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The Intricacies of Iron Deficiency with Lisa Costa Bir and Alison Mitchell

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The Intricacies of Iron Deficiency with Lisa Costa Bir and Alison Mitchell

Naturopath Alison Mitchell is joined by fx Medicine ambassador Lisa Costa- Bir who helps expand your knowledge on the essential mineral - iron. They distinguish between iron deficiency and iron deficiency anaemia, and why heme iron is absorbed more efficiently than non-heme iron.

The finer details of recycling of iron from red blood cells, conditions impacting iron status such as infections, inflammation, and gut dysfunction, the hormone hepcidin are all valuable in understanding the intricacies to iron.

Together the two naturopaths discuss subtle signs of deficiency, why iron is linked to mood swings, why timing matters when testing iron levels and supplementing and they share thoughts on complementary approaches to balancing iron involving specialised pro-resolving mediator, nutrient and herbal therapeutics.

Covered in this episode

(00:45) Welcoming Alison Mitchell
(02:10) Differentiating iron deficiency and iron deficiency anaemia
(04:14) Iron absorption
(06:49) Iron recycling system
(09:57) Hepcidin
(13:45) Lesser none symptoms of iron deficiency
(14:58) Iron and mood
(18:30) Conditions contributing to low iron
(21:54) Menstrual bleeding and iron
(22:29) Autoimmunity and iron
(25:43) Cofactors needed for iron absorption
(31:18) Testing
(35:26) When to supplement
(39:02) Prebiotics and iron
(42:10) Dosing iron
(45:45) Herbs
(46:33) Iron infusions
(49:00) Thanking Alison and final remarks

Key takeaways

  • Differentiating between iron deficiency and iron deficiency anaemia
    • Iron deficiency = low iron, or ferritin, or transferrin without impact on RBC’s, subtle signs of low iron
    • Iron deficiency anaemia = low markers as above, leading to altered haemoglobin and RBC formation/production, overt signs of low iron
  • Optimal absorption depends on the form of iron. Heme iron provides the greatest potential of absorption due to its chemical structure allowing for non-competitive absorption pathways versus non-heme iron which has competing pathways for absorption i.e. bound to phytates/tannins and other heavy metals.
  • Iron recycling from RBC’s aids to reach optimal levels of iron alongside dietary intake. Consider immune, gut dysfunction, infections, and inflammation in cases where iron is difficult to raise.
  • Hepcidin acts as an homeostatic hormone to signal the body’s reduction of absorbing iron via reduction of transporters blocking iron absorption. Hepcidin production can also be increased by:
    • Inflammation (raised to block iron from pathogen utilisation)
    • Stress (physical or emotional)
    • The diurnal rhythm (levels are lowest early morning and at night)
    • Vitamin-D deficiency
  • Subtle signs of deficiency: eye conjunctiva, shortness of breathe, frequent yawning/sighing, mood alterations, sleep issues as iron is required for neurotransmitter production, pica (ice cravings), GIT motility and functional change
  • Testing - test at the same time or pay attention to testing times when assessing iron levels. This is due to diurnal rhythm – testing iron in the morning results in higher levels.
    • Iron studies need: serum Fe, ferritin, transferrin and transferrin saturation at the least
      • Completing the picture with RBC panel inc. haemoglobin and MCV. CRP, WBC, Cu, ceruloplasmin, albumin also useful.
    • Iron sequestering = high ferritin, low serum iron and low transferrin saturation
    • Stealth infections – check WBCs and inflammatory markers
    • Gut pH – acidic is optimal for Fe absorption
    • Autoimmune markers
    • HTMA – 3 month history of storage/excretion, assess for Fe to other mineral imbalances
  • Complementary herbs and nutritionals
    • Specialised pro-resolving mediators to reduce underlying inflammation
    • Antimicrobials and antivirals to resolve infections
    • Lactoferrin – especially useful in pregnancy
    • PHGG/GOS/FOS aids to increase absorption
    • Iron absorption cofactors – Vit-C, A, B2, Cu
    • Wholefood vitamin-C trumps ascorbic acid for various organic micro-cofactors not present in synthetic vitamin-C (kiwi’s, acerola, camu-camu)
    • Rosehip, withania, burdock, yellow dock, nettle, licorice infusion reduced to a syrup for iron deficiency (not anaemia)
  • Forms of iron to consider
    • Ferrous fumarate, polymaltose (high dose) – potentially inflammatory, GIT imbalances, may includes laxatives to counteract constipation
    • Iron bisglycinate or amino acid chelate - generally lower dose, less GIT impacts, consider dietary factors that might impact absorption
    • Heme iron - Beef liver is a good option if other animal forms are not part of the diet
    • Infusions where patient feel worse – treat the underlying cause/inflammation/infection

Resources discussed and further reading

Alison Mitchell

Alison's website
Connect with Alison: Instagram | Facebook

Iron and Immunity

Article: Iron in infection and immunity
Article: Iron sequestration by transferrin 1 mediates nutritional immunity in Drosophila melanogaster
Article: Chronic Inflammation and Iron Metabolism

Iron and Pregnancy

Article: Lactoferrin for Prevention and Treatment of Anemia and Inflammation in Pregnant Women
Review: Lactoferrin supplementation during pregnancy - a review of the literature and current recommendations.

