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Author Topic: Hepcidin  (Read 5841 times)
ironjustice
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« on: November 24, 2010, 07:53:20 AM »

Hormone's Crucial Role in Two Anemic Blood Disorders
Released: 11/23/2010 10:55 AM EST
Source: NewYork-Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College


Two New Studies Illustrate How Hepcidin Affects Beta-Thalassemia and Hemochromatosis Diseases


Newswise — A hormone made by the body may be a potential therapeutic tool for the treatment of two anemic blood disorders -- beta-thalassemia and hemochromatosis. The new research was led by scientists at Weill Cornell Medical College and published in the Journal of Clinical Investigation and the journal Blood.

Commonly known as Cooley's anemia, beta-thalassemia affects nearly 1,000 individuals in the United States; worldwide, approximately 300,000 children are born each year with thalassemias. The conditions cause excessive iron absorption in the body's organs, with symptoms including fatigue, liver disease, heart failure, growth impairment, diabetes and osteoporosis. Standard treatment involves regular blood transfusions, which are often ineffective, or bone marrow transplants, which can help to replace and repair the broken blood production of the body.

Hepcidin, a hormone found naturally in the bloodstream and acting at the level of the digestive tract, has been known to be at low-levels in patients with beta-thalessemia. Now, the researchers have evidence that boosting levels of hepcidin may actually have a direct effect in relieving anemic patients of their body's iron overload, potentially relieving the ravages of these conditions.

"The major consequence of iron-overload is that the lifespan of a red blood cell is half that of a normal red blood cell. These blood cells are not properly formed, are not as healthy as normal blood cells, and, therefore, cannot properly function," explains Dr. Stefano Rivella, associate professor of genetic medicine in the Department of Pediatrics at Weill Cornell Medical College.

In the Journal of Clinical Investigation study published online on Nov. 22, Dr. Rivella and his colleagues report that breeding mice that overproduce hepcidin with other mice suffering from beta-thalassemia led to offspring that were almost as healthy as normal mice. However, when they crossed the hepcidin-expressing mice with normal mice, hepcidin levels were too high, leading to too much iron removal and an inability to produce healthy red blood cells.

"We see from this evidence that there is a balance in the body -- not too much iron and not too little iron -- that must be maintained to keep iron levels normal in order to produce normal blood cells," says Dr. Rivella.

He explains that under normal conditions, hepcidin recognizes when there are not enough red blood cells. In turn, the body will then produce the correct amount of hepcidin, which regulates the amount of iron needed.

"In patients with beta-thalassemia, this mechanism isn't working -- it's as if the raw materials -- the iron -- are being sent into a factory, but since no products -- blood cells -- are being made, more and more iron is being sent in and stored in the body's organs," explains Dr. Rivella.

Hepcidin's Influence on Hemochromatosis and Iron Overload

A second study published in a recent issue of the journal Blood, and authored by Dr. Rivella and his lab, illustrates a potential new dietary treatment for patients with hemochromatosis. This anemic disease is caused by a mutation to the HFE gene, leading to lowered production of hepcidin. The disorder affects nearly 1.5 million individuals in the United States.

Hemochromatosis interferes with the body's ability to break down iron, resulting in too much iron being absorbed from the gastrointestinal tract. Like in beta-thalassemia, patients often have iron buildup within the liver, which could lead to liver failure and sometimes liver cancer.

For treatment, patients often have blood taken out of their body, called phlebotomy. Doing so is believed to force the body to remove iron from the liver, reducing iron overload within the organ. Patients return regularly to the doctor's office to have blood removed, in order to lower iron levels in the body, but the procedure is not so effective and could be improved, as Dr. Rivella and his colleagues describe in their study.

"We've learned that in hemochromatosis the body will always look to the diet in the gut for iron and not take it from the liver," explains Dr. Rivella. "Therefore, a low-iron diet immediately following phlebotomy may force the body to look primarily to the liver for its iron supply."

To test their hypothesis, Dr. Rivella tested three different groups of mice: normal mice on a normal diet (group 1), normal mice given a high-iron diet (group 2), and mice with hemochromatosis on a normal diet (group 3). Group 2 was given a high-iron diet in order to raise iron levels in the liver, similar to mice in group 3.

Each group had blood removed through phlebotomy and then had their hepcidin levels tested. A low level of hepcidin would indicate that the hepcidin is being utilized to absorb iron from the gut.

Results indicated that group 1 behaved as expected: Blood was removed and found to have low levels of hepcidin, meaning that the body was absorbing iron from the digestive tract.

Group 2 had higher levels of hepcidin because the body was able to recognize that there was a reservoir of iron within the liver, illustrating that hepcidin was needed to prevent the iron from being absorbed from the gut.

However, the levels of hepcidin in group 3 was low because the body was unable to recognize a high level of iron in the liver because a genetic mutation lowered the production of hepcidin, resulting in iron being taken from the gut instead of the liver.

"The implications of these findings are that if you take out the blood from patients with hemochromatosis, the body will still look to take readily available iron from the diet, instead of from the overloaded iron packed in the liver," explains Dr. Rivella.

