This Podcast Will Kill You - Ep 152 Hemochromatosis: Ironing out the details

Episode Date: September 24, 2024

For life on this planet, iron is not optional. It is essential. When our iron levels are low, we can get sick, and when they get really really low, we can even die. But you know what they say, too much of a good thing can be a bad thing. In the case of iron, the genetic condition hemochromatosis is often to blame for iron overload, but why is too much iron a bad thing? In this episode, we explore that question and many others, starting with why iron is a biological non-negotiable and how a lack of iron regulation in hemochromatosis can lead to severe tissue damage. Then we’re going Deep Time™ to suss out the origins of our dependence on iron, a journey that eventually leads us to the Neolithic Revolution and the 20th century realization that a certain ancient medical practice is not as obsolete as previously thought. Tune in to catch us ironing out the details of this incredibly common genetic disorder.Support this podcast by shopping our latest sponsor deals and promotions at this link: https://bit.ly/3WwtIAu See omnystudio.com/listener for privacy information.

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My name is Ali. I was diagnosed with hemochromatosis 15 years ago. My symptoms started in high school. I was complaining about being tired all the time, despite sleeping 8, 10, or even 12. hours a night. I was tested for anemia more times that I can count, and when it came back negative, doctors dismissed my symptoms and told me, just go to bed earlier. Finally, when I was 23, I found a doctor willing to test me for other causes, and we found that it was the opposite, and it was iron overload. My ferretin or iron level was around 500 or double what it should have been.

The treatment for hemichromatosis is relatively easy. It's donating blood or phlebotomy. Unfortunately for me, I was afraid of needles and had never donated blood before, so I chose to go to the hospital. At the hospital, I was a bit of a celebrity because I was so young. Most of the other hemachromatosis patients that I met there were retirement age. It's usually diagnosed later in life once you start showing symptoms of the iron buildup in your organs.

My first year, I went for monthly phlebotomy, and it was pretty rough at first. I regularly passed out during the procedure, and then I had zero energy the rest of the day. I ended up having doctors orders to go to McDonald's and get a Big Mac, large fries, and large orange juice to get my blood pressure up before the procedure. Thankfully, my mom would come visit me and take me to the hospital and take care of me while I winded bid. After that first year, I tapered off to quarterly phlebotomy, and thankfully my body did get used to it, so it didn't knock me out like it used to. And now at 37, I get my iron levels checked quarterly, and I just do phlebotomy as needed, which is usually every year or every other year.

Otherwise, it doesn't impact my life that much. I thankfully caught it before I had any damage to my organs, so I don't have to keep a strict diet, but I do try to learn. limits foods or supplements with high iron or vitamin C. Allie, thank you so much for sharing your story with us. We really, really appreciate it. Yeah, thank you. Thank you. Thank you. Thank you. Hi, I'm Aaron Welsh.

And I'm Aaron Alman Updike. And this is, this podcast will kill you. And today we're talking about hemacromatosis. Yeah, which we have gotten a lot of requests for. And I'm excited to get into it because I feel like this is something that I learned about a long time ago and then that was it. Yeah. But it's like really, really common as we'll talk about later. And so I think it's really interesting to get into some of like the why. And then just to also let us think about iron. I'm really excited to talk about iron. I spent a long time talking about iron. Me too. Me too.

So yeah, it's going to be fun. It's going to be good. But before we do that, Aaron, what's time? What is that? What are we drinking this week? We're drinking pumping iron. Pumping iron. I love this name. Yeah, pumping iron, it's great. I mean, first of all, it's a great name because, like, you're pumping iron through your body.

Right. I don't need to over-explain it. I always ruin the joke by over-explaining it. Isn't that how you tell a joke? No, is it not? I know no other way, so. But yes, in pumping iron, it's. It's great. Of course, we had to have pomegranate juice to make it look like a little bit like blood.

But then we're also adding Prosecco to make it not look like pure blood. And maybe a few other ingredients here and there. It's delicious. And yeah, enjoy. Enjoy. We'll post the full recipe for that quarantini as well as our non-alcoholic placebo-a on our website. This podcast will kill you.com and our social media. Are you following us on social media? You really should be. We've got so much good content out there. You know, just check it out. I was going to start listing content, but I'm not going to. But also what you should check out is our website. This podcast will kill you.com. Wow, what a website. I mean, it's got things like links to merch. It's got links to music by Bloodmobile or bookshop.org affiliate account, goodreads list, sources for all of our episodes, transcripts. It's also good.

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Yeah, we are. So let's get started right after this break. hemacromatosis is a genetic condition. It's actually a few different kind of ways that it can present, but they're all genetic conditions that result in iron overload. So I figured that to understand hemacromatosis and what that means, we first have to understand what iron is in our bodies. Is this the first time that we've talked at length about iron on this podcast? I think it is. I think it is, because as I was going through this, I was just thinking about how I feel about iron. And I was like, I've never said these things before. I can't wait to hear how you feel about iron. I do have a lot of feelings

about it. Mostly, it's like a little bit of dread. Like I remember when we learned about iron in med school and like iron studies, the iron studies that you order, if you're thinking about iron in a person, it's like a mini dread because there's just a lot of things and the like, this is going to be high and this is going to be low in this condition versus this condition. It's confusing to me. But luckily, we don't have to do all of that. Today, we just get to talk about what iron is and what it does in our bodies. It did make me realize that, like, we haven't covered anemia's as a topic. Right. That's a huge topic. Exactly. And topics, really, I guess. So, yeah. So today we're not talking about anemia. We're talking about iron and iron overload and hemacromatosis. So what is iron

even? Iron is an element. It's a metal. According to Wikipedia, it's the most common element on Earth by mass. Did you know that? I did know that. I did not know that. It was also on the Wikipedia page for iron. Well, yes. Thank you, Wikipedia. It's because the core of our Earth is iron, if you really want to get into the details of it. But iron is also an essential nutrient for humans. So we need this metal in order to make a variety of different proteins in our bodies. The most famous, I think, of which is hemoglobin. And hemoglobin is the protein that we use in our red blood cells to carry oxygen to our tissues. Pretty vital protein. Yeah. You could say. You could say. that we can't live without it. But iron is also needed as part of things like our cytocromes,

which are proteins in our liver that are really important for metabolism. It's in oxygenases. It's in a lot of other proteins as well. So overall, we need iron and we need quite a bit of it every day to do the things that our body needs to do, like, I don't know, survive. We get iron from our food, so we eat it. And there's a lot of different things that contain iron. There's different forms of iron. There's heem iron that's from animal products and non-heam iron that's mostly from plant products. And we absorb it in our small intestines. But even though we get iron from our diet, it's actually a pretty small percentage of our overall body iron that we're actually getting from eating it.

