A Guide to Understanding Alpha-gal Syndrome’s Paradigm-Shifting Presentation
A Paradigm-Shifting Allergy
Alpha-gal syndrome (AGS) is a unique allergy whose paradigm-shifting features challenge past assumptions about IgE-mediated allergies. Some of these features include:
- The allergen epitope, galactose-alpha-1,3-galactose (alpha-gal), is a carbohydrate, rather than a protein (1).
- Primary sensitization to the allergen occurs through tick bites (3).
- AGS involves both food allergy and sometimes fatal hypersensitivity reactions to drugs and medical products (1,6,57).
- Onset in adulthood is more common than onset in childhood (6,57).
- Lipids (fat), which incorporate alpha-gal, are an important source of the allergen (92).
- Reactions can be delayed and typically occur 2-8 hours after the ingestion of mammalian meat (1,6,57,91).
- Reactions to other exposures, especially the infusion or injection of drugs and other medical products with mammalian ingredients, can be rapid onset or immediate (1,6,57).
Additional Atypical Features
Alpha-gal syndrome differs from other allergies in additional ways. These can include:
- Non-classical symptoms, including:
- Pronounced inter- and intra- individual variation in reactions (57)
- The profound influence of co-factors on reactivity (57)
- Anaphylactic reactions in up to 60% of cases (24,78,87,88,89)
- Reactions to airborne alpha-gal, especially fumes from cooking meat (57)
- An increase (20) or decrease (95) in reactivity based on exposure to or avoidance of additional tick bites (6,57)
- Reactions after exposure to alpha-gal in personal care and household products (6,57)
- Large, local reactions to tick or other arthropod bites (57) that often persist, sometimes for months.
- In some cases, the development of chronic spontaneous urticaria (57)
- In 3-5% of cases, the development of symptoms consistent with a mast cell syndrome (57)
- Very few (>1%) of patients report itching or swelling of the mouth or tongue (6,57,91)
*most of the southeastern U.S. and other populations with high tick exposure, including areas of the Midwest and much of the eastern U.S.
What Is Alpha-gal Syndrome?→
Anything with alpha-gal in it can trigger an alpha-gal allergic reaction. The most common food triggers are mammalian meat and organs, but lard, dairy, gelatin, other mammalian byproducts and carrageenan can also cause reactions when ingested. Medical products that can trigger reactions include medications, plasma volume expanders, vaccines, and many others. Personal care and household products can also trigger reactions.
See What is Alpha-gal Found In for more information.
Mammalian meat and organs
Dairy, gelatin, and other foods derived from mammals
Drugs and other medical products
Personal care products
Based on his experience with over 2,500 patients, leading expert Scott Commins, MD, PhD has identified seven characteristics that occur in 85% of patients with alpha-gal syndrome:
(I) Onset in adult life after eating mammalian meat without problems for many years
(II) Reactions range from pruritus, localized hives or angioedema to anaphylaxis
(III) Patients can report strictly gastrointestinal symptoms (diarrhea, abdominal cramping, emesis) almost to the exclusion of cutaneous, cardiovascular, or respiratory manifestations
(IV) Reactions start 3–8 hours after eating non-primate mammalian meat (or consumption of dairy, gelatin, or other mammalian-derived products)
(V) Positive testing for alpha-gal IgE (>0.1 IU/mL)
(VI) Improvement of symptoms when adhering to an appropriate avoidance diet
(VII) Description of large local reactions to tick or other arthropod bites, often including report of an ‘index’ bite that behaved differently than prior bites (57)
Onset in adulthood
GI symptoms in isolation of other symptoms
Delayed reactions, often striking in the middle of the night
Large, itchy tick bite
Symptoms improve after a change of diet
Exceptions to this classic presentation include:
- A significant number of pediatric cases occur (91), especially in some cohorts (84). Pediatric cases may report:
- Some individuals report onset of symptoms in less than 2 hours (16% of cases in one study) (57,91)
- Not uncommonly, patients do not recall a tick bite. Approximately 50% of people who develop tick-borne diseases do not remember being bitten by a tick (57), so this isn’t particularly surprising.
- Sometimes patients recall being bitten by chiggers (57). In many cases, these “chiggers” may actually be larval tick bites, especially in the late summer and early fall.
…we have seen many children who had been diagnosed with idiopathic urticaria/anaphylaxis, or who had been specifically told that the reactions were not a result of food allergy, who had IgE antibodies to a-Gal and, in retrospect, a history consistent with delayed reactions to mammalian meat (103).
