Understanding Histamine Intolerance with Amy Rolfsen, ND

- Histamine plays an important role in the immune system response, signaling inflammation and helping regulate the respiratory, cardiovascular, and gastrointestinal systems. However, for some patients, histamine levels can exceed the body's ability to eliminate them, potentially leading to a reaction known as histamine intolerance. Whether it is due to low levels of diamine oxidase, also known as DAO, the enzyme responsible for breaking down excess histamine, or whether it is due to other causes, histamine intolerance can result in long-term inflammation and episodes of severe allergic symptoms. Very frequently, histamine intolerance may be hard to determine, often diagnosed as food allergy, IBS, or other chronic conditions. How can clinicians determine if histamine intolerance is a root cause of their patients' symptoms? - When your intake or production of histamine exceeds your ability to clear them, then you have that buildup of histamine in the body, and at a certain threshold, you'll see symptoms in your patients. And often this comes on suddenly or unexpectedly, or unpredictably. So the main ways we can increase histamine is through intake through our diet, so some foods are higher in histamine. - On this episode of "Pathways to Well-being," we welcome Dr. Amy Rolfsen, naturopathic physician, educator, and medical consultant at Diagnostic Solutions Laboratory, to discuss assessment options and treatments that can help patients with histamine-related dysfunction. Welcome to the show, Dr. Rolfsen. - Thank you, Bianca. Thank you for having me. - Well, we are so glad to have you on the show today, and I know we've got a ton to talk about. You're an expert in this area, so we are thrilled to have you and to learn from you today. And I was thinking maybe we can start simply by hearing a bit about you, your background in functional, integrative, and naturopathic medicine. - Fantastic. And again, yeah, thank you for having me here. I'm excited to talk about histamine, which is one of many areas of practice. So I do have a private practice here in British Columbia, Canada, which is where I live, where I see women and children, mostly family medicine, hormonal transitions, a lot of skin conditions, a lot of histamine issues pop up. Even if it is not your practice specialty, you will see a lot of histamine issues showing up in practice. So I also work doing peer-to-peer consults where I'll help people interpret tests. So one of my biggest strengths in practice is in interpretation of clinical history, so how patients are presenting and melding that with test results. So finding those test results, pulling them back into clinical context, and finding the most value. I learned pretty early on in practice that running tests is of very little value without an excellent interpretation. One of my passions in practice is in doing a very, very specific and in-depth interpretation of any tests and only running tests if they are gonna change your clinical outcome. - Yes, that's so important. And I think it's really important for the patients as well, as they see the changes after you've made recommendations and they have integrated the therapeutics. - Absolutely. - Well, we know that histamine, of course, is involved in allergies. That's primarily what we think of, oftentimes for the histamine component. And we've also heard about histamine intolerance, and so I'm wondering if you can tell us a little bit about the basic causes of the histamine intolerance, and then we'll go a little deeper, and sounds like we'll dive into some specific areas as well. - Yeah, so you're gonna see a lot of different issues popping up with histamine, but what I think is really important to acknowledge is that histamine is a normal signaling molecule within the human body. So it's there for a reason. It's part of our normal allergic and immune response. And in healthy, normal amounts for a healthy and normal amount of time, it is very helpful and important for things like wakefulness, blood vessel tone, stomach function, and stomach acid production. It really becomes a problem when we have too much histamine or not enough histamine clearance. So we do produce it within our bodies, and we also clear it from our body. So it's that imbalance of the production and release, sometimes dietary intake, and the clearance, mostly by enzymes and detox pathways. So when that goes out of balance, either short-term or long-term, then histamine becomes a problem. But histamine itself is not the problem. It is normal and helpful for our bodies, but it's that inability to clear it appropriately that would be the problem. - That's such a good point, right? So many of the processes that happen in the body naturally are normal. It's when they get out of balance that we begin to see symptoms and or even disease processes. I'm really glad you brought that up. And so you were talking about clearance, and can you tell me a little bit more about some of the things that might push that normal histamine level to be too high? And/or for the body to have trouble in clearing the histamine, in both cases, it causes histamine levels to be too high overall. - Absolutely. So if we see histamine intolerance really as when your intake or production of histamine exceeds