Andrew: Oh, this is such a needed topic. And please forgive my ignorance in this, because I know that I’m going to be learning a heck of a lot myself. Okay. So, if we dive in, you’ve explored the research on how, let’s say, inflammation affects iron absorption, and mobilization, importantly. So, can you explain how cytokines and how inflammation interacts with iron, as a mineral and nutrient, and to influence the process?

Laura: Yeah. So, it’s quite a complicated process. And to understand this, we really need to look first at how iron is absorbed. So, the small intestine, of course, is where our iron goes from our intestines into our body. And in order for it to get out of the small intestine and into circulation, it has to go through the enterocytes that line the cell, taking us back to nutritional biochemistry, from uni. And that’s essentially the portal that the iron needs to pass through. And I guess the simplified version of what happens there is that the iron arrives in the small intestine, it enters an enterocyte through DMT1, so, that’s that divalent metal transporter. And then once it’s in the enterocyte, the next thing it needs to do is get out the other side, into circulation. To do that, it’s gotta go through, like, I call it the ferroportin door, but it’s just called ferroportin. And when there’s inflammation present, and this doesn’t need to be significant, you know, acute inflammation, it can be subclinical, just chronic, rumbling inflammation, we have elevated levels of inflammatory cytokines. And, you know, our CRP can be elevated, and all these other markers that are showing us there’s inflammation in the body. And these essentially stimulate the liver to produce hepcidin. And what hepcidin does is it acts like the gatekeeper. So, it’s sent to the small intestine, and it basically degrades that ferroportin door. So, now the iron that’s waiting in the enterocyte, ready to be led into circulation, has nowhere to go because this door has disappeared. Then this problem is compounded because enterocytes, as we know, only live for about 72 hours. And so that enterocyte then dies, gets sloughed off the wall of the small intestine, and, you know, we shed into the lumen, and we excrete it through the bowel, with the iron inside of it. So, and this isn’t the only place that hepcidin does this. It does it on ferroportin, on macrophages as well. But, you know, when we’re talking about trying to build up our iron levels through supplements or our diet, we’re really talking about what’s happening in the small intestine, and this is where we really see the impact that inflammation can have. So, you know, even if you’re eating plenty of iron or you’re taking iron supplements, your absorption and your mobilization are gonna dramatically be dropped, because the iron essentially gets trapped.

Andrew: Right. Okay. So, this is gonna be a bigger one than Ben Hur, differentiating between true iron deficiency and inflammation-mediated supposed iron deficiency.

Laura: Yes. Yeah. It gets blurry. So, there are…so, there’s two types of iron deficiency, so, true iron deficiency, being you don’t have enough iron stores left, and functional iron deficiency, which is mainly caused by inflammation, where you might have enough iron left in the body, but it’s not being mobilized, or you can’t access it because of that inflammation. So, in true iron deficiency, the body’s iron stores are generally low. Our ferritin is low, our transferrin will be high, because it goes up, and the liver is signaling that it’s trying to go out and find more iron. Transferrin saturation’s usually low when our CRP will be normal. So, that’s typically what you would see on a blood test. Whereas in functional iron deficiency, the iron is present, but as I said, it’s trapped. And so we might see a normal ferritin, or a high ferritin. But what we’ll see is the transferrin being lower, because the body has enough iron. So, it just can’t access it. It can get a little bit confusing, though, because these two types of iron deficiency can overlap, and I see this a lot in clinic. So, somebody might have started off with, you know, true iron deficiency, and their ferritin might be somewhere, I don’t know, let’s say it’s really low, six or seven, and then they’ve become inflamed. And so that inflammation is now pushing up their ferritin level, because, as we know, when someone’s inflamed, their iron gets sequestered into ferritin. And so now their ferritin might be sitting at 31, 32, and so technically, they’re not deficient, but they feel like they are.

Andrew: Yep.

Laura: Because it’s not a true reading.

Andrew: Okay. What about other markers, though? Like, ferritin, you know, if we’re talking about saturation, if we’re talking about the other markers, take us through what happens there.

Laura: Yeah. So, in, if there’s inflammation that’s affecting the iron transportation, then as I said, we’ll still see the transferrin sitting lower if that person has enough iron stores, because the liver knows there’s iron around. It isn’t going out saying, “we need to get more iron from the small intestine. Let’s go out and send more transferrin to get it.” But what happens is that the saturation level will be lower, because saturation being how much iron is on each of those transferrin molecules. And that’s because the body is trying to protect you from what it perceives to be, like, a bacterial infection. And so it knows that pathogenic types of bacteria use iron to replicate. And so the liver, in all of its infinite wisdom, thinks, “well, we must have an infection if there’s inflammation.” And so, instead of allowing that iron to be saturating the transferrin, and moving around the body where it needs to go, it all gets taken out of circulation. So, you’ll see this reduction in transferrin saturation, and you’ll see an elevation in those acute markers, like CRP, ESR, and potentially some of the more subclinical markers as well, if you’re looking at your neutrophil/lymphocyte ratio, and albumin to globulin as well.