Iron absorption

Article: Iron regulatory proteins control a mucosal block to intestinal iron absorption

Iron and Mood

Research: Iron and ADHD
Research: Post partum depression
Research: Iron deficiency and psychiatric disorders

Iron interpretation

Resource - see figure 2


 Lisa: Hi, and welcome to fx Medicine, where we bring you the latest in evidence-based integrative, functional, and complementary medicine. fx Medicine acknowledges the traditional custodians of country throughout Australia, where we live and work, and their connections to land, sea, and community. We pay our respect to the elders past and present, and extend that respect to all Aboriginal and Torres Strait Islander peoples today.

With us today to discuss the intricacies of iron deficiency is naturopath Alison Mitchell. Alison has been in practice for 16 years and currently works out of her home based clinic in Hawkesbury, New South Wales, seeing people both face to face and online or around the world.

As a family naturopath, while Alison has an interest in women's health, she often treats the whole family—the children, husbands, and outwards from there. And it's this experience with seeing a wide range of diverse clients with iron deficiency that has allowed Alison to get to know this mineral very well, making her the perfect person to chat with us today on understanding the complex issue of iron deficiency better.
Welcome to fx Medicine, Alison.

Alison: Thank you so much for having me. I'm very excited.

Lisa: I'm excited, too. So, iron deficiency is one of the most common nutritional deficiencies in the world, and it's perplexing to think that, even in developed countries like Australia, we still see iron deficiency. I think most practitioners would see it on a regular basis in clinic.

So, correcting deficiency sounds pretty straightforward in theory, but it's actually quite complex. Many of us, me included, would have experienced giving their iron-deficient client an iron supplement and some dietary recommendations to increase their iron and then retesting bloods and seeing no difference.
So, let's explore why this could be.

Alison: Yeah, I'm definitely seeing a lot of low iron in clinic, and it's becoming really rampant in young girls as well. I think it can even be sometimes is the sole reason why someone might come in to see me because they haven't been able to get that iron up no matter what they've tried. But often it's also because it's part of their overall picture.

Lisa: Absolutely. So, can we start first by differentiating between iron deficiency and iron deficiency anaemia? And I'm guilty of this, using the terms interchangeably, but they're actually different, aren't they?

Alison: Yes, that's right. So, typically the differentiation would be based on how much the iron is actually deficient and whether that's going to be impacting the red blood cells. So, iron deficiency might show up as having low ferritin or low transferrin saturation without the haemoglobin being affected. Whereas, iron deficiency anaemia is when the iron deficiency then goes so far as to actually affect that red blood cell formation and development.

Lisa: Okay, so iron deficiency, that low iron state with low transferrin, low ferritin, but the iron deficiency anaemia is where we see those red blood cells affected in the haemoglobin.

Alison: Yes, that's correct. And so often, in that instance, you would be seeing much more subtle signs of iron deficiency. Whereas, when it's more anaemia, it's going to be a lot more overt symptoms.

Lisa: Okay. So, where do we absorb iron and how does the absorption actually happen?

Alison: Well, we absorb iron in our small intestines, and there is a little bit of a difference between how we absorb heme iron and non-heme iron. It's actually a very small amount between 2% or 20% of iron, and that's in a healthy non-pregnant individual. So, the non-heme iron form is actually less absorbed than the heme iron. And it's interesting as well that pregnant women should technically be able to absorb a lot more iron because they get an increase in the amount of receptors, although that doesn't always seem to translate to a clinical situation.

Lisa: Definitely. Yeah, I think we often see a lot of very iron deficient pregnant women, right?

Alison: Mm. Yeah, it's a bit tricky. So, in terms of the absorption, so our heme iron, the way that that works is that has a metalloporphyrin ring. And so when that gets into our stomach, the globin part of that is then cleaved off. And so then that metalloporphyrin ring, it's absorbed through the HCP1 pathway. And the thing about that one is it doesn't have to compete with phytates and tannins like non-heme iron does.

So, non-heme iron has to be absorbed through DMT1 pathways, which is our divalent metal transporter, meaning it has the Fe2. And this transporter has to deal with other divalent metals as well. So, things like cadmium, mercury, manganese, vanadium, zinc, copper, and to a lesser extent calcium and magnesium. So, it is susceptible to competition, and so these pathways can get a little bit sort of blocked up, I guess. And non-heme iron absorption can also be affected by other things like dietary factors like tannins and phytates.

Lisa: Okay. So, within that absorption of iron, we're only absorbing a really small amount via our gut. Is that right?

Alison: Yeah, that's right. So, the things that we have to think about with iron is absorption like accumulating that iron but then also we have these other parts where our body uses the iron as well. So, we have to get it, from the small intestine out, into the blood as well. So, that's where we have something called ferroportin, and that takes it to the transferrin. And so then the transferrin has to move it around. And so you can think of the transferrin like the taxi for the iron.

Lisa: Okay, so ferroportin is the exporter of iron from the mucosal cells. And then transferrin is the taxi that transports the iron around.