Recently, Dr. Rivella and collaborators at UCLA were awarded a $4 million grant from the National Institutes of Health to test a drug that mimics hepcidin in people with beta-thalassemia and hemochromatosis. They hope to show that boosting hepcidin in the body helps to better treat their iron overload and anemia.

First author of the Journal of Clinical Investigation study is Dr. Sara Gardenghi of Weill Cornell Medical College. Co-authors include Pedro Ramos, Maria Franca Marongiu, Luca Melchiori, Laura Breda, Ella Guy, Kristen Muirhead, Niva Rao, Patricia Giardina and Robert Grady, all from Weill Cornell Medical College; Cindy Roy, from Johns Hopkins University School of Medicine, Baltimore, Md.; Nancy Andrews, from Duke University School of Medicine, Durham, N.C.; Elizabeta Nemeth, from the David Geffen School of Medicine, University of California, Los Angeles, Calif.; Antonia Follenzi, from Albert Einstein College of Medicine, Bronx, N.Y.; Xiuli An and Narla Mohandas, from the Red Cell Physiology Laboratory, New York Blood Center, New York, N.Y.; Yelena Ginzburg, from the Erythropoiesis Laboratory, New York Blood Center, New York, N.Y.; and Eliezer A. Rachmilewitz, from the Hematology Department, Edith Wolfson Medical Center, Holon, Israel.

Research conducted in the JCI study is supported by funding from the National Institutes of Health, the Cooley's Anemia Foundation, the Associazione Veneta per la Lotta alla Talassemia, the Carlo and Micol Schejola Foundation, the Children's Cancer and Blood Foundation, and the American Portuguese Biomedical Research Fund.

First author of the Blood study is Dr. Pedro Ramos of Weill Cornell Medical College. Co-authors include Ella Guy, Nan Chen, Sara Gardenghi, Carla Casu, Catia C. Proenca and Robert W. Grady -- all from Weill Cornell; Antonia Follenzi, from the Albert Einstein College of Medicine, Bronx, N.Y.; Nico Van Rooijen, from the Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands; and Maria de Sousa, from the Instituto de Ciências Biomédicas de Abel Salazar, Porto, Portugal.

Research conducted in the BLOOD study was supported by grants from The National Institutes of Health, the Carlo and Micol Schejola Foundation, the Children's Cancer and Blood Foundation, and the American Portuguese Biomedical Research Fund.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing new treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston, making Weill Cornell one of only two medical colleges in the country affiliated with two U.S.News & World Report Honor Roll hospitals. For more information, visit weill.cornell.edu.









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ironjustice
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« Reply #1 on: November 24, 2010, 08:01:03 AM »

Successful Treatment For Mice With Beta-Thalassemia
Main Category: Blood / Hematology
Article Date: 24 Nov 2010 - 0:00 PST

Beta-thalassemia is an inherited blood disorder that results in chronic anemia. A major complication of the condition is iron overload, which damages organs such as the liver and heart. The iron overload has been linked to low levels of the protein hepcidin, a negative regulator of intestinal iron absorption and iron recycling.

A team of researchers, led by Stefano Rivella, at Weill Cornell Medical College, New York, has now shown that increasing the concentration of hepcidin in beta-thalassemic mice limits iron overload and markedly reduces their anemia. They therefore suggest that therapeutic approaches that increase hepcidin levels in patients with beta-thalassemia could be therapeutic, limiting iron overload and mitigating anemia.

In an accompanying commentary, Mark Fleming and Thomas Bartnikas, at Children's Hospital Boston, discuss these data and suggest that modulating hepcidin levels could be a new approach to treating a multitude of diseases associated with iron overload or deficiency.

TITLE: Hepcidin as a therapeutic tool to limit iron overload and improve anemia in beta-thalassemic mice

ACCOMPANYING COMMENTARY TITLE: A tincture of hepcidin cures all: the potential for hepcidin therapeutics

Source:
Karen Honey
Journal of Clinical Investigation
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7assan
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« Reply #2 on: November 24, 2010, 11:14:59 AM »

Thanx ironjustice for this post

I think this will tak many years to come out
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Andy Battaglia
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« Reply #3 on: November 24, 2010, 07:30:15 PM »

Don't be surprised if therapies using things like hepcidin, transferrin, etc. become realities for patients long before a gene therapy cure is available to the public. In January of 2006, I attended the TIF conference in Dubai. At that time, hepcidin was a hot topic because it had been discovered as a key to controlling iron levels in the body. In four years, we have seen this knowledge advanced to the point where they are already discussing using hepcidin therapy in humans to control iron levels.. Things are moving much faster than we realize.
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Andy

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ironjustice
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« Reply #4 on: November 25, 2010, 09:27:49 AM »

This gives even more credence to the theory of high iron in thalassemia AT BIRTH .

"Beta-thalassemia is an inherited blood disorder that results in chronic anemia. A major complication of the condition is iron overload, which damages organs such as the liver and heart. The iron overload has been linked to low levels of the protein hepcidin, a negative regulator of intestinal iron absorption and iron recycling.