Andrew: So, in effect, we’re causing a supplement or medication-driven hemochromatosis. It’s just not hereditary.

Laura: Yeah, essentially. And that can happen. And I have seen people’s ferritin levels jump up into the hundreds as a result of this. I think because the population that I’m mainly working with tend to also have true iron deficiency, I don’t often see it go that high. It usually kind of brings it back into somewhat of a normal range. But it can trip clinicians up, because we can sometimes think, well, we really need to push ferritin higher and higher, which we’ll get into a bit later on. But if we see a ferritin of, say, 70 and think, “Oh, wow, that’s really good. We don’t need to worry about anything there,” and we don’t look any further, we might actually be missing this inflammatory picture.

Andrew: Yeah. So, let’s go into this ferritin story, because I’ve even seen women having two, three, four infusions, and their iron is still “low.”

Laura: Yeah. Yeah.

Andrew: And so, it’s like, even the GP’s scrabbling for answers there. So, tell us what’s going on, yeah.

Laura: Yeah. So, a couple of things. So, with iron infusions, again, if we go back to inflammatory picture, if there’s inflammation around, they’re more likely to be a poor responder to the iron infusion. And there are those people that will say either, “I had an iron infusion, and I didn’t feel any different. On paper, my blood work looks better, but I just still feel the same.” Or, they’ll say “My ferritin peaked, and then it just fell off a cliff again.” And it’s because the body is just rejecting the iron, for the same reason we spoke about last time.

But I think, as you mentioned, it’s also really important to understand what ferritin actually is, because I think it’s quite misunderstood. So, there’s probably two big misconceptions that I see around ferritin. The first one relates to what it actually is. So, often I hear people talking about ferritin as stored iron. But ferritin is actually a self-assembled protein cage. And it’s found throughout the body, so, it’s in the cells and it’s in the blood. And iron is what is stored within the ferritin cage, so they’re two separate things. What I find really fascinating is that the, just not to go into the detail too much, but the ferritin that we have in our cells contains around 1,000 to 4,500 iron atoms. When we look at that same iron in the blood, which is where we’re obviously testing it when we do a blood test, we only find about 150 iron atoms. So, that raises a really big question, right? Like, where did all the iron go? And we don’t actually know. We don’t know. So, there are theories around what happens. There’s theories around how the ferritin goes from in the cell to in the blood. And the working theory at the moment is that it actually happens through cellular damage, so, it’s this uncontrolled leakage of ferritin into the bloodstream, which makes sense when we think about ferritin being an inflammatory marker.

So, that’s the first part. And then the second misconception, which we briefly touched on before, is, well, where should our ferritin actually be? Like, what is the optimal range? Because as naturopaths and natural medicine clinicians, we often talk about, well, the reference range says this, but we really want it up here. With ferritin, what I’ve found in the research, and there’s been large-scale populations that have looked at this, for somebody, let’s take somebody who’s having a fairly regular period, it’s not super heavy, and they have a fairly typical diet. Their ferritin value will quite happily sit somewhere between 30 and 50, and that is okay. We don’t need our ferritin to be pushing up to 100, because, as I said, ferritin is, it’s a protein cage. The iron goes in there, and once the iron is in there, the body’s not actively using it. It’s quite literally stored away. And the analogy that I like to use is if you think about, you know, if you have winter coats, and it’s coming into summer, and you don’t need all of your winter coats, so you put them all into storage, you’re not using them through summer, it starts to cool down again, you think, “I might just pull out one of my coats,” you really only need two or three coats maximum in storage. Having 150 coats in there is not gonna keep you any warmer. So I think about iron in ferritin that way. As long as you’ve got enough that your body can draw on it when it needs it, we don’t need massive amounts of excess iron being stored in ferritin. So, they’re the two things that I’d really like to, yeah, kind of just clear up today.

Andrew: Okay. So, the sweet spot is that 30 to 50. And you were talking about a woman with a normal period. What about men?

Laura: Yeah, so, men, it will definitely be higher, but if I was to see somebody, if I was to see a male, or someone assigned male at birth, in their 30s, and their ferritin was in the 200s, I would be, that would be a red flag for me that potentially there’s hemochromatosis here. So, it will be higher, but usually somewhere in the hundred, between…

Andrew: Okay.