Almost 90% of the iron that we use on a daily basis. And again, we use a lot of it. we're actually recycling within our own bodies, mostly from the breakdown of those red blood cells that contain hemoglobin, and we're reusing this iron. And one of the really interesting and sort of unique things about iron as a metal in our bodies is that we don't have any way to excrete it. There's no mechanisms in our body to like break this down into something else and then excrete it. Right. That doesn't exist, meaning that we can't. lose iron, except if you bleed. So if you bleed, you lose hemoglobin, which has iron. And then there's a

little bit of iron that's lost from like general breakdown in our guts or our skin cells, like just literally sloughing off our cells. Right. Through our various holes. Isn't that fascinating? It is. And it makes sense, I think, given the larger evolutionary context. Oh, actually. can't wait to hear about that because like I am like what I think it's really like we need iron so much right yeah right and so it's like but I do think it's interesting that there isn't a regulated process that happens like those things that you talked about are like not not highly controlled bleed it's not like you're I mean it's not like you're bleeding regularly unless you're menstruating unless you're menstruating but even that you're not bleeding the same amount every month exactly yeah

Not everyone bleeds the same amount every month. And it's like a whole lot of things. Yeah. Right. But it's interesting that you say that it's not regulated because our iron stores are actually, they are very much regulated. And so what happens, and that's what we'll talk about in hemacromatosis, is that if our iron regulatory systems go offline, it's very bad news. Right. So like the storage and maintenance is regulated, but not, there is no regulated process for excretion. Right. There's no way to get rid of it. There's only a way to not get too much of it in the first place. Yeah. But once you have too much of it, there's nothing you can do about it. Yeah. Brutum, brittem-a-maryl. That's hemochromatose is just kidding. What's going? Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again.

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You can order meals when you want them and skip when you don't, without adding another recurring charge. order now at blue apron.com. Get 50% off your first two orders plus free shipping with code this podcast 50. Terms and conditions apply. Visit blue apron.com slash terms for more information. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something.

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winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is outside. We're offering our listeners 15% off their first order of O'Keefs. Just visit O'Keef's company.com slash this podcast and code this podcast at checkout. In 2023, a story gripped the UK, evoking horror and disbelief. who should have been in charge of caring for tiny babies is now the most prolific child killer in modern British history. Everyone thought they knew how it ended. A verdict? A villain? A nurse named Lucy Letby.

Lucy Letby has been found guilty. But what if we didn't get the whole story? The moment you look at the whole picture, the case collapses. I'm Amanda Knox, and in the new podcast, doubt the case of Lucy Letby, we follow the evidence and hear from the people that lived it, to ask what really happened when the world decided who Lucy Lettby was. No voicing of any skepticism or doubt. It'll cause so much harm at every single level of the

British establishment of this is wrong. Listen to Doubt, the case of Lucy Letby on the Iheart Radio app, Apple Podcasts, or wherever you get your podcasts. So that's iron. And it's a really important nutrient. Like I said, it's involved in a lot of our approach. and we need to be able to store it in our bodies. In addition to ingesting it and the fact that we can't excrete it, I mean, I guess because we can't excrete it, we have to be able to store it because there's going to be days when we get an influx of iron in our diets and days when we might not have that. So our bodies have evolved ways to store iron for when we can't intake as much of it and then be able to use that iron. And it turns out that free floating iron, just like actual iron

floating around our bloodstream, is a very terrible idea because the thing that makes iron such an important component of many of our proteins is that it's a great catalyst for reactions, especially redox reactions or oxidation reduction reactions where proteins are moving electrons back and forth. So this is a very reactive element that we can't let just, like, float around our bodies because then it would be causing redox reactions and making things like reactive oxygen species all over our body, which is very bad. Mayhem.

So we store this iron in our bodies in a couple of different ways, and they're bound to proteins. So the first protein that's really important in the story of iron in our bodies is called ferretin. And ferretin is the main way that iron is stored in our bodies. I always think of it as you're ferreting it away. That's a thing, right? I like that. I got more of a reaction out of you than I expected on that one. I feel proud. And then the second protein is called transfarin. And Transferin is the main way that iron is transported or transferred. That one's less cute, but very easy to remember, right? Yeah. So, iron in our bodies is mostly found in these two

forms. And then to a lesser degree, it's found as like free iron floating around. And then, of course, it's also there bound to our hemoglobin in all of our other enzymes, et cetera, et cetera. and just like you can imagine that iron deficiency might be very deadly because if you don't have enough iron you can't make blood cells, then you can't transport oxygen. But so too can iron overload. And hemachromatosis is an example of where the dose really does make the poison. So hemachromatosis, like I said, is a genetic disorder. And the classification system has changed in recent years. And there's a real like push to separate. hemachromatosis, the genetic disorder, from any other disorders that can also lead to iron overload,

and to not really need, it used to be called hereditary hemachromatosis, but there's a push to not need that anymore because, like, what we're talking about when we talk about hemachromatosis is this genetic disorder and not anything else that might cause similar symptoms, if that makes sense. Okay, so the other uses of hemachromatosis have been sort of renamed to other things. Correct, exactly. Okay. So what I'm going to talk about today is just the, what used to be hereditary hemacromatosis. And we'll talk about the different subtypes as well, too.

Okay. So there are, because there are multiple genes that can be mutated. Almost all cases of hemachromatosis, regardless of which gene it is, are inherited in an autosomal recessive manner, which means these are on non-sex chromosomes, and you need two copies of these mutated genes to express the disorder. But even with those two copies of a mutated gene, the penetrance of hemacromatosis, meaning the likelihood that someone is going to have problems or going to have disease from these mutated alleles is actually rather low. So not everyone who has the two genes in this

protein that's associated with hemachromatosis is going to have disease from hemachromatosis. if that makes sense. Yeah, and so what are the determinants for when somebody develops symptoms? Isn't that a great question? What if I had an answer to that, Erin? Dang it, Erin. We have no idea? It's not that we have no idea.

