Gut Check: Jacqueline Squire, MD, on Alpha-Gal Syndrome

Dr Jacqueline Squire returns to the Gut Check podcast to discuss with Dr Lacy the impact of alpha-gal syndrome, a food allergy to red meats that may present as nausea, vomiting, and diarrhea, along with other symptoms of serious allergic reaction.

Brian Lacy, MD, is a professor of medicine at the Mayo Clinic in Jacksonville, Florida. Jacqueline Squire, MD, is an assistant professor of medicine in the division of allergy and immunology at the Mayo Clinic in Jacksonville, Florida

Alpha-Gal Syndrome: Recognizing, Testing, and Managing Delayed Reactions

• Alpha-gal syndrome typically causes reactions 3–6 hours after mammalian meat ingestion, including hives, swelling, anaphylaxis, or isolated episodic abdominal pain, vomiting, and diarrhea.
• Alpha-gal–specific IgE testing requires a compatible clinical history; a positive result alone indicates sensitization, not necessarily symptomatic allergy. Food diaries may help identify delayed reactions and cofactors.
• Management centers on avoiding mammalian meat and further tick bites. Most patients tolerate dairy; consider dairy elimination if symptoms persist. Declining IgE may permit an allergist-supervised meat challenge over time.

Welcome to Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida, and I am absolutely delighted to be speaking today with Dr. Jacqueline Squire, assistant professor of medicine in the division of allergy and immunology at the Mayo Clinic in Jacksonville, Florida. Dr. Squire is an expert in the field of allergy and immunology and was featured on a really interesting prior podcast about mast cell activation syndrome.

But today we're going to focus on a topic of interest to all healthcare providers and patients, the evaluation and treatment of patients with suspected alpha-gal syndrome. So Dr. Squire, welcome. Let's begin simply. Alpha-gal syndrome is a topic that's been all over the news. What exactly is alpha-gal syndrome?

Dr Squire:

Well, it's great to be back. Thank you for having me back on the podcast again. We had sort of talked maybe even in the beginning of a very relevant topic. It's coming up in the news. Patients are asking about it, so I think it's great that we're going to talk about it a little bit more today.

Alpha-gal syndrome is a really unique allergy, and that's one of the things I think that makes it so interesting. It occurs specifically to nonprimate mammalian meat or what most of us would refer to as red meat. So things like beef, pork, lamb, even venison is included in that. It does thankfully not affect ingestion or it's not a reaction to ingestion of poultry, so chicken, anything like that, or seafood. So the patients will not react to that.

It is unique in a couple of ways. One, that it is actually delayed. So most food allergies, and we'll get into this a little bit later, are immediate. Alpha-gal is actually a delayed reaction. And the second thing is that alpha-gal is actually specifically to more of a carbohydrate, which is abnormal for an allergen. Most allergens have to be to a protein, and so that's what makes it unique and also made it sort of hard to identify and diagnose. So it's a newer allergen that we're aware of.

Dr Lacy:

Very interesting. And how common is this disorder?

Dr Squire:

Overall, thankfully, we would say it's not particularly common, though we are seeing an increased rate of diagnosis over time. I think some of that has to do with increased awareness and knowing to test for it. Overall, between 2010 and 2022 in the United States, the best data we have says that approximately 450,000 people were diagnosed during that time. Alpha-gal sensitization, which is where you have a positive IgE, but without really a history that's suggestive of a disease or a condition related to that positive test, is actually quite common, particularly in areas in the Southeast US, which we'll talk about kind of correlates with exposure to the lone star tick. Up to 30% of control populations may come back positive for IgE to alpha-gal. That doesn't necessarily mean that they have the syndrome, though. So that's an important point to take away that depending on the area of the country where you test, you can have a pretty high positive test rate without having alpha-gal syndrome.

Dr Lacy:

That's such an important teaching point for both patients and providers because it's similar to a lot of other conditions, prior viral exposures, that we are all exposed to viruses as kids or young adults. We may do a test in showing that we have the antibody to it, but we don't have that active virus or bacterial infection or fill in the blank, right? And so similarly, it sounds like a lot of people have been exposed, but they don't actively have the disease. Is that right?

Dr Squire:

Exactly. That's a really big key point, is anytime we're talking about testing, particularly in the allergy world, a positive test does not equal a true allergy. You have to also have a history there, which we'll go over, that would really make us suspicious that this is now causing a problem for that patient.

Dr Lacy:

Perfect. And so for this condition, are some people more likely to get this than others? For example, men more than women or certain ethnicities or age groups? And one thing I've seen in the press, is this really just in the southern United States or can this be found anywhere in the United States?

