Misdiagnosis of alpha-gal syndrome as non-celiac gluten sensitivity or lactose intolerance: A diagnostic blind spot for clinicians

Abstract

Alpha-gal syndrome (AGS), an emerging tick-borne carbohydrate hypersensitivity, has gained increasing recognition for its atypical presentation and delayed food-related allergic reactions. While urticaria and anaphylaxis dominate the clinical narrative, gastrointestinal (GI) manifestations-including abdominal pain, diarrhea, bloating, and cramping-are common and often underrecognized. These nonspecific GI symptoms create significant diagnostic overlap with prevalent functional and food-related disorders such as non-celiac gluten sensitivity (NCGS) and lactose intolerance. Consequently, many patients with AGS undergo unnecessary dietary restrictions, prolonged symptom burden, or misdirected therapies before an accurate diagnosis is established. The knowledge gap lies in the limited awareness of AGS as a differential diagnosis for food-related GI complaints, especially in regions endemic to tick exposure. Unlike gluten or lactose intolerance, AGS reactions are characterized by a unique delayed onset (2-6 hours postprandially) and a distinct immunologic mechanism mediated by IgE to galactose-α-1,3-galactose. However, clinicians rarely consider AGS when evaluating chronic, unexplained food-triggered symptoms, perpetuating diagnostic blind spots. Current guidelines for evaluating NCGS and lactose intolerance seldom incorporate testing for alpha-gal IgE, despite growing evidence that a subset of misdiagnosed patients may in fact harbor AGS. Clinically, this misclassification carries significant consequences: Patients may continue mammalian food exposure with risk of escalating allergic reactions, including life-threatening anaphylaxis, while adhering to unnecessary or ineffective gluten-free or lactose-free diets. Raising awareness, integrating alpha-gal IgE testing into gastroenterology workups, and refining diagnostic algorithms are urgently needed. Addressing this blind spot has the potential to reduce morbidity, improve diagnostic accuracy, and optimize individualized patient care.

Key Words: Alpha-gal IgE; Non-celiac gluten sensitivity; Alpha-gal; Lone star tick; Food exposure allergy

Core Tip: Integrating alpha-gal syndrome into the differential diagnosis of unexplained postprandial gastrointestinal symptoms - particularly in individuals from or with travel to tick-endemic areas - is imperative. Awareness of the unique etiologic and immunologic underpinnings of alpha-gal syndrome provides clinicians with a framework to recognize atypical presentations. Concerted efforts are needed to refine diagnostic algorithms, including the judicious use of serum α-gal-specific IgE testing in appropriate clinical contexts, and to develop multidisciplinary pathways linking gastroenterology, allergy/immunology and nutrition.

INTRODUCTION

Alpha-gal syndrome (AGS) is a distinctive IgE-mediated hypersensitivity (type 1) to the oligosaccharide galactose-α-1,3-galactose (α-gal), found in non-primate mammalian meat and derived products[1]. Initially recognized in the context of delayed anaphylaxis following ingestion of red meat, AGS has more recently emerged as a relevant entity in clinical settings given its frequent gastrointestinal (GI) manifestations[2,3]. AGS has been most prominently reported in the United States in regions populated by the Amblyomma americanum tick (lone star tick), which has been implicated in sensitization to α-gal[3,4]. The immunologic mechanism contrasts sharply with more conventional immediate-type food allergies[4]. The delay in symptom onset combined with the carbohydrate-rather than protein-based allergen contributes to under-recognition.

Clinically, the intersection of AGS with other functional GI disorders is increasingly apparent. Many patients present with nonspecific GI complaints - abdominal pain, diarrhea, bloating, nausea - in the absence of classic urticaria, angioedema or overt anaphylaxis[5,6]. These GI-predominant presentations can mirror those of functional disorders such as non-celiac gluten sensitivity (NCGS) or lactose intolerance, conditions characterized by overlapping symptoms and lacking definitive biomarkers. The diagnostic overlap creates a blind spot where patients may be erroneously labelled as NCGS or lactose intolerant, subjected to empirical elimination diets or enzyme replacement, and experience prolonged symptom burden before AGS is considered. Moreover, mis- or under-diagnosis of AGS carries tangible risks: Continued exposure to mammalian-derived products may heighten the risk of more severe allergic reactions, while unnecessary dietary restrictions (e.g., gluten or lactose elimination) may compromise nutrition and delay definitive management.