Alison: That's right. Yeah. And so then in order to make the iron active, we have to make it into a trivalent form. So, the two turns into a three, and that requires copper to do that. So, these pathways that it comes through in the intestines, our DMT 1 transporters, they're going to be really influenced by levels of inflammation in our body but also, interestingly, by how much iron we actually have stored in our system as well. So, the more iron our body thinks that we have or the more inflamed we are, then the less that actually gets absorbed. And then anything that isn't absorbed... So, as we said, it's only quite a small amount that actually does get through. That stays in our gut.

Lisa: Okay, so it was only a couple of years ago that I learnt that we only absorb 2 milligrams, I think, from our diet. And I know that increases a little bit higher when we're really deficient. The body goes, "Okay, I'm going to absorb maybe 4 or 5 milligrams." But if you look at something like the RDI for women, it's 18 milligrams. Where do we get those other milligrams that don't come from the 2 milligrams that we absorb from our diets?

Alison: Well, we actually get that through destruction of our red blood cells for more iron. So, we call it the iron recycling system. So, our body has to actually break down the red blood cells, and then our white blood cells will come in, and they'll transfer the iron that's out of that, so specifically the macrophages. And then it takes it into the transferrin again, and then that gets taken back into the bone marrow and stored.

Lisa: Okay. This blows my mind because for a really long time, I thought we just had to get those whole 18 milligrams or 24 milligrams from the diet alone. And I couldn't work out, how am I supposed to eat that much meat, or spinach, or parsley? I thought there's something not quite right here, but I don't understand how to increase the iron in any other way.

So, it's super, super interesting that iron recycling system. And I guess if that's not working properly, maybe that's one reason why we're seeing people have low iron that are eating plenty of dietary iron.

Alison: That's right. So, there's something going on there where our body's going, "No, thank you. I don't want any more," and so it won't absorb more. And so that's a whole other factor where we have issues in terms of what we call the mucosal block but then also if this iron recycling system isn't working properly because something along the chain of that working isn't there.

So, I know, for instance, any particular issues with gut health, that's going to mean that you're also going to have some iron get stuck in those enterocytes. And so then that will then make the body think that it's... So, that cannot really work out for us, does it?

Lisa: No. Okay. So, can we talk more than about hepcidin? Because I know you can't really talk about iron without talking about hepcidin, but I think a lot of our patients have no idea what hepcidin is and does.

Alison: Hepcidin is a protein, and what that actually helps us do is it regulates iron. So, it's a really smart little cookie, and it helps us to not have too much because unlike other minerals, like for instance, zinc, we're not very good at actually excreting iron and too much iron is a bad thing. But then our body will also be able to know when we have not enough of it. So, the hepcidin will then send a message to the intestines to actually increase those DMT1 pathway receptors, and so then it'll allow the stomach take more in.

So, with hepcidin, if it's too high, then less iron is absorbed and similar situation conversely. So, it will be elevated in cases of also perceived inflammation. So, that could be or what our body might think is an infection because any sort of pathogen like a bacteria or a virus or a parasite, they love iron. And so our body will try and actually take that source of iron away from it.

So, then the hepcidin will come in, and they'll say, "Don't take any more in at the moment." And that's actually quite an evolutionary trait in that regard. Interestingly, because it will respond to perceived inflammation, that could also be things like high levels of exercise, which does have a little bit of an inflammatory impact but also emotional stress sometimes too.

Lisa: Wow, it's incredibly interesting. I've never heard that before. So, emotional stress can increase hepcidin. Wow.

Alison: And you know what else is really interesting is hepcidin has diurnal rhythm. So, it's lowest at sunrise and at sunset. So, if we are to take an iron, we want to be taking it at the time that our hepcidin is the lowest. So then we're going to be taking our iron either first thing in the morning or last thing at night.

Lisa: Interesting, circadian rhythm in everything.

Alison: Yeah. So, it's in everything, isn't it? Even for instance, if you're looking at a blood test, iron levels will always be...the serum iron, in particular, will always be highest in the morning.

Lisa: Okay.

Alison: Yeah. So, we have to always look at the time when we're doing our blood test review.

Lisa: Interesting. So, when hepcidin goes up, iron absorption goes down. And when hepcidin goes down, iron goes up.

Alison: Yes, because then it will change the amount of receptors that are there to absorb the iron in the intestine. So, after we've consumed non-heme iron, then hepcidin will rise for about 36 hours. So, that's why timing matters when it comes to actual taking of our supplements. So, that could be, for instance, you might not want to take it for every single day. You might want to take it every second day or potentially every day and a half.

Lisa: Okay, so interesting. So, timing matters, first thing in the morning or last thing at night and then every second day. We'll talk more about dosing later. It's really, really interesting. I'm writing those down to note.

Alison: It seems so contrary when I tell my patients to not take it every day because you think, "I've just got to get in as much as possible," but it's not how it works.

Lisa: The body is fascinating. All the little nuances that it has is really, really interesting. Okay. So, if we think about symptoms, I think most practitioners are aware that iron deficiency symptoms go just beyond feeling exhausted, and short of breath, and the tachycardia, and pallor, which occur as a result of that reduced blood oxygen. But what are some other symptoms, maybe less common symptoms that we need to be aware of?

Alison: So, definitely in terms of you mentioning pallor, I think that that's going to only show up in much more extreme cases of deficiency, but it is a good thing to do in terms of screening. I'll look at the conjunctiva. I'll look at the palmar creases. So, those are all going to be really, sort of, helpful bits of information. One of the other things that I tend to look at is symptoms of shortness of breath.
And I know, for me, that was always a really big flag when I was pregnant. I just couldn't talk. I couldn't say more than a sentence without gasping for air.