Dr Squire:

Yeah, lots of great questions. So we don't necessarily know that there's a specific personal characteristic in a patient that makes them more likely to get alpha-gal syndrome, but we do know that it is associated with tick bites or tick exposure, particularly to the lone star tick. And so you're going to see it in patients who have those exposures to ticks. So patients who are living in more rural, wooded areas, patients who spend a lot of time outdoors doing activities maybe like hunting, which does often have a gender sort of preference for males. But as far as the condition itself, it's not purely seen in those patients. It can be anyone who has those exposures. It is more commonly diagnosed in patients who are white or Caucasian and more commonly in adults, but it has been seen in children as well. So again, it really can be anybody.

We don't want to exclude based on, rule it out, purely based on those characteristics, but more commonly seen with those patients.

Dr Lacy:

So I'm not a tick expert, but as many listeners know, there are lots of different types of ticks. And if you're in New England, you're worried about Lyme disease. If you're out west, you're worried about Rocky Mountain spotted fever. So is this caused or transmitted only by one tick species or do we have to worry about all kinds of ticks?

Dr Squire:

Yeah, that's a great question, and you did allude to it and I didn't fully answer it in the last question. When we've seen the distribution of even just the positive IgE to alpha-gal without having alpha-gal syndrome or specifically alpha-gal syndrome, it does seem to be more localized to the area where the lone star tick is, which is kind of Southeast, but more so the Carolinas, Virginia, Kentucky sort of area is a higher prevalence of that. But it has been reported all throughout the United States as well as Europe as well as Asia. So it is present universally, just higher prevalence in those areas. It has also been seen in areas where we really don't think that there is lone star tick exposure such as in northern Minnesota. And so there is a suggestion that you can be affected by other ticks as well, but seems to be at much, much lower rates.

Those are still very rare reports that are coming out with other types of ticks. It does seem to be predominantly the lone star tick.

Dr Lacy:

So this topic will be confusing for a lot of our listeners. Really, how does a tick bite cause a meat allergy? That just seems so weird, right? So are they injecting some venom? Is it a chemical? Is it just an allergic reaction? Is it cross-reactivity? And you already mentioned it's kind of unusual because it's due to a carbohydrate, not a protein, right?

Dr Squire:

Yes, lots of great questions. And I'll be honest, we don't fully know. That's always the hard part and we wish we had the full answer, but we don't fully know the mechanism. There's a couple of different reasons why we think this is related to the tick bite. Alpha-gal is found in tick saliva. Alpha-gal is found in the red meat, and so we eat meat and we are exposed to the alpha-gal and hence you have the reaction, but we don't see that patients who eat red meat without any tick exposure will develop an IgE specifically to alpha-gal. We thankfully don't see that. So it does seem to be that you really have to have that exposure of the IgE through the tick saliva in order to mount a response.

Some of the data, too, that has suggested why the lone star tick might be more of an issue and why we're seeing it more specifically with alpha-gal syndrome is that there is some data that patients tend to have more of a localized allergic reaction to those tick bites. They're itchier. Patients are getting more localized welts and rashes at the site where the lone star tick is biting. And so that's suggesting we're already kind of activating the allergy cells just from that bite and that saliva. So potentially that exposure along with that is what's leading to developing this allergy specifically to the alpha-gal that's in the saliva. But as far as the exact mechanism, it's not fully understood.

Dr Lacy:

So I'm hoping that many of our listeners now aren't kind of scratching and itching because they're thinking about tick bites and how funny it feels. So you mentioned that it's in large degree somewhat common. You mentioned 450,000 patients diagnosed in about a 12-year period, but not all people, as you've already highlighted, bitten by a lone star tick develop symptoms. They may have been sensitized, they haven't developed symptoms. So why is that? Why do some people get it and others don't? You kind of touched on this. Is this related to a blood type? Is it related to the volume of red meat that somebody might eat every day versus once a month? Is something else going on related to maybe concomitant or coexisting alcohol use or medications?

Dr Squire:

Yes, lots of great questions. So again, yeah, we don't fully know why is it that some people who are bit develop a reaction and some don't. I would say to reassure most of our listeners is the majority of people who are bit by a tick are not going to develop alpha-gal syndrome. So we don't need to get too worried if we do have one. But there have been some studies that have shown that people who have type B blood, so type B specifically or AB blood, they actually do seem to develop alpha-gal less often. It's not known 100% why. It's thought that it may be that the type B antigen that we have on our blood that our body would not want to react to because it's our own blood, so we don't typically make antibodies against our own antigens. Of course, rare causes of that, but much less common with blood types, that that type B antigen is actually pretty structurally similar to alpha-gal. And so when you already have tolerance to an antigen like type B that is similar to ours, less common that you'll develop an allergen to something that may be similar. So that's been one thought. Again, it's not that type B is completely protective, so it can still happen, but that's been one thought. That's really the only signal that we've seen of how a blood type may play into it.