Pediatric cases: GI symptoms
Children often primarily report GI symptoms
Pediatric cases: sports
With children, there can be a strong association between reactions and sports
In geographic areas where tick bites are common, AGS is likely under-recognized and under-diagnosed. We suggest testing for alpha-gal IgE in tick-endemic areas as part of the evaluation for cases of idiopathic anaphylaxis, recurrent urticaria and/or angioedema, as well as recurrent, episodic gastrointestinal cramping of unestablished cause (57).
- Pruritis (itching) (57,84,90,96)
- Itching of the palms and soles of feet can be the initial symptom of a reaction (96)
- Urticaria (hives) (6,84,57,90,91,96)
- Flushing/erythema (84,90,96)
- Especially the palms and soles of the feet (90)
- Anaphylaxis is a life-threatening condition which can involve a range of different symptoms.
- See FARE guide to anaphylaxis for information about symptoms of anaphylaxis.
- Hypotension (low blood pressure) (90,96,110)
- Light-headedness/dizziness (90,108)
- A weak and rapid pulse
- Pre-syncope (feeling like you will faint) (90)
- Syncope (fainting, loss of consciousness) (90,97,108,110)
- Shock (98,110)
- Other cardiovascular symptoms (see Fare guide to anaphylaxis)
According to allergist Erin McGintee, MD, who has treated over 600 patients:
About 90% of the patients present with skin symptoms. Most often it will start with the palms and the soles of the feet or the ears. They will start with intense itching, and it will progress with hives and/or flushing that can be localized or generalized. The next most common symptom that we see is actually gastrointestinal symptoms. It is very common for patients to complain of severe abdominal pain, cramping, nausea, vomiting, diarrhea–you see these in at least 60% of the patients. Cardiovascular symptoms are not uncommon. 30-40% of the patients will report feeling light-headed and I definitely have a good number of patients who lose consciousness… About 30-40% of the patients will report respiratory symptoms either involving the throat or involving the chest. (90)
During an oral food challenge involving 13 patients with AGS, Commins et al, observed:
…many of the patients with IgE to alpha-gal reported itching as their initial symptom of a food-induced allergic response. Although we were aware of this through patient reports in the past, we were not aware of the prominent palmar and plantar pruritus with erythema and often urticaria (96)
…in 3 of the subjects with IgE to alpha-gal, the initial site of itching during the meat challenge was a prior or recent tick bite site. This might suggest that basophils, mast cells, or eosinophils remain present at tick bite sites (96).
…several of the reactions showed incremental progression, in which a symptom, such as palmar erythema, might be followed in time by discrete and then systemic urticaria, which even progressed further to include gastrointestinal distress or hypotension (96).
Although all positive reactions during the meat challenge were delayed, there was variation in the time of symptom onset…patient FC-06 reported only pruritus at 292 minutes, by 6 hours he was nearly discharged before having systemic urticaria 35 minutes later. Variation was also noted in the progression of symptoms, with some patients experiencing a much more rapid course once symptoms appeared (96).
Four patients who had symptoms during the meat challenge also reported “lingering” symptoms up to 48 hours after challenge (96).
In a study of 261 adults and children reporting red meat allergy, Wilson, et al observed:
The a-Gal syndrome is a regionally common form of food allergy that has a characteristic but not universal delay in symptom onset, includes gastrointestinal symptoms, can develop at any time in life, and is equally common in otherwise nonatopic individuals (91).
We had a cookout. I ate an average piece of steak. That night I woke up around 3:30 am in disarray. Palms blood red, itchy beyond words could describe. Half dollar hives appeared EVERYWHERE from my thighs to my belly button. Internally, it felt like a ping pong ball of fire was bouncing around my chest. Throat was tight. For an entire week after, my digestion system was beyond uncomfortable in ways I couldn’t tastefully explain. Was very ill feeling for many days.
“Any time you see a patient who is coming in saying they are waking up in the middle of the night with an allergic reaction, you better prove that it is not this.”
Delayed and Rapid-Onset Reactions
Unlike other allergies, alpha-gal allergic reactions are typically delayed by three-to-eight hours, at least after ingestion of red meat. The reason for this is unknown, but experts Jeffrey Wilson and Thomas Platts-Mills have proposed that the lengthy process of metabolizing the glycolipid form of alpha-gal may be involved (see below) (92).
Some reactions can be rapid or immediate. Examples include:
- In about 16% of cases, consumption of red meat can result in onset of symptoms in less than two hours (91).