Lisa: They describe it as an air hunger, right?

Alison: And yawning all the time and sighing.

Lisa: Mm, okay. Interesting. Someone's doing that within the session. They're sighing a lot. It could be a clinical clue. What about mood symptoms? Because I think sometimes patients coming in there, they report changes in mood like anxiety and a flatness, issues with sleep, irritability. And I don't know if they always link those with an iron deficiency.

Alison: I think iron can have a pretty big role in terms of our mood and mental health. So, to keep in mind, we need iron in order to make our dopamine because tyrosine, which is a precursor to dopamine and also for our thyroid and our adrenal hormones, that has to be produced by phenylalanine, but low iron can impair the conversion of phenylalanine to tyrosine. So, effectively you can't make dopamine without enough iron. And so that can cause issues like low motivation and low moods and even things like anger and other symptoms like that. But iron is also involved in the conversion of glutamate to GABA. So, then we can see that might have more an excitatory sort of feel and low GABA would be making you feel more anxious.

Lisa: Definitely, and affecting that sleep. And I think there's quite a lot of research in children with that iron deficiency, creating that impaired transmission of dopamine and then that resulting in mood disturbances and sleep disturbances there too and concentration and things like that. It's very interesting.

Alison: Definitely. I always look for low iron if I have a child come in with ADHD or poor concentration. And even in children as well, fussy eating could be...it could be low zinc, but it could also be low iron. So, I think there's a really big crossover between a lot of the symptoms of low zinc, low iron, and potentially even low copper.

Lisa: So, going back to what you were saying about fussy eating and pica is a common iron deficiency, kind of, sign, isn't it, or symptom?

Alison: Specifically ice craving. So, often they'll be going to the freezer all the time and crunching on ice cubes.

Lisa: Interesting.

Alison: Yeah. So, I mean, how does that even work? How does our body do that? I don't know.

Lisa: I don't know.

Alison: It's a good sign.

Lisa: Yeah. I mean, I think these symptoms of iron deficiency are really widespread and very important for practitioners to be aware. I've found some interesting research in terms of iron deficiency in the gut, and that low oxygen from iron deficiency actually causes this decrease in intestinal blood flow, which can lead to motility issues, including malabsorption, nausea, and abdominal pain. And I thought that was really, really interesting, because if someone came into my clinic and they were saying, "Oh, I'm feeling a little bit constipated or nauseous and I'm getting a little bit of pain," iron deficiency is not necessarily the first thing I would be thinking of. I'd be thinking, "Oh, is there some sort of dysbiosis or IBS or something like that?" But really interesting that iron deficiency can even create issues like motility disorders and nausea.

Alison: And that's really interesting too, because then if you've got issues with motility, then you're more likely to have issues with dysbiosis or SIBO, and then you're going to have something there that's going to cause your body to sequester iron. So, the condition just seems to perpetuate itself.

Lisa: Yeah. So, what are some of the most common conditions and factors that you see in your clinic that contribute to low iron—dysbiosis or other things too?

Alison: Well, in a nutshell, I would put it down to either. You're not absorbing it, your body's not recycling it properly, or you're losing too much of it. So, that could be things like gut issues, inflammation, or blood loss. So, there are going to be other cofactors that are less obvious. So, a big one that I'm always looking for is if there's any sign of a stealth infection. Because if there's an infection, our body will sequester the iron into our storage organs, which is things like liver, spleen, heart, and then that will cause a lower level in our blood and potentially some symptoms of low levels.

Lisa: Can I ask? How would you be looking for a stealth infection? How would you know it was that as opposed to something else?

Alison: You'd be able to interpret that through the bloods. So, looking at markers of inflammation but also the white blood cells. So, this was something that. And so you'd be looking at things like the ratio between the neutrophils and the lymphocytes and potentially like a lower level of white cell count that's showing that there's some suppressed activity happening there. But conversely, it could be...if it's more of an acute infection, then that's going to be coming up with higher levels of the white blood cells.

Lisa: Okay. Okay. So, one reason could be stealth infections and I think even H. pylori could decrease, right?

Alison: Yeah, because like with any infection, our body will think of that as inflammation. And so then it will hide the iron in a way because it just doesn't want the bug to be able to use it. So, that could be a stealth infection like a virus, or Lyme, or it could be a gastrointestinal infection like helicobacter or SIBO or something else lower down as well. And so in terms of how you would actually be able to tell if your body is sequestering it, in addition to what we just said, you'd see increased ferritin, lowered serum iron, and reduced transferrin saturation.

Alison: If you are able to get copper done as well, sometimes you can see that that can actually increase, but it will often send out copper because it has an antimicrobial effect. So, then other things that I would say that would affect low iron generally is anything that is going to impair absorption, so things like coeliac disease. I'm going to be looking at... So, you can sometimes see hints in liver function tests for that. If you're not confident, sometimes it doesn't always show up in gut symptoms. And then also I'd be looking at other sorts of markers of inflammation. And so these are going to be having an impact on that hepcidin mechanism. And any inflammatory gut disorder will also increase the gut pH because we need to have a low gut pH and high hydrochloric acid to absorb iron properly.

