Researchers have gained new insights into the most common inherited disease in the Western world--hemochromatosis. The condition affects about one in every 250 people and can be fatal if left untreated.
Normally, when the body has enough iron, the cells stop absorbing it from food and if there is too little iron, they absorb more. If this system breaks down, a person can absorb too much iron from the diet, leading to hemochromatosis (iron overload).
While the mutation that causes the condition was thought to affect primarily the intestine, researchers in the research group of Matthias Hentze at the European Molecular Biology Laboratory in Heidelberg (EMBL) and researchers from Harvard Medical School (U.S.) have linked the response of a gene in the liver to the disease.
The finding may lead to a new understanding of how hemochromatosis develops.
Sufferers of hemochromatosis have inherited a defective copy of a gene called Hfe from each parent. The defect leads a person's intestine to absorb too much iron from his or her diet. Over the course of many years, this builds up, and by middle age, the overload may be very serious.
Until now, most researchers have thought that the problem stems from a faulty intestinal signal that there is too little iron, leading cells in the intestines to produce more transport proteins that draw iron inside.
However, the current study shows that the link between Hfe and iron is probably in the liver, rather than the intestine.
EMBL researchers investigated iron absorption with a technology called DNA chips, which allows scientists to monitor how a cell's genes respond to changes such as a raise in levels of iron. They put together a set of probes to watch for changes in 300 genes known to have some connection to iron.
Meanwhile, Harvard scientists were investigating hemochromatosis in mice and developed strains of mice without Hfe, or with the mutant version found in hemochromatosis. They found that both strains absorbed too much iron and exhibited the symptoms of the disease.
The DNA chips were used to compare cells taken from these mice and their healthy cousins. In the former model, cells with defective Hfe were expected to behave like healthy mice with an iron deficiency, producing more iron-absorbing proteins in the intestine. However, that wasn't the case so researchers started to look for other effects of mutant Hfe.
They found that hepcidin, a molecule in the liver, wasn't being activated properly.
When iron levels rise in a healthy mouse, its liver produces more hepcidin, and hepcidin acts like a hormone to reduce iron absorption by the intestine. This didn't happen in mice with mutant or missing Hfe even when the researchers directly injected them with iron, giving proof that Hfe is necessary to make a connection between iron and hepcidin.
How can hepcidin expression by the liver change iron absorption among intestinal cells? Although a lot of questions remain, according to researchers, without hepcidin the body can't seem to halt an intestinal molecule called Cybrd1.
Normally iron atoms carry three positive charges; in that form they can't be brought into cells. Cybrd1 works by reducing the number of charges to two, making iron transportable. If it were active all the time, a lot more of the body's iron would be absorbable. When it isn't active, there is very little to be absorbed. Hepcidin's normal function might be to lock down Cybrd1, thereby shutting down the supply of available iron. This would make activating hepcidin, which can't happen with a mutant form of Hfe, essential to stopping the flow of iron into the body.
Due to these findings, the focus of hemochromatosis research will likely turn to the liver in order to investigate the circuit that connects iron, Hfe and hepcidin. Additionally, the findings suggest a link between the body's uptake of iron and the immune system, where hepcidin also plays a role.
Eurekalert.org April 25, 2003
In the following exclusive interview, Dr. Matthias Hentze, senior scientist and program coordinator, European Molecular Biology Laboratory in Heidelberg (EMBL), discusses the implications of the study findings on future hemochromatosis research.
Iron overload, or hemochromatosis, is actually the most common inherited disease. You can find out all the technical details from reading my article on how to diagnose iron overload below. In hereditary hemochromatosis deposits of iron appear in practically every major organ, particularly the liver, pancreas and heart, resulting in complete and widespread organ failure.
Further, iron has been known to be associated with infection for 30 years. When excess iron is present, the body’s normal antibacterial mechanisms become severely compromised. Excess iron can also create massive amounts of free radicals.
If you were to listen to traditional medicine the only solution for iron overload is to donate a pint of blood every two weeks. This is not a very effective solution and may require many years before it works as up to 50 therapeutic phlebotomies may be necessary.
Measuring iron levels is a very important part of optimizing your health, especially for men and postmenopausal women since excess iron is most common among these groups. However, simply measuring serum iron is a poor way to do this because frequently the serum iron will be normal. The most useful of the indirect measures of iron status in the body is through a measure of the serum ferritin level in conjunction with a total iron binding level.
