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- [00:00]
David Liu
Welcome to the Australian Prescriber podcast. Australian Prescriber, independent peer review and free. Iron deficiency is incredibly common globally. We often think about it in terms of anaemia. We do know, however, that iron deficiency without anaemia is even more common, especially in Australia. It can have real consequences under recognised, often undertreated. How can we approach this better? I'm David Liu hosting you for today and I'm very glad to welcome Cecily Forsyth to the podcast today. She's a haematologist on the central coast. She's written an article in the December 2021 edition of Australian Prescriber on non anaemic iron deficiency. How we can pick it up and how we can address it. Dr. Forsyth, welcome to the program.
- [00:40]
Cecily Forsyth
Thank you very much. Pleasure to be here.
- [00:42]
David Liu
Dr. Forsyth, why does non anaemic iron deficiency anaemia matter?
- [00:47]
Cecily Forsyth
It matters because this population are at risk of going on to develop iron deficiency anaemia. And we know that iron deficiency anaemia causes problems for patients, for, for pregnant women, for the workforce, et cetera. Picking up non anaemic iron deficiency before patients develop anaemia is important for preventing that. But there are an increasing number of symptoms and problems that are recognised as being associated with iron deficiency in patients who are not anaemic. In fact, some of the studies, and the best studies actually come from the Japanese and they have particularly looked at young women who characteristically are pretty depleted in iron. For a 30 year old woman, the average ferritin is 30, so it doesn't take much to end up with symptomatic iron deficiency. And the Japanese have shown us that this group of patients are prone to increased fatigue, increased lethargy, difficulty in concentrating and really quite interestingly, this mood disturbance with increased irritability and some depression correcting the iron deficiency. We like to think that we are not just preventing the anaemia, but also actually improving people's wellbeing physically and mentally. There are a lot of other areas where non anaemic iron deficiency has been shown to cause some symptoms. Restless leg syndrome, more common in older people, will respond to correction of iron deficiency. We know in pregnant women that there is poor neurodevelopmental outcomes in infants, but born to mothers with iron deficiency, even in those who are not anaemic, there are an increasing range of problems recognised from lacking iron with impacts on the brain muscle, impacts on a variety of organs that use and process iron. So very important for the well being of our community to pick this up and correct it.
- [02:48]
David Liu
So not just a pre anemic state, although that's clearly very important, but this whole constellation of problems that can emerge from it through fatigue, lethargy, irritability, I think these are all things that, as I see in my own life, but common in the community. Is iron deficiency. A large driver of this in the community?
- [03:07]
Cecily Forsyth
Probably not a large driver, but it's there. And from where I work, I'm outside Sydney. A lot of my patients commuting to Sydney, working long hours, long commute back, financial stress, COVID pandemic stress. And realistically a lot of those things aren't reversible. And, and so this may be the one thing that we can correct that may just improve some of their symptoms. When we're looking at what our goals are and what we think is going to be an effective treatment, it is very important to say to patients, if you've got a haemoglobin of 60 and we're correcting your iron deficiency and your haemoglobin's doubling, you are going to feel dramatically better. If you have non anaemic iron deficiency, this may be contributing to your symptoms and correction of your iron deficiency may improve a component of these symptoms. But we have to really distinguish those clinical settings and what is likely to be any benefit for these patients, because certainly some of these people have chronic fatigue, some of them just have mental and physical fatigue that is not due to iron deficiency.
- [04:15]
David Liu
At the same time, if there's a relatively quick and easily reversible cause, then this seems like a really easy win in these patients.
- [04:21]
Cecily Forsyth
Absolutely. If we don't actually understand what the cause is, it just may progress and they then may end up anaemic. The most common group that I see would be menstruating. Women who have very depleted iron stores may not be anaemic, but menstruation continues. They are eventually going to become anaemic. So it is certainly something to think about, think about the cause of it, how much it's contributing to the patient's symptoms, how you can turn that around. It is becoming much more common and I suspect it really is because our diets changed over the last generations. Patients are much less likely to have large amount of red meat in their diet.