Laura: [crosstalk 00:11:37] and it will naturally increase with age, because they don’t have that regular blood loss, which is the same mechanism that we see when someone goes through menopause, their ferritin will then gradually start to rise.

Andrew: Yeah. Okay. So, do we need to discuss the markers, like, how you use them in combination? Do we, you know, this is up, that’s down, that’s equivalent, da, da, da. Do you want to…I’ve seen tables, and I look at them and go, “Ah.”

Laura: Yeah, there’s a lot going on. So, I mean, I guess the basics are that the first thing that I’ll always look at, even ahead of ferritin, is transferrin. Because transferrin is really telling us how hungry the body is for iron. You know, Rachel Arthur talks about this a lot, that your, the liver makes more transferrin and sends it out when the liver decides that the body doesn’t have enough iron. So, if we see a ferritin and it’s 29, for example, but the transferrin is sitting at an optimal level, which I would say is below 2.6, I typically won’t, you know, I won’t supplement. We might do a little bit of dietary strategies, just to make sure their ferritin doesn’t continue to drop, but at that point, their body is telling me, based on their transferrin, they’re not hungry for iron. If I saw that same ferritin value at 29 in someone whose transferrin was 3, 3.1, 3.2, it would be a very different picture, because for that person, their body is saying, “Actually, hold on. I don’t have enough iron for all of my needs, so we need to address it.”

So, that’s the first thing I look at. And then I look at the saturation level, how much iron is actually being moved around the body on that transferrin, because this is when we start to get into, okay, you’ve got enough iron stored away. How come you still feel iron deficient, or how come your red blood cells are showing signs of anemia? And this is where, if I see somebody’s transferrin saturation is a bit low, I’ll consider using things like copper, or other nutrients that we need, to help the iron basically get onto the transferrin. Because if we go back to the ferroportin door on the enterocyte, once that ferroportin door opens and the iron’s now in the bloodstream, we need good levels of copper in order to get that iron onto transferrin.

Andrew: Has that got something to do with superoxide dismutase at all? The copper levels?

Laura: It’s to do with ceruloplasmin and hephaestin.

Andrew: Ceruloplasmin, forgive me.

Laura: Yeah, ceruloplasmin. Yeah, that’s what you meant. Yes. Yeah, exactly. So…

Andrew: Yeah. Yeah. No, it’s not… I was wrong.

Laura: Yeah. So, ceruloplasmin and hephaestin, they both require copper, and that’s what you need in order to get the iron to then basically jump onto the transferrin.

Andrew: Okay. And what do you think about this notion of the sort of golden ratio, if you like, you know, like, 10 to 1 or something like that with copper, iron to copper?

Laura: Ah, yeah.

Andrew: Have you heard about this?

Laura: No, I haven’t. I haven’t. I just usually, you know, I’ll do a blood test and I’ll make sure they have enough. And then I’ll obviously look at it in relation to zinc. But no, I’m not familiar with the golden ratio. You’ll have to fill me in.

Andrew: No. No, look, it’s an old concept. And there was, like, zinc, iron, and copper trying to get into the same keyholes, and, you know, too much zinc and you go on.

Laura: Oh, of course.

Andrew: Yeah. And I’ve utilized that with treating hemochromatosis, hereditary hemochromatosis, where we have to give massive amounts of zinc, but we have to also look at making sure they don’t have a copper deficiency and end up with cardiomyopathy from that, you know.

Laura: Yeah. Yeah.

Andrew: So, can I ask, then, with regards to copper, are you concerned with the type, with the form of copper? Copper as a chloride, or…?

Laura: I haven’t found it’s mattered that much, to be honest.

Andrew: Okay.

Laura: I mean, I have my go-to, you know, supplements that I’ll use in clinic, but they’re usually just practitioner straight copper supplements. I haven’t noticed there’s too much of a difference. And because we don’t need to go super high dose, we don’t need to do it for that long, we really just need to get a little bit in there to help with these processes. So, no, I haven’t found there to be much difference.

Andrew: And, you know, there was a big shift, if you like, in practice, where copper was labeled as the bad guy…

Laura: Yeah.

Andrew: …a copper overload. And I understand, in West Australia, I get it, different types of pipes and things like that, but I’ve never seen it over here. Have you seen copper excess?

Laura: No, I haven’t either, except, as I said, I have a few clients who work in kind of mining roles and that kind of thing. But yeah, unless you’re actively being exposed to it through, usually through industry, or yeah, as I said, through particular types of water pipes, it’s more often that I’ll see copper on the low side.

Andrew: Gotcha. And just along that line, zinc, zinc issues. Do you find that either too much supplementation, for instance, with meals…

Laura: Yeah.