As far as the other risk factors, you did sort of touch on is it related to the type or how much of red meat that we eat? We don't see that the type or necessarily the serving size amount that we eat, but we do see that a higher fat content in the meat is associated with more alpha-gal reactions or maybe more symptomatic. So a patient may actually be able to eat a small lean cut of meat and not have a reaction, but if they eat a fattier cut of meat or something that contains a lot of lard even in their meal, they may react to that, but not the other.

We do think that is because the lipids inside the higher fat content help the alpha-gal cross the intestinal epithelium, get into the bloodstream and have a reaction. So some thought there that higher fat meals maybe could get more of that sort of crossing into the bloodstream from that standpoint. We do also see in general with any form of allergy, but it happens with alpha-gal as well, that cofactors play a part into whether somebody will react to that particular food or other exposure. And what we mean by that, there are certain things that the patient is not allergic to in itself, but when you combine it with something they are allergic to, it sort of lowers the threshold for a reaction. So either a smaller amount will cause a reaction or a more severe reaction to the similar amount they wouldn't have eaten with the cofactor. Common cofactors that we see are NSAIDs, ibuprofen, Aleve, things like that, and alcohol as well are also cofactors.

There are co-factors we think in a couple of ways by one, again, increasing that intestinal absorption, and so you're getting more of that allergen into the bloodstream, but also by just directly activating our allergy cells, which are our mast cells we had talked about before, but those can be directly activated by certain medications like NSAIDs that can sort of prime them to be a little bit more reactive.

Dr Lacy:

All right, so multiple great teaching points. Thank you. So if you have alpha-gal syndrome that's documented and at some point you're going to eat red meat, it sounds like don't drink alcohol with the red meat, don't use anti-inflammatory agents, and if you have the choice, a very lean cut of red meat versus fat.

Dr Squire:

Yes. So those things would all potentially play into a worse reaction. Now, we would say if somebody is officially diagnosed with alpha-gal syndrome, they should avoid red meat and we'll talk about that. But yes, all of those other things we just talked about could lead to a more severe reaction if not adhered to.

Dr Lacy:

Wonderful. And this next question I think actually has kind of two layers to it. So one is, let's say you're bitten by a lone star tick and maybe you have some of those predisposing factors. How quickly after you eat red meat might you develop symptoms? And what I mean by kind of a layer to this is do you need multiple exposures to the red meat to finally have a response? Or if you have it and you eat red meat, do you get symptoms? You kind of said already it's delayed. Is it 2 hours later or 4 hours later or 6 hours later? What do patients expect?

Dr Squire:

Yeah, and so if someone is bit by the lone star tick in particular, or we think a tick that may predispose them to developing alpha-gal syndrome, it's not expected to be immediate, meaning it's not that they would get bit and that day or the next day is when they would start reacting to red meat. Making an antibody to something typically takes weeks. So after whatever mechanism that we have that's stimulating our body to make that antibody, that would be like a vaccine even. We think about making a different type of antibody, but it's still an antibody response, or in this case, making an allergy antibody, that exposure that's sort of triggering our body to now make an antibody will take typically several weeks to really develop a true antibody level that we can measure in the blood. And so patients will typically not report their first reaction or their first concern for an alpha-gal reaction until about 1 to 4 months after what they suspect was their exposure to the tick. So it's not necessarily right away that that would happen.

As far as the typical symptoms then with alpha-gal syndrome, so once someone develops alpha-gal syndrome, what does that look like? And it is, again, we sort of mentioned, it's different than most food allergies. Most food allergies are immediate. The patient will be able to say, "It was the peanut. I ate it within 10 to 15 minutes. I started getting hives, lip or tongue swelling." And they'll come into the allergist office and they'll be able to very easily pinpoint and say, "I know it was that food because it happened very shortly after I ate it." Maybe up to an hour. I would say there's other, again, rare cases where it's later, but most patients with normal food allergies are within minutes to up to an hour after ingestion. Alpha-gal syndrome is different, is it's typically always delayed, and by delayed we mean often, most often 3 to 6 hours after eating meat. So it is not right around the time that they ate it.

