Hypersensitivity to supplemental lactase: another case report — but why?

Hypersensitivity to supplemental lactase: another case report — but why? | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 30 October 2025 V1 Latest version Share on Hypersensitivity to supplemental lactase: another case report — but why? Authors : Maicon Roberto Kviecinski 0000-0002-6703-4040 [email protected] , Eduarda de Aguiar da Rosa , Palloma Aparecida Andretta Gaspar , José Luiz Kracik , Danilo Francisco da Silva Marçal , Aline Lara Fonseca de Souza , and Jane da Silva Authors Info & Affiliations https://doi.org/10.22541/au.176180049.97722033/v1 434 views 126 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Purpose: To report a rare case of IgE-mediated anaphylaxis triggered by an over-the-counter lactase supplement and highlight diagnostic, management, and pharmacovigilance challenges. Methods: A 25-year-old woman with lactose intolerance experienced immediate systemic symptoms after chewing a lactase tablet (10,000 FCC units, Lacday®). Emergency treatment included antihistamines, corticosteroids, and finally epinephrine. Outpatient evaluation included skin prick testing with the lactase preparation, healthy controls, and lactose-free products. Results: Skin prick testing confirmed IgE-mediated lactase sensitization (wheals 5–6 mm) with negative controls. Symptoms resolved only after intramuscular epinephrine. A second reaction occurred after consuming lactose-free mayonnaise containing lactase; prick testing confirmed reactivity to the product but not to milk proteins. Conclusions: OTC lactase supplements can cause severe allergic reactions. “Lactose-free” foods may pose hidden risks. Clinicians and patients must be aware, and prompt epinephrine administration is essential. Improved pharmacovigilance and labeling for enzyme-containing supplements are warranted. Hypersensitivity to supplemental lactase: another case report — but why? Running title: Lactase supplement hypersensitivity Authors: - Maicon Roberto Kviecinski 1,3* (e-mail: [email protected] , ORCID: 0000-0002-6703-4040), - Eduarda de Aguiar da Rosa 2 (e-mail: [email protected] , ORCID: 0009-0007-1179-2786), - Palloma Aparecida Andretta Gaspar 2 (e-mail: [email protected] , ORCID: 0009-0002-1741-7067) - José Luiz Kracik 2 (e-mail: [email protected] , ORCID: 0009-0003-0713-882X), - Danilo Francisco da Silva Marçal 2 (e-mail: [email protected] , ORCID: 0000-0002-9196-4424), - Aline Lara Fonseca de Souza 3 (e-mail: [email protected] , ORCID: 0009-0001-5372-5262), - Jane da Silva 2,3 (e-mail: [email protected] , ORDCID: 0000-0003-1446-6648) Affiliations: 1 Department of Biochemistry, Center for Biological Sciences, Federal University of Santa Catarina, Florianópolis, Brazil. 2 School of Medicine, Center for Health Sciences, Federal University of Santa Catarina, Florianópolis, Brazil. 3 Allergy Service, Professor Polydoro Ernani de São Thiago University Hospital, And Department of Internal Medicine, Federal University of Santa Catarina, Florianopolis, Brazil. Ethics and Integrity Information: Funding statement: Material support was provided by the University Hospital Polydoro Ernani São Thiago, Federal University of Santa Catarina (UFSC). Conflict of interest: The authors declare no conflicts of interest related to this work. Ethics approval and patient consent: Written informed consent was obtained from the patient for the publication of this report. Permissions: No previously published tables, figures, or text excerpts were used. *Corresponding author: Prof. Dr. Maicon Roberto Kviecinski. E-mal: [email protected] Departamento de Bioquímica, Hospital Universitário da Universidade Federal de Santa Catarina, Rua Professora Maria Flora Pausewang, s/nº, CEP: 88036-800, Florianópolis, SC – Brazil. Phone: +55 48 996974123. ABSTRACT Purpose: To report a rare case of IgE-mediated anaphylaxis triggered by an over-the-counter lactase supplement and highlight diagnostic, management, and pharmacovigilance challenges. Methods: A 25-year-old woman with lactose intolerance experienced immediate systemic symptoms after chewing a lactase tablet (10,000 FCC units, Lacday®). Emergency treatment included antihistamines, corticosteroids, and finally epinephrine. Outpatient evaluation included skin prick testing with the lactase preparation, healthy controls, and lactose-free products. Results: Skin prick testing confirmed IgE-mediated lactase sensitization (wheals 5–6 mm) with negative controls. Symptoms resolved only after intramuscular epinephrine. A second reaction occurred after consuming lactose-free mayonnaise containing lactase; prick testing confirmed reactivity to the product but not to milk proteins. Conclusions: OTC lactase supplements can cause severe allergic reactions. “Lactose-free” foods may pose hidden risks. Clinicians and patients must be aware, and prompt epinephrine administration is essential. Improved pharmacovigilance and labeling for enzyme-containing supplements are warranted. Keywords: Lactase; enzyme