your ability to clear them, then you have that buildup of histamine in the body, and at a certain threshold, you'll see symptoms in your patients. And often this comes on suddenly or unexpectedly, or unpredictably. So the main ways we can increase histamine is through intake through our diet. So some foods are higher in histamines. Foods become higher in histamine the longer they age, so things like fermented and aged foods or leftovers. So some histamine diets will have you avoiding leftovers. Fish should theoretically be fine, but fish that is anything other than totally fresh can be higher in histamine. So we've got our dietary intake. We also have foods that are known antigens or known allergies or sensitivities or even unknown that can amplify that immune response. So they're not inherently high histamine, but they might cause the immune system to overreact. So our dietary intake of either histamine-rich foods or foods that can amplify or trigger immune responses. So that's a way we can increase our histamine levels within our body. Histamine is released by white blood cells, mast cells, or basophils. They've got these little pockets called granules that are full of histamine and other mediators, things like tryptase, which you might have heard of. And when those cells get stimulated, they'll release histamine. So that's another source of histamine into the body. And then some of our microorganisms that can be either normal or somewhat normal and reaching abnormal levels, that can be another source of histamine. Our microbiota, or our microbes, or otherwise known as dysbiosis, that can be a source of histamine as well. So those are some of the major sources of histamine increase. But then the way we clear histamine is mostly enzymatic. You brought up DAO, or diamine oxidase, which is the first line of enzymatic defense. That is gonna be our extracellular histamine clearance, so that when you have histamine before it's reached the tissue level, that's when your DAO can work. And there are a lot of things that impact DAO function that we'll get into, but then once the histamine gets into your tissue, so say you've got more than the DAO levels in your body can clear, then the histamine may enter your tissue, or maybe it was released within your tissue to begin with, that's another possibility. Then you've got another set of enzyme systems, and this system is called HNMT, which contains a few different enzymes. So it's a multi-step enzyme process. Histamine N-methyltransferase is the overall name for it. And there are so many cofactors and things that can bring down the function of these enzymes that will impact our patients. But what's exciting about that, knowing what the cofactors are for these various enzymes and the things that can slow their activity or compete for binding sites, that gives us multiple points of leverage clinically where we can look to, you know, eight to 20 different things we can possibly do to help our patients. And that can be a lot of trial and error. Testing can be really helpful. And often it's listening to clinical history and looking at the diet, recent history, things like that, to see what might be reasonable to try and where you might want to start with your patients. What obvious factors are there we can modify? What would we do as step two, step three if we've got someone with continuous histamine issues, which can be really scary for patients? So, working on the enzyme systems, using cofactors, and trying to modify anything that might bring down activity of those enzymes. - Wow. So there's a lot of places that we can really dive into here. So thank you for bringing up all these different spaces. And I think I'd like to start a little bit towards the top of what you were talking about here. You know, a patient comes in, and they've got myriad of symptoms. How might a practitioner, or why might a practitioner, right away suspect that it would be a histamine intolerance that they were dealing with? - Yeah, that's a great question. And differentiating, too, between histamine and allergies. If your patient shows up the classic symptoms of histamine, and to bring it up, there are some classic symptoms, and then there are non-classic, more subtle symptoms where it can show up in day-to-day life, where you might think, "Okay, someone has migraines." Those can be histamine-mediated, but it's not that obvious. But when a patient comes in, and they've got hives, so say they eat a meal, and then they break out in hives, or they get a red rash around their mouths, or a true anaphylactic response that may be histamine-mediated, or it may be an allergy that's a newer onset allergy. And so differentiating between the two is really important, and there's so much overlap between these things. So what you may see clinically is that people show up and they'll have an extravagant reaction to a meal, and then they'll have the exact same meal two weeks later and have no response. And that is something you'll see clinically. That can be a trigger in thinking, "Okay, this might not be a true allergy, it might be histamine-mediated." And because there are so many factors that can impact our levels of histamine and our ability to clear histamine, you may see differences day to day if someone is drinking alcohol, knowing that that's an inhibitor of