From an educational and clinical perspective, integrating AGS into the differential diagnosis of unexplained postprandial GI symptoms - particularly in individuals from or with travel to tick-endemic areas - is imperative. Awareness of the unique etiologic and immunologic underpinnings of AGS provides clinicians with a framework to recognize atypical presentations. Concerted efforts are needed to refine diagnostic algorithms, including the judicious use of serum α-gal-specific IgE testing in appropriate clinical contexts, and to develop multidisciplinary pathways linking gastroenterology, allergy/immunology and nutrition. Addressing this knowledge gap holds the potential to optimize patient care through tailored dietary counselling, tick-bite avoidance strategies, and improved symptom resolution - thereby closing a key diagnostic blind spot in clinical practice.

LITERATURE REVIEW

We performed an integrative review synthesizing current evidence on the clinical, immunologic and diagnostic overlap between AGS, NCGS and lactose intolerance. Mechanisms of misdiagnosis creating a potential blind spot and implications of such in clinical practice were also considered. The literature search targeted PubMed/MEDLINE, EMBASE, Scopus, and guideline repositories (American Gastroenterological Association, specialty society updates) from January 2000 through August 2025, with emphasis on studies, reviews, case series, and clinical practice updates published to capture contemporary epidemiology and diagnostic guidance. Search terms included combinations of “alpha-gal”, “galactose-α-1,3-galactose”, “red meat allergy”, “gastrointestinal symptoms”, “non-celiac gluten sensitivity”, “lactose intolerance”, “diagnosis”, “IgE”, “tick bite”, and “Lone Star tick”. We supplemented database searches with review of reference lists from key articles and guideline statements and queried publicly available alpha-gal resource sites for diagnostic testing practice information.

Eligibility criteria included original articles, systematic/narrative reviews, clinical practice updates, and case series that reported GI-predominant AGS presentations, diagnostic approaches (including α-gal-specific IgE testing and functional testing for NCGS/Lactose intolerance), or outcomes following dietary elimination. Excluded were isolated basic-science reports without clinical translation and editorials lacking data. Two reviewers independently screened titles/abstracts for relevance, retrieved full texts, and extracted data on study design, population, geographic setting, presenting symptoms, diagnostic methods, serologic thresholds, follow-up, and outcomes. Additionally, it was ensured to adhere to the SANRA guidelines-a scale for the quality assessment of narrative review articles.

EPIDEMIOLOGY

AGS exhibits a striking geographic signature that mirrors the distribution and expansion of implicated tick species. In the United States, large laboratory-based surveillance and public-health analyses demonstrate concentrated test-positivity and suspected-case clusters across the southeastern, mid-Atlantic and parts of the Midwest - regions that overlap with established and expanding Amblyomma americanum habitat - and documented increases in testing and positive results between 2017-2022[7]. Outside North America, case series and epidemiologic reports describe analogous associations between local tick species and α-gal sensitization in Australia, parts of Europe (including Sweden and France), South America, and increasingly in Asia (reports from Japan, South Korea and South Asia), indicating that tick-associated α-gal sensitization is a global phenomenon rather than a regional curiosity as shown in Figure 1[8,9].

Figure 1 Geographic distribution of countries with alpha-gal syndrome cases or IgE sensitization. AGS: Alpha-gal syndrome.

The Centers for Disease Control and Prevention (CDC) in the United States identified over 110000 suspected cases of AGS between 2010 and 2022, factoring in under-diagnosis and asymptomatic sensitization. The CDC estimates up to approximately 450000 Americans may have been affected during that period[7]. A commercial laboratory analysis of approximately 295400 persons tested during 2017-2022 found 90018 (30.5%) had positive alpha-gal IgE results. The number of positive people increased from 13371 in 2017 to 18885 in 2021[7]. In 2024, among United States military recruits, a prevalence of alpha-gal IgE positivity of 6.0% was reported, with significant regional variation (highest in Arkansas at 39%) suggesting endemic tick exposure drives sensitization[10].

Internationally, population-based surveys of alpha-gal-specific IgE (not necessarily clinically manifest AGS) reveal prevalence rates of 5.5% (Denmark) and 8.1% (Spain) for ≥ 0.10 kUA/L; when using a higher threshold (≥ 0.35 kUA/L), prevalences were 1.8% and 2.2% respectively[11]. In Sweden, approximately 10% of healthy blood donors in the Stockholm area had detectable IgE to alpha-gal, compared with 0.7% in northern regions with low tick exposure dating around 2018[12]. These data highlight that sensitization (IgE positivity) is far more common than clinically diagnosed AGS, and that geographic tick-exposure gradients are key determinants of burden. Moreover, the lack of global incidence data and heterogeneous thresholds underscore the urgent need for systematic surveillance, standardized testing and populationbased cohort studies to clarify true disease burden and temporal trends.

Key public-health drivers include vector range shifts from climate and land-use change, improved clinician awareness, testing, and variable background exposures (e.g., parasite endemicity) that may serve as hypothesized links or associations for sensitization vs clinical disease. Together, these data underscore AGS as an emergent, geographically heterogeneous allergy with important regional public-health and clinical implications for diagnosis, surveillance, and prevention.