Andrew: …or are you seeing any other aberrations where, A, you might need zinc, along with the iron, or at a different time from the iron, to help iron absorption, or is it mainly copper that you find works?

Laura: No, it’s both. And zinc’s an interesting one, because, again, this, I feel like this is very oversimplified. Well, I had it very oversimplified in my mind before I started looking into it, that, well, zinc and iron interfere for absorption, they compete, and so you shouldn’t have them together. But there’s actually not really consensus in the research about what is going on in the small intestine with zinc and iron, and they seem to have a bit of a push-pull relationship. So, we used to think that they competed because they both use the DMT1 to get into the enterocyte, but zinc actually uses a ZIP14 transporter, not the DMT1. And we do actually have research that shows that the zinc level, if you have adequate zinc levels, it actually helps with the expression of DMT1, so you can increase the uptake capacity of iron. I think, as you said, where you run into trouble is if you’re supplementing with really high doses. From a dietary perspective, it’s fine. And if you think about the sorts of foods that are really high in iron, red meat, it’s also really high in zinc. So, when we have it in a dietary meal, it’s okay. It’s just when we’re going in with too much of it that I think we can destabilize things.

Andrew: Yeah. So, let’s talk about this supplementation strategy. What’s the latest evidence with regards to iron? Because I remember, forgive me, I remember, what was it, back in 2022, say, there was this shift in how we’re looking at iron supplementation, the dosages that we’re using, because of hepcidin, they’re talking about. There was no mention of inflammation or anything like that. It was only that hepcidin blocking the transporter.

Laura: Yeah.

Andrew: Yeah, can we discuss that?

Laura: Yeah, definitely. So, yeah, you’re 100% right. We, as naturopaths and clinicians, we now use alternate-day dosing primarily, and much lower doses. So, around that 24-milligram equivalent iron seems to be the sweet spot, and doing it every second day. I usually recommend in the morning, but you can do it late at night, before bed as well. And we do it every second day, A, from a tolerance perspective, because it helps people if they have digestive issues going on, you know, a bit less iron, and giving them a 48-hour break from it can help, but it also helps with absorption, because, as you said, hepcidin is going to be blocking the iron from being absorbed if there’s too much inflammation. The other reason why hepcidin will block iron being absorbed is if you take too much iron. So, the liver will also send hepcidin out if you, you know, if you take a whole lot of iron supplements because it thinks, “Hang on a second. We don’t need too much iron. Let’s shut the gates until we figure out what’s going on, and then we’ll open them up again.” And so, once hepcidin becomes active, it stays active for about 36 hours.

Andrew: [inaudible 00:19:31] yeah.

Laura: Yeah, about two days. And so, with this alternate-day dosage strategy, we essentially sneak a little bit of iron through before the gates shut, we wait for them to reopen again, and we repeat the process. And, yeah, I get far greater success with that than the old, “We’ll just give them more and more iron,” you know, twice a day, really high doses.

Andrew: Now.

Laura: Just doesn’t get you anywhere except for constipated.

Andrew: Yeah, yeah. And nausea and blah, blah, blah. And horrible-smelling, iron-smelling poos, and the whole kit and caboodle. But, so, two things. Like, one is, forgive me, I forgot to mention before, that was a medical change in 2022, where the medical guidelines were changing. And there were, I remember there was an RACGP, but it was a newspaper thing that I saw. That was probably the one that was the best explanation. But then I saw more and more things, and now I think the guidelines have changed. Having said that, naturopaths have been doing that for 10-odd years.

Laura: Yes.

Andrew: So, it’s like, I was telling somebody else that we’ve podcasted with that medicine’s finally caught up to what…to the science. It’s really dogma. You know, it is. It’s entrenched.

Laura: Yeah, yeah. Yeah, that’s right. And, I mean, you know, we saw the same thing happen with probiotics, right? Like, we’ve been recommending them for decades, and now they’re becoming more accepted, so…

Andrew: Yeah.

Laura: Yeah, and I think, just to add a little bit more nuance to that conversation around alternate-day dosing, there are exceptions to that, right? You know, if somebody comes to me and, you know, they’re, maybe they’re following a vegan diet and they’re not necessarily eating enough different varieties of iron-rich foods, or, you know, whatever’s going on for them, occasionally, I will do daily supplementation, if it’s a fact of you’re just not getting enough iron in, and we can’t fix that at the moment, I will do daily. But 99% of the time, it’s alternate-day, because people just respond so much better.

Andrew: Yeah. I’ve also, when I was researching this, I read a paper, and all I remember is that it was, like, an Iranian researcher, Iraqi researcher. But they had what I thought was a rather arbitrary dose of 60 milligrams per day. And I went, “What, based on body weight?” Like, what are we basing that on? But, so I thought it was rather arbitrary. You’ve gone rather lower than that, though. Yeah?