hypersensitivity; anaphylaxis; epinephrine, dietary supplement safety; pharmacovigilance; OTC enzyme. Key points: • Lactase supplements may trigger IgE-mediated anaphylaxis. • Symptoms may mimic or be mistaken for lactose intolerance. • Skin prick testing can confirm sensitization. • “Lactose-free” products may contain enzyme allergens. • Epinephrine is first-line treatment; awareness and regulatory oversight are essential. Plain Language Summary Lactase supplements are commonly used by people with lactose intolerance to help them digest dairy products, and they are widely perceived as safe over-the-counter products. In this report, we describe a young woman who experienced a severe allergic reaction shortly after taking a lactase tablet. She quickly developed swelling, trouble breathing, and other symptoms of anaphylaxis, a medical emergency. Her symptoms improved only after she received an injection of epinephrine, the recommended first treatment for anaphylaxis. Later, she had another reaction after eating a “lactose-free” food product that also contained lactase, showing that the enzyme may be present in foods where patients may not expect it. Allergy testing confirmed that she was allergic to lactase itself, not to milk. Although these reactions are very rare, this case highlights the need for awareness that enzyme-containing supplements can act as allergens. Clear product labeling, patient and clinician education, and careful reporting of these events can help improve safety and prevent future episodes. Purpose This case is reported to raise awareness of a rare and underrecognized adverse drug-like reaction associated with an enzyme supplement, contributing to post-marketing safety evidence and risk characterization of biologically derived products. It also reinforces the importance of prompt and appropriate management of anaphylaxis, emphasizing the immediate use of epinephrine as first-line treatment and discouraging unsupported reliance on corticosteroids. Furthermore, it highlights that “lactose-free” products may contain supplemental enzymes that pose a risk for sensitized individuals—an issue of relevance to patient safety, labeling transparency, and pharmacovigilance policy development. Methods A 25-year-old Brazilian female medical student, recently diagnosed with lactose intolerance and with a history of allergic rhinitis, raffinose intolerance, and mild overweight, presented to the Allergy and Anaphylaxis Clinic of Federal University Hospital of Santa Catarina, Brazil. She experienced acute systemic symptoms immediately after chewing a lactase tablet (10,000 FCC units, Lacday®, EMS) prior to consuming ice cream, representing her second lifetime exposure. At the emergency department, initial management included intramuscular promethazine (25 mg) and intravenous hydrocortisone (200 mg). As symptoms persisted, intramuscular epinephrine (0.3 mL, left vastus lateralis) was administered, resulting in rapid clinical improvement. Subsequent outpatient evaluation included allergy testing. A solution was prepared by dissolving one 10,000 FCC unit lactase tablet in 10 mL 0.9% saline, following the protocol described by Voisin and Borici-Mazi 1 . Skin prick testing was conducted in duplicate on the patient and three healthy controls, with histamine as a positive control and saline as a negative control. Three months later, the patient experienced a secondary suspected allergic reaction after consuming street food containing lactose-free mayonnaise. Prick-to-prick testing with lactose-free cream and milk proteins was performed 1,2 . To perform this work, ethical compliance was ensured according to the Declaration of Helsinki. Informed consent was obtained, and the study adhered to Guidelines for Good Pharmacoepidemiology Practice (GPP). All authors declared no conflicts of interest. Results Within seconds of chewing the lactase tablet, the patient developed lip pruritus, oral mucosal edema, dysphagia, tachycardia, dyspnea, dysphonia, tongue swelling, and facial rash. Initial antihistamine and corticosteroid therapy was insufficient. Administration of intramuscular epinephrine resulted in rapid resolution of symptoms. Skin prick testing confirmed IgE-mediated sensitization to lactase, with wheals measuring 5–6 mm, while all healthy controls remained negative (Figure 1). The patient was advised to avoid all lactase-containing supplements and to carry an epinephrine autoinjector 1 . Figure 1. Skin prick test results using 1,000 U lactase in the case patient (A) and in three control individuals (B). During the secondary reaction, the patient experienced presyncope, severe abdominal pain with diarrhea, tongue swelling, and dry mouth approximately ten minutes after consuming lactose-free mayonnaise. Self-administered antihistamines (fexofenadine and loratadine) provided gradual improvement. Testing revealed that only the lactose-free cream triggered a positive reaction, confirming hidden enzyme exposure. Additional counseling emphasized reading product labels