Tick species implicated in AGS

The lone star tick (Amblyomma americanum) in the United States is the most well-established vector, while Ixodes ricinus in Europe, Ixodes holocyclus in Australia, and Amblyomma sculptum in South America have been implicated in other regions[13,14]. Frequent tick exposure (especially in endemic rural and wooded areas), outdoor occupational or recreational activity, and prior history of large local reactions to tick bites constitutes the major risk factors for AGS[7]. Expanding tick populations due to altered land use, and wildlife migration are also emerging ecological risk factors that could possibly contribute to increased AGS incidence globally as shown in Table 1[15].

Table 1 Tick species implicated in alpha-gal syndrome and their geographical distribution based on collection from available regional data.

Tick species (common/scientific)	Typical geographic distribution/reported locations	Evidence/notes
Lone star tick - Amblyomma americanum[7]	Southeastern, mid-Atlantic, and parts of the Midwest United States; expanding northward and westward	Principal vector implicated in most United States AGS cases and in large surveillance studies
Sheep/deer tick - Ixodes Ricinus[16]	Europe (Sweden, France, Germany, Spain and other temperate countries)	Reported to carry α-gal-containing antigens and linked to sensitization in European case series
Paralysis tick - Ixodes holocyclus[14]	Eastern Australia (coastal New South Wales, Queensland)	Identified in Australian reports as associated with α-gal sensitization and tick-bite-related meat allergy
Asian longhorned tick – H. longicornis[17]	East Asia (Japan, Korea), parts of China; also detected in other regions	Salivary proteins with α-gal detected; case series from Japan and case reports implicate H. longicornis in sensitization
Amblyomma sculptum[18]	Brazil and other parts of South America	α-gal epitopes detected in saliva; experimental/serologic data support potential for sensitization
Amblyomma hebraeum/Rhipicephalus spp. (Africa)[19]	Sub-Saharan Africa (limited serologic detection; data sparse)	Serologic detection of α-gal in some parasites/ticks reported, but clinical case correlation and surveillance remain limited
Blacklegged/deer tick - Ixodes scapularis (and other Ixodes spp.)[8]	North America (northeast, upper Midwest); occasional recent case reports linking Ixodes spp. to AGS	Emerging reports suggest other Ixodes species may rarely be associated with α-gal sensitization in addition to Amblyomma spp.

AGS: Alpha-gal syndrome; H. longicornis: Haemaphysalis longicornis; α-gal: Α-1,3-galactose.

PATHOPHYSIOLOGIC AND IMMUNOLOGIC UNDERPINNINGS

Tick-mediated sensitization to galactose-α-gal

Tick-mediated sensitization represents the central etiologic mechanism underlying AGS, linking an environmental exposure to a distinct carbohydrate-specific IgE response[16]. This pathogenesis begins with exposure to the oligosaccharide galactose-α-gal, a glycan abundantly expressed on non-primate mammalian cells but absent in humans, apes, and Old-World monkeys due to inactivation of the GGTA1 gene that encodes α-1,3-galactosyltransferase[17]. When the tick feeds on a mammalian host, it acquires α-gal-containing glycoproteins and glycolipids within its salivary glands[18]. During subsequent feeding on humans, the tick’s saliva, enriched with immunomodulatory molecules such as prostaglandins, histamine-binding proteins, and cystatins, introduces α-gal epitopes into the dermis[14]. These components alter the local cutaneous immune microenvironment, promoting dendritic cell activation and Th2 polarization. The tick bite thereby functions as an adjuvant event, skewing the adaptive immune response toward production of α-gal-specific IgE rather than tolerance, a pattern distinct from responses to dietary carbohydrates[19,20].

Once introduced, α-gal antigens are processed by antigen-presenting cells and presented via MHC class II molecules to naïve CD4+ T cells. The cytokine milieu generated by tick saliva-rich in interleukin (IL)-4, IL-5, and IL-13-facilitates class-switch recombination in B cells, converting the immunoglobulin heavy-chain gene sequence from IgM/IgG to IgE through the activation-induced cytidine deaminase pathway[12]. The resulting plasma cells secrete α-gal-specific IgE, which binds to FcεRI receptors on mast cells and basophils, establishing the sensitized state. Upon subsequent ingestion of mammalian meat (such as beef, pork, lamb, venison, organ meats, as well as gelatin-based products, dairy, and other mammalian-derived additives used in processed food) or products containing α-gal, digested glycolipids enter systemic circulation several hours later, cross-linking the α-gal-specific IgE on effector cells and triggering delayed mediator release as shown below in Figure 2[21]. This delay reflects the lipid transport kinetics of α-gal-containing chylomicrons, distinguishing AGS from immediate food allergies that respond to protein antigens.