- Reactions after consumption of pork kidneys (24)
- Reactions to drugs, vaccines, and other medical products, depending on how they are administered, including:
- Reactions to airborne alpha-gal, such as meat fumes, which can occur within minutes (multiple anecdotal reports).
- Reactions to topical exposures, like lotions and bandage adhesives (multiple anecdotal reports).
- Reactions to dairy products and carrageenan (multiple anecdotal reports).
Many alpha-gal reactions occur in the middle of the night (57,90). A common pattern is for people to eat red meat for dinner, and then hours later wake-up with GI issues (most commonly severe abdominal pain), a rash or angioedema (swelling) or other symptoms of anaphylaxis (57,90). Due to the delay between eating meat and the onset of symptoms, many undiagnosed individuals fail to connect their nighttime reactions to what they ate or they attribute their reactions to food poisoning. Late-night anaphylaxis is a red flag that may suggest AGS (57,90).
The Glycolipid Hypothesis
Commins et al write:
On the basis of the process of lipid digestion, absorption, and delivery to the circulation, we believe that the 3- to 6-hour delay in symptoms after eating mammalian meat in subjects with IgE to alpha-gal is best explained by a glycolipid as the antigenic form of alpha-gal in this allergy (96).
Wilson and Platts-Mills write:
The fact that α-Gal is an oligosaccharide is often considered the most important feature of this allergen. However, it could be argued that an equally distinguishing feature of the α-Gal allergen is that it exists in the form of a glycolipid. Indeed, while there are many examples of carbohydrate allergens and of lipids modulating Th2 cell immune responses, the authors are unaware of any other common food allergen that is intrinsically part of a lipid. Thus, it is important to consider the glycolipid content of mammalian meat and organs, as well as the biochemical pathways involved in glycolipid digestion and metabolism, when considering the pathophysiology of α-Gal allergenicity (92).
Intra- and Inter- Individual Variability
AGS is characterized by both inter-individual and intra-individual variability. Alpha-gal allergic reactions are “consistently inconsistent,” as Dr. Scott Commins puts it (6,57,101). In other words, one person’s reactions can be very different from another person’s, and also each individual can have wildly different and unpredictable reactions to the same foods.
Not all exposures to alpha-gal result in a reaction. Some people with AGS may tolerate red meat on some occasions with few or no reactions, but have severe reactions on other occasions. This cannot be fully explained by the amount of meat eaten. (6,57,90)
Factors influencing the threshold for reactivity and severity of reactions may include:
- The quantity or form or alpha-gal in the meat (6,57,101). Organ meats (24) and fattier meats seem to be associated with more severe reactions (6,57,101).
- Recent tick bites (20,6,57,95)
- The presence or absence of co-factors (57,101)
In addition to intra-individual variation, reactions to alpha-gal are also characterized by marked inter-individual variation.
- Many people sensitized to alpha-gal are asymptomatic (57,59)
- Others tolerate mammalian meat but have severe reactions after eating organ meats, like pork kidneys (24,59), or exposure to some medical products, like cetuximab or gelatin-based plasma volume expanders (102).
- Many cannot red meat, but tolerate dairy products and gelatin in foods (although often not in some medical products) (6,57).
- Some cannot tolerate meat, dairy, gelatin, carrageenan, or even trace amounts of alpha-gal in foods, drugs and other medical products, personal care, household, and other products (6,57).
- Titer of alpha-gal specific IgE is not strongly correlated with severity of reactions (57).
According to expert Scott Commins MD PhD, University of North Carolina:
An additional point is that some patients with the syndrome may tolerate mammalian meat on occasion with few or no symptoms but have severe reactions on others. (57)
Whether a reaction occurs to an individual exposure is inconsistent and often appears to follow no identifiable pattern for patients. The lack of consistent reactions is, in itself, almost a diagnostic hallmark. Over time, patients may experience a “progression” to more consistent reactivity and this likely reflects a new tick bite. (57)
According to experts Jörg Fischer and Mariane Hilger:
…it is assumed that the delivery route of α-gal is crucial for the risk of an allergic reaction. Especially the intravenous application of α-gal-containing drugs is associated with a high risk. Due to this potential risk, a special warning regarding the administration of α-gal- containing drugs may be needed in all individuals sensitized to α-gal, even if they are tolerant to mammalian meat and entrails (102)
The Importance of Co-Factors
- The consumption of alcohol
- The use of some medications, such as nonsteroidal anti-inflammatory drugs (NSAIDS)
- Menses (your period)
- Lack of sleep
Exercise and alcohol seem to be the most important co-factors for alpha-gal reactions.