Laura: Yeah. Well, because if you think about what you’re getting from your diet, you know, the average Australian would get somewhere between 10 and 15 milligrams of total dietary iron, and of that, we can absorb about 1 to 2 milligrams a day. And so, having 24 milligrams, for a lot of people, that’s double what they would get through their diet anyway. And so, if you just think about how the body is working, it’s just not going to let you absorb more than that. So, if you can get it closer to what, you know, what you would get from your diet, we’re less likely to cause the body to freak out and block it all from being absorbed.

Andrew: Yeah. But I’m also impressed with the way you’re thinking from a safety standpoint, because, as you were saying, if your body takes it in and your liver says, nah, it’s too much, it’s already in there. Where to now? Spleen, brain, heart, what?

Laura: Well, yeah, that’s right, and that’s where you can potentially run into an issue with oxidative damage, and are we contributing to an inflammatory picture? The other way that it can cause problems, a little bit more indirectly, is if you put in, say, if we go in with a 300-milligram iron supplement that has 100 milligrams of equivalent iron, that is far too much for the small intestine to absorb. And so what happens then is that iron has to go somewhere, and it gets dumped into the colon, where, obviously, all of the gut bacteria live. And as we talked about before, if you have less-friendly bacteria living there, if you’ve got pathobionts, or potentially a pathogen, they’re gonna use that iron to replicate. And what those pathobionts do is create inflammatory substances. And so now you’re feeding into this inflammatory cycle, where that inflammation blocks you being able to absorb it, so you take more iron supplements, you create more inflammation, and the cycle just goes on and on.

Andrew: That’s such a brilliant answer. The other thing, of course, is a horrible, foul-smelling wind.

Laura: Yes.

Andrew: Yeah, yeah, because the iron, the bugs are just eating up the iron in the distal colon. Okay. So, role of cofactors. We’ve mentioned iron and copper, but, you know, there was, I remember, back in the years, the years on…he brushes his grey hairs away. You know, there were some anemias that weren’t responsive to iron, and they were responsive to several of the B vitamins, for instance.

Laura: Mm-hmm. Yeah.

Andrew: We’ve now got an unfortunate situation in the Australian market, where B6 is being restricted.

Laura: Yep.

Andrew: Take us through this. What do you use? How much do you need? What’s safe? What do you look out for?

Laura: Yeah. So, I use a lot of testing in my clinic, blood testing, to work out, well, you know, do we need particularly B12 and folate? Often, people are deficient in those. So that’ll be usually where I’ll start, from a B vitamin perspective in particular. So, B12 vitamins, as we know, are really needed for red blood cell production. So, they make the red blood cells, and then we need iron to make sure that those red blood cells have good levels of hemoglobin to transport oxygen. So, they really go hand in hand. So, this becomes really relevant if someone’s iron deficiency has got to the point where it’s starting to cause anemia. I’ll always make sure that we know what’s going on with their B12 in that scenario. And then of course folate, because it helps to ensure that those red blood cells, you know, divide and mature correctly. So, they all really work in kind of symphony with each other when it comes to red blood cells and oxygen transportation.

But then we have things like vitamin C, of course, you know, good old vitamin C, right? So, it does a few things. It actually helps to increase the acidity in the stomach, and this is really important, particularly if you’re consuming your non-heme, like, plant-based types of iron, because it helps to cleave the iron apart from the food, so that then, when it goes to the small intestine, you’ve got a better chance of it being converted, so you can absorb it. And it also helps the actual iron be absorbed through the enterocyte. And, it can help reduce some of those symptoms that we talked about, that you can get from iron supplementation. So, I love vitamin C alongside of iron. They’d be the main ones that I consider. Yeah, we’ve already talked about zinc, copper. So, zinc, copper, B12, folate, and vitamin C would be the key ones that I’m always looking at.

Andrew: Okay. And particular forms? Like, B12, do you look at methylcobalamin, or you don’t care?

Laura: Yeah, whoa, whoa, yes. It depends. Depends on the client, depends what I know about their methylation status. I have some clients who just can’t tolerate methylated B vitamins at all because of what’s going on with their methylation pathways. It causes extreme irritability. So, if I’m concerned about that, I’ll go in with a hydroxocobalamin B12, potentially. Yeah, I really determine it on a client-by-client basis. If there’s someone who I know has taken stacks of B vitamins in the past, then we can be a little bit more adventurous with the types we use, but yeah, it depends.