many of the enzymes, that can impact your ability to clear. Hormone levels can impact your ability to clear histamines. And also some hormones can what's called destabilize mast cells or cause them to become more active and release more histamines, whereas other hormones are more protective against histamine release. So many day-to-day changes can impact your ability to clear histamine. So you'll see a lot of variability and unpredictability of symptoms, but what you'll see for people, a lot of skin symptoms, a lot of GI, so you'll see stomach pain. I would say stomach pain, reflux, looser stools would be the most classic. You'll see histamine implicated in a lot of IBS cases. So you were talking about misdiagnosis as IBS, but one of the features of IBS can be mismanaged histamines or histamine level changes. And again, why IBS can be so variable, histamine can be involved. It's not always about excluding other conditions, it's about thinking, "Okay, I wonder if histamines might be involved in this particular case at some level." And that can be tricky to find out. - Absolutely. So it sounds like the histamine component here can mimic; it can look like a GI issue, it can look like a neurological component, dermatological, many different areas. So as a clinician, when someone comes in and I'm looking at this and I'm thinking, "This doesn't really fit the picture, I might associate with a typical migraine picture or clinical case," are there certain tests that I can look into that would tell me, actually, this is histamine intolerance at the root cause of your patient's issues? - Absolutely, yes. So there are lab tests that can help you figure out what's going on, and lab tests that might help you differentiate if you have a patient with severe symptoms, severe ongoing symptoms where you think that there might be histamine issues, or you want to rule out mast cell activation syndrome, which is next level. That is an extreme version where the problem is not so much your histamine intake to clearance. The issue is with the mast cells and an inappropriate release of histamine. There are some lab tests you can do to differentiate. Some of what you might do clinically is a trial of mast cell-stabilizing botanicals or some of the cofactors for enzymes that you know to help with histamine clearance. You can trial something like a low-histamine diet, and if somebody did the low-histamine diet for about two weeks and their symptoms completely went away, say they were having daily symptoms to begin with, which can be a gift when we're trying to discern things clinically. Sometimes it's really nice to have daily symptoms. Although we don't want those for our patients, it's when those symptoms are really variable that it can be even trickier to figure things out. But a lot of the time, we're doing clinical trial and error. Even trialing some prescription or over-the-counter antihistamine medications can be helpful, or prescription mast cell destabilizers. Or sorry, mast cell stabilizers is what we wanna do clinically. And then if you have a patient where you've tried all the diet and lifestyle factors that are reasonable and obvious, and say they're avoiding alcohol, they're lowering their stress, they're taking a B vitamin and magnesium, and zinc and all those things, we can look deeper. And I think the gut is an underappreciated source of information. So gut testing is amazing, and you can find things like organisms that can be increasing your histamine burden, or you can see signs of gut dysfunction, where knowing that DAO, that enzyme, that is our first breakdown source of histamine, that's a product of the gut epithelial cells. And so if you've got issues like gut permeability, inflammation in the GI tract, or dysbiosis that might be impacting both your levels of histamine and your ability to clear, and that shows the signs of things like, "Hey, if we want to do some gut repair that might increase our natural ability to produce DAO enzyme." - That's really interesting. So, as a clinician, we might test for dysbiosis, we might be looking at the intestinal permeability component, and we might actually be clearing up some of the histamine symptoms just by clearing up some of the other issues that are going on in the gut. - Yeah, I have clinicians talk to me, and they bring up a test, and they say, "Okay, this patient has dermatographia," which is when you scratch your skin and it turns red for a few hours. That can be a big sign of inappropriate histamine management in the body. Or they'll show up with allergic symptoms. And then we look in a gut test, and we see organisms like Morganella or Candida yeast, both of which can produce histamine, Morganella especially, and then other gram-negative especially organisms like Citrobacter, Klebsiella, Pseudomonas, those are organisms that are classic for producing histamine, but they can also destabilize mast cells. So things like Candida really destabilize our mast cells and can make us more prone to histamine issues. And then the answer is decreasing those organisms carefully because your histamine patients are gonna be some of your most sensitive patients, and you may see paradoxical reactions to supplements, and it may be challenging. - Yeah. That reminds me of when you're talking about, you know, multiple components coming