Alpha-Gal Syndrome: Recognizing and Managing a Tick-Bite–Related Meat Allergy (Part I)

ByZehra Naseem, MD, Aun Muhammad, MD, Arjun Chatterjee, MD and 
Alberto Rubio-Tapia, MD

Editor’s note: This is part one of a two-part series from the Cleveland Clinic Journal of Medicine (2025;92[5]:311-319) on diagnosing and managing and alpha-gal syndrome. Part II, which will post shortly, covers diagnostic and management pearls.

A 37-year-old woman from Virginia with a history of asthma presents with hives and diarrhea. She reports that one week prior, she experienced generalized pruritus, cramping abdominal pain and diarrhea three hours after having a beefsteak for dinner. After a visit to urgent care, diphenhydramine 25 mg and dicyclomine 20 mg four times daily provided symptomatic relief. Notably, she reports having had a similar episode at night one month earlier but does not recall eating red meat that day. She notes that she is an avid hiker and has a history of several spider and tick bites.

Laboratory tests show a serum galactose-alpha-1,3-galactose (alpha-gal) immunoglobulin (Ig) E level of 41.2 kU/L (reference < 0.1 kU/L) and a total IgE level of 475 kU/L (< 130 kU/L). A presumed diagnosis of alpha-gal syndrome is made.

The patient is advised to abstain from eating mammalian meat. She reports another episode of abdominal pain after having a milkshake, despite adhering to a non–mammalian meat diet. She is advised to avoid consuming dairy products. After following an elimination diet for three years, her alpha-gal IgE level declines from 41.2 kU/L to 0.82 kU/L.

Because of the gradual decline in alpha-gal IgE levels, an oral challenge with 100 grams of ground beef is performed in the clinic. After five hours of observation, the patient remains asymptomatic. Due to a successful oral challenge, she resumes consuming mammalian meat and does not have any further reactions.

What is Alpha-gal syndrome?

Alpha-gal syndrome, also known as alpha-gal allergy, mammalian meat allergy, or tick-bite–related meat allergy, is an emerging allergic condition that triggers IgE-mediated anaphylaxis, gastrointestinal symptoms or skin reactions, or both, a few hours after an affected person consumes mammalian meat, such as beef, pork, goat, rabbit, venison or lamb, or mammalian-derived products.¹ Another phenotype, gastrointestinal alpha-gal syndrome, presents with symptoms such as abdominal pain, diarrhea, and nausea or vomiting, but without any skin, respiratory or circulatory complaints.

Alpha-gal syndrome mostly occurs in adults and was first identified in the early 2000s.^2,3 Between 2010 and 2022, more than 100,000 cases of presumed alpha-gal syndrome were identified in the United States⁴; however, the exact prevalence of alpha-gal syndrome is unknown.

Many clinicians are not aware of alpha-gal syndrome. A nationwide survey of 1,500 healthcare professionals by the US Centers for Disease Control and Prevention showed that 42% were unaware of the condition, and 35% lacked confidence in diagnosing or treating patients with alpha-gal syndrome.⁵ Because cases continue to increase and symptoms overlap with other gastrointestinal illnesses and allergies, gastroenterologists and primary care clinicians must be aware of alpha-gal syndrome for timely diagnosis and intervention.

How tick bites can induce a meat allergy

Alpha-gal, the allergen identified in alpha-gal syndrome, is an oligosaccharide found in the cells and tissues of all nonprimate mammals. Sensitization to alpha-gal is thought to occur through parasitic infections, most commonly tick bites, when the immune system produces IgE antibodies directed against alpha-gal present in the parasite’s saliva.^6,7 According to Commins et al,⁸ 80% of patients with suspected alpha-gal syndrome report being bitten by ticks, and these individuals have higher alpha-gal IgE levels than those who have not been bitten.⁹

In the United States, the lone star tick (Amblyomma americanum; Figure 1 - see at top of page), which primarily parasitizes deer and is responsible for 90% of all tick bites in the southern United States,^3,10 has been identified as the vector responsible for alpha-gal syndrome.¹¹ This tick is unique because it is the only tick that bites humans during its larval stage, positioning it as the primary source of alpha-gal sensitization in the United States.³ Other tick species that have been identified as carriers of alpha-gal in their saliva include the blacklegged tick (Ixodes scapularis), also known as the deer tick, in the United States; the Cayenne tick (Amblyomma cajennense) in Central America and Brazil; and the Asian long-horned tick (Haemaphysalis longicornis) in Asia.^11–13

Glycolipid hypothesis

Although the exact pathogenesis of alpha-gal syndrome is unknown, it involves IgE-mediated activation of mast cells after mammalian meat is consumed.¹³ The current “glycolipid hypothesis” describes the mechanism for the delay in response to ingestion of meat products containing alpha-gal and subsequent development of symptoms.

