. This finding gives hope that one day an effective and specific therapy may be developed to treat ACD (featured in Nature Genetics, April 18, 2004). When people are infected with microbes, the level of iron in thei
What makes the body absorb too much iron? Researchers at EMBL and Harvard gain new insights into the most common inherited disease in the Western world
Like most nutrients, iron is good for people - in the right doses. When the body has enough iron, our cells stop absorbing it from food; if there is too little, they absorb more. This system breaks down in the most common inherited disease in the Western world: hemochromatosis, which affects about one in every 250 people and is often fatal if it is not recognized and treated. Now researchers at the European Molecular Biology Laboratory in Heidelberg (EMBL) and Harvard Medical School (U.S.) have linked the response of a gene in the liver to the disease. The study, which appears in the current issue of Nature Genetics, is changing our understanding of how hemochromatosis develops. "Untreated
After a 40-year search, a hormone controlling iron metabolism in mammals is finally identified
Iron is vital for cells, because it catalyzes key enzyme reactions; it is also crucial for respiration, fixing atmospheric oxygen to hemoglobin in red blood cells. Iron deficiency can lead to severe anemia, with inadequate tissue oxygenation. An excess of iron is also toxic, as it facilitates the generation of free radicals that can attack the liver, heart and pancreas. This is the case in hereditary hemochromatosis, a genetic disorder which, in 80% of cases, is linked to a point mutation in the Hfe-1 gene, leading to excessive iron uptake by the intestinal tract. Hereditary hemochromatosis is very frequent in western countries, affecting one in 300 people. The body has no physiological mech
More Hepcidin Current Events and Hepcidin News Articles
| © 2008 BrightSurf.com |