from that one cause, and it's a lot about functional medicine, right? We think about if we can get to the root cause from maybe one symptom we're looking at, but oftentimes we find it clears up many things along the pathway. - Yeah. - Yeah. So that root cause is so important. And I'm thinking about, you know, you talked a lot about allergies, and we talked about histamine; you talked a little bit about the MCAS. How would I differentiate, again, clinically, if a patient comes into me with similar symptoms, but I'm looking at, could this be an IgE-mediated food allergy, might it be an IgG food intolerance, or is this a histamine-mediated sensitivity? Are there certain tips, clues that you look for, or even some labs that you might do? - Yeah, so I think for patients who have come to us with concerns with a more extreme reaction, so say they've eaten something and their throat closes over, and you're wondering, "Is this IgE or is it histamine-mediated?" They've got an appointment with an allergist six months out, we can run a test for IgG reactions and IgE reactions. And I think that's really important to do so for these patients. And often they will be the most motivated patients to run a test because they know, "I ate a food that I've eaten before, and I don't feel safe in the world, so I need to have more information." And that is a way you can get them information. So what is really interesting is that the immune system works as an interconnected web. It is all parts of the immune system rely on other parts. And so histamine is a product of mast cells and basophils, but part of the activation process there is the IgE antibody. So the allergic response, which is eosinophil-mediated, so these are all white blood cells. So you've got your allergic response, which is the release of IgE antibodies. Those IgE antibodies bind onto mast cells and basophils and cause the release of histamine. So histamine is part of the IgE allergy process. So they're not separate necessarily. And then the ability to clear histamine from that reaction may indicate whether you have histamine issues. So sometimes our patients with higher histamine do have IgE-mediated responses and true allergies, and it is worthwhile to rule those out. So whether they've not been tested or if they haven't been tested in five or 10 years, it's worth ruling those out because those can be really scary and dangerous, especially when our patients present with the more pronounced symptoms. Whereas some patients will show up with skin itchings sometimes during their cycle, with some food, sometimes not. It's a little bit less scary in those cases where we're looking at a skin itch. It is annoying, and it's troublesome, but it's not that life-threatening, scary reaction. And then IgG or food sensitivities, they can also amplify immune response, and in some cases, they can be protective against allergic response. So all of those cases, the IgG sensitivities, IgE allergies, and true histamine clearance issues, those can all show up pretty similar in practice, especially the allergy versus histamine. And so there's not just one thing to differentiate between them, but I think it is important to rule out true allergies for our patients that show up with those symptoms. - Absolutely. And with all that overlap, it feels like it's very important to dive in and do that testing when you might suspect that that's an IgE-associated process. - Yeah. - So, onto somewhat of a separate topic, but as you noted, everything is so interconnected that it's not separate. Let's talk a little bit about the hormonal shifts, particularly in a female, during her just normal menstrual cycle throughout those years and/or in perimenopause. And how does that impact or shift the histamine signaling? - It is a huge impactor. And I don't know if you've seen this clinically. If you deal with a lot of this clinically, I think anybody that treats perimenopause will also see some histamine issues cropping up. Perimenopause is a huge opportunity for histamine issues to suddenly present themselves, whether it be through increased estrogen or decreased progesterone, which can change histamine in a way I'll explain in a minute. Sometimes alcohol is a factor at that time in life. Sometimes stress is a factor at that time in life where you've got kids becoming teenagers, potentially, and parents needing more care. Often, stress is really increased in that phase of life. So there's a lot of factors there that can change our clearance of histamine, but specifically the hormones. Generally speaking, estrogen will increase histamine levels, progesterone can be protective. So estrogen can cause the release of histamine from mast cells, and then progesterone will prevent the release of histamine from mast cells. And that is an overgeneralization, I would say. But often we'll see that in practice, either premenopausally or perimenopausally, or even postmenopause, you'll see a different picture. But sometimes in the menstrual cycle, you'll see more pronounced symptoms. Sometimes it'll be right before or around ovulation. Sometimes, premenstrually is the word I'm looking for there, where progesterone is lower, and in our patients that seem to have other hormone imbalances that can be really impactful. And then beyond the release of histamine, estrogen can