What is Alpha-gal Syndrome?

Source: Bianchi J, Walters A, Fitch ZW, Turek JW. Alpha-gal syndrome: Implications for cardiovascular disease. Global Cardiology Science and Practice. 2020 Feb 9;2019(3).

At a threshold for positivity of 0.35IU/ml, up to 9% of people sensitized to alpha-gal have clinical alpha-gal syndrome with anaphylactic reactions after eating mammalian meat or organs (59). At the lower threshold for positivity of 0.1IU/ml, as few as 1% of people sensitized to alpha-gal have clinical alpha-gal syndrome (57). In populations with high rates of infection with endoparasites, sensitization to alpha-gal may be more common but less associated with clinical symptoms (18).

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.

A Lack of Physician Awareness

• Due to its recent discovery, its unusual presentation, and lack of physician awareness, AGS is underdiagnosed and often misdiagnosed (13,14,57).
• Diagnosis tends to be patient-driven, even in areas where AGS is prevalent (14).
• Reports of occurrence are strongly influenced by the efforts of individual research groups and clinicians (15).
• Many people with AGS who only have GI symptoms have had a colonoscopy, endoscopy, and/or cholecystectomy performed before being diagnosed (7).
• In populations with high exposure to known vectors, AGS should be ruled out in cases of unexplained urticaria, angioedema, recurrent anaphylaxis, GI symptoms (7,82,83,84) and even arthritis (60).

Source: Flaherty MG, Threats M, Kaplan SJ. Patients’ Health Information Practices and Perceptions of Provider Knowledge in the Case of the Newly Discovered Alpha-gal Food Allergy. Journal of Patient Experience. 2020 Feb;7(1):132-9.

Primary Sources of Alpha-gal in Food, Drugs, and Other Products

Other Organisms That Express Alpha-gal

A variety of organisms express alpha-gal, sometimes only in specific tissues.  For most of these, there is a lack of evidence as to whether they are associated with reactions in people with alpha-gal syndrome.

• Some fish eggs, in addition to flounder eggs (see above) (58,74,104)
• Green Sea Turtles express high levels of alpha-gal epitopes (108)
• The ocular tissue of some non-mammalian vertebrates (105)
• Cobra venom (58, 110)
• Many invertebrates, including some ticks (8), mosquitoes (111), and helminths (worms) (106)
• Some human pathogens, such as those that cause malaria, leishmaniasis, and Chagas disease (58).
• Some fungi, including
  • Aspergillus mold (107). Whether people with AGS are more likely to have mold allergies is unknown.
  • Schizosaccharomyces pombe (112) –yeast used to make millet beer (pombe) in East Africa
  • There is no evidence of alpha-gal in mushrooms that we commonly eat, and people with AGS usually tolerate mushrooms.
• Many protozoa (58)
• Many bacteria, including those that live in our gut (58)
• Many viruses, depending on the host they are incubated in (58)

Mammal-Derived Foods and Food Ingredients

Mammal-derived food and food ingredients include, but are not limited to, the below. 

Mammalian meat, organs, and other parts of mammals

These include some of the riskiest sources of alpha-gal. Examples include:

• Mammalian meats (1), such as beef, pork, lamb, bison, venison, goat, horse, rabbit, squirrel, kangaroo, antelope, buffalo, camel, guinea pig, bats, whales, etc.
  • If you are not sure which animals are mammals, there is a guide here.
• The internal organs of mammals, like liver (21), lung, heart, intestines (tripe), sweetbreads, and kidneys (6,57)
  • Internal organs can contain even more alpha-gal than meat  (22,23,24,25,26,27,94).
  • Some people who do not react to meat react after eating organs, like pork kidneys (24,59).
• Mammalian gut sausage casings
  • Even turkey and chicken sausages often have these (6,57).
  • Removing the casing from chicken or turkey sausages and then eating the sausage without the casing is not advised, as this can lead to severe reactions. 
• Mammalian fat, like lard, tallow, and suet
  • Mammalian fat is often in cooked foods, such as sauces, pastries, pie crusts, tortillas, tortilla chips, refried beans, baked beans, vegetable dishes, mashed potatoes, and desserts.
  • Some baking mixes (like Jiffy Corn Muffin Mix) contain lard.
  • Beef fat is often added to fry oil to enhance flavor (6,57).
• Bones and bone marrow
• Testicles (Rocky Mountain or prairie oysters)
• Mammalian collagen (e.g. beef collagen sausage casings) (6,57)
• Meat broth, bouillon, and stock (6,57)
• Gravy (6,57)
• Mammalian blood, found in soups, black pudding, blood sausage, blodplättar, and other foods
• Meat extracts, like Bonox and Bovril
• All other mammalian body parts, organs, tissues, cells, and fluids, such as tendons, brain, heart, nerves, skin, mammalian bile (Papait seasoning), and the products that contain them.

