What is alpha-gal syndrome?

What is Alpha-Gal Syndrome?

Alpha-gal syndrome is a tick bite-induced IgE-mediated allergic condition to galactose-alpha-1,3-galactose (alpha-gal), an oligosaccharide found in all non-primate mammalian meat and derived products, causing delayed allergic reactions typically 2-6 hours after consuming beef, pork, venison, dairy, or other mammalian products. 1

Mechanism of Disease

The syndrome develops through a unique two-step process:

• Sensitization occurs through tick bites, specifically from the Lone Star tick (Amblyomma americanum) in the United States, which causes the human immune system to produce IgE antibodies against the alpha-gal sugar molecule 1, 2
• Parasitic infections may also cause sensitization, though this is less common in the United States 2
• When a sensitized person consumes mammalian meat or products, alpha-gal is absorbed bound to fat in glycolipids and incorporated into chylomicrons, entering circulation approximately 2 hours after ingestion 1
• These alpha-gal-containing chylomicrons bind to IgE antibodies on mast cells throughout the GI tract, triggering degranulation and release of histamine and other mediators 1
• The released mediators act on sensory nerve endings causing pain, on intestinal smooth muscle causing contractions, and on mucous glands causing secretion 1

Geographic Distribution

• The syndrome occurs primarily within the range of the Lone Star tick, extending from New York and Iowa southward to Texas and Florida, encompassing the Southeast, mid-Atlantic, Midwest, and East Central U.S. regions 1, 2
• The Lone Star tick is unique as the only tick that bites humans in the larval stage, which may explain why it is the principal cause of sensitization in the United States 1
• Internationally, alpha-gal syndrome has been reported on all continents except Antarctica, including Australia, South Africa, Western Europe, and Japan 1, 2

Clinical Presentations

Alpha-gal syndrome manifests in two distinct phenotypes:

Classic Systemic Presentation

• Urticaria and angioedema (skin symptoms may or may not be present) 1
• Anaphylaxis with respiratory or circulatory symptoms 1
• Delayed onset typically 3-6 hours after mammalian meat consumption 3

Gastrointestinal Phenotype

• Abdominal pain (occurs in 71% of oral food challenge-proven cases) 1
• Vomiting (22% of cases) 1
• Diarrhea and nausea 1
• A significant minority (40.7%) develop GI symptoms alone without skin, respiratory, or circulatory manifestations 1
• Patients often awaken at night from sleep with GI distress due to the delayed reaction timing 1
• These patients are frequently misdiagnosed with irritable bowel syndrome or other functional GI disorders 1

Key Distinguishing Features

Several characteristics make alpha-gal syndrome fundamentally different from typical food allergies:

• Sensitization occurs through environmental exposure (tick bite) rather than food consumption itself 2
• Reactions are delayed 2-6 hours after exposure, unlike immediate reactions seen with typical food allergies 1, 3
• Patients frequently tolerated red meat for many years prior to developing allergic reactions 3
• The allergen is a carbohydrate (oligosaccharide) rather than a protein 1, 4
• History of tick bites or outdoor pursuits increases risk 1

Asymptomatic Sensitization

Most individuals with alpha-gal antibodies in the population are asymptomatic and tolerate mammalian meat ingestion 1, 2. However:

• The consequences of continued mammalian meat intake among sensitized individuals remain unclear 1
• Recent studies suggest potential cardiovascular effects through mast cell activation in coronary arteries, potentially leading to coronary artery disease 1, 2

Scope of the Problem

• During 2010-2018, more than 34,000 suspected cases were identified in the United States 5
• From January 2017 to December 2022,90,018 persons (30.5% of those tested) received positive test results 5
• The number of positive cases increased from 13,371 in 2017 to 18,885 in 2021 5
• Limited awareness exists among healthcare providers: 42% of surveyed HCPs had never heard of AGS, and among those who had, fewer than one-third knew how to diagnose it 6

Important Clinical Caveats

• Red flag symptoms such as anemia, GI bleeding, or weight loss should not be attributed to alpha-gal syndrome, as the allergy does not cause these symptoms 1
• A positive IgE antibody to alpha-gal alone is insufficient to establish diagnosis, particularly in patients with isolated GI distress, because sensitized individuals can be asymptomatic 1
• Alpha-gal is ubiquitously included in foods, medications, personal products, and stabilizing compounds, making complete avoidance difficult 3
• Some medications and medical products contain alpha-gal, which can trigger reactions in sensitive individuals 7