Lisa: So, that part's really interesting, isn't it, because we know so many of our patients are in that sympathetic dominant state and probably have issues with stomach acid.

Alison: That's correct, or taking medications that suppress stomach acid production.

Lisa: Yes.

Alison: Like long-term use of PPIs.

Lisa: That's a really, really big thing. Yeah. So, what about then menstrual bleeding, because I think menstrual bleeding is one of the most common reasons for women. I think it is the most common reason for women being iron deficient.

Alison: Definitely. So, I would think of anything that's going to be causing menorrhagia, so uterine fibroids, endometriosis or adenomyosis, and also clotting disorders can also be another factor there too. And potentially you might also see thalassaemia as being another factor that could have a role too, which is more of a genetic aspect.

Lisa: Interesting. Okay. And then my favourite, autoimmunity. It's a really, really big one. Obviously, you've talked about coeliac, but what about autoimmune thyroid and things like that?
Alison: Well, that's going to be complicated in a few different ways because issues with thyroid function will have an impact on absorption because the thyroid, when that's underactive, that can cause increased heavy bleeding. But then also having low iron can cause issues with thyroid.

Lisa: Yes.

Alison: We know that because of the way that it affects your tyrosine, and you need iron in order to actually make your thyroid work properly. And autoimmune conditions are, again, going to increase that inflammation level as well.

Lisa: So, I think this really highlights an important point for practitioners to be aware of that often there's multiple reasons why a patient may be iron deficient. Say, for example, that autoimmune thyroid patient. It's not just the poor absorption. There's inflammation. The immune system itself might be attacking enzymes required to make iron. And I've often found that even though iron is so incredibly important for overall thyroid function, in these patients when you give them iron, it doesn't budge.

And so I've had patients with a serum iron of 4, ferritin of 4, and I've given them iron and it hasn't moved at all. And so I wonder then, with that kind of anaemia of inflammation, of chronic disease, is it better to not give iron at all and to approach it in a different way by treating that underlying driver, which appears to be the inflammation.

Alison: Yeah, because I do think that, if you are giving iron and it's not helping, then there's something that's not right. And then you might be perpetuating that problem.

Lisa: That's kind of what I'm thinking too. And so I haven't started using them yet, but it's something I want to start trying. And that's the specialised pro-resolving mediators, the SPMs, because with these autoimmune patients that the iron's not going up and I guess it's an issue with hepcidin, based on what you said, being too high because of that inflammation. I wonder, if you work on resolving that inflammation, will that in turn reduce hepcidin and increase iron in that way. It's something to consider. I don't think there's been any trials on that yet.

Alison: I am not familiar with any if there are, but one of the major things I would always be looking at first is resolving any infection that might be there or at least getting it down to a lower level. And the other thing that I probably should have said earlier as well is making sure that they've got the cofactors, because deficiency of cofactors could be another reason why you're not absorbing the iron because your body is just like, "I don't have the things that I need to transport that." So, the molecules that actually get the iron and move it around and mobilize it or recycle it, we need for instance copper for that to work properly and vitamin A for that to work properly. If we're deficient in those, that's no good.

Lisa: Okay. So, can we chat more about those then? You talked a little bit about copper being important for transportation of iron. Can you tell us a little bit more about that?

Alison: Copper particularly has an important role in something called ceruloplasmin, which has a very important role in iron recycling. So, it's really important. It's a protein that has this regulatory effect as well. And it's also a major antioxidant.

So, I guess the thing with copper is that we don't want it to be too high or too low. And similarly with zinc, because copper, zinc and iron, they work very closely together. We just need them to all be in balance.

So, in some cases of this iron refractory anaemia, which is where you've got low haemoglobin and you're giving them all the iron and it's not working, you might actually need to give them copper, because the copper will then bind the iron to the transferrin. And if you're deficient, then this will then eventually make matters worse if you're just giving iron without having the copper deficiency resolved.

Because free iron is bad. It causes oxidative stress, which we know is done through that fenton reaction and then that can lead to more ferroptosis, which is another whole type of inflammation. And so how we've got apoptosis and autophagy, ferruptosis is another aspect of that...it's actually a bad thing. We really don't want to have that happening too much at all.

Lisa: Okay. So, this is really interesting, because a lot of people just get prescribed iron by itself, right? That's what generally happens if you go to the doctor.

Alison: Iron and vitamin C, yeah. So, vitamin C, just how we used to just think of folate as folic acid or ascorbic acid is not the complete form of vitamin C. So, vitamin C in its whole form actually has all these other factors in there. It's like a substance P, substance K, and also has this other molecule within it called tyrosinase. And within that, it's like a little bit of copper.

Lisa: Oh, wow.

Alison: Yeah, so that's why wholefood vitamin C actually has a much better impact on utilising iron than just ascorbic acid, because ascorbic acid is the protective shell of the wholefood molecule, which was what they isolated when they started trying to understand vitamin C back in the day. Whereas, it's like, okay, maybe there's more to it. So, I really like to do wholefood vitamin C supplements like acerola and camu camu, and Kakadu plum because then we know that they're going to have those other little cofactors in it.