So hemacromatosis is a, it's a lifelong thing, right? This gene, these genes are there from birth. and whether someone who's going to have problems from it all depends on the level of iron overload. So there's going to be a lot of things that play into that. There's going to be things like diet, right? How much iron are you exposed to? How much iron are you being able to absorb in the first place? There's going to be things like your age. So most people with hemacromatosis aren't diagnosed until their 40s or 50s. And that's likely because that's the point at which the amount of iron that they absorbed over time and held onto over time is now clinically significant. So you can actually

pick it up. And then there's other things like, are you menstruating? Are you bleeding out every month? And so you're losing that. Are you vegetarian? And so you're really having very low exposure to heme iron, which is more likely to be absorbed. Like there's just so many different things. Do you drink a lot of alcohol? And so the effect on your liver is going to be greater because alcohol is also affecting your liver and some of the same enzymes in your liver. So there's a lot of different things that can play into it, but there's not any characteristics of a person who has these genes that we can look at and say, you will develop symptoms or you won't develop symptoms, or you will develop liver disease, or you won't develop liver disease. But having two copies of those

alleles means that your body will struggle to regulate, like, the storage of iron. You're like, You're still storing excess iron. Let's talk about what these genes are doing so that we can understand what the heck is going on. Because yes. So I said there are different types of hemacromatosis, and there are. But about 90 to 95%, depending on the studies that you read, happen in one particular gene. And this gene is called HFE, which stands for high F.E, high iron. Makes it easy to remember.

But, of course, the name is much harder to remember. remember, and it's the human homeostatic iron regulator protein. Yeah, who cares. High F.E is better. Yeah. Yeah, high F.E. Right? It's a high iron protein. So this particular protein happens to be a protein that sits across our cell membranes. It's present in a whole bunch of our cells, including our intestine, our liver, our blood cells, the placenta. And if you read only the Wikipedia summary, you might think that because this is something that's regulating iron and it sits across our membranes, that this is the mutated protein that if it's mutated is just passing too much iron through that protein and you're absorbing too much of it,

and that's the end. But it turns out that just like iron is complicated, hemacromatosis is more complicated than that. So while it is this abnormal HFE protein or other proteins that sit close to it, that are similar to it, that are abnormal in most cases of hemacromatosis, these abnormal proteins, through a mechanism that we don't fully understand, the end result is that they interact with a hormone, a completely different protein that ends up causing too much iron to be absorbed. So let's talk about it. This other protein is called hepcidin. Hepsyden is a hormone. It's produced in our liver, and its job is to be essentially a referee. So it's produced in our liver. It goes through our bloodstream and has effects on all of the other cells in our bodies. That's what hormones do. And this particular

hormone Hepcidin goes around to all of ourselves. And if our iron levels are high, Hepcidin's job is to say, hey, whoa, whoa, whoa, guys, we've got enough iron. Stop. Stop, quit it. Stop with the absorption. Stop with the releasing ferretin so that we can move it around and use it. Stop, just stop. Stop with the iron. We have enough. Cool. That's Hepcidin's job. In hemachromatosis, What ends up happening is that you block the production of this hormone in the liver. So you no longer have a referee. You no longer have hepcidin going around your cells saying, stop with the iron, we have enough. You can't sense that there's enough iron.

So you continually are going to absorb iron from your guts. You're going to continue releasing ferretin from your cells, moving it around on those other transfer molecules, etc. Now, you can't get rid of this iron, and so now you have iron overload. Okay. So what happens is that there's, just so I understand, there's a mutation in this membrane protein that somehow leads to this other protein not being present or just not, okay, not being present. Or not being produced at enough quantities.

At enough quantities, okay. And then this other protein then that normally just circulates throughout your body doing, saying stuff about iron is now not there saying anything about iron. And so, exactly. So this causes more release into, like more release of free iron and more absorption of free iron. Yeah, not, I wouldn't think about it as free iron necessarily. You will end up getting too much free iron. But that part is a little bit more complicated. But you end up with just too much iron, period. Most of it is still going to be in that ferretin storage form and on those transfer molecules transferrin, but yes, eventually, once you have too much in all those places,

the balls will fall off the iron truck, is the way I think about it. The transferin molecules will have too much, and then, yes, free iron will also be present at higher levels. Got it. And the other forms of hemacromatosis work in really similar ways, just through disruptions in other proteins, but the end result is the same, is that it's the disruption in the ability to produce this hepcidin protein. There's actually one that even affects hepcidin itself, which makes a lot of sense, right? And it also makes sense then why all of the

types of hemacromatosis are autosomal recessive, meaning you have to have two abnormal copies of this gene, all abnormal protein, in order to not make any hepcidin and then have disease because of this. Because even a little bit of hepcidin will be enough to, to go around to be like, hey, guys, stop it. We have enough iron, quit it. Right? But if you really can't make any, then you have no referee, then the game is just a mess, right? Yeah, free for all. There is one form of hemacromatosis that can be autosomal dominant, and that is when it affects one of the receptors of hepcidin. So in that case, doesn't matter how much you have. It can't do its job, right? Yeah, there are so many points along this process that can be disrupted. It's wild.

And here's what I think people maybe don't understand. think about, I don't know how much people are even thinking about hemacromatosis, let's be real, but we think about hormones a lot of times in a very narrow window, right? When we think about hormones, like, as a general public, we think about, like, estrogen and testosterone. Like, those are the main hormones that we're thinking about. But we have so many, like, so many hormones, right? And you might not think that, like, iron regulation is a hormonally regulated process, but it totally is. And all of our hormonally regulated processes are so, wonderfully complicated that like when things go wrong in any step like what it's just and the fact that

we figured this out is just fascinating to me because it's very indirect right it is yeah i that was definitely the class that i struggled with the most in undergrad was endocrinology it's just like i don't understand yeah it's really fun and really like yeah yeah so anyways at the end of it all we end up with iron overload. We have too much iron. So then what happens? What are the symptoms that we actually see with hemacromatosis? Unsurprisingly, this is a progressive disorder. So the symptoms that we see are from actual iron itself being deposited in our cells, because there is just so much of it. and over time, depending on how much is deposited and in what organs, you're going to see a variety of different disorders. The symptoms are very nonspecific most of the time.

And I don't have statistics on like how often does someone get diagnosed because of this symptom versus how often people get diagnosed kind of almost by chance because they find a high ferritin or a high transferent or abnormal liver enzymes without really looking for hemacromatosis specifically. So most of the time diagnosis is not through like genetic screening, but through these indicators of iron in your body. So diagnosis is going to be through genetic testing, definitely. But the first indication might not be symptoms. It might be those other abnormal tests that make you go, huh, that's a little bit weird. Let's look further. Gotcha. Yeah. But in any case, when people do have symptoms, they often can include joint pain.

