Iron deficiency without anaemia

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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 Liew 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.

Thank you very much. Pleasure to be here.

Dr Forsyth, why does non-anaemic iron deficiency anaemia matter?

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 pregnant women, for the workforce etc. 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 well-being physically and mentally. There are a lot of other areas where non-anaemic iron deficiency has been shown to cause some symptoms. Restless legs 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 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, in muscle, impacts on a variety of organs that use and process iron. So very important for the wellbeing of our community to pick this up and correct it.

So not just a pre-anaemic state, although that's clearly very important, but this whole constellation of problems that can emerge from it, fatigue, lethargy, irritability. I think these are all things that I see in my own life but are common in the community. Is iron deficiency a large driver of this in the community?

Probably not a large driver, but it's there. And from where I work, I'm outside Sydney, a lot of my patients are 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 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 of 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.

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.

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, and how you can turn that around. It is becoming much more common, and I suspect it really is because our diet's changed over the last generations. Patients are much less likely to have large amount of red meat in their diet.

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 and exploring this?

It's really important to take history from the patients and look at what's happened. Adolescents going through a growth spurt, puberty, 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 patients, "Oh, are your periods 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 ml. That's three tablespoons." And they're like, "Well, I think mine might be heavy." And I explain to them that 60 ml of blood contains 30 mg of iron, that on an average diet, we only absorb 0.5–1 mg 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 utilise or to lose all of the iron that we consume.

We have to 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 nonsteroidal and codeine and abusing that drug.

I think it really depends on the person, are there physiological reasons for why they're iron deficient, or is it completely unexplained? We do need to think about coeliac disease. We know that that is grossly underdiagnosed and that we miss significant patients with coeliac disease. 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.

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 I suspect is not traditionally done very well. Perhaps you can just take us through a few key pointers there, so what we should be thinking about with iron studies and their interpretation.

It's really hard. 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 are 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 low are these iron stores?" we need to think about, "Are they acutely unwell, and will this 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 [mean corpuscular volume] 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 a clue that they're developing iron deficiency. Methotrexate, their MCV should be high, normal, or slightly increased. And if that MCV's falling and the MCV's 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 it is 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.

Once again, some really important points there. 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?

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 and 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.

Let's speak about correction. There are a number of steps in a general population which we take far before we get to that point, aren't there?

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 Lucky 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 it 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 100 to 200 mg 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 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 not very much. And I 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 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. They 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.

So how does this work in practice?

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 carboxymaltose, which can be readily given, and a lot of general practitioners do this for their patients It can be done very quickly and infused directly within a few minutes or diluted and infused 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 goes under the skin, that that can cause pigmentation that can be very long-lasting. The availability of ferric carboxymaltose 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 derisomaltose 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 carboxymaltose.

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?

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 three, four months. In younger women who might be pregnant, had a pregnancy complicated by a 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 and they're losing iron, then it clearly has to be occult GIT bleeding.

Full of clinical pills today, Dr. Forsyth. Thank you so much for joining us today on the podcast.

It's a pleasure. Thank you very much.

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The views of the guests and the host on this podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm David Liew, and thanks once again for joining us on the Australian Prescriber Podcast.