Lisa: Would you ever just use kiwifruit? Because I saw some research where they were just using kiwifruit with an iron supplement, and they showed the two combined resulted.

Alison: I could see a lot of benefits in that.

Lisa: Just because it's so high in vitamin C, yeah.

Alison: It is. It kind of leaves oranges in the dark, doesn't it? But the kiwifruit would also be really good because it has all the prebiotics and the fibre, which is another thing that I want to consider as well like maybe supplementing with things like that alongside iron, just depending on the situation. So, yeah, there's definitely other sorts of cofactors apart from copper and vitamin C that you need. You need to think about B2 as well because that's involved in that mobilisation stage of iron. And if we can't access our stores, we can't recycle it properly. And then making sure you've also got the vitamin A, particularly in the retinol form, I find that to be a little bit better utilised.

Lisa: Okay.

Alison: Yeah, because we need that to, again, make our iron more effective, and it's got an impact in that ceruloplasmin protein. I was reading something the other day, actually that was really interesting, that back in the 1800s, they used to use cod liver oil by itself to treat anaemia.

Lisa: Okay. Interesting.

Alison: So, yeah, and I reckon that would come back to the iron recycling system. because we need to have that working properly.

Lisa: Yes. Okay. And so going back to the copper that you were talking about, so if we think someone is deficient in copper, would you just be giving the vitamin C and thinking that's enough, or the wholefood vitamin C as a source of copper, I think you were saying, or would you be doing a different supplement with copper or foods?

Alison: I typically won't prescribe copper without having some, sort of proof that they need it.

Lisa: That's what I was thinking.

Alison: Yeah. So, the wholefood vitamin C is a really good option there, but I will usually try to get them to increase their copper foods. So, that'll be things like shellfish and organ meats, if they're amenable to that.

Lisa: Acquired.

Alison: I know not everyone is.

Lisa: Yes.

Alison: And, but then also you can get your copper and your ceruloplasmin done in a blood test. You probably will have to get them to pay out of pocket for that because in terms of the protocols and, the doctor might not be able to say why it can be justified, but then you can also look at things like a hair tissue mineral analysis as well to be able to say, "Okay, what's the ratio there? And do they need more copper that way?"

Lisa: Okay. So, let's talk a little bit more about testing. Obviously, we know that assessing iron levels through a blood test isn't as straightforward as just looking at ferritin. I'd love to know how you interpret the different markers and how do they compare to something like the hair tissue mineral analysis.

Alison: Yeah, it does my head in when I get patients to go back and get their iron studies done and all they come back with is just ferritin. And I'm like, "Okay, we need more than that." So, typically when we're getting iron studies done, it should include serum iron, ferritin, transferrin, and transferrin saturation. So, that's what is actually included in what you would ask for in iron studies.

But you want to be able to, interpret this in the whole picture. So, what I would like to see, at the same time, is red blood cells, which would include things like your haemoglobin, and your mean corpuscular volume, and red cell count. And even better again, put it in context of if there's any inflammation, so C-reactive protein, white blood cells, and bonus points, copper and ceruloplasmin.

So, looking at the red blood cells, you can tell a bit more about if there's any, sort of, end stage anaemia, so like MCV, which is looking at the diameter of the red blood cells, that will be quite small. If you're having iron deficiency anaemia. And then if you're seeing things like C-reactive protein being elevated or white blood cells being elevated or even potentially lowered, then it's going to be telling you that there's some form of inflammation or infection or stealth infection. So, then you go, "Okay, is it actually an infection that's causing our iron studies to become disturbed?"

Alison: And you can even look at albumin because low albumin would tell you if there's going to be a protein deficiency, and that would cause very disrupted iron studies too. So, if you're seeing something that you just don't understand and then you go, "Oh, look, there's low protein." And then you can go, "Okay, that's why."

Lisa: So, that's really interesting because, with a lot of my autoimmune patients that are iron deficient, I will always see low protein and, as a result, low albumin and low transferrin as well.

Alison: And, I mean, potentially they may be iron deficient as well as being inflamed as well. So, there's a few different sorts of situations that you can see it. So, serum iron by itself, it's not particularly useful at assessing iron stores. So, what I like to look at is your transferrin. So, remember, that's your iron taxi. That's a very underrated marker for assessing iron deficiencies, I think, because low levels will occur in chronic disease, and it will be high in iron deficiency and also in pregnancy. Ferritin might be low in iron deficiency, but then that can be something that's going to be really heavily influenced by inflammation or infection.

So, higher transferrin is more common when your body's trying to capture more iron. So, if you've got low haemoglobin with high transferrin, you'll need to give them iron. If your transferrin's low and you've got other inflammatory markers that are high, then don't give iron just yet. Deal with the inflammation and the potential infection.

Lisa: Okay. So, low transferrin, looking for inflammation or infection and don't give iron.

Alison: Before you give it. If you see low or normal transferrin saturation or high ferritin, yeah, that could be inflammation, but it could also be low iron at the same time. So, I wouldn't give iron until their inflammation is being dealt with.
If you see high ferritin, low serum iron, and saturation, that's iron sequestering and inflammation. So, you want to be going, "Okay, searching for those markers of inflammation to confirm that."

Lisa: Okay, so it's not just as simple as just looking at the iron studies in isolation. Can I ask you...

Alison: Not really.