Andrew: Can I ask about B6? Do you ever worry about it? You said…you didn’t mention it, so…

Laura: Yeah, I don’t worry about it. The reason why I don’t worry about it is because, when someone comes to me, if they’re taking a whole lot of different supplements that they’ve sourced themselves, the first thing I’ll always do is go through them and we’ll find out, do we even need them? If so, can we consolidate some of them down? And that usually eliminates any B6 overload, overdosing. And, through the supplements that I’m recommending, I’m not usually not multi-dosing a whole lot of different things that all have B6 in them. So, as you would know, the sorts of products that we have access to, they often do have B6, but it’s at lower levels. Sometimes we’ll use P5P forms, and I know there’s a bit of conjecture about, is that better? Is it not? Depends who you talk to. I just, yeah, use a bit of caution, but I think it’s, not that the downsides of B6 have just been overblown, but I think the amount that it’s happening, and the risk of it happening, has probably been a little bit overblown.

Andrew: Yeah, yeah, yeah. And forgive me, the other thing that we haven’t even discussed, we’ve spoken about the forms that are commonly used in massive amounts, the sulfates, but we haven’t spoken about the doses and the form, the forms that you use.

Laura: Of iron, yeah. So, I use iron bisglycinate, pretty much exclusively. I find it’s better-tolerated, it’s better-absorbed. It’s usually the type that will come in those lower-dose supplements. They’ll always be iron bisglycinate…well, not always, but predominantly. So, anyone with a sensitive gut, it’s better for them. I find that ferrous sulfate tends to be quite rough on the digestive system. You know, all those things we talked about, the bloating, the nausea, the smelly farts, the black poo, like, all of that. Polymaltose does seem to be a little bit gentler, but I just don’t find that it increases iron levels as predictably as a bisglycinate form does. So, yeah, it’s my go-to.

Andrew: Yeah, interesting. I remember, what was it, Argentina, I think Argentina, Chile, was using iron bisglycinate as a fortification in food.

Laura: Oh, right.

Andrew: Yeah, yeah. This was from Albion Laboratories, people that used to make it, or make it still, I don’t know. But yeah, it was, like, a whole national fortification thing. So, it was interesting.

Laura: Yeah, okay. And do you know if they do any population studies to see if it changed [crosstalk 00:29:21]

Andrew: Wouldn’t have a clue. No, never tracked it. Never tracked it that much. Okay. So, clinical applications. So, if we look at… The classic one is gonna be women who are constantly flooding. So, they’ve got another issue over here, endometriosis, polycystic, polyps, something like that, dysfunctional uterine bleeding, where they’re losing blood. There’s also, both males and females, you’ve got blood loss out of the GIT. So, whether that be anything from overuse of NSAIDs, to ulcers, to hemorrhoids, to, obviously, something sinister, a tumor that’s sinister, it’s something like that. Maybe a Meckel’s diverticulum, something weird.

Laura: Yep.

Andrew: And malabsorption syndrome. So, IBS, celiac, blah, blah, blah. I mean, you’ve got a lot on your plate just with iron. [crosstalk 00:30:18]

Laura: I know. Yeah. I know. I often think maybe I should have gone into a different clinical specialty. What have I done?

Andrew: Hematologist much? So, how do you wend your way through of the causes of the iron deficiency, if that’s what you see?

Laura: Yeah. So, it’s a lot of case-taking, a lot of questions. I’ll often start with the digestive system, because, I mean, that’s an area a lot of people that come to see me also have IBS or other digestive things going on, so, typically, that’s where I’ll start, because what I find for most people is there’s some kind of digestive dysfunction. Whether or not it’s the main thing that’s causing the iron deficiency, or if it’s just contributing to it, it’s usually there in some capacity. So, start from the top. So, what are you eating, number one. Are you chewing your food properly? What’s going on in your stomach? Do you have H pylori? Are you taking NSAIDs? Is there something that’s preventing your stomach acid from being able to do the first step of that iron breakdown process? And then what’s going on in the small intestine? Do you have a bacterial overgrowth there? Do you have celiac disease? The amount of people who have celiac disease and don’t know about it, it’s something like 70% of people with celiac disease, they don’t know. And so, whenever anyone says, particularly in children, been iron deficient for years, and no one knows why, like, we have to rule out celiac disease as a number one. Because even if they don’t have obvious digestive symptoms, chronic iron deficiency with no other known cause, celiac disease.