After individuals sensitized to alpha-gal consume mammalian meat or its derivatives, lipid micelles are formed from glycolipids containing alpha-gal.¹⁴ Enzymes in the small intestine, mainly pancreatic lipase, break down triglycerides within the micelles into free fatty acids, monoglycerides and diglycerides, which are absorbed by intestinal cells. The intestinal epithelium then converts the fatty acids and monoglycerides into triglycerides and bundles them into lipoprotein particles, or chylomicrons, that display alpha-gal molecules. The chylomicrons enter the lymphatic system via lacteals and reach the bloodstream about four hours after a meal,¹ where the alpha-gal molecules bind to alpha-gal–specific IgE antibodies on the surface of basophils or mast cells.¹⁴ This triggers an allergic reaction or anaphylaxis as mast cells release a cascade of allergic mediators, which stimulate sensory nerves, inducing visceral pain through the contraction of intestinal smooth muscles, and activate excessive mucous secretion by the mucous glands.³

Range of symptoms and triggers

Alpha-gal syndrome can present with various symptoms, and the intensity of symptoms can vary over time. Symptoms usually occur three to eight hours after exposure to alpha-gal, but can also happen immediately.¹⁵ Common symptoms include pruritus, erythema, hives and angioedema, or severe systemic manifestations such as anaphylaxis with cough, wheezing, shortness of breath and hypotension.

In some instances, patients can have localized gastrointestinal symptoms. A recent study showed that, among 91 individuals with alpha-gal allergy, 40.7% experienced gastrointestinal symptoms exclusively.¹⁶ The predominant symptoms reported in the gastrointestinal phenotype are abdominal pain, nausea, vomiting, diarrhea, and heartburn.^16–18 These patients are frequently misdiagnosed with functional gastrointestinal disorders, commonly irritable bowel syndrome, owing to both the lack of awareness of alpha-gal syndrome and the lack of testing for IgE antibodies to alpha-gal.^1,3

Notably, most sensitized individuals do not experience any symptoms after ingesting mammalian meat.³ In regions where ticks are prevalent, 15% to 35% of the population may be sensitized to alpha-gal, but clinical alpha-gal syndrome occurs in only 1% to 8%.¹⁵ It is crucial to recognize that, even if a person is allergic to alpha-gal, reactions may not always occur after they consume mammalian meat,³ and a sensitized individual who has tolerated meat previously is still prone to allergic reactions in the future.

The likelihood and intensity of these reactions can be exacerbated by multiple exogenous and endogenous factors. Alcohol, nonsteroidal anti-inflammatory drugs, and exercise can enhance intestinal food absorption, potentially raising the concentration of alpha-gal allergens in the body and lowering the threshold for allergic reactions.¹³ Additionally, consuming fatty cuts of meat can enhance an allergic reaction because they contain higher levels of glycolipids containing alpha-gal.^19,20 When digested, these fats form the alpha-gal–coated chylomicrons that can trigger allergic reactions by activating mast cells, as discussed above.

Individuals who have a personal or family history of food or insect allergies are more likely to have alpha-gal syndrome and experience more severe symptoms due to cross-reactivity between oligosaccharides. Those with blood type A or O are also at higher risk of developing alpha-gal syndrome.²¹

Medical products that contain alpha-gal can trigger allergic reactions

Medications and medical products containing alpha-gal may trigger reactions more frequently in patients with alpha-gal antibodies.²² Chung et al²³ observed that antibodies to alpha-gal were present in patients with severe hypersensitivity to cetuximab, a therapeutic monoclonal antibody containing alpha-gal in the fragment antigen-binding portion of the heavy chain. (This led to the first observation of alpha-gal syndrome and its association with higher prevalence in regions where the lone star tick is located; see next section.)

