Greetings. I'm Dr. Javed Butler. I'm a professor of medicine at the University of Mississippi. I also serve as a president of the Baylor Scott & White Research Institute. I am absolutely delighted to talk about the issues related to iron deficiency, the metabolism of iron, how come some patients have iron deficiency and they are not anemic, what is functional iron deficiency versus absolute iron deficiency. So let's get right on to it. Please see my disclosures at the bottom of this slide. So let's start with a deep dive into the physiology so that once and for all we can clarify all these nuances related to the issue of iron metabolism. So there are basically three principal ways by which one can be either absolute or relatively speaking iron deficiency from a functional perspective, from the use of iron perspective. So the first is that, as one can see on this screen, the total body iron score is about four grams. It's in three different pools. So the largest is in the form of hemoglobin. The second is the storage iron. And then the third is the circulating iron in between the two for use by the body. Now iron by itself is toxic. So the iron has to have a detoxifier, like a shell, in which it should be available. Otherwise it creates reactive oxygen in the species and leads to oxidative stress. So in the blood it is combined with transferrin to avoid that. And in the cells it is combined with ferritin. So the storage protein combination is with ferritin and in the blood it is with transferrin. So depending on the ferritin levels and transferrin levels, we can get some idea about what the overall iron content is. Now once we give somebody iron, like IV iron, it also has to have some sort of a detoxifier encapsulating iron. And some of the historical issues related to anaphylaxis is actually related to that detoxifier and not by iron itself. So one can see from an iron metabolism perspective that the first way by which we can get iron deficiency is if we just don't have enough iron intake or we don't absorb enough iron. So either the oral iron intake is not enough or there is enough intake but you have gut edema or other reasons because of which iron is not absorbed. Now what is the second way? The second way is something where a lot of us sometimes get confused in terms of the issues related to iron deficiency. So once it is stored in the cell, as the body requires more iron, it has to be transported from the cells into the place where it needs to go. So how does iron go in and out of the cell? Both at the gut level where the iron is absorbed or at the body level where iron is stored in the liver and the reticular endothelial cells as well. So there's a protein called ferroportin and ferroportin is the one that transports iron in and out of the cell. In conditions where you have inflammation, hepcidin is upregulated and hepcidin binds with ferroportin and makes it inactive. So in pro-inflammatory conditions with the binding of hepcidin, you may have enough iron in the body, your stores may be full, but you cannot transport it in and out of the cell. So you develop functional iron deficiency. The consequences in the body are still the same despite the fact that you have enough iron. This was sort of teleologically speaking a protective mechanism because when you have inflammation, i.e. bacterial overgrowth or infection, those bacteria also require iron and decreasing iron supply to them was a way to deal with that. But obviously other inflammatory conditions, it has an adverse side effect. The second issue beyond iron absorption is decreased bioavailability. And then the third and the last way you can get iron deficient is obviously by excess loss. So you're absorbing enough, you're eating enough, there is no inflammation, but you have either heavy menstrual losses, GI losses, gastritis, ulcers, for whatever reason you are losing more iron. So now that we understand that, what are some of the parameters that we can use? So this is heavily debated, what is the right way to define iron deficiency? One of the parameters is a serum transferrin receptor that actually is not as much affected by inflammation, but it is not common clinically used. So one of the ways to define iron deficiency is what was used in the clinical trial because our therapeutic regimen is based on the clinical trial definition. So for the time being, now again, we can argue whether this is precisely the best way to define iron deficiency, and that is an academic debate, but for our practical purposes, iron deficiency is defined as either low ferritin levels, so you don't have enough iron storage, you have iron depleted less than 100 nanogram per ml, or because ferritin is an acute phase reactant and in inflammatory conditions, the ferritin level may go up, either an absolute ferritin of less than 100 or ferritin between 100 to 300 with a TSAT or transferrin saturation of less than 20. So that defines iron deficiency in a way target of what we are trying to reverse as well. So now that we understand the physiology of iron, the next question is how do you develop iron deficiency and have adverse consequences even if you're not anemic? So a lot of the people equate iron deficiency and anemia, and obviously these are sort of overlapping, but not perfectly so conditions. So of course, it can be anemic without iron deficiency, B12 deficiency, other reasons as well. But iron deficiency eventually leads to anemia. Anemia leads to decreased oxygen carrying capacity in the blood, and the metabolizing tissues require oxygen, so when you're persistently anemic, then you're short of breath and tired and fatigued, and you have all the systems. But remember that if you have milder degrees of iron deficiency, not chronic enough, not severe enough, you're not necessarily anemic in some significant way, you can still develop the same symptoms. And the reason is that not only iron is important in hemoglobin generation, but it is an important cofactor in many other enzymatic processes in the body, including mitochondrial function and ATP generation. So if you don't generate enough ATP, obviously you will be tired and fatigued and will have the same problem. So there are two different pathways with anemia, but even without anemia in terms of aerobic metabolism and generation of ATP is affected in iron deficiency as well. These are some of the enzymes that require iron as a cofactor, obviously mitochondrial function we discussed, but also things like soluble guanylate cyclase, which is so important for normal cardiovascular function that we now even have therapies targeting soluble guanylate cyclase, like Verisiguat and Reosiguat, shown to be effective in improving cardiovascular outcomes as well in patients with heart failure or with pulmonary hypertension. So just to make a point that iron deficiency is much more than anemia itself, decrease ATP