New Guidance on Alpha-Gal Syndrome’s GI Implications: What to Know

This transcript has been edited for clarity.

Hello. I'm Dr David Johnson, professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia.

Alpha-gal syndrome is something you've hopefully heard about, and if you haven't, you need to.

The American Gastroenterological Association (AGA) just released a practice update on alpha-gal syndrome for the gastrointestinal (GI) clinician, which I'd like to give you some highlights from here.

Background on This Emerging Allergy

Alpha-gal syndrome is an emerging allergy first described in the early 2000s. The allergy can cause anaphylaxis and skin and GI symptoms within a couple of hours of the ingestion of mammalian products.

However, there seems to be a GI phenotype that is increasingly apparent and has fairly nonspecific symptoms, including abdominal pain, diarrhea, nausea, and vomiting, without the predominant skin, respiratory, or circulatory symptoms. The GI aspects of this syndrome were the focus of the AGA's update.

The allergy in alpha-gal syndrome is to galactose alpha-1,3-galactose, which is an oligosaccharide on the cells of all nonprimate mammals — basically, any mammals that have hair.

Surprisingly, the sensitization comes through exposure to a tick bite, and in the United States, the lone star tick has been the most commonly implicated. Reported cases are primarily found in the lone star tick's range from the Midwest to the East, with the only region of relative exclusion being the far Northeast.

At that point, the antigen alpha-gal is absorbed by the GI tract, bound to a fat in a glycolipid, and incorporated into chylomicrons that enter the blood within 2 hours. When the antigen binds to IgE antibodies present on mast cells so richly populated in the GI tract, these mast cells then degranulate and release their histamines and other mediators, which can create significant effects on sensory nerve endings and intestinal smooth muscle function, creating contractility and causing mucus glands to secrete mucus.

Observational studies have suggested that these allergic reactions occur when a sensitized person consumes a mammalian or mammalian-derived dietary product. However, most individuals with alpha-gal antibodies in the population are asymptomatic.

A 2023 article from investigators at the University of North Carolina looked at a cross-sectional study of patients undergoing screening colonoscopy. They found that approximately one third of the patients were positive in their epidemiologic evaluation; yet, the majority did not manifest symptoms. So, there seems to be a phenotype of people who are more predisposed to the reaction as it relates to the alpha-gal syndrome.

The initial understanding of the significance of alpha-gal syndrome started with the investigation of some immediate and oftentimes severe allergic reactions to the monoclonal antibody cetuximab, which is used in gastroenterology for colon cancer, as well as for head and neck cancers. Cetuximab is derived from murine antibodies and causes an epidermal growth factor interferant-type interaction. There also seems to be a proclivity for interactions with this drug as it relates to the alpha-gal syndrome.

Considerations When Diagnosing Alpha-Gal Syndrome

Alpha-gal syndrome is something that gastroenterologists should consider as a potential option in their differential diagnosis when they encounter unexplained GI symptoms, such as abdominal pain, diarrhea, nausea, and vomiting. This is particularly true for patients who live or have lived in the alpha-gal–predominant areas — which, as mentioned, extend from the Midwest to the East Coast, including across the Southeast, Central, and mid-Atlantic states, with the far Northeast perhaps being a little bit less likely geographical source.

Conversely, clinicians should consider not testing those with "red flag" symptoms, particularly people who have anemia, GI bleeding, and weight loss. The allergy doesn't cause these types of symptoms, so you wouldn't seek to diagnostically identify alpha-gal in those situations.

Although the lone star tick predominates in the United States, it's important for the people listening around the world to understand that alpha-gal syndrome has also been reported in Australia, South Africa, Western Europe, and even Japan.

The characteristics of alpha-gal syndrome can be quite striking. Some patients report nocturnal awakening from GI distress, because there might be a delay of 2 or more hours after ingestion-related exposure and the degranulation and release of histamines in the small intestine.

The actual diagnosis is made using an alpha-gal IgE titer. An IgE antibody to alpha-gal is not enough to establish a diagnosis, particularly in patients with isolated GI distress. Therefore, our next step is similar to what we would do with celiac disease testing: Patients should be directed toward a dietitian, hopefully to obtain an alpha-gal-avoidance diet.

This diet should focus on things like mammalian products (ie, beef, pork, venison), and related mammalian-derived products (ie, lard, dairy, ice cream), and be followed for at least a month. And, as we do with our patients with celiac disease, it's very important to caution those with alpha-gal syndrome to avoid eating at restaurants during this time, because they can easily cross-contaminate with food and processed foods, in the form of food additives that otherwise may be missed.

Management Strategies

Managing these patients initially comes down to overseeing this restrictive diet.

Patients should be counseled to not eat pork, beef, venison, and other mammalian meat (again, essentially any animal with hair), as well as products made from these animals, such as lard, butter, and milk. Dairy contains small amounts of alpha-gal, particularly ice cream, cream, and cream cheese. These foods also have a high fat content, which seems to trigger alpha-gal syndrome.