The risk of reaction to other medical products that contain alpha-gal such as vaccines with gelatin (especially the live attenuated zoster vaccine), porcine-derived heparin or pancreatic enzymes, equine-derived antivenins, and bioprosthetic heart valves is not known, but cases of such reactions have been reported.^24–28 Heparin products are well tolerated in 98.3% of patients with a documented alpha-gal allergy.²⁶ On the other hand, positive skin prick tests to both antivenins and cetuximab have been seen in patients sensitized to alpha-gal, suggesting a potentially high risk of anaphylaxis with therapeutic doses of antivenin.²⁹

Additionally, medical devices derived from animal materials, such as bioprosthetic cardiac valves, pose risks to those with alpha-gal sensitivity.²⁷ Despite anecdotal evidence of hives and anaphylaxis after porcine or bovine valve replacement, conclusive research on valve failures due to alpha-gal reactions is lacking.²⁵

The probability of a clinically significant reaction is relatively low and may be influenced by the animal source, processing methods, purity level, and administered dose, as well as the patient’s serum alpha-gal antibody titers.^24,26,27,29

When to consider alpha-gal syndrome

Patients should be tested for alpha-gal IgE antibodies if they are experiencing unexplained gastrointestinal symptoms that awaken them at night, as this reflects the characteristic delay from ingestion to reaction observed in individuals sensitized to alpha-gal.² These patients may also report a history of tick bites and frequent engagement in outdoor activities. However, clinicians should be cautious about testing patients exhibiting “red flag” symptoms like anemia, gastrointestinal bleeding, or significant weight loss because these are not typically caused by alpha-gal syndrome.³ The presence of skin symptoms, including urticaria and angioedema, may also vary among patients.

Clinicians should consider alpha-gal syndrome as a potential diagnosis if patients with unexplained gastrointestinal symptoms live or have lived in regions where alpha-gal syndrome is common (Figure 2).⁴ These regions are also where the lone star tick is found, and include the southern, midwestern, and mid-Atlantic United States—particularly parts of Oklahoma, Kansas, Arkansas, Missouri, Mississippi, Tennessee, Kentucky, Illinois, Indiana, North Carolina, Virginia, Maryland and Delaware, and Suffolk County in New York (Figure 3).