Figure 2 Immune-mediated pathogenesis of alpha-gal syndrome. Exposure of alpha-gal protein to the innate immune system (basophil) results in differentiation of naive T cell into Th2 cell. Eventual IgE production mediates symptom manifestation upon subsequent exposures to mammalian meat. IL: Interleukin.

AGS challenges the conventional understanding of allergy by linking ectoparasite exposure, carbohydrate antigenicity, and delayed anaphylaxis. Emerging research has revealed that α-gal-specific IgE is often accompanied by α-gal-specific IgG1 and IgG3, suggesting a broader humoral response that may persist even when IgE titers decline[22]. Moreover, the presence of α-gal epitopes on therapeutic biologics, vaccines, and gelatin-based products poses clinical implications for cross-reactivity and hypersensitivity to pharmaceuticals[23]. The persistence of α-gal-specific IgE can last for years, though repeated tick bites tend to boost titers, perpetuating sensitization. Therefore, AGS serves as a model for the interface between vector biology and adaptive immunity, demonstrating how environmental and molecular factors converge to drive a distinct form of allergic disease.

Beyond the classical IgE pathway, emerging data also suggest that tick saliva-derived prostaglandin E₂, complement inhibitors, and saliva-associated microbiota may further amplify Th2 skewing and dampen regulatory T-cell responses, perpetuating sensitization[24]. Animal studies demonstrate that repeated tick exposures intensify IgE titers and sustain long-lived plasma cell responses, explaining the chronicity of AGS and the observation that avoidance of further tick bites can gradually reduce α-gal-specific IgE levels[25]. Collectively, these mechanisms illustrate how a vector-borne event orchestrates a complex interplay between innate modulation, adaptive immune education, and delayed hypersensitivity, culminating in a uniquely carbohydrate-targeted IgE response unprecedented in other human food allergies.

GI immune interactions and mucosal responses in alpha-gal sensitization

Although the cutaneous route of sensitization via tick bites initiates AGS, the GI tract is the critical site of effector response upon re-exposure to α-gal-containing dietary antigens. The gut mucosa, equipped with a complex immune network that distinguishes commensals from pathogens, becomes a stage for aberrant immune recognition in sensitized individuals. Once α-gal-bearing glycolipids and glycoproteins from mammalian meat undergo digestion, they are absorbed primarily through chylomicron-mediated lipid transport[26]. This process delays systemic antigen presentation and accounts for the characteristic 3-6-hour latency between food ingestion and symptom onset in AGS[13]. Within the intestinal lamina propria, antigenic α-gal fragments interact with mast cells and basophils preloaded with α-gal-specific IgE, triggering histamine, prostaglandin, and leukotriene release[21]. These mediators increase vascular permeability and smooth muscle reactivity, leading to cramping, nausea, and diarrhea-manifestations that overlap with functional GI disorders such as NCGS and lactose intolerance[27].

At the mucosal immune level, α-gal exposure provokes a distinctive interplay between innate and adaptive responses. Dendritic cells and macrophages in Peyer’s patches process lipid-associated α-gal antigens and activate Th2 cytokine cascades (IL-4, IL-5, IL-13), reinforcing IgE-mediated effector pathways[14]. Concurrently, intestinal epithelial cells secrete thymic stromal lymphopoietin and IL-33, further enhancing type 2 inflammation. These responses contrast sharply with the mechanisms underlying NCGS and lactose intolerance-conditions driven primarily by innate immune activation or enzymatic deficiency rather than IgE-mediated hypersensitivity (type 1)[6,12]. The presence of mucosal eosinophilia and elevated tryptase in some AGS patients supports a localized allergic inflammation model within the GI tract, emphasizing that AGS can present predominantly with GI symptoms in the absence of cutaneous or respiratory manifestations[25].

Emerging evidence also points to the modulatory role of gut microbiota in shaping α-gal immune dynamics. Certain commensals express α-gal moieties that may either promote immune tolerance or maintain a basal level of sensitization through cross-reactivity[28]. Disruption of microbial homeostasis following tick exposure or antibiotic use could therefore alter mucosal immune tolerance thresholds, predisposing sensitized individuals to symptomatic responses upon ingestion of α-gal-containing foods.