Most of the foods on this list should be avoided by everyone with alpha-gal syndrome. Many of us need to avoid all of them.

Rennet

Rennet is a complex set of enzymes that is used in the manufacture of some foods, such as cheese. Most rennet is extracted from the stomachs of ruminant mammals, although sometimes vegetable and microbial rennets are used. Some people with AGS can eat dairy products, as long as they don’t contain rennet from mammals.

Milk, other dairy products, and foods that contain them as ingredients (1,6,57,115)

Ten to thirty-three percent of people with AGS react to dairy products, especially those high in fat, like ice cream (6,57,85). A list of dairy products can be found here.

Gelatin and foods that contain gelatin (6,27,28,57)

Fewer than 10% of people with AGS react to gelatin in foods, although many more may have severe reactions after other types of exposure to gelatin, such as the intravenous administration of gelatin-based plasma volume expanders or gelatin-containing vaccines administered via intramuscular injections (6,57).

Natural flavors or flavorings

These are often beef or pork (57) and need to be avoided by many people with AGS. To find out whether the “natural flavors” in a product are derived from a mammal, contact the manufacturer. However, in the U.S., manufacturers are under no legal obligation to disclose the identity of ingredients that they call “natural flavors or flavorings.” Often, when asked, they will not disclose whether are derived from mammals or not.

Mammalian byproducts

An untold number of foods, especially processed foods, contain mammalian byproducts. There are hundreds of these byproducts often with obscure names, like oleic acid and monoglycerides. As of now, there is no comprehensive list of mammalian byproducts added to food in the U.S., much less information about their alpha-gal content. Most people with AGS do not react to mammalian byproducts in food, but some do (6,57), and severe reactions have documented (29). Some mammalian byproducts may not contain alpha-gal at all. Further research is needed to determine alpha-gal content and safety of mammalian byproducts for people with alpha-gal syndrome (6,57). See our guide to mammalian byproducts here.

Cross-contamination

Some people with AGS react if their food is cross-contaminated by foods that contain alpha-gal, for example, if their poultry or seafood is cooked on a grill used for red meats (57).

Flounder Eggs

The eggs (roe) of some flounder have been found to contain alpha-gal, and can cause severe reactions in people with AGS (26, 104).

• The meat of flounder does not seem to contain alpha-gal or cause reactions in people with AGS (104)
• There is no evidence that other commonly consumed fish eggs (salmon, herring, flying fish, caviar) contain alpha-gal, although its possible that some less commonly consumed fish eggs might, as alpha-gal has been found in the eggs of other teleost (bony) fish (58,74).

Carrageenan in Food

Foods that can contain carrageenan include, but are not limited to, the below. 

Foods that can contain carrageenan

• Dulse (Irish Moss, Sea Moss)
• Many dairy products including ice cream; milk shakes, like Dairy Queen blizzards; yogurt; flavored, evaporated, and condensed milk; whipped topping; cheese; and sour cream (76)
• Many dairy-free substitutes (57)
• Desserts, including custard, flan, pudding, mousse, sorbet, gelato, and gel desserts (76,77)
• Drink mixes, such as powdered lemonade (77)
• Juice (76,77)
• Ready to spread icing (76,77)
• Jams and jellies (76,77)
• Candy (76,77)
• Salad dressing, mayonnaise, and relishes (77)
• Poultry and poultry products (77)
• Drinks, such as beer and juice clarified by carrageenan  (77)
• Seafood, such as fish treated with carrageenan to improve moisture retention  (77)
• Infant formula  (77)
• Tofu (77)

Carrageenan as a processing agent

When carrageenan is used as a processing aid, for example when it is used to clarify beer and juice, as a spray on fresh cut fruit, or on fish to aid in retention of moisture, manufacturers are not required to list it on the label.