So, we look at that environment. And then, from there, as I talked about, are there signs that they have some imbalances in their microbiome? So, do they have pathobionts or other things there that [inaudible 00:31:58] So, I kind of work top to bottom from that perspective. And then, yeah, if there’s somebody who’s having a regular period, well, what does that look like? As you said, is there heavy bleeding contributing to it? And I just piece it all together. If I’ve kind of ruled all that out, and I think, well, okay, so, the digestion seems okay, their periods are fairly regular, nothing’s going on there, then I’ll usually look at the thyroid, because the thyroid can interact with iron deficiency as well. And often, if somebody has hypothyroidism, those symptoms mirror iron deficiency. So, I guess that’s the other really important thing, is I’m never just assuming it’s only iron deficiency, or it’s iron deficiency at all, because it could be something else. So, yeah, it’s a bit of a kind of just follow the, just pull the thread, I guess, and see where it goes.

Andrew: Yeah. Well, following on from that, the changes in metabolism, you spoke about thyroid, what about perimenopause and menopausal women? They’re hopefully no longer having that blood loss that they had during their reproductive lives.

Laura: Yeah.

Andrew: But they may have other issues where their thyroid goes down, their digestive processes are slower now, da, da, da, da, da. Tell me how you approach this group of women.

Laura: Yeah. So, it gets tricky, particularly when you’re using blood tests to see what’s going on from an iron perspective. So, obviously, as we know, in perimenopause, estrogen kind of goes like this. And that’s really relevant for iron, because we actually have an iron-estrogen axis. So, just to add another axis to our collection, we have an iron-estrogen axis. And so, what estrogen does is, as it increases, it basically reduces the production of hepcidin. So, and this happens throughout the menstrual cycle. And we have a little temper…like, a little lesser uptick in our estrogen in the luteal phase. And it’s thought that that’s happening to help prepare for the blood loss, so, it’s keeping the iron in the body, it’s letting more of it in. So, there’s this really beautiful relationship between estrogen and iron in the menstrual years, and then when we get into perimenopause, it can be a bit all over the place, so it starts to get harder to get a true understanding of what’s actually going on from an iron deficiency perspective. And then, as you said, we also need to consider, I guess it’s more lifestyle things in that group, because often, these are people who have, potentially still have young kids at school. Maybe now they’re looking after their parents. They’re also in the peak of their careers, and so the last thing they’re doing is making sure they’re eating iron-rich foods to begin with, that, you know, they’re not sitting down to chew their food properly. Maybe they’ve had IBS for 15, 20 years, and it’s just always kind of been put on the back burner. And so it can, again, it’s about what’s going on for that individual person, but it needs to be looked at under a different lens, you know, even just the ferritin level that we were talking about before. Once somebody is now in menopause, or maybe they’re still in perimenopause, but they’re only getting one period every kind of six months, we would expect to see their ferritin start to gradually increase.

Where it gets more complicated, which I think is what you’re alluding to, is if somebody has a metabolic picture starting to develop around that time as well, that can start to drive up inflammation. So, that increasing ferritin might actually be a sign of something more sinister. So, again, this is where I really use a lot of blood testing and pathology markers, just to see, well, what is actually going on here? Is this to be expected, this rise in ferritin, or is it pointing at something that we need to look into?

Andrew: This is awesome. I’ve gotta say, we need to… I wish I could have a seminar with you. This is a… Okay. So, I’ve got a question, and this is more of a personal sort of eyesore, right? So forgive me this sort of example, but I’ve been a long-term advocate of lower to reasonable doses of iron, but I do remember a case where somebody was on, like, three, four tablets of a 24-milligram per day, and wasn’t getting anywhere. And yet, one tablet, once per day, of high-dose iron, 108 milligrams, of a sulfate form, and within a week, picked this woman up. Now, she was exhausted. And my guess was you were so low in iron that your body was just sucking up, out of desperation, whatever it could, before the hepcidin rose.

Laura: Kicked in. Yes. Yeah, I would say so. And it’s a similar thing that we see with iron infusions, because we have, as you would say as well, and we talked about at the start, we have really good responders with iron infusions, and poor responders, and often it comes down to how hungry their body is for iron. So, if someone’s ferritin has dropped below 15, and it’s true iron deficiency, and their transferrin has jumped up to 3.1, 3.2, then they’re gonna be a really good candidate, typically, for an iron infusion. Whereas if your ferritin is, you know, around 23, 24, and maybe your transferrin [inaudible 00:37:01] is around 2.9, so, you’re still technically iron deficient, but you’re not as iron deficient as that person, you’re far less likely to get the benefit from the iron, because, as you said, once you get to such a low point, your body just says that, just give us the iron, and we’ll deal with any fallout that might come from too much of it.

Andrew: Right. So, there’s almost, like, a cut off of ferritin, where it’s like, “no more.”

Laura: Mm. Yes.

Andrew: No more iron. Gotta watch it.

Laura: Yep, yep. Yeah, there definitely is. Yeah.