compete for clearance with histamine or change enzyme activity in those enzyme systems. So DAO, the activity of DAO that can clear histamines extracellularly, that is brought down by higher levels of estrogen. And then within the tissue, the HNMT, there's multiple levels at which estrogen can either competitively inhibit, so competing for enzyme activity or decreasing the activity of enzyme. And then stress hormones as well play in there too, where along the pathway of histamine clearance, there's also some competition with your stress hormones and clearance. - Wow. So, so many pieces. And, you know, thinking about it, no wonder histamine intolerance can easily look like so many other things. It can look like hormonal imbalances. It can look like a dysbiosis component intestine permeability. It can look like stress, right? In some cases. And all of those can impact that level of histamine, either the excessive intake or the excessive production, or the reduction of getting the clearance component of it. - Yeah. - So, can we dive a little bit into the clearance, the DAO, the diamine oxidase, because I'm assuming, like all our other enzymes, that there are certain key nutrients, mineral cofactors that would help us to support that enzyme for the optimal clearance. - Yep, absolutely. And great, great segue there into enzymes. So what we need to know about enzymes, enzymes are compounds that can help... You know, they can help with chemical reactions, and the reaction here is detoxing and clearing histamine from the body. So, DAO again is that extracellular enzyme. There are a lot of cofactors involved, and you need to have good nutrient status to be able to use all these enzymes. Enzymes are protein-based, so you need to be able to absorb and assimilate proteins. And there are some minor cofactors. But major cofactors for DAO activity: copper and B6. When it comes to overall histamine clearance, I think of B vitamins in general, activated B vitamins, and methylated B vitamins. And so the ability to activate your B vitamins, that's somewhere this could go wrong as well. So for DAO and the other enzymes, there's a lot of B vitamins, but it's not just B6, but B6 is one of the major cofactors in DAO activity, as well as copper and other minerals. So when we talk about enzymes and cofactors, what's important to know is that if you have a cofactor like copper or B6, those are crucial to the activity of the enzyme. And that also means that if you're deficient in those nutrients, that can be a point of clinical leverage where you can introduce those nutrients, help with absorption, make sure they're getting into a person, and that might help increase the activity of the enzyme. So those cofactors are what I think of for DAO. And do you wanna talk specifically about DAO right now, or the other enzyme cofactors for the rest of the system? DAO? - Perfect. Love it. - Okay. And then knowing that after DAO, there's another enzyme. So acetyl dehydrogenase, and cofactors for that are going to be, again, B vitamins, but we've got zinc, so we've got both copper and zinc for this pathway, NAD, and the B vitamins. And then with the cofactors in mind. So that's a point of clinical leverage. And then you've got a number of things that can bring down the activity of these enzymes. So, things that bring down DAO activity. So competitively, we're looking at things like the fermented foods. So whether they're fermented outside the body and you're eating things like cheese, cured meats, kimchi, sauerkraut, things like that, that can be competitive with the DAO enzyme, or sorry, competitive with histamine at the DAO enzyme, so it can slow your clearance of histamine. Or if it's within the body and you're not absorbing your proteins well and they're making it through your GI tract, and then there may be organisms. Similar to the organisms that can produce histamines, a lot of those can actually metabolize amino acids and ferment them within the gut. And those protein fermentation products within the GI tract, those can also impact your ability to clear histamine. So that's things like tyramines or higher tyramine foods or, within the body, putrescine, cadaverine, and those things we hear about clinically, that's an area where they can impact us, and they can increase inflammation, but they can also impact our ability to clear histamines. And then, so that's the DAO, where the next step, again, acetyl dehydrogenase, that is an area where alcohol consumption, that's a big inhibitor, as well as estrogen levels. Now, what I have not yet mentioned, I don't think, is that DAO is one of our brush border enzymes. So it's produced in our GI tract by the cells lining our GI tract, which have to be healthy in order to produce good levels of DAO. So, in a patient who you suspect is low in DAO... And then a classic way to find that out is if they have histamine symptoms, and you give them a DAO supplement, and everything gets better. That might be somebody who's low in DAO. And if you're able to clear up their gut and work on gut barrier function, you might greatly increase their endogenous or their own production of the DAO enzyme. So, gut barrier dysfunction, any inflammation in the gut, can impact your ability to produce that enzyme. - It just, you know, it never ceases to amaze me that we always have