So arthritis and arthritis are really common because of iron deposition in the joints. And fatigue is a really, really big one. And what I find frustrating about fatigue, as always, but including in hemacromatosis, is that in hemacromatosis, fatigue is definitely related to iron overload. Because when iron overload is treated, it gets better, like people, get better from their fatigue. But when you read about fatigue as a symptom, it's often cited that, like, well, rates of fatigue aren't significantly different in people with hemacromatosis than in the general population. And I'm like, sorry. I don't accept. Yeah, we also just have poor definitions

of fatigue. Exactly. And our measurement tools are like non-existent, like whatever. But joint pains, fatigue, brain fog, cognitive impairment. And then the thing. that we see less as symptoms and more as signs, and that is damage to your organs, right? Liver damage, which can start as fibrosis and end with cirrhosis or even hepatocellular carcinoma. And that's from iron being deposited in the liver and then causing death and damage to liver cells. Iron also can deposit in the pancreas, which leads to damage and then can end up causing diabetes. and in reality, it can deposit in almost any other organ. Those are just the two kind of most common ones,

but you can also see cardiomyopathy or damage to the heart muscle. Another place that iron is often deposited is on the skin, and this can lead to skin pigmentation changes that are often described as either like grayish or like bronze hyperpigmented spots that's literally iron in the skin. And the treatment for all of this is, to get rid of iron. And the only way that we have to get rid of iron is phlebotomy. It is the time when the olden days of humors were correct. Uh-huh. Right? Yeah. Yeah.

I was trying to remember and make sure that I knew all of the humors, right? Like black bile, yellow bile, phlegm, and blood, right? I think, I mean, okay, you're pop quizzing me. Yes. That's what I would say. I just want to make sure that blood was, in fact, a humor. Yeah. It's, it's, it's, it's, it's, It's blood. It's blood. So that is how we treat hemacromatosis. And we do it to target ferretin concentration. So that's how you can tell if you've let off enough blood. You're looking at ferretin, which is that storage iron protein. So it's going to be very individualized. It's not like everyone needs X number of phlebotomies. It's monitor the ferretin. And then any other additional diseases that have come about as a result of hemacromatosis, like fibrosis or like diabetes

or any of those, have to just be treated separately than the hemacromatosis itself, in addition to making sure that there's no more iron overload. That's hemacromatosis, Aaron. I mean, honestly, like, okay, it's complicated at a cellular protein level. Right, right, right, right. But like, when it comes down to it, it's too much iron and you get rid of it. iron and there's a pretty simple solution, which is kind of great. Yeah. Yeah. I mean, yeah. It is kind of great. Like, as far as genetic disorders that we don't have a cure for, that are lifelong and progressive go, it's like, yeah, the management is, is pretty straightforward. It's manageable. I think that's the biggest thing. Yeah. What's also fascinating, and part of the reason,

maybe it was a little too nitty-gritty to go, like, deep into hepcidin, et cetera, but part of the reason that I did is because, so hepcidin is produced only in our liver, liver transplants can actually be curative. Oh, cool. Right? So if people end up with really severe liver, and liver transplant's not a small thing. It's really like if you have end-stage liver disease, but a liver transplant can be curative because now you have a liver that can produce hepcidin. That's amazing. Right? So it's just so fascinating to me. Yeah. But Aaron. Yeah. So genetics, so it's there. Like, this is very common. And I know I'll talk more about that later, but like, how, why, where, you know what I mean? All those questions. Yeah. I don't finish asking. Yeah. Let me try to answer those half-form

questions right after this break. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture. It's non-greasy, unscented, and absorbs quickly. A little goes a long way.

Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry Colorado winters when it feels like my skin is always on the verge of cracking. It keeps them soft and smooth, no matter how harsh it is outside.

We're offering our listeners 15% off their first order of O'Keefs. Just visit O'Keefscom. This Podcast and code this podcast at checkout. In 2023, a story gripped the UK, evoking horror and disbelief. The nurse who should have been in charge of caring for tiny babies is now the most prolific child killer in modern British history. Everyone thought they knew how it ended. A verdict, a villain, a nurse named Lucy Leppie.

Lucy Letby has been found guilty. But what if we didn't get the whole story? moment you look at the whole picture, the case collapses. I'm Amanda Knox, and in the new podcast, Doubt the case of Lucy Letby, we follow the evidence and hear from the people that lived it to ask what really happened when the world decided who Lucy Lettby was. No voicing of any skepticism or doubt. It'll cause so much harm at every single level of the British establishment of this is wrong.

Listen to Doubt, the case of Lucy Lettby on the IHeart Radio app, Apple Podcast. or wherever you get your podcasts. I'm Clayton Eckerd, and in 2022, I was the lead of ABC's The Bachelor. Unfortunately, it didn't go according to plan. He became the first Bachelor to ever have his final rows rejected. The internet turned on him. If I could press a button and rewind it all I would.

But what happened to Clayton after the show made even bigger headlines. It began as a one-night stand and ended in a courtroom, with Clayton at the center of a very strange paternity scandal. The media is here. This case has gone viral. The dating contract.

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Apple Podcast. or wherever you get your podcasts. When the term mass extinction event is brought up, it's usually in reference to one of the so-called Big Five, the late Ordovician, late Devonian, and Permian, and Triassic, and, and Cretaceous. Or maybe more recently you could throw in the sixth one, the Holocene extinction, which is ongoing and caused by us humans, and there's a great book about it called The Sixth Extinction.

But I bet you didn't expect me to go deep time. on this one? Or maybe you did. I love going deep time, Aaron. I know. You know that about me. Me too. I think like someone had reached out to us recently and was like, love the deep time episodes and I'm like, I should do, I should like see if I should do deep time. And then iron hemacromatosis presented itself as a very much deep time disease. Love it.

Okay. But when it comes to these mass extinction events, what you don't often hear mentioned in terms of like the biggest extinctions of all earthly time is the great oxygenation event. This is deep time, Erin. This is a very deep time. Maybe the deepest. I'm not sure. No, I don't think so. But even though the great oxygenation event is thought to have rivaled or even exceeded

the sheer amount of life lost in the Great Dying, the end Permian extinction event, which was around 250 million years ago, 90% of all. all species went extinct around, which is the biggest of the big five. It's unfathomable. It's wild. Thinking about extinction is how I feel when I think about like space. When I go deep time, I go space and I'm like, it is all just too big. I can't. I can't have my head around it. Comprehension is not possible. No. Keep going. I love it. And we probably don't hear the great oxygenation event referred to as a mass extinction event because the life lost would have been single-cell organisms, which tend to not leave much of a fossil record.