Andrew: This is so interesting. Like, I feel like such an ignoramus. Anyway. Could you, as a last thing for us, Laura, would you mind just summarizing, if you wanted three…do I limit it to three? Three or four practical must-do’s for practitioners to learn from today’s topic?

Laura: Gosh, three. Okay. Forcing me to be succinct. So, always interpret ferritin in the context of other pathology markers, nutrient levels, and what’s going on for that person. Because as I said, ferritin for one person means something vastly different to somebody else. So, that. Not just assuming that the person’s symptoms are all from iron deficiency. They could be something like hypothyroidism or, you know, in chronic fatigue. There’s a lot of other things that have similar symptoms, so don’t just blame low iron. Fix the gut first. If there’s something going on with the absorption, if there’s something going on with the microbiome, no amount of supplementation and iron-rich foods is really gonna get them anywhere. Even if you do see their levels increase temporarily, it’s not going to hold, because that underlying dysfunction hasn’t been addressed. And then I think, going gently with iron supplements, we don’t need to go in really heavy-handed. If we use a, you know, an alternate-day dosing strategy, with a nice, low form of iron, we use those cofactors, make sure that they’re not deficient in the other cofactors for once the iron’s in the body, using things like vitamin C, using certain probiotic strains, all of these things can help ease the iron into the body. So, yeah. I don’t know if that was three or four, but…

Andrew: No, that’s good. I said last question, but I can’t do it very easily. So, can I ask, though, and this is something I forgot earlier with regards to dietary stuff, anti-nutrients. So, phytic acid, for instance. They’re taking an iron tablet and they’re taking it with their Weet-Bix or their All Bran in the morning, or whatever. Do you find that this is a common issue with patients, about how to take their iron supplements, when to take them?

Laura: Yeah, it is for some people, you know, if they’re having like, maybe they’re having a coffee with a whole lot of cow’s milk in it, and they’re having their iron supplement at the same time, and they’re not getting any results, and I can’t see anything else that could be going on, then I’ll get them to change it. I think, for most people, it’s less about those factors. Like, that helps, but that’s kind of the 1%, is, right, like, the tweaking it, getting a little bit more of it in. It’s the other things. It’s what’s happening once the iron is in the small intestine, that we really need to worry about, in terms of dysfunctions there. So, yes, it’s important, and yes, I will guide people on it, but I don’t get too full-on about it, because what I’ve found has happened, if I say to somebody, “You need to avoid dairy with your iron supplement,” they come back and they, you know, in a month’s time, and they say, “I didn’t take it because the only time I can take my supplements is in the morning, and I always have a coffee, and so I just didn’t take it,” and I’m like, “Well now, okay, well that didn’t achieve anything. I’d much rather you take it imperfectly than not take it at all.”

Andrew: Yeah. And you’re obviously somebody that keeps up with the research. What’s new in the research with iron metabolism, let’s say, hemodynamics?

Laura: Yeah. Well, so, I think the area that I’m keeping the closest eye on, which we touched on at the start, is really understanding what is actually going on with ferritin, because it is such a gaping hole in our understanding of iron. And once we can understand that, and unlock this understanding of, well, what is ferritin, and how can, where does all the iron go? Because we don’t see it in the blood, it’s not in the cell anymore, so where did the other 4,000 iron atoms disappear to? You know, that’s the research that I’m really most interested in. You know, I’ve got my PubMed alerts for clinical, you know, applications and things, but that, there’s such a missing link in our understanding of iron, and I think that’s it. If someone, you know, someone with a much smarter brain than me, if they can figure that out, that would be really helpful.

Andrew: No, I know. I think it’s your PhD topic. There we go. We’ve settled it. I’ll introduce [crosstalk 00:41:39]

Laura: Settled it. Love it.

Andrew: Laura, thank you so much for taking us through this today. There’s so much, I think, that we could learn, more than what we’ve discussed here. This is just the tip of the iceberg. So, I just can’t thank you enough for enlightening me, certainly, but enlightening us today, because this is a truly practical application of iron, and how to utilize it, how to test for it, how to see what’s going on, always, in your patients, and I love that about you. You’re always looking to the patient’s picture to guide you, to see what to do. Yeah, well done. Thank you so much for joining us today.

Laura: Thank you. Thanks for having me.

Andrew: And thank you, everyone, for joining us. Remember, we’re gonna be putting up again a whole heap of information, Laura, please, on iron hemodynamics, so please access that, so that we can learn. I do believe, I hope that you will be doing a webinar in the future, for Designs for Health, so look out for that one. And obviously, there’s all the other podcasts on the Designs for Health website. Thanks so much for joining us. I’m Andrew Whitfield-Cook.