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Article
C. Ellervik et al. Total and Cause-Specific Mortality by Moderately and Markedly Increased Ferritin Concentrations: General Population Study and Metaanalysis. Clin Chem 2014;60:1419-1428.
Guest
Dr. Christina Ellervik is an Associate Professor at the University of Copenhagen in Denmark.
Transcript
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Bob Barrett:
This is a podcast from Clinical Chemistry, sponsored by the Department of Laboratory Medicine at Boston Children’s Hospital. I am Bob Barrett.
For decades iron has been thought of as beneficial for the body. Most everyone knows that iron deficiency is harmful and that the condition should be treated by additional iron in the diet. However, too much iron can also be harmful to the body. Ferritin is a protein that stores iron and measurement of ferritin in serum is a measure of the iron deposits in the body. In the November 2014 issue of Clinical Chemistry, researchers involved in the Copenhagen City Heart Study found that increased concentrations of ferritin are associated with increased risk of premature death. In this podcast we are joined by the first and senior author of that paper, Dr. Christina Ellervik. She is a research physician certified in Clinical Biochemistry and an Associate Professor at the University of Copenhagen in Denmark.
Doctor, let me start by asking you why some people have high or low levels of ferritin in their blood?
Christina Ellervik:
Well, we get most of the iron needed for our body by intake of meat, but too much alcohol may also increase the iron levels. And iron levels in the body are tightly regulated and represent the balance between intake and excretion, so there is a complex regulation system in the gut, also regulated by hormone from the liver.
Thus, under normal conditions individuals don't suffer either iron deficiency or overload, but in some conditions the amount of iron needed for the body exceeds the intake and then deficiency develops. And this can be the case in pregnant women, and if it is a disease with occult bleeding, for instance cancer.
But the body can also get too much iron, either by genetic predisposition or by intake; for instance, of intake of too much meat or alcohol, but also by taking supplements if you are not deficient, and then you get iron overload.
But despite the fact that we live in the 21st century, the human body has evolved to be living in the Stone Age. Thus, in the Stone Age it would be detrimental to suffer from bleeding. Therefore, by natural selection, the human body is still build to conserve iron rather than to excrete iron. And since the body has only one way to excrete excess iron in the body, namely by excreting excess gut cells loaded with iron, iron overload is hazardous.
And in the Copenhagen City Heart Study, we used ferritin level of 200 micrograms per liter as a cutoff for iron overland, and 16% of the individuals in that study had ferritin levels above that cutoff, and 15% of the total number of participants had moderately elevated levels, which is levels between 200 and 600 micrograms per liter. While only 1% had what we called markedly elevated levels, which is above 600.
But that said, however, elevated levels of ferritin may also indicate various other pathologies than iron overload, including inflammation or infection since ferritin is an acute phase reactant that increases in those conditions.
Bob Barrett:
What about gender, are there difference in iron concentration between men and women?
Christina Ellervik:
Yes, there is. Women have lower ferritin concentration compared to men in the reproductive age, because they bleed regularly and postmenopausal women have higher ferritin concentration than premenopausal, but still usually not as high as men.
Bob Barrett:
Is the genetically inherited iron overload different from the acquired iron overload?
Christina Ellervik:
We don’t know exactly. We also have shown in other studies that iron overload irrespective of genetics causes the same risk of diabetes as in those with genetic predisposition.
We also know that individuals with a genetically inherited predisposition to iron overload don't always develop iron overload. In fact, what we call penetrance is low for genetically inherited iron overload; it’s higher though in men than in women. We don't know why the genetic disease is not fully penetrant, but some explanations may be the existence of other genetic variations counteracting the genetic predisposition to iron overload.
Nowadays, also, maybe more awareness of the disease and thus earlier treatment or earlier intervention with prevention strategies before severe disease develops. Thus it seems as though it is the iron loading per se that carries the risk.
Bob Barrett:
Are you concerned about iron fortification in foods?