carefully, avoiding self-medication with enzyme supplements, and promptly seeking emergency care for anaphylaxis 2 . The patient was also educated about potential cross-reactivity among lactase sources, including yeast- and fungus-derived enzymes 3 , and trained in correct use of an epinephrine autoinjector. Advice included documenting all reactions in a personal medical diary, maintaining close follow-up, and alerting clinicians and pharmacists about her hypersensitivity prior to any prescription or OTC product use. Discussion Lactase, a glycosidase enzyme naturally produced by enterocytes of the small intestinal brush border, hydrolyzes lactose into glucose and galactose, enabling absorption. In infants, lactase activity is essential for milk digestion; deficiencies manifest as lactose intolerance, with gastrointestinal discomfort due to unabsorbed lactose fermentation. Commercially, microbial lactases derived from Kluyveromyces lactis (yeast) and Aspergillus niger or A. oryzae (fungi) are widely used as OTC supplements and in food and pharmaceutical industries 3 . While human and microbial lactases share catalytic activity, they differ structurally: human lactase is a complex transmembrane glycoprotein (~220 kDa) with multiple functional domains, including catalytic and membrane-anchoring regions, and is heavily glycosylated. Microbial lactases are smaller (~100–120 kDa), soluble, and less or non-glycosylated, typically constructed from hydrolase domains from GH2 (Kluyveromyces) or GH35 (Aspergillus), conferring distinct biochemical stability and potential immunogenicity 3 . These molecular distinctions influence allergenicity and immune recognition, which may explain the rare occurrence of hypersensitivity despite widespread use. Enzyme stability, folding patterns, and glycosylation differences may affect protein processing by antigen-presenting cells, the potential for IgE sensitization, and the likelihood of systemic reactions following oral ingestion. Although lactase supplements are generally considered safe, they introduce exogenous enzymes capable of acting as allergens. Reports of allergic reactions are rare and often misinterpreted as lactose intolerance itself, explaining limited post-marketing documentation 1,2,4 . Previously, Binkley 4 first reported an allergic reaction to oral lactase from Aspergillus . Voisin and Borici-Mazi 1 later described systemic anaphylaxis following a lactase supplement. Lohrenz and Kanani 2 highlighted diagnostic challenges in distinguishing between milk protein allergy and lactase hypersensitivity. According to these reports, sensitization to lactase has been associated with ingestion, handling, and exposure to lactose-free food products 1,2,4 . Our case contributes unique insights: (i) initial ingestion of an intact tablet may prime the immune system, while mastication increases mucosal exposure, triggering immediate systemic reactions; (ii) positive skin prick testing with negative controls confirms IgE-mediated hypersensitivity; and (iii) inadvertent exposure to lactose-free products underscores the real-world challenge of hidden allergens. This case also emphasizes the need for clinician vigilance when managing patients with multiple food intolerances and allergic histories, as such individuals may have heightened susceptibility to enzyme sensitization. In addition, documentation of the event provides valuable evidence for rare adverse reactions and reinforces the role of patient education in preventing future anaphylaxis. Differential diagnosis must consider gastrointestinal intolerances. Raffinose, a trisaccharide present in legumes, cruciferous vegetables, and whole grains, is metabolized via microbial fermentation in the absence of α-galactosidase. Fermentation produces flatulence, abdominal distension, and diarrhea, mimicking lactose intolerance but through a non-immune-mediated mechanism 5 . Careful evaluation distinguishes these fermentative processes from true IgE-mediated reactions, guiding appropriate dietary and pharmacologic management. From a pharmacoepidemiologic perspective, OTC lactase supplements highlight the blurred boundary between foods and pharmaceuticals. Despite being perceived as safe, these biologically derived products can provoke life-threatening reactions, which are often underreported in pharmacovigilance databases 1,2,4 . This underscores the need for clinician awareness, consumer education, and robust adverse event reporting systems. Regulatory initiatives should aim to classify enzyme supplements appropriately, enforce transparent labeling, and educate healthcare providers about rare hypersensitivity risks. Moreover, integrating such cases into national and international pharmacovigilance registries can improve signal detection and prevent recurrence. Management of anaphylaxis is paramount. Despite confirmed lactase hypersensitivity, delayed intramuscular epinephrine administration can increase morbidity and mortality. International guidelines (WAO, AAAAI/ACAAI, EAACI) recommend