- [05:02]
David Liu
So maybe we can talk a little bit about causes. What kind of things should we be thinking about in practice and what's a pragmatic way about going exploring this?
- [05:10]
Cecily Forsyth
It's really important to take history from the patients and look at what's happened. Adolescents going through a growth spurt, puberty, you know, is really important for how much iron people have used. So Thinking about their physiological requirement for iron menstruation and asking patients about what their periods are and how heavy they are, what their tampon use is, what their pad use is. You say to patient, oh, your period's normal? Oh yes, they're fine and they move on. But I often will say to my patients, well we start thinking about your period's heavy. If it's more than 60 plus MLS, that's three tablespoons. And they're like, well, I think mine might be heavy. And you know, I explained to them that 60 mils of blood contains 30 milligrams of iron, that on an average diet we only absorb 0.5 to 1 milligram of iron a day. So patients may say, I have completely normal periods and they don't feel overly heavy to them, but they are certainly enough to utilize or to lose all of the iron that we consume. We have to sort of put it in the context of why is this person iron deficient? What is their diet like? Have they got any red flags that would make us feel that we do need to investigate their gastrointestinal tract? Do they have known hiatus hernia? Are they on multiple anti inflammatory drugs? Before the restrictions came in on combination of anti inflammatories and codeine, we used to see that as an occasional patient would present with iron deficiency anaemia. Who was actually using that combination of a non steroidal and codeine and abusing that drug? I think it really depends on the person. Are there physiological reasons for why they are iron deficient or is it completely unexplained? We do need to think about celiac disease. We know that that is grossly under diagnosed and that we miss significant patients with coeliac disease. That we do need to think about other medications that may impact on blood loss in the gastrointestinal tract. And then in patients with unexplained iron deficiency, we certainly need to escalate it. We also see a lot in older adults because we now use anticoagulants, antiplatelets, much more than we did a decade ago. They may also have an antiplatelet agent if they've also got coronary artery disease or had a cerebrovascular event. We know that they may also be taking fish oil, sometimes they're taking their anti inflammatories. There may be other medications that have an antiplatelet effect, something as simple as hydroxychloroquine. And so if we look at these drugs that patients are now taking in the older age group, we can certainly see that iron deficiency again is common in older patients on multiple blood thinners.
- [07:47]
David Liu
Some real clinical pearls in there. And I think it speaks to the value of that clinical assessment. Before we go to iron studies and talking through that, I think it's an area which suspect is not traditionally done very well. Perhaps you can just take us through a few key pointers there as to what we should be thinking about with iron studies and their interpretation.
- [08:05]
Cecily Forsyth
It's really hard and we do get these lovely tables and certainly it's included in the article we've written. But we actually have to look at the iron studies in the context of the patient in front of us. If we have a young otherwise perfectly well person, the iron studies can be clear cut. And looking at that ferritin and seeing a low ferritin iron deficiency, easy. But it's the complex patients whose ferritin level does not reflect their iron stores. We are understanding that inflammatory states that a ferritin under 100 is often iron deficient, especially if their transferrin saturation is less than 20%. We certainly well aware of kidney disease with ferritins that are even up to 500 may be evidence of iron deficiency, especially if the transferrin saturation is less than 30%. More recent data has shown again in heart failure an improved outcome for correcting non anaemic iron deficiency in heart failure. The numbers that are tossed around there is less than 100 for a ferritin and less than 300 if you've also got a transferrin saturation of less than 20%. What we also see and forget is the masking of iron deficiency by alcohol and by liver disease. Non alcoholic fatty liver disease is an increasing problem and certainly there's been no shortage of people consuming more alcohol than they should during the pandemic. Alcohol increases your ferritin. Interestingly, there's a little bit of data to suggest that beer drinkers have a higher transferrin saturation. Your iron stores can almost look like you've got iron overload in somebody who has alcoholic liver disease. And it really does not correlate at all with their iron status. When we're looking and judging how are these iron stores we need to think about? Are they acutely unwell and will this ferry ferritin have gone up because they're unwell? Is their liver or their comorbidities pushing up their ferritin level? I look at changes in the MCV because the MCV will fall before patients become anaemic. And if you've got a low MCV in somebody who drinks too much alcohol or somebody who's got lung disease, where you would expect a much higher mcv, those can be a little bit of clue that they're developing iron deficiency methotrexate. Their MCV should be high, normal, or slightly increased. And if that MCV is falling and the MCV is low, it should trigger us to think, could this be iron deficiency developing? But ultimately, in some patients, it can be really challenging to diagnose. And suggesting to a patient that we want to have a look at their iron stores in their bone marrow is never well received. We do have the soluble transferrin receptor. That test is not rebated. And it can be useful in certain groups of patients that the soluble transferrin receptor is increased in iron deficiency. There is a little bit of discussion as to how useful in people with renal disease, but in general, I find that often quite useful, particularly in the liver patients where it can be really difficult to pick up iron deficiency because their liver disease itself is putting up their ferritin and their transferrin saturation.