Other edible red seaweeds

As many red seaweeds contain carrageenan (71), it’s possible that some other forms of edible red algae may also contain the alpha-gal epitope.

Other Foods That May or May Not Be a Source of Alpha-gal

Limited data and/or anecdotal evidence suggest that some foods that do not obviously contain mammal or red algae derived ingredients can cause reactions in some people with AGS for reasons that aren’t clear. These include:

• Possibly some other types of edible fish roe (in addition to flounder eggs) (58,74), although as far as we know, there is no evidence that salmon roe, flying fish roe, herring roe, or caviar are a problem.
• Canned tuna (6)
• Koji is made from aspergillus (108), which expresses alpha-gal (107).
  • There is a lack of data as to whether koji can cause reactions in people with AGS, but most of us seem to tolerate products like miso and soy sauce that are made from it.

More Information

Mammal-Derived Drugs, Medical Products, and Ingredients 

Note:
• The risks associated with the use of different medical products that contain mammal-derived ingredients are highly variable and poorly studied.
• There is no data on the risk of reaction associated with many products on this list. They included based on being derived from mammals or containing ingredients derived from mammals. See papers cited for more information.
• Work with your healthcare providers to weigh the relative risks and benefits of using or not using individual medical products that may contain alpha-gal. 

Drugs, medical products, and ingredients used in them that may contain mammal-derived materials or ingredients include, but are not limited to, the below. 