And while the great oxygenation event would have led to the extinction of so many organisms, it also paved the way for the evolution of kind of like life as we know it, like completely new ones. So what happened? Oxygen happened. The bottom line. Around 2.3 to 2.5 billion years ago, a prelude. of photosynthesizing cyanobacteria led to this huge rise in oxygen in the Earth's atmosphere and surface ocean, which had so many consequences for life on the planet. It led to the extinction

for some, because oxygen, to some species that can't do anything with it is toxic, it can be fatal. It led to the evolution of others. It led to the development of more efficient ways to metabolize or produce energy, led to the evolution of eukaryotes and multicellular life. The great oxygenation event is like kind of a big deal when it comes to deep time. And normal time too. We need this. And it's a big deal for this episode because it turned iron from a super available there when you need it kind of element to much, much less so. Not answering calls, taking days to respond to text, etc. was just like kind of not, no longer available. And of course, iron itself was still very abundant. The first in like all of Earth's mass and the fourth most abundant element in the Earth's crust. But it was just that the

oxygenation caused it to switch from being bioavailable to not bioavailable, insoluble. So it was no longer that you could just like have iron there ready to use, use it whenever you want. It was like, no, we need to go through some steps before you can use me. You're going to have to work for this. Right. You're going to have to go through my assistant. Uh-huh. Got it. Exactly. And so the earliest life on this planet had evolved under conditions where iron was easy to come by. And iron itself is thought to have been crucial to the initial development of life. And this is reflected, this long relationship with iron is reflected in the fact that so many of the cellular processes that are shared across the entire kingdom of life require iron,

DNA replication, intermediate metabolism, gene expression, and so on. It's kind of everywhere. And it's also reflected by the fact that the more quote unquote primitive domains of life, like bacteria and archaea, tend to use more iron in processes than the younger eukaria. And so when iron became hard to get, organisms had to adapt or perish. Not using iron doesn't really seem like an option, except I was, as an asterisk. I was amazed to learn that apparently only two organisms are known to not require iron, and that is Borrelia burgdorferi, the causative agent of Lyme disease, and lactobacillac. Wow.

Why? I don't know. Yeah, it's wild. Huh. Yeah. They just don't need it at all. Apparently. Okay. Yeah. I know. I want to know more, but... I do too. Let us know what you find out if anyone is ready to go down the rabbit hole. But for the rest of life on this planet, iron was and is a necessity. And so organisms evolved various ways to acquire or recycle this precious element. because the consequences of not having enough iron can be dangerous, even fatal, as I'm sure we'll discuss one day when we do an episode or episodes on anemia. And iron availability can fluctuate over space and time. And so being able to deal with those times of plenty and times of scarcity

is pretty important. Which brings me to hemachromatosis. Iron, super important, but also, as we just learned, too much of a good thing can be a bad thing. And so the question that often comes up when discussing haemochromatosis is why? Why is hemachromatosis so common? Which is, in some populations, up to one in 200 people, which is like very high. Yeah. Why is it so common if it can lead to such severe outcomes? Why did the allele emerge when it did, and why did it persist? Was, or is it associated with some sort of protective benefit. Let's move out of deep time and into the Neolithic revolution to see if we can find out. Okay. So about 11,000 years ago in the Middle East, humans began to shift from a hunter-gatherer diet to one consisting of domesticated plants and

animals, which is a huge oversimplification. It's not like it happened overnight, and it's not like it was a full transition from like, oh, I'm no longer eating those berries that I used to gather. Like, I'm strictly on bread. No, now we're making scones with our berries. I'm just kidding. Integrating ways of life. This new way of living provided some substantial advantages, like being able to more reliably have food,

which led to higher birth rates and rapid population growth, spending less energy on foraging or hunting and more on shelter building, exchanging ideas, innovating, and so on. It's not called a revolution for nothing. Like it was, again, kind of like the great oxygenation. event, a big deal. By 6,000 years ago, this new diet and lifestyle had spread far beyond the Middle East and had reached basically all parts of Europe. Foraging for wild flora and fauna, like game,

fish, shellfish, insects, nuts, roots, and vegetables began to be replaced primarily by domesticated grains and dairy. Again, this shift was not overnight and it wasn't like people stopped consuming these foraged foods entirely. But it does. It does seem based on archaeological evidence that in some regions there was a dramatic shift to dependence on dairy and grains. As with everything in life, there were trade-offs to the Neolithic Revolution. The sedentary lifestyle ushered in the ability to spend less energy and time foraging and grow larger settlements, but more people in one place also means more germs and parasites

getting traded around and more waste accumulating. animals meant a more reliable food source, but that's also how you get measles and other zoonotic pathogens. Grains and dairy provided more readily available calories, but these food sources were also much lower in iron than those obtained through foraging. Oh, I was not expecting this. I know. Feels like I should have been. Oh. Came out of nowhere. The sedentary lifestyle also allowed for higher fertility. So some estimates are a tripling of fertility from foraging to sedentism, but pregnancy demands a lot of iron. A lot of iron.

And you know who else demands a lot of iron? Intestinal parasites. Oh, parasites, okay. Same, same. I mean, it's kidding. And so these factors may have put all Neolithic farmers at greater risk for iron deficiency, but the consequences of that deficiency may have been more extreme for European Neolithic farmers. Why?

Why? Because of the cold. Because the cold? Because the cold. So humans, having evolved in tropical Africa, have a fairly narrow thermo-neutral range. So if we're in temperatures outside of that range, we do possess mechanisms that help us maintain homeostasis. So, you know, we sweat, we shiver, all of these different things. Iron is involved in some of these mechanisms, especially those that help us maintain our temperature

when it's cold. If we're deficient in iron, we aren't as able to control that internal thermostat in chilly temperatures. And so for the European Neolithic farmer, living in parts of Northern Europe, where it is often cold and damp, not having enough iron in your diet could be very bad news, especially during times of iron stress like pregnancy. Huh. Like pregnancy when you're going to give birth. Uh-huh. Yeah, and spread your genes.

Uh-huh. It makes sense then that if an adaptation emerged that help you cling to iron, this might provide a selective benefit. I love this so much. I don't know how this was not at all what I was expecting because it should have been, but it wasn't. And I thought it was really going to be more of a story of like, oh, well, it's just not disadvantageous because you don't have symptoms until you're after childbearing age. I mean, that could have been it for sure, but, but maybe not. I like this story a lot better. No, it's not what I was expecting either because the first time I learned about hemacromatosis, it was an association with something very different. And I'll mention it in brief a

little bit later on. But this is, yeah, this is one of the leading hypotheses as to why these alleles emerged in the first place, which I think is. That is so, so, so interesting, Aaron. I really love it. Yeah. Okay. So let's get into one of these alleles. that causes hemachromatosis. So the C-282y allel, which is the most common allele associated with hemacromatosis. I love that you, I was like, I'm not touching these alleles. This is the only one I'm touching. H-F-E, there's alleles. This is, yes, yes. But I think when it comes to the emergence and spread of certain alleles, it is like we do have to talk about individual ones because the timing, blah, blah, blah. Anyway.

But this allele, The C-282Y is found at the highest rates in people of European descent, particularly in Ireland and Scandinavia. And so you may have come across, I don't know if you did come across, like, the competing Celtic origin or Viking origin hypotheses. So it's sort of like, did it emerge in Vikings? Did it emerge in Ireland? We don't know. Okay. Yeah.