to get back down to the root cause, and then the foundational components of health. We have to get back to the gut. We have to make sure that things are being digested well, absorbed, and cleared. And there's all of these different cofactors and micronutrients that are supportive of those different processes. Now I heard you say earlier that many histamine patients are very sensitive. And so then I also heard, you know, in my mind, giving someone a food that's high in probiotics, like a kimchi is, it would just be natural. Let's just do it. But is there caution that we have to take in certain cases that may be a patient that has histamine intolerance, may not actually tolerate some of the normal therapeutics that we might consider, like high doses of B vitamins or zinc or copper, or kimchi? Like, do we have to go slower and just really take things at a reduced speed so that we don't exacerbate their symptoms in these cases? - Absolutely, yeah. And in some cases, you might want to work on multiple levels, right? You might want to have somebody on a lower histamine diet while you work on other things, or you might keep them on a DAO supplement while you work on their intrinsic DAO production. So anything you can think of to bring down their levels, because, yes, having higher histamine will increase pain within the GI tract, within the body, and it will impact your ability to tolerate things. So, tolerate foods, tolerate supplements, you'll have some of your most sensitive patients and also some of your most anxious patients. Number one, because they've been shown sometimes recently and sometimes for a long time that the world may not be safe. It is unpredictable. They're seeing unpredictable and variable reactions, and that's scary. But also, histamine can produce anxiety, or it can manifest as anxiety in the mind. And like so many of our immune mediators, what I find the most fascinating is that sometimes our cytokines and our immune mediators, like histamine and cytokines, they can actually impact our mental health in ways that make a lot of sense. So histamine in the body, it can cause anxiety. It causes our patients to not feel safe in the world and to not trust the world around them. And that is part of the impact of histamine on the mind. Just like other cytokines, like IL-6, which is one of the first signs of infection, it causes people to isolate and to be a little bit grumpy. And it's kind of a natural protective mechanism where histamine might make you not feel safe, and other cytokines might make you hide away from the world. It's like, "Hey, I have an infection. I'm gonna go over here." And that is part of the protective mechanisms of our body. It's really magical and wonderful, but you've got very anxious patients often and very sensitive. So yes, going slow and also recognizing that there are some dysbiotic organisms within the gut that can produce histamines. Sometimes, clearing those organisms can be really challenging in our more sensitive patients. - So really coming back to that gut space testing where appropriate, looking at clinical indications and symptomology, modifying stress, supporting their knowledge that we are gonna support their safety, you know, externally and internally helping them to calm down a little bit. I would suspect sleep would be an aspect there to really focus in on. So all the things that we talk about, foundations of health. Go ahead, Amy. - Oh, I was gonna say hydration as well is, I think, underappreciated. Gotta stay hydrated. And some people have urinary symptoms with histamines too, so it's harder to stay hydrated when you've got a very active bladder or a bladder with a lot of signaling. But yeah, great points there, Bianca. I love that. - So your therapeutics, you're really gonna be focusing on monitoring how those go so that you can make those tweaks for your patient and they don't have extra anxiety and feeling that something's gone awry. Amy, I would love to maybe hear an example of a case from your practice that you'd be willing to share where you found that histamine intolerance was the issue, talking a little bit about how they presented, and also what your therapeutics were and how things turned out. - Yeah, absolutely. And I've had so many cases where histamines have been involved. I see a lot of pediatric eczema, things like that, and I see a lot of gut issues in my practice. So the one that comes to mind: I had a female patient. She was 44, and we were actually working on gut. We had a gut test already, and we had made a plan, and then she was going away for her birthday. So she had never presented with any reactions before she went away. So here in British Columbia, there's a central area, the Okanagan. It's really warm and sunny; people go to wine tastings. And so she went away on a weekend with her girlfriends, and they went to two or three different wine tastings, which was not her typical; they had meat and cheese platters, appies, it was warm. I don't know where she was in her cycle, but she was definitely perimenopausal. So the perfect storm of everything histamine, but why would you think of that, right? It's your birthday; you're going away. And so she was fine; they had a great time. And then she woke up on, I think, day two or three, full-body hives. And then she came back to me, and