• Cetuximab (a drug that played a role in the discovery of AGS) (6,30,31,57)
  • Cetuximab has caused fatal reactions in people with AGS (86).
• Other monoclonal antibodies (mAbs) produced in non-primate mammalian cell lines (6,57)
  • Both abatacept (Orencia) (57) and infliximab (Remicade) have been associated with reactions (6,67)
  • Evidence for alpha-gal expression on most other mAbs is minimal (6,57), but expert opinion is to proceed with caution on first-dose of any mAb produced in a mammalian cell line (57).
• Pancreatic enzyme replacements, such as pancrealipase and other enzyme replacements (e.g. Viokase, Pertzye, Zenpep (Allergan), Creon)(6,36,57,103) and Pancreatin (Now Foods, Bloomingdale, Ill)– an over-the-counter dietary aid (103).
• Thyroid hormone replacements, including Armour Thyroid (Allergan) (57,103)
• EnteraGam (Entera Health, Cary, NC), a bovine immunoglobulin and immunoprotein isolate intended for the management of irritable bowel syndrome and inflammatory bowel disease (103)
• Estrogen therapy drugs that contain estrogen derived from horse urine, e.g. Premarin, Prempro
• Heparin, including low molecular weight heparin such as enoxaparin (Lovenox)(57).
  • Dr. Scott Commins reports: “Importantly, we have not had issues with routine heparin prophylaxis for deep venous thrombosis (DVT) and our experience suggests this can be safely administered for the over- whelming majority of patients with AGS. There are, undoubtedly, exceptions that will require alternate forms of DVT prophylaxis. Heparin-based reactions that are much more common include those clinical scenarios where heparin is given at high doses for more complete anti-coagulation, such as during heart catheterization, valve procedures, and extracorporeal membrane oxygenation (ECMO).” (57).
  • There are a number of papers on the use of heparin in patients with AGS, e.g. Safety of Intravenous Heparin for Cardiac Surgery in Patients with Alpha-Gal Syndrome by Hawkins, et al. Search the AGI Publications Database using keyword “heparin” for more information.
  • Perioperative implications of patients with alpha-gal allergies by Nourian, et al includes a risk stratification algorithm for AGS patients requiring perioperative parenteral anticoagulation.
  • NOTE: Fondaparinux, which is NOT animal-derived can sometimes used in place of heparin for some purposes (121).
• Heparin treated products, such as heparin-coated vascular grafts e.g. GORE® PROPATEN® Vascular Graft
• Gelatin-based plasma volume expanders, such as Gelafundin, Gelofusine, Gelaspan, Haemaccel (not commonly used in the U.S. if at all) (6,28,52,57,101).
  • Even some people who are not reactive to mammalian meat react to these products (28). Platts-Mills, et al, recommend avoidance for everyone with active AGS (6).
• Many vaccines, including those that contain gelatin or other mammalian byproducts. Gelatin appears to be the most problematic vaccine ingredient for people with AGS.
  • In the U.S., vaccines that contain gelatin include: Zostavax, MMR, yellow fever, rabies, oral typhoid, FluMist, some tetanus vaccines (including Boostrix), and others (6,28,39,42,43,57,92)
• Antivenom, such as crotalidae polyvalent immune Fab (CroFab) (6,50,51,57)
• Bioprosthetic (bovine and porcine) heart valves (6,45,46,47,48,49,57,103) including:
  • Epic Supra porcine bioprosthetic aortic valve (Abbott, Abbott Park, Ill) (103)
  • Perimount Magna Ease (bovine bioprosthetic aortic valve (Edwards Lifesciences, Irvine, Calif) (103)
  • CryoValve SG pulmonary valve decellularized human pulmonary valve conduit (Cryolife) (103)
• Other products made from mammalian tissue or organs, such as:
  • Heart/pericardial/epicardial patches, e.g. CorMatrix Cor™ PATCH (103) and XenoSure Biologic Patch
  • Photofix (decellularized bovine pericardium (Cryolife, Kennesaw, Ga)– used in heart and vascular repair (103)
  • Collagen scaffolding, e.g. Cardiocel acellular collagen scaffold (LeMaitre Vascular, Burlington, Mass)– used in heart and vascular repair (103)
  • Extracellular matrix (ECM) scaffolds
  • Hernia mesh (121) e.g. OviTex
  • Orthopedic implants (121)
  • Mammal-derived and collagen-impregnated vascular grafts (124) e.g. ProCol bovine mesenteric vein (LeMaitre Vascular) (103),  Artegraft Collagen Vascular Graft, Hemashield
  • And more
• Hemostatic agents, such as:
  • Surgiflo (Ethicon, Cincinnati, OH) (53)
  • FloSeal hemostatic matrix (Baxter International, Deerfield, IL) (6, 121)
  • Surgifoam powder (Ethicon, Raritan, NJ, USA)(6, 121)
  • Absorbable gelatin sponge (6,121), like Gelfoam (Pfizer, New York, NY)
  • Thrombin sprays which are porcine- and hamster-derived, like Recothrom (Baxter, Deerfield, IL, USA)(121)
• Embolics, such as:
  • Obsidio Embolic (Boston Scientific, Marlborough, MA) (123)
• Products that contain hemostatic agents, including vascular closure devices VCDs (123) such as:
  • Angio-Seal VIP Vascular Closure Device (Terumo Medical, Somerset, NJ) (123)
  • Vascade MVP Venous Vascular Closure System (Haemonetics, Boston, MA) (123)
  • Vascade Vascular Closure System (Haemonetics, Boston, MA) (123)
  • Manta Vascular Closure Device (Teleflex, Morrisville, NC) (123)
  • Manual compression or alternative VCDs which do not contain mammal-derived products, such as suture-based closure devices, may be considered as alternatives. (123)
• Other products that contain gelatin/collagen, such as:
  • Gabapentin oral solution (6)
  • Lidocaine patch (6)
  • Gummy supplements (57)
  • Vaginal capsules (37)
  • Suppositories (28,87)
  • Collagen-containing agents, including implants, such as ENDURAGen (28,87, 120)
  • Medications with gelatin capsules (6,57)
• Many other perioperative, prescription, and OTC drugs  (32,33,34,35,57). Some of these pose a known risk to people with AGS; others contain mammalian byproducts for which there is little data on alpha-gal content or their ability to contribute to clinical reactions, such as:
  • Stearic acid
  • Magnesium stearate (38) (in many tablets)
  • Glycerin (in many suspensions)
  • Lactose and lactose derivatives
  • Dairy byproducts in drugs and vaccines including (but are not limited to), casamino acids, casein, and lactalbumin.
  • Lactose alone is used in more than 20% of prescription drugs and about 6% in over-the-counter medicines.
• Many other medical products and devices, may contain mammal-derived products, including (but not limited to):
  • Collagen/catgut and sutures, e.g. chromic sutures, plain gut sutures, mild chromic gut sutures
    • We are not aware of any literature on reactions to collagen sutures, but a number of anecdotes, including reports of adverse outcomes, such as infection and disfigurement, have been shared in AGS support groups.
    • For more information on which sutures are and are not derived from mammals, see this article from the VeganMed pharmacists.
  • Lubricants (e.g. gelatin-based)
  • Topicals (e.g. contain gelatin and lanolin)
  • Adhesives (including bandage adhesives)
  • Collagen/thrombin glues (121)
  • Propofol (e.g. if glycerin used to rehydrate it is mammal-derived) (121)
  • Intralipid (e.g. if glycerin mammal-derived) (121)
  • See  6,32, 33, 34, 35, 102, 121 for more information.
• Some products used in dentistry.