SYMPTOM OVERLAP AND DIAGNOSTIC MIMICRY IN NCGS AND LACTOSE INTOLERANCE

These pathophysiologic and immunologic mechanisms culminate into various signs and symptoms which make the clinical presentation of AGS frequently overlaps with NCGS and lactose intolerance, creating a diagnostic blind spot for clinicians. Many patients with AGS present initially with postprandial bloating, abdominal pain, diarrhea, and nausea-symptoms that mirror functional food intolerances rather than allergic pathology[26]. Unlike classical food allergies, the delayed onset of reactions-typically 2-6 hours after ingestion of mammalian-derived foods-compounds diagnostic uncertainty, as the temporal gap between exposure and symptom manifestation often diverts attention from an immunologic etiology[13]. Furthermore, AGS patients may lack cutaneous or respiratory symptoms typical of systemic allergic responses, reinforcing the misclassification of these cases as NCGS or lactose intolerance[25]. In primary care settings, this overlap frequently leads to empiric dietary exclusions (gluten-free or lactose-free diets) that provide partial or transient symptom relief, delaying accurate diagnosis and appropriate management.

At the pathophysiologic level, AGS differs fundamentally from NCGS and lactose intolerance as shown in Table 2. NCGS involves an innate immune activation characterized by increased toll-like receptor expression, altered intestinal permeability, and cytokine dysregulation without serologic or histologic markers of celiac disease[6]. Lactose intolerance, in contrast, stems from lactase enzyme deficiency at the brush border of enterocytes, resulting in osmotic diarrhea and colonic fermentation[16]. AGS, however, is an IgE-mediated hypersensitivity (type 1) reaction to galactose-α-gal epitopes, with reactions driven by systemic mast cell activation following delayed lipid absorption[12]. Despite this immunologic distinctiveness, the shared GI symptomatology and postprandial timing mimic functional or enzymatic disorders, often leading to years of misdiagnosis before α-gal-specific IgE testing is considered.

Table 2 Comparison between alpha-gal syndrome, non-celiac gluten sensitivity and Lactose Intolerance based on their diagnostic and pathophysiologic mechanisms.

	AGS	NCGS	Lactose intolerance
Etiology	Mammalian products including beef, pork, lamb, venison and sometimes dairy/gelatin	Symptoms are triggered by gluten	Digestive problem caused by deficiency of the lactase enzyme
Onset	Delayed (typically 2-6 hours after eating the trigger food)	Within hours after consuming gluten	Within hours after dairy ingestion
Symptom manifestation	Hives, itching, swelling, nausea, vomiting, abdominal pain and diarrhea. Can potentially manifest as anaphylaxis	Abdominal pain, bloating, diarrhea, fatigue and headache	Nausea, bloating, abdominal cramps, gas and diarrhea
Immune mechanism	Allergic (type 1 hypersensitivity reaction)	Innate immune system	Digestive disorder involving lack of lactase enzyme
Diagnosis	Blood test for alpha-gal-specific IgE antibodies	Clinical diagnosis made by excluding celiac disease and wheat allergy but involving a positive response to gluten-free diet	Hydrogen Breath test and Lactose intolerance test

NCGS: Non-celiac gluten sensitivity; AGS: Alpha-gal syndrome.

Clinical evidence supports that a substantial subset of patients previously diagnosed with NCGS or idiopathic food intolerance later test positive for α-gal-specific IgE, particularly those reporting reactions to red meat, dairy, or gelatin-containing foods[3,5].

DIAGNOSTIC ALGORITHM AND INVESTIGATIVE STRATEGIES TO DIFFERENTIATE AGS FROM FUNCTIONAL GI DISORDERS

The accurate diagnosis of AGS requires a systematic, evidence-based approach that distinguishes it from more common functional GI disorders such as NCGS, lactose intolerance, and irritable bowel syndrome[29]. Misdiagnosis arises primarily from reliance on symptom-based categorization without adequate immunologic evaluation. A structured diagnostic algorithm begins with a comprehensive clinical history, emphasizing symptom onset timing (delayed reactions 2-6 hours post ingestion), dietary triggers (red meat, pork, lamb, gelatin, or mammalian-derived products), history of tick exposure, prior reactions to mammalian-derived medications or vaccines, and any coexisting atopic disorders[27]. The presence of delayed GI symptoms such as bloating, cramping, nausea, and diarrhea after ingestion of mammalian products-especially when unresponsive to gluten or lactose exclusion-should prompt targeted testing for α-gal-specific IgE[5]. Figure 3 shows a diagnostic algorithm that can aid in diagnosis of AGS.

Figure 3  A simplified algorithm to diagnosing alpha-gal syndrome including alternative differential diagnoses.