Christina Ellervik:
Yes, I am. In my opinion fortification of food should be banned. No one needs extra iron except people who are deficient, and then they should rather take supplementation.
The human body has a fine-tuned iron regulatory system and you interfere with that when fortifying food with iron. But in a public health perspective you need to take into account both the burden and the consequences of anemia if you don't fortify, but to the same extent also the burden and consequences of iron overload if you fortify. And I don't think the authorities who decided to fortify food with iron did that, in fact.
Bob Barrett:
Doctor, there are a number of diseases associated with increased ferritin levels, what are the most serious of these conditions?
Christina Ellervik:
The main consequences of iron overload are diabetes and liver disease, but not ischemic cardiovascular disease; we have shown that in other studies. However, iron may have some other harmful effects to the heart, such as heart failure, and these are all serious diseases. Diabetes usually onsets earlier than heart disease, and people would therefore suffer for a long time with diabetes in their life, and it’s usually insulin dependent.
Bob Barrett:
Well, it sounds like increased iron is associated with many conditions also known to be associated with increase lipids. Is iron the new cholesterol?
Christina Ellervik:
Well, yes, to some extent. It definitely appears to be as harmful as cholesterol, but only 16% in the general population have iron overload compared to more than 50% who have elevated lipids. So the population burden is higher for lipids definitely.
Bob Barrett:
It sounds like risk of premature death progressively increases with increasing levels of ferritin, so is there a cutoff?
Christina Ellervik:
Indeed, risk of premature death and the diseases associated with iron overload increases linearly with increasing iron concentration in the body. However, for practical and clinical purposes it is easier to operate with cutoff values. And our data showed that ferritin above 200 micrograms per liter is a reasonable cutoff.
Bob Barrett
Do you think it’s time to take another look at that and revise the clinical reference values for ferritin?
Christina Ellervik:
Yes, there is a need for a revision of the upper reference range. In my opinion, this study, but also supported by other studies, shows that we need to lower the upper reference cutoff. Usually lower and upper reference values are based on the distribution of the values in a population.
However, as for cholesterol, we need to have an upper signal cutoff for ferritin, not a classical reference range, because risk of morbidity and mortality increases when you get values beyond 200 micrograms per liter.
Bob Barrett:
What about treatment; how is iron overload treated?
Christina Ellervik:
Well, genetically inherited iron overload should be treated by phlebotomy; the goal is the ferritin value around 50-100. Iron overload caused by too many blood transfusions is treated with iron chelators in tablet formulations.
However, right now there is no guideline on when and how to treat individuals with iron overload from other courses, and should they be phlebotomized as well, well we don't know, and we don't know if it would be beneficial for diabetics to have an even lower upper cutoff for ferritin like they have for cholesterol or blood pressure, we need intervention studies to show that.
Bob Barrett:
So basically the higher your ferritin, the shorter you live, how can we understand that mechanistically?
Christina Ellervik:
The most likely explanation is that excess iron generates what we call oxidative stress. Most people will know that iron corrodes, and the same applies to iron within the human body. Thus, in severe iron overload the skin is bronze colored and we can see from autopsies of people with severe iron overload that their organs have a brownish, bronze, rust color from corrosion.
Bob Barrett:
Well, looking ahead, is there a need for more studies to even better understand the relationship between ferritin and all-cause mortality?
Christina Ellervik:
Yes, certainly, we need both molecular studies to prove the pathway and intervention studies to prove if phlebotomy is beneficial and has an effect on the endpoint.
Bob Barrett:
And what can people do themselves to try and lower their levels of iron?
Christina Ellervik:
People should definitely eat less red meat and drink less alcohol. They should also not eat iron supplements unless recommended or prescribed by a physician.
Bob Barrett:
Dr. Christina Ellervik is an Associate Professor at the University of Copenhagen in Denmark. She has been our guest in this podcast from Clinical Chemistry on mortality and increased serum ferritin. I am Bob Barrett. Thanks for listening!