See also below information about carrageenan 

Carrageenan in Drugs and Medical Products

Medications other medical products that can contain carrageenan

Carrageenan is made from red algae, not mammals, but contains the alpha-gal epitope (54).

• At least 1-2% of people with AGS react to carrageenan (57) in foods.
• There is no published information about the relevance of carrageenan in medical products for people with AGS and very little even in the way of anecdotal information.
• Carrageenan in drugs and medical products may or may not be medically relevant for people with alpha-gal syndrome; more research is needed.

Based on limited information about carrageenan in medications and medical products, it appears to be used in the below products. There may be many other medical products that contain carrageenan; we have not been able to find much information about this. 

• Numerous medications, both as an active ingredient (for example, in cough remedies, laxatives and medications for other intestinal issues) and as an inactive ingredient, including as a thickening agent in liquid medications, a coating agent, and as a polymer matrix in time-release medications.
•  Bone graft substitutes, entrapping vessels such as biobeads and encapsulation vehicles for drug delivery, hydrogels, and nasal sprays.
• Other medical products (76), including some barium enemas (55).
• An unknown number of other medications and medical products.

Airborne Alpha-gal

Mammal-derived Ingredients in Personal Care and Household Products

Carrageenan in Personal Care and Household Products

Carrageenan

Carrageenan is made from red algae, not mammals, but contains the alpha-gal epitope (54).

• At least 1-2% of people with AGS react to carrageenan (57).
• Some people with AGS react to carrageenan in personal care and household products, as well as in food.

Personal care and household products that can contain carrageenan

• Many toothpastes
• Liquid soaps and other cleansers
• Skin care products
• Hair products
• Make-up
• Air fresheners
• See the Environmental Working Group’s Skin Deep database for more information about personal care products that contain carrageenan.

As far as we know, alpha-gal is not typically found in:

• Birds, like chicken, turkey, quail, and emu don’t normally express alpha-gal (58), although alpha-gal has been found in the ocular tissue (eyes) of some birds (105)
• Most reptiles, like snakes, crocodiles, and lizards (58), although Green Sea Turtles have high levels of alpha-gal epitopes (108) and cobra venom also contains it (58)
  • Alligator meat does not seem to be a problem for most people with AGS
• Amphibians, like frogs, with the exception of some amphibian eggs (58)
• Fish or seafood (58) except for flounder eggs (26, 104) and the eggs of some other teleost (bony) fish (58,74,104)
• Crustaceans, like shrimp, prawns, crawfish, crabs, and lobster
• Molluscs, like oysters, mussels, and clams
• Plants, including fruits, vegetables, and grains
  • Note that algae are not plants, and red algae (seaweed) do contain alpha-gal.
• Edible fungi, like mushrooms
  • Possible exception: koji, which is made from aspergillus fungi

Poultry sausages may have casings made from the intestines of mammals.