If you find elevated serum ferritin levels, you do not have to perform therapeutic phlebotomies. A simple extract from rice bran called phytic acid, or IP6, can serve as a very effective form of iron chelation that is non-toxic, inexpensive and can be done without a prescription.
Tsuno Food & Rice Company of Wakayama, Japan is the only manufacturer of IP6 in the world; any brand you purchase would come from this company.
The following is from a recent interview we conducted with Dr. Matthias Hentze:
Your study found that the problem causing iron overload actually stems from the liver rather than the intestine ... what are the implications of this finding in terms of diagnosing hemochromatosis?
"It was previously assumed that Hfe acts primarily on the intestine, making the body think the body is iron deficient, but this is unlikely. The function of Hfe protein is important to the liver.
I wouldn’t necessarily say that the implications of our findings are in the area of diagnosis. As you may know, hemochromatosis is a very common disease, and when one suspects that a patient suffers from hemochromatosis a genetic test will readily identify the disease in the vast majority of patients. For patients who don’t suffer from the most common form, we don’t know if it’s from a lack of hepcidin, so we don’t know if looking for this would be effective. It’s a very interesting question that we’re looking into in the future."
What implications does the study have in terms of treating the condition?
"The finding is most useful in understanding the condition and very useful in beginning to understand how this recently discovered iron hormone, hepcidin, is controlled, and while hemochromatosis itself is not so difficult to treat by bloodletting, or venesection, which is an old treatment with very few side effects, there are other diseases resulting from disturbances in iron. So, understanding how hepcidin is regulated could provide insight into diseases outside of hemochromatosis, such as anemia, chronic diseases, inflammatory diseases, cancer, autoimmune diseases and chronic infections. All of these diseases may have to do with inappropriate hepcidin expression.
The role of hepcidin appears to be, on one hand, to block iron absorption from the gut. But, also red blood cells have a finite lifespan so all of the blood that we have must be rejuvenated within a four-month time span. You can imagine it’s a huge iron-recycling task. What happens is that when red blood cells are broken down by macrophages it makes the iron that is extracted available again. When hepcidin is being produced by the liver, it appears that the ability of marcrophages to release iron is blocked.
Now, this has nothing to do with hemochromatosis but rather with the other diseases I mentioned above, though the hepcidin molecule could be useful in helping to understand what’s giving rise to problems associated with hemochromatosis."
Sufferers of hemochromatosis have inherited a defective copy of a gene called Hfe from each parent, is there any way to know whether you are predisposed to this defect?
"If people have developed hemochromatosis in the way described above, people receive one copy of the gene from the father and one copy from the mother. But, what very frequently is the case is that their parent’s other copy of the gene might be normal, so the parents may not suffer from the condition.
There’s not a unique way that people find out they have hemochromatosis, but very commonly, patients are within the most common age range of the condition, which is 30 to 50 years old in men and 10 to 20 years later in women. So typically they are within the age range and they can develop liver problems and go to see a doctor because of that. A non-liver related aspect is diabetes; development of diabetes can be a sign of underlying hemochromatosis. Also heart conditions such as irregular heartbeats (arrhythmia) and cardiac insufficiency, rheumatism and impotence in men may be signs. It is a conclusion that quite a variety of different diseases can have hemochromatosis as their underlying pathology. Since the condition is treatable, it’s worth testing patients for hemochromatosis."
The study mentions that there may be a link between the body's uptake of iron and the immune system. Could you expand on this link?
"This brings us back to the molecule hepcidin. The ‘hep’ part of the word means ‘made from the liver,’ and the ‘cidin’ portion comes from the ability of molecule to kill bacteria and fungi. The molecule belongs to the defensins family, which are small molecules made by the body to fight of bacterial infections. Originally, hepcidin was not thought to have anything to do with iron, but rather to innate immunity (the body’s defense system). Rather serendipitously it was found that hepcidin controls aspects of iron metabolism.
Thinking back from an evolution standpoint about why this molecule combines these two functions in and of itself, an interesting hypothesis is that since pathogens often require iron to be present in the blood, and hepcidin’s role leads to a reduction of the amount of iron circulating in the blood, hepcidin could help to prevent the spread of pathogens because iron is less available to them."
Are you conducting further studies to explore the liver’s role in iron overload?
"Yes, absolutely. This published study is refocusing our interest from the gut to the liver as the main place where things go wrong in hemochromatosis. So now what we need to understand is in what way the Hfe molecule is involved in the regulation of hepcidin expression."