she said, "Something went totally wrong. I didn't start your protocol yet." Maybe she had started the digestive enzyme. But she came to see me, and she said, "Oh, no, I have an allergy. I don't know what it is." And I thought, "Okay, what were you doing this weekend?" And just hearing all of these things, it didn't have to be a histamine issue, but it sure presented as such. And so just all of these little micro additions to histamine load were going on, which sounds like a lot of fun, but then you wake up with hives. And luckily for her, it didn't end up being ongoing or a very serious issue. It's more just in that moment, the alcohol, potentially hormones, were impacting her ability to clear histamines, and then she was taking them in internally. She was eating higher histamine foods, probably more than just the meat and cheese platter, but going away and indulging a bit. And within the gut, there were a couple of histamine-producing organisms. It was not one of those obvious cases where I would've looked at it before that reaction and thought, "Oh, my gosh, histamines." But when you look back on the test and see that I think it was Morganella for her, was really high out of range. And I think, "Okay, that's a source of additional histamine here." And if you're not digesting well, breaking down your foods, that can increase your immune reactivity as well. So for her, we actually cut back and said, "Okay, let's do no alcohol for three, four weeks. See how that goes. Try cutting out obvious high-histamine foods." So there's many diets out there for histamine management. Most of them are very similar, but if possible, if our patients can get away with not following a low-histamine diet, I think that's ideal. Our lowest histamine diet contains a lot of really... Or it eliminates a lot of really healthy foods. So not being able to eat leftovers, that's challenging and that will affect your life. Ongoing, things like spinach, strawberries, avocado, tomatoes, we like those foods. For most people, those foods are totally fine. And then in the short run, sometimes it can be helpful to decrease our overall intake of histamines and histamine load, say, cutting out processed meats, that seems totally fine, and that is fine ongoing. So any obvious sources of histamine intake, we were decreasing. So I just said, "Hey, here's a list of high histamine foods. Take a look at these in your diet and see where it might be reasonable to cut back. Here's what I think was happening." And sometimes, for our patients, expectation management and explaining what might have happened can be just as powerful as actually making those symptoms never happen again. So just saying, "Hey, here's the four or five reasons I think that might have happened this day, even though it's never happened to you before in your life." - Yeah. And like you said, that perfect storm, right? All the pieces that just needed to happen happened on her birthday weekend. But you know, I'm thinking about this was really a perfect time now for her to have had this, if there was a perfect time, because you were able to support her in reducing so many of the components that could have been even more detrimental to her health in five years, 10 years, 15 years down the road. So it sounds like you had done some testing, and it wasn't necessarily associated with the histamine, but with those symptoms that came up, that testing itself was really important to be able to see another piece of the puzzle. - Yeah. - When it comes to testing, are there certain... There's likely certain tests that are maybe more in the functional realm that would be very impactful, maybe some SNP testing for some of the different enzymes. I'm wondering as well, are there lower-cost or tests that would just go through your basic insurance, your basic primary care provider that a patient could ask for or get that would help to support the histamine intolerance diagnosis, if you will, if they weren't able to afford or they couldn't find a practitioner that was able to do some of these other tests? - Yeah, great question. And I think in terms of lab testing, there are some basic lab tests that can help us rule things in or out. I think getting a basic CBC with a differential can show us our white blood cell balance. It can show us if we have enough iron stores, if we're adding on ferritin, looking at hemoglobin. So if you see a white blood cell differential with really high eosinophils, that makes me more suspicious of allergy or even parasite, which can drive IgE responses. If we see basophils really high, which is actually not that common in our histamine patients, even in MCAS patients, you won't always see high basophils. So it's tricky to rule that out. When we're looking to actually differentiate someone that we might think has MCAS, that is beyond basic blood work. But you do wanna look at things like your hs-CRP, ferritin, things like that, just to make sure that basic nutrient status is covered. We can look at thyroid function. We could look at serum hormones just to rule those out as causes. I think always in clinical practice, our clinical history will be our most important tool. Lab testing is amazing. It's the icing on the cake that can help us clarify and draw deeper value, but clinical history should be number one. And being curious about