prompt epinephrine as first-line therapy 6–10 . Epinephrine acts via α1-mediated vasoconstriction, β1-mediated cardiostimulation, and β2-mediated bronchodilation and mast cell stabilization, countering the core pathophysiology of anaphylaxis 9,10 . Antihistamines and corticosteroids serve only as adjuncts and must not delay epinephrine administration. Finally, this case emphasizes hidden risks in lactose-free products. Industrial processing, cross-contamination, and incomplete labeling can expose sensitized individuals to sufficient enzyme quantities to trigger severe reactions. Patient education on label reading, carrying epinephrine, and avoiding enzyme-containing supplements is critical. Documentation of rare adverse reactions contributes to post-marketing safety databases, informs clinical guidelines, improves pharmacovigilance strategies, and guides safer formulation of OTC enzyme products. Clinicians should also advise patients on the importance of emergency action plans, recognition of early symptoms, and consistent follow-up with allergy specialists. Conclusions This report adds to the scarce literature on lactase-induced anaphylaxis. Key lessons include: - Supplemental lactase may act as a hidden allergen in tablets and processed foods. - Prompt intramuscular epinephrine is essential for effective anaphylaxis management. - Secondary reactions via lactose-free products highlight the importance of vigilance and clear labeling. - OTC enzyme supplements require improved pharmacovigilance to capture rare but severe adverse events. Even commonly used OTC supplements can trigger severe adverse events, demonstrating the necessity for heightened clinician awareness, patient education, and improved safety monitoring of biologically derived enzyme products. Furthermore, proactive patient counseling, proper emergency preparedness, and integration of rare-event data into pharmacovigilance databases will support safer clinical practice and risk reduction strategies. References 1. Voisin MR, Borici-Mazi R. Anaphylaxis to supplemental oral lactase enzyme. Allergy, Asthma and Clinical Immunology 2016; 12 . doi:10.1186/s13223-016-0171-8. 2. Lohrenz SK, Kanani A. The cow’s milk allergy that wasn’t: allergy to supplemental oral lactase enzyme. Allergy, Asthma and Clinical Immunology 2023; 19 . doi:10.1186/s13223-023-00809-z. 3. Panesar PS, Kumari S, Panesar R. Potential applications of immobilized β-galactosidase in food processing industries. Enzyme Res 2010; 2010 . doi:10.4061/2010/473137. 4. Binkley KE. Allergy to supplemental lactase enzyme. J Allergy Clin Immunol 1996; 97 : 1414–1416. 5. Elango D, Rajendran K, Van der Laan L, et al. Raffinose Family Oligosaccharides: Friend or Foe for Human and Plant Health? Front Plant Sci 2022; 13 . doi:10.3389/fpls.2022.829118. 6. Estelle F, Simons R, Ardusso LRF, et al. World Allergy Organization Guidelines for the Assessment and Management of Anaphylaxis ., 2011. 7. Cardona V, Ansotegui IJ, Ebisawa M, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organization Journal 2020; 13 . doi:10.1016/j.waojou.2020.100472. 8. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: Guidelines from the European Academy of Allergy and Clinical Immunology. Allergy: European Journal of Allergy and Clinical Immunology 2014; 69 : 1026–1045. doi:10.1111/all.12437. 9. Ring J, Klimek L, Worm M. Adrenaline in the acute treatment of anaphylaxis. Dtsch Arztebl Int 2018; 115 : 528–534. doi:10.3238/arztebl.2018.0528. 10. C McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP. Clinical review Adrenaline in the treatment of anaphylaxis: what is the evidence? Information & Authors Information Version history V1 Version 1 30 October 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords anaphylaxis dietary supplement safety enzyme hypersensitivity epinephrine lactase otc enzyme pharmacovigilance Authors Affiliations Maicon Roberto Kviecinski 0000-0002-6703-4040 [email protected] Universidade Federal de Santa Catarina Departamento de Bioquimica View all articles by this author Eduarda de Aguiar da Rosa Universidade Federal de Santa Catarina Centro de Ciencias da Saude View all articles by this author Palloma Aparecida Andretta Gaspar Universidade Federal de Santa Catarina Centro de Ciencias da Saude View all articles by this author José Luiz Kracik Universidade Federal de Santa Catarina Centro de Ciencias da Saude View all articles by this author Danilo Francisco da Silva Marçal Universidade Federal de Santa Catarina Centro de Ciencias da Saude View all articles by this author Aline Lara Fonseca de Souza Hospital Universitario Polydoro Ernani de Sao Thiago View all articles by this author Jane da Silva Hospital Universitario Polydoro Ernani de Sao Thiago View all articles by this author Metrics & Citations Metrics Article Usage 434 views 126 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Maicon Roberto Kviecinski, Eduarda de Aguiar da Rosa, Palloma Aparecida Andretta Gaspar, et al. 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