It's important to recognize that gelatin is a derivative from the collagen in pig or cow bones. Products that contain gelatin include marshmallows, gummy bears, gelatin candies, and desserts.

There are also some medications that may use gelatin in their production process, such as ibuprofen, some of the acetaminophen derivatives, clonidine, and lisinopril. Therefore, it's key to look at all medications that patients are taking, not only prescription medications but also over-the-counter medications.

There have been some patients who have reported reactions from just the inhalation of the alpha-gal; for example, from frying bacon or beef products. These may be things to counsel patients about too.

If you have a patient who experiences a reaction due to alpha-gal syndrome, they should be instructed to take one or two diphenhydramine tablets, typically 25 mg each, so 25-50 mg total. Make sure they have access to an injectable EpiPen as well if they're experiencing severe anaphylaxis-type reactions.

Raising Awareness About Additional Risks

When counseling patients who have alpha-gal syndrome, we must discuss with them about taking measures to avoid further tick bites, which seem to upregulate the sensitivity for the allergic reaction. Some of these good tips I learned myself in the Boy Scouts some 50 years ago now. Patients will want to secure areas where ticks can get into their clothing, such as pulling up their socks over the cuffs on hikes and treating clothes and boots with permethrin, which certainly helps reduce the tick bites. Patients should be performing tick checks when showering soon after activities in wooded areas.

The infusion reaction observed with cetuximab and alpha-gal syndrome certainly made some patients aware of this potentially adverse reaction, as well as the oncologists who are prescribing such drugs. Derivatives of things like pancreatic enzymes are also important to be aware of, because these are made from pigs and may cause problems in allergic individuals.

Regarding medical devices, the alpha-gal allergic reaction has shown potential to create a problem with bovine or porcine bioprosthetics, including cardiac valves, patches, and veins in vitro. Although there are no long-term studies, there were at least two cases reported of anaphylactic reactions after a bioprosthetic valve replacement in patients with alpha-gal syndrome who were allergic.

There are alpha-gal–free medical device products available, so this is something for those who are performing transplants or vascular surgeons to be aware of, especially if you're practicing in an endemic area and patients may be showing this proclivity.

Guidance for Gastroenterologists

For gastroenterologists following up with patients with alpha-gal syndrome, it's important to recognize that this is a dynamic condition. Symptoms may fluctuate over time.

Patients who avoid further tick bites and whose sensitization fades over time may ultimately be able to eat meat in the future. Again, it's extremely important to emphasize to patients that they really need to avoid further tick bites, which can lead to greater sensitization.

If the patients are doing well, the recommendation is to repeat the alpha-gal IgE levels in 6-12 months after the initial diagnosis.

If the level decreases or is negative, the patient may be able to try resuming their prior diet. This can begin with dairy products and then mammalian meat products, although initially in small portions. Anybody who has significant symptomatic reactions should then work with their allergist and be given access to antihistamines and injectable epinephrine.

Referral to an allergist is recommended for patients with more severe reactions and skin or systemic findings that you would expect with anaphylaxis. There are no data that we're aware of that allergists have established a desensitization protocol for alpha-gal syndrome, so this would largely entail working with them on ways to avoid progression of the allergic response.

What happens if patients are having an allergic reaction? Should they expect that it will happen after every exposure? The answer is no. There are certain factors that seem to heighten the phenotypic expression. As previously mentioned, fattier cuts of meat seem to be cofactors, and exposures like nonsteroidal anti-inflammatory drugs and alcohol may increase the reaction potential.

When it comes to consequences beyond the GI tract, there are some reports that IgE-associated–positive patients have an increased proclivity for advanced cardiac disease. This would be something to watch for; however, at this point, there are no significant screening recommendations outside of normal clinical practice.

Parting Advice

There are a few take-home messages with which I'd like to leave you.

Gastroenterologists should be aware of the proper diagnosis and management of alpha-gal syndrome. When it comes to exposures, we should recognize that although this is largely associated with the US lone star tick, there are areas all around the world that are reporting this as well, so please keep that in your differential diagnosis.

I'd also stress avoiding repeat tick bites decreasing sensitization and counseling your patients about the dietary and medication-related exposures, focusing on prescription and nonprescription medications, restaurant exposures, etc.

Alpha-gal syndrome is an important disease with very protean manifestations that overlap with a lot of disease states that we deal with, including functional diseases in the United States. We may be able to do better when we really focus on the underlying etiology.

I'm Dr David Johnson. Thanks for listening.

David A. Johnson, MD, a regular contributor to Medscape, is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. His primary focus is the clinical practice of gastroenterology. He has published extensively in the internal medicine/gastroenterology literature, with principal research interests in esophageal and colon disease, and more recently in sleep and microbiome effects on gastrointestinal health and disease.

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