REFERENCES

1. Lesmana E, Rao S, Keehn A, Edwinson AL, Makol A, Grover M. Clinical presentation and outcomes of Alpha-gal syndrome. Clin Gastroenterol Hepatol 2025; 23(1):69–78. doi:10.1016/j.cgh.2024.06.044
2. Platts-Mills TA, Schuyler AJ, Hoyt AE, Commins SP. Delayed anaphylaxis involving IgE to galactose-alpha-1,3-galactose. Curr Allergy Asthma Rep 2015; 15(4):12. doi:10.1007/s11882-015-0512-6
3. McGill SK, Hashash JG, Platts-Mills TA. AGA clinical practice update on Alpha-gal syndrome for the GI clinician: commentary. Clin Gastroenterol Hepatol 2023; 21(4):891–896. doi:10.1016/j.cgh.2022.12.035
4. Thompson JM, Carpenter A, Kersh GJ, Wachs T, Commins SP, Salzer JS. Geographic distribution of suspected Alpha-gal syndrome cases—United States, January 2017–December 2022. MMWR Morb Mortal Wkly Rep 2023; 72(30):815–820. doi:10.15585/mmwr.mm7230a2
5. Carpenter A, Drexler NA, McCormick DW, et al. Health care provider knowledge regarding Alpha-gal syndrome—United States, March– May 2022. MMWR Morb Mortal Wkly Rep 2023; 72(30):809–814. doi:10.15585/mmwr.mm7230a1
6. Commins SP, James HR, Kelly LA, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose. J Allergy Clin Immunol 2011; 127(5):1286–1293.e6. doi:10.1016/j.jaci.2011.02.019
7. Murangi T, Prakash P, Moreira BP, et al. Ascaris lumbricoides and ticks associated with sensitization to galactose α1,3-galactose and elicitation of the Alpha-gal syndrome. J Allergy Clin Immunol 2022; 149(2):698–707.e3. doi:10.1016/j.jaci.2021.07.018
8. Commins SP, Satinover SM, Hosen J, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol 2009; 123(2):426–433. doi:10.1016/j.jaci.2008.10.052
9. Saadalla A, Jacela J, Poll R, Slev P. Immunoassay testing of alpha-gal specific immunoglobulin-E: data from a national reference laboratory. J Appl Lab Med 2024; 9(2):262–272. doi:10.1093/jalm/jfad115
10. Lee S, Kakumanu ML, Ponnusamy L, et al. Prevalence of Rickettsiales in ticks removed from the skin of outdoor workers in North Carolina. Parasit Vectors 2014; 7:607. doi:10.1186/s13071-014-0607-2
11. Crispell G, Commins SP, Archer-Hartman SA, et al. Discovery of alpha-gal-containing antigens in North American tick species believed to induce red meat allergy. Front Immunol 2019; 10:1056. doi:10.3389/fimmu.2019.01056
12. Araujo RN, Franco PF, Rodrigues H, et al. Amblyomma sculptum tick saliva: α-Gal identification, antibody response and possible association with red meat allergy in Brazil. Int J Parasitol 2016; 46(3):213–220. doi:10.1016/j.ijpara.2015.12.005
13. Platts-Mills TAE, Commins SP, Biedermann T, et al. On the cause and consequences of IgE to galactose-α-1,3-galactose: a report from the National Institute of Allergy and Infectious Diseases workshop on understanding IgE-mediated mammalian meat allergy. J Allergy Clin Immunol 2020; 145(4):1061–1071. doi:10.1016/j.jaci.2020.01.047
14. Román-Carrasco P, Lieder B, Somoza V, et al. Only α-gal bound to lipids, but not to proteins, is transported across enterocytes as an IgE-reactive molecule that can induce effector cell activation. Allergy 2019; 74(10):1956–1968. doi:10.1111/all.13873
15. Commins SP. Diagnosis & management of alpha-gal syndrome: lessons from 2,500 patients. Expert Rev Clin Immunol 2020; 16(7): 667–677. doi:10.1080/1744666X.2020.1782745
16. McGill SK, Levin ME, Shaheen NJ, Cotton CC, Platts-Mills TA, Commins SP. Gastrointestinal-isolated distress is common in alpha-gal allergic patients on mammalian meat challenge. J Clin Gastroenterol 2024; 58(1):80–84. doi:10.1097/MCG.0000000000001827
17. Commins SP, James HR, Stevens W, et al. Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galac-tose-alpha-1,3-galactose. J Allergy Clin Immunol 2014; 134(1): 108–115. doi:10.1016/j.jaci.2014.01.024
18. Mabelane T, Basera W, Botha M, Thomas HF, Ramjith J, Levin ME. Predictive values of alpha-gal IgE levels and alpha-gal IgE: total IgE ratio and oral food challenge-proven meat allergy in a population with a high prevalence of reported red meat allergy. Pediatr Allergy Immunol 2018; 29(8):841–849. doi:10.1111/pai.12969
19. Fischer J, Yazdi AS, Biedermann T. Clinical spectrum of α-Gal syndrome: from immediate-type to delayed immediate-type reactions to mammalian innards and meat. Allergo J Int 2016; 25:55–62. doi:10.1007/s40629-016-0099-z
20. Wilson JM, Platts-Mills TAE. Meat allergy and allergens. Mol Immunol 2018; 100:107–112. doi:10.1016/j.molimm.2018.03.018
21. Taylor ML, Kersh GJ, Salzer JS, et al. Intrinsic risk factors for Alpha-gal syndrome in a case-control study, 2019 to 2020. Ann Allergy Asthma Immunol 2024; 132(6):759–764.e2. doi:10.1016/j.anai.2024.01.029
22. Chinuki Y, Morita E. Alpha-gal-containing biologics and anaphylaxis. Allergol Int 2019; 68(3):296–300. doi:10.1016/j.alit.2019.04.001
23. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 2008; 358(11):1109–1117. doi:10.1056/NEJMoa074943
24. Commins SP. Invited commentary: alpha-gal allergy: tip of the iceberg to a pivotal immune response. Curr Allergy Asthma Rep 2016; 16(9):61. doi:10.1007/s11882-016-0641-6
25. Mozzicato SM, Tripathi A, Posthumus JB, Platts-Mills TAE, Commins SP. Porcine or bovine valve replacement in 3 patients with IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose. J Allergy Clin Immunol Pract 2014; 2(5): 637–638. doi:10.1016/j.jaip.2014.04.016
26. Nwamara U, Kaplan MC, Mason N, Ingemi AI. A retrospective evaluation of heparin product reactions in patients with alpha-gal allergies. Ticks Tick Borne Dis 2022; 13(1):101869. doi:10.1016/j.ttbdis.2021.101869
27. Hawkins RB, Wilson JM, Mehaffey JH, Platts-Mills TAE, Ailawadi G. Safety of intravenous heparin for cardiac surgery in patients with Alpha-gal syndrome. Ann Thorac Surg 2021; 111(6):1991–1997. doi:10.1016/j.athoracsur.2020.07.050
28. Stone CA Jr., Hemler JA, Commins SP, et al. Anaphylaxis after zoster vaccine: Implicating alpha-gal allergy as a possible mechanism. J Allergy Clin Immunol 2017; 139(5):1710–1713.e2. doi:10.1016/j.jaci.2016.10.037
29. Fischer J, Eberlein B, Hilger C, et al. Alpha-gal is a possible target of IgE-mediated reactivity to antivenom. Allergy 2017; 72(5):764–771. doi:10.1111/all.13073