According to expert Scott Commins MD PhD, University of North Carolina:
Activity, alcohol consumption, and exercise can have profound influence on reactivity. Some patients appear to have reactions that require co-factors such that they can tolerate exposures in isolation; consistent with a diagnosis of co-factor-dependent AGS (57).
A group of experts convened by the NIH write:
Patients with a-Gal food allergy report marked intraindividual variability in the dose that causes a reaction. Many describe mild or no reactions with some exposures, yet have severe symptoms on repeat exposure to the same food served in a similar amount and preparation. This variation in susceptibility, at least in part, appears to be modulated by cofactors. In keeping with many other forms of food allergy, the most prominent cofactors associated with a-Gal consumption reactions are exercise, alcohol, and nonsteroidal anti-inflammatory medications. Theoretically, exposure to these cofactors may of response, and/or contribute to the severity of the allergic responses to a-Gal (101).
Two male patients had no atopic background but food allergy to red meat and innards only, particularly at night time. The manifestation of severe symptoms was dependent on cofactors for both, such as alcohol, although mild gastrointestinal symptoms were often present during the daytime. In Patient 2, a very severe reaction occurred to goat’s lung and alcohol (105).
Anaphylaxis is a medical emergency and requires immediate medical care!
Learn about anaphylaxis and discuss it with your healthcare provider.
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AGS Is a Leading Cause of Anaphylaxis
- In one recent study of anaphylaxis, alpha-gal was found to be the number one trigger, accounting for 33% of cases with a definitive cause. The number two cause was all other food allergies combined at 28% (44).
- In the same study, recognition of AGS led to a reduction in the percentage of anaphylaxis cases without a definitive cause from 59% to 35% of total cases. (44)
- In a second study, nine percent of all patients referred with unexplained anaphylaxis were found to have AGS (62).
Figure 1. Etiologies of anaphylaxis based on proposed “definitive cause.” Alpha-gal, galactose-a-1,3-galactose.
Source: Pattanaik D, Lieberman P, Lieberman J, Pongdee T, Keene AT. The changing face of anaphylaxis in adults and adolescents. Annals of Allergy, Asthma & Immunology. 2018 Nov 1;121(5):594-7.
- About 60% of people with AGS have anaphylactic reactions (24,78,87,88,89,91), and 30-40% have cardiac and respiratory symptoms (90).
- Anaphylaxis is a serious reaction that can be fatal.
- Due to the delayed onset of alpha-gal reactions, people with AGS often experience anaphylaxis in the middle of the night, after they have gone to bed (57,90).
FARE's Guide to Anaphylaxis
Please click on the button to learn:
1. About symptoms of anaphylaxis
2. How to determine if you are having an anaphylactic reaction
3. What to do if you are experiencing anaphylaxis
- Over 60% of people with AGS experience gastrointestinal symptoms (84,90,91,101), including one or more of the following:
- abdominal cramping
- abdominal pain
- The most common gastrointestinal symptom of AGS is cramping abdominal pain (57).
- Up to 20% of people with AGS have GI symptoms only (6,57,84).
- Some people with AGS are misdiagnosed with IBS or other gastrointestinal disorders (57).
In addition to the classic allergy symptoms, some of our patients report significant gastrointestinal distress or gynecological symptoms. These symptoms can take the form of abdominal cramping and pain, heartburn, diarrhea, nausea or vomiting and in some cases uterine cramping with spotting. It is not uncommon for a patient who has anaphylaxis to lose consciousness while moving their bowels. Some patients have reactions that are characterized almost entirely of GI or gynecological symptoms while others may not experience these types of symptoms at all.
While GI complaints are not uncommon as part of an allergic reaction, 3–20% of patients with AGS report abdominal pain, nausea, emesis, diarrhea, heartburn in isolation of cutaneous, cardiovascular, or other signs/symptoms. This pattern of signs and symptoms complicates the diagnosis as well as management of AGS because the possibility of food allergy is not obvious, but patients can be severely affected. Indeed, examples of patients with AGS who have had exploratory surgery, removal of gallbladder or appendix, and partial pancreatectomy have been reported (57).
A group of experts convened by the NIH write:
Most α-Gal meat allergy reactions reported in the literature focus on the presentation of delayed pruritus, urticaria, angioedema, and anaphylaxis. More recently, and at the workshop, researchers have described reactions that manifest with abdominal pain—both in conjunction with skin reactions and as isolated gastrointestinal reactions (101).
Anecdotally, there are patients in whom the initial symptoms were restricted to the gastrointestinal tract but over a period of weeks or months, in some cases following additional tick bites, the symptomatology expanded to include the skin and/or anaphylaxis. It is, therefore, possible that isolated abdominal pain is an underreported and underdiagnosed feature of AGS (101).