The sort of classic history that comes up on our boards or things like that is the patient that has a nice steak dinner, goes home, does their usual thing, and then actually wakes up from sleep with hives, lip or tongue swelling, maybe perfuse vomiting, even low blood pressure, or they can pass out, really getting into maybe the anaphylactic shock episodes. So that is sort of the classic history of an alpha-gal allergy. Again, we had sort of talked about it. This can be tricky to diagnose because it can be they needed to have a higher fat meal or they had to have had a glass of alcohol with their dinner at night with their steak dinner in order to have that reaction. So it may not happen every single time after they have red meat, and so it can be a little tricky for the patient to pinpoint and say, "I can clearly tell a pattern that it's happening with these things," which that's one of the reasons it's been a little harder to diagnose.

There is also now known, there's kind of a second presentation of alpha-gal syndrome that doesn't really include the classic allergy symptoms like hives or lip or tongue swelling or trouble breathing. It's just predominantly GI symptoms. These really should be episodic symptoms though, so not chronic GI symptoms, even though someone may have red meat in their diet pretty regularly. We would still expect to see an episode where it gets really more severe and the patient reports severe abdominal pain, recurrent vomiting, severe diarrhea with these sort of symptoms, and again, should hopefully have a little bit of a history of they notice when I do have red meat or particularly certain forms of red meat, maybe even high fat dairy content, that I'll have worsening of my symptoms. Those are things that might lead us to think that it is related to alpha-gal syndrome.

Dr Lacy:

Wonderful. Thank you. And you've kind of already touched on some of the initial points about making an accurate diagnosis in terms of symptoms, but we also know that as you've kind of highlighted, symptoms sometimes, especially in the GI tract, but also in the allergy world, are nonspecific. So thinking about the initial diagnostic plan before we get to testing, are there maybe 3 or 4 things we should really hone in on? You kind of mentioned it so nicely, but maybe what are the 3 or 4 things we want to highlight?

Dr Squire:

Yeah, that's a great question. We sort of talked about a little tricky here and there, but big things would be to look for the episodic symptoms and whether that's allergy type symptoms, do they ever have any hives, lip or tongue swelling, GI symptoms, and thinking are those all coming together at the same time episodically, or are we having severe GI symptoms particularly that may flare? If a patient can't really identify, they're not noticing a pattern to it, sometimes asking them to keep a food diary, so to see if they can try to correlate, and again, knowing that it may be with only higher fat content, even maybe larger serving sizes or maybe high fat dairy products or dairy products as well to be thinking about, see if they notice a pattern with that. And then with any cofactors as well, keeping an eye, sometimes asking them to detail that if we can't really get a clear picture initially can be helpful.

Dr Lacy:

So objective data, a test can be very useful and sometimes reassuring to both patients and providers. Is there a great single test for this? Should we be doing a blood test for this? Is that something I can order? Should we send everybody to an allergist and they do a skin prick test? What's best?

Dr Squire:

Yeah, so there is thankfully a single best test, and that would be the alpha-gal IgE. So if you order it from different labs, it may be alpha-galactose13-galactose is a very long name, or it may come as an alpha-gal panel, and that panel will typically include alpha-gal specific IgE and then beef, pork, lamb. It'll include those main red meats in the panel. The alpha-gal IgE is specific to alpha-gal syndrome. The beef, pork, and lamb is not necessarily specific to alpha-gal syndrome, but we will see some cross-reactivity and it come up positive there. We actually don't have any available skin tests that we can do for alpha-gal syndrome. So if you come to an allergist, we would order the same lab that certainly a gastroenterologist or primary care physician could go ahead and order as well to test for that.

Dr Lacy:

So let's say you've got the classic patient, they had that documented tick bite. They even saw the lone star tick four months ago, they've been eating red meat, they've got some of these classic but nonspecific symptoms. You do a serum blood test and you notice that the level is quite markedly elevated. How do you treat this?

Dr Squire:

Yes, that's a great question. I will say similar to a lot of other food allergies, which certainly for some patients, and I would say a lot of my patients who have been diagnosed with alpha-gal syndrome, a lot of them are very avid meat eaters, and the primary treatment is avoidance, that we really need to cut the mammalian meat. So that includes, again, all the red meat, beef, pork, lamb, venison. We need to remove all of that from our diet. Even though we talked about sometimes patients may say it only occurred with the higher fat foods, the risk with any sort of food allergy is that your prior reaction doesn't necessarily predict your future reaction. So having that positive IgE means they would be at risk for any future exposure to alpha-gal, which would be in red meat, could cause them to have a reaction. And so we would recommend really removing all of that red meat from their diet.