Lisa: Okay. No, I know it's a lot more complex. So, when would you think it is time to supplement with iron in terms of numbers, and I don't know if you have a number, would the ferritin have to be a certainly level for you to go, "Okay, time to supplement," or we can just watch and wait? Because the majority of my patients come in and their ferritin is relatively low in reference to the range, which I think is something like 30 to 200. A lot of my patients are sitting under 30, but a lot of them are feeling okay, too. So, where do you go, "I'm going to supplement," and where do you just say, "Well, I'm going to leave it"?

Alison: I wouldn't have a specific number I can give you, but I would say that where I would reach for, definitely if there's that obvious iron deficiency anaemia picture, and if you have also got ferritin that's lower than 20, I'd be definitely going for it as long as we've confirmed that there's no other sorts of markers there. Above 20 or above 30, I'd just really be putting it in perspective. Can we do this through just getting the recycling system working better with those cofactors? Because I've become very cautious with prescribing iron without making everything else work properly, because I don't like that idea of having too much free iron floating around in the guts, if it's not being absorbed properly.

Lisa: Yeah, I agree with you on that one. I think there's a fair bit of research showing that it can create dysbiosis and free radical damage in those enterocytes. And that also encourages the growth of enteropathogens, which is something we don't want. I guess, can you tell me a little bit more about the hair tissue mineral analysis? Because I know you do that, and it's not something I do at all in my clinics. And I'm thinking, with all these other minerals being involved, it sounds like it would be really useful.

Alison: It's really interesting. I guess there's a bit of a difference in how you interpret it compared to how you interpret a blood test, because a hair tissue mineral analysis is like a three-month snapshot so what's being stored, what's being excreted over that last three months. Whereas, the bloods is like right then and there what's happening. So, that's something that can be changed from hour to hour. We were just saying how serum iron increases in the morning and then it would be lower in the middle of the day. But then hair tissue mineral analysis doesn't really matter what time you cut the hair. It's going to just be what's been happening.

So, really what you're looking for in the hair tissue mineral analysis, what's different is you're seeing patterns of imbalance and you can see whether someone's more inclined to have an iron deficiency or potentially even an excess because of the different ratios. So, if you're seeing low iron to copper, low iron to lead, low iron to mercury, or a high calcium to iron, then that would, sort of, make you think that they're more likely to have that low iron picture.

So, I would be more comfortable supplementing with iron if I'm seeing those sorts of situations because then I think that, okay, that they are in need of it. Whereas, you can see other markers that may be potentially not using your iron properly like the high iron to copper, if that comes up in a hair test, then I would be looking at maybe supplementing with copper in that instance.

Lisa: Okay, you're very insightful, so something to think about if we're not getting where we want to go to with our patient's that are iron deficient. All right, so there's some really interesting research out there on the gut microbiome and iron. And it, kind of, makes sense if you think about where iron is absorbed within the gut. You talked a little bit before about prebiotics. Can you tell us a little bit more about how you use them?"

Alison: Well, I actually really like to use lactoferrin as well, which has a bit of an impact in terms of the gut microbes. And I'll use that iron deficiency if the woman is pregnant particularly. I think that could be really good. My general go-to for a prebiotic is partially hydrolysed guar gum. I know that there are some other research in using different prebiotics as well like GOS, and I also really like using the probiotic, Lactobacillus rhamnosus 299v because that one's really good because not only does it help to reduce constipation, which we know can be a problem with people who are taking iron supplements or maybe taking the wrong types of iron, but a lot of that reduces that gut inflammation and so then that's going to help with modulating those receptors being poised up unnecessarily.

Lisa: Yeah, the research on the GOS and the FOS is really, really interesting when give with iron supplements and I think some studies were showing that it can increase absorption by 50%, which is pretty amazing. And from what I could make out, I think they're not really 100% sure of the mechanism of action, but it seems to reduce inflammation in the cecum, which is that pouch that connects the small intestine and the large intestine and also decreases hepcidin.

So, again, fascinating that those prebiotics can reduce inflammation within the gut. We know that, but decrease hepcidin too. So, it really does often always come back to the gut, doesn't it?

Alison: It does. I was just thinking that.

Lisa: The other thing that's also interesting in relation to the gut is vitamin D. And we know there's receptors for vitamin D all over the gut. And, again, this one seems to be another important vitamin to help with iron absorption. And that's via its effect as a regulator of hepcidin expression, which is super, super interesting. So, when vitamin D is deficient, some of the research was showing it could result in high hepcidin, so it blocks out iron absorption. And then when they gave vitamin D, it actually improved some people's, not all, but it improved some people anaemia by decreasing hepcidin levels, so this might be another one to think of, I guess, where there's that chronic inflammatory picture, so those patients with iron deficiency related to IBDs and autoimmune conditions and things like that.

Lisa: Now let's come back to dosage, which I know you were talking about before and forms of iron, because there are so many different types on the market, and some are really, really high dose, some are low, there's transdermal iron, there's infusions, there's liver. I'm wondering, firstly, with everything we've learnt so far about us only absorbing two milligrams, max five, within the gut, is there any point to taking those really high dose forms like the ferrous sulfate at 100 milligrams. Is there any point? Is that going to be causing a problem?