Clinical presentation

Clinical manifestations of AGS frequently straddle multiple organ-systems and often present with a delayed onset (typically 2-6 hours) after ingestion of mammalian meat or products containing the carbohydrate galactose-α-gal as seen in Figure 4[30]. Dermatologic signs are among the most common: Hives or urticaria, pruritus, angioedema (especially of lips, eyelids, tongue or throat) occur in a substantial proportion of patients (for example 56% of seropositive patients in one series had urticaria)[4,31,32]. Respiratory manifestations (wheezing, cough, shortness of breath) and cardiovascular involvement (hypotension or syncope in severe cases) may occur, particularly when multiple systems are engaged in an anaphylactic reaction as shown in Table 2. GI symptoms are increasingly recognized: In one large United States cohort, 47% of AGS-positive patients reported GI symptoms (abdominal pain, nausea/vomiting, diarrhea)[4,33]. It is these GI-predominant phenotypes that overlap significantly in presentation with functional GI disorders or food intolerance syndromes.

Figure 4  Clinical manifestation of alpha-gal syndrome.

Essentially, the clinical presentation of AGS can mimic entities such as NCGS or Lactose Intolerance, because patients may report recurrent postprandial abdominal pain, bloating, diarrhea or nausea without the classic immediate urticarial or respiratory signs of conventional IgEmediated food allergy. For example, in the Mayo Clinic series, among AGS-positive patients, GI symptoms were more likely in females (69% of females with GI symptoms vs 35% without)[4]. In addition, around 75% of patients in another cohort met criteria for anaphylaxis involving ≥ 2 organ systems (including GI + cutaneous or respiratory) as shown in Table 3[34]. These data underscore that while GI signs are common, many patients will also exhibit multisystem involvement, and that the absence of obvious skin or airway symptoms does not exclude AGS. Clinicians should thus maintain a high index of suspicion in patients with unexplained post-mammalian meat ingestion GI symptoms, especially in the appropriate epidemiologic context.

Table 3 Multiple organ-systems affected by alpha-gal syndrome and associated symptom manifestation[35].

Organ system	Common signs & symptoms	Approximately of patients affected (%)
Cutaneous/skin	Urticaria (hives), pruritus, angioedema (lips, eyelids, tongue, throat)	56-80
GI	Abdominal pain, nausea, vomiting, diarrhea, bloating	47-69
Respiratory	Wheezing, cough, shortness of breath, nasal congestion	15-30
Cardiovascular	Hypotension, dizziness, syncope (especially in anaphylaxis)	10-25
Systemic/anaphylaxis	Multisystem involvement (≥ 2 organ systems), generalized reactions	50-75

GI: Gastrointestinal.

Laboratory confirmation

The first-line laboratory investigation is a serum assay for IgE antibodies specific to galactose-α-gal, with titers ≥ 0.35 kUA/L are generally considered indicative of sensitization[27,34]. Though the degree of clinical reactivity often correlates with higher titters. It is essential to interpret results in the context of clinical history, as alpha-gal IgE may be detectable in asymptomatic individuals, reflecting sensitization rather than disease[4,11]. Total IgE measurement and evaluation for other atopic markers may be adjunctive but are not diagnostic. Skin prick testing with commercially available mammalian extracts can be considered in select cases, though standardized reagents are limited, and false-negative results are common. Complementary diagnostic steps include dietary challenge and withdrawal testing under medical supervision-symptom improvement with avoidance of mammalian-derived foods, followed by recurrence upon reintroduction, provides strong clinical corroboration.

CLINICAL MANAGEMENT AND LONG-TERM FOLLOW-UP OF PATIENTS WITH AGS

After clinical diagnosis has been made and confirmed with laboratory investigation, a proactive measure is required to ensure AGS is well managed. The Management of AGS requires a multifaceted, patient-centered approach that integrates allergen avoidance, acute reaction preparedness, pharmacologic interventions, and long-term monitoring. The cornerstone of therapy remains strict avoidance of galactose-α-gal-containing products, which include all mammalian meats (beef, pork, lamb, venison) and byproducts such as organ meats, gelatin, certain dairy derivatives, and mammalian-based pharmaceuticals or biologics (e.g., cetuximab, heparin, gelatin-containing vaccines)[13,35]. However, unlike classic IgE-mediated food allergies, AGS presents unique dietary and pharmacologic challenges because α-gal is a ubiquitous carbohydrate determinant found in a wide array of processed foods, supplements, and medical formulations. Consequently, medical providers managing AGS must employ a personalized dietary strategy based on the degree of sensitization, symptom severity, and patient lifestyle. Collaboration with a dietitian familiar with α-gal content across food and pharmaceutical sources is critical to prevent malnutrition or undue restriction, particularly when eliminating mammalian-derived calcium and iron sources[36].

In acute management, delayed allergic reactions following α-gal ingestion may present as GI-only or systemic anaphylaxis, and patients must be educated on prompt recognition and emergency response[36,37]. Prescription of epinephrine auto-injectors is indicated for all patients with systemic reactions, accompanied by antihistamines for milder presentations and corticosteroids may be used adjunctively delayed reactions[37]. Importantly, gastroenterologists should recognize that AGS reactions can be potentiated by cofactors such as alcohol, exercise, or concurrent NSAID use, which increase GI permeability and systemic absorption of α-gal antigens.