generation, decrease oxygen carrying capacity, not only have symptoms, fatigue, tiredness, shortness of breath, but also in the long run, end organ damage, cardiac, renal, vascular, and eventually higher risk of morbidity and mortality. Now, these are some of the causes of elevated serum ferritin levels. So if your ferritin levels are low, then that helps in the diagnosis of iron deficiency, but if they are mildly elevated, as we said, then we need to combine that whether the transferrin saturation is normal or less normal as well. Also remember that it is good to know that with inflammation, your ferritin may be an acute phase reactant and may be higher, but again, it's usually in the milder ranges. So if you have somebody with severe elevation, don't blame it on inflammation. Think about then the opposite, the iron overload conditions like hemochromatosis as well. So this one picture basically describes the physiology in a very clear way. So first, you're in a normal state, your iron storage is normal, shown here in purple, the transport pool between the metabolizing tissue and the storage is normal, which is the transport iron, and then you do not have anemia. When you start developing iron depletion initially, you can start decreasing your ferritin, your transferrin saturation is low, but it's not bad enough and you don't have anemia. If you continue to go down that path, then the third true fault, and that is you start developing anemia, but then do keep in mind that A, even without anemia, when iron is down, you can have symptoms and consequences, but then is the last part where you actually have the storage pool is full, but you're not getting it in and out of the cell. So you have this functional or relative iron deficiency, the transport iron is low, and you can develop anemia the very same way. So in this Venn diagram, you can think about anemia because of non-iron deficiency causes like vitamin B12 deficiency, iron deficiency without anemia, and then the combination of the two. How common is it? So if you are anemic, iron deficiency can be seen in upwards of 60% of the patients. If you're non-anemic, still, it's not too shabby. It's about 40% of the people may be iron deficient. Iron deficient people have much worse prognosis than those people without iron deficiency. Now, anemia by itself does not impact health-related quality of life as much, unless obviously it is severe, but in milder ranges, maybe the body compensates, but iron deficiency because of dual mechanism, not only oxygen carrying capacity, but ATP generation has much more impact on quality of life. And that these are really two separate issues. So yes, iron deficiency is associated with poor outcomes as shown here on the left. But if you have iron deficiency alone or anemia alone, the prognosis is not as bad as when you have both of them in combination as is seen on the right side. Now, most of these data that I am telling you about are from HEF-REF study, heart failure with reduced ejection fraction, because that's where we have most of the clinical trial evidence. In HEF-PAF, again, as shown here, if you look at serum transfer and receptors, in HEF-PAF patients also iron deficiency is common, is also associated with exercise intolerance, but the clinical trials are much at an earlier stage and we don't have as much data in terms of the outcomes per se. The American guidelines, the European guidelines, all of that recognize iron deficiency, both as a measure of worsening heart failure, as well as a therapeutic target, and pretty much uses the same definition because these definitions were used in the clinical trial setting. I again want to emphasize that there are multiple different iron preparations out there. Some of the things that are in our mind about anaphylaxis related to IV iron, again, as I mentioned, is not related to IV iron, but the detoxifier that we combined it with, high molecular weight dextrans and stuff like that. So now there are new preparations of iron like ferric carboxymaltose, ferric derisomaltose. These have very fewer side effects, much better tolerated, and we will discuss that more in subsequent presentations as well. What about oral iron? So oral iron has a lot of very easy to ascertain benefits. Say if you just take a pill, you don't have to get an IV, you don't have to go to the hospital, administration is simple, it's more expensive. The problem is that it is ineffective. The problem is that it is ineffective because there are studies that basically show that in patients with heart failure, both with edema and inflammation and high hepsidin level, oral iron just is not absorbed, and therefore you do not get iron replete, and therefore you do not get the benefit, and we have tested that in the clinical trial setting as well. How do you correct it? So again, there are formulas that can give you some idea, like Gonzoni's formula, to find out how much of the total iron deficiency you have, and then depending on your body weight and your starting hemoglobin level, there are different schedules as is seen here, and you replace the iron, if milder, maybe with one injection, with more severe, maybe with more than one injection per se, but to just keep note of a couple of points. One is that once you find somebody with iron deficiency, your job is not done, just make sure that they don't have a cause for iron deficiency related to blood loss, which then leads to making sure that somebody doesn't have peptic ulcer disease, somebody does not have colon cancer, and all that kind of stuff. So again, use your clinical judgment that all iron deficiency, although it's very common in heart failure, but it's not only heart failure, and we have clinicians to look at other causes as well, and then the second thing is that the same conditions that make a person iron deficient in the first place, those things don't go away even if you replete iron, so that we need to follow the iron longitudinally and intermittently, patients may require subsequent iron replacement as well. Lots of data that we will discuss that iron repletion leads to improvement in functional capacity, quality of life, the risk of hospitalizations as well, and I want to end my presentation by saying that this is not an uncommon issue, so not only is it associated with clinical outcomes, but also it is very, very prevalent, and the more the sicker person is, from NYHA 2 to 3 to 4, and sick enough to come into the hospital, the prevalence of iron deficiency continues to go up from 50 to 70 percent range. So again, the issue is our inertia to not look for it, but it's a very prevalent condition, and we can potentially help our patients by screening and treating iron deficiency. Thank you very much, I look forward to further discussions with you.

iron deficiency

health impact

inadequate intake

functional iron deficiency

excess iron loss