Alison: I get very nervous about those really high doses. I mean, I was always trained don't go over 24 milligrams. But it makes sense when you start to read about how anything over that dose makes hepcidin kick in and stop absorption. So, I think that, for me, I don't like the high-dose ones. I guess there is merit in some instances for things like the really high dose, but I wouldn't really ever consider doing it. I certainly wouldn't do it daily and I certainly wouldn't do it long-term.

Lisa: So, it seems like...

Alison: I would only ever think about doing it as well if I've resolved inflammation and dysbiosis first.

Lisa: Yeah, that's what I was thinking. It seems like, if it increases hepcidin that much, which we know basically also, it's creating inflammation in the gut, that does not seem like a good thing.

Alison: Exactly. So, we know that sometimes those common types, the ferrous fumarate forms, they also cause gut irritation and constipation and the ones that are really high, they put a little laxative in there with that too. So, that can cause…

Lisa: Dysbiosis.

Alison: ...gut issues in people too. I've had some people come in and say, "Oh, I love it." It's great. But I still worry about all that free iron in the gut causing that oxidative stress and enteroptosis that makes me nervous.

Lisa: Sure. And I guess there's good reason for that because that constipation, and that nausea, and that discomfort is a sign of gut inflammation. That what's happening. So, it's about I think those naturopathic principles of first doing no harm.

Alison: That's so true. We don't want to be feeding that mucosal block issue that's going on, which is where those receptors just close up and hold onto the ferritin within those enterocytes.

Lisa: So, there's some pretty good research on the lower doses of iron, including the bisglycinate. I was just actually awed by the research on the bisglycinate in relation to the ferrous sulfate and even in relation the polymaltose form. It is a lot lower, but it appears to be just as effective in terms of repletion of iron with less of the side effects.

Alison: As you said, the bisglycinate, that's my go-to one...

Lisa: Okay.

Alison: ...or the amino acid chelate. So, it could be written like. I think that those ones are quite good, I guess, if you're choosing a non-heme iron. And the downside of that is that you do have to think about all of those dietary aspects that are going to be potentially impacting production of that. So, your tannins or your phytates. Whereas, if you're looking at using a non-heme iron supplement, you don't have to be as careful with that.

Lisa: What are your thoughts on iron-rich herbs like withania and codonopsis? I know sometimes practitioners like to use these. Are they enough to correct an iron deficiency?

Alison: I wouldn't say that they're enough in the case of iron deficiency anaemia, but in iron deficiency, yeah, I love them. And I actually sometimes will get people to make a really long infusion and boil it down to a syrup of things like rosehip and liquorice, burdock, nettle and yellow dock. Those ones can be really nice to have as a drink that you regularly take. And then all of your red and, sort of, blood-coloured foods like beetroot also I think are really beautiful as well in nourishing the blood.

Lisa: Okay, lovely, lovely. Very naturopathic.

Lisa: Now, what about iron infusions? Because I have heaps and heaps of patients being recommended these now. And I'm wondering, as to the pros and cons of these, because often a patient will come in and they will say, "I've had four or five infusions," and I feel like the underlying driver as to why they need to have them is not really dealt with.

Alison: And do you sometimes find that they say that they felt really bad afterwards?

Lisa: Definitely with the patients that I see because a majority of them have an autoimmune condition. I don't think there's really been anyone that's come in and said, "Oh, my gosh, I feel amazing." A few of them have actually had an adverse reaction, and I think that's because obviously it's been too inflammatory, but I guess that's because I'm seeing a very kind of niche client base where there is a lot of inflammation. I'm wondering, with infusions like after pregnancy and things like that, I could see why that would be beneficial.

Alison: I know. And I think that I can see why people go for it. But I think that, in some cases, if it's a very obvious iron deficiency anaemia picture where they've been losing a lot of blood or they have lost iron, then I think an infusion can be helpful. I do think sometimes they reach for it too quickly without looking for issues with the recycling or if there's inflammation or deficiency of cofactors, because if any of those things are present, I think an infusion will make you feel worse.

Lisa: Okay. Fantastic.

Alison: I would say, if if someone is going to go for an infusion, to make sure they are getting in some antioxidants around the time that you're getting it done to try and help mop things up. So, vitamin E is one that I've used in the past to support that and also making sure that you're not having a lot of inflammatory foods at the same time and that your gut's happy, so prebiotics.

Lisa: That makes sense. Now, last question, are there any situations where you would avoid supplementing with iron?

Alison: I would avoid it if there's an infection, inflammation, inflammatory gut disease, so definitely things like ulcerative colitis, I wouldn't really give oral iron in that case. Or, if I am suspecting a deficiency of cofactors, I won't give iron with that.

Lisa: Wonderful. Well, thank you so much for joining us today, Alison. You shed so much light on the topic I know many of us struggle with in clinic, and you've just given us so many little tips to try with our clients.

Alison: Oh, thank you. I really hope that it's helpful for people. It's good to be able to talk with you.

Lisa: Thank you. Thank you, everyone, for listening today. Don't forget that you can find all the notes, transcripts, and other resources from today's episode on the fx Medicine website. I'm Lisa Costa-Bir and thanks for joining us. We'll see you next time.

Emma: This podcast is intended as healthcare practitioner education only, and it is not a substitute for medical advice, diagnosis, or treatment.


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