So, Erin, you talked about how you need two copies in order to develop symptoms, if you're going to develop symptoms of hemachromatosis. You need both copies. But it turns out that some studies suggest that even if you have only one copy, there does seem to be some association with more efficient iron utilization, or, like, still having more iron. Makes sense. Yeah, accumulating more iron. But not necessarily to, like, disease level.

Right. Yeah. You can sometimes see, like, slight elevations and ferritin and things like that, but not any clinical disease from it. Exactly. As to when this allele emerged, Estimates vary, but most put it between like 3,500 and 6,000 years ago following the transition to agriculture.

Over the next few thousand years, things like indoor heating solutions, the development of iron cookware, and more varied diets may have reduced the likelihood of iron deficiency, making the hemachromatosis allele not quite as helpful as it once may have been. Okay. But putting all these pieces together, we have this least. leading hypothesis as to why this hemachromatosis allele emerged where it did and when it did and how it became so widespread, which I just think is a really fun, it's a neat little story. And, you know, it's interesting. And I think there are more pieces to it, like what you mentioned,

Aaron, how since symptoms or clinical disease don't often show up until, like, you're older, you're an older adult, then, you know, there's not as much, like, selective pressure against it. Right. But still. So, okay, but this, this of course is not the only hypothesis. When I first learned about hemachromatosis, it was from a book called Survival of the Sickest by Sharon Moellum. Okay. It's been a really long time since I read it, like it was easily 15 years ago. But in this book, he presents various hypotheses about how exposure to disease over human evolution shaped our body's responses. And one of the hypotheses, that he presents is about haemochromatosis. And it's also in a paper that I found, so I'll post it in

our sources list so you don't have to read the entire book. In this hypothesis, he suggests that the same hemachromatosis allele, C-282Y, is so common because it provided a selective advantage during plague epidemics slash pandemics that swept through Europe, particularly the black death during the mid-14th century. Like humans, like all of life, bacteria, like Yersinia pestis, the causative agent of plague, need iron to survive. And sometimes they acquire it from their human host. So according to Molem, people with two copies of the C-282y allel may have had a lot of iron in their system, but it's not evenly distributed throughout your entire system. So apparently it's not as high in macrophages. The level of iron and macrophages, the level of iron in macrophages,

macrophages with in people with hemacromatosis is not as high as in people without. What is your, let me do you want to know why? I'll call on you. Yes, I do want to know why. It's because we're exporting it out of our macrophages in hemachromatosis because you don't have Hepsidin to say stop exporting it out, keep it in. There you go. So yeah, that's amazing.

Yeah. And so he suggests that this then provides protection from plague because then the plague bacteria won't somehow survive, like they won't have the iron that they need. in the macrophages. They need it from the macrophages. Interesting. Well, I don't know. I don't know. But it might not really either, but that's an interesting idea. So then he also extends this to other intracellular pathogens like salmonella typhi and mycobacterium tuberculosis. So it is a fun idea, but frankly, after doing a little digging, I don't see a whole lot of support for it. So first of all, he used an origin estimate for the allele that is on the very, very, very recent end of estimates. And was it self-outesteads?

out of date by the time this paper was published, with more recent analyses putting the origin further back. Secondly, as far as I could tell, there isn't experimental evidence backing up this notion that people with hereditary hemochromatosis are more protected from plague. In fact, it might be the opposite. Yeah, in 2009, a 60-year-old geneticist

who was working on an attenuated, non-virulant strain of ursinia pestis, so this is just like you're working in a lab, you don't need special protection because the bacteria itself has been engineered or selected for it to be not to not make you sick. Right. He came down with symptoms of plague and ultimately died. Oh, no.

And tests later revealed that he had hemachromatosis undiagnosed. Undiagnosed. The plague strain was still not virulent. So they tested it. They injected it into lab mice and the lab mice didn't get sick, as you would expect, for a non-verulant strain. And so researchers hypothesized that. the excess iron in his body allowed this avirulant strain to become virulent, which was shown to be the case when researchers injected the bacterium into mice with hemachromatosis who got sick and died.

Oh, interesting. Isn't that really interesting? Yeah. And I mean, people with hemacromatosis can be at risk for other pathogens as well, too. So, I mean, that part of the problem is just going to say there's an increase, seems to be an increased susceptibility to vibriovolnificus, vibrio colore, e coli, lycleria, lycalaesterea, monocytogalytica, hepatitis B virus, cydomeglovirus. It's like lots of different pathogens, it seems. And it kind of makes sense, right? These pathogens need iron to survive. And so the more iron, the better they survive, the worse, the infection. I know there are also associations with like sepsis overall.

So, and I'm sure that there are more detailed mechanistic explanations, and they're in the papers that we will post on our website. But the bottom line, I think, to all of this is that we don't have a complete picture as to why this allele is so widespread. It might be because it helped protect against iron deficiency. It might be because it's linked to another gene that does something else, like immune function, HLA. It does seem related to that. And that part I didn't get into because it does sort of seem just like we don't really know, but there are relationships. and so maybe it's just hitchhiking. It might be because it doesn't always result in symptoms,

and even when it does, it's not often until later in life, but it's probably not because it conferred any sort of advantage during the Black Death. And, of course, C-282Y is not the only allel associated with hemacromatosis, so the story could be different for the other alleles. Right. But in any case, hemachromatosis is today one of the most common genetic disorders. but how did we find out what it was, why it can make you sick, and how to treat it?

Let's get into it. The first description of haemochromatosis was given by French Dr. Armand Trousseau in 1865, which seems more recent than I expected. Yeah, 1800s? 1800s, yeah. Oh, no, no. I know. Really?

Okay, like, let's acknowledge the possibility that older descriptions exist and just have been recognized as hemacromatosis. Or maybe everyone was just so iron deficient for so long. Honestly, that could be, that could be true too. That could be true. It wasn't until the 1800s that people were iron available enough that someone could have disease from hemacromatosis. Yep, and so that was who Truceau saw in 1865.

So he described a patient who had diabetes, pigmented cirrhosis, and bronze colored skin, which led to the first name given to this disease, bronze diabetes. Yeah. Yeah. I just really thought that was an older name. What do you mean? Oh, like Hippocrates era? Yeah.