Patient counseling must therefore emphasize lifestyle modification alongside dietary vigilance. Additionally, patients with ongoing tick exposure should be advised on rigorous tick-bite prevention strategies-including use of permethrin-treated clothing, repellents (DEET, picaridin), and prompt tick removal-since repeated bites can boost IgE titers and perpetuate disease activity. Avoidance of further sensitization is pivotal, as clinical remission has been documented in patients with sustained tick avoidance and falling α-gal-specific IgE levels over time[38].

Long-term follow-up should be individualized and dynamic. Serial monitoring of α-gal-specific IgE titers every 6-12 months provides an objective measure of immune activity and can guide the gradual, supervised reintroduction of low-α-gal foods in patients demonstrating immunologic down trending[4]. Gastroenterologists should coordinate with allergists to evaluate tolerance through controlled oral food challenges, ideally beginning with dairy or gelatin products, which contain lower α-gal concentrations than red meat[37,38]. Concurrently, clinicians should assess secondary complications, such as nutritional deficiencies, psychological distress from dietary restrictions, and overlapping functional bowel disorders. Evidence suggests that some AGS patients exhibit altered gut permeability and mast cell activation that may sustain visceral hypersensitivity even after antigen avoidance, warranting adjunctive use of mast cell stabilizers (e.g., cromolyn sodium) or leukotriene antagonists[39].

EMERGING THERAPIES AND FUTURE PERSPECTIVE IN RESHAPING LONG-TERM AGS MANAGEMENT

Experimental studies exploring monoclonal anti-IgE therapy (omalizumab) have demonstrated reductions in α-gal-specific IgE levels and symptomatic improvement in refractory cases[38]. Additionally, research into immunomodulatory tick vaccines targeting salivary proteins responsible for Th2 skewing holds potential to prevent future sensitization[38,40]. Advances in component-resolved diagnostics and basophil activation assays may soon enable stratification of patients by risk phenotype, facilitating personalized desensitization protocols[30]. AGS underscores the necessity of integrating immunologic diagnostics into the evaluation of unexplained food-induced GI disorders, reframing what were once considered “functional” symptoms as manifestations of delayed allergic hypersensitivity as summarized in Table 4. Through vigilant long-term follow-up, interprofessional collaboration, and incorporation of emerging immunotherapies, clinicians can transform AGS management from reactive avoidance toward proactive immunologic remission.

Table 4 Clinical pearl summarizing alpha-gal syndrome for clinical practice, estimates may vary based on clinical presentation.

Step	Action	Key decision-points/notes
Clinical suspicion[30,42]	Obtain detailed patient history (tick exposure, delay after mammalian meat ingestion, GI or allergic symptoms)	A high index of suspicion is required, especially in tickendemic regions or unexplained GI symptoms
	Note typical timeline: Ingestion of mammalian (non-primate) meat/products → delayed onset (approximately 2-6 hours) of symptoms (skin, GI, respiratory, cardiovascular)
Initial evaluation[41]	Physical exam (skin, airway, vital signs)	Because AGS can mimic other GI/food-allergy conditions, exclusion of more common diagnoses is prudent
	Consider other causes of symptoms (food intolerance, NCGS, lactose intolerance, IBS, conventional meat allergy)
Laboratory testing[40]	Order serum IgE specific to galactose-α-1,3-galactose (α-gal sIgE)	Typical cutoffs vary; e.g., > 0.1 kUA/L often used, but not strictly diagnostic of clinical allergy
	Understand that a positive test alone does not confirm AGS - must correlate with history and symptoms
Correlation of history + test + response[29]	Confirm delayed reaction after mammalian meat ingestion and positive α-gal sIgE	This triad (history + lab + diet response) is often used in practice to establish diagnosis
	Evaluate response to elimination of mammalian meat/products (clinical improvement)
Further evaluation/referral	If test is negative but suspicion remains high: Consider referral to allergist for intradermal testing, basophil activation test, or supervised food challenge (in experienced center)	Food challenge in AGS requires caution due to delayed onset and potential severity
	If significant allergic/anaphylactic signs (multisystem involvement) → allergy/immunology referral
Diagnosis and management plan[30,40]	If AGS is confirmed: Counsel on avoidance of mammalian meat/products (and possibly mammalianderived medications/biologics)	Although not strictly part of diagnostic algorithm, management planning is integral once the diagnosis is made
	Educate on tickbite prevention (to avoid further sensitization)
	Arrange appropriate follow-up and monitoring (including reconsidering re-introduction under guidance if IgE levels decline)

NCGS: Non-celiac gluten sensitivity; AGS: Alpha-gal syndrome; GI: Gastrointestinal; α-gal: Α-1,3-galactose; IBS: Irritable bowel syndrome.