A team of researchers, led by Stefano Rivella, at Weill Cornell Medical College, New York, has now shown that increasing the concentration of hepcidin in beta-thalassemic mice limits iron overload and markedly reduces their anemia. They therefore suggest that therapeutic approaches that increase hepcidin levels in patients with beta-thalassemia could be therapeutic, limiting iron overload and mitigating anemia."
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Andy Battaglia
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« Reply #5 on: November 25, 2010, 12:27:34 PM »

I find this topic fascinating. Is there a pre-natal trigger for excess iron absorption? If so, can this be affected by treatment before birth? The future will answer these questions.
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Andy

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ironjustice
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« Reply #6 on: November 25, 2010, 03:49:39 PM »

Quote: Is there a pre-natal trigger for excess iron absorption?

I would say the SAME 'trigger' found in hemochromatosis.
Meat BY the mother.

"Our results indicate that specific carbohydrates contribute to the
enhancing effect of meat on iron uptake by the enterocyte. These
carbohydrates may be oligosaccharides originating from
glycosaminoglycans in the extracellular matrix of muscle tissue."

Carbohydrate fractions from cooked fish promote iron uptake by Caco-2
cells.
 J Nutr. 2004 Jul;134(7):1681-9.
Huh EC, Hotchkiss A, Brouillette J, Glahn RP.
Institute of Food Science, Cornell University, Ithaca, NY 14853, USA.

The objective of this study was to isolate and characterize the meat
factor(s) that enhances nonheme iron bioavailability using various
analytical and in vitro cell culture techniques. Nonheme iron
bioavailability was measured via radiolabeled iron uptake or ferritin
formation in Caco-2 cells. Fish haddock fillet was cooked and
lyophilized to be used as the muscle tissue of choice because of its
low intrinsic iron content. It was demonstrated that the low pH of the
stomach (pH 2.0) was the primary factor responsible for initiating the
enhancing effect of fish on nonheme iron uptake. Subsequently, cooked
fish samples were titrated with HCl to pH 2.0 and incubated for 1 h
without digestive enzymes to release the factor(s) from the fish. The
supernatant of this acidic digest was then used as a starting material
for the meat factor isolation procedures. Fractions generated through
Sephadex G-25 size exclusion increased Caco-2 cell iron uptake
approximately 9-fold. Subsequent chromatography of these fractions via
C18 reverse-phase HPLC were conducted, and enhancing activity was
observed only in the "injection peak." This observation coupled with
protein measurement and amino acid composition analysis revealed that
the active fractions contained negligible amounts of proteins or amino
acids. Active fractions were highly enriched with carbohydrates.
Subsequent chromatography via high performance anion exchange
chromatography with pulsed amperometric detection yielded 3 active
peaks that increased Caco-2 cell iron uptake 3.4- to 4.9-fold. Our
results indicate that specific carbohydrates contribute to the
enhancing effect of meat on iron uptake by the enterocyte. These
carbohydrates may be oligosaccharides originating from
glycosaminoglycans in the extracellular matrix of muscle tissue.

PMID: 15226454

---------

"The effect of heme iron intake (from meat, fish, and poultry) was 2.0
times greater (1.2-3.2) on C282Y homozygotes than other groups."

HFE genotype modifies the influence of heme iron intake on iron status.
Epidemiology. 2005 Nov;16(6):802-5.
Greenwood DC, Cade JE, Moreton JA, O'Hara B, Burley VJ, Randerson-Moor
JA, Kukalizch K, Thompson D, Worwood M, Bishop DT.
Biostatistics Unit, University of Leeds, and Genetic Epidemiology
Division, Cancer Genetics Building, St. James's University Hospital,
Leeds, UK. d.c.greenwood@leeds.ac.uk

BACKGROUND:
Public health policy to prevent iron deficiency through food
fortification or other measures may be disadvantageous to
people with hereditary hemochromatosis.
METHODS:
From a cohort of U.K. women, 2531 women were typed for
C282Y and H63D mutations in the hemochromatosis gene.
These women completed food frequency questionnaires and
provided blood for iron status.
RESULTS:
C282Y homozygotes (n=31) had serum ferritin concentrations
2.4 times higher (95% confidence interval=1.9-3.1) than wild
types (n=1774), but heterozygotes (n=726) were not different
from wild types.
H63D genotype had no effect on its own.
The effect of heme iron intake (from meat, fish, and poultry) was
2.0 times greater (1.2-3.2) on C282Y homozygotes than other
groups.
Nonheme iron had little effect.
CONCLUSIONS:
There may be scope for dietary intervention in women homozygous
for the C282Y mutation.
C282Y heterozygotes and H63D homozygotes and heterozygotes
have similar serum ferritin concentrations to wild type and need not
reduce their meat intake other than as part of a normal healthy diet.

PMID: 16222171
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Dori
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« Reply #7 on: December 04, 2010, 04:50:02 AM »

Yes, I have always believed that hepcidin is the most interesting finding in this field. I mean, hepcidin is a very interesting thing. In the Dutch media it was translated as transferrin but I believe -looking at English article - that they messed up and actually talk about hepcidin. Gonna read all your articles later better.
TY
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