What is
Alpha-gal?
Alpha-gal syndrome
(AGS), also known as mammalian meat allergy, is an allergy involving an IgE antibody response to galactose-α-1,3-galactose (1). This sugar, commonly known as alpha-gal, is found in all mammals except for Old World monkeys, apes, and humans (99). Its onset is associated with tick bites (3).
Alpha-gal syndrome was first described in 2009 (1). It is poorly understood within the medical community because of its recent discovery and its varied and atypical presentation. Reactions to alpha-gal are often severe and sometimes fatal. They can be immediate, as with hypersensitivity reactions to injected drugs, or delayed by 2 to 10 hours, as is typical after consumption of mammalian meat (1). Delayed-onset reactions often occur in the middle of the night (1).
Alpha-gal allergic reactions can occur after exposure to:
Mammalian meats, organs, and blood (57)
Dairy products, gelatin, and other foods derived from mammals (57)
Foods that contain mammalian byproducts (57)
Drugs, medical products, personal care, household and other products with mammalian ingredients (57)
Products containing carrageenan, which isn’t from a mammal, but which contains the alpha-gal epitope (54,57)
Flounder eggs (26), for reasons that aren’t clear
Alpha-gal Syndrome: Why Can’t I Eat Meat
Interview with Mateo Bernal, OMD/DOM, LAc, and Martin Huecker, MD, discuss alpha-gal syndrome.
How Do You Get Alpha-gal Syndrome?
- In the United States, the Lone Star Tick (Amblyomma americanum) is thought to be the primary cause of AGS (16), based geographical range and tick salivary factors (57).
- The Asian Longhorned Tick (Haemaphysalis longicornis), recently introduced in the U.S., is known to trigger AGS in Asia (19). As of yet, it has not been tied to any cases in the U.S.
- Alpha-gal has been found in the saliva of Black-Legged Ticks (Ixodes scapularis) (8). It is possible that Black-legged Tick bites may trigger AGS, as do other species in this genus, but this has yet to be demonstrated.
- The Cayenne Tick (Amblyomma cajennense), which is found in southern Texas and Florida (64), has been linked to cases of alpha-gal syndrome in Central America (65).
- Limited data suggests that bee and wasp stings can cause a rise in alpha-gal IgE, but it has not been shown that they can drive the initial alpha-gal IgE response (57).
- It is likely that additional tick species (8), possibly other ectoparasites (like chiggers (17) and mites (66)), and possibly even endoparasites (3,15,18) may be able to sensitize people to alpha-gal. Some may cause levels of sensitization too low to cause clinical reactions (5) and others likely induce full-blown AGS with anaphylactic reactions.
- Only a small percentage of people who are bitten by ticks associated with AGS actually develop clinical symptoms (6).
- Even if you have been bitten by ticks before and did not develop AGS, a future bite could trigger it (3).
- Repeated tick bites are associated with a rise in alpha-gal IgE (20).
- Multiple tick bites are associated with the onset of AGS (3). Many patients report that they were bitten by ticks for many years, and then after being bitten by multiple ticks at once, they developed alpha-gal syndrome.
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:
- In up to 20% of cases, GI symptoms in isolation of other symptoms (6,57,84)
- Joint pain/arthritis (6,57,60)
- Chronic pruritus (6,57)
- 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)
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.
- Mammalian meat and organs
- Mammalian organs
- Dairy, gelatin, and other foods derived from mammals
- Drugs and other medical products
- Vaccines
- Personal care products
Common Symptoms
Skin
- 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)
Angioedema (swelling) (6,84,90)
- Especially the palms and soles of the feet (90)
Gastrointestinal
- Abdominal pain and cramping (57,84,90,96)
- Nausea (57,84,90,96)
- Vomiting(57,84,90,96)
- Diarrhea(57,84,90,96)
- Heartburn (57,96)
Anaphylaxis (6,84,90,91)
- 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.
Cardiovascular symptoms (90,99)
- 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)
Respiratory symptoms (difficulty breathing) (84,90,99)
- Shortness of breath (90)
- Wheezing (90,96)
- Chest tightness (90,96)
- Cough (96)
- Hoarseness (108)
- Dyspnea (difficulty breathing) (108,109)
- Other respiratory symptoms (see Fare guide to anaphylaxis)
Less Common Symptoms
- Arthritis/joint pain (6,57,60,91)
- Chronic pruritis (6,57)
- Symptoms consistent with Mast Cell Syndrome (57)
- Uterine cramping (96)
- Fibromyalgia (anecdotal)
- Migraine (anecdotal)
Rarely reported symptoms
- Exfoliative erythroderma (100)
- Temporary loss of vision (6)
- Other rashes, including urticarial vasculitis, serpiginous urticarial rash, purpuric rash, psoriasiform rash, nummular eczema, and subcutaneous nodules (60)
- Oral lichen planus and other mouth sores (anecdotal)
Symptoms that are typically absent
- Very few (<1%) patients report itching or swelling of the mouth or tongue (6,57,91)
Alpha-gal Triggers and Symptoms
About 90%
of cases present with skin symptoms, including hives and flushing (90,91)
A typical first symptom
Itching of the palms and soles of feet, sometimes with a rash or swelling, is often the first symptom of an alpha-gal reaction (57).
About 60%
of cases have anaphylactic reactions (24,78,87,88,89,91)
30-40%
of cases have cardiac symptoms (90)
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).
UNC School of Medicine
Over 60%
of cases have GI symptoms (84,90,91,101)
Up to 20%
of cases have GI symptoms alone (6,57,84)
3-5%
Symptoms consistent with mast cell syndrome (57)
Unknown %
Chronic pruritis (6,57,91,104)
Unknown %
Arthritis (6,57,60)
Late-Night Anaphylaxis
“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.”
Erin McGintee, MD
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:
Infusions of drugs, such as cetuximab (30, 93). Fatal reactions have occurred one minute after the start of infusion (94).
Infusions and injections of medical products that contain gelatin (28, 42, 43)
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).