that and saying, "Okay, what was the reaction? What was it like? What else happened? How was your mental state? How long did it last? How quickly after eating or drinking, or, you know, how quickly did the symptoms come on? Has this ever happened before?" I think those curious questions are the most important clinical tool we've got. And then we can dive deeper in those patients that are a little bit trickier. Yes, you can run SNP testing. I think down the line, if you've tried other things, if you've tried the diet, you've tried modifying the obvious factors like alcohol, B vitamins, magnesium, copper, zinc, things like that, nutrient status. You've ruled out allergies, you're looking at the gut, and it looks totally clear, or it's not clear, and you've kinda addressed everything that makes sense to address, then you might wanna look at those SNPs, or the genetic testing to see, "Okay, do we have a COMT error in metabolism? Do we have issues with methylation that can impact our ability to have cofactors for enzymes?" So down the road, there's lots of testing options. And then I think our clinical history is the most important. And, you know, if there's skin issues, looking at the skin, seeing what you think, giving your opinion. - I love hearing the breadth of impact a practitioner who is fully engaged and has the time and the resources to support their patient by being curious because you can go from asking the questions, "Oh, it was a birthday party that had these kind of cheeses and this wine and your perimenopause," and really creating that rapport with your patient where you're asking the questions. Maybe they've never had some of these questions before. And being able to run all the way up to doing SNP testing if you needed to, like, to have that huge repertoire and toolbox at your disposal as a naturopathic physician is really wonderful. So Amy, as we wrap up here, I'd love to hear maybe a takeaway, one of your big takeaways that you want us to walk away with today, and any final thoughts that you would have around for functional medicine clinicians for histamine intolerance? - Yeah, thank you again. So I would say, I think taking a good case history, running testing when necessary, but just knowing that in practice we do have a lot of areas where we can help our patients who are struggling with higher histamine, whether it is from mast cell activation syndrome. So the true over-release of histamine, clearance of histamine, is still impactful and helpful. But for patients who have a simpler histamine intake to histamine clearance imbalance, we've got so many areas clinically where we can help them. So, just recognizing the different areas of clinical leverage, what makes sense to do first, second, third, and fourth, so if you have patients that present in certain ways or if they've got a lot of gut symptoms, maybe it is important to look at the gut first, or maybe you wanna start with nutrients and diet first. But knowing that there are so many different ways you can help your patients. And starting with one or two things at a time is really reasonable. And in this patient population, where people are more sensitive, more anxious, reassuring them and giving them the expectation management that, "Hey, we're going low and slow. We're starting with one to two things. How's your sleep? How's your hydration?" If that's all you start with, and a digestive enzyme, that is totally fine. And with our functional practices, like you said, starting with the basics of digestion, hydration, sleep, stress, and what are the basics I'm missing? But those are the basics. Fresh air. Exercise actually has an impact on histamine levels as well. So, just starting with the basics, you might never get to find out what the one singular cause of the issue was, but you can help your patients without even getting into deep supplementation. And then some patients will need to go to the next level and the next level, and some patients may need to be on ongoing management with medications for their histamine. So there's gonna be a huge spectrum, but we've got so many areas where we can help, and setting that expectation with your patients that, "Hey, this is trial and error." A lot of it is, even when we're getting into testing, tests can give us a lot of information, but we're still doing trial and error from there. What will help your symptoms? What will your body be able to tolerate? And what levels do we need? What levels can we handle?" So there's a lot of trust we can build with our patients if we give them the expectation, go really slow, check in frequently. - Well, thank you so much, Dr. Rolfsen. It's been a real pleasure to speak with you today, to learn from you, and to take this very complex topic and really bring it down to a level that feels manageable to a clinician, that we can be curious, and we can definitely support our patients. Starting from that foundational piece, recognizing imbalances and supporting the body and the mind to rebalance in all the different ways that we understand and have knowledge in. So thank you very much. It's again been a pleasure to speak with you today. - Okay. Thank you so much for having me. - [VO] Thank you for listening to "Pathways to Well-being." To learn more about functional medicine, visit ifm.org. The future is functional.