It sounds so great. Like bronze diabetes. Bronze diabetes. The Bronze Age. It's diabetes of the Bronze Age, yeah. That's what I think of. The second name given to this disease is the one that would stick, hemacromatosis. And this was introduced a couple of diabetes.

decades later, by von Reklinghausen, who made the connection between iron and the color of the liver. So excess iron gave the liver its increased pigment. There didn't seem to be too much interest in haemochromatosis for another few decades until the 1935 publication of the book Hemachromatosis by Joseph Harold Sheldon, who is a physician working in Wolverhampton in the West Midlands in England. He included in his book an overview of more than 300 cases. that he had collected over the years. Wow. Describing symptoms, diagnosis,

iron levels in different organs, life expectancy, familial patterns, and so on. He reported that the average time from symptom onset to death was 18 months, which is rapid. Yeah. Yeah. Death was most commonly caused by diabetic coma,

followed by liver disease, and he also mentioned that the sex ratio of cases was 20 to one males to females. And he didn't say anything. He didn't mention anything about the possible role of menstruation in this ratio or provide any other explanation.

This book put haemochromatosis on the map. And things started to move pretty quickly after this. First, with the 1937 discovery that iron is absorbed by the intestinal mucosa and that the intestines are sensitive to iron levels, except in hemochromatosis. So they're like, oh, we're low, we'll absorb more.

Oh, we're good. keep just like flush it out man yeah and and then with the suggestion later on that maybe excess stores of iron could be managed by bleeding thus reducing the damage caused by excess iron in hemacromatosis i'm sorry i just can't get over this you said this is like after the 1930s okay the whole let's like let's use phlebotomy to manage symptoms 1947 is when they finally put it to the test oh my god Aaron, that is literally hilarious to me. I know. It's so bizarre. It seems so surprising. It's so surprising because it literally was like you bleed people in the olden days. And so it's like, but I guess it's because we didn't figure out that hemacromatosis was a thing until so recently

that people are like, well, of course we're not going to bleed people. We don't do that anymore. Maybe that's why it wasn't until the 1800s that people realized because bleeding had fallen out of favor. Oh, my God. I don't know if that's true or not. But that's so logical. Oh, my God. I know, but 1947, almost the mid-20th century for people to realize that, hey, bleeding could actually save lives here. Wow. Yeah. Yeah. And so this idea was put to the test by Davis and Erosmith, and over the course of two years, they bled two patients with hemacromatosis, which they they confirmed by needle biopsy of the liver. Okay.

So one patient, a 69-year-old woman, had 40 liters of blood removed over two years, so 20 grams of iron. And they reported remarkable improvements. Quote, each patient has reported pronounced subjective improvement in sense of well-being, increased energy, and working ability. Serial liver biopsies have revealed significant diminution in the iron pigment content of the biopsy specimens as well as improvement in the appearance of the cirrhosis. There have been no untoward effects from phlebotomy, end quote. Wow. I think it was like probably a little bit not like resisted, but just like there's no way. Like we've come so far. What do you mean that we're

still just going to bleed people like the old humorists from back in the day. Yeah. Humeralists, I guess, not humorous. Well, no, whatever. Whatever. And so that's how an ancient medical practice proved to be a safe and effective treatment for what can often be a deadly disease. The realization that bloodletting could help manage this disease provided hope for those with it, and it also opened the door to more research, understanding exactly how our cells absorb, use, and regulate iron and other metals. Like not just iron, but we use a whole lot of metals. It's kind of amazing. Less invasive diagnostic tests help expand awareness, both for patients and providers. And in the mid-1970s, researchers uncovered the genetic association

between what was then called hereditary hemochromatosis and the HLA A3 complex on chromosome 6. Basically, this is like this whole relationship where there's this HLA immune system region and the link between hemachromatosis. There's more papers out there. But fast forward a couple of decades, and we've got the discovery of the HFE gene and some alleles associated with excess iron absorption. We've got the identification of hepcidin,

and we've got a better but still incomplete understanding of how iron metabolism works. And so, Aaron, we started two and a half billion years ago, and now we got to the 2000s. Uh-huh. Can you tell me where we are, with haemochromatosis today. I would love to right after this break. The single gene mutation that's responsible for, like I said, 90 to 95 percent of cases of hemacromatosis and the allele,

Aaron, the one specific allele that you mentioned is so much more common than I realized. One paper said that this particular mutation is 10 times. more prevalent than the mutation that causes most of cystic fibrosis than the most common cystic fibrosis mutation. Wow. I know. That's very common. I know. So the disorder is estimated to be present. And the numbers really vary. And what's interesting is that I didn't find a single paper that had like an estimated prevalence of like the number of hundreds of thousands of people living with hemacromatosis, I did not find that number anywhere. What I did find is that it's estimated to be present hemacromatosis specifically,

so being homozygous for a mutated allele, in anywhere between one in 150 to one in 220 people of Northern European descent. Okay. The heterozygous rate, so having one allele, is like one in seven people of Northern European descent. Wow. Right? Yeah. Yeah.

And the overall, like, frequency of this allele, like, overall in the Northern European descent population, I saw estimates between, like, six and 10 percent overall. Okay. So including whether you have one or two copies. It's very common. There are, like I mentioned, multiple other forms, some of which can cause disease much earlier in life. So some cause more severe disease or cause disease earlier in life. And those all are uncommon enough or rare enough that I don't have really any data on like the prevalence. I do have a paper that I'll cite that has numbers, but they're like, you know, 0.0001, blah, blah.

They're just not that meaningful on a population level. Mm-hmm. But they're there. When it comes to the epidemiology of symptoms, you mentioned this, Aaron. hemacromatosis tends to affect males significantly more than females, even though the rates of this gene are present equally across all sexes. So the common parlance in all of the literature is that we assume that at least some of this difference that we see in females compared to males in the risks of complications and death are because of the protective effects of menstruation, because when you're

bleeding, you're losing iron. But there actually is no evidence to, like, support this. It's just like, well, it's got to be that because we don't know what else it could possibly be. That's hilarious. But I think what that means is just that no one has done those studies. It doesn't mean that, like, it's not a very logical thing that if we looked for the evidence, it would probably be there. Yeah. But right now that's our best working hypothesis, essentially. But it is true that male or female, there are increased risks of a lot of bad outcomes with hemachromatosis. So in males, the risk of death due to hemacromatosis is increased 1.2 times. So a 20% increased risk of death compared to someone without hemachromatosis. Okay. There's a 12 times increased risk of liver cancer.

answer in males with hemacromatosis. And both men and women have an increased risk of arthritis and fibrosis of the liver. I have a question. So we talked about diagnosis often as like a result of either you have symptoms of hemacromatosis or you're screening for something else and you happen to see something that's like, oh, that's odd. Let's look deeper. Is there a call for or is there reason to do like newborn screenings. Erin, so glad you asked. Let me tell you I have a whole, that's my whole current research section. Okay.