- [11:18]
David Liu
And once again, some really important points I'd really like to focus in on the special populations of heart failure patients and chronic kidney disease patients. Why should we be pushing harder to correct iron deficiency and detect iron deficiency in these patients?
- [11:33]
Cecily Forsyth
There is increasing evidence that correction of iron deficiency in patients with heart failure improves symptoms and quality of life and reduces hospital admission. And I think the amount of data is increasing, and if we can do that in a chronic heart failure patient to improve their symptoms and quality of life, may mean they can get out of home and just do a little bit more. And it's something that can be successfully and easily used, especially now that we have very good iron infusions that can be given in a small volume of fluid very quickly and very easily in an outpatient setting. The renal physicians have been all over iron for a long time, and they understand the need to keep iron levels very high in patients, particularly those who are receiving an erythropoiesis stimulating agent. And they're very good at adding in iron infusions to these patients, both pre dialysis and for those who are on dialysis, it reduces the requirement for blood transfusion, reduces the amount of the erythropoiesis stimulating agents they need to have. And there are thought to be cardiovascular benefits in that population as well.
- [12:44]
David Liu
Let's speak about correction. There are a number of steps out in a general population which we take far before we get to that point, aren't there?
- [12:51]
Cecily Forsyth
There certainly are. There is A fantastic bit of work that was done in Cambodia, it's probably almost a decade ago by a medical student and he invented this luck fish, which is just a lump of iron in the shape of a fish that they use in Cambodian cooking pots. Because they really have a very low iron containing diet in Cambodia and iron deficiency was such a clinical problem, people just leave them in their cooking pot and when they cook their rice and fish, there is increased iron released from this lump of lucky fish iron and has really made a little bit of an impact on clinical problems with iron deficiency anaemia. Correcting your diet is the first step we should make in patients who've got non anaemic iron deficiency and just having a look and seeing what are they eating. Is there something that we can do that can change people's diet and improve their intake of iron? That's often not overly effective for most patients. People may not want to increase their red meat intake. And although we absorb iron from a huge range of foods, the food that we best absorb iron from is clearly red meat. Certainly by the time anyone is asking me about iron deficiency, dietary strategies are not really anything that I would find is going to be successful. I do think that the first option is iron supplementation orally. It's easy, cheap and it's convenient. There is some data recently that has shown that iron actually inhibits its own absorption and that you get better absorption of iron using it on a second daily basis, either sort of 100 to 200 milligrams second daily. So I tend to use a well absorbed and cheap iron preparation and ask the patients to take it second daily. Whether or not you add vitamin C to that probably makes no difference to the iron absorption. So again, you can actually move patients away to cheaper preparations of iron rather than the ones with vitamin C added, which tend to be more expensive. You should be able to get away with, you know, 30 to 60 good iron tablets for clearly under $10. Also, although I say to patients it's better absorbed on an empty stomach if that makes them nauseated, the compromise in absorption is very much and I'll say, well, take it after a meal and often take it after breakfast because that tends not to be such a heavy meal. Oral iron supplementation should be the first strategy for non anaemic iron deficiency as long as there isn't a problem with absorption. We sort of didn't mention the other group of patients who've had bariatric surgery where we certainly do see poor absorption of iron in that group of patients. So as long as the patient is not felt to have an absorption problem with iron or a contraindication with some swallowing or intolerance, oral iron supplementation should be the first avenue. But if we don't correct the reason why they're iron deficient, then we may find that it takes a long time to improve their iron levels. Patients do need to take this consistently. They are going to need to take, in general, three months of therapy to build up their iron stores. Then you may even find their haemoglobin may go up from 115 to 135. So that will take up quite a bit of the iron you've given patients. But in today's sort of lifestyle and today's Internet and access to information, a lot of young patients are not overly keen on taking iron three times a week for three months to correct their iron deficiency. And there is a patient demand for a quick fix for their iron.