They are okay to continue to eat seafood and poultry, as we mentioned, so all forms, chicken, turkey, duck, all of those sort of things. Thankfully—even though I had kind of mentioned a couple times that high-fat dairy or dairy products, they can actually contain alpha-gal—thankfully though, majority of patients with alpha-gGal do not react to dairy, so most of them do not need to actually remove dairy from their diet. If they were to remove red meat and were still having symptoms or still having concerns for developing reactions, then we would certainly move to recommending that they remove dairy from their diet as well, and that's really all forms of dairy. But again, thankfully, most patients don't need to.

Even less common, so I would say quite rare for patients with alpha-gal syndrome, there are other mammalian products that can contain alpha-gal. That includes gelatin, that includes things that list sort of "natural flavorings" that can include things that are coming from a mammalian product that have alpha-gal in it. And even certain medications like heparin, which is often derived from pork, can actually have some alpha-gal in it. Again, our studies so far and a lot of the data that come out with alpha-gal patients is most patients don't react to those things. It's got such low levels or even negative. It's really, even though heparin is, again, pork-derived or animal-derived, it doesn't always contain measurable alpha-gal. So in general, we would not have patients strictly avoid those just due to a diagnosis of alpha-gal syndrome. It would be only if there became a concern that they had reacted to smaller and smaller quantities over time.

If we do have some patients who seem that they are just very sensitive and very reactive to alpha-gal or potentially any alpha-gal cross-reactive exposures, we do actually treat those patients almost a little bit like mast cell activation syndrome patients. We had talked about those patients previously on the podcast, and sometimes we need to sort of calm down the allergy system and prevent it from being so reactive.

So there are some medications we can think about adding in if a patient is needed. There is unfortunately no treatment though that will specifically make you less allergic to alpha-gal, that we can just give you and it will get rid of the allergy and you can go back to eating red meat. Thankfully though, we do know that if you avoid significant exposures, you cut the red meat out of your diet, you're not having reactions anymore, your symptoms are well controlled, and you avoid further tick bites, the alpha-gal allergy can go away with time. We actually can monitor it, and often that IgE level will trend down either to very low or almost negative. And then we can actually do a challenge often here in an allergist office where we'll reintroduce the meat into their diet and they'll be able to resume it going forward.

Dr Lacy:

Wow, wonderful. I want to highlight a couple of amazing teaching points. One is for our listeners, the immune system has a wonderful memory. It remembers what you've done, and that's important because the teaching point number two is that with food allergies, as you so nicely stated, that second reaction can be worse than the first, and the third even more because you're really priming a pump and the immune system responds so favorably. Number three, we all like to take a medicine or use a gel or do something, but it sounds like right now there's not a digestive enzyme or medicine that will prevent this. But number four, there's hope that if our listeners with alpha-gal syndrome avoid red meat over time, this immune response may dampen and they may be able to introduce small amounts, but low fat in the future, right?

Dr Squire:

Yes, exactly.

Dr Lacy:

Wonderful. So Dr. Squire, this has been a wonderful conversation. Any last thoughts for our listeners?

Dr Squire:

So yes, it's been great to talk about this. Alpha-gal syndrome has gotten a lot of publicity lately, and I think it's something that patients may be very concerned about, particularly if they've gotten a tick bite or they have significant symptoms, and so certainly should be on our radar. Number one though, again, we really do want to narrow who we're thinking of this diagnosis in to those patients that are having episodes that would be concerning either for allergic reaction like anaphylaxis or significant GI symptoms that would warrant us going and doing that testing. The test, if it were to come back positive, very reasonable then to do a trial elimination of red meat and remove it from the diet completely.

If that doesn't help with symptoms, I may then suggest the patient remove dairy from their diet just to see, does that make a difference? If the patient really is not noticing any improvement in symptoms with removal of red meat and removal of dairy, I would have a lower concern that the primary problem is alpha-gal syndrome, just even though we have a positive IgE. If we're not seeing significant improvement in our symptoms, that suggests something else may be going on and either myself or maybe gastroenterology with their help as well, we would dig into that a little bit more and try to figure out what's going on. And so again, the positive test by itself wouldn't necessarily diagnose alpha-gal syndrome. We really want to have a history and a response to removing that from our diet.

Dr Lacy:

Dr. Squire, again, thank you so very much for letting your expertise on this important topic. To our listeners on Apple, Spotify, and other streaming networks, I'm Brian Lacey, professor of medicine at the Mayo Clinic in Jacksonville, Florida. You have been listening to Gut Check, a podcast from the Gastroenterology Learning Network. Our guest today was Dr. Jacqueline Squire from the Mayo Clinic in Jacksonville, Florida. I hope you found this just as enjoyable as I did, and I look forward to having you join us for future Gut Check podcasts. Stay well.