So let me just finish telling you about the risks associated and then I will let you know. Because that's my question too. So the last thing I will say is that the risks of iron overload don't just stop with like mortality and liver or even increased risk of diabetes. We also see that in hemacromatosis, in anyone who has, has hemachromatosis, there's also significantly increased risks of other cancers, including colorectal cancer and breast cancer in females. The link between these other types of cancers and hemacromatosis is not entirely understood, but it's thought that it's likely related

to the presence of iron itself. And we talked about how iron is very reactive and can cause the production of free radicals, reactive oxygen species, etc. And so is it that? Is it like a chronic inflammation. We don't really know. But the risks are definitely there. Increased risk of colorectal cancer and breast cancer with hemacromatosis. So, Erin, you asked about screening. Is there a push for screening? I wanted to talk a little bit about screening because whenever I get an opportunity to, it's one of my favorite things to talk about. And we've talked about screening, like the idea of it before on this podcast, right? I don't, I'm sure that we have. sure that we have, but let's refresh everyone who doesn't think about screening on a daily basis.

Screening is like a public health tactic. It's done in your doctor's office, so it's medical testing usually, but it's a public health tactic where we test or check asymptomatic people, like regular old humans doing their human thing, to see if they have a disease that they don't know about or a disorder that they don't know about. And we screen for lots of different things. We screen for colon cancer before people ever have symptoms. We screen for breast cancer, hopefully before people ever have symptoms. We screen for cervical cancer. We screen for high blood pressure. We screen for high cholesterol. We screen for all kinds of different things, right? And organizations make recommendations on who to screen which populations to screen, what ages, what groups, etc.

and when to screen, how often to screen, and what to screen for. And I would love to do a deep dive someday, but when it comes to hemacromatosis, right now, it is not something that is screened for. And as far as I can tell, there's not like a huge movement right now that's like, we definitely need to start screening for it, absolutely. So nobody who's going in for their like annual physical and blood work is getting checked specifically for hemachromatosis. Okay.

But a newer, new-ish study out of the UK called the Biobank Study, which looked at a lot of different things, but also had a lot of data on hemacromatosis because in the UK, there's a lot of people of Northern European descent, so there's a lot that you can get from that population. What we found from that study is that the effects of mortality and increased mortality, increased cancer. The health effects of hemacromatosis are not insignificant, and it's very, very common. And so there is now more of a push, especially as genetic testing becomes much cheaper and more available, because right now that's the only test that we have is genetic testing. So especially as

that becomes cheaper and more available, there is a lot of like mumblings about, should this be something that we test, say, people of Northern European descent, should they all be tested, either after age 18, should it be before they're age 18? And there's a lot of controversy, not controversy, but like there's a lot to go into the decision of what timing do you screen somebody? Because especially with something like hemochromatosis, not everyone who has this is going to get the disease. So what does it mean to get that diagnosis as a child versus as an adult? Like, how many additional tests are you going to need? Like at what point do you need to know, essentially? So usually what we screen for on a newborn screening is things that if you don't

catch it are very, very detrimental, right? You need to catch cystic fibrosis early because you need to start treating it when babies are tiny babies in order to have the best outcomes. With hemacromatosis, that's not necessarily true, right? For the vast majority, for the forms that we would be most likely to screen for, which is the most common form. And so it seems like if there's going to be screening that starts to happen, it will likely be for adults rather than for children. But yeah, it's really interesting because I think it's not, like right now it's not a thing. But I'm interested to see in the next like 10, 15 years, is it going to be on one of the blood panels that you get when we start to genetically screen everyone for everything? It's super interesting.

Yeah. In terms of research on treatments, I didn't find very much, Sharon. I mean, is it because, like, phlebotomy is effective? Phleotomy is so effective. There's no, like, gene therapy type things that... So gene therapy, it definitely is mentioned. Most of the papers that I read were, like, gene therapy is an idea. Finances-wise, it's probably other diseases that are getting a lot more money for doing that

because they're diseases that are killing people, like, right off compared to hemachromatosis, which is, I mean, it's terrible when you think about it in the large-scale things. This is also killing people, but that's how funding works. There are a lot of options that people are still looking into in terms of other ways to treat hemachromatosis, though. Like, can we override this hepcidein regulation failure? Like, can we do something with hepcidin to try and treat hemachromatosis without needing to have phlebotomy?

Are there biologics? Can we somehow independently regulate iron absorption in the guts? And we actually have medicines already that can kind of help reduce the amount of iron that you absorb to a small degree, which can help people with hemacromatosis. So there's a lot of different avenues that people are researching. None of them are like, here's the next slam dunk medicine coming down in the pipeline or anything like that. Right. Okay. Okay. But that is hemacromatosis. I find this so, I just think it's so interesting. I think there's so much more to this story. There's so many different branches you could go off on to be like, what about this? What about this?

about that? What's about the history of bloodletting? What about whatever, you know? If people want to read more, boy, do we have sources for you. Oh, yes. Yeah, I have a lot, Erin, for this one. So I'm just going to shout out three for kind of like what I saw as one of the each, each of the sections that I did. So if you want to learn more about the great oxygenation event, I've got some papers, one by Hodgkiss at all from 2019 called A Productivity Collapse to End Earth's great oxygenation. And then for the sort of evolutionary history and Neolithic Revolution aspects, there was a great paper that I really enjoyed by Heath at all from 2016 called the evolutionary adaptation of the C-282Y mutation to culture and climate during the European Neolithic. And then finally,

for the more of just like the strict human history of hemachromatosis, there's a paper by Adams from 2020 called hemacromatosis ancient to the future. Love it. I had not as many papers for this as I expected, but I have a couple really great reviews that I'll recommend. One was from New England Journal Medicine in 2022, just simply titled hemacromatosis. And the other also titled Hemacromatosis was from the Lancet in 2023. And then I had some other papers digging a little bit more deep dive on iron and how iron is used and stored, et cetera. So I will post the link and we will post all of our sources from this episode and every one of our episodes on our website, this podcast with kill you.com, under the episodes tab. You can find them there. You can read them. You can learn so much more.

So much more. Thank you again, Allie, so much for sharing your story with us. Getting to hear your perspective, I think is so valuable. Yeah. Thank you so, so much for being willing to share your story with us and everyone else. Thank you to Bloodmobile for providing the music for this episode and all of our episodes. Thank you to Tom Brie Fogel and Leanna Skalachi for the incredible audio mixing. Thank you too. Exactly right. And thank you to you, listeners. We really, really appreciate you listening to this episode, rating, reviewing, and subscribing. We appreciate you telling all of your friends. And we really just appreciate you being here and letting us do this podcast because we really love it. Yeah. Thank you, thank you.

Appreciate is the word that doesn't quite cover it, but it's there. And thank you also, again, to our wonderful supportive patrons. We, again, we appreciate your support so very much. It honestly really means the world to us. So thank you. Thank you. Well, until next time, wash your hands. You filthy animals?

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