D’Souza and Howarth write:
This case highlights a novel presentation of the alpha-gal allergy, a recently observed allergy that is increasing in prevalence. It is normally difficult to diagnose given the delayed reaction and generalized symptoms (114).
With individuals with recurrent gastrointestinal symptoms it is necessary to consider alpha-gal as a potential diagnosis. It is an allergy that can be easily missed and if not diagnosed can result in anaphylaxis (114).
I react gastrointestinally only. When I have reactions, the pain starts under my ribs, comes in waves, ten times worse than labor pain, and I get horrible chills and back aches from the pain and shivering. It’s awful. My last reaction in April landed me in the hospital and they gave me pain meds instead of an epi.
Abdominal cramps for hours, threw up sometimes, and four to five days of constipation, followed by uncontrollable diarrhea. Yep, I suffered that for three years. Three years of ultrasound, X-ray and MiraLAX double dose every day. Three years of toxic hell.
My GI doctor got bit by the tick and got it too. Only then did she call me in for the test.
It was always the upper abdomen, to the right side. It felt like a constant burning. It would last for a couple of hours, and there was nothing I could do to alleviate the pain. I had diarrhea every day. I was tested for gallbladder issues, pancreatitis, leukemia, everything except alpha-gal syndrome. I and was eventually diagnosed w IBS. I lost 25 lbs over a period of 6 months and didn’t need to. It took 10 yrs for an accurate diagnosis.
I have been symptom-free for 2 years since I eliminated all mammal meat, dairy, and anything else that might have a slight hint of any kind of mammal byproduct.
Reactions to Airborne Alpha-gal
There is very little published information on reactions to airborne alpha-gal. However, many people with AGS report them. Often, they describe them as almost immediate and severe. Some describe losing consciousness.
- Although no data on the prevalence of reactions to airborne alpha-gal have been published, informally some experts state that anywhere from 10-30% of their patients report them (111, 115).
- The most commonly reported trigger is fumes from cooking meat (57), especially from grills, barbeques, and sometimes frying meat, but people with AGS report that many other forms of airborne alpha-gal can also trigger reactions (multiple anecdotal reports).
Expert Scott Commins, MD, PhD writes:
Patients do report symptoms with exposure to fumes from mammalian meats/fats being cooked; however, no blinded challenges have been published to definitively document the airborne (droplet) route of exposure. Interestingly, experience suggests fumes may pose a more potent risk to reactive patients than moderate levels of pet dander exposure (57).
The scariest part of this whole thing for me has been the fume (aka airborne reactions).
Read Patient Accounts of Airborne Reactions to Alpha-gal→
In areas where Lone Star ticks are present, and in patients with risk factors for tick exposure, alpha gal IgE reactivity should be considered and tested for as part of a “tick panel” in patients who present with symptoms of potential rheumatologic diseases (60).
Arthritis and other forms of joint pain seem to be under-recognized manifestations of alpha-gal syndrome (6,57,60). Very little has been published on it, but many individuals with AGS report that their arthritis improves or resolves in response to an avoidance diet.
- One study of patients referred to a rheumatology practice with known tick exposure or risk for exposure to ticks, found that over 140 patients tested positive for alpha-gal IgE (60).
- Of the 38 patients seen in follow-up:
Though larger studies are needed, we postulate a benefit for screening patients undergoing evaluation for chronic urticaria who have a suggestive dietary history and live in regions where the α-gal syndrome is common (104).
- In one study, a majority of patients who had been diagnosed with chronic urticaria or chronic idiopathic urticaria prior to being diagnosed with AGS experienced complete or partial improvement with an avoidance diet (104).
- The conclusions of this study are supported by an earlier case study (107).
- A third study found that of 83 patients presenting with chronic urticaria at an urban, research center in Germany, only three were sensitized to alpha-gal and none had clinical AGS (106).
Some patients with AGS go on to develop chronic spontaneous urticaria despite an avoidance diet (57).
Expert Scott Commins, MD, PhD writes:
Distinguishing AGS from chronic spontaneous urticaria (CSU) can be challenging, leading to misdiagnosis and, in some cases, the two entities may overlap. Analysis of other cohorts have found that AGS is not a cause of unrecognized CSU. In keeping with both possibilities, we have seen patients develop AGS and achieve control of reactions through an appropriate avoidance diet yet within weeks or months they develop CSU (despite the continued mammalian avoidance diet) (57).
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