- [16:26]
David Liu
So how does this work in practice?
- [16:28]
Cecily Forsyth
So the improvement in the iron that we have available on the market now has really made it very easy for patients to have intravenous iron done by their local practitioner very readily. And we saw that probably with the first fast preparation. We had the ferric carboxy maltose, which can be readily given, and a lot of general practitioners do this for their patients, can be done very quickly and infused directly within a few minutes, or diluted and infused sort of over 15 to 30 minutes. We worry mostly about reactions that can be occasionally seen, but they're low incidence compared to previous iron preparations. My biggest concern, especially if we're doing this in patients who are not anaemic, is to make sure the patients understand the potential for side effects and to understand the potential of skin staining. If the cannula tissues and the iron go under the skin, that that can cause pigmentation that can be very long lasting. The availability of ferric carboxy maltose has been very helpful for patients and they can very rapidly have iron correction. We do have other preparations on the market and the ferric DERA isomaltose preparation, this you can use in a larger volume, which makes it more convenient for patients who have recurrent iron deficiency. Some of the git bleeders who need iron supplementation or intravenous iron infusions regularly, this would be a product that's preferred. The incidence of low phosphate is also less with this product. So I might choose this product for patients who have inflammatory bowel disease or other pathology where they are at risk of developing low phosphate levels following ferric.
- [18:24]
David Liu
Carboxy Maltase so following these patients up because I think once we've started supplementation, there's always a question about how frequently we should be giving intravenous iron or when we should be repeating iron studies. Any advice on that?
- [18:37]
Cecily Forsyth
After you've put somebody on iron supplementation, you certainly want to be having a look and seeing what their ferritin is doing in eight weeks and making sure that your therapeutic strategy has been effective. How often you need to monitor them depends upon what the cause of the iron deficiency was, how likely it is to reoccur. Suddenly, you may have a patient with a bleeding diathesis or git bleeding that we cannot stop that blood loss and they need iron every 3, 4 months. In younger women who might be pregnant had a pregnancy complicated by postpartum bleed, one iron infusion and they may not need anything further. It's a matter of working out what the cause was, how much iron you needed to correct it and then reassessing at a time that is appropriate, depending upon the clinical circumstances. But I certainly would like to check iron levels again. Haemoglobin, if they were anaemic to start with, two to three months after I've commenced someone on oral iron or given them an iron infusion. And again, if they don't correct properly or they redevelop iron deficiency, you need to think why and you need to take a strategy to stop the blood loss. People don't lose iron, they lose blood. So it's a matter of where is that blood going and if you can't see it it and they're losing iron, then it clearly has to be occult git bleeding.
- [19:55]
David Liu
Full of clinical pearls today. Dr. Forsyth, thank you so much for joining us today on the podcast.
- [19:59]
Cecily Forsyth
It's a pleasure. Thank you very much.
- [20:07]
David Liu
The views of the guests on the host on this podcast are there on and may not represent Australian prescriber or NPS medicine wise. I'm David Liu and thanks once again for joining us on the Australian Prescriber podcast.