DISCUSSION

Misdiagnosis of AGS as NCGS or lactose intolerance carries substantial clinical and psychosocial burden. Patients frequently embark on restrictive elimination diets-most commonly gluten-free or dairy-free regimens-that do not target the underlying antigen and therefore fail to produce sustained relief. These misguided dietary changes often lead to nutritional deficiencies, particularly deficiencies in iron, vitamin B12, calcium, and vitamin D, as patients avoid major dietary sources found in fortified dairy products or whole grains[41]. Over time, such deficiencies can contribute to anemia, impaired bone mineralization, neuromuscular symptoms, and worsening fatigue, further complicating the clinical picture and prompting additional, often unnecessary diagnostic testing. Misdiagnosed patients may also suffer recurrent GI distress, which may be mislabeled as functional bowel disorders, leading to inappropriate pharmacotherapy and increased healthcare utilization without addressing the true underlying pathology[42].

The psychosocial consequences of misdiagnosis are equally profound. Unnecessary long-term dietary restrictions generate a sense of hypervigilance, food-related anxiety, and social withdrawal, particularly as patients struggle to identify “trigger foods” that do not align with their presumed diagnosis[41,42]. The unpredictable and delayed nature of AGS reactions often reinforces feelings of loss of control, diminished trust in the healthcare system, and reduced quality of life. Patients may cycle through multiple providers before the correct diagnosis is reached, fostering frustration and diagnostic fatigue. Moreover, restrictive diets imposed without nutritional supervision carry measurable psychological burden, including disordered eating patterns, decreased enjoyment of social meals, and diminished overall well-being.

Perhaps the most significant consequence of missed or delayed recognition is the risk of progression to systemic reactions, including anaphylaxis. AGS is unique among food allergies in that sensitized individuals may experience initially mild or GI-predominant symptoms but later develop severe symptoms[20,21]. Without correct diagnosis, patients remain unaware of the need for avoidance of mammalian-derived products, lack emergency epinephrine prescriptions, and remain vulnerable to severe or life-threatening reactions. Repeated ingestion of α-gal-containing foods may continue to stimulate IgE production, sustain mast cell reactivity, and increase reaction severity over time[25,26]. Early and accurate diagnosis is therefore critical not only for symptom control and quality-of-life improvement but also for preventing catastrophic outcomes in a condition where delayed anaphylaxis is both well-documented and potentially fatal.

When evaluating unexplained postprandial GI symptoms-especially in patients with tick exposure or atypical temporal patterns-AGS should be explicitly considered. We recommend a pragmatic diagnostic pathway that incorporates exposure history, symptom chronology, and low-threshold α-gal-specific IgE testing alongside conventional GI workups. This approach promises to reduce misdiagnosis, avert preventable allergic morbidity, and optimize nutritional care. Prospective studies and standardized diagnostic criteria are urgently needed to refine these recommendations and to elucidate the mechanistic basis of GI-predominant AGS.

Future research should prioritize large, population-based studies to better define the true prevalence of AGS, particularly in regions where tick exposure is expanding. Improved diagnostic biomarkers would be beneficial in enhancing sensitivity and specificity beyond current IgE assays. Longitudinal cohort studies examining the natural history of AGS-including factors influencing sensitization, persistence and remission-would provide valuable clinical insight. Given that this study is a narrative review, the limitation includes but not limited to not employing a formal systematic review or meta-analysis methodology, the article selection process may be subject to potential selection or publication bias and inadequate availability of randomized controlled trials.

CONCLUSION

AGS represents an underrecognized gray area between allergy and gastroenterology, where a delayed carbohydrate hypersensitivity masquerades as a functional GI disorder such as NCGS or Lactose intolerance. The resulting diagnostic blind spot perpetuates patient morbidity, unnecessary dietary restriction and potential risk in anaphylaxis to mammalian meat due to delayed recognition of the underlying problem. Clinicians must therefore adopt a consideration for AGS in individuals presenting with unexplained postprandial GI symptoms-particularly in those with recent tick exposure or travel to regions endemic to tick exposure. Integrating alpha-gal specific IgE testing into the standard gastroenterological workup can bridge the current diagnostic gap, enhancing accuracy (standardization of α-gal IgE thresholds) and improving patient outcomes. Future studies should focus on improving standard algorithms, expanding clinician awareness and exploring interventions to mitigate symptom manifestation. Recognizing AGS as not merely an allergic curiosity but as a distinct, systemic disorder will prove to be vital in improving timely diagnosis, targeted management and overall quality of care.