Some of these foods–especially chicken, turkey, and seafood–may be injected, treated or sprayed with mammalian substances or carrageenan or otherwise contaminated by them. These may be listed among the ingredients, but if they are considered a processing aid, as with gelatin used to clarify juice and wine or carrageenan sprayed on cut fruit or fish, they will not be.

Some people with AGS report reacting to canned tuna (6) for reasons that are not clear but which may be related to the use of processing agents or fillers.

There are unverified, anecdotal reports of people who are highly sensitive to alpha-gal reacting to chicken eggs when the chicken are not fed a vegetarian diet. Duck eggs or eggs from chickens fed a vegetarian diet may be better tolerated in these rare cases.

In general, the less processed your food, the less likely it is to contain alpha-gal. Read labels and buy from trusted sources. Be careful when eating out. Cooking your own food will help you avoid alpha-gal.

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21. Bianchi, John (2019). Personal communication

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31. Berg EA, Platts-Mills TA, Commins SP. Drug allergens and food—the cetuximab and galactose-α-1, 3-galactose story. Annals of Allergy, Asthma & Immunology. 2014 Feb 1;112(2):97-101.

32. Dunkman WJ, Rycek W, Manning MW. What does a red meat allergy have to do with anesthesia? Perioperative management of alpha-gal syndrome. Anesthesia & Analgesia. 2019 Nov 1;129(5):1242-8.

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37. Vidal C, Mendez-Brea P, Lopez-Freire S, Gonzalez-Vidal T. Vaginal Capsules: An Unsuspected Probable Source of Exposure to α-Gal. Journal of investigational allergology & clinical immunology. 2016;26(6):388.

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40. Bakhtiar MF, Leong KW, Kwok FY, Hui MT, Tang MM, Joseph CT, Bathumana‐Appan PP, Nagum AR, ZHM Y, Murad S. P66: ALLERGIC REACTION TO BOVINE GELATIN COLLOID: THE ROLE OF IMMUNOGLOBULIN E TOWARDS GALACTOSE‐ALPHA‐1, 3‐GALACTOSE: IMPLICATIONS BEYOND RED MEAT ALLERGIES. Internal Medicine Journal. 2017 Sep;47:24-.

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42. Stone CA, Commins SP, Choudhary S, Vethody C, Heavrin JL, Wingerter J, Hemler JA, Babe K, Phillips EJ, Norton AE. Anaphylaxis after vaccination in a pediatric patient: further implicating alpha-gal allergy. The Journal of Allergy and Clinical Immunology: In Practice. 2019 Jan 1;7(1):322-4.

43. Stone CA, Hemler JA, Commins SP, Schuyler AJ, Phillips EJ, Peebles RS, Fahrenholz JM. Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism. Journal of Allergy and Clinical Immunology. 2017 May 1;139(5):1710-3.

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48. Mozzicato SM, Tripathi A, Posthumus JB, Platts-Mills TA, Commins SP. Porcine or bovine valve replacement in three patients with IgE antibodies to the mammalian oligosaccharide galactose-alpha-1, 3-galactose. The journal of allergy and clinical immunology. In practice. 2014 Sep;2(5):637.

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56. Steinke JW, Platts-Mills TAE, Schuyler A, Commins SP. Reply to “The common food additive carrageenan and the alpha-gal epitope”. Journal of Allergy and Clinical Immunology. 2015 Oct 28;136(6):1709-10

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66. Ohshita N, Ichimaru Y, Gamoh S, Tsuji K, Kishimoto N, Tsutsumi YM, Momota Y. Management of infusion reactions associated with cetuximab treatment: A case report. Molecular and Clinical Oncology. 2017 Jun 1;6(6):853-5.

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